Updated on 2024/10/23

写真a

 
TOYOKUNI Shinya
 
Organization
Graduate School of Medicine Program in Integrated Medicine Pathology Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine
Title
Professor
Contact information
メールアドレス
External link

Degree 1

  1. 医学博士 ( 1991.3   京都大学 ) 

Research Interests 11

  1. ferroptosis

  2. mutation

  3. DNA damage

  4. mesothelioma

  5. carbon nanotube

  6. asbestos

  7. oxidative stress

  8. iron

  9. Carcinogenesis

  10. mutation

  11. ferroptosis

Research Areas 4

  1. Others / Others  / Human Pathology

  2. Others / Others  / Experimental Pathology

  3. Life Science / Experimental pathology

  4. Others / Others  / Human Pathology

Current Research Project and SDGs 10

  1. 細胞外微粒子への生体応答と発がん・動脈硬化症との関連の解析

  2. 低温プラズマの医療応用

  3. Analysis of asbestos-induced mesothelial carcinogenesis

  4. Development of evaluation systems for the carcinogenicity of fibrous inorganic materials

  5. Significance of oxygen radicals in carcinogenesis

  6. AdAMS: Support for Pathologic Analysis

  7. フェロトーシスにおける細胞内鉄制御機構の破綻

  8. Analysis of genomic localization of oxidative DNA damage from the standpoint of transcription and chromosomal territory

  9. 酸化ストレス発がん克服のための標的分子の同定

  10. Evaluation of novel nanomaterials for human risks

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Research History 10

  1. Nagoya University   Professor

    2008.7

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    Country:Japan

  2. Nagoya University   Center for Low-temperature Plasma Sciences   Vice Director

    2020.4

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  3. Nagoya University   Graduate School of Medicine   Editor-in-chief, Nagoya Journal of Medical Science

    2010.4

  4. Nagoya University   Graduate School of Medicine   Internal Review Board, member

    2010.4 - 2016.3

  5. Associate professor, Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, japan

    2004.4 - 2008.6

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    Country:Japan

  6. Associate professor, Department of Pathology, Faculty of Medicine, Kyoto University, Japan

    1998.6 - 2004.3

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    Country:Japan

  7. Assistant professor, Department of Pathology, Faculty of Medicine, Kyoto University, Japan

    1993.4 - 1998.5

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    Country:Japan

  8. Instructor, Department of Pathology, Faculty of Medicine, Kyoto University, Japan

    1992.10 - 1993.4

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    Country:Japan

  9. US National Research Council Research Associate; MBB, CDRH, FDA, Rockville, MD

    1990.9 - 1992.9

  10. 天理よろづ相談所病院ジュニアレジデント

    1985.5 - 1987.4

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    Country:Japan

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Education 3

  1. Kyoto University   Graduate School, Division of Medicine   Pathology

    1987.4 - 1991.3

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    Country: Japan

  2. Kyoto University   Graduate School, Division of Medicine   Pathology

    1987.4 - 1991.3

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    Country: Japan

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  3. Kyoto University   Faculty of Medicine

    1979.4 - 1985.3

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    Country: Japan

Professional Memberships 18

  1. Society for Free Radical Research Japan

    2015.1

  2. Japan Cancer Association

    2002.4

  3. The Japanese Society of Pathology

    1995.4

  4. Japan BioIron Society

    2012.4

  5. 日本がん予防学会   理事

    2009.4

  6. 日本微量元素学会   理事

    2017.4

  7. Society for Free Radical Research Asia/International   President

    2014.1

  8. 日本微量元素学会

    2017.4

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  9. 日本医学教育学会

  10. 日本セルデス学会

  11. The New York Academy of Sciences

  12. 日本分子生物学会

  13. International Academy of Pathology

  14. American Association for the Advancement of Science

  15. American Association for Investigative Pathology

  16. American Association for Cancer Research

  17. 日本分子生物学会

  18. 日本生化学会

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Committee Memberships 4

  1. 名古屋大学附属図書館医学部分館   分館長  

    2021.4   

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  2. 編入学制度運用委員会   委員  

    2012.4   

  3. 学部教育委員会   委員  

    2012.4   

  4. 学部教育委員会   委員  

    2012.4   

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Awards 10

  1. 日本微量元素学会学会賞

    2022.3   日本微量元素学会   発がん機構における過剰鉄の関与とフェロトーシス抵抗性の分子機構の解明

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

  2. 日本酸化ストレス学会学会賞

    2021.5   日本酸化ストレス学会  

    豊國 伸哉

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    Award type:Award from Japanese society, conference, symposium, etc. 

    本学医学系研究科 豊國伸哉 教授が、日本酸化ストレス学会 学会賞を受賞しました。本学会は本研究科(故)八木国夫名誉教授(生化学)が1977年に設立された過酸化脂質・フリーラジカル学会の流れを汲むものです。豊國教授は、京都大学医学部在学時から現在にいたるまで一貫して、実験病理学の立場から過剰鉄による発がん過程の解明という、酸化ストレス分野における主要な課題の一つに精力的に取組み、世界の酸化ストレス研究の発展に大きく貢献してきました。

  3. Life time achievement award

    2017.1   Society for Free Radical Research India (SFRR India)  

    Shinya Toyokuni

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    Award type:International academic award (Japan or overseas)  Country:India

  4. the Japan Pathology Award

    2015.5   the Japanese Society of Pathology  

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    Country:Japan

  5. The SFRR Japan Award of Scientific Excellence

    2009.6   SFRR Japan  

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    Country:Japan

  6. 日本病理学会学術奨励賞

    2000.4   日本病理学会  

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    Country:Japan

  7. SFRR (Society for Free Radical Research) Japan 学術奨励賞

    1998.5   SFRR Japan  

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    Country:Japan

  8. National Research Council Research Associate Award

    1990.9   US National Research Council  

  9. Society for Free Radical Research JAPAN award

    2021.5   Society for Free Radical Research JAPAN   Significance of oxidative stress in carcinogenesis

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  10. the Japan Pathology Award

    2015.5   the Japanese Society of Pathology  

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    Country:Japan

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Papers 1184

  1. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Invited Reviewed

    Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD.

    Cell   Vol. 171 ( 2 ) page: 273-285   2017.10

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    Language:English  

    DOI: doi: 10.1016/j.cell.2017.09.021.

  2. The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy. Invited Reviewed

    Toyokuni S.

    Pathol Int.   Vol. 66 ( 5 ) page: 245-259   2016.5

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    Authorship:Lead author   Language:English  

    DOI: doi: 10.1111/pin.12396.

  3. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. Reviewed

    Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S.

    Cancer Science     2017.11

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: doi: 10.1111/cas.13460.

  4. Diameter and rigidity of multi-walled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. Reviewed

    Nagai H, Okazaki Y, Chew SH, Misawa N, Yamashita Y, Akatsuka S, Ishihara T, Yamashita K, Yoshikawa Y, Yasui H, Jiang L, Ohara H, Takahashi T, Ichihara G, Kostarelos K, Miyata Y, Shinohara H and Toyokuni S.

    Proc. Natl. Acad. Sci. USA   Vol. 108   page: E1330-1338   2011

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  5. Iron overload signature in chrysotile-induced malignant mesothelioma. Reviewed

    Jiang L, Akatsuka S, Nagai H, Chew SH, Ohara H, Okazaki Y, Yamashita Y, Yoshikawa Y, Yasui H, Ikuta K, Sasaki K, Kohgo Y, Hirano S, Shinohara Y, Kohyama N, Takahashi T and Toyokuni S.

    J Pathol   Vol. 228   page: 366-377   2012.8

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  6. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer. Reviewed

    Akatsuka S, Yamashita Y, Ohara H, Liu YT, Izumiya M, Abe K, Ochiai M, Jiang L, Nagai H, Okazaki Y, Murakami H, Sekido Y, Arai E, Kanai Y, Hino O, Takahashi T, Nakagama H and Toyokuni S.

    PLoS ONE   Vol. 7 ( 8 ) page: e43403   2012.8

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

  7. Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. Reviewed

    Jiang L, Yamashita Y, Chew SH, AKatsuka S, Ukai S, Wang S, Nagai H, Okazaki Y, Takahashi T and Toyokuni S.

    J Pathol   Vol. 233   page: 502-414   2014

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: doi: 10.1002/path.4377.

  8. Iron as Soul of Life on Earth Revisited: From Chemical Reaction, Ferroptosis to Therapeutics

    Harigae Hideo, Hino Keisuke, Toyokuni Shinya

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 133   page: 1-2   2019.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.freeradbiomed.2019.01.042

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  9. A guideline on the molecular ecosystem regulating ferroptosis. Reviewed International coauthorship International journal

    Dai E, Chen X, Linkermann A, Jiang X, Kang R, Kagan VE, Bayir H, Yang WS, Garcia-Saez AJ, Ioannou MS, Janowitz T, Ran Q, Gu W, Gan B, Krysko DV, Zhu X, Wang J, Krautwald S, Toyokuni S, Xie Y, Greten FR, Yi Q, Schick J, Liu J, Gabrilovich DI, Liu J, Zeh HJ, Zhang DD, Yang M, Iovanna J, Kopf M, Adolph TE, Chi JT, Li C, Ichijo H, Karin M, Sankaran VG, Zou W, Galluzzi L, Bush AI, Li B, Melino G, Baehrecke EH, Lotze MT, Klionsky DJ, Stockwell BR, Kroemer G, Tang D

    Nature cell biology   Vol. 26 ( 9 ) page: 1447 - 1457   2024.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Nature Cell Biology  

    Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

    DOI: 10.1038/s41556-024-01360-8

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  10. Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. Reviewed International journal

    Danyang Mi, Izumi Yanatori, Hao Zheng, Yingyi Kong, Tasuku Hirayama, Shinya Toyokuni

    Free radical research   Vol. 58 ( 4 ) page: 261 - 275   2024.3

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    Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Though direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

    DOI: 10.1080/10715762.2024.2340711

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  11. Elaborate cooperation of poly(rC)-binding proteins 1/2 and glutathione in ferroptosis induced by plasma-activated Ringer's lactate. Reviewed

    Jiang L, Zheng H, Ishida M, Lyu Q, Akatsuka S, Motooka Y, Sato K, Sekido Y, Nakamura K, Tanaka H, Ishikawa K, Kajiyama H, Mizuno M, Hori M, Toyokuni S

    Free radical biology & medicine   Vol. 214   page: 28 - 41   2024.3

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    Reactive species are involved in various aspects of neoplastic diseases, including carcinogenesis, cancer-specific metabolism and therapeutics. Non-thermal plasma (NTP) can directly provide reactive species, by integrating atmospheric and interjacent molecules as substrates, to represent a handy strategy to load oxidative stress in situ. NTP causes apoptosis and/or ferroptosis specifically in cancer cells of various types. Plasma-activated Ringer's lactate (PAL) is another modality at the preclinical stage as cancer therapeutics, based on more stable reactive species. PAL specifically kills malignant mesothelioma (MM) cells, employing lysosomal ·NO as a switch from autophagy to ferroptosis. However, the entire molecular mechanisms have not been elucidated yet. Here we studied cytosolic iron regulations in MM and other cancer cells in response to PAL exposure. We discovered that cells with higher catalytic Fe(II) are more susceptible to PAL-induced ferroptosis. PAL caused a cytosolic catalytic Fe(II)-associated pathology through iron chaperones, poly (rC)-binding proteins (PCBP)1/2, inducing a disturbance in glutathione-regulated iron homeostasis. PCBP1/NCOA4-mediated ferritinophagy started at a later phase, further increasing cytosolic catalytic Fe(II), ending in ferroptosis. In contrast, PCBP2 after PAL exposure contributed to iron loading to mitochondria, leading to mitochondrial dysfunction. Therapeutic effect of PAL was successfully applied to an orthotopic MM xenograft model in mice. In conclusion, PAL can selectively sensitize MM cells to ferroptosis by remodeling cytoplasmic iron homeostasis, where glutathione and PCBPs play distinct roles, resulting in lethal ferritinophagy and mitochondrial dysfunction. Our findings indicate the clinical application of PAL as a ferroptosis-inducer and the potential of PCBPs as novel targets in cancer therapeutics.

    DOI: 10.1016/j.freeradbiomed.2024.02.001

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  12. Formalin-Fixed Paraffin-Embedded Proteomics of Malignant Mesothelioma and New Candidate Biomarkers Thioredoxin and Superoxide Dismutase 2 for Immunohistochemistry. Reviewed

    Hiratsuka T, Yoshizawa A, Endo T, Yamamoto T, Toyokuni S, Tsuruyama T

    Laboratory investigation; a journal of technical methods and pathology   Vol. 104 ( 2 ) page: 100299   2024.2

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    The pathogenesis of malignant mesothelioma (MM) has been extensively investigated, focusing on stress derived from reactive oxygen species. We aimed to identify diagnostic biomarkers of MM by analyzing proteins in formalin-fixed paraffin-embedded specimens using liquid chromatography-mass spectrometry. We extracted proteins from formalin-fixed paraffin-embedded sections of MM tissues (n = 7) and compared their profiles with those of benign mesothelial tissues (n = 4) and alveolar tissue (n = 1). Proteomic data were statistically assessed and profiled using principal component analysis. We were successful in the classification of MM and healthy tissue. The levels of superoxide dismutase 2 (SOD2), an enzyme that converts superoxide anion into oxygen and hydrogen peroxide, and thioredoxin (TXN), which plays a crucial role in reducing disulfide bonds in proteins, primarily contributed to the classification. Other redox-related proteins, such as pyruvate dehydrogenase subunit X, and ceruloplasmin also contributed to the classification. Protein-protein interaction analysis demonstrated that these proteins play essential roles in MM pathogenesis. Immunohistochemistry revealed that TXN levels were significantly lower, whereas SOD2 levels were significantly higher in MM and lung cancer tissues than in controls. Proteomic profiling suggested that MM tissues experienced increased exposure to hydrogen peroxide and other reactive oxygen species. Combining immunohistochemistry for TXN and SOD2 allows for differentiation among MM, lung cancer, and control tissues; hence, TXN and SOD2 may be promising MM biomarkers and therapeutic targets.

    DOI: 10.1016/j.labinv.2023.100299

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  13. Brca2((p.T1942fs/+)) dissipates ovarian reserve in rats through oxidative stress in follicular granulosa cells. Reviewed International journal

    Tanaka H, Motooka Y, Maeda Y, Sonehara R, Nakamura T, Kajiyama H, Mashimo T, Toyokuni S

    Free radical research   Vol. 58 ( 2 ) page: 130 - 143   2024.2

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Free Radical Research  

    Pathogenic variants of BRCA1/2 constitute hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1/2 mutant is a risk for various cancers. Whereas the clinical guideline for HBOC patients has been organized for the therapy and prevention of cancer, there is no recommendation on the female reproductive discipline. Indeed, the role of BRCA1/2 pathogenic variants in ovarian reserve has not been established due to the deficiency of appropriate animal models. Here, we used a rat model of Brca2(p.T1942fs/+) mutant of Sprague-Dawley strain with CRISPR-Cas9 editing to evaluate ovarian reserve in females. Fertility and ovarian follicles were evaluated and anti-Müllerian hormone (AMH) was measured at 8–32 weeks of age with a comparison between the wild-type and the mutant rats (MUT). MUT revealed a significantly smaller number of deliveries with fewer total pups. Furthermore, MUT showed a significant decrease in primordial follicles at 20 weeks and a low AMH level at 28 weeks. RNA-sequencing of the ovary at 10 weeks detected acceleration of the DNA damage repair pathway, which was accompanied by oxidative stress-induced DNA double-strand breaks, a decrease in PTEN, and an increase in mTOR in follicular granulosa cells. In conclusion, Brca2(p.T1942fs/+) dissipates primordial follicles via early activation of granulosa cells through oxidative stress, leading to earlier termination of fertility.

    DOI: 10.1080/10715762.2024.2320405

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  14. Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation. Reviewed

    Sagou K, Sato Y, Okuno Y, Watanabe T, Inagaki T, Motooka Y, Toyokuni S, Murata T, Kiyoi H, Kimura H

    PLoS pathogens   Vol. 20 ( 2 ) page: e1011954   2024.2

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    Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis. We found that lymphoblastoid cell lines (LCLs) established by BNRF1-knockout EBV exhibited remarkably lower pathogenicity in a mice xenograft model than LCLs produced by wild-type EBV (LCLs-WT). RNA-seq analyses revealed that BNRF1 elicited the expression of interferon-inducible protein 27 (IFI27), which promotes cell proliferation. IFI27 knockdown in LCLs-WT resulted in excessive production of reactive oxygen species, leading to cell death and significantly decreased their pathogenicity in vivo. We also confirmed that IFI27 was upregulated during primary infection in B-cells. Our findings revealed that BNRF1 promoted robust proliferation of the B-cells that were transformed by EBV latent infection via IFI27 upregulation both in vitro and in vivo.

    DOI: 10.1371/journal.ppat.1011954

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  15. Tetrachloroaurate (III)–induced oxidation increases nonthermal plasma-induced aldehydes Reviewed

    Okazaki Y., Yoshitake J., Ito N., Sasaki K., Tanaka H., Hori M., Shibata T., Toyokuni S.

    Advances in Redox Research   Vol. 9   2023.12

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    Research on nonthermal plasma (NTP) devices first began almost five decades ago. NTP devices discharge electrons, positive ions, ultraviolet light, reactive oxygen species (ROS) and reactive nitrogen species (RNS) at near-physiological temperatures. Advances in plasma science have enabled the manipulation of ROS/RNS irradiation for medical applications. During preclinical stages and in human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral, and biofilm-related infections, wound healing, and cancer therapy. Previously, tetrachloroaurate (III) increased NTP-induced oxidative stress that was attenuated by reduced and oxidized glutathione, indicating that the presence of interactions between metal ions and biomolecules may modulate biological effects. In this study, using 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) as a spin probe in electron paramagnetic resonance (EPR), we observed that the tetrachloroaurate-induced M4PO-X spin adduct was significantly suppressed by ascorbate and α-tocopherol, while dehydroascorbate (DHA) and Trolox were ineffective. Tetrachloroaurate-induced lipid peroxidation, which was measured by 2-thiobarbituric acid-reactive substances (TBARS) in combination with NTP exposure, was suppressed by ascorbate, α-tocopherol and Trolox, while DHA was ineffective. Furthermore, N-acetyl-L-cysteine and dithiothreitol efficiently suppressed tetrachloroaurate-induced M4PO-X spin adduct and lipid peroxidation. LC‒MS/MS analyzes identified hexanal that was significantly elevated by NTP exposure and/or tetrachloroaurate. However, 25 and 250 μM ascorbate did not significantly suppress the formation of aldehydes, such as acetaldehyde, hexanal, nonanal, nonenal, and 4‑hydroxy-2-nonenal. Further studies are warranted to elucidate the redox reactions between metal ions, including gold (III), and biomolecules to expand the possibility of NTP application in medicine and agriculture.

    DOI: 10.1016/j.arres.2023.100074

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  16. Generation and measurement of low-temperature plasma for cancer therapy: a historical review Reviewed

    Kenji Ishikawa, Keigo Takeda, Shinji Yoshimura, Takashi Kondo, Hiromasa Tanaka, Shinya Toyokuni, Kae Nakamura, Hiroaki Kajiyama, Masaaki Mizuno, Masaru Hori

    Free Radical Research   Vol. 57 ( 3 ) page: 239 - 270   2023.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Informa UK Limited  

    DOI: 10.1080/10715762.2023.2230351

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  17. Retinal ferroptosis as a critical mechanism for the induction of retinochoroiditis during ocular toxoplasmosis. Reviewed

    Yamada K, Tazaki A, Ushio-Watanabe N, Usui Y, Takeda A, Matsunaga M, Suzumura A, Shimizu H, Zheng H, Ariefta NR, Yamamoto M, Hara H, Goto H, Sonoda KH, Nishiguchi KM, Kato M, Nishikawa Y, Toyokuni S, Kaneko H

    Redox biology   Vol. 67   page: 102890   2023.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Redox Biology  

    Toxoplasmosis is a major infectious disease, affecting approximately one-third of the world's population; its main clinical manifestation, ocular toxoplasmosis (OT), is a severe sight-threatening disease. Nevertheless, the diagnosis of OT is based on clinical findings, which needs improvement, even with biochemical tests, such as polymerase chain reaction and antibody detections. Furthermore, the efficacy of OT-targeted treatment is limited; thus, additional measures for diagnosis and treatments are needed. Here, we for the first time report a significantly reduced iron concentration in the vitreous humor (VH) of human patients infected with OT. To obtain further insights into molecular mechanisms, we established a mouse model of T. gondii infection, in which intravitreally injected tracer 57Fe, was accumulated in the neurosensory retina. T. gondii-infected eyes showed increased lipid peroxidation, reduction of glutathione peroxidase-4 expression and mitochondrial deformity in the photoreceptor as cristae loss. These findings strongly suggest the involvement of ferroptotic process in the photoreceptor of OT. In addition, deferiprone, an FDA-approved iron chelator, reduced the iron uptake but also ameliorated toxoplasma-induced retinochoroiditis by reducing retinal inflammation. In conclusion, the iron levels in the VH could serve as diagnostic markers and iron chelators as potential treatments for OT.

    DOI: 10.1016/j.redox.2023.102890

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  18. Three-dimensional regulation of ferroptosis at the intersection of iron, sulfur and oxygen executing scrap and build toward evolution. Reviewed International journal

    Shinya Toyokuni, Yingyi Kong, Hao Zheng, Yuki Maeda, Misako Katabuchi, Yashiro Motooka

    Antioxidants & redox signaling   Vol. 39 ( 10-12 ) page: 807 - 815   2023.10

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    Iron is an essential element for every life on earth as a primary media for electron flow. Sulfur compounds as sulfhydryls counteract catalytic activity of iron whereas sulfur overdose is also toxic. In aerobic organisms, oxygen is the major media for electron transfer with higher intracellular mobility, which cooperates with the iron system. Based on the importance of iron, there is no active pathway to excrete iron outside the body in higher species. Whereas bacterial infection causes a scramble for iron in situ, cancer can be the outcome of the side effects of long use of iron and oxygen. Ferroptosis is a recently coined cell death, defined as catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation. Researchers recently recognized that ferroptosis is involved in a variety of physiological and pathological contexts, including embryonic erythropoiesis, aging, neurodegeneration and cancer cell death. Alternatively, carcinogenesis is a process to obtain iron addiction with ferroptosis-resistance, based on rodent animal studies. Here we propose that ferroptosis is three-dimensionally regulated by iron, sulfur and oxygen, which correspond to oxidants, antioxidants and membrane fluidity with susceptibility to lipid peroxidation, respectively. Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron.

    DOI: 10.1089/ars.2022.0142

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  19. New iron export pathways acting via holo-ferritin secretion. Reviewed International journal

    Izumi Yanatori, Fumio Kishi, Shinya Toyokuni

    Archives of biochemistry and biophysics   Vol. 746   page: 109737 - 109737   2023.9

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    Ferritin is a spherical nanocage protein for iron storage, composed of 24 light- or heavy-polypeptide chain subunits. A single ferritin molecule can carry up to 4500 iron atoms in its core, which plays an important role in suppressing intracellular iron toxicity. Serum ferritin levels are used as a marker for the total amount of iron stored in the body. Most serum ferritin is iron-free (apo-ferritin) and it is unclear how ferritin is released from cells. Ferritin is secreted into serum via extracellular vesicles (EVs) or the secretory autophagy pathway but not via the classical endoplasmic reticulum (ER)-to-Golgi secretion pathway. We recently discovered that the level of tetraspanin CD63, a common EV marker, is post-transcriptionally regulated by the intracellular iron level and both CD63 and ferritin expression is induced by iron loading. Ferritin is incorporated into CD63(+)-EVs through the ferritin-specific autophagy adapter molecule, NCOA4, and then secreted from cells. EV production differs drastically depending on cell type and physiological conditions. Extracellular matrix detached cells express pentaspanin prominin 2 and prominin 2(+)-EVs secrete ferritin independently of NCOA4 trafficking. Ferritin is tightly bound to iron in EVs and functions as an iron-carrier protein in the extracellular environment. Cells can suppress ferroptosis by secreting holo-ferritin, which reduces intracellular iron concentration. However, this exposes the neighboring cells receiving the secreted holo-ferritin to a large excess of iron. This results in cellular toxicity through increased generation of reactive oxygen species (ROS). Here we review the machinery by which ferritin is incorporated into EVs and its role as an intercellular communication molecule.

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  20. Iron links endogenous and exogenous nanoparticles. Reviewed International journal

    Shinya Toyokuni, Yingyi Kong, Misako Katabuchi, Yuki Maeda, Yashiro Motooka, Fumiya Ito, Izumi Yanatori

    Archives of biochemistry and biophysics   Vol. 745   page: 109718 - 109718   2023.9

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    Current progress in biology and medical science is based on the observation at the level of nanometers via electron microscopy and computation. Of note, the size of most cells in higher species exists in a limited range from 5 to 50 μm. Recently, it was demonstrated that endogenous extracellular nanoparticles play a role in communication among various cellular types in a variety of contexts. Among them, exosomes in serum have been established as biomarkers for human diseases by analyzing the cargo molecules. No life on the earth can survive without iron. However, excess iron can be a risk for carcinogenesis in rodents and humans. Nano-sized molecules may cause unexpected bioeffects, including carcinogenesis, which is a process to establish cellular iron addiction with ferroptosis-resistance. Asbestos and carbon nanotubes are the typical examples, leading to carcinogenesis by the alteration of iron metabolism. Recently, we found that CD63, one of the representative markers of exosomes, is under the regulation of iron-responsive element/iron-regulatory protein system. This is a safe strategy to share excess iron in the form of holo-ferritin between iron-sufficient and -deficient cells. On the other hand, damaged cells may secrete holo-ferritin-loaded exosomes as in the case of macrophages in ferroptosis after asbestos exposure. These holo-ferritin-loaded exosomes can cause mutagenic DNA damage in the recipient mesothelial cells. Thus, there is an iron link between exogenous and endogenous nanoparticles, which requires further investigation for better understanding and the future applications.

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  21. Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. Reviewed

    Van San E, Debruyne AC, Veeckmans G, Tyurina YY, Tyurin VA, Zheng H, Choi SM, Augustyns K, van Loo G, Michalke B, Venkataramani V, Toyokuni S, Bayir H, Vandenabeele P, Hassannia B, Vanden Berghe T

    Cell death and differentiation   Vol. 30 ( 9 ) page: 2092 - 2103   2023.9

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    Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by central nervous (CNS) demyelination resulting in axonal injury and neurological deficits. Essentially, MS is driven by an auto-amplifying mechanism of inflammation and cell death. Current therapies mainly focus on disease modification by immunosuppression, while no treatment specifically focuses on controlling cell death injury. Here, we report that ferroptosis, an iron-catalyzed mode of regulated cell death (RCD), contributes to MS disease progression. Active and chronic MS lesions and cerebrospinal fluid (CSF) of MS patients revealed several signs of ferroptosis, reflected by the presence of elevated levels of (labile) iron, peroxidized phospholipids and lipid degradation products. Treatment with our candidate lead ferroptosis inhibitor, UAMC-3203, strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. In conclusion, the results identify ferroptosis as a detrimental and targetable factor in MS. These findings create novel treatment options for MS patients, along with current immunosuppressive strategies. [Figure not available: see fulltext.]

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  22. Ferroptosis as ultimate target of cancer therapy. Reviewed International journal

    Yashiro Motooka, Shinya Toyokuni

    Antioxidants & redox signaling   Vol. 39 ( 1-3 ) page: 206 - 223   2023.7

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    Ferroptosis is a new form of regulated non-apoptotic cell death, which is characterized by iron-dependent lipid peroxidation, leading eventually to plasma membrane rupture. Its core mechanisms have been elucidated consisting of a driving force as catalytic Fe(II)-dependent Fenton reaction and an incorporation of polyunsaturated fatty acids to membrane phospholipids via peroxisome-dependent and -independent pathways, whereas suppressing factors are the prevention of lipid peroxidation by glutathione peroxidase 4 to protect lipid peroxidation and direct membrane repair via coenzyme Q10 and ESCRT-III pathways. The significance of ferroptosis in cancer therapeutics has now been unveiled. Specific ferroptosis inducers are expected as a promising strategy for cancer treatment, especially in cancers with epithelial mesenchymal transition and possibly in cancers with activated Hippo signaling pathways, both of which cause resistance to traditional chemotherapy but tend to show ferroptosis susceptibility. Developments of ferroptosis inducers are in progress by nanotechnology-based drugs or by innovative engineering devices. Especially, low-temperature (non-thermal) plasma is a novel technology at the preclinical stage. The exposure can induce ferroptosis selectively in cancer cells which are generally rich in catalytic Fe(II). Here we summarize and discuss the recently uncovered responsible molecular mechanisms in association with iron metabolism, ferroptosis and cancer therapeutics. Finally, we also highlight the current classification of ferroptosis inducers.

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  23. Carbon nanotube recognition by human Siglec-14 provokes inflammation. Reviewed International journal

    Shin-Ichiro Yamaguchi, Qilin Xie, Fumiya Ito, Kazuki Terao, Yoshinobu Kato, Miki Kuroiwa, Satoshi Omori, Hideo Taniura, Kengo Kinoshita, Takuya Takahashi, Shinya Toyokuni, Kota Kasahara, Masafumi Nakayama

    Nature nanotechnology   Vol. 18 ( 6 ) page: 628 - 636   2023.6

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    For the design and development of innovative carbon nanotube (CNT)-based tools and applications, an understanding of the molecular interactions between CNTs and biological systems is essential. In this study, a three-dimensional protein-structure-based in silico screen identified the paired immune receptors, sialic acid immunoglobulin-like binding lectin-5 (Siglec-5) and Siglec-14, as CNT-recognizing receptors. Molecular dynamics simulations showed the spatiotemporally stable association of aromatic residues on the extracellular loop of Siglec-5 with CNTs. Siglec-14 mediated spleen tyrosine kinase (Syk)-dependent phagocytosis of multiwalled CNTs and the subsequent secretion of interleukin-1β from human monocytes. Ectopic in vivo expression of human Siglec-14 on mouse alveolar macrophages resulted in enhanced recognition of multiwalled CNTs and exacerbated pulmonary inflammation. Furthermore, fostamatinib, a Syk inhibitor, blocked Siglec-14-mediated proinflammatory responses. These results indicate that Siglec-14 is a human activating receptor recognizing CNTs and that blockade of Siglec-14 and the Syk pathway may overcome CNT-induced inflammation.

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  24. Organic decomposition and synthesis reactions in lactated solution exposed to nonequilibrium atmospheric pressure plasma Reviewed

    Liu Y., Ishikawa K., Tanaka H., Miron C., Kondo T., Nakamura K., Mizuno M., Kajiyama H., Toyokuni S., Hori M.

    Plasma Processes and Polymers   Vol. 20 ( 5 )   2023.5

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    Lactate is used in the food and pharmaceutical industries and is a crucial intermediate for synthesis. Plasma-activated lactate (PAL) in Ringer's solution was recently shown to have effective antitumor action. Small molecule aldehydes, ketones, and organic acids were produced from lactate during plasma exposure, and five-membered conjugated lactone isomers of furanone (C5H6O2) were detected formed by interactions of lactate or its fragments with •OH, organic radicals, and H2O2. 2,3-Dimethyl-tartaric acid may be the effective component in PAL for the selective killing of cancer but not normal cells and possible pathways for its synthesis are provided. Aqueous reaction mechanisms are explained, including dehydration, esterification, hydrolysis, and dimerization. This study will help develop novel cancer therapies and further plasma organic chemistry.

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  25. BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis-resistance. Reviewed International journal

    Yaguang Luo, Shinya Akatsuka, Yashiro Motooka, Yingyi Kong, Hao Zheng, Tomoji Mashimo, Tatsuhiko Imaoka, Shinya Toyokuni

    Cancer science   Vol. 114 ( 4 ) page: 1423 - 1436   2023.4

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    Malignant mesothelioma (MM) is still a social burden associated with asbestos exposure. Local iron accumulation thereby represents the major pathogenesis, followed by oxidative DNA strand breaks and genomic alterations in the mesothelium. BRCA1 is a critical component of homologous recombination repair directed to DNA double-strand breaks. Whereas BRCA1 germline mutation is an established risk for breast/ovarian cancer, its role in MM development remains to be elucidated. Murine Brca1 mutant models thus far have not reproduced human phenotypes. However, a rat Brca1 mutant model (Mut; L63X/+) recently reproduced them at least partially. Here we describe the differential induction of MM in Brca1 mutant rats by intraperitoneal injection of chrysotile or crocidolite. Only Mut males injected with chrysotile revealed a promotional effect on mesothelial carcinogenesis in comparison to wild-type and/or females, with all the MMs Brca1-haploinsufficient. Array-based comparative genomic hybridization of MMs disclosed a greater extent of chromosomal deletions in Brca1 mutants, including Cdkn2a/2b accompanied by Tfr2 amplification, in comparison to wild-type tumors. Mutant MMs indicated iron metabolism dysregulation, such as increase in catalytic Fe(II) and Ki67-index as well as decrease in Fe(III) and ferritin expression. Simultaneously, mutant MMs revealed ferroptosis-resistance by upregulation of Slc7A11 and Gpx4. At an early carcinogenic stage of 4 weeks, induced Brca1 expression in mesothelial cells was significantly suppressed in chrysotile/Mut in comparison to crocidolite/Mut whereas significant preference to iron with decrease in Fe(III) has been already established. In conclusion, chrysotile exposure can be a higher risk for MM in BRCA1 mutant males, considering the rat results.

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  26. Field-effect transistor antigen/antibody-TMDs sensors for the detection of COVID-19 samples. Reviewed International journal

    Ruben Canton-Vitoria, Kotaro Sato, Yashiro Motooka, Shinya Toyokuni, Zheng Liu, Ryo Kitaura

    Nanoscale   Vol. 15 ( 9 ) page: 4570 - 4580   2023.3

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    We fabricated sensors by modifying the surface of MoS2 and WS2 with COVID-19 antibodies and investigated their characteristics, including stability, reusability, sensitivity, and selectivity. Thiols and disulfanes in antibodies strongly interact with vacant Mo or W sites of MoS2 or WS2, yielding durable devices that are stable for several days in the air or water. More importantly, detachment of the antibodies is suppressed even during the aggressive cleaning process of the devices at pH 3, which allows reusing the same device in several experiments without appreciable loss of sensitivity. Therefore, the nanodevice may be employed in samples of different patients. Further, we found a limit of detection (LOD) of 1 fg ml-1 at room temperature, time responses of 1 second, and selectivity against interferences such as KLH protein or Albumin.

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  27. Cancer-specific cytotoxicity of Ringer’s acetate solution irradiated by cold atmospheric pressure plasma Reviewed

    Camelia Miron, Kenji Ishikawa, Satoshi Kashiwagura, Yuki Suda, Hiromasa Tanaka, Kae Nakamura, Hiroaki Kajiyama, Shinya Toyokuni, Masaaki Mizuno, Masaru Hori

    Free Radical Research   Vol. 57 ( 2 ) page: 91 - 104   2023.2

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  28. Environmental impact on carcinogenesis under BRCA1 haploinsufficiency. Reviewed

    Toyokuni S, Kong Y, Motooka Y, Akatsuka S

    Genes and environment : the official journal of the Japanese Environmental Mutagen Society   Vol. 45 ( 1 ) page: 2   2023.1

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    Cancer is the primary cause of human mortality in Japan since 1981. Although numerous novel therapies have been developed and applied in clinics, the number of deaths from cancer is still increasing worldwide. It is time to consider the strategy of cancer prevention more seriously. Here we propose a hypothesis that cancer can be side effects of long time-use of iron and oxygen and that carcinogenesis is an evolution-like cellular events to obtain “iron addiction with ferroptosis-resistance” where genes and environment interact each other. Among the recognized genetic risk factors for carcinogenesis, we here focus on BRCA1 tumor suppressor gene and how environmental factors, including daily life exposure and diets, may impact toward carcinogenesis under BRCA1 haploinsufficiency. Although mice models of BRCA1 mutants have not been successful for decades in generating phenotype mimicking the human counterparts, a rat model of BRCA1 mutant was recently established that reasonably mimics the human phenotype. Two distinct categories of oxidative stress, one by radiation and one by iron-catalyzed Fenton reaction, promoted carcinogenesis in Brca1 rat mutants. Furthermore, mitochondrial damage followed by alteration of iron metabolism finally resulted in ferroptosis-resistance of target cells in carcinogenesis. These suggest a possibility that cancer prevention by active pharmacological intervention may be possible for BRCA1 mutants to increase the quality of their life rather than preventive mastectomy and/or oophorectomy.

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  29. Plasma activated Ringer's lactate solution. Reviewed

    Tanaka H, Mizuno M, Ishikawa K, Miron C, Okazaki Y, Toyokuni S, Nakamura K, Kajiyama H, Hori M

    Free radical research   Vol. 57 ( 1 ) page: 14 - 20   2023.1

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    Low-temperature plasma (LTP) has been widely used in life science. Plasma-activated solutions were defined as solutions irradiated with LTP, and water, medium, and Ringer’s solutions have been irradiated with LTP to produce plasma-activated solutions. They contain chemical compounds produced by reactions among LTP, air, and solutions. Reactive oxygen and nitrogen species (RONS) are major components in plasma-activated solutions and recent studies revealed that plasma-activated organic compounds are produced in plasma-activated Ringer’s lactate solution (PAL). Many in vitro and in vivo studies demonstrated that PAL exhibits anti-tumor effects on cancers, and biochemical analyses revealed intracellular molecular mechanisms of cancer cell death by PAL.

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  30. Exposure of low-temperature plasma after vaccination in tongue promotes systemic IgM induction against spike protein of SARS-CoV-2. Reviewed International journal

    Kotaro Sato, Kouki Fujii, Hiromasa Tanaka, Masaru Hori, Hideharu Hibi, Shinya Toyokuni

    Free radical research   Vol. 57 ( 1 ) page: 30 - 37   2023.1

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    COVID-19 has been pandemic since 2020 with persistent generation of new variants. Cellular receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), where transmembrane serine protease-2 (TMPRSS2) is essential for viral internalization. We recently reported abundant expression of ACE2 and TMPRSS2 in the oral cavity of humans and mice. Therefore, oral cavity may work for COVID-19 infection gates. Here we undertook to evaluate whether vaccination in the tongue harbors any merit in comparison to subcutaneous injection. Low-temperature plasma (LTP) is the fourth physical state of matters with ionization above gas but at body temperature. LTP provides complex chemistry, eventually supplying oxidative and/or nitrosative stress on the interface. LTP-associated cellular death has been reported to cause apoptosis and/or ferroptosis. However, there is few data available on immunogenicity retention after LTP exposure. We therefore studied the effect of LTP exposure after the injection of keyhole limpet hemocyanin (KLH) or spike 2 protein of SARS-CoV-2 to the tongue of six-week-old male BALB/c mice, compared to subcutaneous vaccination. Whereas LTP did not change the expression of ACE2 and TMPRSS2 in the tongue, repeated LTP exposure after tongue vaccination significantly promoted systemic and specific IgM production at day 11. In contrast, repeated LTP exposure after subcutaneous vaccination of KLH decreased systemic IgM production. Of note, tongue injection produced significantly higher titer of IgM and IgG in the case of KLH. In conclusion, LTP significantly reinforced humoral immunity by IgM after tongue injection. Vaccination to the tongue can be a novel strategy to acquire immediate immunity.

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  31. Low-temperature plasma as magic wand to differentiate between the good and the evil. Reviewed International journal

    Shinya Toyokuni, Hao Zheng, Yingyi Kong, Kotaro Sato, Kae Nakamura, Hiromasa Tanaka, Yasumasa Okazaki

    Free radical research   Vol. 57 ( 1 ) page: 38 - 46   2023.1

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    Plasma is the fourth physical state of matter, characterized by an ionized gaseous mixture, after solid, liquid, and gas phases, and contains a wide array of components such as ions, electrons, radicals, and ultraviolet ray. Whereas the sun and thunder are typical natural plasma, recent progress in the electronics enabled the generation of body-temperature plasma, designated as low-temperature plasma (LTP) or non-thermal plasma since the 1990s. LTP has attracted the attention of researchers for possible biological and medical applications. All the living species on earth utilize water as essential media for solvents and molecular transport. Thus, biological application of LTP naturally intervenes water whether LTP is exposed directly or indirectly, where plasma-activated lactate (PAL) is a standard, containing H2O2, NO2- and other identified molecules. Electron spin resonance and immunohistochemical studies demonstrated that LTP exposure is a handy method to load local oxidative stress. Cancer cells are characterized by persistent self-replication and high cytosolic catalytic Fe(II). Therefore, both direct exposure of LTP and PAL can provide higher damage to cancer cells in comparison to non-tumorous cells, which has been demonstrated in a variety of cancer types. The cell death mode is either apoptosis or ferroptosis, depending on the cancer-type. Thus, LTP and PAL are expected to work as an additional cancer therapy to the established guideline protocols, especially for use in somatic cavities or surgical margins.

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  32. Chemical reaction mechanism in non-thermal plasma from the viewpoint of oxidative stress toward clinical cancer applications Reviewed International coauthorship International journal

    Toyokuni, S; Shi, L; Okazaki, Y; Richardson, DR

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 100   page: S131 - S131   2016.11

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  33. Biphasic effects of L-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells Reviewed International coauthorship International journal

    Lei Shi, Yue Wang, Fumiya Ito, Yasumasa Okazaki, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Des R. Richardson, Shinya Toyokuni

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 605   page: 109 - 116   2016.9

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    Non-thermal plasma (NTP) is a recently developed technology that elicits a variety of biological effects. This includes cancer cell-specific cytotoxicity, which is mainly attributed to the regional generation of reactive oxygen species (ROS). We studied the effects of NTP on malignant mesothelioma (MM) and its modulation by L-ascorbate. L-ascorbate is a major water-soluble anti-oxidant in vivo, but its pro-oxidant activity in vitro has been well recognized. Thus, the effects of ascorbate on the efficacy of NTP is important to examine. NTP exposure dose-dependently killed MM cells, whereas MM cells tolerated 1 mM L-ascorbate. However, brief pre-treatment with a pharmacological dose (250-750 mu M) of L-ascorbate immediately prior to NTP exposure significantly increased its cytotoxicity in a dose-dependent manner, which was inhibited by the iron chelator, deferoxamine. However, paradoxically, this potentiating effect of L-ascorbate was completely abolished by a prolonged 4 h pre-incubation with L-ascorbate (500 mu M). MM cytotoxicity induced by NTP was associated with immediate oxidative stress evaluated by 2',7'-dichlorodihydrofluorecein diacetate, which was followed by an increase in the expression of the autophagosome marker, LC3B-II. In conclusion, MM can be a target for NTP treatment and L-ascorbate can increase or decrease its efficacy depending on the length of the pre-incubation period. (C) 2016 Elsevier Inc. All rights reserved.

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  34. Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin Reviewed International journal

    Shinya Toyokuni, Li Jiang, Shenqi Wang, Ayaka Hirao, Tamae Wada, Chieko Soh, Kazumi Toyama, Akira Kawada

    PATHOLOGY INTERNATIONAL   Vol. 65 ( 8 ) page: 415 - 419   2015.8

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    Sunlight exposure and aging are two major factors in the deterioration of skin function. In the present study, we used eighty formalin-fixed human skin samples from sun-exposed and unexposed areas from old and young individuals to evaluate the presence of miR-125b-positive epidermal stem cells (ESCs) by in situ hybridization. miR-125b-positive ESCs were detected in the basal layer of the epidermis. The density of miR-125b-positive ESCs was significantly associated with age rather than sun exposure, whereas the density of miR-125b-positive ESCs tended to decrease in the sun-exposed area. These data suggest the potential use of miR-125b as a surrogate marker for the quality of epidermal cells.

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  35. Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells Reviewed International journal

    Satomi Funahashi, Yasumasa Okazaki, Daiki Ito, Atsushi Asakawa, Hirotaka Nagai, Masafumi Tajima, Shinya Toyokuni

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 56 ( 2 ) page: 111 - 117   2015.3

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    Asbestos exposure is considered a social burden by causing mesothelioma. Despite the use of synthetic materials, multi-walled carbon nanotubes (MWCNTs) are similar in dimension to asbestos and produce mesothelioma in animals. The role of inflammatory cells in mesothelial carcinogenesis remains unclear. Here, we evaluated the differences in inflammatory cell responses following exposure to these fibrous materials using a luminometer and L-012 (8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H) dione) to detect reactive oxygen species (ROS). Rat peripheral blood or RAW264.7 cells were used to assess the effects on neutrophils and macrophages, respectively. Crocidolite and amosite induced significant ROS generation by neutrophils with a peak at 10 min, whereas that of chrysotile was similar to 25% of the crocidolite/amosite response. MWCNTs with different diameters (similar to 15, 50, 115 and 145 nm) and different carcinogenicity did not induce significant ROS in peripheral blood. However, the MWCNTs induced a comparable amount of ROS in RAW264.7 cells to that following asbestos treatment. The peaks for MWCNTs (0.5-1.5 h) were observed earlier than those for asbestos (1-5 h). Apocynin and superoxide dismutase significantly inhibited ROS generation for each fiber, suggesting an involvement of NADPH oxidase and superoxide. Thus, asbestos and MWCNTs induce different oxidative responses in inflammatory cells, indicating the importance of mesothelial cell evaluation for carcinogenesis.

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  36. Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders Reviewed International journal

    Hattori Yuka, Mukaide Takahiro, Jiang Li, Kotani Tomomi, Tsuda Hiroyuki, Mano Yukio, Sumigama Seiji, Hirayama Tasuku, Nagasawa Hideko, Kikkawa Fumitaka, Toyokuni Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 56 ( 1 ) page: 57 - 63   2015

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    Amniotic fluid contains numerous biomolecules derived from fetus and mother, thus providing precious information on pregnancy. Here, we evaluated oxidative stress of human amniotic fluid and measured the concentration of catalytic Fe(II). Amniotic fluid samples were collected with consent from a total of 89 subjects in Nagoya University Hospital, under necessary medical interventions: normal pregnancy at term, normal pregnancy at the 2nd trimester, preterm delivery with maternal disorders but without fetal disorders, congenital diaphragmatic hernia, fetal growth restriction, pregnancy-induced hypertension, gestational diabetes mellitus, Down syndrome and trisomy 18. Catalytic Fe(II) and oxidative stress markers (8-hydroxy-2'-deoxyguanosine, 8-OHdG; dityrosine) were determined with RhoNox-1 and specific antibodies, respectively, using plate assays. Levels of 8-OHdG and dityrosine were higher in the 3rd trimester compared with the 2nd trimester in normal subjects, and the abnormal groups generally showed lower levels than the controls, thus suggesting that they represent fetal metabolic activities. In contrast, catalytic Fe(II) was higher in the 2nd trimester than the 3rd trimester in the normal subjects, and overall the abnormal groups showed higher levels than the controls, suggesting that high catalytic Fe(II) at late gestation reflects fetal pathologic alterations. Notably, products of H<sub>2</sub>O<sub>2</sub> and catalytic Fe(II) remained almost constant in amniotic fluid.

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  37. Connective tissue growth factor and beta-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma Reviewed International journal

    Li Jiang, Yoriko Yamashita, Shan-Hwu Chew, Shinya Akatsuka, Shun Ukai, Shenqi Wang, Hirotaka Nagai, Yasumasa Okazaki, Takashi Takahashi, Shinya Toyokuni

    JOURNAL OF PATHOLOGY   Vol. 233 ( 4 ) page: 402 - 414   2014.8

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    Due to the formerly widespread use of asbestos, malignant mesothelioma (MM) is increasingly frequent worldwide. MM is classified into epithelioid (EM), sarcomatoid (SM), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM, and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM, we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor (Ctgf), whose expression was significantly increased in SM compared with EM; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM, Ctgf was a major regulator of MM proliferation and invasion through activation of the beta-catenin-TCF-LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial-mesenchymal transition in MM. Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6-GSK3 beta-beta-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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  38. Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production International journal

    Shan Hwu Chew, Yasumasa Okazaki, Hirotaka Nagai, Nobuaki Misawa, Shinya Akatsuka, Kyoko Yamashita, Li Jiang, Yoriko Yamashita, Michio Noguchi, Kiminori Hosoda, Yoshitaka Sekido, Takashi Takahashi, Shinya Toyokuni

    CARCINOGENESIS   Vol. 35 ( 1 ) page: 164 - 172   2014.1

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    Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos-induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse transcriptionPCR revealed that adipocytes respond directly to asbestos exposure with an increased production of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y-MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.

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  39. CANCER AS A FERROTOXIC DISEASE: WHAT WE HAVE LEARNED FROM ANIMAL STUDIES TOWARD ITS PREVENTION Reviewed International journal

    Toyokuni, S, Jiang, L, Okazaki, Y, Akatsuka, S

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 88 ( 5 ) page: E168 - E169   2013.5

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  40. Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary Reviewed International journal

    Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

    LABORATORY INVESTIGATION   Vol. 92   page: 302A - 302A   2012.2

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  41. Asbestos surface provides a niche for oxidative modification Reviewed International journal

    Hirotaka Nagai, Toshikazu Ishihara, Wen-Hua Lee, Hiroki Ohara, Yasumasa Okazaki, Katsuya Okawa, Shinya Toyokuni

    CANCER SCIENCE   Vol. 102 ( 12 ) page: 2118 - 2125   2011.12

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    Asbestos is a potent carcinogen associated with increased risks of malignant mesothelioma and lung cancer in humans. Although the mechanism of carcinogenesis remains elusive, the physicochemical characteristics of asbestos play a role in the progression of asbestos-induced diseases. Among these characteristics, a high capacity to adsorb and accommodate biomolecules on its abundant surface area has been linked to cellular and genetic toxicity. Several previous studies identified asbestos-interacting proteins. Here, with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry, we systematically identified proteins from various lysates that adsorbed to the surface of commercially used asbestos and classified them into the following groups: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. The surfaces of crocidolite and amosite, two iron-rich types of asbestos, caused more protein scissions and oxidative modifications than that of chrysotile by in situ-generated 4-hydroxy-2-nonenal. In contrast, we confirmed the intense hemolytic activity of chrysotile and found that hemoglobin attached to chrysotile, but not silica, can work as a catalyst to induce oxidative DNA damage. This process generates 8-hydroxy-2'-deoxyguanosine and thus corroborates the involvement of iron in the carcinogenicity of chrysotile. This evidence demonstrates that all three types of asbestos adsorb DNA and specific proteins, providing a niche for oxidative modification via catalytic iron. Therefore, considering the affinity of asbestos for histones/DNA and the internalization of asbestos into mesothelial cells, our results suggest a novel hypothetical mechanism causing genetic alterations during asbestos-induced carcinogenesis. (Cancer Sci 2011; 102: 21182125)

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  42. Age- and sun exposure-dependent differences in 8-hydroxy-2'-deoxyguanosine and N-(carboxymethyl)lysine in human epidermis. Reviewed International journal

    Shinya Toyokuni, Ayaka Hirao, Tamae Wada, Ryoji Nagai, Akira Date, Takashi Yoshii, Shinya Akatsuka, Yoriko Yamashita, Akira Kawada

    Journal of clinical biochemistry and nutrition   Vol. 49 ( 2 ) page: 121 - 4   2011.9

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    Aging and exposure to sunlight are two major factors in the deterioration of skin function. In this study, thirty-six fixed human skin samples from sun-exposed and unexposed areas from young and old individuals were used to evaluate the localization of oxidative stress according to levels and distribution of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine in samples using immunohistochemistry. In the epidermis of the young, negligible amounts of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine were detected in unexposed areas, whereas nuclear 8-hydroxy-2'-deoxyguanosine and cytoplasmic N-epsilon-(carboxymethyl)lysine were increased in the lower epidermis in sun-exposed areas. In contrast, the aged presented prominent nuclear 8-hydroxy-2'-deoxyguanosine and nuclear N-epsilon-(carboxymethyl)lysine in the epidermis of unexposed areas, concomitant with dermal increase in N-epsilon-(carboxymethyl)lysine. However, the immunostaining of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine revealed a decrease in the epidermis of sun-exposed areas in the aged. These results suggest an age-dependent difference in the adaptation and protective mechanisms of the epidermis against sunlight-associated oxidative stress, thus necessitating distinct standards for evaluation in each age group. Further investigation is warranted to elucidate underlying molecular mechanisms.

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  43. Mechanisms of Asbestos-Induced Carcinogenesis Reviewed

    TOYOKUNI Shinya, JIANG Li, HU Qian, NAGAI Hirotaka, OKAZAKI Yasumasa, AKATSUKA Shinya, YAMASHITA Yoriko

    Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene)   Vol. 66 ( 3 ) page: 562 - 7   2011.5

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    Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.<br>

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  44. Biopersistent fiber-induced inflammation and carcinogenesis: lessons learned from asbestos toward safety of fibrous nanomaterials. Reviewed International journal

    Hirotaka Nagai, Shinya Toyokuni

    Archives of biochemistry and biophysics   Vol. 502 ( 1 ) page: 1 - 7   2010.10

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    Nano-sized durable fibrous materials such as carbon nanotubes have raised safety concerns similar to those raised by asbestos However, the mechanism by which particulates with ultrafine structure cause inflammation and ultimately cancer (e.g malignant mesothelioma and lung cancer) is largely unknown. This is partially because the particulates are not uniform and they vary in a plethora of factors Such variances include length, diameter, surface area, density, shape, contaminant metals (including iron) and crystallinity Each of these factors is involved in particulate toxicity both in vitro and in vivo Thus, the elicited biological responses are incredibly complicated Various kinds of fibeis were evaluated with different cells, animals and methods The aim of this review is to concisely summarize previous reports from the standpoint that activation of macrophages and mesothelial injury are the two major mechanisms of inflammation and possibly cancer Importantly, these two mechanisms appear to be interacting with each other However, there is a lack of data on the interplay of macrophage and mesothelium especially in vivo. Since fibrous nanomaterials present potential applications in various fields, it is necessary to develop standard evaluation methods to minimize risks for human health. (C) 2010 Elsevier Inc All rights reserved

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  45. Asbestos-induced Carcinogenesis is Oxidative Stress-dependent Reviewed International journal

    Shinya Toyokuni, Li Jiang, Hirotaka Nagai, Hiroki Ohara, Yasumasa Okazaki, Shinya Akatsuka, Yoriko Yamashita

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 49   page: S72 - S72   2010

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  46. Characteristics and modifying factors of asbestos-induced oxidative DNA damage Reviewed International journal

    Li Jiang, Hirotaka Nagai, Hiroki Ohara, Shigeo Hara, Mitsuhiro Tachibana, Seishiro Hirano, Yasushi Shinohara, Norihiko Kohyama, Shinya Akatsuka, Shinya Toyokuni

    CANCER SCIENCE   Vol. 99 ( 11 ) page: 2142 - 2151   2008.11

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    Respiratory exposure to asbestos has been linked with mesothelioma in humans. However, its carcinogenic mechanism is still unclear. Here we studied the ability of chrysotile, crocidolite and amosite fibers to induce oxidative DNA damage and the modifying factors using four distinct approaches. Electron spin resonance analyses revealed that crocidolite and amosite containing high amounts of iron, but not chrysotile, catalyzed hydroxyl radical generation in the presence of H(2)O(2), which was enhanced by an iron chelator, nitrilotriacetic acid, and suppressed by desferal. Natural iron chelators, such as citrate, adenosine 5&apos;-triphosphate and guanosine 5&apos;-triphosphate, did not inhibit this reaction. Second, we used time-lapse video microscopy to evaluate how cells cope with asbestos fibers. RAW264.7 cells, MeT-5 A and HeLa cells engulfed asbestos fibers, which reached not only cytoplasm but also the nucleus. Third, we utilized supercoiled plasmid DNA to evaluate the ability of each asbestos to induce DNA double strand breaks (DSB). Crocidolite and amosite, but not chrysotile, induced DNA DSB in the presence of iron chelators. We cloned the fragments to identify break sites. DSB occurred preferentially within repeat sequences and between two G:C sequences. Finally, i.p. administration of each asbestos to rats induced not only formation of nuclear 8-hydroxy-2&apos;-deoxyguanosine in the mesothelia, spleen, liver and kidney but also significant iron deposits in the spleen. Together with the established carcinogenicity of i.p. chrysotile, our data suggest that asbestos-associated catalytic iron, whether constitutional or induced by other mechanisms, plays an important role in asbestos-induced carcinogenesis and that chemoprevention may be possible through targeting the catalytic iron. (Cancer Sci 2008; 99: 2142-2151).

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  47. Antioxidant alpha-tocopherol improves glycemic control of GK rats, a model of type 2 diabetes Reviewed International journal

    Ihara Y, Yamada Y, Toyokuni S, Ban N, Kuroe A, Seino Y

    DIABETES   Vol. 49   page: A429 - A429   2000.5

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  48. 4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress - Identification of proteasomes as target molecules Reviewed International coauthorship International journal

    Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 274 ( 34 ) page: 23787 - 23793   1999.8

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  49. 8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure (vol 107, pg 733, 1996) Reviewed International journal

    Hattori, Y, Nishigori, C, Tanaka, T, Uchida, K, Nikaido, O, Osawa, T, Hiai, H, Imamura, S, Toyokuni, S

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 108 ( 2 ) page: 237 - 237   1997.2

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  50. ACUTE NEPHROTOXICITY OF A CARCINOGENIC IRON CHELATE - SELECTIVE-INHIBITION OF A PROTEOLYTIC CONVERSION OF ALPHA(2U)-GLOBULIN TO THE KIDNEY FATTY-ACID-BINDING PROTEIN Reviewed International journal

    UCHIDA K, FUKUDA A, KAWAKISHI S, TOYOKUNI S, HIAI H, IKEDA S, HORIO F

    FEBS LETTERS   Vol. 357 ( 2 ) page: 165 - 167   1995.1

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  51. Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.

    Peleman C, Hellemans S, Veeckmans G, Arras W, Zheng H, Koeken I, Van San E, Hassannia B, Walravens M, Kayirangwa E, Beyene NT, Van Herck MA, De Vos WH, Pintelon I, van Nassauw L, Oosterlinck B, Smet A, Vits L, Dirinck E, Verrijken A, De Man J, Van Eyck A, Kwanten WJ, Vonghia L, Driessen A, Augustyns K, Toyokuni S, De Winter B, Van Steenkiste C, Francque S, Vanden Berghe T

    Cell death and differentiation   Vol. 31 ( 9 ) page: 1113 - 1126   2024.9

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    There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD. (Figure presented.)

    DOI: 10.1038/s41418-024-01348-9

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  52. Ferroptosis in health and disease.

    Berndt C, Alborzinia H, Amen VS, Ayton S, Barayeu U, Bartelt A, Bayir H, Bebber CM, Birsoy K, Böttcher JP, Brabletz S, Brabletz T, Brown AR, Brüne B, Bulli G, Bruneau A, Chen Q, DeNicola GM, Dick TP, Distéfano A, Dixon SJ, Engler JB, Esser-von Bieren J, Fedorova M, Friedmann Angeli JP, Friese MA, Fuhrmann DC, García-Sáez AJ, Garbowicz K, Götz M, Gu W, Hammerich L, Hassannia B, Jiang X, Jeridi A, Kang YP, Kagan VE, Konrad DB, Kotschi S, Lei P, Le Tertre M, Lev S, Liang D, Linkermann A, Lohr C, Lorenz S, Luedde T, Methner A, Michalke B, Milton AV, Min J, Mishima E, Müller S, Motohashi H, Muckenthaler MU, Murakami S, Olzmann JA, Pagnussat G, Pan Z, Papagiannakopoulos T, Pedrera Puentes L, Pratt DA, Proneth B, Ramsauer L, Rodriguez R, Saito Y, Schmidt F, Schmitt C, Schulze A, Schwab A, Schwantes A, Soula M, Spitzlberger B, Stockwell BR, Thewes L, Thorn-Seshold O, Toyokuni S, Tonnus W, Trumpp A, Vandenabeele P, Vanden Berghe T, Venkataramani V, Vogel FCE, von Karstedt S, Wang F, Westermann F, Wientjens C, Wilhelm C, Wölk M, Wu K, Yang X, Yu F, Zou Y, Conrad M

    Redox biology   Vol. 75   page: 103211   2024.9

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    Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

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  53. Ferroptosis induced by plasma-activated Ringer's lactate solution prevents oral cancer progression.

    Sato K, Yang M, Nakamura K, Tanaka H, Hori M, Nishio M, Suzuki A, Hibi H, Toyokuni S

    Oral diseases   Vol. 30 ( 6 ) page: 3912 - 3924   2024.9

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    Objective: This study aimed to investigate the effect of plasma-activated Ringer's lactate solution (PAL) on oral squamous cell carcinoma (OSCC) cells and carcinogenic processes with a particular focus on iron and collagenous matrix formation. Materials and Methods: We used three OSCC cell lines, one keratinocyte cell line, and two fibroblast lines, and cell viability assays, immunoblotting, flow cytometry, and transmission electron microscopy were performed to evaluate the effect and type of cell death. The effect of PAL treatment on lysyl oxidase (LOX) expression was investigated in vitro and in vivo. Tamoxifen-inducible Mob1a/b double-knockout mice were used for the in vivo experiment. Results: PAL killed OSCC cells more effectively than the control nontumorous cells and suppressed cell migration and invasion. Ferroptosis occurred and the protein level of LOX was downregulated in cancer cells in vitro and in vivo. Additionally, PAL improved the survival rate of mice and suppressed collagenous matrix formation. Conclusions: We demonstrated that PAL specifically kills OSCC cells and that ferroptosis occurs in vitro and in vivo. Furthermore, PAL can prevent carcinogenesis and improve the survival rate of oral cancer, especially tongue cancer, by changing collagenous matrix formation via LOX suppression.

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  54. 特集 フェロトーシス(鉄依存性細胞死)--そのメカニズムの解明と,治療への応用 フェロトーシス抵抗性と発がん

    前田 勇貴, 豊國 伸哉

    医学のあゆみ   Vol. 290 ( 2 ) page: 174 - 177   2024.7

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  55. Special issue: Extracellular fine particles in life, death and disease.

    Toyokuni S

    Archives of biochemistry and biophysics   Vol. 757   page: 110027   2024.7

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  56. Heat-treated and/or lysozyme-treated <i>Enterococcus faecalis</i> (FK-23) improves the progression of renal disease in a unilateral ischemia-reperfusion injury rat model

    Takemura Shigekazu, Minamiyama Yukiko, Ito Norihiko, Yamamoto Atsushi, Ichikawa Hiroshi, Nakagawa Kanako, Toyokuni Shinya, Osada-Oka Mayuko, Yoshikawa Toshikazu

    Journal of Clinical Biochemistry and Nutrition   Vol. 75 ( 1 ) page: 78 - 89   2024.7

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    <p>The prevalence of chronic kidney disease (CKD) is increasing owing to the elderly population. Here, we investigated the effects of heat-treated <i>Enterococcus faecalis</i> (FK-23) and lysozyme-treated FK-23 (LFK) on the progression of CKD in rats. A CKD model was established using male Wistar rats by subjecting them to right nephrectomy (1K), followed by ischemia and reperfusion (IR). FK-23 or LFK was fed <i>ad libitum</i> as a mixed diet after right nephrectomy. Animals subjected to renal ischemia-reperfusion injury (IRI) showed increased plasma creatinine and blood urea nitrogen levels. Furthermore, in the kidneys, collagen accumu­lation and α-smooth muscle actin, indicative of fibroblast activation and fibrosis-related gene and protein expression, increased 3 weeks after IRI. FK-23 and LFK suppressed the increase in the mRNA levels of some of these genes. The increase in oxidative stress markers, 4-hydroxy-2-nonenal, endothelial nitric oxide synthase, and nitrotyrosine in the kidney, as well as increased plasma uremic toxins after IRI, were also ameliorated by FK-23 and LFK. Metagenomic analysis of fecal samples revealed that gut microbial alteration caused by IRI was also ameliorated by LFK treatment. These results suggest that <i>Enterococcus faecalis</i> ingre­dients may improve CKD progression by suppressing oxidative stress and correcting the balance of the intestinal microflora.</p>

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  57. International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.

    Chen X, Tsvetkov AS, Shen HM, Isidoro C, Ktistakis NT, Linkermann A, Koopman WJH, Simon HU, Galluzzi L, Luo S, Xu D, Gu W, Peulen O, Cai Q, Rubinsztein DC, Chi JT, Zhang DD, Li C, Toyokuni S, Liu J, Roh JL, Dai E, Juhasz G, Liu W, Zhang J, Yang M, Liu J, Zhu LQ, Zou W, Piacentini M, Ding WX, Yue Z, Xie Y, Petersen M, Gewirtz DA, Mandell MA, Chu CT, Sinha D, Eftekharpour E, Zhivotovsky B, Besteiro S, Gabrilovich DI, Kim DH, Kagan VE, Bayir H, Chen GC, Ayton S, Lünemann JD, Komatsu M, Krautwald S, Loos B, Baehrecke EH, Wang J, Lane JD, Sadoshima J, Yang WS, Gao M, Münz C, Thumm M, Kampmann M, Yu D, Lipinski MM, Jones JW, Jiang X, Zeh HJ, Kang R, Klionsky DJ, Kroemer G, Tang D

    Autophagy   Vol. 20 ( 6 ) page: 1213 - 1246   2024.6

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    Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results. Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

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  58. Fatal COVID-19 pulmonary disease involves ferroptosis.

    Qiu B, Zandkarimi F, Saqi A, Castagna C, Tan H, Sekulic M, Miorin L, Hibshoosh H, Toyokuni S, Uchida K, Stockwell BR

    Nature communications   Vol. 15 ( 1 ) page: 3816   2024.5

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    Ferroptosis is a form of cell death that has been associated with different diseases. Here the authors describe an association of ferroptosis with COVID-19 pulmonary pathologies in both patient samples and hamster model and suggest that the dysregulation in iron and lipid metabolism could provide targets to reduce pathology.

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  59. 特集 活性酸素と酸化ストレス がんとフェロトーシス

    豊國 伸哉

    医学のあゆみ   Vol. 289 ( 4 ) page: 263 - 266   2024.4

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  60. Protocol for the isolation of GFP-expressing ferroptosis-dependent extracellular vesicles in in vitro cell culture models. Reviewed International journal

    Fumiya Ito, Izumi Yanatori, Katsuhiro Kato, Shinya Toyokuni

    STAR protocols   Vol. 5 ( 1 ) page: 102892 - 102892   2024.3

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    Extracellular vesicles (EVs) are complex structures that transport various DNA, RNA, and protein. Recently, new EV secretion mechanisms have been identified through the iron regulatory system in mammalian cells. We revealed that ferroptosis increases EV secretion, which is named ferroptosis-dependent EVs (FedEVs). Here, we describe a step-by-step procedure to isolate GFP-expressing FedEVs for in vitro analysis. The FedEVs are further analyzed by imaging and flow cytometry analysis. For complete details on the use and execution of this protocol, please refer to Ito et al.1.

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  61. Txn1 mutation is a monogenic cause of chronic kidney disease associated with mitochondrial dysfunction in rats

    Iori Ohmori, Mamoru Ouchida, Yoshiko Hada, Haruhito, A. Uchida, Shinya Toyokuni, Tomoji Mashimo

    BioRxiv     2023.8

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  62. Sleep-wake patterns are altered with age, Prdm13 signaling in the DMH, and diet restriction in mice. Reviewed International journal

    Shogo Tsuji, Cynthia S Brace, Ruiqing Yao, Yoshitaka Tanie, Hirobumi Tada, Nicholas Rensing, Seiya Mizuno, Julio Almunia, Yingyi Kong, Kazuhiro Nakamura, Takahisa Furukawa, Noboru Ogiso, Shinya Toyokuni, Satoru Takahashi, Michael Wong, Shin-Ichiro Imai, Akiko Satoh

    Life science alliance   Vol. 6 ( 6 )   2023.6

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    Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specific Prdm13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during SD. These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep fragmentation and increased sleep attempts during SD, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated increased sleep attempts during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging.

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  63. Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1. Reviewed International journal

    Fumiya Ito, Katsuhiro Kato, Izumi Yanatori, Yuki Maeda, Toyoaki Murohara, Shinya Toyokuni

    BMC cancer   Vol. 23 ( 1 ) page: 487 - 487   2023.5

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    Organoids are a three-dimensional (3D) culture system that simulate actual organs. Therefore, tumor organoids are expected to predict precise response to chemotherapy in patients. However, to date, few studies have studied the drug responses in organoids of malignant mesothelioma (MM). The poor prognosis of MM emphasizes the importance of establishing a protocol for generating MM-organoid for research and clinical use. Here, we established murine MM organoids from p53+/- or wild-type C57BL/6 strain by intraperitoneal injection either with crocidolite or carbon nanotube. Established MM-organoids proliferated in Matrigel as spheroids. Subcutaneous injection assays revealed that the MM-organoids mimicked actual tissue architecture and maintained the original histological features of the primary MM. RNA sequencing and pathway analyses revealed that the significant expressional differences between the 2D- and 3D-culture systems were observed in receptor tyrosine kinases, including IGF1R and EGFR, glycosylation and cholesterol/steroid metabolism. MM-organoids exhibited a more sensitive response to cisplatin through stable plasma membrane localization of a major cisplatin transporter, copper transporter 1/Slc31A1 (Ctr1) in comparison to 2D-cultures, presumably through glycosylation and lipidation. The Matrigel culture system facilitated the localization of CTR1 on the plasma membrane, which simulated the original MMs and the subcutaneous xenografts. These results suggest that the newly developed protocol for MM-organoids is useful to study strategies to overcome chemotherapy resistance to cisplatin.

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  64. DNA oxidative damage caused by the aromatic amine MOCA —Examination of 8-hydroxy-2’-deoxyguanosine levels in rat liver— Reviewed

    KOBAYASHI Saho, MOTOOKA Yashiro, KASHIWAGI Hiroki, TOYOKUNI Shinya

    Journal of Occupational Safety and Health   Vol. 16 ( 1 ) page: 45 - 49   2023.2

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    <p>MOCA (4,4’-methylenebis (2-chloroaniline)) , an aromatic amine, is industrially used as a curing agent for urethane resins; however, it is classified as a Group 1 compound (carcinogenic to humans) by the International Agency for Research on Cancer, and there is concern regarding its health effects on workers. The mechanism underlying MOCA-mediated carcinogenesis is thought to be related to DNA damage caused by reactive oxygen species (ROS) and DNA adducts, which are mainly generated during metabolism in the liver. 8-Oxoguanine (8-OHdG), a product of ROS-induced oxidation, occurs at high frequency and can induce G→T transversion mutations during DNA replication. However, to the best of our knowledge, no study has examined whether MOCA induces the formation of highly mutagenic 8-OHdG in experimental animals. Here, F344 rats were orally exposed to 0, 0.4, 2, 10, or 50 mg/kg/day MOCA three times a week for 2 weeks; this is expected to exert toxicity through the hepatic metabolism of MOCA. Livers obtained from these animals were examined for pathology and 8-OHdG levels. In pathological sections, vacuolar degeneration was observed with 50 mg/kg/day MOCA. Further, MOCA-induced 8-OHdG levels showed a slight increasing trend, except at 0.4 mg/kg/day. However, none of these differences were significant. Thus, 8-OHdG is unlikely the main cause of carcinogenesis.</p>

    DOI: 10.2486/josh.josh-2022-0022-ta

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  65. Toward the next century of the Nagoya Journal of Medical Science: message from the Editor-in-chief. Reviewed

    Toyokuni S

    Nagoya journal of medical science   Vol. 85 ( 1 ) page: 1 - 4   2023.2

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    It is my great pleasure and honor as the Editor-in-chief to congratulate the centennial anniversary of the Nagoya Journal of Medical Science in 2023 with all the editorial board members and the technical staffs as well as the authors and the readers. One hundred years are quite a long period, and the persistent publication from a medical school of national university in Japan has not been so easy. Especially, the publication was suspended from 1940 to 1950 due to the World War II.

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  66. Commentary on "Mechanisms of asbestos-induced carcinogenesis" published in 2009. Reviewed

    Toyokuni S

    Nagoya journal of medical science   Vol. 85 ( 1 ) page: 13 - 15   2023.2

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    Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM and the development of animal models, the carcinogenic mechanisms of the disease remain unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be summarized as follows: (1) the “oxidative stress theory” is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of free radicals due to their inability to digest the fibers, and epidemiological studies indicating that iron-containing asbestos fibers appear more carcinogenic; (2) the “chromosome tangling theory” postulates that asbestos fibers damage chromosomes when cells divide; and (3) the “theory of adsorption of many specific proteins as well as carcinogenic molecules” states that asbestos fibers in vivo concentrate proteins or chemicals including the components of cigarette smoke. Elucidation of the major mechanisms underlying DMM would be helpful for the development of novel strategies to prevent DMM induction in people who have already been exposed to asbestos

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  67. Extracellular fine particles and carcinogenesis Invited

    Toyokuni Shinya

      Vol. 95 ( 2 ) page: 177 - 183   2023

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    DOI: 10.14952/SEIKAGAKU.2023.950177

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  68. Thioredoxin deficiency increases oxidative stress and causes bilateral symmetrical degeneration in rat midbrain. International journal

    Iori Ohmori, Mamoru Ouchida, Hirohiko Imai, Saeko Ishida, Shinya Toyokuni, Tomoji Mashimo

    Neurobiology of disease   Vol. 175   page: 105921 - 105921   2022.12

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    Thioredoxin, encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of thioredoxin in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with wild-running seizures revealed the importance of Txn1 mutations in CNS degeneration. Genetic mapping identified Txn1-F54L in the epileptic rats. The insulin-reducing activity of Txn1-F54L was approximately one-third of that of the wild-type (WT). Bilateral symmetrical vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocytic cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration peaked at five weeks of age, and spontaneous repair began at seven weeks. The TUNEL assay showed that fibroblasts derived from homozygotes were susceptible to cell death under oxidative stress. In five-week-old WT rats, energy metabolism in the thalamus was significantly higher than that in the cerebral cortex. In conclusion, in juvenile rats, Txn1 seems to play an essential role in reducing oxidative stress in the midbrains with high energy metabolism.

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  69. RhoA and vigilin are candidates for immunohistochemical markers for epithelioid malignant mesothelioma.

    Hiratsuka T, Yamamoto T, Yoshizawa A, Toyokuni S, Tsuruyama T

    Scientific reports   Vol. 12 ( 1 ) page: 18519   2022.11

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    Diagnostic markers of malignant mesothelioma (MM) have been extensively investigated. Immunohistochemistry (IHC) markers, such as calretinin, have been used for pathologic diagnosis. However, more diagnostic markers are required to improve the specificity and sensitivity of pathologic diagnosis. This study proposed two proteins as diagnostic markers for epithelioid MM. One is RhoA, an MM mutation-susceptible locus-derived protein, and another is vigilin, a lung small cell carcinoma marker. IHC was performed using 93 MM (epithelioid, 71 cases; sarcomatoid, 13 cases; and biphasic, 9 cases), 64 lung adenocarcinoma (LAC), 60 lung squamous cell carcinoma (LSC), and 14 normal mesothelial (NM) tissues. The majority of epithelioid MM cases were positive for both RhoA and vigilin, whereas both IHCs showed lower stainability in biphasic and sarcomatoid MM. Besides, both IHCs showed significantly higher stainability for RhoA and vigilin in epithelioid MM than in LAC and LSC (p < 0.05). Chi-square tests showed that both RhoA and vigilin IHC positive rate in epithelioid MM was not significantly different from that of calretinin (p > 0.05). In the differential diagnosis of MM from lung cancer, the accuracy and specificity of RhoA, vigilin, and calretinin staining were almost equivalent. Further, H-score test showed that there was no significant difference between RhoA versus calretinin and vigilin versus calretinin in IHC positivity in epithelioid MM (p > 0.05). In conclusion, RhoA and vigilin may be candidates for immunohistochemical markers for epithelioid MM.

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  70. Molecular hydrogen has a positive impact on pregnancy maintenance through enhancement of mitochondrial function and immunomodulatory effects on T cells. International journal

    Chieko Aoki, Kenji Imai, Teruyuki Mizutani, Daisuke Sugiyama, Rika Miki, Yoshihiro Koya, Tomoko Kobayashi, Takafumi Ushida, Yukako Iitani, Noriyuki Nakamura, Taro Owaki, Hiroyoshi Nishikawa, Shinya Toyokuni, Hiroaki Kajiyama, Tomomi Kotani

    Life sciences   Vol. 308   page: 120955 - 120955   2022.11

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    AIMS: Molecular hydrogen (H2) has attracted growing interest because of its implications in various diseases. However, the molecular mechanisms underlying the remarkable effect of a small amount of H2 remain elusive. No knowledge has been available on the role of H2 in the etiology of pregnancy disorders or its direct influence on human immune cells. Since maternal immunity, T cells in particular, plays a critical role in pregnancy maintenance. We investigated the effects of H2 on T cells and its relation to preterm birth (PTB). MAIN METHODS: Exhaled H2 concentrations in pregnant women were measured and correlated with cytokine concentrations in maternal and umbilical cord blood. H2 was added to T cells collected from healthy donors, and differentiation and proliferation were examined. Energy metabolism was also examined. H2 was administered to mice and cytokine expression was compared. KEY FINDINGS: Our prospective observational study revealed that maternal production of H2 is significantly lower in pregnant women with PTB, suggesting its potential as a biomarker for predicting PTB. We found that H2 has clear associations with several maternal cytokines, and acts as an immunomodulator by exerting mitochondrial function in human T cells. Moreover, in vivo administration of H2 to pregnant mice regulated inflammatory responses and reduced PTB caused by T cell activation, which further supports the notion that H2 may contribute to prolonged gestation through its immunomodulatory effect. SIGNIFICANCE: Measuring maternal H2-production could be a potential clinical tool in the management of PTB, and H2 may have positive impact on pregnancy maintenance.

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  71. Commentary for an article on photooxidation in isolated chloroplasts. International journal

    Shinya Toyokuni, Yingyi Kong, Danyang Mi

    Archives of biochemistry and biophysics   Vol. 726   page: 109133 - 109133   2022.9

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    This commentary concerns a highly cited paper by Robert L Heath and Lester Packer in Archives of Biochemistry and Biophysics published in 1968. Chloroplasts are organelles in algae and plants that use light energy for carbon fixation and oxygen production. These authors discovered that isolated chloroplasts exposed to visible light undergo a cyclic peroxidation of tri-unsaturated fatty acids, contributing to the double-edged sword concept of electron transfer reactions.

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  72. Iron as spirit of life to share under monopoly.

    Shinya Toyokuni, Yingyi Kong, Hao Zheng, Yuki Maeda, Yashiro Motooka, Shinya Akatsuka

    Journal of clinical biochemistry and nutrition   Vol. 71 ( 2 ) page: 78 - 88   2022.9

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    Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multi-system organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.

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  73. Association of alcohol intake and female gender with high expression of TMPRSS2 in tongue as potential risk for SARS-CoV-2 infection

    Kotaro Sato, Koki Fujii, Noriyuki Yamamoto, Norihisa Ichimura, Satoshi Yamaguchi, Hirohisa Yamada, Hideharu Hibi, Shinya Toyokuni

    Journal of Clinical Biochemistry and Nutrition   Vol. 71 ( 2 ) page: 129 - 135   2022.9

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    <p>COVID-19 is pandemic since 2020 and further information is necessary on the risk factors associated with the infection of SARS-CoV-2. As an entry mechanism, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as receptor and transmembrane serine protease 2 (TMPRSS2) to activate fusion with host plasma membrane. Because dysgeusia is an early symptom of COVID-19, we here studied the expression of ACE2 and TMPRSS2 in the tongue and the associated tissues of mice and humans with immunohistochemistry and immunoblot analysis. ACE2 expression was low in the human tongue but was observed in the squamous epithelium, perineurium, arterial wall, salivary glands as well as taste buds. In contrast, mice showed high expression. In sharp contrast, TMPRSS2 expression was high in all the cells mentioned above in humans but relatively low in mice except for salivary glands. We then performed semi-quantitation of immunohistochemistry data of human ACE2 and TMPRSS2 and analyzed for age, sex, alcohol intake, and smoking habit with logistic regression analysis. We found that alcohol intake and female gender were the significant risk factors for increasing TMPRSS2 expression. In conclusion, TMPRSS2 is an important factor to be considered regarding SARS-CoV-2 entry and amplification in the oral cavity, which is promoted through drinking habit.</p>

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  74. 環境因子であるタルクおよびアスベストの卵巣発がん性とゲノム毒性の検討(Carcinogenic genome toxicity of environmental factors, asbestos and talc in ovary)

    本岡 大社, 鬼丸 洸, 鈴木 洋, 片渕 充沙子, 近藤 英治, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 81回   page: P - 2007   2022.9

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  75. BRCA1遺伝子ハプロ不全モデルラットを用いた卵巣予備能低下の検証(Validation of reduced ovarian reserve in BRCA1 haploinsufficient rats.)

    曽根原 玲菜, 本岡 大社, 梶山 広明, 真下 知士, 今岡 達彦, 豊國 伸哉

    日本癌学会総会記事   Vol. 81回   page: P - 3012   2022.9

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  76. BRCA1欠損はフェロトーシス抵抗性を誘導することによりアスベスト誘発性腹膜中皮腫を促進する(Ferroptosis resistance is induced by BRCA1 deficiency in asbestos-induced mesothelioma)

    羅 亜光, 本岡 大社, 赤塚 慎也, 真下 知士, 今岡 達彦, 豊國 伸哉

    日本癌学会総会記事   Vol. 81回   page: P - 2003   2022.9

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  77. BRCA1のハプロ不全は発がん過程において、フェロトーシス抵抗性を獲得することにより染色体増幅を促進する(BRCA1 haploinsufficiency promotes carcinogenic chromosomal amplification by ferroptosis-resistance)

    孔 穎怡, 赤塚 慎也, 本岡 大社, 鄭 好, 白木 之浩, 真下 知士, 今岡 達彦, 豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 33 ( 1 ) page: 130 - 130   2022.9

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  78. Non-thermal plasma elicits ferrous chloride-catalyzed DMPO-OH.

    Okazaki Y, Ito N, Tanaka H, Hori M, Toyokuni S

    Free radical research   Vol. 56 ( 9-10 ) page: 595 - 606   2022.9

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    Non-thermal plasma (NTP) induces the generation of reactive oxygen species (ROS) and reactive nitrogen species, such as hydroxyl radicals (•OH), hydrogen peroxide (H2O2), singlet oxygen, superoxide, ozone, and nitric oxide, at near-physiological temperatures. These molecules promote blood coagulation, wound healing, disinfection, and selective cancer cell death. Based on these evidences, clinical trials of NTP have been conducted for treating chronic wounds and head and neck cancers. Although clinical applications have progressed, the stoichiometric quantification of NTP-induced ROS remains unclear in the liquid phase in the presence of FeCl2 or FeCl3 in combination with biocompatible reducing agents, which may modulate the final biological effects of NTP. In this study, we employed electron paramagnetic resonance spectroscopy to quantify ROS using spin-trapping probe, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and H2O2, using luminescent probe in the presence of FeCl2 or FeCl3. NTP-induced DMPO-OH levels were elevated 10–100 µM FeCl2 or 500 and 1000 µM FeCl3. NTP-induced DMPO-OH with 10 µM FeCl2 or FeCl3 was significantly scavenged by ascorbate, α-tocopherol, dithiothreitol, reduced glutathione, or oxidized glutathione, whereas dehydroascorbate was ineffective in 2 mM DMPO. NTP-induced H2O2 was significantly degraded by 100 µM FeCl2 and FeCl3 in an iron-dependent manner. Meanwhile, decomposition of H2O2 by catalase decayed DMPO-OH efficiently in the presence of iron, indicating iron causes DMPO-OH production and degradation simultaneously. These results suggest that NTP-induced DMPO-OH is generated by the H2O2-consuming, iron-dependent Fenton reaction and ferryl intermediates. The potential iron-mediated ROS production by NTP is also discussed to clarify the interaction between NTP-induced ROS and biomolecules.

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  79. プラズマ活性化された乳酸リンゲルに誘導されたフェロトーシスにおけるpcbp1/2とグルタチオンとの協同作用(Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasma-activated Ringer's Lactate)

    鄭 好, 蒋 麗, 呂 沁穎, 赤塚 慎也, 本岡 大社, 関戸 好孝, 中村 香江, 田中 宏昌, 石川 健治, 梶山 広明, 水野 正明, 堀 勝, 豊國 伸哉

    日本癌学会総会記事   Vol. 81回   page: E - 2004   2022.9

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  80. 個別化予防医療・先制医療 BRCA1のハプロ不全は、腎臓発がん過程において、フェロトーシス抵抗性を獲得することにより染色体増幅を促進する(BRCA1 haploinsufficiency promotes chromosomal amplification under renal carcinogenesis through ferroptosis-resistance)

    孔 穎怡, 赤塚 慎也, 本岡 大社, 鄭 好, 白木 之浩, 真下 知士, 今岡 達彦, 豊國 伸哉

    日本癌学会総会記事   Vol. 81回   page: S20 - 7   2022.9

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  81. 環境因子であるタルクおよびアスベストの卵巣発がん性とゲノム毒性の検討(Carcinogenic genome toxicity of environmental factors, asbestos and talc in ovary)

    本岡 大社, 鬼丸 洸, 鈴木 洋, 片渕 充沙子, 近藤 英治, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 81回   page: P - 2007   2022.9

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  82. BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance. International journal

    Yingyi Kong, Shinya Akatsuka, Yashiro Motooka, Hao Zheng, Zhen Cheng, Yukihiro Shiraki, Tomoji Mashimo, Tatsuhiko Imaoka, Shinya Toyokuni

    Redox biology   Vol. 54   page: 102356 - 102356   2022.8

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    Germline-mutation in BRCA1 tumor suppressor gene is an established risk for carcinogenesis not only in females but also in males. Deficiency in the repair of DNA double-strand breaks is hypothesized as a responsible mechanism for carcinogenesis. However, supporting data is insufficient both in the mutation spectra of cancers in the patients with BRCA1 germline-mutation and in murine knockout/knock-in models of Brca1 haploinsufficiency. Furthermore, information on the driving force toward carcinogenesis in BRCA1 mutation carriers is lacking. Here we applied Fenton reaction-based renal carcinogenesis to a rat heterozygously knockout model of BRCA1 haploinsufficiency (mutant [MUT] model; L63X/+). Rat MUT model revealed significant promotion of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Array-based comparative genome hybridization of the RCCs identified significant increase in chromosomal amplification, syntenic to those in breast cancers of BRCA1 mutation carriers, including c-Myc, in comparison to those in the wild-type. Subacute-phase analysis of the kidney after repeated Fe-NTA treatment in the MUT model revealed dysregulated iron metabolism with mitochondrial malfunction assessed by expression microarray and electron microscopy, leading to renal tubular proliferation with iron overload. In conclusion, we for the first time demonstrate that biallelic wild-type BRCA1 provides more robust protection for mitochondrial metabolism under iron-catalyzed oxidative stress, preventing the emergence of neoplastic cells with chromosomal amplification. Our results suggest that oxidative stress via excess iron is a major driving force for carcinogenesis in BRCA1 haploinsufficiency, which can be a target for cancer prevention and therapeutics.

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  83. Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers

    Hirotoshi Soyama, Miki Nishio, Junji Otani, Toshiko Sakuma, Shintaro Takao, Shigeo Hara, Takaaki Masuda, Koshi Mimori, Shinya Toyokuni, John P. Lydon, Kazuwa Nakao, Hiroshi Nishina, Takumi Fukumoto, Tomohiko Maehama, Akira Suzuki

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 119 ( 29 ) page: e2123134119   2022.7

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    Breast cancer is the most frequent malignancy in women worldwide. Basal-like breast cancer (BLBC) is the most aggressive form of this disease, and patients have a poor prognosis. Here, we present data suggesting that the Hippo-transcriptional coactivator with PDZ-binding motif (TAZ) pathway is a key driver of BLBC onset and progression. Deletion of Mob1a/b in mouse mammary luminal epithelium induced rapid and highly reproducible mammary tumorigenesis that was dependent on TAZ but not yes-associated protein 1 (YAP1). In situ early-stage BLBC-like malignancies developed in mutant animals by 2 wk of age, and invasive BLBC appeared by 4 wk. In a human estrogen receptor(+) luminal breast cancer cell line, TAZ hyperactivation skewed the features of these luminal cells to the basal phenotype, consistent with the aberrant TAZ activation frequently observed in human precancerous BLBC lesions. TP53 mutation is rare in human precancerous BLBC but frequent in invasive BLBC. Addition of Trp53 deficiency to our Mob1a/b-deficient mouse model enhanced tumor grade and accelerated cancer progression. Our work justifies targeting the Hippo-TAZ pathway as a therapy for human BLBC, and our mouse model represents a powerful tool for evaluating candidate agents.

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  84. Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells. International journal

    Nanase Igarashi, Kenichi Miyata, Tze Mun Loo, Masatomo Chiba, Aki Hanyu, Mika Nishio, Hiroko Kawasaki, Hao Zheng, Shinya Toyokuni, Shunsuke Kon, Keiji Moriyama, Yasuyuki Fujita, Akiko Takahashi

    Nature communications   Vol. 13 ( 1 ) page: 4157 - 4157   2022.7

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    Cellular senescence and cell competition are important tumor suppression mechanisms that restrain cells with oncogenic mutations at the initial stage of cancer development. However, the link between cellular senescence and cell competition remains unclear. Senescent cells accumulated during the in vivo aging process contribute toward age-related cancers via the development of senescence-associated secretory phenotype (SASP). Here, we report that hepatocyte growth factor (HGF), a SASP factor, inhibits apical extrusion and promotes basal protrusion of Ras-mutated cells in the cell competition assay. Additionally, cellular senescence induced by a high-fat diet promotes the survival of cells with oncogenic mutations, whereas crizotinib, an inhibitor of HGF signaling, provokes the removal of mutated cells from mouse livers and intestines. Our study provides evidence that cellular senescence inhibits cell competition-mediated elimination of oncogenic cells through HGF signaling, suggesting that it may lead to cancer incidence during aging.

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  85. Diluted aqueous extract of heat-not-burn tobacco product smoke causes less oxidative damage in fibroblasts than conventional cigarette

    Qinying Lyu, Li Jiang, Hao Zheng, Shotaro Hayashi, Kotaro Sato, Shinya Toyokuni

    Journal of Clinical Biochemistry and Nutrition   Vol. 71 ( 1 ) page: 55 - 63   2022.7

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    <p>Smoke from conventional cigarettes (C-cigarettes) contains various reactive oxygen species and toxic chemicals, which potentially cause oxidative damage not only to airways but also to the whole body, leading eventually to diseases, including emphysema, advanced atherosclerosis, and cancer. Many heat-not-burn tobacco products (HTPs) have been commercialized recently in Japan to maintain the smoking population by advertising that HTPs are less toxic. However, there were few studies reported from neutral organizations whether HTPs are indeed less damaging. To evaluate the potential capacity of HTPs to induce oxidative stress, we here compared two different HTPs with two types of C-cigarettes, using human fibroblast IMR90SV cells and 5% aqueous extracts in 10-ml phosphate-buffered saline (50-ml smoke/10 s). HTPs exhibited significantly lower oxidative toxicity in comparison to C-cigarettes. Whereas C-cigarettes induced ferroptosis in fibroblasts, the effects of HTPs were significantly reduced by measuring the levels of peroxides, pro-inflammatory cytokine expression, autophagy, catalytic Fe(II) and 8-hydroxy-2'-deoxyguanosine. Notably, major portions of C-cigarettes-induced pathogenic responses were inhibited by catalase. However, HTPs still induced p62 autophagy-adaptor at 5%-dilution and caused lethal effects to fibroblasts with undiluted solution. In conclusion, HTPs smoke <i>per se</i> can be toxic despite less toxicity in comparison to C-cigarettes, which warrants further investigation.</p>

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  86. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo.

    Murphy MP, Bayir H, Belousov V, Chang CJ, Davies KJA, Davies MJ, Dick TP, Finkel T, Forman HJ, Janssen-Heininger Y, Gems D, Kagan VE, Kalyanaraman B, Larsson NG, Milne GL, Nyström T, Poulsen HE, Radi R, Van Remmen H, Schumacker PT, Thornalley PJ, Toyokuni S, Winterbourn CC, Yin H, Halliwell B

    Nature metabolism   Vol. 4 ( 6 ) page: 651 - 662   2022.6

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    Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo.

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  87. Cytotoxicity of plasma-irradiated lactate solution produced under atmospheric airtight conditions and generation of the methyl amino group

    Daiki Ito, Naoyuki Iwata, Kenji Ishikawa, Kae Nakamura, Hiroshi Hashizume, Camelia Miron, Hiromasa Tanaka, Hiroaki Kajiyama, Shinya Toyokuni, Masaaki Mizuno, Masaru Hori

    APPLIED PHYSICS EXPRESS   Vol. 15 ( 5 )   2022.5

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    Ringer's lactate solution was irradiated with non-equilibrium plasma under airtight conditions. The plasma-activated lactate (PAL) was produced with argon, oxygen, and nitrogen gases following purging of Ar. Cytotoxicity could be controlled by diluting PAL, and a killing effect was selectively obtained on cancer cells compared to normal cells for Ar+O-2+N-2 PALs. Nonetheless, cytotoxicity was partly reproduced by similar concentrations of H2O2 and NO2 (-) in the PALs. The organics produced by plasma irradiation to lactate were investigated using nuclear magnetic resonance, and the generation of methyl amino species was confirmed.

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  88. PCBP2 knockdown promotes ferroptosis in malignant mesothelioma. International journal

    Lin Yue, Yaguang Luo, Li Jiang, Yoshitaka Sekido, Shinya Toyokuni

    Pathology international   Vol. 72 ( 4 ) page: 242 - 251   2022.4

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    Malignant mesothelioma (MM) is still increasing worldwide. The pathogenesis depends on asbestos-induced iron accumulation, which eventually leads to ferroptosis-resistance of mesothelial cells via somatic mutations. Poly (rC)-binding proteins 1 and 2 (PCBP1/2) are recently recognized cytosolic Fe(II) chaperones. Here we studied the role of PCBP1/2 in rat/human mesothelial and MM cells as well as rat/human MM specimens. Normal peritoneal mesothelial cells in rats exhibited PCBP1 but not PCBP2 immunopositivity whereas primary/immortalized mesothelial cells showed PCBP1/2 immunopositivity. Rat MM specimens induced by intraperitoneal injection of chrysotile, including in situ lesion, revealed PCBP1/2 immunopositivity (90% for both) in the nucleus and cytoplasm with a tendency of higher expression in epithelioid subtype. Knockdown of PCBP2 but not PCBP1 significantly decreased both TfR1 and FTH expression in MM cells with inhibition of proliferation, indicating stagnation of intracellular iron transport. Erastin, a cysteine-deprivation type ferroptosis inducer, decreased the expression of both PCBP1/2 in MM cells. Furthermore, PCBP2 knockdown significantly increased the sensitivity of MM cells to erastin-induced ferroptosis with increased catalytic Fe(II). In conclusion, PCBP2 works for ferroptosis-resistance not only during mesothelial carcinogenesis but also in MM, which warrants further investigation as a novel therapeutic target.

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  89. Editorial: Centennial anniversary of vitamin E discovery.

    Toyokuni S, Noguchi N, Niki E

    Free radical biology & medicine   Vol. 183   page: 125 - 126   2022.4

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    DOI: 10.1016/j.freeradbiomed.2022.03.018

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  90. タルクは曝露卵巣に鉄過剰状態とフェロトーシス抵抗性を誘導し発がんに関わる

    井上 陽太, 本岡 大社, 豊國 伸哉

    日本病理学会会誌   Vol. 111 ( 1 ) page: 353 - 353   2022.3

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  91. アスベストはヘモグロビンを吸着し卵巣表層上皮に鉄過剰状態を形成することで卵巣がん形成に関わる

    本岡 大社, 豊國 伸哉

    日本病理学会会誌   Vol. 111 ( 1 ) page: 249 - 249   2022.3

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  92. CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

    Sato Yuki, Oguchi Akiko, Fukushima Yuji, Masuda Kyoko, Toriu Naoya, Taniguchi Keisuke, Yoshikawa Takahisa, Cui Xiaotong, Kondo Makiko, Hosoi Takeshi, Komidori Shota, Shimizu Yoko, Fujita Harumi, Jiang Li, Kong Yingyi, Yamanashi Takashi, Seita Jun, Yamamoto Takuya, Toyokuni Shinya, Hamazaki Yoko, Hattori Masakazu, Yoshikai Yasunobu, Boor Peter, Floege Jürgen, Kawamoto Hiroshi, Murakawa Yasuhiro, Minato Nagahiro, Yanagita Motoko

    Journal of Clinical Investigation   Vol. 132 ( 2 )   2022.1

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    Tertiary lymphoid tissues (TLTs) facilitate local T- and B-cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here we identify TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, CD153⁺PD-1⁺CD4⁺ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL21 and IFNγ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153-CD30 signaling in TLT formation and propose targeting CD153-CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

  93. CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury. International journal

    Yuki Sato, Akiko Oguchi, Yuji Fukushima, Kyoko Masuda, Naoya Toriu, Keisuke Taniguchi, Takahisa Yoshikawa, Xiaotong Cui, Makiko Kondo, Takeshi Hosoi, Shota Komidori, Yoko Shimizu, Harumi Fujita, Li Jiang, Yingyi Kong, Takashi Yamanashi, Jun Seita, Takuya Yamamoto, Shinya Toyokuni, Yoko Hamazaki, Masakazu Hattori, Yasunobu Yoshikai, Peter Boor, Jürgen Floege, Hiroshi Kawamoto, Yasuhiro Murakawa, Nagahiro Minato, Motoko Yanagita

    The Journal of clinical investigation   Vol. 132 ( 2 )   2022.1

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    Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

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  94. CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

    Sato Yuki, Oguchi Akiko, Fukushima Yuji, Masuda Kyoko, Toriu Naoya, Taniguchi Keisuke, Yoshikawa Takahisa, Cui Xiaotong, Kondo Makiko, Hosoi Takeshi, Komidori Shota, Shimizu Yoko, Fujita Harumi, Jiang Li, Kong Yingyi, Yamanashi Takashi, Seita Jun, Yamamoto Takuya, Toyokuni Shinya, Hamazaki Yoko, Hattori Masakazu, Yoshikai Yasunobu, Boor Peter, Floege Jürgen, Kawamoto Hiroshi, Murakawa Yasuhiro, Minato Nagahiro, Yanagita Motoko

    Journal of Clinical Investigation   Vol. 132 ( 2 )   2022.1

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    Tertiary lymphoid tissues (TLTs) facilitate local T- and B-cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here we identify TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, CD153⁺PD-1⁺CD4⁺ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL21 and IFNγ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153-CD30 signaling in TLT formation and propose targeting CD153-CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

  95. Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis. International journal

    Zhen Cheng, Shinya Akatsuka, Guang Hua Li, Kiyoshi Mori, Takashi Takahashi, Shinya Toyokuni

    Cancer science   Vol. 113 ( 1 ) page: 65 - 78   2022.1

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    Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe-NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe-NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter-strain difference in the susceptibility to Fe-NTA-induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe-NTA-induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe-NTA treatment. After 3-week Fe-NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe-NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin-2. Lipocalin-2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe-NTA-induced RCC in A/J strain.

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  96. Tetrachloroaurate (III)-induced oxidation increases non-thermal plasma-induced oxidative stress. International journal

    Yasumasa Okazaki, Kanako Sasaki, Nanami Ito, Hiromasa Tanaka, Ken-Ichiro Matsumoto, Masaru Hori, Shinya Toyokuni

    Free radical research   Vol. 56 ( 1 ) page: 17 - 27   2022.1

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    Non-thermal plasma (NTP) devices have been explored for medical applications. NTP devices discharge electrons, positive ions, ultraviolet (UV), reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as the hydroxyl radical (•OH), singlet oxygen (1O2), superoxide (O2•-), hydrogen peroxide (H2O2), ozone, and nitric oxide, at near-physiological temperature. At preclinical stages or in human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral, and biofilm-related infections, wound healing, and cancer cell death. Here, we observed that ferric, vanadium, and gold(III) ions significantly elevated lipid peroxidation, which was measured by 2-thiobarbituric acid-reactive substances (TBARS) in combination with NTP exposure. Using 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) as a spin probe in electron paramagnetic resonance (EPR), we observed that tetrachloroaurate (III) yielded an M4PO-X spin adduct. Tetrachloroaurate-induced oxidation was attenuated efficiently by reduced (GSH) and oxidized glutathione (GSSG), while glycine (Gly), and L-glutamate (Glu), components of GSH, were ineffective. Furthermore, GSH and GSSG efficiently suppressed tetrachloroaurate-induced lipid peroxidation, while Gly and Glu were ineffective in suppressing TBARS elevation. These results indicate that tetrachloroaurate-induced oxidation is attenuated by GSH as well as GSSG. Further studies are warranted to elucidate the redox reactions between metal ions and biomolecules to advance the clinical application of NTP.

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  97. Enhancement of ethanol production and cell growth in budding yeast by direct irradiation of low-temperature plasma

    Hiromasa Tanaka, Shogo Matsumura, Kenji Ishikawa, Hiroshi Hashizume, Masafumi Ito, Kae Nakamura, Hiroaki Kajiyama, Fumitaka Kikkawa, Mikako Ito, Kinji Ohno, Yasumasa Okazaki, Shinya Toyokuni, Masaaki Mizuno, Masaru Hori

    Japanese Journal of Applied Physics   Vol. 61 ( SA )   2022.1

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    Ethanol production by budding yeast was compared between direct and indirect plasma irradiation. We observed enhancement of ethanol production and cell growth not by indirect plasma irradiation but by direct plasma irradiation. Glucose consumption was increased in budding yeast by direct plasma irradiation. Extracellular flux analysis revealed that glycolytic activity in the budding yeast was elevated by direct plasma irradiation. These results suggest that direct plasma irradiation enhances ethanol production in budding yeast by elevating the glycolytic activity.

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  98. Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles. International journal

    Shinya Toyokuni, Yingyi Kong, Hao Zheng, Danyang Mi, Misako Katabuchi, Yashiro Motooka, Fumiya Ito

    Journal of cancer prevention   Vol. 26 ( 4 ) page: 244 - 249   2021.12

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    Human epidemiological and animal studies have demonstrated that excess iron is a risk for cancer. The responsible mechanisms are: 1) increased intracellular iron catalyzes the Fenton reaction to generate hydroxyl radicals, leading to mutagenic oxidative DNA lesions; 2) iron is necessary for cellular proliferation as cofactors of many enzymes. Thus, iron-excess milieu promotes selecting cellular evolution to ferroptosis-resistance, a major basis for carcinogenesis. Ferritin is a 24-subunit nanocage protein required for iron storage under the regulation of the iron-regulatory protein (IRP)/iron-responsive element (IRE) system. Ferritin is a serum marker, representing total body iron storage. However, how ferritin is secreted extracellularly has been unelucidated. We recently discovered that an exosomal marker CD63 is regulated by the IRP/IRE system and that iron-loaded ferritin is secreted as extracellular vesicles under the guidance of nuclear receptor coactivator 4 (NCOA4). On the other hand, we found that macrophages under asbestos-induced ferroptosis emit ferroptosis-dependent extracellular vesicles (FedEVs), which are received by nearby mesothelial cells, resulting in significant mutagenic DNA damage. Therefore, cells, including macrophages, can share excess iron with other cells, via iron-loaded ferritin packaged in extracellular vesicles as safe non-catalytic iron. However, similar process, such as one involving FedEVs, may cause accumulation of excess iron in other specific cells, which may eventually promote carcinogenesis.

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  99. Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin. International journal

    Fumiya Ito, Katsuhiro Kato, Izumi Yanatori, Toyoaki Murohara, Shinya Toyokuni

    Redox biology   Vol. 47   page: 102174 - 102174   2021.11

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    Asbestos-associated diseases remain a social burden worldwide. Our previous studies identified asbestos-induced iron-rich milieu for mesothelial cells with ceaseless macrophage ferroptosis. However, molecular mechanisms how this mutagenic milieu influences mesothelial cells have not been elucidated yet. Here, we propose a novel mechanism that extracellular vesicles (EVs) mediate asbestos-associated mutagenic factors to mesothelial cells. In a mice model of intraperitoneal crocidolite injection, mutagenic milieu highly expressed CD63, an exosomal marker. We then used a GFP-CD63 labeled THP-1 macrophage model exposed to crocidolite/iron, which generated EVs under ferroptotic process. We observed that MeT-5A mesothelial cells can receive and internalize these EVs. Furthermore, we comprehensively analyzed the ferroptosis-dependent EVs (FedEVs) for transported proteins and identified ferritin heavy/light chains as major components. Therefore, we inferred that FedEVs transport iron from ferroptotic macrophages to mesothelial cells. RNA sequencing revealed that the mesothelial cells receiving higher amounts of the FedEVs were mitotic, especially at the S and G2/M phases, by the use of Fucci mesothelial cells. Nuclear 8-hydroxy-2'-deoxyguanosine and γ-H2AX were significantly increased in the recipient mesothelial cells after exposure to FedEVs. Collectively, we here demonstrate a novel mechanism that FedEVs act as a key mutagenic mediator by transporting iron, which contribute to asbestos-induced mesothelial carcinogenesis.

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  100. Mitochondrial involvement in the development and progression of diseases. International journal

    Giuseppe Valacchi, Alessandra Pecorelli, Shinya Toyokuni

    Archives of biochemistry and biophysics   Vol. 711   page: 109006 - 109006   2021.10

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  101. Embryonal erythropoiesis and aging exploit ferroptosis. International journal

    Hao Zheng, Li Jiang, Tsuyoshi Tsuduki, Marcus Conrad, Shinya Toyokuni

    Redox biology   Vol. 48   page: 102175 - 102175   2021.10

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    Ferroptosis is a form of regulated cell necrosis, as a consequence of Fe(II)-dependent lipid peroxidation. Although ferroptosis has been linked to cancer cell death, neurodegeneration and reperfusion injury, physiological roles of ferroptosis have not been elucidated to date mostly due to the lack of appropriate methodologies. Here, we show that 4-hydroxy-2-nonenal (HNE)-modified proteins detected by a HNEJ-1 mouse monoclonal antibody is a robust immunohistochemical technology to locate ferroptosis in tissues in combination with morphological nuclear information, based on various models of ferroptosis, including erastin-induced cysteine-deprivation, conditional Gpx4 knockout and Fe(II)-dependent renal tubular injury, as well as other types of regulated cell death. Specificity of HNEJ-1 with ferroptosis was endorsed by non-selective identification of HNE-modified proteins in an Fe(II)-dependent renal tubular injury model. We further comprehensively searched for signs of ferroptosis in different developmental stages of Fischer-344 rats from E9.5-2.5 years of age. We observed that there was a significant age-dependent increase in ferroptosis in the kidney, spleen, liver, ovary, uterus, cerebellum and bone marrow, which was accompanied by iron accumulation. Not only phagocytic cells but also parenchymal cells were affected. Epidermal ferroptosis in ageing SAMP8 mice was significantly promoted by high-fat or carbohydrate-restricted diets. During embryogenesis of Fischer-344 rats, we found ferroptosis in nucleated erythrocytes at E13.5, which disappeared in enucleated erythrocytes at E18.5. Administration of a ferroptosis inhibitor, liproxstatin-1, significantly delayed erythrocyte enucleation. Therefore, our results demonstrate for the first time the involvement of ferroptosis in physiological processes, such as embryonic erythropoiesis and aging, suggesting the evolutionally acquired mechanism and the inevitable side effects, respectively.

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  102. CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. International journal

    Izumi Yanatori, Des R Richardson, Herschel S Dhekne, Shinya Toyokuni, Fumio Kishi

    Blood   Vol. 138 ( 16 ) page: 1490 - 1503   2021.10

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    Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can be also secreted by the exosome pathway (Truman-Rosentsvit M. et al. BLOOD 131 (2018) 342-352), with serum ferritin levels classically reflecting body iron stores. Iron metabolism-associated proteins, such as ferritin, are intricately regulated by cellular iron levels via the iron responsive element (IRE)-iron regulatory protein (IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein, CD63, is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5'-untranslated region (UTR) of CD63 mRNA responsible for regulating its expression in response to increased iron. Cellular iron-loading caused a marked increase in CD63 expression and the secretion from cells of CD63 positive (i.e., CD63(+)) EVs, which were shown to contain ferritin-H (FtH) and -L (FtL). Our results demonstrate that under iron-loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63(+) EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63(+) EVs, poses significant impact for understanding the local cell-to-cell exchange of ferritin and iron.

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  103. Mice lacking DYRK2 exhibit congenital malformations with lung hypoplasia and altered Foxf1 expression gradient. International journal

    Satomi Yogosawa, Makiko Ohkido, Takuro Horii, Yasumasa Okazaki, Jun Nakayama, Saishu Yoshida, Shinya Toyokuni, Izuho Hatada, Mitsuru Morimoto, Kiyotsugu Yoshida

    Communications biology   Vol. 4 ( 1 ) page: 1204 - 1204   2021.10

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    Congenital malformations cause life-threatening diseases in pediatrics, yet the molecular mechanism of organogenesis is poorly understood. Here we show that Dyrk2-deficient mice display congenital malformations in multiple organs. Transcriptome analysis reveals molecular pathology of Dyrk2-deficient mice, particularly with respect to Foxf1 reduction. Mutant pups exhibit sudden death soon after birth due to respiratory failure. Detailed analyses of primordial lungs at the early developmental stage demonstrate that Dyrk2 deficiency leads to altered airway branching and insufficient alveolar development. Furthermore, the Foxf1 expression gradient in mutant lung mesenchyme is disrupted, reducing Foxf1 target genes, which are necessary for proper airway and alveolar development. In ex vivo lung culture system, we rescue the expression of Foxf1 and its target genes in Dyrk2-deficient lung by restoring Shh signaling activity. Taken together, we demonstrate that Dyrk2 is essential for embryogenesis and its disruption results in congenital malformation.

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  104. Role of ferroptosis in nanofiber-induced carcinogenesis

    Toyokuni Shinya, Ito Fumiya, Motooka Yashiro

    Metallomics Research   Vol. 1 ( 1 ) page: rev-14 - rev-21   2021.10

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    <p>Biopersistent nanofibers with specified physical dimension are unexpected human carcinogens whether they are natural or synthetic. Asbestos, a natural fibrous mineral, is classified as a definite human carcinogen (IARC Group 1) to cause malignant mesothelioma (MM) and lung cancer. Multi-walled carbon nanotube of 50 nm-diameter was defined in 2014 as a possible carcinogen (IARC Group 2B) toward MM, fortunately with no authorized patients thus far. Carcinogenic mechanism of asbestos has been a mystery for a long time. It is now recognized that asbestos goes through lung parenchyma by collecting hemoglobin-derived iron to reach pleural cavity, which takes several decades. Iron-loaded asbestos can induce oxidative damage directly to mesothelial cells, carcinogenesis-target cells lining somatic cavities. Recently, it was clarified that surrounding stromal environment are as important for mesothelial carcinogenesis. The novel concept here is ceaseless ferroptosis of macrophages, which forms a Fe(II)-dependent stromal mutagenic milieu indirectly for mesothelial cells and indeed is a revised understanding of frustrated phagocytosis. Deposition of foreign materials eventually causes iron accumulation <i>in situ</i> due to the innate characteristic of preserving iron inside cells. Nanofiber-induced carcinogenesis may be involved in other human carcinogenesis, including ovarian cancer. Alternatively, iron excess can be an optimal target of cancer prevention and cancer treatment. </p>

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  105. Txn1 mutation causes epilepsy associated with vacuolar degeneration in the midbrain

    Iori Ohmori, Mamoru Ouchida, Hirohiko Imai, Saeko Ishida, Shinya Toyokuni, Tomoji Mashimo

    bioRxiv     2021.10

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    <title>Abstract</title>Thioredoxin (TXN), encoded by <italic>Txn1</italic>, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of TXN in the central nervous system (CNS) is largely unknown. A phenotype-driven study of <italic>N</italic>-ethyl-<italic>N</italic>-nitrosourea-mutated rats with running seizures at around five-week of age revealed the relevance of <italic>Txn1</italic> mutations to CNS disorders. Genetic mapping identified <italic>Txn1</italic>-F54L in epileptic rats. The insulin-reducing activity of <italic>Txn1</italic>-F54L rats was approximately one-third that of the wild-type. Vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the <italic>Txn1</italic>-F54L rats. The lesions displayed neuronal and oligodendrocyte cell death. Neurons in <italic>Txn1</italic>-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration began at three weeks of age, and spontaneous repair began at seven weeks; a dramatic change from cell death to repair occurred in the midbrain during a restricted period. In conclusion, <italic>Txn1</italic> is essential for the development of the midbrain in juvenile rats.

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  106. Plasma-activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells

    Hiromasa Tanaka, Shogo Maeda, Kae Nakamura, Hiroshi Hashizume, Kenji Ishikawa, Mikako Ito, Kinji Ohno, Masaaki Mizuno, Yashiro Motooka, Yasumasa Okazaki, Shinya Toyokuni, Hiroaki Kajiyama, Fumitaka Kikkawa, Masaru Hori

    PLASMA PROCESSES AND POLYMERS   Vol. 18 ( 10 )   2021.10

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    Nonequilibrium atmospheric pressure plasma has enabled a variety of new applications in medicine, agriculture, and other industries. It is particularly noteworthy that plasma itself and/or plasma-activated culture medium have been shown to preferentially kill various cancer cells. We have previously developed a plasma-activated Ringer's lactate solution (PAL) for use as a new cancer treatment. In this study, behaviors of extracellular and intracellular reactive oxygen and nitrogen species in the cellular respiratory system of PAL-treated HeLa cells were investigated using an extracellular flux analyzer and a probe to measure mitochondrial membrane potential. In PAL-treated HeLa cells, extracellular hydrogen peroxide in PAL was found to be responsible for the induction of intracellular hydrogen peroxide and apoptosis, while other components in PAL are responsible for the induction of non-H2O2 intracellular ROS and non-apoptotic cell death, which should be clarified by further experiments. We believe that these are long-lived species derived from plasma-activated lactates. Furthermore, we found that the plasma-activated lactates inhibited glycolysis and the tricarboxylic acid (TCA) cycle, but not the electron transport chain in HeLa cells. These results suggest that PAL induces multiple modes of cell death, including apoptosis through hydrogen peroxide, and non-apoptotic cell death associated with the impairment of mitochondrial functions (glycolysis and TCA cycle). These findings shed light on the novel mechanism underlying plasma-activated lactate-induced cell death.

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  107. Low temperature plasma irradiation products of sodium lactate solution that induce cell death on U251SP glioblastoma cells were identified. International journal

    Hiromasa Tanaka, Yugo Hosoi, Kenji Ishikawa, Jun Yoshitake, Takahiro Shibata, Koji Uchida, Hiroshi Hashizume, Masaaki Mizuno, Yasumasa Okazaki, Shinya Toyokuni, Kae Nakamura, Hiroaki Kajiyama, Fumitaka Kikkawa, Masaru Hori

    Scientific reports   Vol. 11 ( 1 ) page: 18488 - 18488   2021.9

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    Low-temperature plasma is being widely used in the various fields of life science, such as medicine and agriculture. Plasma-activated solutions have been proposed as potential cancer therapeutic reagents. We previously reported that plasma-activated Ringer's lactate solution exhibited selective cancer-killing effects, and that the plasma-treated L-sodium lactate in the solution was an anti-tumor factor; however, the components that are generated through the interactions between plasma and L-sodium lactate and the components responsible for the selective killing of cancer cells remain unidentified. In this study, we quantified several major chemical products, such as pyruvate, formate, and acetate, in plasma-activated L-sodium lactate solution by nuclear magnetic resonance analysis. We further identified novel chemical products, such as glyoxylate and 2,3-dimethyltartrate, in the solution by direct infusion-electrospray ionization with tandem mass spectrometry analysis. We found that 2,3-dimethyltartrate exhibited cytotoxic effects in glioblastoma cells, but not in normal astrocytes. These findings shed light on the identities of the components that are responsible for the selective cytotoxic effect of plasma-activated solutions on cancer cells, and provide useful data for the potential development of cancer treatments using plasma-activated L-sodium lactate solution.

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  108. 女性器へのタルクの曝露は鉄過剰環境を形成し卵巣がんの発がんに関わる

    本岡 大社, 伊藤 文哉, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 80回   page: [E1 - 6]   2021.9

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  109. BRCA1欠損は腎臓における鉄代謝の変化と酸化ストレスによる腎発がんに関わる

    孔 穎怡, 本岡 大社, 赤塚 慎也, 真下 知士, 今岡 達彦, 豊國 伸哉

    日本癌学会総会記事   Vol. 80回   page: [P2 - 1]   2021.9

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  110. 変革する病理学:形態診断から普遍的研究プラットフォームへ 実験病理学に起源を持つがんのフェロトーシス抵抗性

    豊國 伸哉, Zheng Hao, Kong Yingyi, Yaguang Luo, 本岡 大社

    日本癌学会総会記事   Vol. 80回   page: [S10 - 6]   2021.9

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  111. Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer. International journal

    Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada, Liying Yang, Tomoyoshi Nakadai, Reo Maruyama, Risa Fujii, Koji Ueda, Li Jiang, Hao Zheng, Shinya Toyokuni, Toyonori Sakata, Katsuhiko Shirahige, Ryosuke Kojima, Mizuho Nakayama, Masanobu Oshima, Satoshi Nagayama, Hiroyuki Seimiya, Toru Hirota, Hideyuki Saya, Eiji Hara, Akiko Takahashi

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 118 ( 35 )   2021.8

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    Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non-cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

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  112. Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia. International journal

    Mayo Miura, Kenji Imai, Hiroyuki Tsuda, Rika Miki, Sho Tano, Yumiko Ito, Shima Hirako-Takamura, Yoshinori Moriyama, Takafumi Ushida, Yukako Iitani, Tomoko Nakano-Kobayashi, Shinya Toyokuni, Hiroaki Kajiyama, Tomomi Kotani

    International journal of molecular sciences   Vol. 22 ( 17 )   2021.8

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    Oxidative stress plays a pathological role in pulmonary hypoplasia and pulmonary hypertension in congenital diaphragmatic hernia (CDH). This study investigated the effect of molecular hydrogen (H2), an antioxidant, on CDH pathology induced by nitrofen. Sprague-Dawley rats were divided into three groups: control, CDH, and CDH + hydrogen-rich water (HW). Pregnant dams of CDH + HW pups were orally administered HW from embryonic day 10 until parturition. Gasometric evaluation and histological, immunohistochemical, and real-time polymerase chain reaction analyses were performed. Gasometric results (pH, pO2, and pCO2 levels) were better in the CDH + HW group than in the CDH group. The CDH + HW group showed amelioration of alveolarization and pulmonary artery remodeling compared with the CDH group. Oxidative stress (8-hydroxy-2'-deoxyguanosine-positive-cell score) in the pulmonary arteries and mRNA levels of protein-containing pulmonary surfactant that protects against pulmonary collapse (surfactant protein A) were significantly attenuated in the CDH + HW group compared with the CDH group. Overall, prenatal H2 administration improved respiratory function by attenuating lung morphology and pulmonary artery thickening in CDH rat models. Thus, H2 administration in pregnant women with diagnosed fetal CDH might be a novel antenatal intervention strategy to reduce newborn mortality due to CDH.

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  113. Role and management of oxidative stress in human disease. International journal

    Rahul Checker, Deepak Sharma, Santosh K Sandur, Shinya Toyokuni

    Free radical research   Vol. 55 ( 8 ) page: 755 - 757   2021.8

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    DOI: 10.1080/10715762.2021.1991083

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  114. Non-thermal plasma-induced DMPO-OH yields hydrogen peroxide. International journal

    Yasumasa Okazaki, Hiromasa Tanaka, Ken-Ichiro Matsumoto, Masaru Hori, Shinya Toyokuni

    Archives of biochemistry and biophysics   Vol. 705   page: 108901 - 108901   2021.7

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    Recent developments in electronics have enabled the medical applications of non-thermal plasma (NTP), which elicits reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as hydroxyl radical (●OH), hydrogen peroxide (H2O2), singlet oxygen (1O2), superoxide (O2●-), ozone, and nitric oxide at near-physiological temperatures. In preclinical studies or human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral and biofilm-related infections, wound healing, and cancer cell death. To elucidate the solution-phase biological effects of NTP in the presence of biocompatible reducing agents, we employed electron paramagnetic resonance (EPR) spectroscopy to quantify ●OH using a spin-trapping probe, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO); 1O2 using a fluorescent probe; and O2●- and H2O2 using luminescent probes in the presence of thiols or tempol. NTP-induced ●OH was significantly scavenged by dithiothreitol (DTT), reduced glutathione (GSH), and oxidized glutathione (GSSG) in 2 or 5 mM DMPO. NTP-induced O2●- was significantly scavenged by 10 μM DTT and GSH, while 1O2 was not efficiently scavenged by these compounds. GSSG degraded H2O2 more effectively than GSH and DTT, suggesting that the disulfide bonds reacted with H2O2. In the presence of 1-50 mM DMPO, NTP-induced H2O2 quantities were unchanged. The inhibitory effect of tempol concentration (50 and 100 μM) on H2O2 production was observed in 1 and 10 mM DMPO, whereas it became ineffective in 50 mM DMPO. Furthermore, DMPO-OH did not interact with tempol. These results suggest that DMPO and tempol react competitively with O2●-. Further studies are warranted to elucidate the interaction between NTP-induced ROS and biomolecules.

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  115. Lysosomal nitric oxide determines transition from autophagy to ferroptosis after exposure to plasma-activated Ringer's lactate. International journal

    Li Jiang, Hao Zheng, Qinying Lyu, Shotaro Hayashi, Kotaro Sato, Yoshitaka Sekido, Kae Nakamura, Hiromasa Tanaka, Kenji Ishikawa, Hiroaki Kajiyama, Masaaki Mizuno, Masaru Hori, Shinya Toyokuni

    Redox biology   Vol. 43   page: 101989 - 101989   2021.7

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    Non-thermal plasma (NTP), an engineered technology to generate reactive species, induces ferroptosis and/or apoptosis specifically in various-type cancer cells. NTP-activated Ringer's lactate (PAL) is another modality for cancer therapy at preclinical stage. Here we found that PAL induces selective ferroptosis of malignant mesothelioma (MM) cells, where non-targeted metabolome screening identified upregulated citrulline-nitric oxide (.NO) cycle as a PAL target. .NO probe detected biphasic peaks transiently at PAL exposure with time-dependent increase, which was responsible for inducible . NO synthase (iNOS) overexpression through NF-κB activation. .NO and lipid peroxidation occupied lysosomes as a major compartment with increased TFEB expression. Not only ferrostatin-1 but inhibitors for . NO and/or iNOS could suppress this ferroptosis. PAL-induced ferroptosis accompanied autophagic process in the early phase, as demonstrated by an increase in essential amino acids, LC3B-II, p62 and LAMP1, transforming into the later phase with boosted lipid peroxidation. Therefore, .NO-mediated lysosomal impairment is central in PAL-induced ferroptosis.

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  116. L-Dehydroascorbate efficiently degrades non-thermal plasma-induced hydrogen peroxide International journal

    Okazaki Y.

    Archives of Biochemistry and Biophysics   Vol. 700   2021.3

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    DOI: 10.1016/j.abb.2021.108762

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  117. Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy. International journal

    Kae Nakamura, Nobuhisa Yoshikawa, Yuko Mizuno, Miwa Ito, Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa, Hiroaki Kajiyama

    Cancers   Vol. 13 ( 5 ) page: 1 - 15   2021.3

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    Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC's lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in vitro and in vivo. Here we investigated how PAM inhibits intraperitoneal metastasis. We studied PAM's inhibition of micro-dissemination onto the omentum by performing in vivo imaging in combination with a sequential histological analysis. The results revealed that PAM induced macrophage infiltration into the disseminated lesion. The iNOS-positive signal was co-localized at the macrophages in the existing lesion, indicating that PAM might induce M1-type macrophages. This may be another mechanism of the antitumor effect through a PAM-evoked immune response. Intraperitoneal lavage with plasma-activated lactate Ringer's solution (PAL) significantly improved the overall survival rate in an ovarian cancer mouse model. Our results demonstrated the efficiency and practicality of aqueous plasma for clinical applications.

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  118. Role of ferroptosis in carcinogenesis and tumor biology

    Toyokuni Shinya

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 165   2021.3

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    DOI: 10.1016/j.freeradbiomed.2020.12.249

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  119. Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation. International journal

    Satoshi Omori, Misato Tsugita, Yasuto Hoshikawa, Masanobu Morita, Fumiya Ito, Shin-Ichiro Yamaguchi, Qilin Xie, Osamu Noyori, Tomoya Yamaguchi, Ayato Takada, Tatsuya Saitoh, Shinya Toyokuni, Hisaya Akiba, Shigekazu Nagata, Kengo Kinoshita, Masafumi Nakayama

    Cell reports   Vol. 34 ( 6 ) page: 108734 - 108734   2021.2

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    Macrophage recognition and phagocytosis of crystals is critical for the associated fibrosis and cancer. Of note, multi-walled carbon nanotubes (MWCNTs), the highly representative products of nanotechnology, induce macrophage NLRP3 inflammasome activation and cause asbestosis-like pathogenesis. However, it remains largely unknown how macrophages efficiently recognize MWCNTs on their cell surfaces. Here, we identify by a targeted screening of phagocyte receptors the phosphatidylserine receptors T cell immunoglobulin mucin 4 (Tim4) and Tim1 as the pattern-recognition receptors for carbon crystals. Docking simulation studies reveal spatiotemporally stable interfaces between aromatic residues in the extracellular IgV domain of Tim4 and one-dimensional carbon crystals. Further, CRISPR-Cas9-mediated deletion of Tim4 and Tim1 reveals that Tim4, but not Tim1, critically contributes to the recognition of MWCNTs by peritoneal macrophages and to granuloma development in a mouse model of direct mesothelium exposure to MWCNTs. These results suggest that Tim4 recognizes MWCNTs through aromatic interactions and mediates phagocytosis leading to granulomas.

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  120. Mechanism of asbestos-induced carcinogenesis via dysregulation of redox-active iron International journal

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   Vol. 112   page: 998 - 998   2021.2

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  121. Mechanism of asbestos-induced carcinogenesis via dysregulation of redox-active iron International journal

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   Vol. 112   page: 998 - 998   2021.2

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  122. Signature analysis of genomic mutations in asbestos-induced rat mesothelioma

    Akatsuka Shinya, Jiang Li, Elzawahry Asmaa, Kato Mamoru, Totsuka Yukari, Shibata Tatsuhiro, Toyokuni Shinya

    CANCER SCIENCE   Vol. 112   page: 610 - 610   2021.2

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  123. Asbestos and talc contribute to ovarian carcinogenesis via iron overload

    Motooka Yashiro, Ito Fumiya, Tashiro Hironori, Katabuchi Hidetaka, Toyokuni Shinya

    CANCER SCIENCE   Vol. 112   page: 245 - 245   2021.2

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  124. Role of redox-active metals for the prevention and treatment of cancer in the era of precision medicine

    Toyokuni Shinya, Richardson Des R.

    CANCER SCIENCE   Vol. 112   page: 996 - 996   2021.2

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  125. Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue International journal

    Homma T.

    Free Radical Biology and Medicine   Vol. 162   page: 255 - 265   2021.1

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    DOI: 10.1016/j.freeradbiomed.2020.10.023

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  126. Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma International journal

    Yamashita K.

    Genes Chromosomes and Cancer   Vol. 60 ( 1 ) page: 26 - 37   2021.1

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    DOI: 10.1002/gcc.22899

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  127. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. International journal

    Daniel J Klionsky, Amal Kamal Abdel-Aziz, Sara Abdelfatah, Mahmoud Abdellatif, Asghar Abdoli, Steffen Abel, Hagai Abeliovich, Marie H Abildgaard, Yakubu Princely Abudu, Abraham Acevedo-Arozena, Iannis E Adamopoulos, Khosrow Adeli, Timon E Adolph, Annagrazia Adornetto, Elma Aflaki, Galila Agam, Anupam Agarwal, Bharat B Aggarwal, Maria Agnello, Patrizia Agostinis, Javed N Agrewala, Alexander Agrotis, Patricia V Aguilar, S Tariq Ahmad, Zubair M Ahmed, Ulises Ahumada-Castro, Sonja Aits, Shu Aizawa, Yunus Akkoc, Tonia Akoumianaki, Hafize Aysin Akpinar, Ahmed M Al-Abd, Lina Al-Akra, Abeer Al-Gharaibeh, Moulay A Alaoui-Jamali, Simon Alberti, Elísabet Alcocer-Gómez, Cristiano Alessandri, Muhammad Ali, M Abdul Alim Al-Bari, Saeb Aliwaini, Javad Alizadeh, Eugènia Almacellas, Alexandru Almasan, Alicia Alonso, Guillermo D Alonso, Nihal Altan-Bonnet, Dario C Altieri, Élida M C Álvarez, Sara Alves, Cristine Alves da Costa, Mazen M Alzaharna, Marialaura Amadio, Consuelo Amantini, Cristina Amaral, Susanna Ambrosio, Amal O Amer, Veena Ammanathan, Zhenyi An, Stig U Andersen, Shaida A Andrabi, Magaiver Andrade-Silva, Allen M Andres, Sabrina Angelini, David Ann, Uche C Anozie, Mohammad Y Ansari, Pedro Antas, Adam Antebi, Zuriñe Antón, Tahira Anwar, Lionel Apetoh, Nadezda Apostolova, Toshiyuki Araki, Yasuhiro Araki, Kohei Arasaki, Wagner L Araújo, Jun Araya, Catherine Arden, Maria-Angeles Arévalo, Sandro Arguelles, Esperanza Arias, Jyothi Arikkath, Hirokazu Arimoto, Aileen R Ariosa, Darius Armstrong-James, Laetitia Arnauné-Pelloquin, Angeles Aroca, Daniela S Arroyo, Ivica Arsov, Rubén Artero, Dalia Maria Lucia Asaro, Michael Aschner, Milad Ashrafizadeh, Osnat Ashur-Fabian, Atanas G Atanasov, Alicia K Au, Patrick Auberger, Holger W Auner, Laure Aurelian, Riccardo Autelli, Laura Avagliano, Yenniffer Ávalos, Sanja Aveic, Célia Alexandra Aveleira, Tamar Avin-Wittenberg, Yucel Aydin, Scott Ayton, Srinivas Ayyadevara, Maria Azzopardi, Misuzu Baba, Jonathan M Backer, Steven K Backues, Dong-Hun Bae, Ok-Nam Bae, Soo Han Bae, Eric H Baehrecke, Ahruem Baek, Seung-Hoon Baek, Sung Hee Baek, Giacinto Bagetta, Agnieszka Bagniewska-Zadworna, Hua Bai, Jie Bai, Xiyuan Bai, Yidong Bai, Nandadulal Bairagi, Shounak Baksi, Teresa Balbi, Cosima T Baldari, Walter Balduini, Andrea Ballabio, Maria Ballester, Salma Balazadeh, Rena Balzan, Rina Bandopadhyay, Sreeparna Banerjee, Sulagna Banerjee, Ágnes Bánréti, Yan Bao, Mauricio S Baptista, Alessandra Baracca, Cristiana Barbati, Ariadna Bargiela, Daniela Barilà, Peter G Barlow, Sami J Barmada, Esther Barreiro, George E Barreto, Jiri Bartek, Bonnie Bartel, Alberto Bartolome, Gaurav R Barve, Suresh H Basagoudanavar, Diane C Bassham, Robert C Bast Jr, Alakananda Basu, Henri Batoko, Isabella Batten, Etienne E Baulieu, Bradley L Baumgarner, Jagadeesh Bayry, Rupert Beale, Isabelle Beau, Florian Beaumatin, Luiz R G Bechara, George R Beck Jr, Michael F Beers, Jakob Begun, Christian Behrends, Georg M N Behrens, Roberto Bei, Eloy Bejarano, Shai Bel, Christian Behl, Amine Belaid, Naïma Belgareh-Touzé, Cristina Bellarosa, Francesca Belleudi, Melissa Belló Pérez, Raquel Bello-Morales, Jackeline Soares de Oliveira Beltran, Sebastián Beltran, Doris Mangiaracina Benbrook, Mykolas Bendorius, Bruno A Benitez, Irene Benito-Cuesta, Julien Bensalem, Martin W Berchtold, Sabina Berezowska, Daniele Bergamaschi, Matteo Bergami, Andreas Bergmann, Laura Berliocchi, Clarisse Berlioz-Torrent, Amélie Bernard, Lionel Berthoux, Cagri G Besirli, Sebastien Besteiro, Virginie M Betin, Rudi Beyaert, Jelena S Bezbradica, Kiran Bhaskar, Ingrid Bhatia-Kissova, Resham Bhattacharya, Sujoy Bhattacharya, Shalmoli Bhattacharyya, Md Shenuarin Bhuiyan, Sujit Kumar Bhutia, Lanrong Bi, Xiaolin Bi, Trevor J Biden, Krikor Bijian, Viktor A Billes, Nadine Binart, Claudia Bincoletto, Asa B Birgisdottir, Geir Bjorkoy, Gonzalo Blanco, Ana Blas-Garcia, Janusz Blasiak, Robert Blomgran, Klas Blomgren, Janice S Blum, Emilio Boada-Romero, Mirta Boban, Kathleen Boesze-Battaglia, Philippe Boeuf, Barry Boland, Pascale Bomont, Paolo Bonaldo, Srinivasa Reddy Bonam, Laura Bonfili, Juan S Bonifacino, Brian A Boone, Martin D Bootman, Matteo Bordi, Christoph Borner, Beat C Bornhauser, Gautam Borthakur, Jürgen Bosch, Santanu Bose, Luis M Botana, Juan Botas, Chantal M Boulanger, Michael E Boulton, Mathieu Bourdenx, Benjamin Bourgeois, Nollaig M Bourke, Guilhem Bousquet, Patricia Boya, Peter V Bozhkov, Luiz H M Bozi, Tolga O Bozkurt, Doug E Brackney, Christian H Brandts, Ralf J Braun, Gerhard H Braus, Roberto Bravo-Sagua, José M Bravo-San Pedro, Patrick Brest, Marie-Agnès Bringer, Alfredo Briones-Herrera, V Courtney Broaddus, Peter Brodersen, Jeffrey L Brodsky, Steven L Brody, Paola G Bronson, Jeff M Bronstein, Carolyn N Brown, Rhoderick E Brown, Patricia C Brum, John H Brumell, Nicola Brunetti-Pierri, Daniele Bruno, Robert J Bryson-Richardson, Cecilia Bucci, Carmen Buchrieser, Marta Bueno, Laura Elisa Buitrago-Molina, Simone Buraschi, Shilpa Buch, J 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Villalba, Antonio Villalobo, Beatriz Villarejo-Zori, Francesc Villarroya, Joan Villarroya, Olivier Vincent, Cecile Vindis, Christophe Viret, Maria Teresa Viscomi, Dora Visnjic, Ilio Vitale, David J Vocadlo, Olga V Voitsekhovskaja, Cinzia Volonté, Mattia Volta, Marta Vomero, Clarissa Von Haefen, Marc A Vooijs, Wolfgang Voos, Ljubica Vucicevic, Richard Wade-Martins, Satoshi Waguri, Kenrick A Waite, Shuji Wakatsuki, David W Walker, Mark J Walker, Simon A Walker, Jochen Walter, Francisco G Wandosell, Bo Wang, Chao-Yung Wang, Chen Wang, Chenran Wang, Chenwei Wang, Cun-Yu Wang, Dong Wang, Fangyang Wang, Feng Wang, Fengming Wang, Guansong Wang, Han Wang, Hao Wang, Hexiang Wang, Hong-Gang Wang, Jianrong Wang, Jigang Wang, Jiou Wang, Jundong Wang, Kui Wang, Lianrong Wang, Liming Wang, Maggie Haitian Wang, Meiqing Wang, Nanbu Wang, Pengwei Wang, Peipei Wang, Ping Wang, Ping Wang, Qing Jun Wang, Qing Wang, Qing Kenneth Wang, Qiong A Wang, Wen-Tao Wang, Wuyang Wang, Xinnan Wang, Xuejun Wang, Yan Wang, Yanchang Wang, Yanzhuang Wang, Yen-Yun Wang, Yihua Wang, Yipeng Wang, Yu Wang, Yuqi Wang, Zhe Wang, Zhenyu Wang, Zhouguang Wang, Gary Warnes, Verena Warnsmann, Hirotaka Watada, Eizo Watanabe, Maxinne Watchon, Anna Wawrzyńska, Timothy E Weaver, Grzegorz Wegrzyn, Ann M Wehman, Huafeng Wei, Lei Wei, Taotao Wei, Yongjie Wei, Oliver H Weiergräber, Conrad C Weihl, Günther Weindl, Ralf Weiskirchen, Alan Wells, Runxia H Wen, Xin Wen, Antonia Werner, Beatrice Weykopf, Sally P Wheatley, J Lindsay Whitton, Alexander J Whitworth, Katarzyna Wiktorska, Manon E Wildenberg, Tom Wileman, Simon Wilkinson, Dieter Willbold, Brett Williams, Robin S B Williams, Roger L Williams, Peter R Williamson, Richard A Wilson, Beate Winner, Nathaniel J Winsor, Steven S Witkin, Harald Wodrich, Ute Woehlbier, Thomas Wollert, Esther Wong, Jack Ho Wong, Richard W Wong, Vincent Kam Wai Wong, W Wei-Lynn Wong, An-Guo Wu, Chengbiao Wu, Jian Wu, Junfang Wu, Kenneth K Wu, Min Wu, Shan-Ying Wu, Shengzhou Wu, Shu-Yan Wu, Shufang Wu, William K K Wu, Xiaohong Wu, Xiaoqing Wu, Yao-Wen Wu, Yihua Wu, Ramnik J Xavier, Hongguang Xia, Lixin Xia, Zhengyuan Xia, Ge Xiang, Jin Xiang, Mingliang Xiang, Wei Xiang, Bin Xiao, Guozhi Xiao, Hengyi Xiao, Hong-Tao Xiao, Jian Xiao, Lan Xiao, Shi Xiao, Yin Xiao, Baoming Xie, Chuan-Ming Xie, Min Xie, Yuxiang Xie, Zhiping Xie, Zhonglin Xie, Maria Xilouri, Congfeng Xu, En Xu, Haoxing Xu, Jing Xu, JinRong Xu, Liang Xu, Wen Wen Xu, Xiulong Xu, Yu Xue, Sokhna M S Yakhine-Diop, Masamitsu Yamaguchi, Osamu Yamaguchi, Ai Yamamoto, Shunhei Yamashina, Shengmin Yan, Shian-Jang Yan, Zhen Yan, Yasuo Yanagi, Chuanbin Yang, Dun-Sheng Yang, Huan Yang, Huang-Tian Yang, Hui Yang, Jin-Ming Yang, Jing Yang, Jingyu Yang, Ling Yang, Liu Yang, Ming Yang, Pei-Ming Yang, Qian Yang, Seungwon Yang, Shu Yang, Shun-Fa Yang, Wannian Yang, Wei Yuan Yang, Xiaoyong Yang, Xuesong Yang, Yi Yang, Ying Yang, Honghong Yao, Shenggen Yao, Xiaoqiang Yao, Yong-Gang Yao, Yong-Ming Yao, Takahiro Yasui, Meysam Yazdankhah, Paul M Yen, Cong Yi, Xiao-Ming Yin, Yanhai Yin, Zhangyuan Yin, Ziyi Yin, Meidan Ying, Zheng Ying, Calvin K Yip, Stephanie Pei Tung Yiu, Young H Yoo, Kiyotsugu Yoshida, Saori R Yoshii, Tamotsu Yoshimori, Bahman Yousefi, Boxuan Yu, Haiyang Yu, Jun Yu, Jun Yu, Li Yu, Ming-Lung Yu, Seong-Woon Yu, Victor C Yu, W Haung Yu, Zhengping Yu, Zhou Yu, Junying Yuan, Ling-Qing Yuan, Shilin Yuan, Shyng-Shiou F Yuan, Yanggang Yuan, Zengqiang Yuan, Jianbo Yue, Zhenyu Yue, Jeanho Yun, Raymond L Yung, David N Zacks, Gabriele Zaffagnini, Vanessa O Zambelli, Isabella Zanella, Qun S Zang, Sara Zanivan, Silvia Zappavigna, Pilar Zaragoza, Konstantinos S Zarbalis, Amir Zarebkohan, Amira Zarrouk, Scott O Zeitlin, Jialiu Zeng, Ju-Deng Zeng, Eva Žerovnik, Lixuan Zhan, Bin Zhang, Donna D Zhang, Hanlin Zhang, Hong Zhang, Hong Zhang, Honghe Zhang, Huafeng Zhang, Huaye Zhang, Hui Zhang, Hui-Ling Zhang, Jianbin Zhang, Jianhua Zhang, Jing-Pu Zhang, Kalin Y B Zhang, Leshuai W Zhang, Lin Zhang, Lisheng Zhang, Lu Zhang, Luoying Zhang, Menghuan Zhang, Peng Zhang, Sheng Zhang, Wei Zhang, Xiangnan Zhang, Xiao-Wei Zhang, Xiaolei Zhang, Xiaoyan Zhang, Xin Zhang, Xinxin Zhang, Xu Dong Zhang, Yang Zhang, Yanjin Zhang, Yi Zhang, Ying-Dong Zhang, Yingmei Zhang, Yuan-Yuan Zhang, Yuchen Zhang, Zhe Zhang, Zhengguang Zhang, Zhibing Zhang, Zhihai Zhang, Zhiyong Zhang, Zili Zhang, Haobin Zhao, Lei Zhao, Shuang Zhao, Tongbiao Zhao, Xiao-Fan Zhao, Ying Zhao, Yongchao Zhao, Yongliang Zhao, Yuting Zhao, Guoping Zheng, Kai Zheng, Ling Zheng, Shizhong Zheng, Xi-Long Zheng, Yi Zheng, Zu-Guo Zheng, Boris Zhivotovsky, Qing Zhong, Ao Zhou, Ben Zhou, Cefan Zhou, Gang Zhou, Hao Zhou, Hong Zhou, Hongbo Zhou, Jie Zhou, Jing Zhou, Jing Zhou, Jiyong Zhou, Kailiang Zhou, Rongjia Zhou, Xu-Jie Zhou, Yanshuang Zhou, Yinghong Zhou, Yubin Zhou, Zheng-Yu Zhou, Zhou Zhou, Binglin Zhu, Changlian Zhu, Guo-Qing Zhu, Haining Zhu, Hongxin Zhu, Hua Zhu, Wei-Guo Zhu, Yanping Zhu, Yushan Zhu, Haixia Zhuang, Xiaohong Zhuang, Katarzyna Zientara-Rytter, Christine M Zimmermann, Elena Ziviani, Teresa Zoladek, Wei-Xing Zong, Dmitry B Zorov, Antonio Zorzano, Weiping Zou, Zhen Zou, Zhengzhi Zou, Steven Zuryn, Werner Zwerschke, Beate Brand-Saberi, X Charlie Dong, Chandra Shekar Kenchappa, Zuguo Li, Yong Lin, Shigeru Oshima, Yueguang Rong, Judith C Sluimer, Christina L Stallings, Chun-Kit Tong

    Autophagy   Vol. 17 ( 1 ) page: 1 - 382   2021.1

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    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

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  128. Cancer Treatments Using Low-Temperature Plasma. International journal

    Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Shinya Toyokuni, Hiroaki Kajiyama, Fumitaka Kikkawa, Masaru Hori

    Current medicinal chemistry   Vol. 28 ( 41 ) page: 8549 - 8558   2021

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    Low-temperature plasma (LTP) is a partially ionized gas that contains electrons, ions, radicals, light, etc. Recently, the bio-medical application of LTP has become a hot topic in plasma science and biological science. Cancer treatment with plasma is the most challenging topic in plasma bio-medical applications. Many in vitro and in vivo experiments have been conducted to investigate the anti-tumor effects of LTP. Extracellular reactive oxygen and nitrogen species (RONS) in plasma-activated solutions are key factors for the anti-tumor effects, and amino acid modifications by LTP may affect cellular responses. Intracellular RONS are also key factors for the anti-tumor effects. Various signaling pathways, such as p53 signaling pathways, survival and proliferation signaling pathways, and oxidative stress-dependent signaling pathways are activated by LTP.

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  129. Mechanisms of toxicity caused by carbon nanotubes

    YAMAGUCHI Shin-Ichiro, MORITA Masanobu, ITO Fumiya, XIE Qilin, TOYOKUNI Shinya, NAKAYAMA Masafumi

    Annual Meeting of the Japanese Society of Toxicology   Vol. 48.1 ( 0 ) page: O-4 - 4   2021

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    <p>Multi-walled carbon nanotubes (MWCNTs), the highly representative products of nanotechnology, induce macrophage cell death and NLRP3 inflammasome activation leading to granuloma and mesothelioma in rodents; however, it remains unknown how macrophages recognize MWCNTs. By a target screening of phagocyte receptors, we here demonstrated that T cell immunoglobulin mucin 4 (Tim4) and Tim1 recognize MWCNTs. Using <i>Tim4<sup>-/-</sup> Tim1<sup>-/-</sup> </i>mice, we revealed that Tim4 is involved in MWCNT-associated pathogenesis. Taken together, these results indicate that Tim4 and Tim1 are receptors for MWCNTs.</p>

    DOI: 10.14869/toxpt.48.1.0_o-4

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  130. The new era for research on polyphenols and food factors International journal

    Oteiza P.I.

    Archives of Biochemistry and Biophysics   Vol. 696   2020.12

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    DOI: 10.1016/j.abb.2020.108678

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  131. The new era for redox research. International journal

    Yuji Naito, Koji Uchida, Shinya Toyokuni

    Free radical research   Vol. 54 ( 11-12 ) page: 787 - 789   2020.12

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  132. Neural stem cell-specific ITPA deficiency causes neural depolarization and epilepsy. International journal

    Yuichiro Koga, Daisuke Tsuchimoto, Yoshinori Hayashi, Nona Abolhassani, Yasuto Yoneshima, Kunihiko Sakumi, Hiroshi Nakanishi, Shinya Toyokuni, Yusaku Nakabeppu

    JCI insight   Vol. 5 ( 22 )   2020.11

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    Inosine triphosphate pyrophosphatase (ITPA) hydrolyzes inosine triphosphate (ITP) and other deaminated purine nucleotides to the corresponding nucleoside monophosphates. In humans, ITPA deficiency causes severe encephalopathy with epileptic seizure, microcephaly, and developmental retardation. In this study, we established neural stem cell-specific Itpa-conditional KO mice (Itpa-cKO mice) to clarify the effects of ITPA deficiency on the neural system. The Itpa-cKO mice showed growth retardation and died within 3 weeks of birth. We did not observe any microcephaly in the Itpa-cKO mice, although the female Itpa-cKO mice did show adrenal hypoplasia. The Itpa-cKO mice showed limb-clasping upon tail suspension and spontaneous and/or audiogenic seizure. Whole-cell patch-clamp recordings from entorhinal cortex neurons in brain slices revealed a depolarized resting membrane potential, increased firing, and frequent spontaneous miniature excitatory postsynaptic current and miniature inhibitory postsynaptic current in the Itpa-cKO mice compared with ITPA-proficient controls. Accumulated ITP or its metabolites, such as cyclic inosine monophosphates, or RNA containing inosines may cause membrane depolarization and hyperexcitability in neurons and induce the phenotype of ITPA-deficient mice, including seizure.

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  133. Carcinogenesis as Side Effects of Iron and Oxygen Utilization: From the Unveiled Truth toward Ultimate Bioengineering. International journal

    Shinya Toyokuni, Yingyi Kong, Zhen Cheng, Kotaro Sato, Shotaro Hayashi, Fumiya Ito, Li Jiang, Izumi Yanatori, Yasumasa Okazaki, Shinya Akatsuka

    Cancers   Vol. 12 ( 11 ) page: 1 - 20   2020.11

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    Simple Summary: Cancer is a major cause of human mortality worldwide. No life on earth can live without iron. Persistent oxidative stress resulting from continuous use of iron and oxygen may be a fundamental cause of carcinogenesis. Many animal models demonstrated that excess iron may lead to carcinogenesis. This is supported by a variety of human epidemiological data on cancer risk and prognosis. Cancer is basically a disease of the genome with persistently activated oncogenes and inactivated tumor suppressor genes through which iron addiction with ferroptosis-resistance is established. We predict that fine use of nanomaterials and non-thermal plasma may be able to reverse this situation.Evolution from the first life on earth to humans took similar to 3.8 billion years. During the time there have been countless struggles among the species. Mycobacterium tuberculosis was the last major uncontrollable species against the human public health worldwide. After the victory with antibiotics, cancer has become the leading cause of death since 1981 in Japan. Considering that life inevitably depends on ceaseless electron transfers through iron and oxygen, we believe that carcinogenesis is intrinsically unavoidable side effects of using iron and oxygen. Many animal models unequivocally revealed that excess iron is a risk for carcinogenesis. This is supported by a variety of human epidemiological data on cancer risk and prognosis. Cancer is basically a disease of the genome with persistently activated oncogenes and inactivated tumor suppressor genes through which iron addiction with ferroptosis-resistance is maintained. Engineering has made a great advance in the past 50 years. In particular, nanotechnology is distinct in that the size of the engineered molecules is similar to that of our biomolecules. While some nano-molecules are found carcinogenic, there are principles to avoid such carcinogenicity with a smart possibility to use nano-molecules to specifically kill cancer cells. Non-thermal plasma is another modality to fight against cancer.

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  134. Induction of cancer cell-specific ferroptosis by non-thermal plasma exposure

    Okazaki Yasumasa, Toyokuni Shinya

    JAPANESE JOURNAL OF APPLIED PHYSICS   Vol. 59 ( 11 )   2020.11

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  135. Induction of cancer cell-specific ferroptosis by non-thermal plasma exposure International journal

    Okazaki Y.

    Japanese Journal of Applied Physics   Vol. 59 ( 11 )   2020.11

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    DOI: 10.35848/1347-4065/abbc56

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  136. The new role of poly (rC)-binding proteins as iron transport chaperones: Proteins that could couple with inter-organelle interactions to safely traffic iron International journal

    Yanatori I.

    Biochimica et Biophysica Acta - General Subjects   Vol. 1864 ( 11 )   2020.11

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    DOI: 10.1016/j.bbagen.2020.129685

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  137. Adjusted multiple gases in the plasma flow induce differential antitumor potentials of plasma-activated solutions International journal

    Nakamura K.

    Plasma Processes and Polymers   Vol. 17 ( 10 )   2020.10

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    DOI: 10.1002/ppap.201900259

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  138. Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice International journal

    Nishio M.

    Cancer Science   Vol. 111 ( 10 ) page: 3576 - 3587   2020.10

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    DOI: 10.1111/cas.14581

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  139. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice International journal

    Hayashi S.

    Redox Biology   Vol. 37   2020.10

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    DOI: 10.1016/j.redox.2020.101726

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  140. アスベストとタルクは鉄過剰環境を形成し卵巣がんの発がんに関わる

    本岡 大社, 伊藤 文哉, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 79回   page: OJ1 - 1   2020.10

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  141. Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and β-catenin induction in mesothelium International journal

    Ito F.

    Redox Biology   Vol. 36   2020.9

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    DOI: 10.1016/j.redox.2020.101616

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  142. Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma International journal

    Ohara Y.

    Oncology Reports   Vol. 44 ( 3 ) page: 838 - 848   2020.9

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    DOI: 10.3892/or.2020.7669

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  143. Role of carbonic anhydrases in ferroptosis-resistance International journal

    Li Z.

    Archives of Biochemistry and Biophysics   Vol. 689   2020.8

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    DOI: 10.1016/j.abb.2020.108440

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  144. Ferroptosis at the crossroads of infection, aging and cancer International journal

    Toyokuni S.

    Cancer Science   Vol. 111 ( 8 ) page: 2665 - 2671   2020.8

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    DOI: 10.1111/cas.14496

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  145. Non-thermal plasma-activated lactate solution kills U251SP glioblastoma cells in an innate reductive manner with altered metabolism International journal

    Ishikawa Kenji, Hosoi Yugo, Tanaka Hiromasa, Jiang Li, Toyokuni Shinya, Nakamura Kae, Kajiyama Hiroaki, Kikkawa Fumitaka, Mizuno Masaaki, Hori Masaru

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 688   2020.7

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  146. Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats International journal

    Okazaki Y.

    Cancer Science   Vol. 111 ( 6 ) page: 2016 - 2027   2020.6

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  147. Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats. Reviewed International journal

    Yasumasa Okazaki, Nobuaki Misawa, Shinya Akatsuka, Norihiko Kohyama, Yoshitaka Sekido, Takashi Takahashi, Shinya Toyokuni

    Cancer science   Vol. 111 ( 4 ) page: 1180 - 1192   2020.4

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    The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.

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  148. Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice Reviewed International journal

    Funahashi S.

    Free Radical Research   Vol. 54 ( 2-3 ) page: 195 - 205   2020.3

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  149. アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣がんの発がんに関わる

    本岡 大社, 伊藤 文哉, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 314 - 314   2020.3

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  150. Plasma-activated medium promotes autophagic cell death along with alteration of the mTOR pathway International journal

    Yoshikawa Nobuhisa, Liu Wenting, Nakamura Kae, Yoshida Kosuke, Ikeda Yoshiki, Tanaka Hiromasa, Mizuno Masaaki, Toyokuni Shinya, Hori Masaru, Kikkawa Fumitaka, Kajiyama Hiroaki

    SCIENTIFIC REPORTS   Vol. 10 ( 1 )   2020.1

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  151. Augmented oxidative stress increases 8-oxoguanine preferentially in the transcriptionally active genomic regions Reviewed International journal

    Akatsuka S.

    Free Radical Research     2020

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  152. Oxidative stress-dependent and -independent death of glioblastoma cells induced by non-thermal plasma-exposed solutions Reviewed International journal

    Tanaka Hiromasa, Mizuno Masaaki, Katsumata Yuko, Ishikawa Kenji, Kondo Hiroki, Hashizume Hiroshi, Okazaki Yasumasa, Toyokuni Shinya, Nakamura Kae, Yoshikawa Nobuhisa, Kajiyama Hiroaki, Kikkawa Fumitaka, Hori Masaru

    SCIENTIFIC REPORTS   Vol. 9 ( 1 ) page: 13657   2019.9

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  153. How iron is handled in the course of heme catabolism: Integration of heme oxygenase with intracellular iron transport mechanisms mediated by poly (rC)-binding protein-2. International journal

    Yanatori I, Richardson DR, Toyokuni S, Kishi F

    Archives of biochemistry and biophysics   Vol. 672   page: 108071   2019.9

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  154. Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia. Reviewed International journal

    Zan Li, Li Jiang, Shan Hwu Chew, Tasuku Hirayama, Yoshitaka Sekido, Shinya Toyokuni

    Redox biology   Vol. 26   page: 101297 - 101297   2019.9

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    Hypoxia and acidity provide microenvironment for selection under evolutionary pressure and proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present in all life kingdoms, equilibrating the reactions among CO2, bicarbonate and H+. CA9, a membrane-associated α-CA, has been a drug target for various cancers. Whereas iron is essential not only for cancer cells but also for all the lives on earth, little is known on the association among hypoxia, iron metabolism, extracellular acidity and redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, is an intriguing model in that asbestos-associated pathogenesis includes excess iron environment during carcinogenesis. Re-analysis of rat asbestos-induced MM model revealed an inverse association between high CA9 expression and survival. Here we used human MMs to identify the molecular events surrounding CA9 from the viewpoint of iron metabolism. CA9 expression was significantly higher in MM cells than in MeT-5A mesothelial cells, which was further amplified under hypoxia (1%O2) with increased catalytic Fe(II). CA9 suppression by inhibitors (S4 and U104) decreased viability and migration of MM cells, accompanied by overexpression of TFRC, IREB1/2 and FPN1(SLC40A1) and by downregulation of FTH/FTL. This expressional pattern was similar to that of erastin-induced ferroptosis in the same cells. Furthermore, we observed mitochondrial fission and enhanced autophagy with increased catalytic Fe(II) in both mitochondria and lysosomes after CA9 inhibition, accompanied by increased peroxides, mitochondrial O2- and lipid peroxidation. The eventual cell death was significantly inhibited by deferoxamine, ferrostatin-1 and Z-VAD-FMK, suggesting a mixed cell death of ferroptosis and apoptosis. Therefore, CA9 plays a role in equilibrating among hypoxia, iron metabolism and redox regulation in MM cells.

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  155. アスベストは鉄過剰環境を形成し卵巣癌の発癌に関わる(Asbestos contributes to ovarian carcinogenesis via iron overload)

    本岡 大社, 伊藤 文哉, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 78回   page: E - 1077   2019.9

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  156. l-Dehydroascorbic acid recycled by thiols efficiently scavenges non-thermal plasma-induced hydroxyl radicals Reviewed International journal

    Yasumasa Okazaki, Hiromasa Tanaka, Masaru Hori, Shinya Toyokuni

    Archives of Biochemistry and Biophysics   Vol. 669   page: 87 - 95   2019.7

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  157. アスベストの曝露は上皮性悪性卵巣腫瘍の発癌に関与する

    水野 勇太, 本岡 大社, 豊國 伸哉

    日本病理学会会誌   Vol. 108 ( 1 ) page: 460 - 461   2019.4

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  158. A scrutiny of circulating microRNA biomarkers for drug-induced tubular and glomerular injury in rats.

    Toxicology   Vol. 415   page: 26-36   2019.3

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  159. Non-thermal plasma-activated medium modified metabolomic profiles in the glycolysis of U251SP glioblastoma International journal

    Kurake Naoyuki, Ishikawa Kenji, Tanaka Hiromasa, Hashizume Hiroshi, Nakamura Kae, Kajiyama Hiroaki, Toyokuni Shinya, Kikkawa Fumitaka, Mizuno Masaaki, Hori Masaru

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 662   page: 83 - 92   2019.2

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  160. Twist1 was detected in mesenchymal cells of mammary fibroadenoma and invasive components of breast carcinoma in rats.

    Funahashi S, Okazaki Y, Nagai H, Chew SH, Ogawa K, Toyoda T, Cho YM, Toyokuni S

    Journal of toxicologic pathology   Vol. 32 ( 1 ) page: 19-26   2019.1

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  161. Non-thermal plasma specifically kills oral squamous cell carcinoma cells in a catalytic Fe(II)-dependent manner Reviewed International journal

    Kotaro Sato, Lei Shi, Fumiya Ito, Yuuki Ohara, Yashiro Motooka, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Tasuku Hirayama, Hideharu Hibi, Shinya Toyokuni

    Journal of Clinical Biochemistry and Nutrition   Vol. 65 ( 4 ) page: 8 - 15   2019

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  162. Iron Metabolism and Ferroptosis Reviewed International journal

    Toyokuni Shinya, Yanatori Izumi

    FERROPTOSIS IN HEALTH AND DISEASE     page: 27 - 41   2019

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    DOI: 10.1007/978-3-030-26780-3_2

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  163. A scrutiny of circulating microRNA biomarkers for tubular and glomerular injury in rats

    KAGAWA Takumi, ZÁRYBNICKÝ Tomáš, OMI Takanao, SHIRAI Yuji, TOYOKUNI Shinya, ODA Shingo, YOKOI Tsuyoshi

    Annual Meeting of the Japanese Society of Toxicology   Vol. 46 ( 0 ) page: P - 233   2019

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    <p><b>[Introduction]</b> Drug-induced acute kidney injury (AKI) is a frequent cause of adverse drug reaction. Serum creatinine (CRE) and blood urea nitrogen (BUN) are widely used as standard biomarkers for kidney injury; however, the sensitivity and specificity are considered to be low. In recent years, circulating microRNA (miRNAs) have been attracting considerable attention as novel biomarkers for organ injury, but there are currently no established miRNA biomarkers for drug-induced AKI. The present study aimed to identify plasma miRNAs that may enable early and specific detection of drug-induced tubular and glomerular injury through next-generation sequencing analysis. <b>[Methods]</b> Six-week old male Sprague-Dawley rats were administered cisplatin and gentamicin to induce tubular injury. To create glomerular injury models, puromycin and doxorubicin were administered, and these models were always accompanied by tubular damage. Small RNA-sequencing was performed to analyze time-dependent changes in the plasma miRNA profiles. <b>[Results and Discussion]</b> In the differential analysis, miR-3473 was specifically up-regulated in the glomerular injury models. miR-143-3p and miR-122-5p were commonly down-regulated in all models, and the changes were earlier than the traditional biomarkers, such as plasma CRE and BUN. These data indicated that changes in the specific miRNAs in plasma may enable the early and sensitive detection of tubular and glomerular injuries. The present study suggests the potential utility of plasma miRNAs in the early and type-specific detection of drug-induced AKI.</p>

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  164. Chemiluminescence imaging of UVA induced reactive oxygen species in mouse skin using L-012 as a probe

    Liu Jiao-Li, Xue Qiao, Liu Chen-Guang, Bai Feng-Wu, Wada Satoshi, Wang Jin-Ye

    FREE RADICAL RESEARCH   Vol. 52 ( 11-12 ) page: 1424 - 1431   2018.12

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  165. Analysis of the involvement of cancer-associated fibroblasts in the progression of malignant mesothelioma

    Ohara Yuuki, Enomoto Atsushi, Takahashi Masahide, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 454-454   2018.12

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  166. Multifaceted roles of Ptger2 (Prostaglandin E receptor 2) in asbestos-induced inflammation and malignant mesothelioma

    Jiang Li, Akatsuka Shinya, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 830-830   2018.12

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  167. Inflammatory microenvironment derived from asbestos increases mutagenesis to repairing mesothelial cell

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 830 - 830   2018.12

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  168. Ferroptosis in Cancer Research

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 195-195   2018.12

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  169. Critical role of Hippo signaling pathway at the onset of squamous cell carcinomas

    Suzuki Akira, Nishio Miki, Omori Hirofumi, To Yoko, Maehama Tomohiko, Aono Yukari, Kiyono Tohru, Taguchi Kenichi, Masuda Muneyuki, Toyokuni Shinya, Tashiro Hironori, Katabuchi Hidetaka

    CANCER SCIENCE   Vol. 109   page: 781-781   2018.12

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  170. Asbestos exposure as a possible cause of ovarian carcinogenesis

    Yashiro Motooka, Ito Fumiya, Tashiro Hironori, Katabuchi Hidetaka, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 255-255   2018.12

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  171. Ferroptosis in Cancer Research International journal

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 195-195   2018.12

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  172. Critical role of Hippo signaling pathway at the onset of squamous cell carcinomas International journal

    Suzuki Akira, Nishio Miki, Omori Hirofumi, To Yoko, Maehama Tomohiko, Aono Yukari, Kiyono Tohru, Taguchi Kenichi, Masuda Muneyuki, Toyokuni Shinya, Tashiro Hironori, Katabuchi Hidetaka

    CANCER SCIENCE   Vol. 109   page: 781-781   2018.12

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  173. Asbestos exposure as a possible cause of ovarian carcinogenesis International journal

    Yashiro Motooka, Ito Fumiya, Tashiro Hironori, Katabuchi Hidetaka, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 255-255   2018.12

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  174. Analysis of the involvement of cancer-associated fibroblasts in the progression of malignant mesothelioma International journal

    Ohara Yuuki, Enomoto Atsushi, Takahashi Masahide, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 454-454   2018.12

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  175. Inflammatory microenvironment derived from asbestos increases mutagenesis to repairing mesothelial cell International journal

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 830-830 - 830   2018.12

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  176. Multifaceted roles of Ptger2 (Prostaglandin E receptor 2) in asbestos-induced inflammation and malignant mesothelioma International journal

    Jiang Li, Akatsuka Shinya, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 830-830   2018.12

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  177. Polymer coating on carbon nanotubes into Durobeads is a novel strategy for human environmental safety.

    Fumiya Ito, Hideyuki Hisashi, Shinya Toyokuni

    Nagoya journal of medical science   Vol. 80 ( 4 ) page: 597 - 604   2018.11

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    Carbon nanotubes (CNTs) have attracted much business interest in industrial applications due to their high electrical and heat conductivities while being both durable and versatile. However. multiwall CNTs (MWCNTs) of similar to 50 nm diameter (NT50) have been shown to cause mesothelioma in rodents after direct exposure to mesothelial cells, and thus were classified as a Group 213 carcinogen to humans, which requires considerable regulations for use. In contrast, tangled MWCNTs of similar to 15 nm diameter (NTtngl) are not carcinogenic to rats, indicating that the physical dimension linked with mesothelial cellular uptake is an important factor for human environmental risk. In the present study, hypothesizing that dustability is another distinct risk factor, for the first time, we evaluated the toxicity of CNT granules (Durobeads) that were generated with a polymer coating to mesothelial cells. Polymer coating induced prominent agglomeration and significantly suppressed the dustability of CNTs in a dose-dependent manner, with a 10% polymer coating resulting in 730 times less dustability. These CNT granules revealed significantly lower mesothelial uptake and cytotoxicity in comparison to NT50 in in vitro assays. Similarly, in in vivo analyses, CNT granules induced limited peritoneal inflammation 4 weeks after intraperitoneal injection, whereas NT50 caused severe fibrosing inflammation. Previously, we demonstrated that the severity of inflammation by intraperitoneal injection in the subacute studies are in agreement with the mesothelial carcinogenicity by CNTs. Therefore, we suggest that adding a polymer coating to CNTs provides another smart strategy for the safe use of CNTs.

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  178. Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice.

    Funahashi S, Okazaki Y, Nishiyama T, Ohyoshi H, Yasui H, Nishida K, Matsui S, Toyokuni S

    Free radical research     page: 1-10   2018.10

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  179. Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention.

    Toyokuni S

    Free radical biology & medicine     2018.10

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  180. Molecular mechanisms of non-thermal plasma-induced effects in cancer cells.

    Tanaka H, Mizuno M, Ishikawa K, Toyokuni S, Kajiyama H, Kikkawa F, Hori M

    Biological chemistry     2018.10

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    DOI: 10.1515/hsz-2018-0199

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  181. A special issue of SFRR Asia: Cross talk between free radicals and mitochondria in health and disease.

    Liu J, Toyokuni S, Surh YJ

    Free radical research     page: 1-51   2018.9

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    DOI: 10.1080/10715762.2018.1528501

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  182. Plasma Biology for a Novel Cancer Treatment

    Toyokuni Shinya

    JSAP Annual Meetings Extended Abstracts   Vol. 2018.2 ( 0 ) page: 37 - 37   2018.9

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    DOI: 10.11470/jsapmeeting.2018.2.0_37

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  183. 動物モデルを用いたがん研究 扁平上皮癌発症におけるHippo経路の役割(Animal models in cancer research Critical role of Hippo signaling pathway at the onset of squamous cell carcinomas)

    鈴木 聡, 西尾 美希, 大森 裕文, 藤 庸子, 前濱 朝彦, 青野 ゆかり, 清野 透, 田口 健一, 益田 宗幸, 豊國 伸哉, 田代 浩徳, 片渕 秀隆

    日本癌学会総会記事   Vol. 77回   page: 1110 - 1110   2018.9

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  184. アスベストが卵巣癌を起こす可能性について クロシドライトは卵巣表層上皮におけるDNAの二本鎖切断を惹起する(Asbestos exposure as a possible cause of ovarian carcinogenesis)

    本岡 大社, 伊藤 文哉, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 77回   page: 118 - 118   2018.9

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  185. Development of a novel monoclonal antibody against 4-hydroxy-2E,6Z-dodecadienal (4-HDDE)-protein adducts: Immunochemical application in quantitative and qualitative analyses of lipid peroxidation in vitro and ex vivo. International journal

    Koji Uchida, Takahiro Shibata, Shinya Toyokuni, Bareket Daniel, Kamelija Zarkovic, Neven Zarkovic, Shlomo Sasson

    Free radical biology & medicine   Vol. 124   page: 12 - 20   2018.8

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    Non-enzymatic peroxidation of polyunsaturated fatty acids (PUFA) results in the formation of various α,β-unsaturated aldehydes, of which 4-hydroxyalkenals are abundant. The propensity of n-6 PUFA, such as linoleic acid, γ-linolenic acid and arachidonic acid, to undergo radical-induced peroxidation and generate 4-hydroxy-2E-nonenal (4-HNE) has been widely demonstrated. The ability of the latter to form covalent adducts with macromolecules and modify cellular functions has been linked to numerous pathological processes. Concomitantly, evidence has accumulated on specific signaling properties of low concentrations of 4-HNE that may induce hormetic and protective responses to peroxidation stress in cells. It has long been known that peroxidation of PUFA, and particularly arachidonic acid, also give rise to 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), which is more chemically reactive than 4-HNE. Few studies on 4-HDDE revealed its ability to avidly interact covalently with electronegative moieties in macromolecules and to its ability to selectively activate the transcriptional regulator Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ. The research on 4-HDDE has been impeded due to the lack of available pure 4-HDDE and antibodies that recognize 4-HDDE-modified epitopes in proteins. The purpose of this study was to employ an established procedure to synthesize 4-HDDE and use it to create and characterize a monoclonal antibody against 4-HDDE-modified proteins and establish its application for ELISA and immunohistochemical analysis of cells and tissues and further expand lipid peroxidation research.

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  186. Non-thermal plasma as a simple ferroptosis inducer in cancer cells: A possible role of ferritin International journal

    Furuta Takahiro, Shi Lei, Toyokuni Shinya

    PATHOLOGY INTERNATIONAL   Vol. 68 ( 7 ) page: 442 - 443   2018.7

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  187. Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model Reviewed International journal

    Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Tomoko Nakano, Takafumi Ushida, Akira Iwase, Taku Nagai, Shinya Toyokuni, Akio Suzumura, Fumitaka Kikkawa

    Scientific Reports   Vol. 8 ( 1 ) page: 9221   2018.6

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    The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H2) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H2 attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H2 administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H2 on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H2-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H2 administration. Overall, these findings indicate that maternal H2 administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.

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  188. Acute fulminant invasive pulmonary aspergillosis in an immunocompetent host: An autopsy case report Reviewed International journal

    Yuuki Ohara, Takahiko Ito, Makoto Ito, Kyoko Yamashita, Shinya Toyokuni

    Medical Mycology Case Reports   Vol. 20   page: 39 - 42   2018.6

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    A 62-year-old previously healthy male who was a welder/smoker/drinker was admitted to Kani Tono Hospital for severe hypoxemia (Day 0). Initial physical and radiological examinations suggested an acute exacerbation of chronic obstructive pulmonary disease. However, respiratory failure developed rapidly, and he died on Day + 4. Aspergillus fumigatus was identified after his death, and he was diagnosed with invasive pulmonary aspergillosis. The clinical and pathological features are precisely described with pathogenetic considerations.

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  189. An autopsy case report: Differences in radiological images correlate with histology in Erdheim-Chester disease. Reviewed International journal

    Yuuki Ohara, Seiichi Kato, Daisuke Yamashita, Akira Satou, Yoshie Shimoyama, Chie Hamaie, Motoki Sato, Nobutaro Ban, Koji Yamamoto, Takehiro Yamada, Hisashi Kawai, Koichi Ohshima, Shigeo Nakamura, Shinya Toyokuni

    Pathology international   Vol. 68 ( 6 ) page: 374 - 381   2018.6

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    p16 activation caused by oncogenic mutations may represent oncogene-induced senescence (OIS), a protective mechanism against oncogenic events. However, OIS can contribute to tumor development via tissue remodeling in some tumors. Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is one such tumor. Its clinical and histological features vary, making it difficult to diagnose. Herein, we describe an autopsy of an ECD patient. The patient underwent radiological examinations, including 18 F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS-induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio-histological correlation can help further both the understanding and diagnosis of ECD.

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  190. タルクへの曝露は卵巣表層上皮細胞内の2価鉄イオンの増加に寄与し卵巣癌の発癌に関わる

    本岡 大社, 伊藤 文哉, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 29 ( 1 ) page: 71 - 71   2018.6

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  191. Ferroptosis in carcinogenesis and tumor biology International journal

    Toyokuni Shinya

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 120   page: S19 - S19   2018.5

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  192. Expression of P-REX2a is associated with poor prognosis in endometrial malignancies. International journal

    Sho Takeshita, Yoriko Yamashita, Kosuke Shiomi, Nako Suzuki, Jun Yoshida, Aya Naiki-Ito, Shugo Suzuki, Shinya Akatsuka, Shinya Toyokuni, Takashi Takahashi, Shoko Mase, Atsushi Arakawa, Mayumi Sugiura-Ogasawara, Satoru Takahashi

    Oncotarget   Vol. 9 ( 37 ) page: 24778 - 24786   2018.5

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    P-REX2a is a PTEN inhibitor that also activates Rac 1. No associations with P-REX2a and human endometrial cancers have been reported to date. In this study, we immunohistochemically analyzed 155 uterine endometrial malignancies for P-REX2a expression. The P-REX2a-positive tumors displayed worse prognosis independent of PTEN expression. Then, we transduced either P-REX2a expression vector or short hairpin RNAs targeting P-REX2a into 2 uterine endometrioid carcinoma cell lines, OMC-2 and JHUEM-14. Ectopic expression of P-REX2a led to increased cell proliferation only in the PTEN-expressing OMC-2 cells but did not show any change in the PTEN-negative JHUEM-14 cells or the P-REX2a-knockdown cells. Induction of P-REX2a increased and knockdown of P-REX2a decreased cell migration in both cell lines. Then, we performed expression microarray analysis using these cells, and pathway analysis revealed that the expression of members of the GPCR downstream pathway displayed the most significant changes induced by the knockdown of P-REX2a. Immunohistochemical analysis revealed that Vav1, a member of the GPCR downstream pathway, was expressed in 139 of the 155 endometrial tumors, and the expression levels of Vav1 and P-REX2a showed a positive correlation (r = 0.44, p < 0.001). In conclusion, P-REX2a enhanced cell motility via the GPCR downstream pathway independently of PTEN leading to progression of uterine endometrioid malignancies and poor prognosis of the patients.

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  193. Superiority of rat over murine model for studies on the evolution of cancer genome.

    Akatsuka S, Li GH, Toyokuni S

    Free radical research     page: 1-5   2018.5

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  194. Effect of molecular hydrogen on uterine inflammation during preterm labour International journal

    Tomoko Nakano, Tomomi Kotani, Kenji Imai, Yukako Iitani, Takafumi Ushida, Hiroyuki Tsuda, Hua Li, Akira Iwase, Shinya Toyokuni, Fumitaka Kikkawa

    Biomedical Reports   Vol. 8 ( 5 ) page: 454 - 460   2018.5

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    Intrauterine inflammation causes preterm birth and is associated with complications in preterm neonates. Thus, strategies aimed at suppressing inflammation are expected to be effective for reducing the risk of preterm birth and associated complications. Our previous studies demonstrated that molecular hydrogen (H2), an anti-inflammatory agent, prevented inflammation-induced impairment in foetal brain and lung tissues in lipopolysaccharide (LPS)-induced rodent models. However, it remains unclear whether H2 is capable of inhibiting preterm labour. The aim of the current study was therefore to investigate the effect of H2 on inflammation-induced preterm labour. Pregnant ICR (CD-1) mice were divided into three groups: Control, LPS and H2 water (HW) + LPS. In the control and LPS groups, vehicle and LPS, respectively, were intraperitoneally injected on embryonic day 15.5. In the HW + LPS group, HW was administered 24 h prior to LPS injection. The time from LPS administration to parturition was compared between the LPS and HW + LPS groups. Maternal uterus was collected 6 h after LPS injection and the transcript levels of pro-inflammatory cytokines, contractile-associated proteins (CAPs), matrix metalloproteinase-3 (Mmp3) and endothelin-1 (Et1) were assessed by reverse transcription-quantitative polymerase chain reaction. The protein levels of cyclooxygenase-2 (Cox2) were also evaluated by immunohistochemistry. The time from LPS administration to parturition in the HW + LPS group was significantly increased compared with that in the LPS group (33.5±3.4 vs. 18.3±8.8 h, respectively, P=0.020). H2 administration also resulted in significantly higher progesterone levels compared with LPS treatment alone (P=0.002). The transcript levels of pro-inflammatory cytokines, CAPs, Mmp3 and Et1 in the uteri of the LPS group were significantly higher than those in the control group (all P&lt
    0.05). In turn, all these levels with the exception of interleukin-8 and Mmp3 were significantly lower in the HW + LPS group compared with those in the LPS group (all P&lt
    0.05). The protein levels of Cox2 in the LPS group were also significantly increased compared with those in the control (P&lt
    0.001) and HW + LPS (P=0.003) groups. These results suggest that inflammation-induced changes in the uterus may be ameliorated through maternal H2 administration. Preventive H2 administration may therefore represent an effective strategy for the suppression of inflammation during preterm labour.

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  195. Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model International journal

    Yuuki Ohara, Shan Hwu Chew, Nobuaki Misawa, Shenqi Wang, Daiki Somiya, Kae Nakamura, Hiroaki Kajiyama, Fumitaka Kikkawa, Yuta Tsuyuki, Li Jiang, Kyoko Yamashita, Yoshitaka Sekido, Kenneth E. Lipson, Shinya Toyokuni

    Oncotarget   Vol. 9 ( 26 ) page: 18494 - 18509   2018.4

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    Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

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  196. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification International journal

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Takeaki Ishii, Yoshihiro Nishida, Hiroshi Urakawa, Ichiro Ito, Mitsuru Takahashi, Takeshi Inoue, Masafumi Ito, Yuuki Ohara, Yoshinao Oda, Shinya Toyokuni

    Histopathology   Vol. 72 ( 5 ) page: 729 - 738   2018.4

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    Aims: Ossification is found occasionally in dedifferentiated liposarcoma (DDLPS). The aims of this study were to elucidate whether the formed bone tissue is usually produced by tumour cells or by reactive non-neoplastic cells, and to reveal the clinicopathological characteristics of DDLPS with ossification. Methods and results: We examined 36 cases of ossified DDLPS by comparing them to 31 cases of non-ossified DDLPS. MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all but one ossified DDLPS cases (27 of 28) using fluorescence in-situ hybridisation, although the morphological impression of ossification appeared to be mainly metaplastic (27 of 36) or high-grade osteosarcoma-like (six of 36). The bone tissue was often formed predominantly at the periphery of the DDLPS area near the well-differentiated liposarcoma component (18 of 36), and an organised structure such as bone marrow-like differentiation was not uncommon (12 of 36). According to a modified French Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, ossified DDLPS tended to be lower grade than non-ossified DDLPS (mean grade: 1.88 and 2.15, respectively). Ossification in DDLPS was associated significantly with shorter local recurrence-free survival by multivariate analysis (P = 0.02347), but metaplastic-appearing ossification tended to be associated with longer overall survival (P = 0.1400). Conclusions: The bone tissue formed in DDLPS was mainly neoplastic regardless of its morphology and maturity, which highlighted the osteogenic differentiation of the tumour cells. DDLPS patients with osteogenic differentiation tended to suffer from earlier local recurrences, which did not necessarily lead to poor life outcomes.

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  197. 脱分化型脂肪肉腫における骨形成の特徴と予後との関連

    山下 享子, 孝橋 賢一, 山田 裕一, 伊藤 以知郎, 小田 義直, 豊國 伸哉

    日本病理学会会誌   Vol. 107 ( 1 ) page: 291 - 291   2018.4

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  198. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats International journal

    Yuuki Ohara, Shan-Hwu Chew, Takahiro Shibata, Yasumasa Okazaki, Kyoko Yamashita, Shinya Toyokuni

    Cancer Science   Vol. 109 ( 2 ) page: 330 - 339   2018.2

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    Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial–mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

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  199. Phlebotomy attenuates the growth of malignant mesothelioma on rat model

    Ohara Yuuki, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 781 - 781   2018.1

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  200. Molecular mechanisms in oxidative stress-induced carcinogenesis

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 163 - 163   2018.1

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  201. Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice

    Akatsuka Shinya, Li Guang-Hua, Sakumi Kunihiko, Nakabeppu Yusaku, Futakuchi Mitsuru, Suzuki Hiromu, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 167 - 167   2018.1

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  202. Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice International journal

    Akatsuka Shinya, Li Guang-Hua, Sakumi Kunihiko, Nakabeppu Yusaku, Futakuchi Mitsuru, Suzuki Hiromu, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 167-167   2018.1

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  203. Molecular mechanisms in oxidative stress-induced carcinogenesis International journal

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 163-163   2018.1

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  204. Phlebotomy attenuates the growth of malignant mesothelioma on rat model International journal

    Ohara Yuuki, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 781-781   2018.1

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  205. Glioblastoma Cell Lines Display Different Sensitivities to Plasma-Activated Medium International journal

    Tanaka Hiromasa, Mizuno Masaaki, Ishikawa Kenji, Takeda Keigo, Hashizume Hiroshi, Nakamura Kae, Utsumi Fumi, Kajiyama Hiroaki, Okazaki Yasumasa, Toyokuni Shinya, Akiyama Shinichi, Maruyama Shoichi, Kikkawa Fumitaka, Hori Masaru

    IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES   Vol. 2 ( 2 ) page: 99 - 102   2018

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    Plasma-activated medium (PAM) is a novel chemotherapy that induces reactive oxygen species (ROS) and cell death in a wide range of cancer cell types, suggesting that PAM may be a promising therapeutic option for cancer treatment. However, dose response experiments suggest that PAM sensitivity is cell line specific. We examined the sensitivities of three glioblastoma cell lines to PAM, and found a wide variation in cell killing that was linked to differences in PAM induced ROS and apoptosis. These results indicate that the PAM sensitivity of glioblastoma cells, and potentially cancer cells more generally, is heterogeneous and likely to be dependent on the regulation of apoptosis and antioxidant pathways in target cells.

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  206. State of the art in medical applications using non-thermal atmospheric pressure plasma

    Hiromasa Tanaka, Kenji Ishikawa, Masaaki Mizuno, Shinya Toyokuni, Hiroaki Kajiyama, Fumitaka Kikkawa, Hans-Robert Metelmann, Masaru Hori

    Plasma Physics, Association of Asia Pacific Physical Societies 2017   Vol. 1 ( 1 )   2017.12

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  207. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. Reviewed International journal

    Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S

    Cancer Science     2017.11

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  208. Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. Reviewed

    Li GH, Akatsuka S, Chew SH, Jiang L, Nishiyama T, Sakamoto A, Takahashi T, Futakuchi M, Suzuki H, Sakumi K, Nakabeppu Y, Toyokuni S.

    Pathology International   Vol. 67 ( 11 ) page: 564-574   2017.11

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  209. Role of catalytic iron and oxidative stress in nitrofen-induced congenital diaphragmatic hernia and its amelioration by Saireito (TJ-114) International journal

    Hirako Shima, Tsuda Hiroyuki, Ito Fumiya, Okazaki Yasumasa, Hirayama Tasuku, Nagasawa Hideko, Nakano Tomoko, Imai Kenji, Kotani Tomomi, Kikkawa Fumitaka, Toyokuni Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 61 ( 3 ) page: 176 - 182   2017.11

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    <p>Congenital diaphragmatic hernia (CDH) is a life-threatening neonatal disease that leads to lung hypoplasia and pulmonary hypertension. We recently found that maternal prenatal administration of Saireito (TJ-114) ameliorates fetal CDH in a nitrofen-induced rat model. Here, we studied the role of iron and oxidative stress in neonates of this model and in lung fibroblasts IMR90-SV in association with nitrofen and Saireito. We observed increased immunostaining of 8-hydroxy-2'-deoxyguanosine in the lungs of neonates with CDH, which was ameliorated by maternal Saireito intake. Pulmonary <i>transferrin receptor</i> expression was significantly decreased in both CDH and CDH after Saireito in comparison to normal controls, indicating functional lung immaturity, whereas catalytic Fe(II) and pulmonary <i>DMT1/ferroportin</i> expression remained constant among the three groups. Saireito revealed a dose-dependent scavenging capacity with electron spin resonance spin trapping <i>in vitro</i> against hydroxyl radicals but not against superoxide. Finally, nitrofen revealed dose-dependent cytotoxicity to IMR90-SV cells, accompanied by an increase in oxidative stress, as seen by 5(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and catalytic Fe(II). Saireito ameliorated all of these in IMR90-SV cells. In conclusion, catalytic Fe(II)-dependent oxidative stress by nitrofen may be the pathogenic cause of CDH, and the antioxidative activity of Saireito is at least partially responsible for improving nitrofen-induced CDH.</p>

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  210. Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model International journal

    Guang Hua Li, Shinya Akatsuka, Shan Hwu Chew, Li Jiang, Takahiro Nishiyama, Akihiko Sakamoto, Takashi Takahashi, Mitsuru Futakuchi, Hiromu Suzuki, Kunihiko Sakumi, Yusaku Nakabeppu, Shinya Toyokuni

    PATHOLOGY INTERNATIONAL   Vol. 67 ( 11 ) page: 564 - 574   2017.11

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    Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P=0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16(INKA) inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.

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  211. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. International journal

    Brent R Stockwell, José Pedro Friedmann Angeli, Hülya Bayir, Ashley I Bush, Marcus Conrad, Scott J Dixon, Simone Fulda, Sergio Gascón, Stavroula K Hatzios, Valerian E Kagan, Kay Noel, Xuejun Jiang, Andreas Linkermann, Maureen E Murphy, Michael Overholtzer, Atsushi Oyagi, Gabriela C Pagnussat, Jason Park, Qitao Ran, Craig S Rosenfeld, Konstantin Salnikow, Daolin Tang, Frank M Torti, Suzy V Torti, Shinya Toyokuni, K A Woerpel, Donna D Zhang

    Cell   Vol. 171 ( 2 ) page: 273 - 285   2017.10

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    Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q(10). Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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  212. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. Reviewed

    Yamashita K, Kohashi K, Yamada Y, Ishii T, Nishida Y, Urakawa H, Ito I, Takahashi M, Inoue T, Ito M, Ohara Y, Oda Y, Toyokuni S.

    Histopathology     2017.10

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    DOI: doi: 10.1111/his.13421.

  213. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. Reviewed International journal

    Yamashita K, Kohashi K, Yamada Y, Ishii T, Nishida Y, Urakawa H, Ito I, Takahashi M, Inoue T, Ito M, Ohara Y, Oda Y, Toyokuni S

    Histopathology     2017.10

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  214. The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. Reviewed

    Yanatori I, Richardson DR, Toyokuni S, Kishi F.

    Journal of Biological Chemistry   Vol. 292 ( 32 ) page: 13205-13229   2017.8

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    DOI: doi: 10.1074/jbc.M117.776021.

  215. The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer International journal

    Izumi Yanatori, Des R. Richardson, Shinya Toyokuni, Fumio Kishi

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 292 ( 32 ) page: 13205 - 13229   2017.8

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    Mammals incorporate a major proportion of absorbed iron as heme, which is catabolized by the heme oxygenase 1 (HO1)-NADPH-cytochrome P450 reductase (CPR) complex into biliverdin, carbon monoxide, and ferrous iron. Moreover, intestinal iron is incorporated as ferrous iron, which is transported via the iron importer, divalent metal transporter 1 (DMT1). Recently, we demonstrated that the iron chaperone poly(rC)-binding protein 2 (PCBP2) can directly receive ferrous iron from DMT1 or transfer iron to the iron exporter, ferroportin 1. To promote intracellular iron flux, an iron chaperone may be essential for receiving iron generated by heme catabolism, but this hypothesis is untested so far. Herein, we demonstrate that HO1 binds to PCBP2, but not to other PCBP family members, namely PCBP1, PCBP3, or PCBP4. Interestingly, HO1 formed a complex with either CPR or PCBP2, and it was demonstrated that PCBP2 competes with CPR for HO1 binding. Using PCBP2-deletion mutants, we demonstrated that the PCBP2 K homology 3 domain is important for the HO1/PCBP2 interaction. In heme-loaded cells, heme prompted HO1-CPR complex formation and decreased the HO1/PCBP2 interaction. Furthermore, in vitro reconstitution experiments with purified recombinant proteins indicated that HO1 could bind to PCBP2 in the presence of heme, whereas loading of PCBP2 with ferrous iron caused PCBP2 to lose its affinity for HO1. These results indicate that ferrous iron released from heme can be bound by PCBP2 and suggest a model for an integrated heme catabolism and iron transport metabolon.

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  216. The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. Reviewed International journal

    Yanatori I, Richardson DR, Toyokuni S, Kishi F

    Journal of Biological Chemistry   Vol. 292 ( 32 ) page: 13205-13229   2017.8

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  217. IRON OVERLOAD ENHANCED CELL DEATH INDUCED BY CARCINOGENIC FIBROUS MATERIALS

    Ito Fumiya, Shi Lei, Toyokuni Shinya

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 92 ( 8 ) page: E365 - E365   2017.8

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  218. IRON OVERLOAD ENHANCED CELL DEATH INDUCED BY CARCINOGENIC FIBROUS MATERIALS International journal

    Fumiya Ito, Lei Shi, Shinya Toyokuni

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 92 ( 8 ) page: E365 - E365   2017.8

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  219. Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells. Reviewed

    Nakamura K, Peng Y, Utsumi F, Tanaka H, Mizuno M, Toyokuni S, Hori M, Kikkawa F, Kajiyama H.Sci

    Scientific Reports   Vol. 7 ( 1 ) page: 6085   2017.7

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  220. Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells. International journal

    Kae Nakamura, Yang Peng, Fumi Utsumi, Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa, Hiroaki Kajiyama

    Scientific reports   Vol. 7 ( 1 ) page: 6085 - 6085   2017.7

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    Non-thermal atmospheric pressure plasma has been proposed as a new therapeutic tool for cancer treatment. Recently, plasma-activated medium (PAM) has been widely studied in various cancer types. However, there are only few reports demonstrating the anti-tumour effects of PAM in an animal model reflecting pathological conditions and the accompanying mechanism. Here we investigated the inhibitory effect of PAM on the metastasis of ovarian cancer ES2 cells in vitro and in vivo. We demonstrated that ES2 cell migration, invasion and adhesion were suppressed by PAM at a certain PAM dilution ratio, whereas cell viability remained unaffected. In an in vivo mouse model of intraperitoneal metastasis, PAM inhibited peritoneal dissemination of ES2 cells, resulting in prolonged survival. Moreover, we assessed the molecular mechanism and found that MMP-9 was decreased by PAM. On further investigation, we also found that PAM prevented the activation of the MAPK pathway by inhibiting the phosphorylation of JNK1/2 and p38 MAPK. These findings indicate that PAM inhibits the metastasis of ovarian cancer cells through reduction of MMP-9 secretion, which is critical for cancer cell motility. Our findings suggest that PAM intraperitoneal therapy may be a promising treatment option for ovarian cancer.

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  221. Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy. Reviewed

    Shi L, Ito F, Wang Y, Okazaki Y, Tanaka H, Mizuno M, Hori M, Hirayama T, Nagasawa H, Richardson DR, Toyokuni S.

    Free Radical Biology & Medicine   Vol. 108   page: 904-917   2017.7

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  222. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats. Reviewed

    Okazaki Y, Okada S, Toyokuni S.

    Journal of Clinical Biochemistry and Nutrition   Vol. 61 ( 1 ) page: 18-24   2017.7

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  223. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats.

    Yasumasa Okazaki, Shigeru Okada, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 61 ( 1 ) page: 18 - 24   2017.7

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    Daily intake of vegetables can reduce the risk of cancer and lifestyle-related diseases. However, supplementary intake of 13 carotene alone has been reported to increase the risk of lung cancer in male cigarette smokers and people who were exposed to asbestos. The mechanism of the antioxidative properties of carotenoids in vivo, especially under oxidative stress conditions, still remains unclear. To investigate the antioxidant properties of dietary compounds, we examined the effects of chemically modified astaxanthin (Ax-C-8) using a rat model of ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative injury. Ax-C-8 demonstrated lethally toxic effects on the rats in a dose-dependent manner. Following supplementation with Ax-C-8 (0.02%, w/w) for 30 days, the rats were euthanized 1, 4 and 24 h after injection of Fe-NTA. After 4 h, Ax-C-8 pretreatment suppressed the elevation of creatinine and blood urea nitrogen and protected the rats from renal tubular necrosis and the formation of 4-hydroxy-2-nonenal-modified proteins. After 24 h, pretreatment with Ax-C-8 maintained the renal antioxidant enzyme levels and renal tubules. Here, we demonstrate the antioxidant effects of Ax-C-8 against Fe-NTA-induced oxidative injury in rats receiving a regular diet. These data suggest that dietary intake of astaxanthin may be useful for the prevention of renal tubular oxidative damage.

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  224. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis International journal

    Shinya Toyokuni, Fumiya Ito, Kyoko Yamashita, Yasumasa Okazaki, Shinya Akatsuka

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 108   page: 610 - 626   2017.7

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    Epidemiological data indicate a constant worldwide increase in cancer mortality, although the age of onset is increasing. Recent accumulation of genomic data on human cancer via next-generation sequencing confirmed that cancer is a disease of genome alteration. In many cancers, the Nrf2 transcription system is activated via mutations either in Nrf2 or Keap1 ubiquitin ligase, leading to persistent activation of the genes with antioxidative functions. Furthermore, deep sequencing of passenger mutations is clarifying responsible cancer causative agent (s) in each case, including aging, APOBEC activation, smoking and UV. Therefore, it is most likely that oxidative stress is the principal initiating factor in carcinogenesis, with the involvement of two essential molecules for life, iron and oxygen. There is evidence based on epidemiological and animal studies that excess iron is a major risk for carcinogenesis, suggesting the importance of ferroptosis-resistance. Microscopic visualization of catalytic Fe (II) has recently become available. Although catalytic Fe(II) is largely present in lysosomes, proliferating cells harbor catalytic Fe(II) also in the cytosol and mitochondria. Oxidative stress catalyzed by Fe(II) is counteracted by thiol systems at different functional levels. Nitric oxide, carbon monoxide and hydrogen (per) sulfide modulate these reactions. Mitochondria generate not only energy but also heme/iron sulfur cluster cofactors and remain mostly dysfunctional in cancer cells, leading to Warburg effects. Cancer cells are under persistent oxidative stress with a delicate balance between catalytic iron and thiols, thereby escaping ferroptosis. Thus, high-dose L-ascorbate and non-thermal plasma as well as glucose/glutamine deprivation may provide additional benefits as cancer therapies over preexisting therapeutics.

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  225. Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy International journal

    Lei Shi, Fumiya Ito, Yue Wang, Yasumasa Okazaki, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Tasuku Hirayama, Hideko Nagasawa, Des R. Richardson, Shinya Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 108   page: 904 - 917   2017.7

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    Non-thermal plasma (NTP) is a potential new therapeutic modality for cancer. However, its mechanism of action remains unclear. Herein, we studied the effect of NTP on mesothelioma cells and fibroblasts to understand its anti-proliferative efficacy. Interestingly, NTP demonstrated greater selective anti-proliferative activity against mesothelioma cells relative to fibroblasts than cisplatin, which is used for mesothelioma treatment. The anti-proliferative effect of NTP was enhanced by pre-incubation with the cellular iron donor, ferric ammonium citrate (FAC), and inhibited by iron chelation using desferrioxamine (DFO). Three oxidative stress probes (CM-H2DCFDA, MitoSOX and C11-BODIPY) demonstrated reactive oxygen species (ROS) generation by NTP, which was inhibited by DFO. Moreover, NTP decreased transferrin receptor-1 and increased ferritin-H and -L chain expression that was correlated with decreased iron-regulatory protein expression and RNA-binding activity. This regulation was potentially due to increased intracellular iron in lysosomes, which was demonstrated via the Fe (II)-selective probe, HMRhoNox-M, and was consistent with autophagic-induction. Immunofluorescence using LysoTracker and Pepstatin A probes demonstrated increased cellular lysosome content, which was confirmed by elevated LAMP1 expression. The enhanced lysosomal biogenesis after NTP could be due to the observed increase in fluid-phase endocytosis and early endosome formation. These results suggest NTP acts as a stressor, which results in increased endocytosis, lysosome content and autophagy. In fact, NTP rapidly increased autophagosome formation, as judged by increased LC3B-II expression, which co-localized with LAMP1, indicating autophagolysosome formation. Autophagic-induction by NTP was confirmed using electron microscopy. In summary, NTP acts as a cellular stressor to rapidly induce fluid-phase endocytosis, lysosome biogenesis and autophagy.

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  226. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats. Reviewed International journal

    Okazaki Y, Okada S, Toyokuni S

    Journal of Clinical Biochemistry and Nutrition   Vol. 61 ( 1 ) page: 18-24   2017.7

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  227. Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics. Reviewed

    Yoshimaru T, Aihara K, Komatsu M, Matsushita Y, Okazaki Y, Toyokuni S, Honda J, Sasa M, Miyoshi Y, Otaka A, Katagiri T.

    Scientific Reports   Vol. 7 ( 1 ) page: 1821   2017.5

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  228. Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics International journal

    Tetsuro Yoshimaru, Keisuke Aihara, Masato Komatsu, Yosuke Matsushita, Yasumasa Okazaki, Shinya Toyokuni, Junko Honda, Mitsunori Sasa, Yasuo Miyoshi, Akira Otaka, Toyomasa Katagiri

    SCIENTIFIC REPORTS   Vol. 7 ( 1 ) page: 1821   2017.5

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    Estradiol (E2) and the oestrogen receptor-alpha (ER alpha) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ER alpha signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERa activity-regulator synthetic peptide (ERAP: 165-177 amino acids), derived from a-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable a-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.

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  229. Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells. Reviewed

    Han YP, Enomoto A, Shiraki Y, Wang SQ, Wang X, Toyokuni S, Asai N, Ushida K, Ara H, Ohka F, Wakabayashi T, Ma J, Natsume A, Takahashi M.

    Nero Oncology   Vol. 19 ( 5 ) page: 636-647   2017.5

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    DOI: doi: 10.1093/neuonc/now237.

  230. Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells International journal

    Yi-Peng Han, Atsushi Enomoto, Yukihiro Shiraki, Shen-Qi Wang, Xiaoze Wang, Shinya Toyokuni, Naoya Asai, Kaori Ushida, Hosne Ara, Fumiharu Ohka, Toshihiko Wakabayashi, Jie Ma, Atsushi Natsume, Masahide Takahashi

    NEURO-ONCOLOGY   Vol. 19 ( 5 ) page: 636 - 647   2017.5

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    The significance of mammalian target of rapamycin complex 1 (mTORC1) activity in the maintenance of cancer stem cells (CSCs) remains controversial. Previous findings showed that mTORC1 activation depleted the population of leukemia stem cells in leukemia, while maintaining the stemness in pancreatic CSCs. The purpose of this study was to examine the currently unknown role and significance of mTORC1 activity in brain tumor stem cells (BTSCs).
    Basal mTORC1 activity and its kinetics were investigated in BTSC clones isolated from patients with glioblastoma and their differentiated progenies (DIFFs). The effects of nutrient deprivation and the mTORC1 inhibitors on cell proliferation were compared between the BTSCs and DIFFs. Tissue sections from patients with brain gliomas were examined for expression of BTSC markers and mTORC1 activity by immunohistochemistry.
    BTSCs presented lower basal mTORC1 activity under each culture condition tested and a more rapid decline of mTORC1 activity after nutrient deprivation than observed in DIFFs. The self-renewal capacity of BTSCs was unaffected by mTORC1 inhibition, whereas it effectively suppressed DIFF proliferation. In agreement, immunohistochemical staining of glioma tissues revealed low mTORC1 activity in tumor cells positive for BTSC markers. In in vitro culture, BTSCs exhibited resistance to the antitumor agent temozolomide.
    Our findings indicated the importance of low mTORC1 activity in maintaining the undifferentiated state of BTSCs, implicating the relevance of manipulating mTORC1 activity when developing future strategies that target BTSCs.

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  231. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status International journal

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Yoshihiro Nishida, Hiroshi Urakawa, Yoshinao Oda, Shinya Toyokuni

    Human Pathology   Vol. 63   page: 63 - 69   2017.5

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    Extraskeletal osteosarcoma (ESOS) is an uncommon malignant neoplasm. Most ESOSs are high grade, although some low-grade cases have been reported. A few cases of ESOS with MDM2 amplification have also been reported, suggesting some similarity to skeletal low-grade osteosarcoma such as parosteal osteosarcoma, where MDM2 is often amplified. However, the frequency of low-grade cases and cases with MDM2 amplification among ESOSs remains unknown, and their relationship is unclear. To clarify this, we examined 18 primary ESOS cases clinically, pathologically, and genetically, focusing on their MDM2 amplification status. Our cases comprised 10 men and 8 women whose mean age was 58.6 years
    the most common site of the lesion was the thigh and buttock. There were one histologically low-grade case evaluated by biopsy specimen with an aggressive course and 2 relatively low-grade cases whose lesions were of low grade for the most part. MDM2 amplification status was revealed by fluorescence in situ hybridization in all 18 cases
    2 patients—histologically intermediate- and high-grade cases—were found to have MDM2 amplification. In conclusion, this study indicates that histologically low-grade and relatively low-grade cases of ESOS are not always associated with MDM2 amplification. The ESOS case with MDM2 amplification could be high grade, although MDM2-amplified dedifferentiated liposarcoma with osteogenic differentiation should be ruled out in making the diagnosis.

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  232. In response to Sharing different perspectives to understand asbestos-induced carcinogenesis: Acomment to Jiang et al. (2016) by Alessandro Francesco Gualtieri (2017) International journal

    Shinya Toyokuni, Li Jiang

    CANCER SCIENCE   Vol. 108 ( 5 ) page: 1089 - 1090   2017.5

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  233. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. International journal

    Shan Hwu Chew, Yasumasa Okazaki, Shinya Akatsuka, Shenqi Wang, Li Jiang, Yuuki Ohara, Fumiya Ito, Hideyuki Saya, Yoshitaka Sekido, Shinya Toyokuni

    Free radical biology & medicine   Vol. 106   page: 91 - 99   2017.5

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    CD44 exists as a standard (CD44s) isoform and different variant isoforms (CD44v) due to alternative splicing. While the complex nature of these different isoforms has not been fully elucidated, CD44v expression has been shown to exert oncogenic effects by promoting tumor progression, metastasis and resistance of tumor cells to chemotherapy. One of the CD44v isoforms, CD44v8-10, was recently shown to protect cancer cells from oxidative stress by increasing the synthesis of glutathione (GSH). However, data regarding CD44 isoform expression in malignant mesothelioma (MM) are still lacking. Here, we show that most of the MM cell lines express both the CD44s and CD44v isoforms, in contrast to non-tumorigenic mesothelial cells, which express only CD44s. Moreover, we show here that these MM cell lines are positive for CD44 variable axon 9, with CD44v8-10 among the variant isoforms expressed. The expression of CD44 variable axon 9 was found to be statistically associated with NF2 inactivation, a common occurrence in MM. Knockdown of CD44 reduced the protein level of xCT, a cystine transporter, and increased oxidative stress. However, an increase in GSH was also observed and was associated with enhanced chemoresistance in CD44-knockdown cells. Increased GSH was mediated by the Nrf2/AP-1-induced upregulation of GCLC, a subunit of the enzyme catalyzing GSH synthesis. Our results thus suggest that the response to CD44 depletion is cell type-dependent and, in cases such as MM cells, compensatory pathway(s) might be activated rheostatically to account for the loss of CD44 and counteract enhanced oxidative stress.

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  234. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor. Reviewed

    Shikata Y, Yoshimaru T, Komatsu M, Katoh H, Sato R, Kanagaki S, Okazaki Y, Toyokuni S, Tashiro E, Ishikawa S, Katagiri T, Imoto M.

    Cancer Science   Vol. 108 ( 4 ) page: 785-794   2017.4

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    DOI: doi: 10.1111/cas.13175.

  235. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. Reviewed

    Toyokuni S, Ito F, Yamashita K, Okazaki Y, Akatsuka S.

    Free Radical Biology & Medicine   Vol. 108   page: 610-626   2017.4

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    DOI: doi: 10.1016/j.freeradbiomed.2017.04.024.

  236. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. Reviewed International journal

    Toyokuni S, Ito F, Yamashita K, Okazaki Y, Akatsuka S

    Free Radical Biology & Medicine   Vol. 108   page: 610-626   2017.4

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  237. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor. International journal

    Yuki Shikata, Tetsuro Yoshimaru, Masato Komatsu, Hiroto Katoh, Reiko Sato, Shuhei Kanagaki, Yasumasa Okazaki, Shinya Toyokuni, Etsu Tashiro, Shumpei Ishikawa, Toyomasa Katagiri, Masaya Imoto

    Cancer science   Vol. 108 ( 4 ) page: 785 - 794   2017.4

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    Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.

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  238. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. Reviewed

    Yamashita K, Kohashi K, Yamada Y, Nishida Y, Urakawa H, Oda Y, Toyokuni S.

    Human Pathology   Vol. 63   page: 63-69   2017.2

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  239. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. Reviewed International journal

    Yamashita K, Kohashi K, Yamada Y, Nishida Y, Urakawa H, Oda Y, Toyokuni S

    Human Pathology   Vol. 63   page: 63-69   2017.2

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  240. Cancer and trace metal element

      Vol. 61 ( 2 ) page: 168 - 173   2017.2

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  241. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. Reviewed

    Chew SH, Okazaki Y, Akatsuka S, Wang S, Jiang L, Ohara Y, Ito F, Saya H, Sekido Y, Toyokuni S.

    Free Radical Biology & Medicine   Vol. 106   page: 91-99   2017.2

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    DOI: doi: 10.1016/j.freeradbiomed.2017.02.011.

  242. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. Reviewed International journal

    Chew SH, Okazaki Y, Akatsuka S, Wang S, Jiang L, Ohara Y, Ito F, Saya H, Sekido Y, Toyokuni S

    Free Radical Biology & Medicine   Vol. 106   page: 91-99   2017.2

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  243. Clinicopathological and Molecular Features of Dedifferentiated Liposarcoma with Ossification: A Comparative Study with Dedifferentiated Liposarcoma without Ossification and Extraskeletal Osteosarcoma

    Yamashita Kyoko, Kohashi Kenichi, Yamada Yuichi, Oda Yoshinao, Toyokuni Shinya

    MODERN PATHOLOGY   Vol. 30   page: 27A-27A   2017.2

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  244. Clinicopathological and Molecular Features of Dedifferentiated Liposarcoma with Ossification: A Comparative Study with Dedifferentiated Liposarcoma without Ossification and Extraskeletal Osteosarcoma

    Yamashita Kyoko, Kohashi Kenichi, Yamada Yuichi, Oda Yoshinao, Toyokuni Shinya

    LABORATORY INVESTIGATION   Vol. 97   page: 27A - 27A   2017.2

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  245. Clinicopathological and Molecular Features of Dedifferentiated Liposarcoma with Ossification: A Comparative Study with Dedifferentiated Liposarcoma without Ossification and Extraskeletal Osteosarcoma International journal

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Yoshinao Oda, Shinya Toyokuni

    LABORATORY INVESTIGATION   Vol. 97   page: 27A - 27A   2017.2

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  246. Clinicopathological and Molecular Features of Dedifferentiated Liposarcoma with Ossification: A Comparative Study with Dedifferentiated Liposarcoma without Ossification and Extraskeletal Osteosarcoma International journal

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Yoshinao Oda, Shinya Toyokuni

    MODERN PATHOLOGY   Vol. 30   page: 27A - 27A   2017.2

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  247. Future perspective of strategic non-thermal plasma therapy for cancer treatment.

    Hiroaki Kajiyama, Fumi Utsumi, Kae Nakamura, Hiromasa Tanaka, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa

    Journal of clinical biochemistry and nutrition   Vol. 60 ( 1 ) page: 33 - 38   2017.1

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    The therapeutic effects of non-thermal plasma are expected in the medical fields, including hemostasis, vascularization, prevention of organ adhesion, and cell proliferation. Cancer is an internal enemy arising from normal tissue in the body. The prognosis of metastatic and recurrent cancers is still poor despite advances in medicine. To apply non-thermal plasma in cancer treatment is now on going. The mechanism of the proliferation-inhibitory effect of plasma is reactive nitrogen oxide species/reactive oxygen species production in cells. There are a number of problems to be overcome, such as existence of intrinsic reactive oxygen species/reactive nitrogen species scavengers and the shallow infiltration of plasma on tumor surface. The current reviews makes referral to the study results of plasma therapy clarified so far, the possibility of its application in the future.

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  248. Primary cause of carcinogenesis: what toxicology can contribute

    TOYOKUNI Shinya

    Annual Meeting of the Japanese Society of Toxicology   Vol. 44 ( 0 ) page: S11 - S11   2017

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  249. がんと微量金属元素 (Cancer and trace metal element)

    伊藤 文哉, 豊國 伸哉

    臨床検査Journal of clinical laboratory medicine   Vol. 61   2017

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  250. Future perspective of strategic non-thermal plasma therapy for cancer treatment. Reviewed

    Kajiyama H, Utsumi F, Nakamura K, Tanaka H, Toyokuni S, Hori M, Kikkawa F.

    Journal of Clinical Biochemistry and Nutrition   Vol. 60 ( 1 ) page: 33-38   2016.12

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  251. Future perspective of strategic non-thermal plasma therapy for cancer treatment. Reviewed International journal

    Kajiyama H, Utsumi F, Nakamura K, Tanaka H, Toyokuni S, Hori M, Kikkawa F

    Journal of Clinical Biochemistry and Nutrition   Vol. 60 ( 1 ) page: 33-38   2016.12

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  252. Editorial: The cutting edge of zinc biology. International journal

    Taiho Kambe, Toshiyuki Fukada, Shinya Toyokuni

    Archives of biochemistry and biophysics   Vol. 611   page: 1 - 2   2016.12

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  253. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. International journal

    Cahill MA, Jazayeri JA, Catalano SM, Toyokuni S, Kovacevic Z, Richardson DR

    Biochimica et biophysica acta   Vol. 1866 ( 2 ) page: 339 - 349   2016.12

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  254. Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. International journal

    Takafumi Ushida, Tomomi Kotani, Hiroyuki Tsuda, Kenji Imai, Tomoko Nakano, Shima Hirako, Yumiko Ito, Hua Li, Yukio Mano, Jingwen Wang, Rika Miki, Eiko Yamamoto, Akira Iwase, Yasuko K Bando, Masaaki Hirayama, Kinji Ohno, Shinya Toyokuni, Fumitaka Kikkawa

    Free radical biology & medicine   Vol. 101 ( 16 ) page: 524 - 533   2016.12

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    Oxidative stress plays an important role in the pathogenesis of preeclampsia. Recently, molecular hydrogen (H2) has been shown to have therapeutic potential in various oxidative stress-related diseases. The aim of this study is to investigate the effect of H2 on preeclampsia. We used the reduced utero-placental perfusion pressure (RUPP) rat model, which has been widely used as a model of preeclampsia. H2 water (HW) was administered orally ad libitum in RUPP rats from gestational day (GD) 12-19, starting 2 days before RUPP procedure. On GD19, mean arterial pressure (MAP) was measured, and samples were collected. Maternal administration of HW significantly decreased MAP, and increased fetal and placental weight in RUPP rats. The increased levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and diacron reactive oxygen metabolites as a biomarker of reactive oxygen species in maternal blood were decreased by HW administration. However, vascular endothelial growth factor level in maternal blood was increased by HW administration. Proteinuria, and histological findings in kidney were improved by HW administration. In addition, the effects of H2 on placental villi were examined by using a trophoblast cell line (BeWo) and villous explants from the placental tissue of women with or without preeclampsia. H2 significantly attenuated hydrogen peroxide-induced sFlt-1 expression, but could not reduce the expression induced by hypoxia in BeWo cells. H2 significantly attenuated sFlt-1 expression in villous explants from women with preeclampsia, but not affected them from normotensive pregnancy. The prophylactic administration of H2 attenuated placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress. These results support the theory that H2 has a potential benefit in the prevention of preeclampsia.

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  255. Preclinical Use of CTGF-Specific Monoclonal Antibody for the Treatment of Malignant Mesothelioma

    Ohara, Y; Wang, SQ; Jiang, L; Toyokuni, S

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 100   page: S127 - S127   2016.11

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  256. Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma. International journal

    Shenqi Wang, Li Jiang, Yipeng Han, Shan Hwu Chew, Yuuki Ohara, Shinya Akatsuka, Liang Weng, Koji Kawaguchi, Takayuki Fukui, Yoshitaka Sekido, Kohei Yokoi, Shinya Toyokuni

    Oncotarget   Vol. 7 ( 43 ) page: 69565 - 69578   2016.10

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    Malignant mesothelioma (MM) is a rare neoplasm associated with asbestos exposure. The prognosis of MM is poor because it is aggressive and highly resistant to chemotherapy. Using a rat model of asbestos-induced MM, we found elevated urokinase-type plasminogen activator receptor (uPAR
    Plaur) expression in rat tissues, which was associated with poor prognosis. The proliferation, migration and invasion of MM cells were suppressed by uPAR knockdown and increased by overexpression experiments, irrespective of urokinase-type plasminogen activator (uPA
    Plau) levels. More importantly, we found that uPAR expression is associated with sensitivity to cisplatin in MM through the PI3K/AKT pathway, which was demonstrated with specific inhibitors, LY294002 and Akti-1/2. uPAR knockdown significantly increased sensitivity to cisplatin whereas its overexpression significantly decreased cisplatin sensitivity. Furthermore, sera and tissues from MM patients showed significantly high uPAR levels, which suggested the pathogenic role of uPAR in the tumor biology of human MM. In conclusion, our findings indicate that uPAR levels are associated with malignant characteristics and cisplatin sensitivity of MM. In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM.

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  257. Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. Reviewed

    Ushida T, Kotani T, Tsuda H, Imai K, Nakano T, Hirako S, Ito Y, Li H, Mano Y, Wang J, Miki R, Yamamoto E, Iwase A, Bando YK, Hirayama M, Ohno K, Toyokuni S, Kikkawa F.

    Free Radic Biol Med.   Vol. pii: S0891-5849 ( 16 ) page: 30978-9.   2016.10

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  258. Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. Reviewed International journal

    Ushida T, Kotani T, Tsuda H, Imai K, Nakano T, Hirako S, Ito Y, Li H, Mano Y, Wang J, Miki R, Yamamoto E, Iwase A, Bando YK, Hirayama M, Ohno K, Toyokuni S, Kikkawa F

    Free Radic Biol Med.   Vol. pii: S0891-5849 ( 16 ) page: 30978-9.   2016.10

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  259. Non-thermal plasma prevents progression of endometriosis in mice. Reviewed

    Ishida C, Mori M, Nakamura K, Tanaka H, Mizuno M, Hori M, Iwase A, Kikkawa F, Toyokuni S.

    Free Radical Research   Vol. 50 ( 10 ) page: 1131-1139   2016.10

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  260. Non-thermal plasma prevents progression of endometriosis in mice International journal

    Chiharu Ishida, Masahiko Mori, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Akira Iwase, Fumitaka Kikkawa, Shinya Toyokuni

    FREE RADICAL RESEARCH   Vol. 50 ( 10 ) page: 1131 - 1139   2016.10

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    Endometriosis is observed in approximate to 10% of reproductive age women. Ovarian endometriosis not only causes dysmenorrhea but also causes infertility and a high risk of adenocarcinoma. Due to its scattered nature, complete surgical resection is difficult. Endometriosis consists of glandular and stromal cells. Previously, we showed that endometrial stromal cells (ESCs) play a role in the protection against pathologic events caused by monthly repeated hemorrhage. Here, we undertook a preclinical study of non-thermal plasma (NTP) as a surgical treatment of endometriosis. Epithelial cells were most sensitive to NTP-activated medium in vitro, whereas ectopic ESCs were most resistant. We then transplanted excised uteruses into BALB/c mice from donors of the same strain with estradiol supplementation. Four weeks after the transplantation, we exposed NTP to each endometriotic lesion after laparotomy. Immunohistochemical analysis revealed that immediately after NTP exposure, epithelial cells exhibited significantly higher levels of nuclear immunostaining for 8-hydroxy-2-deoxyguanosine than did stromal cells. Four weeks after NTP exposure, the total surface area consisting of endometriotic cysts was significantly smaller with less epithelial proliferative activity than the helium-exposed control, whereas the number of endometriotic lesions had not changed. Therefore, NTP exposure may be useful to prevent the progression and recurrence of endometriosis.

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  261. Special issue for the 7th Biennial Meeting of Society for Free Radical Research-Asia (SFRR-Asia 2015 Thailand). International journal

    Malyn Ungsurungsie, Young-Joon Surh, Shinya Toyokuni, Michael Jonathan Davies

    Free radical research   Vol. 50 ( 10 ) page: 1045 - 1046   2016.10

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  262. Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. International journal

    Cai Zong, C Edwin Garner, Chinyen Huang, Xiao Zhang, Lingyi Zhang, Jie Chang, Shinya Toyokuni, Hidenori Ito, Masashi Kato, Toshihiro Sakurai, Sahoko Ichihara, Gaku Ichihara

    Toxicology letters   Vol. 258   page: 249 - 258   2016.9

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    Neurotoxicity of 1-bromopropane (1-BP) has been reported in both human cases and animal studies. To date, neurotoxicity of 1-BP has been induced in rats but not in mice due to the lethal hepatotoxicity of 1-BP. Oxidization by cytochromes P450 and conjugation with glutathione (GSH) are two critical metabolism pathways of 1-BP and play important roles in toxicity of 1-BP. The aim of the present study was to establish a murine model of 1-BP neurotoxicity, by reducing the hepatotoxicity of 1-BP with 1-aminobenzotriazole (1-ABT); a commonly used nonspecific P450s inhibitor. The results showed that subcutaneous or intraperitoneal injection of 1-ABT at 50mg/kg body weight BID (100mg/kg BW/day) for 3days, inhibited about 92-96% of hepatic microsomal CYP2E1 activity, but only inhibited about 62-64% of CYP2E1 activity in brain microsomes. Mice treated with 1-ABT survived even after exposure to 1200ppm 1-BP for 4 weeks and histopathological studies showed that treatment with 1-ABT protected mice from 1-BP-induced hepatic necrosis, hepatocyte degeneration, and hemorrhage. After 4-week exposure to 1-BP, the brain weight of 1-ABT(+)/1200ppm 1-BP group was decreased significantly. In 1-ABT-treated groups, expression of hippocampal Ran protein and cerebral cortical GRP78 was dose-dependently increased by exposure to 1-BP. We conclude that the control of hepatic P450 activity allows the observation of effects of 1-BP on the murine brain at a higher concentration by reduction of hepatotoxicity. The study suggests that further experiments with liver-specific control of P450 activity using gene technology might provide better murine models for 1-bromopropane-induced neurotoxicity.

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  263. Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. Reviewed International journal

    Shima Hirako, Hiroyuki Tsuda, Tomomi Kotani, Seiji Sumigama, Yukio Mano, Tomoko Nakano, Kenji Imai, Hua Li, Shinya Toyokuni, Fumitaka Kikkawa

    Phytotherapy research : PTR   Vol. 30 ( 9 ) page: 1474 - 1480   2016.9

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    Congenital diaphragmatic hernia (CDH) can induce lung hypoplasia and pulmonary hypertension and is associated with high mortality. The purpose of this study is to examine the efficacy and safety of antenatal Saireito (TJ-114), a traditional Japanese herbal medicine, in a rat CDH model. Sprague-Dawley rats were exposed to an herbicide (nitrofen, 100 mg) on embryonic day 9 (E9) to induce CDH, and antenatal Saireito (2000 mg/kg/day) was orally administered from E10 to E20. On E21, fetuses were delivered. Antenatal Saireito significantly decreased the incidence of CDH (p &lt; 0.01), increased lung volume (p &lt; 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p &lt; 0.05, and PCO2; p &lt; 0.01). In addition, antenatal Saireito significantly decreased endothelin-1 and endothelin receptor A expression in the pulmonary arteries. Taken together, our results demonstrated that antenatal Saireito can improve fetal pulmonary hypoplasia and pulmonary vascular remodeling and, as a result, can improve respiratory function in a rat CDH model. Copyright (C) 2016 John Wiley & Sons, Ltd.

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  264. Low-temperature plasma in biology and medicine Reviewed International journal

    Hori M.

    Archives of Biochemistry and Biophysics   Vol. 605   page: 1 - 2   2016.9

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    DOI: 10.1016/j.abb.2016.06.014

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  265. Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. Reviewed

    Hirako S, Tsuda H, Kotani T, Sumigama S, Mano Y, Nakano T, Imai K, Li H, Toyokuni S, Kikkawa F.

    Phytother Res.   Vol. 30 ( 9 ) page: 1474-80   2016.9

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    DOI: doi: 10.1002/ptr.5645.

  266. Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma. Reviewed

    Wang S, Jiang L, Han Y, Hwu Chew S, Ohara Y, Akatsuka S, Weng L, Kawaguchi K, Fukui T, Sekido Y, Yokoi K, Toyokuni S.

    Oncotarget. 2016 Sep 2.     page: 11829   2016.9

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    DOI: doi: 10.18632/oncotarget.11829.

  267. Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. Reviewed

    Zong C, Garner CE, Huang C, Zhang X, Zhang L, Chang J, Toyokuni S, Ito H, Kato M, Sakurai T, Ichihara S, Ichihara G.

    Toxicol Lett.   Vol. 258   page: 249-58   2016.9

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    DOI: doi: 10.1016/j.toxlet.2016.07.006.

  268. Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells. Reviewed

    Shi L, Wang Y, Ito F, Okazaki Y, Tanaka H, Mizuno M, Hori M, Richardson DR, Toyokuni S.

    Arch Biochem Biophys.   Vol. 605   page: 106-16   2016.9

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    DOI: doi: 10.1016/j.abb.2016.05.016.

  269. Molecular hydrogen suppresses activated Wnt/beta-catenin signaling Reviewed International journal

    Yingni Lin, Bisei Ohkawara, Mikako Ito, Nobuaki Misawa, Kentaro Miyamoto, Yasuhiko Takegami, Akio Masuda, Shinya Toyokuni, Kinji Ohno

    SCIENTIFIC REPORTS   Vol. 6 ( 6 ) page: 31986   2016.8

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    Molecular hydrogen (H-2) is effective for many diseases. However, molecular bases of H-2 have not been fully elucidated. Cumulative evidence indicates that H-2 acts as a gaseous signal modulator. We found that H-2 suppresses activated Wnt/beta-catenin signaling by promoting phosphorylation and degradation of beta-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of beta-catenin abolished the suppressive effect of H-2. H-2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H-2 has no direct effect on GSK3 itself. Knockdown of adenomatous polyposis coli (APC) or Axin1, which form the beta-catenin degradation complex, minimized the suppressive effect of H2 on beta-catenin accumulation. Accordingly, the effect of H-2 requires CK1/GSK3-phosphorylation sites of beta-catenin, as well as the beta-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H-2 reduces the activation of Wnt/beta-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H-2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating beta-catenin accumulation. We first demonstrate that H-2 suppresses abnormally activated Wnt/beta-catenin signaling, which accounts for the protective roles of H-2 in a fraction of diseases.

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  270. Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. International journal

    Fumiya Ito, Takahiro Nishiyama, Lei Shi, Masahiko Mori, Tasuku Hirayama, Hideko Nagasawa, Hiroyuki Yasui, Shinya Toyokuni

    Biochemical and biophysical research communications   Vol. 476 ( 4 ) page: 600 - 606   2016.8

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    Iron is an essential nutrient for every type of life on earth. However, excess iron is cytotoxic and can lead to an increased cancer risk in humans. Catalytic ferrous iron [Fe(II)] is an initiator of the Fenton reaction, which causes oxidative stress by generating hydroxyl radicals. Recently, it became possible to localize catalytic Fe(II) in situ with a turn-on fluorescent probe, RhoNox-1. Here, we screened each organ/cell of rats to globally evaluate the distribution of catalytic Fe(II) and found that eosinophils showed the highest abundance. In various cells, lysosomes were the major organelle, sharing 40-80% of RhoNox-1 fluorescence. We then used an ovalbumin-induced allergic peritonitis model to study the dynamics of catalytic Fe(II). Peritoneal lavage revealed that the total iron contents per cell were significantly decreased, whereas an increase in the number of inflammatory cells (macrophages, neutrophils, eosinophils and lymphocytes) resulted in an increased total iron content of the peritoneal inflammatory cells. Notably, macrophages, eosinophils and neutrophils exhibited significantly increased catalytic Fe(II) with increased DMT1 expression and decreased ferritin expression, though catalytic Fe(II) was significantly decreased in the peritoneal lavage fluid. In conclusion, catalytic Fe(II) in situ more directly reflects cellular activity and the accompanying pathology than total iron does. (C) 2016 Elsevier Inc. All rights reserved.

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  271. Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. Reviewed

    Ito F, Nishiyama T, Shi L, Mori M, Hirayama T, Nagasawa H, Yasui H, Toyokuni S.

    Biochem Biophys Res Commun.   Vol. 476 ( 4 ) page: 600-6   2016.8

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    DOI: doi: 10.1016/j.bbrc.2016.06.003.

  272. Molecular hydrogen suppresses activated Wnt/β-catenin signaling. Reviewed

    Lin Y, Ohkawara B, Ito M, Misawa N, Miyamoto K, Takegami Y, Masuda A, Toyokuni S, Ohno K.

    Sci Rep.   Vol. 25 ( 6 ) page: 31986   2016.8

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    DOI: doi: 10.1038/srep31986.

  273. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. Reviewed

    Cahill MA, Jazayeri JA, Catalano SM, Toyokuni S, Kovacevic Z, Richardson DR.

    Biochim Biophys Acta. 2016 Jul 22.   Vol. pii: S0304-419X ( 16 ) page: 30049-X.   2016.7

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  274. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis Reviewed International journal

    Jiang Li, Chew Shan-Hwu, Nakamura Kosuke, Ohara Yuuki, Akatsuka Shinya, Toyokuni Shinya

    CANCER SCIENCE   Vol. 107 ( 7 ) page: 908 - 915   2016.7

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  275. Possible therapeutic option of aqueous plasma for refractory ovarian cancer Reviewed International journal

    Kajiyama Hiroaki, Utsumi Fumi, Nakamura Kae, Tanaka Hiromasa, Mizuno Masaaki, Toyokuni Shinya, Hori Masaru, Kikkawa Fumitaka

    CLINICAL PLASMA MEDICINE   Vol. 4 ( 1 ) page: 14 - 18   2016.7

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  276. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. Reviewed International journal

    Cahill MA, Jazayeri JA, Catalano SM, Toyokuni S, Kovacevic Z, Richardson DR

    Biochim Biophys Acta. 2016 Jul 22.   Vol. pii: S0304-419X ( 16 ) page: 30049-X.   2016.7

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  277. [Iron function and carcinogenesis].

    Akatsuka S, Toyokuni S

    Nihon rinsho. Japanese journal of clinical medicine   Vol. 74 ( 7 ) page: 1168 - 75   2016.7

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  278. [Iron function and carcinogenesis].

    Akatsuka S, Toyokuni S

    Nihon rinsho. Japanese journal of clinical medicine   Vol. 74 ( 7 ) page: 1168 - 75   2016.7

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  279. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium. Reviewed

      Vol. 35 ( 6 ) page: 3169-77   2016.6

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    DOI: doi: 10.3892/or.2016.4726.

  280. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis. Reviewed

    Jiang L, Chew SH, Nakamura K, Ohara Y, Akatsuka S, Toyokuni S.

    Cancer Sci. 2016 Jul;107(7):908-15.   Vol. 107 ( 7 ) page: 908-15   2016.6

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  281. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis. Reviewed International journal

    Jiang L, Chew SH, Nakamura K, Ohara Y, Akatsuka S, Toyokuni S

    Cancer Sci. 2016 Jul;107(7):908-15.   Vol. 107 ( 7 ) page: 908-15   2016.6

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  282. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium International journal

    Fumi Utsumi, Hiroaki Kajiyama, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Shinnya Toyokuni, Masaru Hori, Fumitaka Kikkawa

    ONCOLOGY REPORTS   Vol. 35 ( 6 ) page: 3169 - 77   2016.6

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    Non-thermal atmospheric pressure plasma has been widely studied in recent years in many fields, including cancer treatment. However, its efficiency for inducing apoptosis sometimes varies depending on the cell species and experimental conditions. The aim of this study was to elucidate what causes these differences in responses to plasma treatment. Using four ovarian cancer cell lines, the cell density had a markedly negative impact on the proliferation inhibition rate (PIR) and it was more obvious in OVCAR-3 and NOS2 cells. Furthermore, TOV21G and ES-2 cells were drastically sensitive to plasma-activated medium (PAM) compared with the other two cell lines. We demonstrated that the proportion of reactive oxygen species and cell number had a marked impact on the effect of PAM against ovarian cancer cells. Additionally it was suggested that the morphological features of cells were also closely related to the sensitivity of cancer cells to the plasma treatment.

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  283. The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy Reviewed International journal

    Toyokuni S.

    Pathology International   Vol. 66 ( 5 ) page: 245 - 259   2016.5

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    DOI: 10.1111/pin.12396

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  284. The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis-resistance to non-thermal plasma therapy. Invited Reviewed International journal

    Toyokuni S

    Pathol Int.   Vol. 66 ( 5 ) page: 245-259   2016.5

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  285. Oxidative stress as an iceberg in carcinogenesis and cancer biology Reviewed International journal

    Toyokuni Shinya

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 595   page: 46 - 49   2016.4

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  286. Oxidative stress as an iceberg in carcinogenesis and cancer biology. Reviewed

    Toyokuni S.

    Arch Biochem Biophys. 2016 Apr 1;595:46-9.   Vol. 595   page: 46-9   2016.4

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  287. Oxidative stress as an iceberg in carcinogenesis and cancer biology. Reviewed International journal

    Toyokuni S

    Arch Biochem Biophys. 2016 Apr 1;595:46-9.   Vol. 595   page: 46-9   2016.4

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  288. Tribute issue: Helmut Sies and oxidative stress: Venit, vidit, vicit Reviewed International journal

    Forman H.

    Archives of Biochemistry and Biophysics   Vol. 595   2016.4

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  289. Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics.

    Kalinowski DS, Stefani C, Toyokuni S, Ganz T, Anderson GJ, Subramaniam NV, Trinder D, Olynyk JK, Chua A, Jansson PJ, Sahni S, Lane DJ, Merlot AM, Kovacevic Z, Huang ML, Lee CS, Richardson DR.

    Biochim Biophys Acta.   Vol. 1863 ( 4 ) page: 727-748   2016.4

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  290. Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics. International journal

    Danuta S Kalinowski, Christian Stefani, Shinya Toyokuni, Tomas Ganz, Gregory J Anderson, Nathan V Subramaniam, Debbie Trinder, John K Olynyk, Anita Chua, Patric J Jansson, Sumit Sahni, Darius J R Lane, Angelica M Merlot, Zaklina Kovacevic, Michael L H Huang, C Soon Lee, Des R Richardson

    Biochimica et biophysica acta   Vol. 1863 ( 4 ) page: 727 - 48   2016.4

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    Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics. (C) 2016 Elsevier B.V. All rights reserved.

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  291. Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. Reviewed

    Wang Y, Okazaki Y, Shi L, Kohda H, Tanaka M, Taki K, Nishioka T, Hirayama T, Nagasawa H, Yamashita Y, Toyokuni S.

    Cancer Sci.   Vol. 107 ( 3 ) page: 250-257   2016.3

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    DOI: doi: 10.1111/cas.12865.

  292. Pain-reducing anesthesia prevents oxidative stress in human term placenta. Reviewed

    Tsuzuki Y, Yamashita Y, Hattori Y, Hua Li G, Akatsuka S, Kotani T, Kikkawa F, Naiki-Ito A, Takahashi S, Nishiwaki K, Toyokuni S.

    J Clin Biochem Nutr.   Vol. 58 ( 2 ) page: 156-60   2016.3

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  293. Pain-reducing anesthesia prevents oxidative stress in human term placenta International journal

    Tsuzuki, Y., Yamashita, Y., Hattori, Y., Li, G.H., Akatsuka, S., Kotani, T., Kikkawa, F., Naiki-Ito, A., Takahashi, S., Nishiwaki, K., Toyokuni, S.

    Journal of Clinical Biochemistry and Nutrition   Vol. 58 ( 2 ) page: 156 - 60   2016.3

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    Anesthesia is sometimes used for the reduction of maternal pain in normal human term labor, but whether the drugs affect oxidative stress remains unclear. The placenta serves as an interface between the maternal and fetal vasculature. In this study, we immunohistochemically analyzed two markers for oxidative stress, namely 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal–modified proteins (HNE), using placentas from 21 cases of normal tansvaginal delivery (V group), 20 Caesarean sections (C group), and 17 normal transvaginal deliveries with epidural anesthesia (E group). 8-OHdG staining in the nuclei of trophoblasts lining the chorionic villi was significantly stronger in the V group either compared with the C or E group (<i>p</i><0.001), without significant differences in the C and E groups (<i>p</i> = 0.792). Moderate to intense staining by HNE of the intravascular serum of chorionic villi vasculature was frequently observed in the placentas from the V group, but less frequently of those in either C or E groups (<i>p</i><0.001), nor the <i>p</i> value comparing the C and E groups was significant (<i>p</i> = 0.128) for HNE staining. Our results suggest that although the role of oxidative stress and its influences on fetal state in the placenta in labor remains unclear, it seems to be lessened by epidural anesthesia.

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  294. Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. Reviewed International journal

    Yue Wang, Yasumasa Okazaki, Lei Shi, Hiro Kohda, Minoru Tanaka, Kentaro Taki, Tomoki Nishioka, Tasuku Hirayama, Hideko Nagasawa, Yoriko Yamashita, Shinya Toyokuni

    Cancer science   Vol. 107 ( 3 ) page: 250 - 7   2016.3

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    Multi-wall carbon nanotubes (MWCNT) are a form of flexible fibrous nanomaterial with high electrical and thermal conductivity. However, 50-nm MWCNT in diameter causes malignant mesothelioma (MM) in rodents and, thus, the International Agency of Research on Cancer has designated them as a possible human carcinogen. Little is known about the molecular mechanism through which MWCNT causes MM. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100; 150 nm, NT150; and 15 nm/tangled, NTtngl) using mass spectrometry. We identified &gt;400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNT to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMC). Cytotoxicity to RPMC was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMC, with an increase in cellular catalytic ferrous iron and DNA damage also observed. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor 1. Modifications of NT50 surface may decrease this human risk.

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  295. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. Reviewed

    Imai K, Kotani T, Tsuda H, Mano Y, Nakano T, Ushida T, Li H, Miki R, Sumigama S, Iwase A, Hirakawa A, Ohno K, Toyokuni S, Takeuchi H, Mizuno T, Suzumura A, Kikkawa F.

    Free Radic Biol Med.   Vol. 91   page: 154-163   2016.2

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    DOI: doi: 10.1016/j.freeradbiomed.2015.12.015.

  296. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia International journal

    Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Yukio Mano, Tomoko Nakano, Takafumi Ushida, Hua Li, Rika Miki, Seiji Sumigama, Akira Iwase, Akihiro Hirakawa, Kinji Ohno, Shinya Toyokuni, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura, Fumitaka Kikkawa

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 91   page: 154 - 63   2016.2

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    Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H-2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H-2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H-2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H-2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H-2, involved in the process of activating microglia. These results suggested that H-2 holds promise for the prevention of inflammation related to perinatal brain injury. (C) 2015 Elsevier Inc. All rights reserved.

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  297. Plasma with high electron density and plasma-activated medium for cancer treatment Reviewed International journal

    Tanaka Hiromasa, Mizuno Masaaki, Ishikawa Kenji, Kondo Hiroki, Takeda Keigo, Hashizume Hiroshi, Nakamura Kae, Utsumi Fumi, Kajiyama Hiroaki, Kano Hiroyuki, Okazaki Yasumasa, Toyokuni Shinya, Akiyama Shin'ichi, Maruyama Shoichi, Yamada Suguru, Kodera Yasuhiro, Kaneko Hiroki, Terasaki Hiroko, Hara Hirokazu, Adachi Tetsuo, Iida Machiko, Yajima Ichiro, Kato Masashi, Kikkawa Fumitaka, Hori Masaru

    CLINICAL PLASMA MEDICINE   Vol. 3 ( 2 ) page: 72 - 76   2015.12

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  298. Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. Reviewed

    Mori M, Ito F, Shi L, Wang Y, Ishida C, Hattori Y, Niwa M, Hirayama T, Nagasawa H, Iwase A, Kikkawa F, Toyokuni S.

    Redox Biol.   Vol. 6   page: 578-586   2015.12

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    DOI: doi: 10.1016/j.redox.2015.10.001.

  299. Cancer therapy using non-thermal atmospheric pressure plasma with ultra-highelectron density International journal

    H. Tanaka, M. Mizuno, S. Toyokuni, S. Maruyama, Y. Kodera, H. Terasaki, T. Adachi, M. Kato, F. Kikkawa, M. Hori

    Phys Plasmas   Vol. 22 ( 12 ) page: 122004   2015.12

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  300. Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron International journal

    Masahiko Mori, Fumiya Ito, Lei Shi, Yue Wang, Chiharu Ishida, Yuka Hattori, Masato Niwa, Tasuku Hirayama, Hideko Nagasawa, Akira Iwase, Fumitaka Kikkawa, Shinya Toyokuni

    REDOX BIOLOGY   Vol. 6   page: 578 - 586   2015.12

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    Ovarian endometriosis is a recognized risk for infertility and epithelial ovarian cancer, presumably due to iron overload resulting from repeated hemorrhage. To find a clue for early detection and prevention of ovarian endometriosis-associated cancer, it is mandatory to evaluate catalytic (labile) ferrous iron (catalytic Fe(II)) and to study iron manipulation in ovarian endometriotic lesions. By the use of tissues from women of ovarian endometriosis as well as endometrial tissue from women with and without endometriosis, we for the first time performed histological analysis and cellular detection of catalytic Fe(II) with a specific fluorescent probe (HMRhoNox-M), and further evaluated iron transport proteins in the human specimens and in co-culture experiments using immortalized human eutopic/ectopic endometrial stromal cells (ESCs) in the presence or absence of epithelial cells (EpCs). The amounts of catalytic Fe(II) were higher in ectopic endometrial stromal cells (ecESCs) than in normal eutopic endometrial stromal cells (n-euESCs) both in the tissues and in the corresponding immortalized ESCs. ecESCs exhibited higher transferrin receptor 1 expression both in vivo and in vitro and lower ferroportin expression in vivo than n-euESCs, leading to sustained iron uptake. In co-culture experiments of ESCs with iron-loaded EpCs, ecESCs received catalytic ferrous iron from EpCs, but n-euESCs did not. These data suggest that ecESC play a protective role for cancer-target epithelial cells by collecting excess iron, and that these characteristics are retained in the immortalized ecESCs. (C) 2015 The Authors. Published by Elsevier B.V.

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  301. Effects of Plasma-Activated Medium on Cells

    TANAKA Hiromasa, MIZUNO Masaaki, TOYOKUNI Shinya, MARUYAMA Shoichi, KODERA Yasuhiro, ADACHI Tetsuo, TERASAKI Hiroko, KATO Masashi, KIKKAWA Fumitaka, HORI Masaru

      Vol. 91 ( 12 ) page: 776 - 779   2015.12

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  302. Effects of Plasma-Activated Medium on Cells

    TANAKA Hiromasa, MIZUNO Masaaki, TOYOKUNI Shinya, MARUYAMA Shoichi, KODERA Yasuhiro, ADACHI Tetsuo, TERASAKI Hiroko, KATO Masashi, KIKKAWA Fumitaka, HORI Masaru

      Vol. 91 ( 12 ) page: 776 - 779   2015.12

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  303. Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury Reviewed International journal

    Tomoko Nakano, Tomomi Kotani, Yukio Mano, Hiroyuki Tsuda, Kenji Imai, Takafumi Ushida, Hua Li, Rika Miki, Seiji Sumigama, Yoshiaki Sato, Akira Iwase, Akihiro Hirakawa, Masato Asai, Shinya Toyokuni, Fumitaka Kikkawa

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 57 ( 3 ) page: 178 - 182   2015.11

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    Fetal brain injury is often related to prenatal inflammation; however, there is a lack of effective therapy. Recently, molecular hydrogen (H-2), a specific antioxidant to hydroxyl radical and peroxynitrite, has been reported to have anti-inflammatory properties. The aim of this study was to investigate whether maternal H-2 administration could protect the fetal brain against inflammation. Pregnant C3H/HeN mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15.5 and were provided with H2 water for 24 h prior to LPS injection. Pup brain samples were collected on gestational day 16.5, and the levels of apoptosis and oxidative damage were evaluated using immunohistochemistry. Interleukin-6 (IL-6) levels were examined using real-time PCR. The levels of apoptosis and oxidative damage, as well as the levels of IL-6 mRNA, increased significantly when the mother was injected with LPS than that in the control group. However, these levels were significantly reduced when H2 was administered prior to the LPS-injection. Our results suggest that LPS-induced apoptosis, oxidative damage and inflammation in the fetal brain were ameliorated by maternal H2 administration. Antenatal H2 administration might protect the premature brain against maternal inflammation.

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  304. Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury. Reviewed

    Nakano T, Kotani T, Mano Y, Tsuda H, Imai K, Ushida T, Li H, Miki R, Sumigama S, Sato Y, Iwase A, Hirakawa A, Asai M, Toyokuni S, Kikkawa F.

    J Clin Biochem Nutr.   Vol. 57 ( 3 ) page: 178-182   2015.11

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  305. A trial to find appropriate animal models of dichloropropaneinduced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases

    Zhang Lingyi, Zong Cai, Ichihara Sahoko, Naito Hisao, Toyokuni Shinya, Kumagai Shinji, Ichihara Gaku

    JOURNAL OF OCCUPATIONAL HEALTH   Vol. 57 ( 6 ) page: 548 - 554   2015.11

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  306. Hepatic distribution of GST cannot explain the gap between humans and rodents for induction of cholangiocarcioma following exposure to dichloropropane

    L. Zhang, C. Zong, S. Ichihara, H. Naito, S. Toyokuni, S. Kumagai, G. Ichihara

    TOXICOLOGY LETTERS   Vol. 238 ( 2 ) page: S245 - S245   2015.10

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  307. Recent information on the outbreak of cholangiocarcinoma in a printing company

    Occupational Health Review   Vol. 28 ( 2 ) page: 131 - 156   2015.9

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    DOI: 10.34354/ohpfrev.28.2_131

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  308. Malignant mesothelioma as an oxidative stress-induced cancer: An update. International journal

    Shan Hwu Chew, Shinya Toyokuni

    Free radical biology & medicine   Vol. 86   page: 166 - 78   2015.9

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    Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. On fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasomes in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and TGF-beta pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP] as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still similar to 8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by beta-catenin, has been recognized as a hopeful target for therapy, especially in sarcomatoid subtype. Recent research outcomes related to microRNAs and cancer stem cells also offer additional novel targets for the treatment of MM. Iron reduction as chemoprevention of mesothelioma is helpful at least in an animal preclinical study. Integrated approaches to fiber-induced oxidative stress would be necessary to overcome this currently fatal disease. (C) 2015 Elsevier Inc. All rights reserved.

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  309. Receptor role of the annexin A2 in the mesothelial endocytosis of crocidolite fibers Reviewed International journal

    Yamashita Kyoko, Nagai Hirotaka, Toyokuni Shinya

    LABORATORY INVESTIGATION   Vol. 95 ( 7 ) page: 749 - 764   2015.7

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    DOI: 10.1038/labinvest.2015.28

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  310. Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials.

    Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 56 ( 3 ) page: 165 - 165   2015.5

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  311. [Plasma-Activated Solution: Mechanism of Action, Clinical Application, and Industrialization].

    Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Shoichi Maruyama, Yasuhiro Kodera, Fumitaka Kikkawa, Masaru Hori

    Fukuoka igaku zasshi = Hukuoka acta medica   Vol. 106 ( 4 ) page: 71 - 6   2015.4

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  312. 血栓内膜摘除術後に体外循環から離脱できずに死亡した慢性血栓塞栓性肺高血圧症の一剖検例

    山下 享子, 榎本 篤, 大島 英揮, 平敷 安希博, 近藤 隆久, 豊国 伸哉, 中村 栄男

    日本病理学会会誌   Vol. 104 ( 1 ) page: 336 - 336   2015.3

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  313. Possible involvement of iron-induced oxidative insults in neurodegeneration International journal

    Takeshi Asano, Masato Koike, Shin-ichi Sakata, Yukiko Takeda, Tomoko Nakagawa, Taku Hatano, Satoshi Ohashi, Manabu Funayama, Kenji Yoshimi, Masato Asanuma, Shinya Toyokuni, Hideki Mochizuki, Yasuo Uchiyama, Nobutaka Hattori, Kazuhiro Iwai

    NEUROSCIENCE LETTERS   Vol. 588 ( 1 ) page: 29 - 35   2015.2

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    Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  314. MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES Reviewed International journal

    Shinya Toyokuni, Li Jiang, Ryo Kitaura, Hisanori Shinohara

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 77 ( 1-2 ) page: 195 - 202   2015.2

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    Carbon nanotubes (CNTs) are a novel synthetic material comprising only carbon atoms. Based on its rigidity, its electrical and heat conductivity and its applicability to surface manufacturing, this material is expected to have numerous applications in industry. However, due to the material's dimensional similarity to asbestos fibers, its carcinogenicity was hypothesized during the last decade, and indeed, we have shown that multi- wall CNTs (MWCNTs) of 50 nm in diameter are potently carcinogenic to mesothelial cells after intraperitoneal injection. Additionally, we suggested that inflammogenicity after intraperitoneal injection can predict mesothelial carcinogenesis. However, few data have been published on the intraperitoneal inflammogenicity of single-wall CNTs (SWCNTs). Here, we conducted a series of studies on SWCNTs using both intraperitoneal injection into rats and MeT5A mesothelial cells. Intraperitoneal injection of 10 mg SWCNTs caused no remarkable inflammation in the abdominal cavity, and the exposure of MeT5A cells to up to 25 mu g/cm(2) SWCNTs did not alter proliferation. MWCNTs of 50 nm in diameter were used as a positive control, and tangled MWCNTs of 15 nm in diameter were used as a negative control. The results suggest that SWCNTs are a low- risk material with respect to mesothelial carcinogenesis.

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  315. Minimal inflammogenicity of pristine single-wall carbon nanotubes.

    Toyokuni S, Jiang LI, Kitaura R, Shinohara H

    Nagoya journal of medical science   Vol. 77 ( 1-2 ) page: 195 - 202   2015.2

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  316. Minimal inflammogenicity of pristine single-wall carbon nanotubes.

    Toyokuni S, Jiang LI, Kitaura R, Shinohara H

    Nagoya journal of medical science   Vol. 77 ( 1-2 ) page: 195 - 202   2015.2

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  317. MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES

    Toyokuni Shinya, Jiang Li, Kitaura Ryo, Shinohara Hisanori

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 77 ( 1-2 ) page: 195 - 202   2015.2

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  318. Napsin A is a specific marker for ovarian clear cell adenocarcinoma. Reviewed International journal

    Yoriko Yamashita, Tetsuro Nagasaka, Aya Naiki-Ito, Shinya Sato, Shugo Suzuki, Shinya Toyokuni, Masafumi Ito, Satoru Takahashi

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   Vol. 28 ( 1 ) page: 111 - 7   2015.1

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    Ovarian clear cell adenocarcinoma has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Differential diagnosis of clear cell adenocarcinoma from other ovarian surface epithelial tumors is important for its treatment. Napsin A is a known diagnostic marker for lung adenocarcinoma, and expression of napsin A is reported in a certain portion of thyroid and renal carcinomas. However, napsin A expression in ovarian surface epithelial tumors has not previously been examined. In this study, immunohistochemical analysis revealed that in 71 of 86 ovarian clear cell adenocarcinoma patients (83%) and all of the 13 patients with ovarian clear cell adenofibroma, positive napsin A staining was evident. No expression was observed in 30 serous adenocarcinomas, 11 serous adenomas or borderline tumors, 19 endometrioid adenocarcinomas, 22 mucinous adenomas or borderline tumors, 10 mucinous adenocarcinomas, or 3 yolk sac tumors of the ovary. Furthermore, expression of napsin A was not observed in the normal surface epithelium of the ovary, epithelia of the fallopian tubes, squamous epithelium, endocervical epithelium, or the endometrium of the uterus. Therefore, we propose that napsin A is another sensitive and specific marker for distinguishing ovarian clear cell tumors (especially adenocarcinomas) from other ovarian tumors.

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  319. Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials. Invited

    Toyokuni S.

    J Clin Biochem Nutr   Vol. 56   page: 165   2015

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  320. Application of intermittent microwave irradiation to western blot analysis. Reviewed

    Liu YT, Toyokuni S.

    Methods Mol Biol   Vol. 1314   page: 185-190   2015

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  321. Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin. Reviewed

    Toyokuni S, Jiang L, Wang S, Hirao A, Wada T, Soh C, Tohyama K and Kawada A.

    Pathol Int   Vol. 65   page: 415-419   2015

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  322. Malignant mesothelioma as an oxidative stress-induced cancer: An update. Reviewed

    Chew SH and Toyokuni S.

    Free Radic Biol Med   Vol. 86   page: 166-178   2015

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  323. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury. Reviewed

    Hattori Y, Kotani T, Tsuda H, Mano Y, Rei T, Li H, Hirako S, Ushida T, Imai K, Nakano T, Sato Y, Miki R, Sumigama S, Iwase A, Toyokuni S and Kikkawa F.

    Free Radic Res   Vol. 49   page: 1026-1037   2015

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  324. Possible involvement of iron-induced oxidative insults in neurodegeneration. Reviewed

    Asano T, Koike M, Sakata S, Takeda Y, Nakagawa T, Hatano T, Ohshi S, Funayama M, Yoshimi K, Sanuma M, Toyokuni S, Mochizuki H, Uchiyama Y, Hattori N and Iwai K.

    Neurosci Lett   Vol. 588   page: 29-35   2015

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  325. Receptor role of annexin A2 in the mesothelial endocytosis of crocidolite fibers. Reviewed

    Yamashita K, Nagai H and Toyokuni S.

    Lab Invest   Vol. 95   page: 749-764   2015

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  326. Minimal inflammogenicity of pristine single-wall carbon nanotubes. Reviewed

    Toyokuni S, Jiang L, Kitaura R and Shinohara S.

    Nagoya J Med Sci   Vol. 77   page: 195-202   2015

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  327. Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells. Reviewed

    Funahashi F, Okazaki Y, Ito D, Asakawa A, Nagai H, Tajima M and Toyokuni S.

    J Clin Biochem Nutr 56: 111-117, 2015.   Vol. 56   page: 111-117   2015

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  328. Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders. Reviewed

    Hattori Y, Mukaide T, Jiang L, Kotani T, Tsuda H, Mano Y, Sumigama S, Hirayama T, Nagasawa H, Kikkawa F and Toyokuni S.

    J Clin Biochem Nutr 56: 57-63, 2015.   Vol. 56   page: 57-63   2015

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  329. Napsin A is a specific marker for ovarian clear cell adenocarcinoma. Reviewed

    Yamashita Y, Nagasaka T, Naiki-Ito A, Sato S, Suzuki S, Toyokuni S, Ito M and Takahashi S.

    Mod Pathol   Vol. 28   page: 111-117   2015

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  330. A trial to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases. Reviewed

    Zhang L, Zong C, Ichihara S, Naito H, Toyokuni S, Kumagai S, Ichihara G.

    J Occup Health.   Vol. 57 ( 6 ) page: 548-554   2015

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  331. A trial to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases International journal

    Zhang Lingyi, Zong Cai, Ichihara Sahoko, Naito Hisao, Toyokuni Shinya, Kumagai Shinji, Ichihara Gaku

    Journal of Occupational Health   Vol. 57 ( 6 ) page: 548 - 554   2015

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    <b>Objectives:</b> It has been reported that 1,2-Dichloropropane (DCP) induced cholangiocarcinoma (CCA) in offset color proof-printing workers. However, exposure to DCP by inhalation or gavage for 2 year did not induce CCA in mice and rats. The present study mapped the hepatic distribution of GST, which is known to activate dihalogenated alkanes, and proliferative and fibrotic changes in bile ducts in various species to find the most appropriate animal model of DCP-induced CCA. <b>Methods:</b> First, 12 each of C57BL/6J mice, Balb/cA mice, F344 rats, Syrian hamsters, and guinea pigs were divided into four equal groups and exposed to DCP at 0, 300, 1,000, or 3,000 ppm 8 hours/day for 7 days. Second, 32 Balb/cA mice and 32 Syrian hamsters were each divided into four equal groups and exposed to DCP at 0, 200, 400, and 800 ppm 6 hours/day for 14 days. After the last exposure, the animals were decapitated, and the livers were dissected out for histopathological evaluation. Immunostaining was conducted to determine the distribution of GSTT1, GSTM1, and GSTPi, as well as the expression of proliferation marker Ki67. <b>Results:</b> GSTT1, GSTM1, and GSTPi were expressed in both hepatocytes and bile duct cells in all control and exposed animals. There was no clear difference in the expression of Ki67 between the exposed groups and the control. No fibrotic changes were observed in any species or strains examined. <b>Conclusions:</b> Expression of GSTT1 or other GST isozymes might not explain the difference in sensitivity of hepatocytes and the bile duct to DCP between humans and rodents.(J Occup Health 2015; 57: 548–554)

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  332. Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials. Invited International journal

    Toyokuni S

    J Clin Biochem Nutr   Vol. 56   page: 165   2015

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  333. Application of intermittent microwave irradiation to western blot analysis. Reviewed International coauthorship International journal

    Liu YT, Toyokuni S

    Methods Mol Biol   Vol. 1314   page: 185-190   2015

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  334. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury International journal

    Y. Hattori, T. Kotani, H. Tsuda, Y. Mano, L. Tu, H. Li, S. Hirako, T. Ushida, K. Imai, T. Nakano, Y. Sato, R. Miki, S. Sumigama, A. Iwase, S. Toyokuni, F. Kikkawa

    FREE RADICAL RESEARCH   Vol. 49 ( 8 ) page: 1026 - 37   2015

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    Maternal inflammation is associated with spontaneous preterm birth and respiratory impairment among premature infants. Recently, molecular hydrogen (H-2) has been reported to have a suppressive effect on oxidative stress and infl ammation. The aim of this study was to evaluate the effects of H-2 on fetal lung injury caused by maternal infl ammation. Cell viability and the production of interleukin-6 (IL-6) and reactive oxygen species (ROS) were examined by treatment with lipopolysaccharide (LPS) contained in ordinal or H-2-rich medium (HM) using a human lung epithelial cell line, A549. Pregnant Sprague Dawley rats were divided into three groups: Control, LPS, and HW + LPS groups. Rats were injected with phosphate-buffered saline (Control) or LPS intraperitoneally (LPS) on gestational day 19 and provided H-2 water (HW) ad libitum for 24 h before LPS injection (HW + LPS). Fetal lung samples were collected on day 20, and the levels of apoptosis, oxidative damage, IL-6, and vascular endothelial growth factor (VEGF) were evaluated using immunohistochemistry. The number of apoptotic cells, and levels of ROS and IL-6 were significantly increased by LPS treatment, and repressed following cultured with HM in A549 cells. In the rat models, the population positive for cleaved caspase-3, 8-hydroxy-2'-deoxyguanosine, IL-6, and VEGF was significantly increased in the LPS group compared with that observed in the Control group and significantly decreased in the HW + LPS group. In this study, LPS administration induced apoptosis and oxidative damage in fetal lung cells that was ameliorated by maternal H-2 intake. Antenatal H-2 administration may decrease the pulmonary mobility associated with infl ammation in premature infants.

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  335. Minimal inflammogenicity of pristine single-wall carbon nanotubes International journal

    Toyokuni S., Jiang L., Kitaura R., Shinohara H.

    Nagoya Journal of Medical Science   Vol. 77 ( 1-2 ) page: 195 - 202   2015

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    Carbon nanotubes (CNTs) are a novel synthetic material comprising only carbon atoms. Based on its rigidity, its electrical and heat conductivity and its applicability to surface manufacturing, this material is expected to have numerous applications in industry. However, due to the material's dimensional similarity to asbestos fibers, its carcinogenicity was hypothesized during the last decade, and indeed, we have shown that multi-wall CNTs (MWCNTs) of 50 nm in diameter are potently carcinogenic to mesothelial cells after intraperitoneal injection. Additionally, we suggested that inflammogenicity after intraperitoneal injection can predict mesothelial carcinogenesis. However, few data have been published on the intraperitoneal inflammogenicity of single-wall CNTs (SWCNTs). Here, we conducted a series of studies on SWCNTs using both intraperitoneal injection into rats and MeT5A mesothelial cells. Intraperitoneal injection of 10 mg SWCNTs caused no remarkable inflammation in the abdominal cavity, and the exposure of MeT5A cells to up to 25 μg/cm2 SWCNTs did not alter proliferation. MWCNTs of 50 nm in diameter were used as a positive control, and tangled MWCNTs of 15 nm in diameter were used as a negative control. The results suggest that SWCNTs are a low-risk material with respect to mesothelial carcinogenesis.

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  336. Application of Intermittent Microwave Irradiation to Western Blot Analysis. International journal

    Yu-Ting Liu, Shinya Toyokuni

    Methods in molecular biology (Clifton, N.J.)   Vol. 1314   page: 185 - 190   2015

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    We established a shortened protocol for Western blot analysis using intermittent microwave irradiation. With this method, the procedure is completed within 1 h after applying the primary antibody, and thus greatly saves time. This procedure appears to be applicable to any antibody based on our experience of several years.

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  337. Receptor role of annexin A2 in the mesothelial endocytosis of crocidolite fibers. Reviewed

    Yamashita K, Nagai H, Toyokuni S

    Lab Invest   Vol. 95   page: 749-764   2015

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  338. Elucidation of asbestos-induced mesothelial carcinogenesis and risk assessment of nanomaterials

    TOYOKUNI Shinya

    Annual Meeting of the Japanese Society of Toxicology   Vol. 42 ( 0 ) page: S4 - 2   2015

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  339. Establishment of murine model for neurotoxicity of 1-bromopropane, an alternative to ozone-depleting solvents

    ZONG Cai, GARNER Edwin, HUANG Chin-Yen, ZHANG Lingyi, ZHANG Xiao, SAKURAI Toshihiro, TOYOKUNI Shinya, ICHIHARA Sahoko, ICHIHARA Gaku

    Annual Meeting of the Japanese Society of Toxicology   Vol. 42 ( 0 ) page: P - 13   2015

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  340. Hepatic distribution of GST cannot explain the gap between human and rodents for induction of cholangiocarcioma following exposure to dichloropropane

    ZHANG Lingyi, ZONG Cai, ICHIHARA Sahoko, NAITO Hisao, TOYOKUNI Shinya, KUMAGAI Shinji, ICHIHARA Gaku

    Annual Meeting of the Japanese Society of Toxicology   Vol. 42 ( 0 ) page: P - 165   2015

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    <i>Purpose:</i> 1,2-Dichloropropane(DCP) is thought to induce cholangiocarcinoma(CCA) among Japanese printing workers in 2013. However no studies have shown DCP-induced CCA in rodents. Five kinds of rodents were exposed to DCP to find an appropriate animal model for DCP-induced CCA.<br><i>Methods: </i>First, 12 C57BL/6J mice, Balb/cA mice, F344 rats, Syrian Hamsters and Guinea Pigs were divided into 4 groups equally and exposed to DCP at 0, 300, 1000 and 3000 ppm respectively. Then 32 Balb/cA mice and Syrian Hamsters were divvied into 4 groups equally and exposed to DCP at 0, 200, 400 and 800ppm respectively. After the last exposure livers were dissected out for immunohistochemistry with anti- GSTT1, GSTM1, GSTPi antibodies.<br><i>Result:</i> Either in control or exposed group all of the animals expressed GSTT1 both at liver cells and bile duct cells. <br><i>Conclusion:</i> GSTT1 expression cannot explain the gap between human and rodents in the case of DCP inducing CCA.

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  341. 鉄過剰症による発がんの分子機構 特集:鉄代謝制御機構と鉄過剰症

    豊國 伸哉

    病理と臨床   Vol. 70   page: 337 - 242   2015

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  342. Minimal inflammogenicity of pristine single-wall carbon nanotubes Reviewed International journal

    Toyokuni S

    Nagoya Journal of Medical Science   Vol. 77 ( 1-2 ) page: 195 - 202   2015

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  343. Genome-wide profiling of 8-oxoguanine reveals its association with spatial positioning in nucleus. International journal

    Minako Yoshihara, Li Jiang, Shinya Akatsuka, Mikita Suyama, Shinya Toyokuni

    DNA research : an international journal for rapid publication of reports on genes and genomes   Vol. 21 ( 6 ) page: 603 - 12   2014.12

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    8-Oxoguanine (8-oxoG) is one of the most common DNA lesions generated by reactive oxygen species. In this study, we analysed the genome-wide distribution profile of 8-oxoG by combining immunoprecipitation by antibodies specific for the DNA fragments containing 8-oxoG with a microarray that covers rat genome. Genome-wide mapping of 8-oxoG in normal rat kidney revealed that 8-oxoG is preferentially located at gene deserts. We did not observe differences in 8-oxoG levels between groups of genes with high and low expression, possibly because of the generally low 8-oxoG levels in genic regions compared with gene deserts. The distribution of 8-oxoG and lamina-associated domains (LADs) were strongly correlated, suggesting that the spatial location of genomic DNA in the nucleus determines the susceptibility to oxidative modifications. One possible explanation for high 8-oxoG levels in LADs is that the nuclear periphery is more susceptible to the oxidative damage caused by the extra-nuclear factors. Moreover, LADs have a rather compact conformation, which may limit the recruitment of repair components to the modified bases.

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  344. Plasma Medical Science for Cancer Therapy: Toward Cancer Therapy Using Nonthermal Atmospheric Pressure Plasma

    Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Keigo Takeda, Kae Nakamura, Fumi Utsumi, Hiroaki Kajiyama, Hiroyuki Kano, Yasumasa Okazaki, Shinnya Toyokuni, Shoichi Maruyama, Fumitaka Kikkawa, Masaru Hori

    IEEE TRANSACTIONS ON PLASMA SCIENCE   Vol. 42 ( 12 ) page: 3760 - 3764   2014.12

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    We have been developing novel ultrahigh density atmospheric pressure plasma sources and succeeded in the selective killing ovarian cancer cells against normal ones. Furthermore, we have found out the plasma- activated medium (PAM) also killed glioblastoma brain tumor cells selectively against normal ones and the chemical products in the PAM have long lifetime healing effects. To clarify the mechanism, interactions of plasma with the organism and the medium where the organism belongs were investigated on the viewpoint of intracellular molecular mechanism.

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  345. Direct exposure of non-equilibrium atmospheric pressure plasma confers simultaneous oxidative and ultraviolet modifications in biomolecules

    Okazaki Yasumasa, Wang Yue, Tanaka Hiromasa, Mizuno Masaaki, Nakamura Kae, Kajiyama Hiroaki, Kano Hiroyuki, Uchida Koji, Kikkawa Fumitaka, Hori Masaru, Toyokuni Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 55 ( 3 ) page: 207 - 15   2014.11

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    Thermal plasmas and lasers are used in medicine to cut and ablate tissues and for coagulation. Non-equilibrium atmospheric pressure plasma (NEAPP) is a recently developed, non-thermal technique with possible biomedical applications. Although NEAPP reportedly generates reactive oxygen/nitrogen species, electrons, positive ions, and ultraviolet radiation, little research has been done into the use of this technique for conventional free radical biology. Recently, we developed a NEAPP device with high electron density. Electron spin resonance spin-trapping revealed <sup>•</sup>OH as a major product. To obtain evidence of NEAPP-induced oxidative modifications in biomolecules and standardize them, we evaluated lipid peroxidation and DNA modifications in various <i>in vitro</i> and <i>ex vivo</i> experiments. Conjugated dienes increased after exposure to linoleic and α-linolenic acids. An increase in 2-thiobarbituric acid-reactive substances was also observed after exposure to phosphatidylcholine, liposomes or liver homogenate. Direct exposure to rat liver in saline produced immunohistochemical evidence of 4-hydroxy-2-nonenal- and acrolein-modified proteins. Exposure to plasmid DNA induced dose-dependent single/double strand breaks and increased the amounts of 8-hydroxy-2'-deoxyguanosine and cyclobutane pyrimidine dimers. These results indicate that oxidative biomolecular damage by NEAPP is dose-dependent and thus can be controlled in a site-specific manner. Simultaneous oxidative and UV-specific DNA damage may be useful in cancer treatment.

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  346. Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model. International journal

    T Mukaide, Y Hattori, N Misawa, S Funahashi, L Jiang, T Hirayama, H Nagasawa, S Toyokuni

    Free radical research   Vol. 48 ( 9 ) page: 990 - 5   2014.9

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    Iron overload of a chronic nature has been associated with a wide variety of human diseases, including infection, carcinogenesis, and atherosclerosis. Recently, a highly specific turn-on fluorescent probe (RhoNox-1) specific to labile ferrous iron [Fe(II)], but not to labile ferric iron [Fe(III)], was developed. The evaluation of Fe(II) is more important than Fe(III) in vivo in that Fe(II) is an initiating component of the Fenton reaction. In this study, we applied this probe to frozen sections of an established Fenton reaction-based rat renal carcinogenesis model with an iron chelate, ferric nitrilotriacetate (Fe-NTA), in which catalytic iron induces the Fenton reaction specifically in the renal proximal tubules, presumably after iron reduction. Notably, this probe reacted with Fe(II) but with neither Fe(II)-NTA, Fe(III) nor Fe(III)-NTA in vitro. Prominent red fluorescent color was explicitly observed in and around the lumina of renal proximal tubules 1 h after an intraperitoneal injection of 10-35 mg iron/kg Fe-NTA, which was dose-dependent, according to semiquantitative analysis. The RhoNox-1 signal colocalized with the generation of hydroxyl radicals, as detected by hydroxyphenyl fluorescein (HPF). The results demonstrate the transformation of Fe(III)-NTA to Fe(II) in vivo in the Fe-NTA-induced renal carcinogenesis model. Therefore, this probe would be useful for localizing catalytic Fe(II) in studies using tissues.

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  347. FREE FERROUS IRON IN AMNIOTIC FLUID AS A PREDICTIVE MARKER OF FETAL DISORDERS IN PREGNANCY

    Yuka Hattori, Tomomi Kotani, Tomoko Nakano, Yukio Mano, Seiji Sumigama, Hiroyuki Tsuda, Takafumi Usida, Hideko Nagasawa, Shinya Toyokuni, Fumitaka Kikkawa

    PLACENTA   Vol. 35 ( 9 ) page: A71 - A71   2014.9

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  348. Iron and thiols as two major players in carcinogenesis: friends or foes? International journal

    Shinya Toyokuni

    Frontiers in pharmacology   Vol. 5   page: 200 - 200   2014.8

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    Iron is the most abundant metal in the human body and mainly works as a cofactor for proteins such as hemoglobin and various enzymes. No independent life forms on earth can survive without iron. However, excess iron is intimately associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Biomolecules with redox-active sulfhydryl function(s) (thiol compounds) are necessary for the maintenance of mildly reductive cellular environments to counteract oxidative stress, and for the execution of redox reactions for metabolism and detoxification. Involvement of glutathione S-transferase and thioredoxin has long attracted the attention of cancer researchers. Here, I update recent findings on the involvement of iron and thiol compounds during carcinogenesis and in cancer cells. It is now recognized that the cystine/glutamate transporter (antiporter) is intimately associated with ferroptosis, an iron-dependent, non-apoptotic form of cell death, observed in cancer cells, and also with cancer stem cells; the former with transporter blockage but the latter with its stabilization. Excess iron in the presence of oxygen appears the most common known mutagen. Ironically, the persistent activation of antioxidant systems via genetic alterations in Nrf2 and Keapl also contributes to carcinogenesis. Therefore, it is difficult to conclude the role of iron and thiol compounds as friends or foes, which depends on the quantity/distribution and induction/flexibility, respectively. Avoiding further mutation would be the most helpful strategy for cancer prevention, and myriad of efforts are being made to sort out the weaknesses of cancer cells.

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  349. Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation. Reviewed International journal

    Kanako Shinjo, Yoriko Yamashita, Eiko Yamamoto, Shinya Akatsuka, Nozomi Uno, Akihiro Kamiya, Kaoru Niimi, Yuka Sakaguchi, Tetsuro Nagasaka, Takashi Takahashi, Kiyosumi Shibata, Hiroaki Kajiyama, Fumitaka Kikkawa, Shinya Toyokuni

    International journal of cancer   Vol. 135 ( 2 ) page: 308 - 318   2014.7

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    Ovarian cancer is the most lethal gynecologic malignancy, and clear cell adenocarcinoma of the ovary (OCCA), in particular, has a relatively poor prognosis among the ovarian cancer subtypes because of its high chemoresistance. Chromobox (CBX) 7 is a polycomb repressive complex 1 component that prolongs the lifespan of normal human cells by downregulating the INK4a/ARF expression which promotes cell-cycle progression. However, recent reports studying the relationship between CBX7 expression and patient survival have differed regarding the tumor cell origins, and the precise role of CBX7 in human carcinomas remains obscure. In this study, we analyzed CBX7 expression by immunohistochemistry in 81 OCCA patients and evaluated its association with their clinical outcomes. Both the overall and progression-free survival rates of the CBX7-positive patients were significantly shorter than those of the CBX7-negative patients (p &lt; 0.05). CBX7 knockdown experiments using two OCCA cell lines, TOV21G and KOC-7C, revealed that cell viability was significantly reduced compared to the control cells (p &lt; 0.001). Expression microarray analysis revealed that apoptosis-related genes, particularly tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), were significantly upregulated in CBX7 knockdown cells (p &lt; 0.01). We further confirmed that CBX7 knockdown resulted in TRAIL-induced apoptosis in the OCCA cells. Thus, in this study, we showed for the first time that CBX7 was associated with a decreased OCCA prognosis. We also successfully demonstrated that the TRAIL pathway is a novel target for CBX7 expression modulation in these cells, and therapeutic agents utilizing the TRAIL pathway may be particularly effective for targeted OCCA therapy.
    What's new? Ovarian cancer is the most lethal gynecologic malignancy, with clear celladenocarcinoma of the ovary (OCCA) having a particularly poor prognosis due to high chemoresistance. Chromobox homolog 7 (CBX7) is a polycomb group transcriptional repressor whose role in human cancer remains controversial. Here, the authors showed for the first time that CBX7 expression is related to worse prognosis in OCCA. Furthermore, knockdown of CBX7 in vitro induced apoptosis in OCCA cell lines, possibly via regulation of the TRAIL-pathway. The findings thus indicate CBX7 as a good prognostic marker, andthe TRAIL-pathway as a potential target for OCCA diagnosis and therapy.

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  350. Lack of presence of the human cytomegalovirus in human glioblastoma

    Yoriko Yamashita, Yoshinori Ito, Hiroki Isomura, Naoaki Takemura, Akira Okamoto, Kazuya Motomura, Takashi Tsujiuchi, Atsushi Natsume, Toshihiko Wakabayashi, Shinya Toyokuni, Tatsuya Tsurumi

    MODERN PATHOLOGY   Vol. 27 ( 7 ) page: 922 - 9   2014.7

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    Recent reports have indicated human cytomegalovirus (HCMV) to be associated with human glioblastoma carcinogenesis. In established examples of viral carcinogenesis, viral DNA and one or more of its products have been detected in most tumor cells of biopsies in the majority of cases. To test whether HCMV is associated with human glioblastoma based on this criterion, we measured the number of viral DNA molecules per cell in both frozen and paraffin-embedded tumor biopsies from 58 patients using real-time quantitative PCR (QPCR). Immunohistochemical and fluorescence in situ hybridization (FISH) to detect HCMV proteins and genome was performed in 10 cases using formalin-fixed paraffin-embedded glioblastoma tissues. Southern blotting using DNA extracted from four glioblastoma cell lines together with immunoblotting using the four cell lines and five glioblastoma tissue samples were also performed. We further confirmed the immunoblot bands using liquid chromatography-tandem mass spectrometry assay. As a result, HCMV DNA was not detected in the tumor cells from any of the glioblastoma cases by QPCR detecting two different HCMV genes, in clear contrast to samples from patients with HCMV infection. Southern blotting and immunoblotting of cell lines and FISH using paraffin sections were all negative. However, immunoblotting and immunohistochemistry using tissue samples were partly positive, but HCMV proteins were not detected by proteomic analysis, suggesting false positivity of the analyses. As our QPCR analysis could detect 10 copies of HCMV DNA mixed with DNA extracted from 10(4) HCMV-negative cells, we conclude that HCMV is not persistent, at least in the tumor cells, of developed human glioblastoma.

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  351. Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions. Reviewed International journal

    Satoshi Nishiwaki, Takayuki Nakayama, Makoto Murata, Tetsuya Nishida, Seitaro Terakura, Shigeki Saito, Tomonori Kato, Hiroki Mizuno, Nobuhiko Imahashi, Aika Seto, Yukiyasu Ozawa, Koichi Miyamura, Masafumi Ito, Kyosuke Takeshita, Hidefumi Kato, Shinya Toyokuni, Keisuke Nagao, Ryuzo Ueda, Tomoki Naoe

    PloS one   Vol. 9 ( 5 ) page: e96252   2014.5

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    Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-alpha and IFN-gamma, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

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  352. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion. Reviewed International journal

    Yukio Mano, Tomomi Kotani, Mikako Ito, Taku Nagai, Yuko Ichinohashi, Kiyofumi Yamada, Kinji Ohno, Fumitaka Kikkawa, Shinya Toyokuni

    Free radical biology & medicine   Vol. 69   page: 324 - 30   2014.4

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    Molecular hydrogen (H-2) scavenges hydroxyl radicals. Recently, H-2 has been reported to prevent a variety of diseases associated with oxidative stress in model systems and in humans. Here, we studied the effects of H-2 on rat fetal hippocampal damage caused by ischemia and reperfusion (IR) on day 16 of pregnancy with the transient occlusion of the bilateral utero-ovarian arteries. Starting 2 days before the operation, we provided the mothers with hydrogen-saturated water ad libitum until vaginal delivery. We observed a significant increase in the concentration of H-2 in the placenta after the oral administration of hydrogen-saturated water to the mothers, with less placental oxidative damage after IR in the presence of H-2. Neonatal growth retardation was observed in the IR group, which was alleviated by the H-2 administration. We analyzed the neuronal cell damage in the CA1 and CA3 areas of the hippocampus at day 7 after birth by immunohistochemical analysis of the 8-oxo-7,8-dihydro-2 '-deoxyguanosine- and 4-hydroxy-2-nonenal-modified proteins. Both oxidative stress markers were significantly increased in the IR group, which was again ameliorated by the H-2 intake. Last, 8-week-old rats were subjected to a Morris water maze test. Maternal H-2 administration improved the reference memory of the offspring to the sham level after IR injury during pregnancy. Overall, the present results support the idea that maternal H-2 intake helps prevent the hippocampal impairment of offspring induced by IR during pregnancy. (C) 2014 Elsevier Inc. All rights reserved.

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  353. Ovarian mucinous tumors arising from mature cystic teratomas-a molecular genetic approach for understanding the cellular origin

    Kaho Fujii, Yoriko Yamashita, Toshimichi Yamamoto, Koji Takahashi, Katsunori Hashimoto, Tomoko Miyata, Kumi Kawai, Fumitaka Kikkawa, Shinya Toyokuni, Tetsuro Nagasaka

    HUMAN PATHOLOGY   Vol. 45 ( 4 ) page: 717 - 724   2014.4

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    Mucinous tumors of the ovary are frequently associated with mature cystic teratomas, and it has been speculated that the mucinous tumors arise from teratoma components. The cellular origins of mature cystic teratomas are believed to be post-meiotic ovarian germ cells, and the analysis of microsatellite markers such as short tandem repeats is suitable for determining the cellular origin of tumors. In this study, we analyzed 3 ovarian mature cystic teratomas, all of which were associated with simultaneous ovarian mucinous tumors within the same ovary. Two of the 3 mucinous tumors were intestinal-type and the other was endocervical type. A laser capture microdissection technique was used to separate the epithelial component of the mucinous tumor, the components of the mature cystic teratoma, and control ovarian somatic tissue. Using short tandem repeat analysis based on 6 markers (D20S480, D6S2439, D6S1056, D9S1118, D4S2639, and D17S1290), we could distinguish the germ cell (homozygous) or somatic (heterozygous) origin of a given component in each sample. The epithelial components of the intestinal-type mucinous tumors in cases 1 and 2 were homozygous, and the epithelial component in case 3 (endocervical type) was heterozygous. All teratomatous components were homozygous, and the control components were heterozygous. In addition, we analyzed 3 mature cystic teratomas without mucinous tumors, and all 3 were homozygous in the tumor component. Our data suggest that the origin of mucinous tumors in the ovary may differ among histological subtypes, and intestinal-type mucinous tumors may arise from mature cystic teratomas, although endocervical-type mucinous tumors may not. (C) 2014 Elsevier Inc. All rights reserved.

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  354. From Nagoya to the world

    Toyokuni S.

    Nagoya Journal of Medical Science   Vol. 76 ( 1-2 ) page: 1 - 2   2014.3

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  355. From Nagoya to the world

    Toyokuni S

    Nagoya Journal of Medical Science   Vol. 76 ( 1-2 ) page: 1 - 2   2014.3

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  356. RAT MODEL DEMONSTRATES A HIGH RISK OF TREMOLITE BUT A LOW RISK OF ANTHOPHYLLITE FOR MESOTHELIAL CARCINOGENESIS Reviewed

    Dilinuer Aierken, Yasumasa Okazaki, Shan Hwu Chew, Akihiro Sakai, Yue Wang, Hirotaka Nagai, Nobuaki Misawa, Norihiko Kohyama, Shinya Toyokuni

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 76 ( 1-2 ) page: 149 - 160   2014.2

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    Asbestos was abundantly used in industry during the last century. Currently, asbestos confers a heavy social burden due to an increasing number of patients with malignant mesothelioma ( MM), which develops after a long incubation period. Many studies have been conducted on the effects of the asbestos types that were most commonly used for commercial applications. However, there are few studies describing the effects of the less common types, or minor asbestos. We performed a rat carcinogenesis study using Japanese tremolite and Afghan anthophyllite. Whereas more than 50% of tremolite fibers had a diameter of &lt; 500 nm, only a small fraction of anthophyllite fibers had a diameter of &lt; 500 nm. We intraperitoneally injected 1 or 10 mg of asbestos into F1 Fischer-344/Brown-Norway rats. In half of the animals, repeated intraperitoneal injections of nitrilotriacetate (NTA), an iron chelator to promote Fenton reaction, were performed to evaluate the potential involvement of iron overload. Tremolite induced MM with a high incidence (96% with 10 mg; 52% with 1 mg), and males were more susceptible than females. Histology was confirmed using immunohistochemistry, and most MMs were characterized as the sarcomatoid or biphasic subtype. Unexpectedly NTA showed an inhibitory effect in females. In contrast, anthophyllite induced no MM after an observation period of 550 days. The results suggest that the carcinogenicity of anthophyllite is weaker than formerly reported, whereas that of tremolite is as potent as major asbestos as compared with our previous data.

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  357. Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis.

    Aierken D, Okazaki Y, Chew SH, Sakai A, Wang Y, Nagai H, Misawa N, Kohyama N, Toyokuni S

    Nagoya journal of medical science   Vol. 76 ( 1-2 ) page: 149 - 60   2014.2

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  358. Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis.

    Aierken D, Okazaki Y, Chew SH, Sakai A, Wang Y, Nagai H, Misawa N, Kohyama N, Toyokuni S

    Nagoya journal of medical science   Vol. 76 ( 1-2 ) page: 149 - 60   2014.2

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  359. RAT MODEL DEMONSTRATES A HIGH RISK OF TREMOLITE BUT A LOW RISK OF ANTHOPHYLLITE FOR MESOTHELIAL CARCINOGENESIS

    Aierken Dilinuer, Okazaki Yasumasa, Chew Shan Hwu, Sakai Akihiro, Wang Yue, Nagai Hirotaka, Misawa Nobuaki, Kohyama Norihiko, Toyokuni Shinya

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 76 ( 1-2 ) page: 149 - 160   2014.2

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  360. Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis. Reviewed International journal

    Shinya Toyokuni

    Redox report : communications in free radical research   Vol. 19 ( 1 ) page: 1 - 7   2014.1

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    Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated

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  361. As a host society to SFRRI 2014 in Kyoto.

    Osamu Handa, Yuji Naito, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 54 ( 1 ) page: 1 - 1   2014.1

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    DOI: 10.3164/jcbn.54-1E1

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  362. Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production. Reviewed

    Chew SH, Okazaki Y, Nagai H, Misawa N, Akatsuka S, Yamashita K, Jiang L, Noguchi M, Hosoda K, Sekido Y, Takahashi T and Toyokuni S.

    Carcinogenesis   Vol. 35   page: 164-172   2014

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    DOI: doi: 10.1093/carcin/bgt267.

  363. Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. Reviewed

    Tsujiuchi T, Natsume A, Motomura K, Kondo G, Ranjit M, Hachisu R, Sugimura I, Tomita S, Takehara I, Woolley M, Barua NU, Gill SS, Bienemann AS, Yamashita Y, Toyokuni S, Wakabayashi T.

    Am J Transl Res   Vol. 15   page: 169-178   2014

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  364. Dexamethasone palmitate ameliorates macrophages-1 rich graft-versus-host disease by inhibiting macrophage functions. Reviewed

    Nishiwaki S, Nakayama T, Murata M, Nishida T, Terakura S, Saito S, Kato T. Mizuno H, Imahashi N, Seto S, Ozawa Y, Miyamura K, Ito M, Takeshita K, Kato H, Toyokuni S, Nagao K, Ueda R and Naoe T.

    PLoS ONE   Vol. 9   page: e96252   2014

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    DOI: doi: 10.1371/journal.pone.0096252.

  365. Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model. Reviewed

    Mukaide T, Hatori Y, Misawa N, Funahashi S, Jiang L, Hirayama T, Nagasawa H and Toyokuni S.

    Free Radic Res   Vol. 48   page: 990-995   2014

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    DOI: doi: 10.3109/10715762.2014.898844.

  366. Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis. Reviewed

    Aierken D, Okazaki Y, Chew SH, Sakai A, Wang Y, Nagai H, Misawa N, Kohyama N and Toyokuni S.

    Nagoya J Med Sci   Vol. 76   page: 149-160   2014

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  367. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage by in ut ero ischemia-reperfusion. Reviewed

    Mano Y, Kotani T, Ito M, Nagai T, Ichinohashi Y, Yamada K, Ohno K, Kikkawa F and Toyokuni S.

    Free Radic Biol Med   Vol. 69   page: 324-330   2014

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    DOI: doi: 10.1016/j.freeradbiomed.2014.01.037.

  368. Lack of presence of the human cytomegalovirus in human glioblastoma. Modern Pathol 27: 922-929, 2014. Reviewed

    Yamashita Y, Ito Y, Isomura H, Takemura N, Okamoto A, Motomura K, Tsujiuchi T, Natsume A, Wakabayashi T, Toyokuni S and Tsurumi T.

    Modern Pathology   Vol. 27   page: 922-929   2014

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    DOI: doi: 10.1038/modpathol.2013.219.

  369. Ovarian mucinous tumors arising from mature cystic teratomas-a molecular genetic approach for understanding the cellular origin. Reviewed

    Fujii K, Yamashita Y, Yamamoto T, Takahashi K, Hashimoto K, Miyata T, Kawai K, Kikkawa F, Toyokuni S, Nagasaka T.

    Human Pathol   Vol. 45   page: 717-724   2014

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    DOI: doi: 10.1016/j.humpath.2013.10.031.

  370. Iron as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis. Reviewed

    Toyokuni, S.

    Redox Rep.   Vol. 19   page: 1-7   2014

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    DOI: doi: 10.1179/1351000213Y.0000000075.

  371. Direct exposure of non-equilibrium atmospheric pressure plasma confers simultaneous oxidative and ultraviolet modifications in biomolecules. Reviewed

    Okazaki Y, Wang Y, Tanaka H, Mizuno M, Nakamura K, Kajiyama H, Kano H, Uchida K, Kikkawa F, Hori M and Toyokuni S.

    J Clin Biochem Nutr   Vol. 55   page: 207-215   2014

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  372. Plasma medical science for cancer therapy using non-thermal atomospheric pressure plasma. Reviewed

    Tanaka H, Mizuno M, Ishikawa K, Takeda K, Nakamura K, Utsumi F, Kajiyama H, Nano H, Okazaki Y, Toyokuni S, Maruyama S, Kikkawa F and Hori M.

    IEEE Trans Plasma Sci   Vol. 42   page: 3760-3764   2014

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  373. Iron and thiols as two major players in carcinogenesis: friends or foes? Invited Reviewed

    Toyokuni S.

    Front Pharmacol   Vol. 5   page: 200   2014

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  374. Genome-wide profiling of 8-oxoguanine reveals its association with spatial positioning in nucleus. Reviewed

    Yoshihara M, Jiang L, Akatsuka S, Suyama M and Toyokuni S.

    DNA Res   Vol. 21   page: 603-612   2014

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  375. Iron and thiols as two major players in carcinogenesis: friends or foes? Invited Reviewed

    Toyokuni S

    Front Pharmacol   Vol. 5   page: 200   2014

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  376. Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains.

    Tsujiuchi T, Natsume A, Motomura K, Kondo G, Ranjit M, Hachisu R, Sugimura I, Tomita S, Takehara I, Woolley M, Barua NU, Gill SS, Bienemann AS, Yamashita Y, Toyokuni S, Wakabayashi T

    American journal of translational research   Vol. 6 ( 2 ) page: 169 - 78   2014

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  377. Preclinical evaluation of an O<sup>6</sup>-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains

    Tsujiuchi T., Natsume A., Motomura K., Kondo G., Ranjit M., Hachisu R., Sugimura I., Tomita S., Takehara I., Woolley M., Barua N.U., Gill S.S., Bienemann A.S., Yamashita Y., Toyokuni S., Wakabayashi T.

    American Journal of Translational Research   Vol. 6 ( 2 ) page: 169 - 178   2014

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    The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O6-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O6-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

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  378. Preclinical evaluation of an O-6-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains Reviewed

    Takashi Tsujiuchi, Atsushi Natsume, Kazuya Motomura, Goro Kondo, Melissa Ranjit, Rei Hachisu, Itsuro Sugimura, Shinpei Tomita, Isao Takehara, Max Woolley, Neil U. Barua, Steven S. Gill, Alison S. Bienemann, Yoriko Yamashita, Shinya Toyokuni, Toshihiko Wakabayashi

    AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH   Vol. 6 ( 2 ) page: 169 - 178   2014

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    The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O-6-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O-6-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

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  379. 脳梗塞発症前の運動はsuperoxide dismutase活性を増加させ脳梗塞障害を軽減する

    野口 泰司, 石田 和人, 濱川 みちる, 玉越 敬悟, 高松 泰行, 戸田 拓弥, 加藤 寛聡, 早稲田 雄也, 赤塚 慎也, 豊國 伸哉

    理学療法学Supplement   Vol. 2013 ( 0 ) page: 0007 - 0007   2014

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    【はじめに,目的】脳梗塞の後遺症に苦しむ患者数の増大から,脳梗塞の予防的介入が重要視されている。動物実験では,脳梗塞発症前に一定期間運動を行うことで,脳梗塞後の運動機能障害が軽減し,脳梗塞体積も減少するという報告がなされている(Wang RY. et al., 2001)。この作用機序について,我々の研究室では脳梗塞の二次的傷害の主要な要因である酸化ストレスに着目し,脳梗塞発症前に運動を行うことで酸化ストレス産物(8-OHdG,4-HNE修飾タンパク)の生成が軽減されることを報告し,酸化ストレス抑制の関連を示唆した(Hamakawa M. et al., 2013)。しかし,この酸化ストレス抑制の機序は明らかになっていない。そこで,本研究では脳内の主要な抗酸化ストレス物質の1つであるsuperoxide dismutase(SOD)に着目し,事前の運動による脳梗塞障害軽減効果の作用機序を検討することを目的とする。【方法】実験動物にはWistar系雄性ラット(5週齢)を用いた。無作為にSham群(n=6),運動+sham群(n=6),脳梗塞群(n=8),運動+脳梗塞群(n=12)の4群に分け,運動+sham群と運動+脳梗塞群は3週間のトレッドミル運動(15m/min,30分/日)を毎日行った。Sham群と脳梗塞群は走行させずにトレッドミル装置内に曝露させた。3週間後,脳梗塞群と運動+脳梗塞群に対し,小泉法により90分間左中大脳動脈を閉塞することで脳梗塞モデル作成手術を施した。手術24時間後に,感覚-運動機能に関し,麻痺の重症度の評価としてneurological deficits(ND)を,前肢の感覚運動機能の評価としてlimb placing test(LP)を,前肢の協調運動機能の評価としてladder testを,歩行時のバランス能力の評価としてbeam walking test(BW)を行った。その直後に脳梗塞周囲の大脳皮質感覚運動野を採取し,SOD-Assay kit-WST(同仁化学研究所)を用いてSOD活性を測定した。また,SODの遺伝子発現について,real-time PCR法によりSOD1(Cu,Zn-SOD),SOD2(Mn-SOD),SOD3(EC-SOD)のmRNA発現量を定量化した。統計学的解析はSPSS ver. 16.0を用い,感覚-運動機能評価に関しND,LP,BWについてはMann-Whitney U testを,ladder testについてはStudent's t-testを行った。また,SOD活性,SOD1,2,3の遺伝子発現については一元配置分散分析にて比較し,事後検定としてTukey's testを行った。統計学的検定における有意水準は5%未満とした。【倫理的配慮,説明と同意】本研究における前処置は名古屋大学動物実験指針に従って実施した。【結果】運動+脳梗塞群は脳梗塞群に比べて,ND,LP,ladder testにおいて有意に障害が軽度であった(<i>p</i><0.05)。一方でBWでは群間に有意差は認められなかった。またSOD活性は,運動+脳梗塞群が脳梗塞群に比べ有意に高値を示した(<i>p</i><0.05)。さらにSOD1は,運動+脳梗塞群が脳梗塞群に比べ有意に発現が高かった(<i>p</i><0.05)。SOD2,3は群間に有意差は認められなかった。【考察】脳梗塞モデル作成前に3週間のトレッドミル運動を行うことで,脳梗塞後の感覚-運動機能障害が軽減することが示された。またSOD活性およびSOD1発現量の増加が示された。これらの結果より,事前に運動を行うことは,脳梗塞時のSOD発現,活性が促進され,虚血/再灌流により生じる大量の活性酸素を迅速に消去し,酸化ストレスを抑制する作用があると考えられる。よって,脳梗塞発症前の運動が及ぼす障害軽減効果には,SODの抗酸化ストレス能に伴う神経保護作用が関与していることが示唆された。【理学療法学研究としての意義】脳梗塞発症前の運動による脳梗塞障害軽減効果の作用機序の一端を分子生物学的に示した。これらの結果は,脳梗塞の予防として推奨されている運動の効果を科学的に検討し,予防医療分野における理学療法のさらなる発展に寄与するものと考える。

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  380. 【職業・環境発がん:メカニズムと病理】 繊維性ナノマテリアルの発がん機構

    豊國 伸哉

    病理と臨床   Vol. 32   page: 632 - 637   2014

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  381. Preclinical evaluation of an O-6-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains

    Tsujiuchi Takashi, Natsume Atsushi, Motomura Kazuya, Kondo Goro, Ranjit Melissa, Hachisu Rei, Sugimura Itsuro, Tomita Shinpei, Takehara Isao, Woolley Max, Barua Neil U., Gill Steven S., Bienemann Alison S., Yamashita Yoriko, Toyokuni Shinya, Wakabayashi Toshihiko

    AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH   Vol. 6 ( 2 ) page: 169 - 178   2014

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  382. Genotoxicity and carcinogenicity risk of carbon nanotubes. International journal

    Shinya Toyokuni

    Advanced drug delivery reviews   Vol. 65 ( 15 ) page: 2098 - 2110   2013.12

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    Novel materials are often commercialized without a complete assessment of the risks they pose to human health because such assessments are costly and time-consuming; additionally, sometimes the methodology needed for such an assessment does not exist. Carbon nanotubes have the potential for widespread application in engineering, materials science and medicine. However, due to the needle-like shape and high durability of multiwalled carbon nanotubes (MWCNTs), concerns have been raised that they may induce asbestos-like pathogenicity when inhaled. Indeed, experiments in rodents supported this hypothesis. Notably, the genetic alterations in MWCNT-induced rat malignant mesothelioma were similar to those induced by asbestos. Single-walled CNTs (SWCNTs) cause mitotic disturbances in cultured cells, but thus far, there has been no report that SWCNTs are carcinogenic. This review summarizes the recent noteworthy publications on the genotoxicity and carcinogenicity of CNTs and explains the possible molecular mechanisms responsible for this carcinogenicity. The nanoscale size and needle-like rigid structure of CNTs appear to be associated with their pathogenicity in mammalian cells, where carbon atoms are major components in the backbone of many biomolecules. Publishing adverse events associated with novel materials is critically important for alerting people exposed to such materials. CNTs still have a bright future with superb economic and medical merits. However, appropriate regulation of the production, distribution and secondary manufacturing processes is required, at least to protect the workers. (C) 2013 Elsevier B.V. All rights reserved.

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  383. Deferasirox Induces Mesenchymal-Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

    Toyokuni, S; Nagai, H; Okazaki, Y; Chew, SH; Yasui, H

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 65   page: S25 - S25   2013.11

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  384. Deferasirox Induces Mesenchymal-Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

    Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Hiroyuki Yasui, Shinya Toyokuni

    CANCER PREVENTION RESEARCH   Vol. 6 ( 11 ) page: 1222 - 30   2013.11

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    Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction.

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  385. From nagoya to the world

    Toyokuni S.

    Nagoya Journal of Medical Science   Vol. 75 ( 1-2 ) page: 1 - 2   2013.9

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  386. From nagoya to the world

    Toyokuni S

    Nagoya Journal of Medical Science   Vol. 75 ( 1-2 ) page: 1 - 2   2013.9

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  387. Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15nm in diameter does not induce mesothelial carcinogenesis in rats International journal

    Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Yasumitsu Miyata, Hisanori Shinohara, Shinya Toyokuni

    Pathology International   Vol. 63 ( 9 ) page: 457 - 62   2013.9

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    Multiwalled carbon nanotubes (MWCNTs) have attracted public attention not only for their potential applications in engineering and materials science but also for possible environmental risks. MWCNTs share similar properties with asbestos, a definite human carcinogen causing malignant mesothelioma (MM), in that they are both biopersistent thin fibers with a high aspect ratio. Certain types of MWCNTs do induce MM in animal experiments. Though there are many different types of MWCNTs awaiting use in industry, there is little evidence about what types of MWCNTs present a high risk for MMin vivo. We have previously shown that the diameter of MWCNTs is one of the critical factors for mesothelial injury, which eventually leads to MM. Because of the extensive commercial use of MWCNTs, the properties of MWCNTs that determine carcinogenic activity should be clarified. Here we report that a high dose (10mg) of a tangled form of pristine MWCNT (with a diameter of 15nm) did not induce MM after intraperitoneal administration in rats, which were followed for up to 3 years after injection. This observation strengthens our previous finding that the rigidity, diameter, length and surface properties of MWCNTs are important factors in MM induction in vivo. © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

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  388. Erratum to Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice, [International Union of Biochemistry and Molecular Biology, 23, 2, (2005) 85-95] Reviewed

    Yuji Naitoa, Satomi Akagiri, Kazuhiko Uchiyama, Satoshi Kokura, Norimasa Yoshida, Goji Hasegawa, Naoto Nakamura, Hiroshi Ichikawa, Shinya Toyokuni, Tetsuo Ijichi, Toshikazu Yoshikawa

    BioFactors   Vol. 39 ( 5 ) page: 589 - 589   2013.9

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  389. CD146 and insulin-like growth factor 2 mRNA-binding protein 3 predict prognosis of asbestos-induced rat mesothelioma Reviewed International journal

    Yasumasa Okazaki, Hirotaka Nagai, Shan H. Chew, Jiang Li, Satomi Funahashi, Tohru Tsujimura, Shinya Toyokuni

    CANCER SCIENCE   Vol. 104 ( 8 ) page: 989 - 995   2013.8

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    Malignant mesothelioma (MM), which is associated with asbestos exposure, is one of the most deadly tumors in humans. Early MM is concealed in the serosal cavities and lacks specific clinical symptoms. For better treatment, early detection and prognostic markers are necessary. Recently, CD146 and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) were reported as possible positive markers of MM to distinguish from reactive mesothelia in humans. However, their application on MM of different species and its impact on survival remain to be elucidated. To disclose the utility of these molecules as early detection and prognostic markers of MM, we injected chrysotile or crocidolite intraperitoneally to rats, thus obtaining 26 peritoneal MM and establishing 11 cell lines. We immunostained CD146 and IMP3 using paraffin-embedded tissues and cell blocks and found CD146 and IMP3 expression in 58% (15/26) and 65% (17/26) of MM, respectively, but not in reactive mesothelia. There was no significant difference in both immunostainings for overexpression among the three histological subtypes of MM and the expression of CD146 and IMP3 was proportionally associated. Furthermore, the overexpression of CD146 and/or IMP3 was proportionally correlated with shortened survival. These results suggest that CD146 and IMP3 are useful diagnostic and prognostic markers of MM.

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  390. Lewis y antigen is expressed in oral squamous cell carcinoma cell lines and tissues, but disappears in the invasive regions leading to the enhanced malignant properties irrespective of sialyl-Lewis x

    Hiroshi Hotta, Kazunori Hamamura, Kyoko Yamashita, Hidenobu Shibuya, Noriyo Tokuda, Noboru Hashimoto, Keiko Furukawa, Noriyuki Yamamoto, Hisashi Hattori, Shinya Toyokuni, Minoru Ueda, Koichi Furukawa

    GLYCOCONJUGATE JOURNAL   Vol. 30 ( 6 ) page: 585 - 97   2013.8

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    Expression and implication of carbohydrate antigens in squamous cell carcinomas (SCCs) in oral cavity was examined. In the cell lines, type 2H and Lewis y antigens were markedly expressed. In the tissues from SCC patients and benign disorders, type 2H was highly expressed in hyperplasia (96.4 %), displasia (92.9 %) and SCC (100 %). Lewis y was, in turn, expressed mainly in cancer tissues (91.3 %), suggesting that Lewis y is a cancer-associated antigen. Normal oral mucosa showed no expression of these blood group antigens. Surprisingly, Lewis y antigen disappeared in the invasion sites where Ki-67 was definitely stained. Over-expression of Lewis y with manipulation of a fucosyltransferase cDNA resulted in suppression of cell growth and invasion, and knockdown of Lewis y also brought about increased cell growth and invasion. In either situations, no changes in the expression of sialyl-Lewis x could be found. Lowered tumor growth and invasion into surrounding tissues were also shown in Lewis y-positive SCC grafts in nu/nu mice. All these results together with alternative staining between Lewis y and Ki-67 in cancer tissues and FUT1 transfectants suggested that loss of Lewis y is a crucial event for the late stage of SCCs.

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  391. Evaluation of two distinct methods to quantify the uptake of crocidolite fibers by mesothelial cells International journal

    Yamashita Kyoko, Nagai Hirotaka, Kondo Yuji, Misawa Nobuaki, Toyokuni Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 53 ( 1 ) page: 27 - 35   2013.7

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    Exposure to asbestos fibers increases the risk of mesothelioma in humans. One hypothetical carcinogenic mechanism is that asbestos fibers may directly induce mutations in mesothelial cells. Although the uptake of asbestos fibers by mesothelial cells is recognized, methods for the quantification of the uptake have not been well established. In the present study, we evaluated two distinct methods, using crocidolite fibers and MeT5A mesothelial cells. One method is histological evaluation using the cell-block technique, which allows for the direct cross-sectional observation of cells and fibers. We found the bright field observation with ×1000 magnification (oil-immersion) of the sample with Kernechtrot staining was most suitable for this purpose. The other method is flow cytometric analysis, which permits the evaluation of a much larger number of cells. We observed that the side scatter (SSC) increased with the intracellular fibers, and that the “mean SSC ratio (treated/control)” was useful for quantification. We could collect the cells with abundant internalized crocidolite fibers by sorting. Results of the two methodologies were correlated well in the experiments. The quantities of internalized fibers increased with incubation time and loaded dosage, but they were inversely associated with cellular density in culture.

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  392. Repeated short-term daily exercise ameliorates oxidative cerebral damage and the resultant motor dysfunction after transient ischemia in rats.

    Michiru Hamakawa, Akimasa Ishida, Keigo Tamakoshi, Haruka Shimada, Hiroki Nakashima, Taiji Noguchi, Shinya Toyokuni, Kazuto Ishida

    Journal of clinical biochemistry and nutrition   Vol. 53 ( 1 ) page: 8 - 14   2013.7

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    Long-term exercise prior to brain ischemia enhances the activities of antioxidant enzymes and leads to a significant reduction in brain damage and neurological deficits in rats subjected to transient middle cerebral artery occlusion. However, it has not been established whether relatively short-term exercise generates similar results following middle cerebral artery occlusion. We aimed to determine whether short-term exercise could reduce oxidative damage and prevent sensori-motor dysfunction. Male Wistar rats were subjected to perform daily exercise on a treadmill for 30 min at a speed of 15 m/min for 3 weeks, followed by a 90-mm middle cerebral artery occlusion. Animals were assessed after middle cerebral artery occlusion for neurological deficits and sensori-motor function. Brain tissues were processed to evaluate infarct volume and oxidative damage. Oxidative stress was assessed using immunohistochemistry for 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Antioxidant enzymes were evaluated using immunohistochemistry for thioredoxin and activity assay for superoxide dismutase. Exercise for 3 weeks decreased the severity of paralysis and impairment in forelimb motor coordination. Furthermore, exercise had effect on superoxide dismutase and reduced the infarct volume and the number of cells immunopositive for 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Our results suggest that pre-conditioning treadmill exercise for 3 weeks is useful for ameliorating ischemia-induced brain injury.

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  393. Multispecificity of Immunoglobulin M Antibodies Raised against Advanced Glycation End Products

    Miho Chikazawa, Natsuki Otaki, Takahiro Shibata, Hiroaki Miyashita, Yoshichika Kawai, Shoichi Maruyama, Shinya Toyokuni, Yasuyuki Kitaura, Tsukasa Matsuda, Koji Uchida

    Journal of Biological Chemistry   Vol. 288 ( 19 ) page: 13204 - 14   2013.5

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    DOI: 10.1074/jbc.M113.452177

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  394. CANCER AS A FERROTOXIC DISEASE: WHAT WE HAVE LEARNED FROM ANIMAL STUDIES TOWARD ITS PREVENTION International journal

    Toyokuni, S; Jiang, L; Okazaki, Y; Akatsuka, S

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 88 ( 5 ) page: E168 - E169   2013.5

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  395. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. Reviewed International journal

    Yoriko Yamashita, Shinya Akatsuka, Kanako Shinjo, Yasushi Yatabe, Hiroharu Kobayashi, Hiroshi Seko, Hiroaki Kajiyama, Fumitaka Kikkawa, Takashi Takahashi, Shinya Toyokuni

    PloS one   Vol. 8 ( 3 ) page: e57724   2013.3

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    Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR
    37.0% demonstrated Met gene amplification (&gt
    4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p&lt
    0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC. © 2013 Yamashita et al.

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  396. FROM NAGOYA TO THE WORLD International journal

    Toyokuni, S

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 75 ( 1-2 ) page: 1 - 2   2013.2

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  397. Protective effect of cardioplegia with poly (ADP-ribose) polymerase-1 inhibitor against myocardial ischemia-reperfusion injury: in vitro study of isolated rat heart model

    Kazuhiro Yamazaki, Seigo Tanaka, Ryuzo Sakata, Senri Miwa, Wnimonk Oriyanhan, Kiyoaki Takaba, Kenji Minakata, Akira Marui, Tadashi Ikeda, Shinya Toyokuni, Masashi Komeda, Kunihiro Ueda

    JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY   Vol. 28 ( 1 ) page: 143 - 7   2013.2

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    Poly(ADP-ribose) polymerase (PARP)-1 inhibitor has been suggested to attenuate the ischemia-reperfusion injury. We investigated the protective effect of the cardioplegia with a PARP-1 inhibitor, 4-hydoxyquinazoline (4-HQ), against myocardial ischemia-reperfusion injury. Isolated rat hearts were perfused on a Langendorff apparatus and cardioplegically arrested for 90 min by perfusion with St. Thomas' Hospital solution (ST-solution). In the Group ST (n = 8), the hearts were arrested with the ST-solution alone. The Group HQ (n = 8) were treated with the ST-solution containing 4-HQ (10 mu M) for cardioplegia. During reperfusion, the Group HQ showed significantly greater functional recovery of +dp/dt(max) (p = 0.005) and lower enzymatic leakage (p &lt; 0.01). NAD(+) levels were also preserved higher in the Group HQ (p &lt; 0.01). Immunohistochemical study revealed lesser extents of oxidative stress and apoptosis, in the Group HQ. Thus, addition of 4-HQ in the cardioplegia may provide a new intervention for myocardial protection against ischemia-reperfusion injury by decreasing NAD+ consumption and suppressing oxidative stress.

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  398. FROM NAGOYA TO THE WORLD Reviewed International journal

    Toyokuni Shinya

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 75 ( 1-2 ) page: 1 - 2   2013.2

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  399. Deferasirox induces mesenchymal-epithelial transition in crocidolite-induced mesothelila carcinogenesis in rats. Reviewed

    Nagai H, Okazaki Y, Chew SH, Misawa N, Yasui H and Toyokuni S.

    Cancer Prev Res   Vol. 6 ( 11 ) page: 1222-1230   2013

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  400. Genotoxicity and carcinogenicity risk of carbon nanotubes. Reviewed

    Toyokuni S.

    Adv Drug Deliver Rev     2013

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    DOI: doi:pii: S0169-409X(13)00149-X. 10.1016/j.addr.2013.05.011.

  401. Repeated short-term daily exercise ameliorates oxidative cerebral damage and the resultant motor dysfunction after transient ischemia in rats. Reviewed

    Hamakawa M, Ishida A, Tamakoshi K, Shimada H, Nakashima H, Noguchi T, Toyokuni S and Ishida K.

    J Clin Biochem Nutr   Vol. 53   page: 8-14   2013

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  402. CD146 and IMP3 predict prognosis of asbestos-induced rat mesothelioma. Reviewed

    Okazaki Y, Nagai H, Chew SH, Jiang L, Funahashi S, Tsujimura T and Toyokuni S.

    Cnacer Sci   Vol. 104   page: 989-995   2013

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  403. Multi-specificity of IgM antibodies raised against advanced glycation end products: Involvement of electronegative potential of antigens. Reviewed

    Chikazawa M, Otaki N, Shibata T, Miyashita H, Kawai Y, Maruyama S, Toyokuni S, Kitaura Y, Matsuda T, Uchida K.

    J Biol Chem   Vol. 288   page: 13204-13214   2013

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  404. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. Reviewed

    Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, Kajiyama H, Kikkawa F, Takahashi T and Toyokuni S.

    PLoS One   Vol. 8 ( 3 ) page: e57724   2013

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  405. Evaluation of two distinct methods to quantify the uptake of crocidolite fibers by mesothelial cells. Reviewed

    Yamashita K, Nagai H, Kondo Y, Misawa N and Toyokuni S.

    J Clin Biochem Nutr   Vol. 53   page: 27-35   2013

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  406. Metamorphosis of mesothelial cells with active horizontal motility in tissue culture. Reviewed

    Nagai H, Chew SH, Okazaki Y, Funahashi S, Namba T, Kato T, Enomoto A, Jiang L, Akatsuka S and Toyokuni S.

    Sci Rep   Vol. 3   page: 1144   2013

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  407. Protective effect of cardioplegia with poly(ADP-ribose)polymerase-1 inhibitor aganst myocardial ischemia-reperfusion injury: in vitro study if isolated rat heart model. Reviewed

    Yamazaki K, Tanaka S, Sakata R, Miwa S, Oriyanhan W, Takaba K, Minakata K, Marui A, Ikeda T, Toyokuni S, Komeda M and Ueda K.

    J Enzyme Inhibition Medicinal Chem   Vol. 28   page: 143-147   2013

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  408. Lewis y antigen is expressed in oral squamous cell carcinoma cell lines and tissues, but disappears in the invasive regions leading to the enhanced malignant properties irrespective of sialyl-Lewis x. Reviewed

    Hotta H, Hamamura K, Yamashita K, Shibuya H, Tokuda N, Hashimoto N, Furukawa K, Yamamoto N, Hattori H, Toyokuni S, Ueda M, Furukawa K.

    Glycoconj J   Vol. 30   page: 585-597   2013

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  409. Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15 nm in diameter does not induce mesothelial carcinogenesis in rats. Reviewed

    Nagai H, Okazaki Y, Chew SH, Misawa N, Miyata Y, Shinohara N and Toyokuni S.

    Pathol. Int.   Vol. 63   page: 457-462   2013

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    DOI: doi: 10.1111/pin.12093.

  410. Metamorphosis of mesothelial cells with active horizontal motility in tissue culture International journal

    Hirotaka Nagai, Shan Hwu Chew, Yasumasa Okazaki, Satomi Funahashi, Takashi Namba, Takuya Kato, Atsushi Enomoto, Li Jiang, Shinya Akatsuka, Shinya Toyokuni

    SCIENTIFIC REPORTS   Vol. 3   page: 1144   2013

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    Mesothelial cells, which have diverse roles in physiology and pathology, constitute the mesothelium along with connective tissue and the basement membrane; the mesothelium serves to shield the somatic cavities. After mesothelial injury, mesothelial cells undergo tissue recovery. However, the mechanism of mesothelial regeneration remains poorly understood. In this study, we used confocal time-lapse microscopy to demonstrate that transformed mesothelial cells (MeT5A) and mouse peritoneal mesothelial cells can randomly migrate between cells in cell culture and in ex vivo tissue culture, respectively. Moreover, peritoneal mesothelial cells changed their morphology from a flattened shape to a cuboidal one prior to the migration. Conversely, MDCKII epithelial cells forming tight cell-cell contacts with one another do not alter the arrangement of adjacent cells during movement. Our evidence complements the current hypotheses of mesothelial regeneration and suggests that certain types of differentiated mesothelial cells undergo morphological changes before initiating migration to repair injured sites.

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  411. Genotoxicity and carcinogenicity risk of carbon nanotubes. Reviewed

    Toyokuni S

    Adv Drug Deliver Rev     2013

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  412. Multi-specificity of IgM antibodies raised against advanced glycation end products: Involvement of electronegative potential of antigens. Reviewed

    Chikazawa M, Otaki N, Shibata T, Miyashita H, Kawai Y, Maruyama S, Toyokuni S, Kitaura Y, Matsuda T, Uchida K

    J Biol Chem   Vol. 288   page: 13204-13214   2013

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  413. Factors regulating the carcinogenicity of multiwalled carbon nanotubes

    TOYOKUNI Shinya

    Annual Meeting of the Japanese Society of Toxicology   Vol. 40 ( 0 ) page: 1044   2013

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  414. 脳梗塞発症前の運動による脳梗塞障害軽減効果及びその作用機序の検討〜酸化ストレスに着目して〜

    野口 泰司, 濱川 みちる, 玉越 敬悟, 戸田 拓弥, 豊國 伸哉, 石田 和人

    理学療法学Supplement   Vol. 2012 ( 0 ) page: 48101465 - 48101465   2013

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    【はじめに、目的】脳梗塞発症時には活性酸素やフリーラジカルが大量に産生され、その酸化ストレスは組織障害を拡大させ脳梗塞を増悪させる因子である。一方で、健常なラットに長期間運動させると、脳内で抗酸化物質が増加し酸化ストレスの減少がもたらされることが報告されており、運動は脳内の抗酸化作用を高めることが示されている。また、先行研究では脳梗塞モデルラット作成前に一定期間の運動を行うと、運動していないラットに比べて、脳梗塞後の梗塞体積が減少し運動機能障害も軽減するといった脳梗塞障害軽減効果が報告されている。しかし、この運動により高まる脳内の抗酸化作用が、脳梗塞時の酸化ストレスに影響を及ぼしているかどうかは不明である。そこで本研究では、脳梗塞発症前の運動による脳梗塞障害軽減効果およびその作用機序を、脳内の抗酸化作用に着目して検討することを目的とする。【方法】実験動物にはWistar系雄性ラット(5 週齢)を用いた。無作為に(1)Sham群、(2)運動+sham群、(3)脳梗塞群、(4)運動+脳梗塞群に分け、脳梗塞+運動群と運動+sham群は3 週間のトレッドミル運動(15 m/min,30 分/日)を毎日行った。脳梗塞群とSham群は走行させずにトレッドミル装置内に暴露させた(1 日30 分間)。3 週間後、運動+脳梗塞群と脳梗塞群に対し、小泉法による脳梗塞モデル作成手術を施行した。手術24 時間後に、運動-感覚機能評価として、麻痺の重症度を評価するneurological deficits(ND)、歩行時のバランス能力の評価としてbeam walking(BW)、はしごの上の歩行における前肢の協調運動機能の評価としてladder test、前肢の感覚運動機能の評価としてlimb placing(LP)を行った。その直後に脳を採取し、TTC染色により非梗塞半球体積に対する梗塞体積の割合を算出した。また、酸化ストレス関連指標として、脂質過酸化の指標である4-hydroxy-2-nonenal(4-HNE)とDNAの酸化的損傷の指標となる8-Hydroxydeoxyguanosine(8-OHdG)、抗酸化酵素であるthioredoxin(TRX)の免疫組織化学染色を行い、陽性細胞数及び光学濃度を計測した。またSOD Assay kit-WST(同仁化学研究所)を用いて抗酸化酵素であるsuperoxide dismutase(SOD)活性を計測した。【倫理的配慮、説明と同意】本研究における全処置は名古屋大学動物実験指針に従って実施した。【結果】運動+脳梗塞群は脳梗塞群に比べて、NDとladder testのスコアが低値となり有意に障害が軽度であった。LPとBWは群間に有意差は認められなかった。また、梗塞体積割合は運動+脳梗塞群の方が脳梗塞群よりも有意に小さかった。4-HNE 及び8-OHdG陽性細胞数は、運動+脳梗塞群の方が脳梗塞群に比べ有意に少なかった。一方、TRXの光学濃度は群間に有意な差は認められなかったが、SOD活性は運動+脳梗塞群が脳梗塞群に比べ高値を示す傾向にあった。【考察】脳梗塞モデル作成前に3 週間のトレッドミル運動を継続することで、脳梗塞後の麻痺の重症度および前肢の協調運動機能障害が軽減すること、梗塞体積が縮小すること、また脳梗塞時の脂質やDNAに対する酸化ストレスを抑制することが示された。さらに抗酸化酵素であるSOD活性が高められることが示された。これらの結果より、脳梗塞前の運動による脳梗塞の障害軽減効果には酸化ストレスの抑制とSODの活性化が関与していることが示唆された。【理学療法学研究としての意義】脳梗塞発症前の運動による脳梗塞障害軽減効果を行動学的、組織化学的に示した。加えて、運動による酸化ストレスの抑制と抗酸化作用の増加の関連も示され、その作用機序の一端を明らかにした。これらの結果は、脳梗塞の予防として推奨されている運動の効果を科学的に検討し、予防医療分野における理学療法のさらなる発展に寄与するものと考える。

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  415. CD146 and IMP3 predict prognosis of asbestos-induced rat mesothelioma. Reviewed

    Okazaki Y, Nagai H, Chew SH, Jiang L, Funahashi S, Tsujimura T, Toyokuni S

    Cnacer Sci   Vol. 104   page: 989-995   2013

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  416. がんモデルマウス・ラットライブラリ 第7回 中皮腫モデル

    豊國 伸哉

    細胞工学   Vol. 32   page: 220 - 224   2013

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  417. The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. Reviewed International journal

    Momen Elshazley, Mitsuo Sato, Tetsunari Hase, Ryo Yamashita, Kenya Yoshida, Shinya Toyokuni, Futoshi Ishiguro, Hirotaka Osada, Yoshitaka Sekido, Kohei Yokoi, Noriyasu Usami, David S Shames, Masashi Kondo, Adi F Gazdar, John D Minna, Yoshinori Hasegawa

    International journal of cancer   Vol. 131 ( 12 ) page: 2820 - 31   2012.12

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    Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21(WAF1/CIP1) and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.

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  418. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes Reviewed

    T. Mizuno, H. Murakami, M. Fujii, F. Ishiguro, I. Tanaka, Y. Kondo, S. Akatsuka, S. Toyokuni, K. Yokoi, H. Osada, Y. Sekido

    ONCOGENE   Vol. 31 ( 49 ) page: 5117 - 5122   2012.12

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    Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 (NF2) -tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2, LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro. We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1, in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells. Oncogene (2012) 31, 5117-5122; doi:10.1038/onc.2012.5; published online 30 January 2012

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  419. Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite International journal

    Yurika Kubo, Hiroyuki Takenaka, Hirotaka Nagai, Shinya Toyokuni

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 51 ( 3 ) page: 221 - 6   2012.11

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    The inhalation of asbestos is a risk factor for the development of malignant mesothelioma and lung cancer. Based on the broad surface area of asbestos fibers and their ability to enter the cytoplasm and nuclei of cells, it was hypothesized that proteins that adsorb onto the fiber surface play a role in the cytotoxicity and carcinogenesis of asbestos fibers. However, little is known about which proteins adsorb onto asbestos. Previously, we systematically identified asbestos-interacting proteins and classified them into eight sub-categories: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. Here, we report an adsorption profile of proteins for the three commercially used asbestos compounds: chrysotile, crocidolite and amosite. We quantified the amounts of adsorbed proteins by analyzing the silver-stained gels of sodium dodecyl sulfate-polyacrylamide gel electrophoresis with ImageJ software, using the bands for amosite as a standard. We found that histones were most adsorptive to crocidolite and that chromatin-binding proteins were most adsorptive to chrysotile. The results suggest that chrysotile and crocidolite directly interact with chromatin structure through different mechanisms. Furthermore, RNA-binding proteins preferably interacted with chrysotile, suggesting that chrysotile may interfere with transcription and translation. Our results provide novel evidence demonstrating that the specific molecular interactions leading to carcinogenesis are different between chrysotile and crocidolite.

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  420. Iron overload signature in chrysotile-induced malignant mesothelioma

    Jiang L., Akatsuka S., Nagai H., Chew S.H., Ohara H., Okazaki Y., Yamashita Y., Yoshikawa Y., Yasui H., Ikuta K., Sasaki K., Kohgo Y., Hirano S., Shinohara Y., Kohyama N., Takahashi T., Toyokuni S.

    Journal of Pathology   Vol. 228 ( 3 ) page: 366 - 377   2012.11

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    Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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  421. Asbestos surface provides a niche for oxidative modification: A novel role of free radicals in carcinogenesis

    H. Nagai, Y. Okazaki, L. Jiang, S. Akatsuka, Y. Yamashita, S. Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 53   page: S51 - S52   2012.9

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  422. Bovine lactoferrin ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats. Reviewed International journal

    Yasumasa Okazaki, Isato Kono, Takayoshi Kuriki, Satomi Funahashi, Soichiro Fushimi, Mohammad Iqbal, Shigeru Okada, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 51 ( 2 ) page: 84 - 90   2012.9

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    Milk provides a well-balanced source of amino acids and other ingredients. One of the functional ingredients in milk is lactoferrin (LF). LF presents a wide variety of bioactivities and functions as a radical scavenger in models using iron-ascorbate complexes and asbestos. Human clinical trials of oral LF administration for the prevention of colon polyps have been successful and demonstrated that dietary compounds exhibit direct interactions. However, antioxidative properties of IF in distant organs require further investigation. To study the antioxidant property of LF, we employed bovine lactoferrin (bLF) using the rat model of ferric nitrilotriacetate (Fe-NTA)-induced renal tubular oxidative injury. We fed rats with bLF (0.05%, w/w) in basal chow for 4 weeks and sacrificed them after Fe-NTA treatment. After intraperitoneal administration of 9.0 mg iron/kg Fe-NTA for 4 and 24 h, bLF pretreatment suppressed elevation of serum creatinine and blood urea nitrogen levels. In addition, we observed protective effects against renal oxidative tubular damage and maintenance of antioxidant enzyme activities in the bLF-pretreated group. We thus demonstrated the antioxidative effect of bLF against Fe-NTA-induced renal oxidative injury. These results suggest that LF intake is useful for the prevention of renal tubular oxidative damage mediated by iron.

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  423. Iron overload signature in chrysotile-induced malignant mesothelioma. Reviewed

    Jiang L, Akatsuka S, Nagai H, Chew SH, Ohara H, Okazaki Y, Yamashita Y, Yoshikawa Y, Yasui H, Ikuta K, Sasaki K, Kohgo Y, Hirano S, Shinohara Y, Kohyama N, Takahashi T, Toyokuni S

    J Pathol   Vol. 228   page: 366-377   2012.8

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  424. Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis: shedding light on fiber entry mechanism. International journal

    Hirotaka Nagai, Shinya Toyokuni

    Cancer science   Vol. 103 ( 8 ) page: 1378 - 1390   2012.8

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    The emergence of nanotechnology represents an important milestone, as it opens the way to a broad spectrum of applications for nanomaterials in the fields of engineering, industry and medicine. One example of nanomaterials that have the potential for widespread use is carbon nanotubes, which have a tubular structure made of graphene sheets. However, there have been concerns that they may pose a potential health risk due to their similarities to asbestos, namely their high biopersistence and needle-like structure. We recently found that despite these similarities, carbon nanotubes and asbestos differ in certain aspects, such as their mechanism of entry into mesothelial cells. In the study, we showed that non-functionalized, multi-walled carbon nanotubes enter mesothelial cells by directly piercing through the cell membrane in a diameter- and rigidity-dependent manner, whereas asbestos mainly enters these cells through the process of endocytosis, which is independent of fiber diameter. In this review, we discuss the key differences, as well as similarities, between asbestos fibers and carbon nanotubes. We also summarize previous reports regarding the mechanism of carbon nanotube entry into non-phagocytic cells. As the entry of fibers into mesothelial cells is a crucial step in mesothelial carcinogenesis, we believe that a comprehensive study on the differences by which carbon nanotubes and asbestos fibers enter into non-phagocytic cells will provide important clues for the safer manufacture of carbon nanotubes through strict regulation on fiber characteristics, such as diameter, surface properties, length and rigidity. (Cancer Sci 2012; 103: 13781390)

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  425. Mitochondria and free radical studies on health, disease and pollution. Invited International journal

    Hideyuki J Majima, Shinya Toyokuni

    Free radical research   Vol. 46 ( 8 ) page: 925 - 6   2012.8

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    DOI: 10.3109/10715762.2012.700784

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  426. The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. International journal

    Hiroharu Kobayashi, Yoriko Yamashita, Akira Iwase, Yutaka Yoshikawa, Hiroyuki Yasui, Yoshichika Kawai, Koji Uchida, Nozomi Uno, Shinya Akatsuka, Takashi Takahashi, Fumitaka Kikkawa, Shinya Toyokuni

    Fertility and sterility   Vol. 98 ( 2 ) page: 415 - 22.e1   2012.8

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    Objective: To understand the role of ectopic endometriotic stromal cells in ovarian endometriosis (OEM) and the associated risks for infertility and carcinogenesis.
    Design: Analyses of secreted proteins and gene expression using immortalized eutopic/ectopic endometrial(-otic) stromal cells from OEM.
    Setting: University.
    Patient(s): Women with and without OEM.
    Intervention(s): Samples of endometrial(-otic) tissue from women with or without OEM.
    Main Outcome Measure(s): Immunohistochemical analysis of oxidative stress in OEM, gene expression profiles, and the identification of secreted proteins by mass spectrometry in immortalized endometrial(-otic) stromal cells.
    Result(s): 4-Hydroxy-2-nonenal-modified proteins and carboxymethyllysine were abundant in the stroma, rather than epithelia, of OEM patients, indicating the presence of oxidative stress. Immortalized ectopic endometriotic stromal cells exhibited high IRP1/IRP2/HIF-1 beta expression and contained lower amounts of iron and copper than their eutopic counterparts. Expression profiles, in combination with protein identification, revealed that complement component 3 (C3) and pentraxin-3 (PTX3) are the major proteins secreted from immortalized ectopic endometriotic stromal cells. Complement-3/PTX3 promoted the secretion of various cytokines by THP1 macrophage cells and thus supported M1 differentiation.
    Conclusion(s): Immortalized ectopic endometriotic stromal cells in OEM predominantly secrete C3 and PTX3 and exhibit a differential regulation of iron metabolism. (Fertil Steril (R) 2012;98:415-22. (C) 2012 by American Society for Reproductive Medicine.)

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  427. Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells. Reviewed International journal

    Mihoko Horio, Mitsuo Sato, Yoshihiro Takeyama, Momen Elshazley, Ryo Yamashita, Tetsunari Hase, Kenya Yoshida, Noriyasu Usami, Kohei Yokoi, Yoshitaka Sekido, Masashi Kondo, Shinya Toyokuni, Adi F Gazdar, John D Minna, Yoshinori Hasegawa

    Annals of surgical oncology   Vol. 19 Suppl 3 ( Suppl 3 ) page: S634-45 - S645   2012.7

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    Background. The role of ZEB1, a master epithelial-to-mesenchymal transition gene, in malignant pleural mesothelioma (MPM) is unclear.
    Methods. The expression of ZEB1, E-cadherin, vimentin, and epithelial cell adhesion molecule (EpCAM) in 18 MPM cell lines and a normal pleural mesothelial cell line MeT-5A was determined by quantitative real-time polymerase chain reaction and Western blot testing. RNA interference-mediated transient and/or stable knockdown of ZEB1 and EpCAM was performed. Microarray expression analysis was performed with a TORAY-3D gene chip. Growth was evaluated by colorimetric proliferation and colony formation assays. Luciferase reporter assay was performed to access the effects of ZEB1 knockdown on EpCAM promoter activity.
    Results. Most MPM cell lines exhibited mesenchymal phenotype and expressed ZEB1. Transient ZEB1 knockdown suppressed growth in all four cell lines studied (ACC-MESO-1, H2052, Y-MESO-8A, Y-MESO-29) while stable ZEB1 knockdown suppressed growth only in Y-MESO-29. Genome-wide gene expression analysis revealed that EpCAM was the most prominently up-regulated gene by both transient and stable ZEB1 knockdown in ACC-MESO-1, with more marked up-regulation in stable knockdown. We hypothesized that EpCAM up-regulation counteracts the stable ZEB1 knockdown-induced growth inhibition in ACC-MESO-1. Transient EpCAM knockdown suppressed growth dramatically in ACC-MESO-1 cells expressing shZEB1 but only modestly in those expressing shGFP, supporting our hypothesis. Luciferase reporter assay showed that ZEB1 knockdown resulted in increased EpCAM promoter activity. EpCAM was also up-regulated in Y-MESO-29 expressing shZEB1, but this EpCAM up-regulation did not counteract ZEB1knockdown-induced growth suppression, suggesting that the counteracting effects of EpCAM may be cellular context dependent.
    Conclusions. RNA interference-mediated ZEB1 knockdown may be a promising therapeutic strategy for MPM, but one has to consider the possibility of diminished growth inhibitory effects of long-term ZEB1 knockdown, possibly as a result of EpCAM up-regulation and/or other gene expression changes resulting from ZEB1 knockdown.

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  428. FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation. International journal

    Kei Ishii, Mito Kanatsu-Shinohara, Shinya Toyokuni, Takashi Shinohara

    Development (Cambridge, England)   Vol. 139 ( 10 ) page: 1734 - 1743   2012.5

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    Fibroblast growth factor 2 (FGF2) and glial cell line-derived neurotrophic factor (GDNF) are required to recapitulate spermatogonial stem cell (SSC) self-renewal in vitro. Although studies have revealed the role of the GDNF signaling pathway in SSCs, little is known about how FGF2 is involved. In the present study, we assessed the role of the FGF2 signaling pathway using a mouse germline stem (GS) cell culture system that allows in vitro expansion of SSCs. Adding GDNF or FGF2 induced phosphorylation of MAPK1/3, and adding the MAP2K1 inhibitor PD0325091 reduced GS cell proliferation and MAPK1/3 phosphorylation. Moreover, GS cells transfected with an activated form of Map2k1 not only upregulated Etv5 and Bcl6b gene expression, but also proliferated in an FGF2-independent manner, suggesting that they act downstream of MAP2K1 signaling to drive SSC self-renewal. Although GS cells transfected with Map2k1, Etv5 or Bcl6b showed normal spermatogonial markers, transplanting GS cells expressing Bcl6b into infertile mouse testes resulted in the formation of a germ cell tumor, suggesting that excessive self-renewal signals causes tumorigenic conversion. These results show that FGF2 depends on MAP2K1 signaling to drive SSC self-renewal via upregulation of the Etv5 and Bcl6b genes.

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  429. In vitro transformation of mouse testis cells by oncogene transfection. Reviewed

    Morimoto H, Lee J, Tanaka T, Ishii K, Toyokuin S, Kanatsu-Shinohara M and Shinohara T.

    Biol Reprod   Vol. 86 ( 5 ) page: 1-11   2012.5

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  430. In vitro transformation of mouse testis cells by oncogene transfection. International journal

    Hiroko Morimoto, Jiyoung Lee, Takashi Tanaka, Kei Ishii, Shinya Toyokuni, Mito Kanatsu-Shinohara, Takashi Shinohara

    Biology of reproduction   Vol. 86 ( 5 ) page: 148, 1 - 11   2012.5

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    Germ cell tumors (GCTs) are unique in that they exhibit diverse biological characteristics and pathological features. Although several in vivo GCT models are available, studies on GCTs are hampered because in vivo development of GCTs is time consuming and prevents a detailed molecular analysis of the transformation process. Here we developed a novel strategy to transform mouse testis cells in vitro. Lentivirus-mediated transfection of dominant negative Trp53, Myc, and activated Hras1 into a CD9-expressing testis cells caused tumorigenic conversion in vitro. Although these cells resembled embryonic stem (ES) cells, they were aneuploid and lacked Nanog expression, which is involved in the maintenance of the undifferentiated state in ES cells. Euploid ES-like cells were produced by transfecting the Yamanaka factors (Pou5f1, Myc, Klf4, and Sox2) into the same cell population. Although these cells expressed Nanog, they were distinct from ES cells in that they expressed CD44, a cancer stem cell antigen. Both treatments induced similar changes in the DNA methylation patterns in differentially methylated regions of imprinted genes. Moreover, despite the differences in their phenotype and karyotype, both cell types similarly produced mixed GCTs on transplantation, which were composed of teratomas, seminomas, and embryonal carcinomas. Thus, in vitro testis cell transformation facilitates an analysis of the GCT formation process, and our results also suggest the close similarity between GCT formation and reprogramming.

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  431. Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy

    TOYOKUNI Shinya

      Vol. 53 ( 4 ) page: 401 - 408   2012.4

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  432. Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy

    TOYOKUNI Shinya

      Vol. 53 ( 4 ) page: 401 - 408   2012.4

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  433. Genome-wide assessment of oxidatively generated DNA damage. Reviewed International journal

    Shinya Akatsuka, Shinya Toyokuni

    Free radical research   Vol. 46 ( 4 ) page: 523 - 30   2012.4

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    In the tide of science nouveau after the completion of genome projects of various species, there appeared a movement to understand an organism as a system rather than the sum of cells directed for certain functions. With the advent and spread of microarray techniques, systematic and comprehensive genome-wide approaches have become reasonably possible and more required on the investigation of DNA damage and the subsequent repair. The immunoprecipitation-based technique combined with high-density microarrays or next-generation sequencing is one of the promising methods to provide access to such novel research strategies. Oxygen is necessary for most of the life on earth for electron transport. However, reactive oxygen species are inevitably generated, giving rise to steady-state levels of DNA damage in the genome, that may cause mutations leading to cancer, ageing and degenerative diseases. Previously, we showed that there are many factors involved in the genomic distribution of oxidatively generated DNA damage including chromosome territory, and proposed this sort of research area as oxygenomics. Recently, RNA is also recognized as a target of this kind of modification.

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  434. [Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy].

    Toyokuni S

    [Rinsho ketsueki] The Japanese journal of clinical hematology   Vol. 53 ( 4 ) page: 401 - 8   2012.4

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  435. [Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy].

    Toyokuni S

    [Rinsho ketsueki] The Japanese journal of clinical hematology   Vol. 53 ( 4 ) page: 401 - 8   2012.4

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  436. Age- and sun exposure-dependent differences in 8-hydroxy-2 '-deoxyguanosine and N epsilon-(carboxymethyl)lysine in human epidermis

    Akira Kawada, Akira Date, Shinya Toyokuni

    JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY   Vol. 66 ( 4 ) page: AB174 - AB174   2012.4

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  437. 多層カーボンナノチューブの直径と剛性は、中皮細胞傷害と中皮腫形成に重要な因子である

    永井 裕崇, 岡崎 泰昌, 周 珊瑚, 三澤 伸明, 山下 依子, 赤塚 慎也, 石原 敏和, 山下 享子, 吉川 豊, 安井 裕之, 蒋 麗, 高橋 隆, 市原 学, 宮田 耕充, 篠原 久典, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 280 - 280   2012.3

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  438. Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary

    Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

    MODERN PATHOLOGY   Vol. 25   page: 302A - 302A   2012.2

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  439. FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b genes through MAP2K1 activation. Reviewed

    Ishii K, Kanatsu-Shinohara M, Toyokuni S and Shinohara T.

    Development   Vol. 139   page: 1734-1743   2012

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  440. Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis. Reviewed

    Nagai H and Toyokuni S.

    Cancer Sci   Vol. 103   page: 1378-1390   2012

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  441. The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. Reviewed

    Kobayashi H, Yamashita Y, Iwase A, Yoshikawa Y, Yasui H, Kawai Y, Uchida K, Uno N, Akatsuka S, Takahashi T, Kikkawa F, Toyokuni S.

    Fertil Steril   Vol. 98   page: 415-422   2012

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  442. Bovine lactoferrin ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats. Reviewed

    Okazaki Y, Kono H, Kuriki R, Funahashi S, Fushimi S, Iqbal M, Okada S and Toyokuni S.

    J Clin Biochem Nutr   Vol. 51   page: 84-90   2012

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  443. Mitochondria and free radical studies on health, disease and pollusion (editorial). Invited

    Majima HJ and Toyokuni S.

    Free Radic Res   Vol. 46   page: 925-926   2012

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  444. Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. Invited Reviewed

    Kubo Y, Takenaka H, Nagai H and Toyokuni S.

    J Clin Biochem Nutr   Vol. 51   page: 221-226   2012

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  445. The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. Reviewed

    Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S, Ishiguro F, Osada H, Sekido Y, Yokoi K, Usami N, Shames DS, Kondo M, Gazdar AF, Minna JD and Hasegawa Y.

    INt J Cancer   Vol. 131   page: 2820-2831   2012

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  446. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle promoting genes. Reviewed

    Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, Akatsuka S, Toyokuni S and Sekido Y.

    Oncogene   Vol. 31   page: 5117-5122   2012

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  447. Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothalioma cells. Reviewed

    Horio M, Sato M, Takayama Y, Elshazley M, Yamashita R, Hase T, Yoshida K, Usami N, Yokoi K, Sekido Y, Kondo M, Toyokuni S, Gazdar AF, Minna JD and Hasegawa Y.

    Ann Surg Oncol   Vol. 19 ( Suppl 3 ) page: 634-645   2012

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  448. Genome-wide assessment of oxidatively generated DNA damage. Reviewed

    Akatsuka S and Toyokuni S.

    Free Radic Res   Vol. 46   page: 523-530   2012

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  449. Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis. Reviewed

    Nagai H, Toyokuni S

    Cancer Sci   Vol. 103   page: 1378-1390   2012

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  450. Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer

    Shinya Akatsuka, Yoriko Yamashita, Hiroki Ohara, Yu-Ting Liu, Masashi Izumiya, Koichiro Abe, Masako Ochiai, Li Jiang, Hirotaka Nagai, Yasumasa Okazaki, Hideki Murakami, Yoshitaka Sekido, Eri Arai, Yae Kanai, Okio Hino, Takashi Takahashi, Hitoshi Nakagama, Shinya Toyokuni

    PLOS ONE   Vol. 7 ( 8 ) page: e43403   2012

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    Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

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  451. FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b genes through MAP2K1 activation. Reviewed

    Ishii K, Kanatsu-Shinohara M, Toyokuni S, Shinohara T

    Development   Vol. 139   page: 1734-1743   2012

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  452. Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy

    Rinsho Ketsueki   Vol. 53 ( 4 ) page: 401 - 408   2012

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  453. 酸化ストレスによるゲノム変化と発がん

    赤塚 慎也, 豊國 伸哉

    実験医学   Vol. vol.30   page: 2779 - 2785   2012

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  454. Asbestos surface provides a niche for oxidative modification

    NAGAI Hirotaka, ISHIHARA Toshikazu, LEE Wen-Hua, OHARA Hiroki, OKAZAKI Yasumasa, OKAWA Katsuya, TOYOKUNI Shinya

    Cancer Sci.   Vol. 102 ( 12 ) page: 2118 - 2125   2011.12

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  455. Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. International journal

    Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Yoriko Yamashita, Shinya Akatsuka, Toshikazu Ishihara, Kyoko Yamashita, Yutaka Yoshikawa, Hiroyuki Yasui, Li Jiang, Hiroki Ohara, Takashi Takahashi, Gaku Ichihara, Kostas Kostarelos, Yasumitsu Miyata, Hisanori Shinohara, Shinya Toyokuni

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 108 ( 49 ) page: E1330 - 8   2011.12

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    Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter ∼ 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammogenicity and mesotheliomagenicity in vivo. In contrast, thick (diameter ∼ 150 nm) or tangled (diameter ∼ 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.

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  456. miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. Reviewed International journal

    Eri Nishikawa, Hirotaka Osada, Yasumasa Okazaki, Chinatsu Arima, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Yasushi Yatabe, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

    Cancer research   Vol. 71 ( 19 ) page: 6165 - 6173   2011.10

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    Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. Cancer Res; 71(19); 6165-73. (C)2011 AACR.

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  457. BMAL1 depletion represses growth of mesothelioma through induction of mitotic catastrophe Reviewed International coauthorship International journal

    Elshazley, MHKA; Hasegawa, Y; Sato, M; Hase, T; Yoshida, K; Toyokuni, S; Seikido, Y; Yokoi, K; Usami, N; Kondo, M

    CANCER RESEARCH   Vol. 71   2011.9

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  458. MET Amplification is a Molecular Hallmark in Endometriosis-associated Ovarian Clear Cell Carcinoma and Correlates With Worse Prognosis

    Y. Yamashita, Y. Yatabe, S. Akatsuka, H. Kajiyama, F. Kikkawa, T. Takahashi, S. Toyokuni

    EUROPEAN JOURNAL OF CANCER   Vol. 47   page: S529 - S529   2011.9

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  459. Elucidation of Asbestos-induced Mesothelial Carcinogenesis toward Its Prevention

    JIANG Li, TOYOKUNI Shinya

    Environmental Mutagen Research   Vol. 33 ( 1 ) page: 4 - 9   2011.8

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    Human exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in the pleural and abdominal cavity. Despite advancements in the molecular analyses of human cases of DMM and animal models, the understanding of the carcinogenic mechanisms remains still limited. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be integrated as follows; (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of reactive oxygen species (ROS) due to their inability to digest the fibers, and that iron contained in crocidolite and amosite fibers works as a catalyst for the generation of ROS, (2) the "chromosome tangling theory" postulates that asbestos fibers impair the equivalent distribution of chromosomes during mitosis, and (3) the "theory of adsorbing many specific proteins as well as carcinogenic molecules" states that asbestos fibers <i>in vivo</i> concentrate specific proteins or chemicals including the components of cigarette smoke and radioactive chemical element. Recent studies suggest that local iron overload is a key event. Elucidation of the major mechanisms underlying DMM would be helpful for the development of strategies to prevent DMM generation in people who have been exposed to asbestos.<br>

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  460. Iron as a target of chemoprevention for longevity in humans. International journal

    Shinya Toyokuni

    Free radical research   Vol. 45 ( 8 ) page: 906 - 917   2011.8

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    Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron&apos;s carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer&apos;s disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.

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  461. Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. Reviewed International journal

    Yang-Yi Fan, Qitao Ran, Shinya Toyokuni, Yasumasa Okazaki, Evelyn S Callaway, Joanne R Lupton, Robert S Chapkin

    Cancer prevention research (Philadelphia, Pa.)   Vol. 4 ( 8 ) page: 1267 - 74   2011.8

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    An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2(Het), Gpx4(Het), and transgenic Gpx4(Tg) mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4(Het) &gt; SOD2(Het) &gt; Wt &gt; Gpx4(Tg)), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4(Het) and SOD2(Het) mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4(Tg) mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P &lt; 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk. Cancer Prev Res; 4(8); 1267-74. (C) 2011 AACR.

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  462. The Human Cytomegalovirus Gene Products Essential for Late Viral Gene Expression Assemble into Prereplication Complexes before Viral DNA Replication Reviewed

    Hiroki Isomura, Mark F. Stinski, Takayuki Murata, Yoriko Yamashita, Teru Kanda, Shinya Toyokuni, Tatsuya Tsurumi

    JOURNAL OF VIROLOGY   Vol. 85 ( 13 ) page: 6629 - 6644   2011.7

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    The regulation of human cytomegalovirus (HCMV) late gene expression by viral proteins is poorly understood, and these viral proteins could be targets for novel antivirals. HCMV open reading frames (ORFs) UL79, -87, and -95 encode proteins with homology to late gene transcription factors of murine gammaherpesvirus 68 ORFs 18, 24, and 34, respectively. To determine whether these HCMV proteins are also essential for late gene transcription of a betaherpesvirus, we mutated HCMV ORFs UL79, -87, and -95. Cells were infected with the recombinant viruses at high and low multiplicities of infection (MOIs). While viral DNA was detected with the recombinant viruses, infectious virus was not detected unless the wild-type viral proteins were expressed in trans. At a high MOI, mutation of ORF UL79, -87, or -95 had no effect on the level of major immediate-early (MIE) gene expression or viral DNA replication, but late viral gene expression from the UL44, -75, and -99 ORFs was not detected. At a low MOI, preexpression of UL79 or -87, but not UL95, in human fibroblast cells negatively affected the level of MIE viral gene expression and viral DNA replication. The products of ORFs UL79, -87, and -95 were expressed as early viral proteins and recruited to prereplication complexes (pre-RCs), along with UL44, before the initiation of viral DNA replication. All three HCMV ORFs are indispensable for late viral gene expression and viral growth. The roles of UL79, -87, and -95 in pre-RCs for late viral gene expression are discussed.

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  463. YAP TRANSCRIPTION COACTIVATOR INDUCES MALIGNANT MESOTHELIOMA CELL PROLIFERATION BY UP-REGULATING CELL CYCLE PROGRESSION

    Tetsuya Mizuno, Hideki Murakami, Makiko Fujii, Futoshi Ishiguro, Yutaka Kondo, Shinya Akatsuka, Shinya Toyokuni, Kohei Yokoi, Hirotaka Osada, Yoshitaka Sekido

    JOURNAL OF THORACIC ONCOLOGY   Vol. 6 ( 6 ) page: S707 - S708   2011.6

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  464. [Archives of "comprehensive approach on asbestos-related diseases" supported by the "special coordination funds for promoting science and technology (H18-1-3-3-1)"-- overview of group research project, care and specimen registration, cellular characteristics of mesothelioma and immunological effects of asbestos]. Reviewed

    Takemi Otsuki, Takashi Nakano, Seiki Hasegawa, Morihito Okada, Tohru Tsujimura, Yoshitaka Sekido, Shinya Toyokuni, Hiroshi Nishimoto, Kazuya Fukuoka, Fumihiro Tanaka, Naoko Kumagai, Megumi Maeda, Yasumitsu Nishimura

    Nihon eiseigaku zasshi. Japanese journal of hygiene   Vol. 66 ( 3 ) page: 543 - 52   2011.5

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    The research project entitled "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Funds for Promoting Science and Technology (H18-1-3-3-1)" began in 2006 and was completed at the end of the Japanese fiscal year of 2010. This project included four parts; (1) malignant mesothelioma (MM) cases and specimen registration, (2) development of procedures for the early diagnosis of MM, (3) commencement of clinical investigations including multimodal approaches, and (4) basic research comprising three components; (i) cellular and molecular characterization of mesothelioma cells, (ii) immunological effects of asbestos, and (iii) elucidation of asbestos-induced carcinogenesis using animal models. In this special issue of the Japanese Journal of Hygiene, we briefly introduce the achievements of our project. The second and third parts and the third component of the fourth part are described in other manuscripts written by Professors Fukuoka, Hasegawa, and Toyokuni. In this manuscript, we introduce a brief summary of the first part "MM cases and specimen registration", the first component of the fourth part "Cellular and molecular characterization of mesothelioma cells" and the second component of the fourth part "Immunological effects of asbestos". In addition, a previous special issue presented by the Study Group of Fibrous and Particulate Substances (SGFPS) (chaired by Professor Otsuki, Kawasaki Medical School, Japan) for the Japanese Society of Hygiene and published in Environmental Health and Preventive Medicine Volume 13, 2008, included reviews of the aforementioned first component of the fourth part of the project. Taken together, our project led medical investigations regarding asbestos and MM progress and contributed towards the care and examination of patients with asbestos-related diseases during these five years. Further investigations are required to facilitate the development of preventive measures and the cure of asbestos-related diseases, particularly in Japan, where asbestos-related diseases are predicted to increase in the next 10 to 20 years.

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  465. Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features

    Osada Hirotaka, Eri Nishikawa, Chinatsu Arima, Yasumasa Okazaki, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   Vol. 71   2011.4

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  466. XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. Reviewed International journal

    Yoriko Yamashita, Dai Kajiura, Lee Tang, Yuichi Hasegawa, Tomohiro Kinoshita, Shigeo Nakamura, Shinya Akatsuka, Shinya Toyokuni, Naoyoshi Mori

    American journal of clinical pathology   Vol. 135 ( 4 ) page: 556 - 64   2011.4

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    A total of 29 cases of diffuse large B-cell lymphoma initially manifesting in the bone marrow (BM-DLBCL) were analyzed for V-H gene sequence, and expression microarray of chemokines and chemokine receptors and immunohistochemical analysis were done. Seminested polymerase chain reaction (PCR) and sequencing analyses of 18 cases revealed that the V-H gene usage in 6 cases was restricted to V(H)3-7, in 3 cases to V(H)4-34, and in 2 cases to V(H)4-39, which were all previously reported to be autoreactive. In total, 14 of 18 V-H genes were those associated with autoimmune diseases, including V(H)3-21, V(H)3-23, and V(H)3-48. Furthermore, cDNA microarray analysis specific for chemokine and chemokine receptors revealed that chemokine receptor XCR1 expression was significantly elevated in the BM-DLBCL cases (P &lt; .05), which was confirmed by quantitative reverse transcriptase PCR and immunohistochemical analysis. Expression of the chemokine receptor XCR1 and frequent usage of autoreactive V-H genes seem to be distinct characteristics of BM-DLBCL.

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  467. LATS2 is a tumor suppressor gene of malignant mesothelioma

    Murakami H.

    Cancer Research   Vol. 71 ( 3 ) page: 873 - 883   2011.2

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  468. LATS2 is a tumor suppressor gene of malignant mesothelioma.

    Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y

    Cancer research   Vol. 71 ( 3 ) page: 873 - 83   2011.2

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  469. Stage-specific roles of fibulin-5 during oxidative stress-induced renal carcinogenesis in rats. International journal

    Hiroki Ohara, Shinya Akatsuka, Hirotaka Nagai, Yu-Ting Liu, Li Jiang, Yasumasa Okazaki, Yoriko Yamashita, Tomoyuki Nakamura, Shinya Toyokuni

    Free radical research   Vol. 45 ( 2 ) page: 211 - 220   2011.2

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    By using a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA), this study performed genome-wide analysis to identify target genes during carcinogenesis. It screened for genes with decreased expression in RCCs, with simultaneous loss of heterozygosity, eventually to focus on the fibulin-5 (fbln5) gene. Oxidative damage via Fe-NTA markedly increased Fbln5 in the proximal tubules. RCCs presented lower levels of Fbln5. However, a fraction of RCCs presenting pulmonary metastasis revealed significantly higher levels of Fbln5 than those without metastasis, accompanied by immunopositivity of RCC cells and myofibroblast proliferation. Experiments revealed that RCC cell lines showed lower expression of fbln5 than its non-transformed counterpart NRK52E, but that fbln5 transfection to RCC cell lines changed neither proliferation nor migration/invasion. The data suggest that Fbln5 plays a role not only in the tissue repair and remodelling after renal tubular oxidative damage but also in RCC metastasis, presumably as a cytokine.

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  470. LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma Reviewed

    Hideki Murakami, Tetsuya Mizuno, Tetsuo Taniguchi, Makiko Fujii, Futoshi Ishiguro, Takayuki Fukui, Shinya Akatsuka, Yoshitsugu Horio, Toyoaki Hida, Yutaka Kondo, Shinya Toyokuni, Hirotaka Osada, Yoshitaka Sekido

    CANCER RESEARCH   Vol. 71 ( 3 ) page: 873 - 883   2011.2

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    Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. Cancer Res; 71(3); 873-83. (C)2011 AACR.

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  471. Mysterious link between iron overload and CDKN2A/2B.

    Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 48 ( 1 ) page: 46 - 49   2011.1

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    Persistent oxidative stress has been associated with carcinogenesis. Iron overload is considered one such condition that causes oxidative stress. Epidemiological studies support a close link between iron overload and carcinogenesis. Reportedly, regular semiannual phlebotomies reduced cancer risk in an otherwise normal population. More specifically, genetic hemochromatosis, chronic viral hepatitis, ovarian endometriosis and asbestosis induce iron overload, which can lead to hepatocellular carcinoma, ovarian carcinoma or mesothelioma in humans. Through a combination of animal experiments and microarray analyses, homozygous deletion of CDKN2A/2B has been recognized as one of the major target genes involved in iron overload-induced carcinogenesis. CDKN2A/2B are the second most frequently inactivated tumor suppressing genes in human cancers. Currently, when infection is becoming sufficiently controlled worldwide, iron regulation may be the next target for human longevity.

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  472. 3-morpholinosydnonimine participates in the attenuation of neointima formation via inhibition of annexin A2-mediated vascular smooth muscle cell migration. International journal

    Kyung-Jong Won, Philyoung Lee, Seung Hyo Jung, Xiaowen Jiang, Chang-Kwon Lee, Hai Yue Lin, Hyun Kang, Hwan Myung Lee, Junghwan Kim, Shinya Toyokuni, Bokyung Kim

    Proteomics   Vol. 11 ( 2 ) page: 193 - 201   2011.1

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    3-Morpholinosydnonimine (SIN-1) affects vascular smooth muscle cell migration and proliferation, processes essential for atherosclerosis. However, the mechanism by which SIN-1 exerts these effects has not been elucidated. We used 2-DE followed by MALDI-TOF/TOF MS to identify responses in protein expression to SIN-1 in rat aortic smooth muscle. Platelet-derived growth factor-BB increased cell migration and proliferation in rat aortic smooth muscle cells, and subsequent SIN-1 treatment inhibited it. Administration of SIN-1 in vivo attenuated neointima formation in balloon-injured rat carotid arteries. Proteomic analysis showed that glutathione peroxidase and 40S ribosomal protein S12 were differentially expressed in aortic strips exposed to SIN-1. Expression of annexin A2 was decreased by SIN-1. Platelet-derived growth factor-BB-induced cell migration was increased and inhibited in rat aortic smooth muscle cells with overexpression and knockdown of annexin A2 gene, respectively. The expression of annexin A2 was increased in vascular neointima compared with the intact control, which was inhibited by SIN-1 treatment. These results demonstrate that SIN-1 may attenuate vascular neointima formation by inhibiting annexin A2-mediated migration. Therefore, annexin A2 may be a potential target for therapeutic strategies for atherosclerosis.

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  473. CD8+CD122+ regulatory T cells (Tregs) and CD4+ Tregs cooperatively prevent and cure CD4+ cell-induced colitis. Reviewed International journal

    Agustina Tri Endharti, Yusuke Okuno, Zhe Shi, Nobuaki Misawa, Shinya Toyokuni, Masafumi Ito, Ken-ichi Isobe, Haruhiko Suzuki

    Journal of immunology (Baltimore, Md. : 1950)   Vol. 186 ( 1 ) page: 41 - 52   2011.1

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    We identified CD8(+)CD122(+) regulatory T cells (Tregs) and demonstrated their importance in the maintenance of immune homeostasis and in the recovery from experimental autoimmune encephalomyelitis. In this paper, we show that CD8(+)CD122(+) Tregs effectively prevent and cure colitis in a mouse model. In our experiments, colitis was induced in lymphocyte-deficient RAG-2(-/-) mice by transferring CD4(+)CD45RB(high) cells that were excluded with CD4(+) Tregs. Cotransfer of CD8(+)CD122(+) cells clearly suppressed the development of colitis, and this suppressive effect was similar to that of CD4(+)CD45RB(low) cells that were mostly CD4(+) Tregs. CD8(+)CD122(+) cells obtained from IL-10(-/-) mice were unable to suppress colitis, indicating that IL-10 is an important effect-transmitting factor in the suppression of colitis. CD8(+)CD122(+) cells showed a suppressive effect when they were transferred 4 wk after CD4(+)CD45RB(high) cells, indicating the therapeutic potential of CD8(+)CD122(+) cells. A mixture of CD8(+)CD122(+) cells and CD4(+)CD45RB(low) cells was far more effective than single Tregs, indicating the synergistic effect of these Tregs. These overall findings demonstrate the potential role of CD8(+) Tregs, and possibly together with CD4(+) Tregs, in the medical care of inflammatory bowel disease patients.

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  474. Iron as a target of chemoprevention for longevity in humans. Reviewed

    Toyokuni S.

    Free Radic Res   Vol. 45   page: 906-917   2011

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  475. The human cytomegalovirus gene products essential for late viral gene expression assemble into prereplication complexes before viral DNA replication. Reviewed

    Isomura H, Stinski MF, Murata T, Yamashita Y, Kanda T, Toyokuni S and Tsurumi T.

    J Virol   Vol. 85   page: 6629-6644   2011

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  476. Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. Reviewed

    Fan YY, Ran Q, Toyokuni S, Okazaki Y, Callaway ES, Lupton JR, and Chapkin RS.

    Cancer Prev Res   Vol. 4   page: 1267-1274   2011

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  477. Age- and sun exposure-dependent differences in 8-hydroxy-2'-deoxyguanosine and Nε-(carboxymethyl)lysine in human epidermis. Reviewed

    Toyokuni S, Hirao A, Wada T, Nagai R, Date A, Yoshii T, Akatsuka S, Yamashita Y, and Kawada A.

    J Clin Biochem Nutr   Vol. 49   page: 1-4   2011

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  478. Mysterious link between iron overload and CDKN2A/2B. Reviewed

    Toyokuni S.

    J   Vol. 48   page: 46-49   2011

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  479. LATS2 is a tumor suppressor gene of malignancy mesothelioma. Reviewed

    Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, HIda T, Kondo Y, Toyokuni S, Osada H and Sekido Y.

    Cancer Res   Vol. 71   page: 873-883   2011

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  480. XCR1 expression and biased VH gene usage are distinct features of diffuse large B-cell lymphoma initially manifesting in the bone marrow. Reviewed

    Yamashita Y, Kajiura D, Tang L, Hasegawa Y, Kinoshita T, Nakamura S, Akatsuka S, Toyokuni S and Mori N.

    Am J Clin Pathol   Vol. 135   page: 556-564   2011

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  481. Asbetos provides a niche for oxidative modification. Reviewed

    Nagai H, Ishihara T, Lee WH, Ohara H, Okazaki Y, Okawa K and Toyokuni S.

    Cancer Sci   Vol. 102   page: 2118-2125   2011

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  482. miR-375 is activated by ASH1 and inhibits YAP1 in a lineage dependent manner in lung cancer. Reviewed

    Nishikawa E, Osada H, Okazaki Y, Arima C, Tomida S, Tatematsu Y, Taguchi A, Shimada Y, Yanagisawa K, Yatabe Y, Toyokuni S, Sekido Y and Takahashi T

    Cancer Res   Vol. 71   page: 6165-6173   2011

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  483. Oxidative DNA Damage and Carcinogenesis

    Jiang, L; Toyokuni, S

    FREE RADICAL BIOLOGY IN DIGESTIVE DISEASES   Vol. 29   page: 55 - 63   2011

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  484. Iron as a target of chemoprevention for longevity in humans. Reviewed

    Toyokuni S

    Free Radic Res   Vol. 45   page: 906-917   2011

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  485. Mysterious link between iron overload and CDKN2A/2B. Reviewed

    Toyokuni S

    J   Vol. 48   page: 46-49   2011

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  486. LATS2 is a tumor suppressor gene of malignant mesothelioma.

    Murakami Hideki, Mizuno Tetsuya, Taniguchi Tetsuo, Fujii Makiko, Ishiguro Futoshi, Fukui Takayuki, Akatsuka Shinya, Horio Yoshitsugu, Hida Toyoaki, Kondo Yutaka, Toyokuni Shinya, Osada Hirotaka, Sekido Yoshitaka

    Cancer research   Vol. 71 ( 3 )   2011

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    :Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive

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  487. 脳梗塞発症前の運動の効果及び酸化ストレスに着目した作用機序の検討

    濱川 みちる, 嶋田 悠, 中島 宏樹, 石田 章真, 玉越 敬悟, 豊國 伸哉, 石田 和人

    理学療法学Supplement   Vol. 2010 ( 0 ) page: AcOF1030 - AcOF1030   2011

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    【目的】脳梗塞時には活性酸素やフリーラジカルが大量に産生され、酸化ストレスとして組織損傷を拡大させるため、酸化ストレスは脳梗塞を増悪させる主要な因子である。一方、健常なラットを長期間運動させると、脳内で抗酸化酵素が増加し酸化ストレスの減少をもたらすことが報告されており、運動は脳内の抗酸化作用を高めることが示されている。また、先行研究では、脳梗塞モデルラット作成前に一定期間の運動をさせると、運動していないラットに比べて、脳梗塞後の梗塞体積が減少し運動機能障害も軽減するといった脳梗塞障害軽減効果が報告されている。しかし、運動により高まる脳内の抗酸化作用が、脳梗塞時の酸化ストレスに影響を及ぼしているかどうかは不明である。そこで本研究では、脳梗塞発症前の運動の効果および作用機序を酸化ストレスに着目して検討することを目的とした。<BR>【方法】実験動物には Wistar系雄性ラット(5週齢)を用いた。無作為に運動群と非運動群に分け、運動群は3週間トレッドミル運動(15 m / min、30分/日)を毎日行った。非運動群は走行させずにトレッドミル装置内に暴露させた(1日30分間)。3週間後、各群に小泉法による脳梗塞モデル作成手術を施行した。手術24時間後に、運動機能評価として、麻痺の重症度を評価する Neurological Deficits(ND)、歩行時のバランス能力の評価として Beam Walking(BW)、はしご上の歩行における前肢の協調運動機能を評価するLadder test、前肢の感覚運動機能の評価として Limb Placing(LP)を行った。その直後に脳を採取し、TTC染色により非梗塞半球体積に対する梗塞体積の割合を算出した。また、酸化ストレスの指標として、酸化ストレスによる細胞膜障害の指標となる 4-hydroxy-2-nonenal [4-HNE]及びDNA障害の指標となる 8-Hydroxydeoxyguanosine[8-OHdG]の免疫染色を行った。統計学的検定には、対応のない t検定と Mann-WhitneyのU検定を用い、有意水準は5%未満とした。<BR>【説明と同意】本研究は、名古屋大学医学部保健学科動物実験委員会の承諾を得て実施した(承認番号:022-028号)。<BR>【結果】脳梗塞手術24時間後の運動機能のうち、 ND(麻痺の重症度)と Ladder test(前肢の協調運動機能障害)は運動群の方が非運動群に比べて軽度で、有意差が認められた(<I>p</I> < 0.05)。一方、 LP(前肢の感覚機能)や BW(歩行時の後肢機能)は群間に有意差は認められなかった。また、梗塞体積割合は、運動群の方が非運動群よりも有意に小さく(<I>p</I> < 0.05)、脳梗塞発症前の運動はその後の脳梗塞による組織損傷を軽減することが示された。酸化ストレス指標のうち、過酸化脂質の指標である4-HNEの免疫染色では、非運動群に比べて運動群は陽性細胞が少ない傾向にあった。また、DNAの酸化的損傷を示す8-OHdGは、梗塞側では運動群の方が陽性細胞が少ない傾向にあったが、非梗塞側は両群とも陽性細胞は見られなかった。<BR>【考察】本研究は、脳梗塞発症前に3週間運動を継続することが、その後の脳梗塞の障害に及ぼす効果を酸化ストレスに着目して検討した。その結果、脳梗塞前に運動を行った運動群は非運動群と比較して、脳梗塞後の梗塞体積が減少し運動機能障害が軽減され、先行研究の結果と一致した。また、脳梗塞による細胞膜及びDNAに対する酸化ストレスが運動群で減少したことから、運動によって高められる脳内の抗酸化作用は、正常時だけでなく、脳梗塞時の酸化ストレスに対しても抑制効果をもたらす可能性が示唆された。これらのことから、3週間の運動が脳梗塞後の障害軽減効果をもたらした作用機序として、脳内の抗酸化作用を高めて脳梗塞の酸化ストレスを抑制したことにより、組織損傷が軽減し、運動機能障害が改善されたと考えられる。しかし、今回の運動条件がどの程度の抗酸化作用を有しているかは確認していないため、今後検討していく必要がある。<BR>【理学療法学研究としての意義】本研究は、健常時の運動習慣の有無が脳梗塞を発症した場合の障害程度に及ぼす影響について検討した基礎研究であり、発症前の運動習慣が脳梗塞の予後を改善する可能性を示唆している。また、今後理学療法士が活躍の場を広げ予防医療の分野に携わる際、運動を推奨することの科学的根拠となる有用な知見である。

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  488. Oxidative DNA Damage and Carcinogenesis

    Jiang Li, Toyokuni Shinya

    FREE RADICAL BIOLOGY IN DIGESTIVE DISEASES   Vol. 29   page: 55 - 63   2011

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  489. Diameter and rigidity of multi-walled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis.

    Nagai, H; Okazaki, Y; Chew, S; Misawa, N; Yamashita, Y; Akatsuka, S; Ishihara, T; Yamashita, K; Yoshikawa, Y; Yasui, H; Jiang, L; Ohara, H; Takahashi, T; Ichihara, G; Miyata, Y; Shinohara, H; Toyokuni, S

    MOLECULAR BIOLOGY OF THE CELL   Vol. 22   2011

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  490. Oxidative DNA damage and carcinogenesis

    Jiang L., Toyokuni S.

    Free Radical Biology in Digestive Diseases   Vol. 29   page: 55 - 63   2010.12

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    Carcinogenesis follows multi-step processes involving both genetic alteration and increased cell proliferation. Oxidative stress can occur via overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Oxidative stress is always associated with inflammation, radiation, reperfusion, and iron overload. Epidemiological observations have shown that oxidative stress is one of the major pathologic mechanisms for cancer, the top-ranked cause of human mortality worldwide. During carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation through generation of oxidative DNA damage. Furthermore, signal transduction pathways are activated by reactive species, and they lead to the transcription of genes involved in cellular growth regulatory and stress protection pathways. This review examines the involvement of oxidative stress in the carcinogenic process starting from its history, and presents future perspectives.

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  491. Oxidative DNA damage and carcinogenesis

    Jiang L., Toyokuni S.

    Frontiers of Gastrointestinal Research   Vol. 29   page: 55 - 63   2010.12

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    Carcinogenesis follows multi-step processes involving both genetic alteration and increased cell proliferation. Oxidative stress can occur via overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Oxidative stress is always associated with inflammation, radiation, reperfusion, and iron overload. Epidemiological observations have shown that oxidative stress is one of the major pathologic mechanisms for cancer, the top-ranked cause of human mortality worldwide. During carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation through generation of oxidative DNA damage. Furthermore, signal transduction pathways are activated by reactive species, and they lead to the transcription of genes involved in cellular growth regulatory and stress protection pathways. This review examines the involvement of oxidative stress in the carcinogenic process starting from its history, and presents future perspectives. © 2011 S. Karger AG, Basel.

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  492. A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats Reviewed

    Yasumasa Okazaki, Mohammad Iqbal, Norito Kawakami, Yorihiro Yamamoto, Shinya Toyokuni, Shigeru Okada

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 47 ( 3 ) page: 198 - 207   2010.11

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    It is beneficial to seek scientific basis for the effects of functional foods. Natural pigments derived from plants are widely known as possible antioxidants. Black soybean contains a larger amount of anthocyanins than regular soybean. Here we studied the anti-oxidative effect of a beverage obtained via citric acid fermentation of black soybean (BBS), using a rat model of renal oxidative injury induced by a renal carcinogen, ferric nitrilotriacetate. BBS (10 ml/kg) was orally administered 30 min before ferric nitrilotriacetate treatment. Renal lipid peroxidation was significantly suppressed in the BBS-pretreated animals concomitant with decrease in 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2`-deoxyguanosine. Maintenance of renal activities of antioxidative enzymes including catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, glucose-6-phosphate dehydrogenase and quinone reductase was significantly better in the BBS-pretreated rats. Elevation of serum creatinine and urea nitrogen was significantly suppressed in the BBS-pretreated rats. These data suggest that dietary intake of BBS is useful for the prevention of renal tubular oxidative damage mediate by iron, and warrant further investigation.

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  493. A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats

    Okazaki Yasumasa, Iqbal Mohammad, Kawakami Norito, Yamamoto Yorihiro, Toyokuni Shinya, Okada Shigeru

    Journal of Clinical Biochemistry and Nutrition   Vol. 47 ( 3 ) page: 198 - 207   2010.11

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    It is beneficial to seek scientific basis for the effects of functional foods. Natural pigments derived from plants are widely known as possible antioxidants. Black soybean contains a larger amount of anthocyanins than regular soybean. Here we studied the antioxidative effect of a beverage obtained via citric acid fermentation of black soybean (BBS), using a rat model of renal oxidative injury induced by a renal carcinogen, ferric nitrilotriacetate. BBS (10 ml/kg) was orally administered 30 min before ferric nitrilotriacetate treatment. Renal lipid peroxidation was significantly suppressed in the BBS-pretreated animals concomitant with decrease in 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Maintenance of renal activities of antioxidative enzymes including catalase, glutathione peroxidase, glutathione reductase, glutathione <i>S</i>-transferase, glucose-6-phosphate dehydrogenase and quinone reductase was significantly better in the BBS-pretreated rats. Elevation of serum creatinine and urea nitrogen was significantly suppressed in the BBS-pretreated rats. These data suggest that dietary intake of BBS is useful for the prevention of renal tubular oxidative damage mediate by iron, and warrant further investigation.<br>

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  494. A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats

    Okazaki Yasumasa, Iqbal Mohammad, Kawakami Norito, Yamamoto Yorihiro, Toyokuni Shinya, Okada Shigeru

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 47 ( 3 ) page: 198 - 207   2010.11

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  495. Genome-Scale Approaches to Investigate Oxidative DNA Damage Reviewed International journal

    Akatsuka Shinya, Toyokuni Shinya

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 47 ( 2 ) page: 91 - 97   2010.9

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  496. Genome-Scale Approaches to Investigate Oxidative DNA Damage Reviewed

    Shinya Akatsuka, Shinya Toyokuni

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 47 ( 2 ) page: 91 - 97   2010.9

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    In the trend of biological science after the completion of the human genome project, appreciation of an organism as a system rather than the sum of many molecular functions is necessary. On the investigation of DNA damage and repair, therefore, the orientation toward systematic and comprehensive genome-scale approaches is rapidly growing. The immuno-precipitation-based technique combined with high-density microarrays is one of the promising methods to provide access to such novel research strategies. We propose this sort of research area as oxygenomics.

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  497. Genome-Scale Approaches to Investigate Oxidative DNA Damage

    Akatsuka Shinya, Toyokuni Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 47 ( 2 ) page: 91 - 97   2010.9

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    In the trend of biological science after the completion of the human genome project, appreciation of an organism as a system rather than the sum of many molecular functions is necessary. On the investigation of DNA damage and repair, therefore, the orientation toward systematic and comprehensive genome-scale approaches is rapidly growing. The immunoprecipitation-based technique combined with high-density microarrays is one of the promising methods to provide access to such novel research strategies. We propose this sort of research area as oxygenomics.<br>

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  498. Suppression of SLC11A2 expression is essential to maintain duodenal integrity during dietary iron overload. International journal

    Tomoyuki Shirase, Kiyoshi Mori, Yasumasa Okazaki, Ken Itoh, Masayuki Yamamoto, Mitsuaki Tabuchi, Fumio Kishi, Li Jiang, Shinya Akatsuka, Kazuwa Nakao, Shinya Toyokuni

    The American journal of pathology   Vol. 177 ( 2 ) page: 677 - 85   2010.8

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    Iron is essential for the survival of mammals, but iron overload causes fibrosis and carcinogenesis. Reduced iron absorption and regulated release into circulation in duodenal mucosa constitute two major mechanisms of protection against dietary iron overload; however, their relative contribution remains elusive. To study the significance of the former process, we generated SLC11A2 transgenic mice (TGs) under the control of the chicken beta-actin promoter. TGs were viable and fertile, and displayed no overt abnormalities up to 20 months. No significant difference in iron concentration was observed in major solid organs between TGs and their wild-type littermates, suggesting that increased number of iron transporters does not lead to increased iron absorption. To test the sensitivity to iron overload, TGs and wild-type mice were fed with an iron-rich diet containing 2% ferric citrate. Iron supplementation caused suppression of endogenous duodenal SLC11A2 expression, down-regulation of duodenal ferroportin, and overexpression of hepatic hepcidin, precluding excessive iron uptake both in the TGs and wild-type mice. However, iron-treated TGs revealed increased mortality, resulting from oxidative mucosal damage leading to hemorrhagic erosion throughout the whole intestinal area. These findings suggest that reduced iron release from duodenal cells into circulation plays a role in mitigating excessive iron uptake from the diet and that finely regulated duodenal absorption is essential to protect intestinal mucosa from iron-induced oxidative damage. (Am J Pathol 2010, 177:677-685; DOI: 10.2353/ajpath.2010.090823)

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  499. TOWARD A NEW ERA OF THE NAGOYA JOURNAL OF MEDICAL SCIENCE: MESSAGE FROM THE NEW EDITOR-IN-CHIEF International journal

    Toyokuni Shinya

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 72 ( 3-4 ) page: 107 - 109   2010.8

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  500. Toward a new era of the Nagoya journal of medical science: message from the new editor-in-chief.

    Toyokuni S

    Nagoya journal of medical science   Vol. 72 ( 3-4 ) page: 107 - 9   2010.8

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  501. Lipid Peroxidation Generates Body Odor Component trans-2-Nonenal Covalently Bound to Protein in Vivo International journal

    Kousuke Ishino, Chika Wakita, Takahiro Shibata, Shinya Toyokuni, Sachiko Machida, Shun Matsuda, Tomonari Matsuda, Koji Uchida

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 285 ( 20 ) page: 15302 - 15313   2010.5

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    trans-2-Nonenal is an unsaturated aldehyde with an unpleasant greasy and grassy odor endogenously generated during the peroxidation of polyunsaturated fatty acids. 2-Nonenal covalently modified human serum albumin through a reaction in which the aldehyde preferentially reacted with the lysine residues. Modified proteins were immunogenic, and a specific monoclonal antibody (mAb) 27Q4 that cross-reacted with the protein covalently modified with 2-nonenal was raised from mouse. To verify the presence of the protein-bound 2-nonenal in vivo, the mAb 27Q4 against the 2-nonenal-modified keyhole limpet hemocyanin was raised. It was found that a novel 2-nonenal-lysine adduct, cis- and trans-N(epsilon)-3-[(hept-1-enyl)-4-hexyl-pyridinium]lysine (HHP-lysine), constitutes an epitope of the antibody. The immunoreactive materials with mAb 27Q4 were detected in the kidney of rats exposed to ferric nitrilotriacetate, an iron chelate that induces free radical-mediated oxidative tissue damage. Using high performance liquid chromatography with on-line electrospray ionization tandem mass spectrometry, we also established a highly sensitive method for detection of the cis- and trans-HHP-lysine and confirmed that the 2-nonenal-lysine adducts were indeed formed during the lipid peroxidation-mediated modification of protein in vitro and in vivo. Furthermore, we examined the involvement of the scavenger receptor lectin-like oxidized low density lipoprotein receptor-1 in the recognition of 2-nonenal-modified proteins and established that the receptor recognized the HHP-lysine adducts as a ligand.

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  502. A Novel Method for Efficient Collection of Normal Mesothelial Cells In Vivo Reviewed International journal

    Jiang Li, Yamashita Yoriko, Toyokuni Shinya

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 46 ( 3 ) page: 265 - 268   2010.5

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  503. A Novel Method for Efficient Collection of Normal Mesothelial Cells In Vivo Reviewed

    Li Jiang, Yoriko Yamashita, Shinya Toyokuni

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 46 ( 3 ) page: 265 - 268   2010.5

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    Asbestos-induced mesothelioma is a challenging social problem in many countries, and oxidative stress via iron is closely associated with its carcinogenesis. Mesothelioma is thought to originate from the mesothelial cells that cover the somatic cavity such as pleural, pericardial and peritoneal cavities. They are single layered and so flat that it is extremely difficult to obtain pure mesothelial cells as control samples from experimental animals. Here we describe a novel method to collect mesothelial cells from animals by the use of simple equipments. Surface of the most organs including lung, spleen and liver are covered with a single layer of mesothelial cells. Scraping the surface of those organs with razor blades after snap-freeze in liquid nitrogen satisfactorily confers almost pure population of mesothelial cells. This simple method would be helpful for obtaining mesothelial control samples from animals to elucidate the molecular mechanisms of a variety of mesothelial pathology.

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  504. A Novel Method for Efficient Collection of Normal Mesothelial Cells In Vivo

    Jiang Li, Yamashita Yoriko, Toyokuni Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 46 ( 3 ) page: 265 - 268   2010.5

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    Asbestos-induced mesothelioma is a challenging social problem in many countries, and oxidative stress via iron is closely associated with its carcinogenesis. Mesothelioma is thought to originate from the mesothelial cells that cover the somatic cavity such as pleural, pericardial and peritoneal cavities. They are single layered and so flat that it is extremely difficult to obtain pure mesothelial cells as control samples from experimental animals. Here we describe a novel method to collect mesothelial cells from animals by the use of simple equipments. Surface of the most organs including lung, spleen and liver are covered with a single layer of mesothelial cells. Scraping the surface of those organs with razor blades after snap-freeze in liquid nitrogen satisfactorily confers almost pure population of mesothelial cells. This simple method would be helpful for obtaining mesothelial control samples from animals to elucidate the molecular mechanisms of a variety of mesothelial pathology.<br>

    DOI: 10.3164/jcbn.10-01

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  505. リンパ腫ゲノムにおけるマイクロサテライト多型不安定性集積の空間統計学解析

    鶴山 竜昭, リチャード・カシンスキー, 赤塚 慎也, 今井 裕紀子, 竹内 晴哉, 尾関 宗孝, 奥野 知子, 豊國 伸哉, 玉木 敬二

    日本法医学雑誌   Vol. 64 ( 1 ) page: 54 - 54   2010.5

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  506. n-3 polyunsaturated fatty acids promote apoptosis in oxidatively stressed transgenic mouse models

    Fan, YY; Toyokuni, S; Callaway, ES; Ran, Q; Lupton, JR; Chapkin, RS

    CANCER RESEARCH   Vol. 70   2010.4

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    DOI: 10.1158/1538-7445.AM10-955

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  507. A Quantitative trait locus responsible for inducing B-cell lymphoblastic lymphoma is a hotspot for microsatellite instability

    KASZYNSKI Richard H., AKATSUKA Shinya, HIRATSUKA Takuya, JIN Guang, OZEKI Munetaka, OKUNO Tomoko, NAKAMURA Takuro, MANABE Toshiaki, TAKAKUWA Tetsuya, HIAI Hiroshi, TOYOKUNI Shinya, TAMAKI Keiji, TSURUYAMA Tatsuaki

      Vol. 101 ( 3 ) page: 800 - 805   2010.3

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  508. Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. International journal

    Qian Hu, Shinya Akatsuka, Yoriko Yamashita, Hiroki Ohara, Hirotaka Nagai, Yasumasa Okazaki, Takashi Takahashi, Shinya Toyokuni

    Laboratory investigation; a journal of technical methods and pathology   Vol. 90 ( 3 ) page: 360 - 373   2010.3

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    In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by micro-array. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2&apos;-deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

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  509. A Quantitative trait locus responsible for inducing B-cell lymphoblastic lymphoma is a hotspot for microsatellite instability Reviewed International coauthorship International journal

    Richard H. Kaszynski, Shinya Akatsuka, Takuya Hiratsuka, Guang Jin, Munetaka Ozeki, Tomoko Okuno, Takuro Nakamura, Toshiaki Manabe, Tetsuya Takakuwa, Hiroshi Hiai, Shinya Toyokuni, Keiji Tamaki, Tatsuaki Tsuruyama

    CANCER SCIENCE   Vol. 101 ( 3 ) page: 800 - 805   2010.3

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    While the molecular mechanisms underlying microsatellite instability (MSI) have been exhaustively investigated, identifying the patterns of MSI distribution within diverse cancer genomes has remained an elusive issue. In the present study, we conducted genome-wide MSI screening in B-cell lymphoblastic lymphomas (B-LBL) which spontaneously develop in the SL/Kh strain of mice. Tumor samples harvested from 16 mice were investigated using a framework map consisting of 150 microsatellite markers spaced at increments of roughly 0.5-3.0 centimorgans, spanning the entirety of mouse chromosomes (mus musculus chromosomes [MMU]) 3-6. MMU3 contains a quantitative trait locus (QTL), Bomb1 (bone marrow pre-B1), known to induce an aberrant expansion of pre-B cells in bone marrow prior to the onset of B-LBL in SL/Kh mice. The remaining chromosomes were selected on the basis of those most closely resembling MMU3 in terms of total estimated length (maximum variance 10 Mb). MSI was confirmed at 2 &lt;= markers in DNA derived from tumor tissues in 15 SL/Kh mice (93.7%), while healthy splenic DNA samples screened in parallel were consistently negative for MSI. The overall MSI incidence was significantly higher on MMU3 compared with MMU4-6 (P = 0.031). Additionally, by applying spatial point pattern analysis combined with a 1-D version of Ripley&apos;s K-function, we successfully demonstrated the predilection of MSI-susceptible loci to structure a massive cluster within the Bomb1 locus. Our study is the first to suggest that a QTL concomitantly serves as a hotspot for MSI-susceptible loci and sheds new light on somatic cancer genetics. (Cancer Sci 2010; 101: 800-805)

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  510. 前駆B芽球性リンパ腫におけるマイクロサテライト不安定性解析とポイントパターン解析の応用

    鶴山 竜昭, リチャード・カシンスキー, 赤塚 慎也, 中村 卓郎, 真鍋 敏明, 日合 弘, 玉木 敬二, 豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 217 - 217   2010.3

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  511. From the Special Session of the "Special Coordination Funds for Promoting Science and Technology (H18-13-3-1)" Entitled "Malignant Mesothelioma" in the 55^<th> Annual Meeting of the Japanese Society of Occupational Medicine and Traumatology : Brief Overview and Approaches from the Basic Science

    OTSUKI Takemi, NAKANO Takashi, HASEGAWA Seiki, OKADA Morihito, TSUJIMURA Tohru, SEKIDO Yoshitaka, TOYOKUNI Shinya, NISHIMOTO Hiroshi, FUKUOKA Kazuya, TANAKA Fumihiro

    Japanese journal of occupational medicine and traumatology   Vol. 58 ( 1 ) page: 1 - 8   2010.1

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  512. *Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. Reviewed

    Hu Q, Akatsuka S, Yamashita Y, Ohara H, Nagai H, Okazaki Y, Takahashi T, Toyokuni S.

    Lab. Invest.   Vol. 90   page: 360-372   2010.1

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  513. Stage-specific roles of fibulin-5 during oxidative stress-induced renal carcinogenesis in rats. Reviewed

    Ohara H, Akatsuka S, Nagai H, Liu YT, Jiang L, Okazaki Y, Yamashita Y, Nakamura T and Toyokuni S.

    Free Radic Res     page: (in press)   2010

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  514. A quantitative trait locus for inducing B-cell lymphoblastic lymphoma is a hot spot for microsatellite instability. Reviewed

    Kaszynski RH, Akatsuka S, Hiratsuka T, Jin G, Ozeki M, Okuno T, Nakamura T, Manabe T, Takakuwa T, Hiai H, Toyokuni S, Tamaki K and Tsuruyama T.

    Cancer Sci   Vol. 101   page: 800-805   2010

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  515. CD8+CD122+ Regulatory T Cells and CD4+ Treg Cooperatively Prevent and Cure CD4+ cell-induced Colitis. Reviewed

    Endharti AT, Okuno Y, Shi Z, Misawa N, Toyokuni S, Ito M, Isobe KI and Suzuki H.

      Vol. 186   page: 41-52   2010

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  516. Toward a new era of the Nagoya Journal of Medical Science: message from the new editor-in-chief. Invited

    Toyokuni S.

    Nagoy J Med Sci   Vol. 72   page: 107-109   2010

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  517. A beverage containing fermented black soybean ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats. Reviewed

    Okazaki Y, Iqbal M, Kawakami N, Yamamoto Y, Toyokuni S and Okada S.

    J Clin Biochem Nutr   Vol. 47   page: 198-207   2010

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  518. Biopersistent fiber-induced inflammation and carcinogenesis: lessons learned from asbestos toward safety of fibrous nanomaterials. Reviewed

    Nagai H and Toyokuni S.

    Arch Biochem Biophys   Vol. 502   page: 1-7   2010

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  519. Genome-scale approaches to investigate oxidative DNA damage. Reviewed

    Akatsuka S and Toyokuni S.

    J Clin Biochem Nutr   Vol. 47   page: 91-97   2010

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  520. Lipid peroxidation generates a body odor component trans-2-nonenal covalently bound to protein in vivo. Reviewed

    Ishino K, Wakita C, Shibata T, Toyokuni S, Machida S, Matsuda S, Matsuda T and Uchida K.

    J Biol Chem   Vol. 285   page: 15302-15313   2010

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  521. Suppression of SLC11A2 expression is essential to maintain duodenal integrity during dietary iron overload. Reviewed

    Shirase T, Mori K, Okazaki Y, Itoh K, Yamamoto M, Tabuchi M, Kishi F, Jiang L, Akatsuka S, Nakao K and Toyokuni S.

    Am J Pathol   Vol. 177   page: 677-685   2010

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  522. Novel method for efficient collection of normal mesothelial cells in vivo. Reviewed

    Jiang L, Yamashita Y and Toyokuni S.

    J Clin Biochem Nutr   Vol. 46   page: 265-268   2010

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  523. Homozygous Deletion of CDKN2A/2B is a Hallmark of Iron-induced High-grade Rat Mesothelioma International journal

    Yasumasa Okazaki, Quan Hu, Shinya Akatsuka, Hiroki Ohara, Hirotaka Nagai, Takashi Takahashi, Shinya Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 49   page: S67 - S67   2010

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    DOI: 10.1016/j.freeradbiomed.2010.10.162

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  524. Biopersistent fiber-induced inflammation and carcinogenesis: lessons learned from asbestos toward safety of fibrous nanomaterials. Reviewed

    Nagai H, Toyokuni S

    Arch Biochem Biophys   Vol. 502   page: 1-7   2010

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  525. CD8+CD122+ Regulatory T Cells and CD4+ Treg Cooperatively Prevent and Cure CD4+ cell-induced Colitis. Reviewed

    Endharti AT, Okuno Y, Shi Z, Misawa N, Toyokuni S, Ito M, Isobe KI, Suzuki H

      Vol. 186   page: 41-52   2010

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  526. Stage-specific roles of fibulin-5 during oxidative stress-induced renal carcinogenesis in rats. Reviewed

    Ohara H, Akatsuka S, Nagai H, Liu YT, Jiang L, Okazaki Y, Yamashita Y, Nakamura T, Toyokuni S

    Free Radic Res     page: (in press)   2010

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  527. Toward a new era of the Nagoya Journal of Medical Science: message from the new editor-in-chief. Invited

    Toyokuni S

    Nagoy J Med Sci   Vol. 72   page: 107-109   2010

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  528. 脳梗塞モデルラット作成前に実施する運動の効果および作用機序の検討:~抗酸化作用に着目して~

    濱川 みちる, 石田 章真, 玉越 敬悟, 嶋田 悠, 中島 宏樹, 豊國 伸哉, 石田 和人

    東海北陸理学療法学術大会誌   Vol. 26 ( 0 ) page: 35 - 35   2010

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    【目的】脳梗塞モデル作成前の運動には、梗塞体積減少、運動機能改善などの脳梗塞の障害軽減効果があると報告されている。また、運動は抗酸化作用を高めることが報告されているが、抗酸化作用が脳梗塞の障害軽減効果にいかに関与するかについては不明である。そこで本研究では、脳梗塞発症前に運動を行うことの効果および作用機序を抗酸化作用に着目して検討する。【方法】実験動物にはWistar系雄性ラット(5週齢)を用いた。無作為に運動群と非運動群に分け、運動群はトレッドミル運動(15 m / min、30分/日)を3週間毎日行った。非運動群は1日30分間走行させずにトレッドミル装置内に暴露させた。介入終了の翌日、各群に脳梗塞モデル作成手術を施行した。手術24時間後に、麻痺の重症度を評価するNeurological Deficits(ND)、歩行時のバランス能力の評価としてBeam Walking(BW)、はしご上の歩行における前肢の協調運動機能を評価するLadder test、前肢の感覚運動機能の評価としてLimb Placing(LP)を行った。その直後に脳を採取し、TTC染色により非梗塞半球体積に対する梗塞体積の割合を算出した。また、酸化ストレス産物の指標として4-hydroxy-2-nonenal (4-HNE)及び8-Hydroxydeoxyguanosine(8-OHdG)の免疫染色を行った。統計学的検定には、対応のないt検定とMann-WhitneyのU検定を用い、有意水準は5%未満とした。【結果】NDとladder testにおいて、運動群が非運動群と比較して有意に障害が軽減した(<I>p</I> < 0.05)。また、他の機能評価や梗塞体積については群間に有意差は認められなかった。免疫染色では、非梗塞側半球で運動群に比べ非運動群は4-HNE陽性細胞が多くみられた。しかし、8-OHdG染色では差を認めなかった。【まとめ】脳梗塞前の運動は、梗塞後の運動機能改善効果をもたらしたものの、梗塞体積は非運動群と同程度であった。しかし、脂質過酸化の指標である4-HNE陽性細胞は非運動群の非梗塞側でより多く見られ、運動による酸化ストレス抑制効果が示された。<BR>本研究は科研費(22500456)の助成を受けたものである。

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  529. S1-3 Elucidation of asbestos-induced mesothelial carcinogenesis and its prevention stragegy(Symposium 1: Biomarkers in Environmental Mutagen Research: Lifestyle-related and Environmental Factors)

    ToyokuniShinya

      ( 38 ) page: 75   2009.11

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  530. ITPase-deficient mice show growth retardation and die before weaning. Reviewed

    Behrmanech M, Sakumi K, Abolhassani N, Toyokuni S, Oka S, Ohnishi YN, Tsuchimoto D, Nakabeppu Y.

    Cell Death Differ.   Vol. 16   page: 1315-1322   2009.10

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  531. Potent antioxidative acticity of Vineatrol&reg; 30 grapevine-shoot extract. Reviewed

    M&uuml;ller C, Ullmann K, Wilkins A, Winterhalter P, Toyokuni S and Steinberg P.

    Biosci Biotechnol Biochem   Vol. 73   page: 1831-1836   2009.8

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  532. Elucidation of Asbestos-induced Carcinogenesis and Its Application to Prevention, Diagnosis and Treatment in Relation to Iron

    Toyokuni Shinya

    Haigan   Vol. 49 ( 4 ) page: 362 - 367   2009.8

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    <i><b>Objective</b></i>. Respiratory exposure to asbestos has been associated with mesothelioma in humans. However, its carcinogenic mechanism is still unclear. <i><b>Methods</b></i>. Here we studied the ability of chrysotile, crocidolite and amosite fibers to induce oxidative DNA damage and the modifying factors using 4 distinct approaches. <i><b>Results</b></i>. Electron spin resonance analyses showed that crocidolite and amosite containing high amounts of iron, but not chrysotile, catalyzed hydroxyl radical formation in the presence of hydrogen peroxide, which was enhanced by an iron chelator, nitrilotriacetic acid, and suppressed by Desferal<sup>&reg;</sup>. Iron chelators, such as citrate, ATP and GTP, did not inhibit this reaction. Second, we used time-lapse videomicroscopy to evaluate how cells deal with asbestos fibers. RAW264.7 cells, MeT-5A and HeLa cells engulfed asbestos fibers, which reached not only cytoplasm but also the nucleus. Third, we utilized supercoiled plasmid DNA to evaluate the ability of each type of asbestos to induce DNA double strand breaks (DSBs). Crocidolite and amosite, but not chrysotile, induced DNA DSBs in the presence of iron chelators. We cloned the fragments to identify break ends. DSBs tended to occur within repeat sequences and between two G: C sequences. Finally, intraperitoneal administration of each type of asbestos to rats induced not only formation of nuclear 8-hydroxy-2'-deoxyguanosine in the mesothelium but also significant iron deposits in the spleen. <i><b>Conclusion</b></i>. Together with the established carcinogenicity of intraperitoneal chrysotile, our data suggest that asbestos-associated catalytic iron, whether constitutional or induced by other mechanisms, plays a role in asbestos-induced carcinogenesis and that chemoprevention may be possible through targeting the catalytic iron.<br>

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  533. Potent Antioxidative Activity of Vineatrol (R) 30 Grapevine-shoot Extract Reviewed

    Carsten Mueller, Kristina Ullmann, Andrea Wilkens, Peter Winterhalter, Shinya Toyokuni, Pablo Steinberg

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY   Vol. 73 ( 8 ) page: 1831 - 1836   2009.8

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    The health promoting effects of a grapevine-shoot extract named Vineatrol (R) 30, which contains resveratrol (Resv) as well as considerable amounts of Resv oligomers, have recently been investigated. In the present study, we analyzed the free radical scavenging capacity, the ability to inhibit lipid peroxidation, and the capacity to enhance the human glutathione peroxidase 1 (GPx) and the human superoxide dismutase 1 (SOD) gene promoter activities of Vineatrol (R) 30. Vineatrol (R) 30 was able to scavenge the 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid radical cation and led to concentration-dependent inhibition of lipid peroxidation, Vineatrol (R) 30 not being superior to Resv alone in both cases. Vineatrol (R) 30 also enhanced the gene promoter activities of human GPx and SOD expressed in V79 cells, whereas this effect could not be demonstrated for Resv. In summary, the results presented in this study show that the Vineatrol (R) 30 grapevine-shoot extract is a free radical scavenger and potent antioxidant at non-eytotoxic concentrations.

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  534. B細胞性芽球型リンパ腫ゲノムにおけるマイクロサテライト不安定性(Microsatellite instability in the genome of B-lymphoblastic lymphoma)

    リチャード・カシンスキー, 鶴山 竜昭, 河野 文彦, 平塚 拓也, 尾関 宗孝, 豊國 伸哉, 日合 弘, 玉木 敬二

    日本癌学会総会記事   Vol. 68回   page: 163 - 163   2009.8

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  535. Genetic Reconstruction of Mouse Spermatogonial Stem Cell Self-Renewal In Vitro by Ras-Cyclin D2 Activation Reviewed International journal

    Jiyoung Lee, Mito Kanatsu-Shinohara, Hiroko Morimoto, Yasuhiro Kazuki, Seiji Takashima, Mitsuo Oshimura, Shinya Toyokuni, Takashi Shinohara

    CELL STEM CELL   Vol. 5 ( 1 ) page: 76 - 86   2009.7

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    Spermatogonial stem cells (SSCs) undergo self-renewal division and support spermatogenesis. Although several cytokines coordinate to drive SSC self-renewal, little is known about the mechanisms underlying this process. We investigated the molecular mechanism by reconstructing SSC self-renewal in vitro without exogenous cytokines. Activation of Ras or overexpression of cyclins D2 and E1, both of which were induced by Ras; enabled long-term self-renewal of cultured spermatogonia. SSCs with activated Ras responded properly to differentiation signals and underwent spermatogenesis, whereas differentiation was abrogated in cyclin transfectants after spermatogonial transplantation. Both Ras- and cyclin-transfected cells produced seminomatous tumors, suggesting that excessive self-renewing stimulus induces oncogenic transformation. In contrast, cells that overexpressed cyclin D1 or D3 failed to make germ cell colonies after transplantation, which indicated that cyclin expression pattern is an important determinant to long-term SSC recolonization. Thus, the Ras-cyclin D2 pathway regulates the balance between tissue maintenance and tumorigenesis in the SSC population.

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  536. Abnormal DNA methyltransferase expression in mouse germline stem cells results in spermatogenic defects. Reviewed

    Takashima S, Takehashi M, Lee J, Chuma S, Okano M, Hata K, Suetake I, Nakatsuji N, Miyoshi H, Tajima S, Tanaka Y, Toyokuni S, Sasaki H, Kanatsu-Shinohara M, Shinohara S.

      Vol. 81   page: 155-164   2009.7

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  537. Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro by Ras-cyclin D2 activation. Reviewed

    Lee J, Kanatsu-Shinohara M, Morimoto H, Kazuki Y, Takashima S, Oshimura M, Toyokuni S and Shinohara T.

    Cell Stem Cell   Vol. 5   page: 76-86   2009.7

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  538. Abnormal DNA Methyltransferase Expression in Mouse Germline Stem Cells Results in Spermatogenic Defects Reviewed International journal

    Seiji Takashima, Masanori Takehashi, Jiyoung Lee, Shinichiro Chuma, Masaki Okano, Kenichiro Hata, Isao Suetake, Norio Nakatsuji, Hiroyuki Miyoshi, Shoji Tajima, Yoriko Tanaka, Shinya Toyokuni, Hiroyuki Sasaki, Mito Kanatsu-Shinohara, Takashi Shinohara

    BIOLOGY OF REPRODUCTION   Vol. 81 ( 1 ) page: 155 - 164   2009.7

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    Although spermatogonial stem cells (SSCs) are committed to spermatogenesis, they may also convert to an embryonic stem cell-like pluripotent state at a low frequency. Because changes in DNA methylation patterns are associated with this conversion, we examined the effect of manipulating DNA methyltransferase (Dnmt) expression on the fate of cultured SSCs, germline stem (GS) cells. Dnmt1 knockdown induced apoptosis in GS cells, which was attenuated by the loss of Trp53. In contrast, GS cells proliferated normally in vitro after Dnmt3a/Dnmt3b ablation or during Dnmt3l overexpression. However, Dnmt3a/Dnmt3b double-mutant cells showed hypomethylation in the SineB1 repetitive sequence, and Dnmt3l-overexpressing cells showed hypermethylation in major and minor satellite sequences; neither cell type formed teratomas and completed spermatogenesis following transplantation into the seminiferous tubules. Although genetic manipulation did not increase the conversion of GS cells to a pluripotent state, these results underscore the important role of DNMTs in survival and spermatogenic differentiation in SSCs.

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  539. Proapoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of manganese-dependent superoxide dismutase knockout mice. International journal

    Yang-Yi Fan, Yang Zhan, Harold M Aukema, Laurie A Davidson, Lan Zhou, Evelyn Callaway, Yanan Tian, Brad R Weeks, Joanne R Lupton, Shinya Toyokuni, Robert S Chapkin

    The Journal of nutrition   Vol. 139 ( 7 ) page: 1328 - 1332   2009.7

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    We recently demonstrated that (n-3) PUFA trigger the induction of apoptosis in the colon by enhancing phospholipid oxidation and mitochondrial Ca2+ accumulation. To further elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, a 2 x 2 experiment was designed using both wild type (control) and manganese-dependent superoxide dismutase (SOD2) heterozygous knockout mice (SOD2(+/-)), which exhibit increased mitochondrial oxidative stress. Mice were fed diets differing only in the type of fat [corn oil or fish oil containing (n-3) PUFA] at 15% by weight for 4 wk. Dietary (n-3) PUFA treatment enhanced (22%) apoptosis in colonic crypts. In addition, SOD2 haploinsufficiency enhanced (20%) apoptosis, which was further increased (36%) by (n-3) PUFA feeding. Dietary lipid source and genotype interactively modulated nitrotyrosine levels (P = 0.027) and inflammation (P = 0.032). These findings demonstrate that the proapoptotic effects of (n-3) PUFA are enhanced in oxidatively stressed SOD2(+/-) mice. Thus, (n-3) PUFA appear to promote an oxidation-reduction imbalance in the intestine, which may directly or indirectly trigger apoptosis and thereby reduce colon cancer risk.

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  540. The potential role of reactive oxygen species in mammary neoplasm

    Arafah M., Khabaz M., Toyokuni S.

    Australian Journal of Basic and Applied Sciences   Vol. 3 ( 3 ) page: 2949 - 2954   2009.7

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    The current study investigated the presence of oxidative stress markers (8-OHdG and HNE) in breast carcinoma in females from Saudi Arabia, and to examine the growth modulatory effects of HNE (induce cell growth inhibition) by measuring the expression of Ki-67 protein (cell proliferation antigen). Furthermore, to record if there is any significant prognostic indicator of these markers. In order to estimate the level of oxidative damage in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE) expressions were investigated in breast carcinoma and benign lesions of breast, and were estimated by semi-quantitative immunohistochemical method. The observations of the present study showed that the level of expressions of 8-OHdG and HNE were significantly higher than those in controls. Reduction of oxidative stress is thought to be a very important measure for primary prevention of breast carcinoma. © 2009, INSInet Publication.

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  541. The potential role of reactive oxygen species in mammary neoplasm

    Arafah M

    Australian Journal of Basic and Applied Sciences   Vol. 3 ( 3 ) page: 2949 - 2954   2009.7

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  542. ITPase-deficient mice show growth retardation and die before weaning

    M. Behmanesh, K. Sakumi, N. Abolhassani, S. Toyokuni, S. Oka, Y. N. Ohnishi, D. Tsuchimoto, Y. Nakabeppu

    CELL DEATH AND DIFFERENTIATION   Vol. 16 ( 10 ) page: 1315 - 1322   2009.6

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    Inosine triphosphate pyrophosphatase (ITPase), the enzyme that hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding purine nucleoside monophosphate and pyrophosphate, is encoded by the Itpa gene. In this study, we established Itpa knockout (KO) mice and used them to show that ITPase is required for the normal organization of sarcomeres in the heart. Itpa(-/-) mice died about 2 weeks after birth with features of growth retardation and cardiac myofiber disarray, similar to the phenotype of the cardiac alpha-actin KO mouse. Inosine nucleotides were found to accumulate in both the nucleotide pool and RNA of Itpa(-/-) mice. These data suggest that the role of ITPase in mice is to exclude ITP from the ATP pool, and the main target substrate of this enzyme is rITP. Our data also suggest that cardiomyopathy, which is mainly caused by mutations in sarcomeric protein-encoding genes, is also caused by a defect in maintaining the quality of the ATP pool, which is an essential requirement for sarcomere function.

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  543. Pro-apoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of SOD2 knockout mice. Reviewed

    Fan YY, Zhan Y, Aukema HM, Davidson LA, Zhou L, Callaway E, Tian Y, Weeks BR, Lupton JR, Toyokuni S, Chapkin RS.

    J. Nutr.   Vol. 139   page: 1328-1332   2009.5

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  544. Effect of edaravone, a novel free radical scavenger, supplemented to cardioplegia on myocardial function after cardioplegic arrest: in vitro study of isolated rat heart. Reviewed

    Yamazaki K, Miwa S, Toyokuni S, Nemoto S, Oriyanhan W, Takaba K, Saji Y, Marui A, Nishina T, Ikeda T and Komeda M.

    Heart Vessels   Vol. 24   page: 228-235   2009.5

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  545. Effect of edaravone, a novel free radical scavenger, supplemented to cardioplegia on myocardial function after cardioplegic arrest: in vitro study of isolated rat heart. Reviewed

    Kazuhiro Yamazaki, Senri Miwa, Shinya Toyokuni, Shintaro Nemoto, Wnimunk Oriyanhan, Kiyoaki Takaba, Yoshiaki Saji, Akira Marui, Takeshi Nishina, Tadashi Ikeda, Masashi Komeda

    Heart and vessels   Vol. 24 ( 3 ) page: 228 - 235   2009.5

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    Cardioplegic arrest has been the main mechanism of myocardial protection during open-heart surgery; however, it causes myocardial injury during ischemia-reperfusion. Free radical scavengers are widely known to attenuate ischemia-reperfusion injury in various settings. We investigated the effects of edaravone, a novel free radical scavenger that was originally used for cerebral protection, on myocardial function during ischemia-reperfusion after cardioplegic arrest. Rat hearts were excised and perfused using Langendorff apparatus. The hearts were cardioplegically arrested for 90 min using St. Thomas' Hospital cardioplegic solution (ST solution) at 4A degrees C every 45 min and then reperfused for 20 min. The hearts were divided into 4 groups (n = 13 in each group). In Group ST, the hearts were arrested using the ST solution alone. In Groups L, M, and H, the hearts were arrested using the ST solution supplemented with a low-dose (1 mu M), moderate dose (10 mu M), and high dose (100 mu M) of edaravone, respectively. Left ventricular function (+dp/dt (max)) and the levels of the cardiac enzymes released were measured before and after cardioplegic arrest. At the end of the study, the water content and the tissue oxidative stress (8-hydroxy-2'-deoxyguanosine) of the heart were measured. During reperfusion, the edaravone-treated groups showed a greater functional recovery with regard to the +dp/dt (max) (P &lt; 0.05). The lactate level was the lowest (P &lt; 0.01) in Group M. The water content of the hearts in the edaravone-treated groups was significantly lower (P &lt; 0.05) than that in Group ST. Oxidative stress was significantly lower (P &lt; 0.01) in the edaravone-treated hearts than in Group ST, and it was the lowest in Group M. The addition of edaravone to the cardioplegic solution ameliorates the impairment in myocardial function by reducing the oxidative stress after cardioplegic arrest. In this study, the maximum improvement in the myocardial function was achieved by addition of a moderate dose (10 mu M) of edaravone.

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  546. Pro-apoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of SOD2 knockout mice. Reviewed

    Fan YY, Zhan Y, Aukema HM, Davidson LA, Zhou L, Callaway E, Tian Y, Weeks BR, Lupton JR, Toyokuni S, Chapkin RS

    J. Nutr.   Vol. 139   page: 1328-1332   2009.5

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  547. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury. Reviewed

    Hiraumi Y, Iwai-Kanai E, Baba S, Yui Y, Kamitsuji Y, Mizushima Y, Matsubara H, Watanabe M, Watanabe KI, Toyokuni S, Matsubara H, Nakahata T, Adachi S.

    Am. J. Physiol. Heart Circ. Physiol.   Vol. 296   page: H823-H832   2009.3

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  548. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury Reviewed

    Yoshimi Hiraumi, Eri Iwai-Kanai, Shiro Baba, Yoshihiro Yui, Yuri Kamitsuji, Yasuhiro Mizushima, Hiroshi Matsubara, Motonobu Watanabe, Ken-ichirou Watanabe, Shinya Toyokuni, Hiroaki Matsubara, Tatsutoshi Nakahata, Souichi Adachi

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   Vol. 296 ( 3 ) page: H823 - H832   2009.3

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    Hiraumi Y, Iwai-Kanai E, Baba S, Yui Y, Kamitsuji Y, Mizushima Y, Matsubara H, Watanabe M, Watanabe K, Toyokuni S, Matsubara H, Nakahata T, Adachi S. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury. Am J Physiol Heart Circ Physiol 296: H823-H832, 2009. First published January 9, 2009; doi:10.1152/ajpheart.00774.2008.-Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.

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  549. Mechanisms of asbestos-induced carcinogenesis.

    Toyokuni S.

    Nagoya J. Med. Sci.   Vol. 71   page: 1-10   2009.2

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  550. MECHANISMS OF ASBESTOS-INDUCED CARCINOGENESIS International journal

    Toyokuni Shinya

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 71 ( 1-2 ) page: 1 - 10   2009.2

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  551. MECHANISMS OF ASBESTOS-INDUCED CARCINOGENESIS

    TOYOKUNI S.

    Nagoya Journal of Medical Science   Vol. 71 ( 1 ) page: 1 - 10   2009.2

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    Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM and the development of animal models, the carcinogenic mechanisms of the disease remain unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be summarized as follows: (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of free radicals due to their inability to digest the fibers, and epidemiological studies indicating that iron-containing asbestos fibers appear more carcinogenic; (2) the "chromosome tangling theory" postulates that asbestos fibers damage chromosomes when cells divide; and (3) the "theory of adsorption of many specific proteins as well as carcinogenic molecules" states that asbestos fibers in vivo concentrate proteins or chemicals including the components of cigarette smoke. Elucidation of the major mechanisms underlying DMM would be helpful for the development of novel strategies to prevent DMM induction in people who have already been exposed to asbestos.

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  552. Mechanisms of asbestos-induced carcinogenesis.

    Toyokuni S.

    Nagoya journal of medical science   Vol. 71 ( 1-2 ) page: 1 - 10   2009.2

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    Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM and the development of animal models, the carcinogenic mechanisms of the disease remain unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be summarized as follows: (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of free radicals due to their inability to digest the fibers, and epidemiological studies indicating that iron-containing asbestos fibers appear more carcinogenic; (2) the "chromosome tangling theory" postulates that asbestos fibers damage chromosomes when cells divide; and (3) the "theory of adsorption of many specific proteins as well as carcinogenic molecules" states that asbestos fibers in vivo concentrate proteins or chemicals including the components of cigarette smoke. Elucidation of the major mechanisms underlying DMM would be helpful for the development of novel strategies to prevent DMM induction in people who have already been exposed to asbestos.

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  553. Mechanisms of asbestos-induced carcinogenesis.

    Toyokuni S

    Nagoya journal of medical science   Vol. 71 ( 1-2 ) page: 1 - 10   2009.2

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  554. Mechanisms of asbestos-induced carcinogenesis.

    Toyokuni S

    Nagoya J. Med. Sci.   Vol. 71   page: 1-10   2009.2

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  555. Role of iron in carcinogenesis : Cancer as a ferrotoxic disease

    TOYOKUNI Shinya

    Cancer Sci.   Vol. 100 ( 1 ) page: 9 - 16   2009.1

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  556. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inihibitor FK228 through AIF translocation.

    Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe KI, Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Tokuchida J, Nakahata T

    Int. J. Cancer   Vol. 124 ( 1 ) page: 55 - 67   2009.1

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  557. *Role of iron in carcinogenesis: Cancer as a ferrotoxic disease. Invited Reviewed

    Toyokuni S.

    Cancer Sci.   Vol. 100   page: 6-16   2009.1

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  558. Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Reviewed

    Zhong Y, Onuki J, Yamasaki T. Ogawa O, Akatsuka S and Toyokuni S.

    Carcinogenesis   Vol. 30   page: 158-164   2009.1

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  559. Biased Immunoglobulin VH Recombination and Increased Expression of Chemokine Receptor XCR1 Are Distinct Features of Bone Marrow-Derived Diffuse Large B-Cell Lymphoma International journal

    Yamashita, Y; Kajiura, D; Nakamura, S; Toyokuni, S; Mori, N

    LABORATORY INVESTIGATION   Vol. 89   page: 292A - 292A   2009.1

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  560. Biased Immunoglobulin VH Recombination and Increased Expression of Chemokine Receptor XCR1 Are Distinct Features of Bone Marrow-Derived Diffuse Large B-Cell Lymphoma International journal

    Yamashita, Y; Kajiura, D; Nakamura, S; Toyokuni, S; Mori, N

    MODERN PATHOLOGY   Vol. 22   page: 292A - 292A   2009.1

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  561. Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Reviewed International journal

    Yi Zhong, Janice Onuki, Toshinari Yamasaki, Osamu Ogawa, Shinya Akatsuka, Shinya Toyokuni

    Carcinogenesis   Vol. 30 ( 1 ) page: 158 - 64   2009.1

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    A growing number of studies indicate a link between oxidative stress and cancer. We previously developed a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Here, we performed a genome-wide analysis to study characteristics of genomic alteration and identify putative genes involved in the development of Fe-NTA-induced RCCs. Array-based comparative genomic hybridization analyses revealed a chromosomal loss spanning chromosome 8 in most of the RCCs studied, with a common deletion at 8q31-32, which was confirmed by loss of heterozygosity (LOH) analysis. Studies of gene expression in RCCs or following Fe-NTA treatment revealed globally decreased transcription levels of 34 genes derived from chromosome 8 that are expressed in the kidney. Among them, the aminoacylase 1 (Acy1) gene, which maps to 8q32 and is highly expressed in the kidney, displayed a significantly decreased level of expression in RCCs. Significant amounts of the Acy1 protein were detected in the cytoplasm as well as in the nuclei of renal proximal tubular cells of untreated rats. Transfection of Acy1 into RCC cell lines inhibited proliferation and colony formation on soft agar. An increased number of apoptotic cells were observed following Acy1 transfection. The rat 8q31-32 chromosomal region corresponds to human 3p21.31-24.1, a hot spot where LOH is frequently found in various human cancers. Thus, Fe-NTA-induced renal tumor model is ideal for studying the link between deletions within this region and tumor formation. Our data demonstrate that Acy1 functions as a tumor suppressor in this rat RCC model. © The Author 2008. Published by Oxford University Press. All rights reserved.

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  562. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. International journal

    Shinya Toyokuni

    Cancer science   Vol. 100 ( 1 ) page: 9 - 16   2009.1

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    Iron is abundant universally. During the evolutionary processes, humans have selected iron as a carrier of oxygen inside the body. However, iron works as a double-edged sword, and its excess is a risk for cancer, presumably via generation of reactive oxygen species. Thus far, pathological conditions such as hemochromatosis, chronic viral hepatitis B and C, exposure to asbestos fibers, as well as endometriosis have been recognized as iron overload-associated risks for human cancer. Indeed, iron is carcinogenic in animal experiments. These reports unexpectedly revealed that there are target genes in iron-induced carcinogenesis and that iron-catalyzed oxidative DNA damage is not random in vivo. Several iron transporters and hepcidin, a peptide hormone regulating iron metabolism, were discovered in the past decade. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy decreased cancer risk in the apparently normal population. These results warrant reconsideration of the role of iron in carcinogenesis and suggest that fine control of body iron stores would be a wise strategy for cancer prevention. (Cancer Sci 2009; 100: 9-16).

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  563. *Role of iron in carcinogenesis: Cancer as a ferrotoxic disease. Invited Reviewed

    Toyokuni S

    Cancer Sci.   Vol. 100   page: 6-16   2009.1

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  564. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis. Invited

    Liu YT, Toyokuni S.

    Methods Mol. Biol.   Vol. 536   page: 307-312   2009

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  565. Lipid Peroxidation Generates a Body Odor Component Trans-2-Nonenal Covalently Bound to Protein in vivo International journal

    Ishino Kousuke, Wakita Chika, Shibata Takahiro, Toyokuni Shinya, Machida Sachiko, Matsuda Shun, Matsuda Tomonari, Uchida Koji

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 47   page: S76 - S76   2009

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  566. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis. Invited

    Liu YT, Toyokuni S

    Methods Mol. Biol.   Vol. 536   page: 307-312   2009

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  567. Lipid Peroxidation Generates a Body Odor Component Trans-2-Nonenal Covalently Bound to Protein in vivo Reviewed

    Kousuke Ishino, Chika Wakita, Takahiro Shibata, Shinya Toyokuni, Sachiko Machida, Shun Matsuda, Tomonari Matsuda, Koji Uchida

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 47   page: S76 - S76   2009

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  568. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis. International journal

    Yu-Ting Liu, Shinya Toyokuni

    Methods in molecular biology (Clifton, N.J.)   Vol. 536   page: 307 - 312   2009

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    We established a shortened protocol for western blot analysis using intermittent microwave irradiation. With this method, the procedure is completed within 1 h after applying the primary antibody, and thus greatly saves time. This procedure appears to be applicable to any antibody based on our experience of several years.

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  569. S1-3 Elucidation of asbestos-induced mesothelial carcinogenesis and its prevention stragegy(Symposium 1: Biomarkers in Environmental Mutagen Research: Lifestyle-related and Environmental Factors)

    Toyokuni Shinya

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  570. Characteristics and modifying factors of asbestos-induced oxidative DNA damage

    JIANG Li, NAGAI Hirotaka, OHARA Hiroki, HARA Shigeo, TACHIBANA Mitsuhiro, HIRANO Seishiro, SHINOHARA Yasushi, KOHYAMA Norihiko, AKATSUKA Shinya, TOYOKUNI Shinya

    Cancer Sci   Vol. 99 ( 11 ) page: 2142 - 2151   2008.11

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  571. *Characteristics and modifying factors of asbestos-induced oxidative DNA damage. Reviewed

    Jiang L, Nagai H; Ohara H, Hara S, Tachibana M, Hirano S, Shinohara Y, Kohyama N, Akatsuka S and Toyokuni S.

    Cancer Sci.   Vol. 99 ( 11 ) page: 2142-2151   2008.11

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  572. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias Reviewed

    Y. Kamitsuji, J. Kuroda, S. Kimura, S. Toyokuni, K. Watanabe, E. Ashihara, H. Tanaka, Y. Yui, M. Watanabe, H. Matsubara, Y. Mizushima, Y. Hiraumi, E. Kawata, T. Yoshikawa, T. Maekawa, T. Nakahata, S. Adachi

    CELL DEATH AND DIFFERENTIATION   Vol. 15 ( 11 ) page: 1712 - 1722   2008.11

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    Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis ( CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.

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  573. Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Reviewed International journal

    Jie Liao, Darren N Seril, Gary G Lu, Meng Zhang, Shinya Toyokuni, Allison L Yang, Guang-Yu Yang

    Molecular carcinogenesis   Vol. 47 ( 8 ) page: 638 - 646   2008.8

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    Ogg1 DNA repair enzyme recognizes and excises oxidative stress-caused 8-hydroxyl-deoxyguanosine (8-OHdG) from GC base-pairs. Ogg1 knockout mice are phenotypically normal, but exhibit elevated levels of 8-OHdG in nuclear and mitochondrial DNA, as well as moderately elevated mutagenesis and spontaneous lung tumors and UV-induced skin tumors. To elucidate the mechanistic role of inflammation-caused oxidative stress in carcinogenesis, the development of chronic ulcerative colitis (UC)-induced carcinoma in Ogg1 knockout mice was studied using a dextran sulfate sodium (DSS)-induced UC model without the use of a carcinogen. Ogg1 (-/-), Ogg1 (+/-), and wild type C57BL/6 mice were subjected to long-term, cyclic DSS treatment to induce chronic UC and carcinogenesis. In wild type C57BL/6 control mice after 15 cycles of DSS treatment, colorectal adenocarcinoma incidence was 24.1 % (7/29 mice), with a tumor volume of 27.9 +/- 5.2 mm(3). Ogg1 (-/-) mice showed significantly increased adenocarcinoma development in the colon with a tumor incidence of 57.1 % (12 of 21 mice, P &lt; 0.05) and a tumor volume of 35.1 +/- 6.1 mm(3). Ogg1 mice (+/-) also exhibited significantly increased tumor development in the colon with a tumor incidence of 50.0% (13/26 mice) and a tumor volume of 29.1 +/- 7.2 mm(3). Histopathologic analyses revealed that colorectal tumors were well-differentiated tubular adenocarcinomas or mucinous carcinoma and adjacent colonic mucosa showed mild to moderate chronic UC. Using immunohistochemical approaches, Ogg1 (-/-) and (+/-) mice exhibited similar numbers and staining intensities of macrophages in UC areas as seen in Ogg1 (+/+) mice, but markedly increased numbers and staining intensities of 8-OHdG positive inflammatory and epithelial cells. These results provide important evidence on the relationship between inflammation-caused oxidative stress, DNA repair enzyme Ogg1, and carcinogenesis. (C) 2008 Wiley-Liss, Inc.

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  574. Molecular mechanisms of oxidative stress-induced carcinogenesis: From epidemiology to oxygenomics

    Toyokuni, S

    IUBMB LIFE   Vol. 60 ( 7 ) page: 441 - 447   2008.7

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    Oxidative stress is associated with inflammation, radiation, reperfusion, and iron overload. Epidemiological observations have shown that oxidative stress is one of the major sources of carcinogenesis, the top-ranked cause of human mortality worldwide. In situations of oxidative stress, reactive oxygen and nitrogen species contribute to the alteration of genome information, presumably followed by selection of the adapted proliferating cells in a given environment. Recent data suggest that common molecular mechanisms exist in oxidative stress-induced carcinogenesis, including p16INK4A inactivation. Thus far, oxidative DNA damage in the genome as a cause of mutation has been recognized to be randomly distributed based on in vitro experiments, while localization of oxidative DNA damage in vivo has not been pursued. However, using a novel technique based on DNA immunoprecipitation in combination with genome information, we now know that the localization of oxidative DNA damage is not random in vivo. We propose to call this rather novel research area "oxygenomics." Many signaling pathways start from the recognition of DNA damage. Thus, possible underlying principles should be elucidated in association with each cell type, the genomic location of the damage with its transcriptional activity as well as the chromatin status determining the epigenetic effect. © 2008 IUBMB.

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  575. Protein N-acylation: H2O2-mediated covalent modification of protein by lipid peroxidation-derived saturated aldehydes. Reviewed International journal

    Kousuke Ishino, Takahiro Shibata, Takeshi Ishii, Yu-Ting Liu, Shinya Toyokuni, Xiaochun Zhu, Lawrence M Sayre, Koji Uchida

    Chemical research in toxicology   Vol. 21 ( 6 ) page: 1261 - 1270   2008.6

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    Various lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the degenerated proteins have been found in cells and tissues during aging, oxidative stress, and in a variety of pathological states. The critical agents that give rise to this protein degeneration may be represented by aldehydes. Although the covalent modification of proteins by aldehydes alone has been well-studied, the effect of reactive oxygen species, such as H2O2, upon aldehyde modification of the protein has received little attention. We have now established a unique protein modification in which H2O2 and, to a lesser extent, alkyl hydroperoxides mediate the binding of alkanals to the lysine residues of protein to generate structurally unusual N-acylation products. Upon the reaction of a lysine-containing peptide, N-alpha-benzoylglycyl-lysine, with hexanal in the presence of H2O2, a product containing one molecule of hexanal per peptide was detected. On the basis of the chemical and spectroscopic evidence, the product was identified to be the acylation product, N-epsilon-hexanoyllysine. H2O2 mediated the N-acylation of the lysine derivative by the saturated aldehydes of 1-6 carbons in length. The H2O2-mediated acylation of the protein was immunochemically confirmed by reaction of the proteins with hexanal in the presence of H2O2. Furthermore, the enhanced N-acylations (N-acetylation and N-hexanoylation) were also observed in the kidney of rats exposed to ferric nitrilotriacetate, a well-characterized inducer of oxidative stress. Mechanistic studies using a phosphonium lysine derivative suggest a Baeyer-Villiger-like reaction proceeding through peroxide addition to the aldehyde Schiff base. These data suggest that the hydroperoxides, including H2O2, might be involved not only in the oxidative modification of protein but also in the covalent binding of the saturated aldehydes to proteins under oxidative stress.

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  576. Pluripotency of a single spermatogonial stem cell in mice Reviewed

    Mito Kanatsu-Shinohara, Jiyoung Lee, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokun, Masahito Ikawa, Tomoyuki Nakamura, Atsuo Gura, Takashi Shinohara

    BIOLOGY OF REPRODUCTION   Vol. 78 ( 4 ) page: 681 - 687   2008.4

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    Although pluripotent stem cells were recently discovered in postnatal testis, attempts to analyze their developmental potential have led to conflicting claims that spermatogonial stem cells are pluripotent or that they lose spermatogenic potential after conversion into pluripotent stem cells. TO 11 examine this issue, we analyzed the developmental fate of a single spermatogonial stem cell that appeared during transfection experiments. After transfection of a neomycin-resistance gene into germline stem cells, we obtained an embryonic stem-like, multipotent germline stem cell line. Southern blot analysis revealed that the germline stem and multipotent germline stem clones have the same transgene integration pattern, demonstrating their identical origin. The two lines, however, have different DNA methylation patterns. The multipotent germline stem cells formed chimeras after blastocyst injection but did not produce sperm after germ cell transplantation, whereas the germline stem cells could produce only spermatozoa and did not differentiate into somatic cells. interestingly, the germline stem cells expressed several transcription factors (Pou5f1, Sox2, Myc, and KIf4) required for reprogramming fibroblasts into a pluripotent state, suggesting that they are potentially pluripotent. Thus, our study provides evidence that a single spermatogonial stem cell can acquire pluripotentiality but that conversion into a pluripotent cell type is accompanied by loss of spermatogenic potential.

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  577. Visualization and characterization of UVB-induced reactive oxygen species in a human skin equivalent model

    Hakozaki, T; Date, A; Yoshii, T; Toyokuni, S; Yasui, H; Sakurai, H

    ARCHIVES OF DERMATOLOGICAL RESEARCH   Vol. 300 ( SUPPL. 1 ) page: S51 - S56   2008.4

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    Reactive oxygen species (ROS) play important roles in the process of ultraviolet-induced skin damage or photoaging. Although many enzymatic and chemical methods have been developed for evaluating ROS, evaluation methods for ROS generation in living systems are quite limited. Here we propose a unique system to visualize UVB-induced ROS and investigate the biological impact of ROS. In brief, a human skin equivalent model (HSEM) was exposed to UVB. Emitted luminescence from the HSEM was visualized and semi-quantified by using a chemiluminescent probe (CLA) and an ultra low-light imaging apparatus. The effects of anti-oxidative compounds such as ascorbate, β-carotene, superoxide dismutase (SOD), and yeast ferment filtrate (YFF) on the HSEM were evaluated by semi-quantification of emitted chemiluminescence (CL) intensities, MTT assay and 8-hydroxy-2′-deoxyguanosine (8-OHdG) staining. Visualization of time- and space-dependent dynamics of ROS generation in the HSEM was successfully achieved by utilizing a sensitive two-dimensional ultra-low light luminograph. Treatments with β-carotene and SOD effectively suppressed CL intensity, indicating the generation of 1O2 and O 2.- in the HSEM under UVB exposure. Tested anti-oxidative compounds also attenuated UVB-induced CL and ameliorated the induced skin damages in terms of 8-OHdG formation and cell death. As a conclusion, this model is useful for not only visualizing the production of UVB-induced ROS in real-time but also evaluating the efficacy of topically applied anti-oxidative compounds to suppress ROS generation and attenuate sequential chemical and biological responses. © 2007 Springer-Verlag.

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  578. Target Genes of Oxidative Stress-induced Carcinogenesis

    TOYOKUNI Shinya

      Vol. 63 ( 2 ) page: 282   2008.3

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  579. Target Genes of Oxidative Stress-induced Carcinogenesis

    TOYOKUNI Shinya

      Vol. 63 ( 2 ) page: 282 - 282   2008.3

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  580. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress.

    Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K, Fujii S

    Clinical cancer research : an official journal of the American Association for Cancer Research   Vol. 14 ( 1 ) page: 32 - 40   2008.1

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    Purpose: Endometriotic cysts are known to transforminto ovarian cancers, such as clear cell and endometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Experimental Design: Contents of human ovarian cysts, including 21 endometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts,were analyzed for the concentrations of free "catalytic" iron, lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-hydroxy-2′- deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in endometriotic cyst were determined in vitro. Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxidant, lipidperoxide, and 8-OHdG were also significantly higher in endometriotic cysts (P < 0.01). There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01). The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of endometriotic cyst couldproducemore reactiveoxygen species and could induce genemutations more frequently than the contents in the other cysts. Conclusions: Abundant free iron in the contents of endometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst. © 2008 American Association for Cancer Research.

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  581. Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats

    TAKEMURA Shigekazu, MINAMIYAMA Yukiko, TOYOKUNI Shinya, IMAOKA Susumu, HAI Seikan, KUBO Shoji, HIROHASHI Kazuhiro, FUNAE Yoshihiko, OKADA Shigeru

      Vol. 38 ( 1 ) page: 70 - 78   2008.1

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  582. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress

    Yamaguchi Ken, Mandai Masaki, Toyokuni Shinya, Hamanishi Junzo, Higuchi Toshihiro, Takakura Kenji, Fujii Shingo

    CLINICAL CANCER RESEARCH   Vol. 14 ( 1 ) page: 32 - 40   2008.1

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  583. Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats Reviewed

    Shigekazu Takemura, Yukiko Minamiyama, Shinya Toyokuni, Susumu Imaoka, Seikan Hai, Shoji Kubo, Kazuhiro Hirohashi, Yoshihiko Funae, Shigeru Okada

    HEPATOLOGY RESEARCH   Vol. 38 ( 1 ) page: 70 - 78   2008.1

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    Aim: CYP3A2 is a male-specific isoform of cytochrome P450 enzyme which is expressed abundantly in male rats but not in intact female rats. Having previously reported that hepatic CYP3A2 promotes lipopolysaccharide (LPS)-induced liver injury in male rats, we further examined the impact of CYP3A on LPS-induced liver injury by comparing intact and hypophysectomized female rats. In hypophysectomized female rats, phenobarbital (PB), a cytochrome P450 inducer, markedly increased the hepatic content and activity of CYP3A1/2, but did not do so in intact rats. CYP2B1 increased to similar levels in PB-treated hypophysectomized and intact rats.
    Methods: Rats were administered 10 mg/kg LPS intravenously and some were given PB for three days before LPS injection. Liver injury was analyzed 8 h after LPS injection.
    Results: PB-LPS increased plasma alanine aminotransferase significantly more in hypophysectomized female rats than in intact female rats. Ketoconazole, a CYP3A inhibitor, inhibited the increase of liver injury. Hepatic 8-hydroxydeoxyguanosine in nuclei and 4-hydroxy-2-nonenal-modified proteins, measured to evaluate oxidative stress by LPS treatment, increased markedly more in PB-treated, hypophysectomized female rats, than in intact female rats.
    Conclusions: Overexpression of CYP3A aggravated LPS-induced liver injury in rats, apparently through the formation of reactive oxygen species.

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  584. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress Reviewed

    Ken Yamaguchi, Masaki Mandai, Shinya Toyokuni, Junzo Hamanishi, Toshihiro Higuchi, Kenji Takakura, Shingo Fujii

    CLINICAL CANCER RESEARCH   Vol. 14 ( 1 ) page: 32 - 40   2008.1

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    Purpose: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and enclometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress.
    Experimental Design: Contents of human ovarian cysts, including 21 enclometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free "catalytic" iron, lactose clehydrogenase, potential antioxiclant, lipid peroxide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in enclometriotic cyst were determined in vitro.
    Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P &lt; 0.01). The average concentrations of lactose dehydrogenase, potential antioxiclant, lipid peroxide, and 8-OHdG were also significantly higher in enclometriotic cysts (P &lt; 0.01).There was a correlation between the concentration of free iron and that of 8-OHdG (P &lt; 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P &lt; 0.01).The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P &lt; 0.05). In vitro analyses showed that the contents of enclometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts.
    Conclusions: Abundant free iron in the contents of enclometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.

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  585. Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Reviewed

    Zhong Y, Onuki J, Yamasaki T. Ogawa O, Akatsuka S and Toyokuni S.

    Carcinogenesis     page: in press   2008

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  586. Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats. Reviewed

    Takemura S, Minamiyama Y, Toyokuni S, Imaoka S, Hai S, Kubo S, Hirohashi K, Funae Y and Okada S.

    Hepatol. Res.   Vol. 38   page: 70-78   2008

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  587. Pluripotency of a single spermatogonial stem cell. Reviewed

    Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Yoshida S, Toyokuni S, Lee J, Ogura A and Shinohara T.

    Biol. Reprod.   Vol. 78   page: 681-687   2008

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  588. Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Reviewed

    Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K and Fujii S.

    Clin. Cancer Res.   Vol. 14   page: 32-40   2008

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  589. Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. Invited Reviewed

    Toyokuni S.

    IUBMB Life   Vol. 60   page: 441-447   2008

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  590. Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Reviewed

    Liao J, Seril DN, Lu GG, Zhang M, Toyokuni S, Yang AL and Yang GY.

    Mol. Carcinog.   Vol. 47   page: 638-646   2008

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  591. Protein N-acylation: H2O2-mediated covalent modification of protein by lipid peroxidation-derived saturated aldehydes. Reviewed

    Ishino K, Shibata T, Ishii T, Liu YT, Toyokuni S, Zhu X, Sayre LM and Uchida K.

    Chem. Res. Toxicol.   Vol. 21   page: 1261-1270   2008

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  592. A reporter gene assay to prove the ability of natural compounds to modulate gluthathione peroxidase, superoxide dismutase and catalase gene promoters in V79 cells. Reviewed

    Ullmann K, Wiencierz A M, M&uuml;ller C, Thierbach R, Steege A, Toyokuni S and Steinberg P.

    Free Radic. Res.   Vol. 42   page: 746-753   2008

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  593. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Reviewed

    Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S.

    Cell Death Differ.   Vol. 15   page: 1712-1722   2008

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  594. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inihibitor FK228 through AIF translocation. Reviewed

    Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe KI, Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Tokuchida J and Nakahata T.

    Int. J. Cancer   Vol. 124   page: 55-67   2008

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  595. A high-throughput reporter gene assay to prove the ability of natural compounds to modulate glutathione peroxidase, superoxide dismutase and catalase gene promoters in V79 cells. Reviewed International journal

    Kristina Ullmann, Anne Maria Wiencierz, Carsten Müller, Rene Thierbach, Andreas Steege, Shinya Toyokuni, Pablo Steinberg

    Free radical research   Vol. 42 ( 8 ) page: 746 - 753   2008

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    The aim of the study was to establish a 96-well microtiter plate-based reporter gene assay to test the influence of natural compounds on the promoter activities of rat catalase, human glutathione peroxidase and human superoxide dismutase expressed in V79 cells. Luciferase expression vectors with the promoter regions of the genes coding for the three above-mentioned enzymes were constructed and transfected into V79 cells. Thereafter the ability of sodium ascorbate, L-carnitine, catechin, epigallocatechin gallate, genistein, paraquat, quercetin, 12-O-tetradecanoylphorbol-13-acetate and Trolox to enhance the promoter activities was evaluated. Genistein, paraquat and quercetin led to a statistically significant increase in the glutathione peroxidase and superoxide dismutase gene promoter activities. None of the compounds tested enhanced the catalase gene promoter activity. The reporter gene assay described in this report is easy to perform, fast and allows one to test a high number of compounds and different concentrations of a single compound at the same time.

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  596. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inihibitor FK228 through AIF translocation. Reviewed

    Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe KI, Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Tokuchida J, Nakahata T

    Int. J. Cancer   Vol. 124   page: 55-67   2008

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  597. Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. Invited Reviewed

    Toyokuni S

    IUBMB Life   Vol. 60   page: 441-447 - 447   2008

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  598. Association of microRNA-34a overexpression with proliferation is cell type-dependent

    DUTTA Khokon Kumar, ZHONG Yi, LIU Yu-Ting, YAMADA Takuji, AKATSUKA Shinya, HU Qian, YOSHIHARA Minako, OHARA Hiroki, TAKEHASHI Masanori, SHINOHARA Takashi, MASUTANI Hiroshi, ONUKI Janice, TOYOKUNI Shinya

    Cancer Sci.   Vol. 98 ( 12 ) page: 1845 - 1852   2007.12

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  599. Production of knockout mice by gene targeting in multipotent germline stem cells Reviewed

    Masanori Takehashi, Mito Kanatsu-Shinohara, Hiromi Miki, Jiyoung Lee, Yasuhiro Kazuki, Kimiko Inoue, Narumi Ogonuki, Shinya Toyokuni, Mitsuo Oshimura, Atsuo Ogura, Takashi Shinohara

    DEVELOPMENTAL BIOLOGY   Vol. 312 ( 1 ) page: 344 - 352   2007.12

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    Spermatogonial stein cells can convert into embryonic stem (ES) cell-like multipotent germline stem (mGS) cells in vitro and produce germline chimeras by blastocyst microinjection. Although homologous recombination was previously demonstrated in mGS cells, spermatogenesis was not found in chimeras, suggesting that they are not competent for germline modification. Here we conducted detailed analysis of chimeric animals to determine whether mGS cells retain germline potential after genetic manipulation. Spermatozoa that were deficient in the occludin gene could be recovered from animals that were chimeric with mGS cells that underwent homologous recombination. The phenotypes of the occludin knockout (KO) mice were similar to those reported for KO mice produced using ES cells, and the animals showed growth retardation, gastritis and male infertility. Furthermore, we found that heterozygous mGS cells acquire two copies of the G418-resistant genes and become homozygous for the targeted allele by culturing at high concentrations of G418. Cytogenetic analysis showed that the aneuploid mGS cells observed during genetic manipulation were trisomic for chromosome 8 or 11, which is a common chromosomal abnormality in ES cells. Thus, mGS cells can be used to produce KO animals, and this novel method of germline manipulation may prove useful in diverse mammalian species. (c) 2007 Elsevier Inc. All rights reserved.

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  600. Association of microRNA-34a overexpression with proliferation is cell type-dependent Reviewed

    Khokon Kumar Dutta, Yi Zhong, Yu-Ting Liu, Takuji Yamada, Shinya Akatsuka, Qian Hu, Minako Yoshihara, Hiroki Ohara, Masanori Takehashi, Takashi Shinohara, Hiroshi Masutani, Janice Onuki, Shinya Toyokuni

    CANCER SCIENCE   Vol. 98 ( 12 ) page: 1845 - 1852   2007.12

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    Recently Welch et al. reported that microRNA (miRNA)-34a functions as a potential tumor suppressor in neuroblastoma cells (Oncogene 26: 5017-22, 2007). Here, we conversely show that miRNA-34a supports cell proliferation in rat oxidative stress-induced renal carcinogenesis and is overexpressed in various types of human cancers. While searching for genetically unstable chromosomal areas in rat renal carcinogenesis, we found the miRNA-34 family reciprocally overexpressed in chromosomal areas with frequent allelic loss. By in situ hybridization and reverse transcription-polymerase chain reaction, cerebral neurons and Purkinje cells showed the highest expression of a major type, miRNA-34a, followed by a variety of endocrine cells and proliferating cells including germinal center lymphocytes and mouse embryonic fibroblasts and stem cells. In contrast, normal renal tubules, hepatocytes and myocardial cells showed faint expression. After 3 weeks of ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress, regenerating renal proximal tubular cells showed high miRNA-34a expression. All of the Fe-NTA-induced rat renal carcinomas and an array of human cancers (151 positive cases of 177) showed high expression of miRNA-34a. Furthermore, knockdown of miRNA-34a with small interfering RNA significantly suppressed proliferation not only of renal carcinoma cells but also of HeLa and MCF7 cells. These results indicate that miRNA-34a overexpression, an acquired trait during carcinogenesis, supports cell proliferation in the majority of cancers suggesting an unexpected link in the cellular metabolism between cancer and neuronal and/or endocrine cells, which warrants further investigation.

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  601. Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway

    Liu Yu-Ting, Shang Donghao, Akatsuka Shinya, Ohara Hiroki, Dutta Khokon Kumar, Mizushima Katsura, Naito Yuji, Yoshikawa Toshikazu, Izumiya Masashi, Abe Kouichiro, Nakagama Hitoshi, Noguchi Noriko, Toyokuni Shinya

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 171 ( 6 ) page: 1978 - 1988   2007.12

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    Ferric nitrilotriacetate induces oxidative renal tubular damage via Fenton-reaction, which subsequently leads to renal cell carcinoma (RCC) in rodents. Here, we used gene expression microarray and array-based comparative genomic hybridization analyses to find target oncogenes in this model. At the common chromosomal region of amplification (4q22) in rat RCCs, we found ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase ζ or receptor tyrosine phosphatase β) highly expressed in the RCCs. Analyses revealed genomic amplification up to eightfold. Despite scarcity in the control kidney, the amounts of PTPRZ1 were increased in the kidney after 3 weeks of oxidative stress, and mRNA levels were increased 16∼552-fold in the RCCs. Network analysis of the expression revealed the involvement of the β-catenin pathway in the RCCs. In the RCCs, dephosphorylated β-catenin was translocated to nuclei, resulting in the expression of its target genes cyclin D1, c-myc, c-jun, fra-1, and CD44. Furthermore, knockdown of ptprz1 with small interfering RNA (siRNA), in FRCC-001 and FRCC-562 cell lines established from the induced RCCs, decreased the amounts of nuclear β-catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes. These results demonstrate that chronic oxidative stress can induce genomic amplification of ptprz1, activating β-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification. Copyright © American Society for Investigative Pathology.

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  602. Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway Reviewed

    Yu-Ting Liu, Donghao Shang, Shinya Akatsuka, Hiroki Ohara, Khokon Kumar Dutta, Katsura Mizushima, Yuji Naito, Toshikazu Yoshikawa, Masashi Izumiya, Kouichiro Abe, Hitoshi Nakagama, Noriko Noguchi, Shinya Toyokuni

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 171 ( 6 ) page: 1978 - 1988   2007.12

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    Ferric nitrilotriacetate induces oxidative renal tubular damage via Fenton-reaction, which subsequently leads to renal cell carcinoma (RCC) in rodents. Here, we used gene expression microarray and array-based comparative genomic hybridization analyses to find target oncogenes in this model. At the common chromosomal region of amplification (4q22) in rat RCCs, we found ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase zeta or receptor tyrosine phosphatase beta) highly expressed in the RCCs. Analyses revealed genomic amplification up to eightfold. Despite scarcity in the control kidney, the amounts of PTPRZ1 were increased in the kidney after 3 weeks of oxidative stress, and mRNA levels were increased 16 similar to 552-fold in the RCCs. Network analysis of the expression revealed the involvement of the beta-catenin pathway in the RCCs. in the RCCs, dephosphorylated beta-catenin was translocated to nuclei, resulting in the expression of its target genes cyclin D1, c-myc, c-jun, fra-1, and CD44. Furthermore, knockdown of ptprz1 with small interfering RNA (siRNA), in FRCC-001 and FRCC-562 cell lines established from the induced RCCs, decreased the amounts of nuclear beta-catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes. These results demonstrate that chronic oxidative stress can induce genomic amplification of ptprz1, activating beta-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification.

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  603. FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL(+) Kupffer cells are indicators of rejection activity in human liver Allografts Reviewed

    Aya Miyagawa-Hayashino, Tatsuaki Tsuruyama, Hiroto Egawa, Hironori Haga, Hirorni Sakashita, Tomoko Okuno, Shinya Toyolkuni, Keiji Tamaki, Hirohiko Yamabe, Toshialki Manabe, Shinji Uemoto

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 171 ( 5 ) page: 1499 - 1508   2007.11

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    Fas-Fas figand (FasL) interaction and apoptosis are important in the mechanism of allograft rejection. However, the interaction between donor and recipient cells, specifically focusing on antigen-presenting cells (APCs), under various conditions is poorly understood in human liver allografts. FasL expression on APCs, its association with apoptosis, and the origin of apoptotic lymphocytes in human liver allografts were assessed by immunohistochemistry and in situ hybridization. We found increased expression of FasL on Kupffer cells (KCs) and endothelium in acute cellular rejection (n = 20) and to lesser extent in chronic rejection (n = 6) and septic cholangitis (n = 5) compared with stable grafts and normal controls. in addition, the graft specificity of infiltrating T cells was confirmed by polymerase chain reaction examination of T-cell receptor-gamma loci. T-cell apoptosis occurred at a higher rate in acute cellular rejection than in chronic rejection or septic cholangitis. The number of apoptotic bodies derived from recipient lymphocytes correlated with the severity of rejection and was reversed by treatment. FasL(+) KCs phagocytosed CD4(+) interferon-gamma(+) T cells, rather than CD4(+) interleukin-4(+) T cells, suggesting a role of KCs in regulating CD4+ T-cell subset differentiation. in conclusion, our data suggest that FasL expression on APCs and phagocytosis of apoptotic T cells by FasL(+) KCs are indicators of rejection activity in human liver allografts.

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  604. Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice Reviewed

    Y. Zhong, L. Jiang, H. Hiai, S. Toyokuni, Y. Yamada

    ONCOGENE   Vol. 26 ( 48 ) page: 6937 - 6947   2007.10

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    LYL1, a member of the class II basic helix-loop-helix transcription factors, is aberrantly expressed in a fraction of human T-cell acute lymphoblastic leukemia. Here, we generated transgenic mice ubiquitously overexpressing LYL1 using a construct expressing full-length cDNA driven by a human elongation factor lot promoter. Four independent lines exhibiting high LYL1 expression were established. Of these transgenic mice, 96% displayed loss of hair with a short kinked tail. Furthermore, 30% of them developed malignant lymphoma, with an average latent period of 352 days. In these mice, histological examination revealed tumor cell infiltration in multiple organs and immunohistochemical analysis showed that the infiltrated tumor cells were either CD3 or CD45R/B220-positive; fluorescence-activated cell sorter analysis indicated that each tumor consisted either of mainly CD4, CD8 double-positive T cells or mature B cells; the clonality of LYL1-induced lymphoma was confirmed by T-cell receptor rearrangement and immunoglobulin heavy-chain gene rearrangement analyses. Mammalian two-hybrid analysis and luciferase assay suggested that excess LYL1 blocked the dimerization of E2A and thus inhibited the regulatory activity of E2A on the CD4 promoter. Reverse transcription-polymerase chain reaction results showed that the expression of certain E2A/HEB target genes was downregulated. Taken together, our results provide direct evidence that aberrant expression of LYL1 plays a role in lymphomagenesis.

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  605. Pathological investigation of oxidative stress in the post-genomic era Invited Reviewed

    Shinya Toyokuni, Shinya Akatsuka

    PATHOLOGY INTERNATIONAL   Vol. 57 ( 8 ) page: 461 - 473   2007.8

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    Aerobes, including humans, are consistently exposed to oxidative stress by consuming oxygen. The biological significance of oxidative stress via reactive oxygen and nitrogen species consists of two stages: reversible redox regulation and irreversible oxidative molecular damage, which are sometimes intermingled. During the past decade, many signaling cascades associated with oxidative stress have been discovered. An interaction between Keap1 and the Nrf2 transcription factor is among the most fundamental mechanisms of the defense system against oxidative or similar stress. Furthermore, it became apparent that reactive oxygen species are actively produced through enzymes such as xanthine oxidoreductase and nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidases in non-phagocytic cells as well. The role of alpha-tocopherol solely as an anti-oxidant was also questioned. Now there is a long list of pathological states implicating oxidative stress. At the same time, genome projects on various species have been completed. These efforts convincingly led to a new era of oxidative stress investigation, contributing powerful strategies to select candidate genes or biomolecules. Herein are reviewed recent advances and novel concepts in this field, including oxygenomics. These fruitful results may lead to more accurate and useful pathological diagnosis and more efficient prophylaxis and therapeutic interventions on human diseases.

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  606. アレイCGH法を用いた酸化ストレス誘発ラット腎癌における染色体変化の解析(Analysis of chromosomal alterations in oxidative stress-induced rat renal carcinomas using array-based CGH)

    赤塚 慎也, 泉谷 昌志, 阿部 浩一郎, 劉 玉亭, 胡 茜, 大原 浩貴, 落合 雅子, 中釜 斉, 豊國 伸哉

    日本癌学会総会記事   Vol. 66回   page: 343 - 344   2007.8

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  607. Oxidative stress is related to the formation of Antoni B patterns and eosinophilic hyaline droplets in schwannomas

    YOKOO Hideaki, OISHI Takuma, ISODA Koji, NAKAZATO Yoichi, TOYOKUNI Shinya

      Vol. 27 ( 3 ) page: 237 - 244   2007.6

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  608. Analysis of genes associated with karyomegalic cells in rat kidney after ferric nitilotriacetate treatment

    Lee, WH; Toyokuni, S

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 82 ( 6 ) page: 602 - 602   2007.6

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  609. Novel approach for elucidation of iron-induced carcinogenesis: Oxygenomics and micro-RNA

    Toyokuni, S; Dutta, KK; Akatsuka, S

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 82 ( 6 ) page: 512 - 512   2007.6

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  610. Oxidative stress is related to the formation of Antoni B patterns and eosinophilic hyaline droplets in schwannomas

    Yokoo, H; Oishi, T; Isoda, K; Nakazato, Y; Toyokuni, S

    NEUROPATHOLOGY   Vol. 27 ( 3 ) page: 237 - 244   2007.6

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    Schwannomas, particularly of vestibular origin, often accompany degenerative hypocellular areas known as Antoni B patterns; however, the detailed mechanism is uncertain. Eosinophilic hyaline droplets (EHD), the substantial nature of which are autophagic vacuoles, preferentially appear in acoustic schwannomas and distribute around areas of Antoni B. We investigated their common background using schwannomas with (15 cases) or without (10 cases) EHD, and demonstrated that EHD showed selective immunoreactivity with an anti-nitrotyrosine antibody, suggesting the overproduction of nitric oxide in this condition. The expression of inducible nitric oxide synthase was emphasized in infiltrating macrophages around hyalinized vessels. Protein-bound 4-hydroxy 2-nonenal, another oxidative stress marker, was detected in Antoni B tissue, but not in EHD. Antibodies to cleaved caspase-3 and single strand DNA, indicators of apoptosis, did not label tumors cells in Antoni B areas as well as EHD-bearing cells. The morphology and the mitotically static state of EHD-laden cells are phenotypically similar to autophagic cell death; however, autophagy in normal cells is a cell survival strategy against starvation, so the possibility remains that EHD are formed in that context. In either case, schwannomas may show a characteristic autophagic change by an endogenous mechanism. Tumor growth in a narrow intracranial space and resultant ischemia by self-oppression were postulated to be an initial event, because ischemia-reperfusion injury is a major source of reactive oxygen species and ischemia is also a potent trigger of autophagy as well as of tissue degeneration. Moreover, potential roles of chemokines and hemosiderosis are discussed. © 2007 Japanese Society of Neuropathology.

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  611. Novel approach for elucidation of iron-induced carcinogenesis: Oxygenomics and micro-RNA

    Toyokuni S, Dutta K. K, Akatsuka S

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 82 ( 6 ) page: 512 - 512   2007.6

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  612. Analysis of genes associated with karyomegalic cells in rat kidney after ferric nitilotriacetate treatment Reviewed International coauthorship International journal

    Lee, WH, Toyokuni, S

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 82 ( 6 ) page: 602 - 602   2007.6

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  613. Akt mediates self-renewal division of mouse spermatogonial stem cells Reviewed

    Jiyoung Lee, Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokuni, Tohru Kimura, Toru Nakano, Atsuo Ogura, Takashi Shinohara

    DEVELOPMENT   Vol. 134 ( 10 ) page: 1853 - 1859   2007.5

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    Spermatogonial stem cells have unique properties to self-renew and support spermatogenesis throughout their lifespan. Although glial cell line-derived neurotrophic factor ( GDNF) has recently been identified as a self-renewal factor for spermatogonial stem cells, the molecular mechanism of spermatogonial stem cell self-renewal remains unclear. In the present study, we assessed the role of the phosphoinositide-3 kinase (PI3K)-Akt pathway using a germline stem (GS) cell culture system that allows in vitro expansion of spermatogonial stem cells. Akt was rapidly phosphorylated when GDNF was added to the GS cell culture, and the addition of a chemical inhibitor of PI3K prevented GS cell self-renewal. Furthermore, conditional activation of the myristoylated form of Akt-Mer (myr-Akt-Mer) by 4-hydroxy-tamoxifen induced logarithmic proliferation of GS cells in the absence of GDNF for at least 5 months. The myr-Akt-Mer GS cells expressed spermatogonial markers and retained androgenetic imprinting patterns. In addition, they supported spermatogenesis and generated offspring following spermatogonial transplantation into the testes of infertile recipient mice, indicating that they are functionally normal. These results demonstrate that activation of the PI3K-Akt pathway plays a central role in the self-renewal division of spermatogonial stem cells.

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  614. Adenovirus-mediated gene delivery into mouse spermatogonial stem cells Reviewed

    Masanori Takehashi, Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokuni, Atsuo Ogura, Takashi Shinohara

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 104 ( 8 ) page: 2596 - 2601   2007.2

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    Spermatogonial stem cells represent a self-renewing population of spermatogonia, and continuous division of these cells supports spermatogenesis throughout the life of adult male animals. Previous attempts to introduce adenovirus vectors into spermatogenic cells, including spermatogonial stem cells, have failed to yield evidence of infection, suggesting that male germ cells may be resistant to adenovirus infection. In this study we show the feasibility of transducing spermatogonial stem cells by adenovirus vectors. When testis cells from ROSA26 Cre reporter mice were incubated in vitro with a Cre-expressing adenovirus vector, Cre-mediated recombination occurred at an efficiency of 49-76%, and the infected spermatogonial stem cells could reinitiate spermatogenesis after transplantation into seminiferous tubules of infertile recipient testes. No evidence of germ-line integration of adenovirus vector could be found in offspring from infected stem cells that underwent Cre-mediated recombination, which suggests that the adenovirus vector infected the cells but did not stably integrate into the germ line. Nevertheless, these results suggest that adenovirus may inadvertently integrate into the patient's germ line and indicate that there is no barrier to adenovirus infection in spermatogonial stem cells.

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  615. Adult pancreatic islets require differential pax6 gene dosage Reviewed

    Akihiro Hamasaki, Yuichiro Yamada, Takeshi Kurose, Nobuhiro Ban, Kazuaki Nagashima, Akira Takahashi, Shimpei Fujimoto, Dai Shimono, Michio Fujiwara, Shinya Toyokuni, Yutaka Seino, Nobuya Inagaki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 353 ( 1 ) page: 40 - 46   2007.2

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    Pax6, a paired homeodomain transcription factor, plays crucial roles in morphogenesis of eye, central nervous system, and pancreatic islets. Recently, heterozygosity for pax6 mutation has been reported in some individuals with glucose intolerance and aniridia. To investigate the role of pax6 for pancreatic islet function, we examined the pancreatic phenotype of small eye rat strain (rSey(2)) with a point mutation in the pax6 locus resulting in truncated PAX6 proteins. Analyses of the insulin secretory profile of heterozygous rSey(2)/+ revealed that insulin secretion is significantly increased in response to membrane-depolarizing stimuli such as arginine, tolbutamide, and KCl. The processes of insulin granule exocytosis were suggested to be enhanced in rSey(2)/+. On the other hand, pancreatic insulin and glucagon content and islet architecture in rSey(2)/+ showed no significant differences compared to wild-type. These findings indicate differential requirements for pax6 gene dosage in displaying function and maintaining architecture of adult pancreatic islets. (c) 2006 Elsevier Inc. All rights reserved.

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  616. Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes Reviewed

    Masaaki Okuno, Kohtaro Minami, Akinori Okumachi, Kazumasa Miyawaki, Norihide Yokoi, Shinya Toyokuni, Susumu Seino

    AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM   Vol. 292 ( 1 ) page: E158 - E165   2007.1

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    We recently found that pancreatic acinar cells isolated from normal adult mouse can transdifferentiate into insulin-secreting cells in vitro. Using two different animal models of type 1 diabetes, we show here that insulin- secreting cells can also be generated from pancreatic acinar cells of rodents in the diabetic state with absolute insulin deficiency. When pancreatic acinar cells of streptozotocin-treated mice were cultured in suspension in the presence of epidermal growth factor and nicotinamide under low-serum condition, expressions of insulin genes gradually increased. In addition, expressions of other pancreatic hormones, including glucagon, somatostatin, and pancreatic polypeptide, were also induced. Analysis by the Cre/loxP-based direct cell lineage tracing system revealed that these newly made cells originated from amylase-expressing pancreatic acinar cells. Insulin secretion from the newly made cells was significantly stimulated by high glucose and other secretagogues. In addition, insulin- secreting cells were generated from pancreatic acinar cells of Komeda diabetes-prone rats, another animal model of type 1 diabetes. The present study demonstrates that insulin- secreting cells can be generated by transdifferentiation from pancreatic acinar cells of rodents in the diabetic state and further suggests that pancreatic acinar cells represent a potential source of autologous transplantable insulin- secreting cells for treatment of type 1 diabetes.

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  617. Leukemia inhibitory factor enhances formation of germ cell colonies in neonatal mouse testis culture

    Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shosei Yoshida, Shinya Toyokuni, Jiyoung Lee, Atsuo Ogura, Takashi Shinohara

    BIOLOGY OF REPRODUCTION   Vol. 76 ( 1 ) page: 55 - 62   2007.1

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    Spermatogonial stem cells continuously divide in the testis to support spermatogenesis throughout the life of adult male animals. Although very few spermatogonial stem cells are present in vivo, we recently succeeded in expanding these cells in vitro. Germ cells from postnatal testes were able to proliferate in the presence of several types of cytokines, and they formed uniquely shaped colonies of spermatogonia (germline stem or GS cells). These cells reinitiated normal spermatogenesis when transplanted into seminiferous tubules. However, much remains unknown about the contributions of cytokines to successful stem cell culture. In the present study, we examined the role of leukemia inhibitory factor (LIF) in GS cell culture. We found that the addition of LIF to newborn testis cell culture enhances the formation of germ cell colonies. Ciliary neurotrophic factor, but not oncostatin M, had the same effect, although they both bind to the IL-6ST (gp130) receptor. On the other hand, GS cells could be established from pup or adult testes in the absence of LIF. No phenotypic or functional difference was found between GS cells established from different stages, and normal offspring were born from pup-derived GS cells that had been maintained in the absence of LIF, indicating that LIF per se is not involved in the self-renewal of GS cells. These results demonstrate that LIF is useful in the initiation of GS cell culture and suggest that LIF or a related cytokine is involved in the maturation of gonocytes into spermatogonia.

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  618. *Chronic oxidative stress causes amplification and overexpresson of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway. Reviewed

    Liu YT, Shang DH, Akatsuka S, Ohara H, Dutta KK, Mizushima K, Naito Y, Yoshikawa T, Izumiya M, Abe K, Nakagama H, Noguchi N and Toyokuni S.

    Am. J. Pathol.   Vol. 171   page: 1978-1988   2007

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  619. Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes. Reviewed

    Okuno M, Minami K, Okumachi A, Miyawaki K, Yokoi N, Toyokuni S, Seino S.

    Am. J. Physiol. Endocrinol. Metab.   Vol. 292   page: E158-165   2007

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  620. Oxidative stress is related to formation of Antoni B pattern and eosinophilic hyaline droplets in schwannoma. Reviewed

    Yokoo H, Oishi T, Isoda, K, Nakazato Y and Toyokuni S.

    Neuropathology   Vol. 27   page: 237-244   2007

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  621. Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension. Reviewed

    Takenaka H, Kihara Y, Iwanaga Y, Onozawa Y, Toyokuni S, Kita T.

    J. Mol. Cell. Cardiol.   Vol. 41   page: 989-997   2007

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  622. Leukemia inhibitory factor enhances formation of germ cell colonies in neonatal mouse testis culture.

    Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Yoshida S, Toyokuni S, Lee J, Ogura A and Shinohara T.

    Biol. Reprod.   Vol. 76   page: 55-62   2007

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  623. Adult pancreatic islets require differential pax6 gene dosage. Reviewed

    Hamasaki A, Yamada Y, Kurose T, Ban N, Nagashima K, Takahashi A, Fujimoto S, Shimono D, Fujiwara M, Toyokuni S, Seino Y and Inagaki N.

    Biochem. Biophys. Res. Commun.   Vol. 353   page: 40-46   2007

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  624. Adenovirus-mediated gene delivery into mouse spermatogonial stem cells. Reviewed

    Takehashi M, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Ogura A, and Shinohara T.

    Proc. Natl. Acad. Sci. USA   Vol. 104   page: 2596-2601   2007

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  625. Pathological investigation of oxidative stress in the post-genomic era. Invited Reviewed

    Toyokuni S and Akatsuka S.

    Pathol. Int.   Vol. 57   page: 461-473   2007

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  626. Overexpressin of a transcription factor LYL-1 induces T- and B-cell lymphoma in mice. Reviewed

    Zhong Y, Li J, Hiai H, Toyokuni S* and Yamada Y* (*corresponding author).

    Oncogene   Vol. 26   page: 6937-6947   2007

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  627. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. Reviewed

    Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J, Naitoh M, Koizumi A and Nagata K.

    Cell Struct. Funct.   Vol. 32   page: 41-50   2007

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  628. Akt mediates self-renewal division of mouse spermatogonial stem cells. Reviewed

    Lee J, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Kimura T, Nakano T, Ogura A and Shinohara T.

    Development   Vol. 134   page: 1853-1859   2007

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  629. Association of microRNA-34a overexpression with proliferation is cell type-dependent. Reviewed

    Dutta KK, Zhong Y, Liu YT, Yamada T, Akatsuka S, Hu Q, Yoshihara M, Ohara H, Takehashi M, Shinohara T, Masutani H, Onuki J and Toyokuni S.

    Cancer Sci.   Vol. 98   page: 1845-1852   2007

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  630. FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL+ Kupffer cells are indicators of rejection activity in human liver allografts. Reviewed

    Miyagawa-Hayashino A, Tsuruyama T, Egawa H, Haga H, Sakashita H, Okuno T, Toyokuni S, Tamaki K, Yamabe H, Manabe T and Uemoto S.

    Am J. Pathol.   Vol. 171   page: 1499-1508   2007

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  631. Production of knockout mice by gene targeting in multipotent germline stem cells. Reviewed

    Takehashi M, Kanatsu-Shinohara M, Miki H, Lee J, Kazuki Y, Inoue K, Ogonuki N, Toyokuni S, Oshimura M, Ogura A and Shinohara T.

    Dev. Biol.   Vol. 312   page: 344-352   2007

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  632. Visualization and characterization of UVB-induced reactive oxygen species in a human skin equivalent model. Reviewed

    Hakozaki T, Date A, Yoshii T, Toyokuni S, Yasui H and Sakurai H.

    J. Dermatol. Res.   Vol. 300 (Supplement 1)   page: S51-56   2007

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  633. Analysis of genes associated with karyo-megalic cells in rat kidney after ferric nitilotriacetate treatment International journal

    Lee, WH; Toyokuni, S

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 43   page: S24 - S24   2007

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  634. ARMET is a Soluble ER Protein Induced by the Unfolded Protein Response via ERSE-II Element

    Mizobuchi Naomi, Hoseki Jun, Kubota Hiroshi, Toyokuni Shinya, Nozaki Jun-ichi, Naitoh Motoko, Koizumi Akio, Nagata Kazuhiro

    Cell Structure and Function   Vol. 32 ( 1 ) page: 41 - 50   2007

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    Arginine rich, mutated in early stage of tumors (ARMET) was first identified as a human gene highly mutated in a variety of cancers. However, little is known about the characteristics of the ARMET protein and its expression. We identified ARMET as a gene upregulated by endoplasmic reticulum (ER) stress. Here, we show that the mouse homologue of ARMET is an 18-kDa soluble ER protein that is mature after cleavage of a signal sequence and has four intramolecular disulfide bonds, including two in CXXC sequences. ER stress stimulated ARMET expression, and the expression patterns of ARMET mRNA and protein in mouse tissues were similar to those of Grp78, an Hsp70-family protein required for quality control of proteins in the ER. A reporter gene assay using a mouse ARMET promoter revealed that the unfolded protein response of the ARMET gene is regulated by an ERSE-II element whose sequence is identical to that of the HERP gene. ARMET is the second fully characterized ERSE-II-dependent gene and likely contributes to quality control of proteins in the ER.<br>

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  635. Chronic oxidative stress causes amplification and overexpresson of ptprzl protein tyrosine phosphatase to activate beta-catenin pathway

    Liu, Y; Toyokuni, S

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 43   page: S154 - S155   2007

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  636. Visualization and characterization of UVB-induced reactive oxygen species in a human skin equivalent model. Reviewed

    Hakozaki T, Date A, Yoshii T, Toyokuni S, Yasui H, Sakurai H

    J. Dermatol. Res.   Vol. 300 (Supplement 1)   page: S51-56   2007

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  637. Oxidative stress is related to formation of Antoni B pattern and eosinophilic hyaline droplets in schwannoma. Reviewed

    Yokoo H, Oishi T, Isoda, K, Nakazato Y, Toyokuni S

    Neuropathology   Vol. 27   page: 237-244   2007

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  638. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element Reviewed

    Naomi Mizobuchi, Jun Hoseki, Hiroshi Kubota, Shinya Toyokuni, Jun-ichi Nozaki, Motoko Naitoh, Akio Koizumi, Kazuhiro Nagata

    CELL STRUCTURE AND FUNCTION   Vol. 32 ( 1 ) page: 41 - 50   2007

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    Arginine rich, mutated in early stage of tumors ( ARMET) was first identified as a human gene highly mutated in a variety of cancers. However, little is known about the characteristics of the ARMET protein and its expression. We identified ARMET as a gene upregulated by endoplasmic reticulum ( ER) stress. Here, we show that the mouse homologue of ARMET is an 18- kDa soluble ER protein that is mature after cleavage of a signal sequence and has four intramolecular disulfide bonds, including two in CXXC sequences. ER stress stimulated ARMET expression, and the expression patterns of ARMET mRNA and protein in mouse tissues were similar to those of Grp78, an Hsp70- family protein required for quality control of proteins in the ER. A reporter gene assay using a mouse ARMET promoter revealed that the unfolded protein response of the ARMET gene is regulated by an ERSE- II element whose sequence is identical to that of the HERP gene. ARMET is the second fully characterized ERSE- II- dependent gene and likely contributes to quality control of proteins in the ER.

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  639. Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension. Reviewed

    Takenaka H, Kihara Y, Iwanaga Y, Onozawa Y, Toyokuni S, Kita T

    J. Mol. Cell. Cardiol.   Vol. 41   page: 989-997 - 997   2007

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  640. ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element

    Mizobuchi Naomi, Hoseki Jun, Kubota Hiroshi, Toyokuni Shinya, Nozaki Jun-ichi, Naitoh Motoko, Koizumi Akio, Nagata Kazuhiro

    CELL STRUCTURE AND FUNCTION   Vol. 32 ( 1 ) page: 41 - 50   2007

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  641. Novel screening method for ultraviolet protection : Combination of a human skin-equivalent model and 8-hydroxy-2'-deoxyguanosine

    TOYOKUNI Shinya, YASUI Hiroyuki, DATE Akira, HAKOZAKI Tomohiro, AKATSUKA Shinya, KOHDA Haruyasu, YOSHII Takashi, SAKURAI Hiromu

      Vol. 56 ( 12 ) page: 760 - 762   2006.12

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  642. Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension

    Takenaka, H; Kihara, Y; Iwanaga, Y; Onozawa, Y; Toyokuni, S; Kita, T

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   Vol. 41 ( 6 ) page: 989 - 997   2006.12

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    Angiotensin II (Ang-II) plays pivotal roles in the progression of left ventricular (LV) remodeling in diseased hearts; it remains to be elucidated how Ang-II links to degradation of the extracellular matrix (ECM). Using hypertensive Dahl salt-sensitive rats that show the distinctive transition from concentric LV hypertrophy to LV remodeling, we chronically treated them with an angiotensin type-1 receptor blocker (telmisartan 5 mg/kg/day, ARB group) or vehicle (0.5% CMC, CHF group). During the process of LV remodeling, we assessed, (1) in-vivo LV shape and function; (2) animal survival; (3) amounts of ECM in LV using a scanning electron microscope (SEM); (4) mRNA (by real time RT-PCR) and protein (by immunoblotting) levels in LV of NADPH oxidase, glutathione peroxidase-1 (GPX-1), and matrix metalloproteinase (MMP)-2, -9, and -13; (5) immunohistochemical staining of myocardial 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine; (6) nuclear factor kappa-B (NFκB) protein levels in the nuclear extract; and (7) endogenous activities of MMP-2 and -9 by an antibody capture method. Compared with CHF, ARB group showed an improvement of survival and preserved LV shape and function, and ECM density in SEM that was accompanied by decreases in oxidative stress-mediated protein degenerations, activities of GPX-1, NADPH oxidase, NFκB, and MMP-2, -9, and -13. Local activation of Ang-II in hypertrophic LV triggers MMP-mediated ECM degradation, namely LV remodeling, at least in part, through NADPH oxidase-induced oxidative stress and the subsequent NFκB activation. © 2006 Elsevier Inc. All rights reserved.

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  643. Novel screening method for ultraviolet protection: Combination of a human skin-equivalent model and 8-hydroxy-2 '-deoxyguanosine Reviewed

    Shinya Toyokuni, Hiroyuki Yasui, Akira Date, Tomohiro Hakozaki, Shinya Akatsuka, Haruyasu Kohda, Takashi Yoshii, Hiromu Sakurai

    PATHOLOGY INTERNATIONAL   Vol. 56 ( 12 ) page: 760 - 762   2006.12

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  644. Deletion and single nucleotide substitution at G:C in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment

    JIANG Li, ZHONG Yi, AKATSUKA Shinya, LIU Yu-Ting, DUTTA Khokon Kumar, LEE Wen-Hua, ONUKI Janice, MASUMURA Ken-ichi, NOHMI Takehiko, TOYOKUNI Shinya

    Cancer Sci   Vol. 97 ( 11 ) page: 1159 - 1167   2006.11

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  645. Deletion and single nucleotide substitution at G:C in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment. Reviewed International journal

    Li Jiang, Yi Zhong, Shinya Akatsuka, Yu-Ting Liu, Khokon Kumar Dutta, Wen-Hua Lee, Janice Onuki, Ken-ichi Masumura, Takehiko Nohmi, Shinya Toyokuni

    Cancer science   Vol. 97 ( 11 ) page: 1159 - 1167   2006.11

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces oxidative renal proximal tubular damage that subsequently leads to a high incidence of renal cell carcinoma in rodents, presenting an intriguing model of free radical-induced carcinogenesis. In the present study, we used gpt delta transgenic mice, which allow efficient detection of point mutations and deletions in vivo, to evaluate the mutation spectra, in association with the formation of 8-oxoguanine and acrolein-modified adenine during the first 3 weeks of carcinogenesis. Immunohistochemical analysis revealed the highest levels of 8-oxoguanine and acrolein-modifed adenine in the renal proximal tubules after 1 week of repeated administration. DNA immunoprecipitation and quantitative polymerase chain reaction analysis showed that the relative abundance of 8-oxoguanine and acrolein-modified adenine at the gpt reporter gene were increased at the first week in the kidney. Similarly, in both 6-thioguanine and Spi(-) selections performed on the renal specimens after Fe-NTA administration, the mutant frequencies were increased in the Fe-NTA-treated mice at the first week. Further analyzes of 79 mutant clones and 93 positive plaques showed a high frequency of G:C pairs as preferred targets for point mutation, notably G:C to C:G transversion-type mutation followed by deletion, and of large-size (>1 kilobase) deletions with short homologous sequences in proximity to repeated sequences at the junctions. The results demonstrate that the iron-based Fenton reaction is mutagenic in vivo in the renal tubular cells and induces characteristic mutations.

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  646. Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis

    Akatsuka, S; Aung, TT; Dutta, KK; Jiang, L; Lee, WH; Liu, YT; Onuki, J; Shirase, T; Yamasaki, K; Ochi, H; Naito, Y; Yoshikawa, T; Kasai, H; Tominaga, Y; Sakumi, K; Nakabeppu, Y; Kawai, Y; Uchida, K; Yamasaki, A; Tsuruyama, T; Yamada, Y; Toyokuni, S

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 169 ( 4 ) page: 1328 - 1342   2006.10

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    Oxidative stress is a persistent threat to the genome and is associated with major causes of human mortality, including cancer, atherosclerosis, and aging. Here we established a method to generate libraries of genomic DNA fragments containing oxidatively modified bases by using specific monoclonal antibodies to immunoprecipitate enzyme-digested genome DNA. We applied this technique to two different base modifications, 8-hydroxyguanine and 1,N 6-propanoadenine (acrotein-Ade), in a ferric nitrilotriacetate- induced murine renal carcinogenesis model. Renal cortical genomic DNA derived from 10- to 12-week-old male C57BL/6 mice, of untreated control or 6 hours after intraperitoneal injection of 3 mg iron/kg ferric nitrilotriacetate, was enzyme digested, immunoprecipitated, cloned, and mapped to each chromosome. The results revealed that distribution of the two modified bases was not random but differed in terms of chromosomes, gene size, and expression, which could be partially explained by chromosomal territory. In the wild-type mice, low GC content areas were more likely to harbor the two modified bases. Knockout of OGG1, a repair enzyme for genomic 8-hydroxyguanine, increased the amounts of acrolein-Ade as determined by quantitative polymerase chain reaction analyses. This versatile technique would introduce a novel research area as a high-throughput screening method for critical genomic loci under oxidative stress. Copyright © American Society for Investigative Pathology.

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  647. alpha-Tocopherol induces calnexin in renal tubular cells: Another protective mechanism against free radical-induced cellular damage Reviewed

    Wen-Hua Lee, Shinya Akatsuka, Tomoyuki Shirase, Khokon Kumar Dutta, Li Jiang, Yu-Ting Liu, Janice Onuki, Yoshihiro Yamada, Katsuya Okawa, Youichiro Wada, Akira Watanabe, Takahide Kohro, Noriko Noguchi, Shinya Toyokuni

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 453 ( 2 ) page: 168 - 178   2006.9

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    Pre-administration of alpha-tocopherol is protective against oxidative renal tubular damage and subsequent carcinogenesis by ferric nitrilotriacetate (Fe-NTA) in rats. We searched for mechanisms other than the scavenging effect of alpha-tocopherol with microarray analyses, which implicated calnexin, a chaperone for glycoproteins. Renal mRNA levels of calnexin significantly increased 3 h after an injection of Fe-NTA in rats fed a standard diet whereas those fed an alpha-tocopherol-supplemented diet showed an increase prior to injection, but after injection showed a decrease in renal calnexin mRNA levels, with unaltered protein levels. In experiments using LLG-PK1 cells, addition of alpha-tocopherol was protective against oxidative stress by H,0, concomitant with calnexin induction. Knockdown of calnexin by siRNA significantly reduced this protection. Furthermore, COS-7 cells transfected with the calnexin gene were more resistant to H2O2. Together with the fact that alpha-tocopherol induced N-acetylglucosaminyltransferase 3, our data suggest that alpha-tocopherol modifies glycoprotein metabolism partially by conferring mild ER stress. This adds another molecular mechanism of alpha-tocopherol toward cancer prevention. (c) 2006 Elsevier Inc. All rights reserved.

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  648. Overexpression of LYL1 gene induces T- and B-cell leukemia in mice

    Zhong, Y; Jiang, L; Toyokuni, S; Hiai, H; Yamada, Y

    EXPERIMENTAL HEMATOLOGY   Vol. 34 ( 9 ) page: 47 - 47   2006.9

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  649. Overexpression of LYL1 gene induces T- and B-cell leukemia in mice

    Zhong Y, Jiang L, Toyokuni S, Hiai H, Yamada Y

    EXPERIMENTAL HEMATOLOGY   Vol. 34 ( 9 ) page: 47 - 47   2006.9

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  650. Historical aspects of free radical chemistry and biology: What's new in oxidative stress-induced carcinogenesis and its prevention? Reviewed International journal

    Toyokuni Shinya

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 39 ( 1 ) page: 1 - 2   2006.7

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  651. Historical Aspects of Free Radical Chemistry and Biology: What’s New in Oxidative Stress-induced Carcinogenesis and Its Prevention?

    Toyokuni Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 39 ( 1 ) page: 1 - 2   2006.7

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  652. Novel aspects of oxidative stress-associated carcinogenesis Reviewed

    Shinya Toyokuni

    Antioxidants and Redox Signaling   Vol. 8 ( 7-8 ) page: 1373 - 7   2006.7

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    Oxidative stress is associated with carcinogenesis. Reactive oxygen and nitrogen species contribute to the accumulation of mutations in the genome, presumably followed by selective processes. Recent data suggest that preferred signaling pathways exist for oxidative stress-associated carcinogenesis. Whether this completely depends on random mutations induced by reactive species or whether instead some fragile genomic loci are sensitive to oxidative damage in association with changes of transcriptional activity or other topologic or non-topologic effects remains to be explored. Reliable markers for oxidative stress as well as for oxidative stress-induced preneoplastic lesions must be established. © Mary Ann Liebert, Inc.

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  653. What has been Learned from the Studies of Oxidative Stress-induced Carcinogenesis: Proposal of the Concept of Oxygenomics

    Toyokuni Shinya, Akatsuka Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 39 ( 1 ) page: 3 - 10   2006.7

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    Epidemiological studies have demonstrated that oxidative stress associated with a variety of pathological conditions is one of the major causes of carcinogenesis. Reactive oxygen and nitrogen species contribute to genomic alterations, presumably followed by selection of the best-adapted proliferating cells in a given environment. Recent data suggest that there exist common signaling pathways for oxidative stress-associated carcinogenesis. So far, oxidative DNA damage has been assumed to be randomly distributed based on <i>in vitro</i> experiments, and localization of oxidative DNA damage in the genome <i>in vivo</i> has rarely been studied. However, by the use of novel techniques in combination with constructed genome databases, it was found that the localization of oxidative DNA appears to be not random <i>in vivo</i>. We propose to call this rather novel research area "oxygenomics". Not a few signaling pathways start from the recognition of DNA damage. Possible underlying principles should be elucidated in association with cell type, the function of each genomic location, and its transcriptional activity as well as chromatin status determining epigenetic information. Furthermore, this concept may contribute to the development of novel oxidative stress biomarkers. Thus, oxygenomics is a promising research area.<br>

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  654. What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics Reviewed

    Shinya Toyokuni, Shinya Akatsuka

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 39 ( 1 ) page: 3 - 10   2006.7

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    Epidemiological studies have demonstrated that oxidative stress associated with a variety of pathological conditions is one of the major causes of carcinogenesis. Reactive oxygen and nitrogen species contribute to genomic alterations, presumably followed by selection of the best-adapted proliferating cells in a given environment. Recent data suggest that there exist common signaling pathways for oxidative stress-associated carcinogenesis. So far, oxidative DNA damage has been assumed to be randomly distributed based on in vitro experiments, and localization of oxidative DNA damage in the genome in vivo has rarely been studied. However, by the use of novel techniques in combination with constructed genome databases, it was found that the localization of oxidative DNA appears to be not random in vivo. We propose to call this rather novel research area "oxygenomics". Not a few signaling pathways start from the recognition of DNA damage. Possible underlying principles should be elucidated in association with cell type, the function of each genomic location, and its transcriptional activity as well as chromatin status determining epigenetic information. Furthermore, this concept may contribute to the development of novel oxidative stress biomarkers. Thus, oxygenomics is a promising research area.

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  655. What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics

    Toyokuni Shinya, Akatsuka Shinya

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 39 ( 1 ) page: 3 - 10   2006.7

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  656. Historical aspects of free radical chemistry and biology: What's new in oxidative stress-induced carcinogenesis and its prevention? Reviewed International journal

    Toyokuni Shinya

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 39 ( 1 ) page: 1 - 2   2006.7

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  657. Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells Reviewed

    M Kanatsu-Shinohara, M Ikawa, M Takehashi, N Ogonuki, H Miki, K Inoue, Y Kazuki, J Lee, S Toyokuni, M Oshimura, A Ogura, T Shinohara

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 103 ( 21 ) page: 8018 - 8023   2006.5

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    Stem cells represent a unique population of cells with self-renewal capacity. Although they are important therapeutic targets, the genetic manipulation of tissue-specific stem cells has been limited, which complicates the study and practical application of these cells. Here, we demonstrate successful gene trapping and homologous recombination in spermatogonial stem cells. Cultured spermatogonial stem cells were transfected with gene trap or gene targeting vectors. Mutagenized stem cells were expanded clonally by drug selection. These cells underwent spermatogenesis and produced heterozygous offspring after transplantation into the seminiferous tubules of infertile mouse testes. Heterozygous mutant mice were intercrossed to produce homozygous gene knockouts. Using this strategy, the efficiency of homologous recombination for the occludin gene focus was 1.7% using a nonisogenic DNA construct. These results demonstrate the feasibility of altering genes in tissue-specific stem cells in a manner similar to embryonic stem cells and have important implications for gene therapy and animal transgenesis.

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  658. ヒト大腸癌予後因子としてのNKT細胞腫瘍内浸潤

    鶴山 竜昭, 橘 強, 小野寺 久, 幸田 晴康, 豊國 伸哉, 日合 弘, 山邉 博彦, 玉木 敬二, 真鍋 俊明

    日本病理学会会誌   Vol. 95 ( 1 ) page: 213 - 213   2006.4

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  659. Anchorage-independent growth of mouse male germline stem cells in vitro Reviewed

    M Kanatsu-Shinohara, K Inoue, J Lee, H Miki, N Ogonuki, S Toyokuni, A Ogura, T Shinohara

    BIOLOGY OF REPRODUCTION   Vol. 74 ( 3 ) page: 522 - 529   2006.3

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    Spermatogenesis originates from a small number of spermatogonial stem cells that reside on the basement membrane and undergo self-renewal division to support spermatogenesis throughout the life of adult animals. Although the recent development of a technique to culture spermatogonial stem cells allowed reproduction of self-renewal division in vitro, much remains unknown about how spermatogonial stem cells are regulated. In this study, we found that spermatogonial stem cells could be cultured in an anchorage-independent manner, which is characteristic of stem cells from other types of self-renewing tissues. Although the cultured cells grew slowly (doubling time, similar to 4.7 days), they expressed markers of spermatogonia, and grew exponentially for at least 5 months to achieve 1.5 x 10(10)-fold expansion. The cultured cells underwent spermatogenesis following transplantation into the seminiferous tubules of infertile animals and fertile offspring were obtained by microinsemination of germ cells that had developed within the testes of recipients of the cultured cells. These results indicate that spermatogonial stem cells can undergo anchorage-independent, self-renewal division, and suggest that stem cells have the common property to survive and proliferate in the absence of exogenous substrata.

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  660. Differences in oxidative stress dependence between gastric adenocarcinoma subtypes

    Bancel Brigitte, Esteve Jacques, Souquet Jean-Christophe, Toyokuni Shinya, Ohshima Hiroshi, Pignatelli Brigitte

    WORLD JOURNAL OF GASTROENTEROLOGY   Vol. 12 ( 7 ) page: 1005 - 1012   2006.2

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  661. Differences in oxidative stress dependence between gastric adenocarcinoma subtypes.

    Bancel B, Esteve J, Souquet JC, Toyokuni S, Ohshima H, Pignatelli B

    World journal of gastroenterology   Vol. 12 ( 7 ) page: 1005 - 12   2006.2

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    Aim: To investigate the extent of oxidative stress in preneoplastic and neoplastic gastric mucosa in relation to their pathological criteria and histological subtypes. Methods: A total of 104 gastric adenocarcinomas from 98 patients (88 infiltrative and 16 intraepithelial tumors) were assessed immunohistochemically for expression of iNOS and occurrence of nitrotyrosine (NTYR)-containing proteins and 8-hydroxy-2′-deoxyguanosine (8-OH-dG)-containing DNA, as markers of NO production and damages to protein and DNA. Results: Tumor cells staining for iNOS, NTYR and 8-OH-dG were detected in 41%, 62% and 50% of infiltrative carcinoma, respectively. The three markers were shown for the first time in intraepithelial carcinoma. The expression of iNOS was significantly more frequent in tubular carcinoma (TC) compared to diffuse carcinoma (DC) (54% vs 18%; P=0.008) or in polymorphous carcinoma (PolyC) (54% vs 21%; P=0.04). NTYR staining was obviously more often found in TC than that in PolyC (72% vs 30%; P=0.03). There was a tendency towards a higher rate of iNOS staining when distant metastasis (pM) was present. In infiltrative TC, the presence of oxidative stress markers was not significantly correlated with histological grade, density of inflammation, the depth of infiltration (pT), lymph nodes dissemination (pN) and pathological stages (pTNM). Conclusion: The iNOS-oxidative pathway may play an important role in TC, but moderately in PolyC and DC. DNA oxidation and protein nitration occur in the three subtypes. Based on the significant differences of NTYR levels, TC and PolyC appear as two distinct subtypes. © 2006 The WJG Press. All rights reserved.

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  662. An N-glycan structure correlates with pulmonary metastatic ability of cancer cells Reviewed

    K Sakuma, Fujimoto, I, S Hitoshi, F Tanaka, T Ikeda, K Tanabe, S Toyokuni, H Wada, T Mio, M Mishima, K Ikenaka

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 340 ( 3 ) page: 829 - 835   2006.2

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    N-Glycan structures on the surface of cancer cells have diverse structures and play significant roles in metastatic process. However, little is known about their roles in organ-selective metastasis. Our study revealed that an alpha 1,6-fucosylated biantennary N-glycan structure designated A2G2F is characteristic of lungs, with far more abundant expression in normal human and murine lungs than in other organs. In this study, we further examined the role of A2G2F in pulmonary metastasis. We stained metastatic cancers by of alpha 1,6-fucose-specific Lens culinaris agglutinin lectin and revealed that pulmonary metastatic nodules more abundantly expressed alpha 1,6-fucosylated N-glycans than hepatic metastatic nodules from common primary cancers. The most specific alpha 1,6-fucosylated N-glycan structure in pulmonary metastatic cancer was identified to be A2G2F. Using a B16 melanoma cell metastasis model, we showed that A2G2F-rich B16 cells formed more Pulmonary metastatic nodules than A2G2F-poor cells. Our results suggest that A2G2F plays a critical role in Pulmonary metastasis. (c) 2005 Elsevier Inc. All rights reserved.

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  663. Differences in oxidative stress dependence between gastric adenocarcinoma subtypes Reviewed

    Brigitte Bancel, Jacques Esteve, Jean-Christophe Souquet, Shinya Toyokuni, Hiroshi Ohshima, Brigitte Pignatelli

    WORLD JOURNAL OF GASTROENTEROLOGY   Vol. 12 ( 7 ) page: 1005 - 1012   2006.2

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    AIM: To investigate the extent of oxidative stress in pre-neoplastic and neoplastic gastric mucosa in relation to their pathological criteria and histological subtypes.
    METHODS: A total of 104 gastric adenocarcinomas from 98 patients (88 infiltrative and 16 intraepithelial tumors) were assessed immunohistochemically for expression of iNOS and occurrence of nitrotyrosine (NTYR)-containing proteins and 8-hydroxy-2'-deoxyguanosine (8-OH-dG)-containing DNA, as markers of NO production and damages to protein and DNA.
    RESULTS: Tumor cells staining for NOS, NTYR and 8-OH-dG were detected in 41%, 62% and 50% of infiltrative carcinoma, respectively. The three markers were shown for the first time in intraepithelial carcinoma. The expression of iNOS was significantly more frequent in tubular carcinoma (TC) compared to diffuse carcinoma (DC) (54% vs 18%; P = 0.008) or in polymorphous carcinoma (PolyC) (54% vs 21%; P = 0.04). NTYR staining was obviously more often found in TC than that in PolyC (72% vs 30%; P = 0.03). There was a tendency towards a higher rate of iNOS staining when distant metastasis (pM) was present. In infiltrative TC, the presence of oxidative stress markers was not significantly correlated with histological grade, density of inflammation, the depth of infiltration (pT), lymph nodes dissemination (pN) and pathological stages (pTNM).
    CONCLUSION: The iNOS-oxidative pathway may play an important role in TC, but moderately in PolyC and DC. DNA oxidation and protein nitration occur in the three subtypes. Based on the significant differences of NTYR levels, TC and PolyC appear as two distinct subtypes. (C) 2006 The WJG Press. All rights reserved.

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  664. A novel screening method for ultraviolet protection: combination of a human skin-equivalent model and 8-hydroxy-2'-deoxyguanosine. Reviewed

    Toyokuni S, Yasui H, Date A, Hakozaki T, Akatsuka S, Kohda H, Yoshii T and Sakurai H.

    Pathol. Int.   Vol. 56   page: 760-762   2006

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  665. An N-glycan structure correlates with pulmonary metastatic ability of cancer cells. Reviewed

    Sakuma K, Fujimoto I, Hitoshi S, Tanaka F, Ikeda T, Tanabe K, Toyokuni S, Wada H, Mio T, Mishima M, Ikenaka K.

    Biochem. Biophys. Res. Commun.   Vol. 349   page: 829-835   2006

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  666. Novel aspects of oxidative stress-associated carcinogenesis. Reviewed

    Toyokuni S.

    Antiox. Redox Signal.   Vol. 8   page: 1373-1377   2006

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  667. Differences in oxidative stress dependence between gastric adenocarcinoma subtypes. Reviewed

    Bancel B, Esteve J, Souquet JC, Toyokuni S, Ohshima H, Pignatelli B.

    World J. Gastroenterol.   Vol. 12   page: 1005-1012   2006

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  668. What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics. Reviewed

    Toyokuni S, Akatsuka S.

    J. Clin. Biochem. Nutr.   Vol. 39   page: 3-10   2006

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  669. Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells. Reviewed

    Kanatsu-Shinohara M, Ikawa M, Takehashi M, Ogonuki N, Miki H, Inoue K, Kazuki Y, Lee J, Toyokuni S, Oshimura M, Ogura A, Shinohara T.

    Proc. Natl. Acad. Sci. USA   Vol. 103   page: 8018-8023   2006

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  670. alfa-Tocopherol induces calnexin in renal tubular cells: Another protective mechanism against free radical-induced cellular damage. Reviewed

    Lee W-H, Akatsuka S, Shirase T, Dutta KK, Jiang L, Liu Y-T, Onuki J, Yamada Y, Okawa K, Wada Y, Watanabe A, Kohro T, Noguchi N and Toyokuni S.

    Arch. Biochem. Biophys.   Vol. 453   page: 168-178   2006

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  671. *Contrasting Genome-wide Distribution of 8-Hydroxyguanine and Acrolein-modified Adenine during Oxidative Stress-induced Renal Carcinogenesis. Reviewed

    Akatsuka S, Aung TT, Dutta KK, Jiang L, Lee W-H, Liu Y-T, Onuki J, Shirase T, Yamasaki K, Ochi H, Naito Y, Yoshikawa T, Kasai H, Tominaga Y, Sakumi K, Nakabeppu Y, Kawai Y, Uchida K, Yamasaki A, Tsuruyama T, Yamada Y and Toyokuni S.

    Am. J. Pathol.   Vol. 169   page: 1328-1342   2006

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  672. Deletion and single nucleotide substitution at G:C are major mutations in the kidney of gpt delta transgenic mice after the Fenton reaction. Reviewed

    Jiang L, Zhong Y, Akatsuka S, Liu Y-T, Dutta KK, Lee W-H, Onuki J, Masumura K, Nohmi T and Toyokuni S.

    Cancer Sci.   Vol. 97   page: 1159-1167   2006

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  673. Anchorage-independent growth of mouse male germline stem cells in vitro. Reviewed

    Shinohara M, Inoue K, Lee J, Miki H, Ogonuki N, Toyokuni S, Ogura A and Shinohara T.

    Biol. Reprod.   Vol. 74   page: 522-529   2006

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  674. Involvement of aminoacylase 1 in ferric nitrilotriacetate (Fe-NTA)-induced rat renal cell carcinoma

    Onuki, J; Liu, Y; Lee, W; Jiang, L; Dutta, KK; Akatsuka, S; Toyokuni, S

    FREE RADICAL RESEARCH   Vol. 40   page: S128 - S128   2006

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  675. Iron-Induced Carcinogenesis

    Toyokuni, S

    OXIDATIVE STRESS, DISEASE AND CANCER     page: 789 - 805   2006

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    DOI: 10.1142/9781860948046_0027

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  676. Novel aspects of oxidative stress-associated carcinogenesis

    Toyokuni Shinya

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 8 ( 7-8 ) page: 1373 - 1377   2006

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  677. Oxidative stress and cancer

    Toyokuni Shinya

    Annual Meeting of the Japanese Society of Toxicology   Vol. 33 ( 0 ) page: 15 - 15   2006

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  678. Molecular characteristics of ferric nitrilotriacetate-induced deletions and base substitutions in the kidney of gpt delta transgenic mice

    Jiang, L; Zhong, Y; Akatsuka, S; Onuki, J; Masumura, K; Nohmi, T; Toyokuni, S

    FREE RADICAL RESEARCH   Vol. 40   page: S128 - S128   2006

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  679. Iron-Induced Carcinogenesis

    Toyokuni Shinya

    OXIDATIVE STRESS, DISEASE AND CANCER     page: 789 - 805   2006

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  680. Deletion and single nucleotide substitution at G:C are major mutations in the kidney of gpt delta transgenic mice after the Fenton reaction. Reviewed

    Jiang L, Zhong Y, Akatsuka S, Liu Y-T, Dutta KK, Lee W-H, Onuki J, Masumura K, Nohmi T, Toyokuni S

    Cancer Sci.   Vol. 97   page: 1159-1167   2006

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  681. Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis

    Akatsuka S., Aung T. T., Dutta K. K., Jiang L., Liu Y., Lee W., Onuki J., Shirase T., Naito Y., Yoshikawa T., Uchida K., Toyokuni S.

    FREE RADICAL RESEARCH   Vol. 40   page: S129 - S129   2006

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  682. Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis Reviewed

    S. Akatsuka, T. T. Aung, K. K. Dutta, L. Jiang, Y. Liu, W. Lee, J. Onuki, T. Shirase, Y. Naito, T. Yoshikawa, K. Uchida, S. Toyokuni

    FREE RADICAL RESEARCH   Vol. 40   page: S129 - S129   2006

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  683. Imidapril, an Angiotensin-Converting Enzyme Inhibitor, Reduces Diabetes-Induced Renal Oxidative Damage in Mice

    Naito Yuji, Uchiyama Kazuhiko, Akagiri Satomi, Aoi Wataru, Hasegawa Goji, Nakamura Naoto, Kokura Satoshi, Yoshida Norimasa, Ichikawa Hiroshi, Toyokuni Shinya, Yoshikawa Toshikazu

    Journal of Clinical Biochemistry and Nutrition   Vol. 37 ( 1 ) page: 29 - 37   2005.12

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    The aim of the present study was to determine whether imidapril, an angiotensin-converting enzyme inhibitor, prevents diabetic nephropathy and to determine the effect of imidapril on oxidative damage in the diabetic glomeruli in mice. We used female BKS.cg-m+Lepr<sup>db</sup>/+Lepr<sup>db</sup> (db/db) mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into the following four groups: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with imidapril at doses of 1 mg/kg and 5 mg/kg. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the imidapril-treated group and the non-treated db/db group. The systolic blood pressure was significantly increased in db/db mice compared with db/m mice. The increased blood pressure was significantly reduced by the treatment with imidapril at a dose of 5 mg/kg. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the imidapril-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with imidapril in a dose-dependent manner. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than in the imidapril-treated db/db mice. In conclusion, imidapril prevented the progression of diabetic nephropathy in mice, not only by decreasing the glomerular pressure but also by decreasing the oxidative stress in glomerular cells.

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  684. Susceptibility of actin to modification by 4-hydroxy-2-nonenal. Reviewed International journal

    Munetaka Ozeki, Aya Miyagawa-Hayashino, Shinya Akatsuka, Tomoyuki Shirase, Wen-Hua Lee, Koji Uchida, Shinya Toyokuni

    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences   Vol. 827 ( 1 ) page: 119 - 126   2005.11

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    4-Hydroxy-2-nonenal (HNE), a major lipid peroxidation product, reacts with histidine, lysine or cysteine residues of proteins to form hemiacetal Michael adducts and thus interferes with the functions of the proteins. Here we undertook to identify HNE-modified proteins in the target organ of a ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis model with histidine-specific HNEJ-2 antibody. Immunoaffinity column separation and sequencing identified one of the major modified proteins as actin. To further explore the characteristics of actin as an HNE acceptor, we produced four novel monoclonal antibodies against HNE-modified keyhole limpet hemocyanin. All these antibodies (HNEJ-1, 3-5) recognized histidine adducts, but were different from HNEJ-2 in recognizing lysine and cysteine adducts to some extent. Actin, albumin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), metallothionein and superoxide dismutase were treated in vitro with HNE and evaluated with these antibodies. The results revealed that actin was most sensitive to HNE modification and metallothionein most resistant. Furthermore, the residue-specificity of GAPDH was in accord with that shown by our recent mass spectrometry data. Immunohistochemistry with the antibodies revealed cytoplasmic staining with or without nuclear staining in the renal proximal tubules after Fe-NTA administration. The results suggest that actin is a major target protein for HNE modification in vivo, and that our monoclonal antibodies are useful for evaluating the HNE adducts produced.

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  685. Susceptibility of actin to modification by 4-hydroxy-2-nonenal

    OZEKI Munetaka, MIYAGAWA HAYASHINO Aya, AKATSUKA Shinya, SHIRASE Tomoyuki, LEE Wen-hua, UCHIDA Koji, TOYOKUNI Shinya

    J Chromatogr B Anal Technol Biomed Life Sci   Vol. 827 ( 1 ) page: 119 - 126   2005.11

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  686. Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p35

    Yajima N, Yamada S, Morisaki T, Toyokuni S, Yonehara S, Sakamaki K

    TRANSGENIC RESEARCH   Vol. 14 ( 5 ) page: 593 - 604   2005.10

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    Baculovirus p35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficent animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development. © Springer 2005.

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  687. Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p 35. International journal

    Nobuyuki Yajima, Shu-Ichi Yamada, Takayuki Morisaki, Shinya Toyokuni, Shin Yonehara, Kazuhiro Sakamaki

    Transgenic research   Vol. 14 ( 5 ) page: 593 - 604   2005.10

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    Baculovirus p 35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p 35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficient animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p 35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p 35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development.

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  688. Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1. International journal

    Kimio Kawasaki, Akiyoshi Nishio, Hajime Nakamura, Kazushige Uchida, Toshiro Fukui, Masaya Ohana, Hazuki Yoshizawa, Shinya Ohashi, Hiroyuki Tamaki, Minoru Matsuura, Masanori Asada, Toshiki Nishi, Hiroshi Nakase, Shinya Toyokuni, Wenrui Liu, Junji Yodoi, Kazuichi Okazaki, Tsutomu Chiba

    Laboratory investigation; a journal of technical methods and pathology   Vol. 85 ( 9 ) page: 1104 - 1117   2005.9

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    Thioredoxin-1 (TRX-1) is a redox-active protein involved in scavenging reactive oxygen species and regulating redox-sensitive transcription factors. TRX-1 is induced in various inflammatory conditions and shows cytoprotective action. We investigated the roles of TRX-1 in the host defense mechanism against Helicobacter felis (H. felis) infection. Transgenic (TG) mice overexpressing human TRX-1 and wild-type (WT) mice were orally inoculated with H. felis. After 2 months, histology, oxidative damage, and gene expression of several cytokines, including macrophage inflammatory protein-2 (MIP-2), a murine equivalent to interleukin (IL)-8, in the gastric mucosa were investigated. Furthermore, the effects of TRX-1 on oxidative stress and neutrophil migration were studied both in vivo and in vitro. The gastric mucosa was thickened in H. felis-infected WT mice, but not in infected TRX-1-TG mice. Histologically, all H. felis-infected WT mice developed moderate-to-severe gastritis, whereas the development of gastritis was significantly suppressed in infected TRX-1-TG mice. Oxidative damage markers, 8-hydroxy-2′-deoxyguanosine and malondialdehyde, increased in the stomach of infected WT mice, but not TRX-1-TG mice. Upregulation of IL-1β and tumor necrosis factor-α gene expression in H. felis-infected TRX-1-TG mice was significantly lower than in WT mice. However, upregulation of MIP-2 and IL-7 was not different between the two groups. TRX-1 suppressed oxidative cytotoxicity and DNA damage, and inhibited neutrophil migration both in vivo and in vitro. The present study suggests that overexpression of TRX-1 suppresses H. felis-induced gastritis by inhibiting chemotaxis of neutrophils and reducing oxidative stress. © 2005 USCAP, Inc All Rights Reserved.

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  689. Genetic and epigenetic properties of mouse male germline stem cells during long-term culture Reviewed

    M Kanatsu-Shinohara, N Ogonuki, T Iwano, J Lee, Y Kazuki, K Inoue, H Miki, M Takehashi, S Toyokuni, Y Shinkai, M Oshimura, F Ishino, A Ogura, T Shinohara

    DEVELOPMENT   Vol. 132 ( 18 ) page: 4155 - 4163   2005.9

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    Although stem cells are believed to divide infinitely by self-renewal division, there is little evidence that demonstrates their infinite replicative potential. Spermatogonial stem cells are the founder cell population for spermatogenesis. Recently, in vitro culture of spermatogonial stem cells was described. Spermatogonial stem cells can be expanded in vitro in the presence of glial cell line-derived neurotrophic factor (GDNF), maintaining the capacity to produce spermatogenesis after transplantation into testis. Here, we examined the stability and proliferative capacity of spermatogonial stem cells using cultured cells. Spermatogonial stem cells were cultured over 2 years and achieved similar to 10(85)-fold expansion. Unlike other germline cells that often acquire genetic and epigenetic changes in vitro, spermatogonial stem cells retained the euploid karyotype and androgenetic imprint during the 2-year experimental period, and produced normal spermatogenesis and fertile offspring. However, the telomeres in spermatogonial stem cells gradually shortened during culture, suggesting that they are not immortal. Nevertheless, the remarkable stability and proliferative potential of spermatogonial stem cells suggest that they have a unique machinery to prevent transmission of genetic and epigenetic damages to the offspring, and these characteristics make them an attractive target for germline modification.

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  690. Germline niche transplantation restores fertility in infertile mice Reviewed

    M Kanatsu-Shinohara, H Miki, K Inoue, N Ogonuki, S Toyokuni, A Ogura, T Shinohara

    HUMAN REPRODUCTION   Vol. 20 ( 9 ) page: 2376 - 2382   2005.9

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    BACKGROUND: Stem cells interact closely with their microenvironment or niche, and abnormalities in niche compromise the self-renewing tissue. In testis, for example, Sertoli cells interact with germ cells, and defects in Sertoli cells compromises spermatogenesis, leading to male infertility. However, it has not been possible to restore spermatogenesis from endogenous stem cells in infertile testis with environmental defects METHODS AND RESULTS: When healthy Sertoli cells from infertile white spotting (W) mouse were transplanted into the seminiferous tubules of infertile Steel (SI) mouse testis that had defective Sertoli cells, spermatogenesis occurred from SI stem cells in the recipient testis. On average, 1.1% of the recipient tubules showed spermatogenesis. Furthermore, in a microinsemination experiment with germ cells that developed in the testis, we obtained four normal offspring from 114 successfully injected oocytes. CONCLUSIONS: This study demonstrates that defects in male germline microenvironment can be corrected by Sertoli cell transplantation. Although further improvements are required to enhance the low efficiency of spermatogenesis, the ability to correct environmental defect by niche transplantation has important implications in developing new strategies for treating incurable disorders in self-renewing tissues.

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  691. Nestin-positive cells in adult pancreas express amylase and endocrine precursor cells

    Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

    PANCREAS   Vol. 31 ( 2 ) page: 126 - 131   2005.8

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  692. Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells.

    Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

    Pancreas   Vol. 31 ( 2 ) page: 126 - 31   2005.8

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    The neural precursor cell-specific marker nestin is expressed in fetal and adult pancreas, but its role is not fully understood. Using nestin-enhanced green fluorescent protein (EGFP) transgenic mice and fluorescence activated cell sorter, we characterized nestin-positive cells in adult mice pancreas. EGFP mRNA- and protein-positive cells expressed amylase, a pancreatic exocrine marker. Interestingly, EGFP mRNA-negative and protein-positive cells expressed insulin, glucagon, somatostatin and pancreatic polypeptide, pancreatic endocrine markers. These findings demonstrate that nestin-positive cells comprise a portion of pancreatic exocrine cells and suggest that they can be differentiated into pancreatic endocrine cells. Copyright © 2005 by Lippincott Williams & Wilkins.

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  693. Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells. International journal

    Hiroyuki Ueno, Yuichiro Yamada, Rie Watanabe, Eri Mukai, Masaya Hosokawa, Akira Takahashi, Akihiro Hamasaki, Hideya Fujiwara, Shinya Toyokuni, Masahiro Yamaguchi, Jun Takeda, Yutaka Seino

    Pancreas   Vol. 31 ( 2 ) page: 126 - 31   2005.8

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    The neural precursor cell-specific marker nestin is expressed in fetal and adult pancreas, but its role is not fully understood. Using nestin-enhanced green fluorescent protein (EGFP) transgenic mice and fluorescence activated cell sorter, we characterized nestin-positive cells in adult mice pancreas. EGFP mRNA- and protein-positive cells expressed amylase, a pancreatic exocrine marker. Interestingly, EGFP mRNA-negative and protein-positive cells expressed insulin, glucagon, somatostatin and pancreatic polypeptide, pancreatic endocrine markers. These findings demonstrate that nestin-positive cells comprise a portion of pancreatic exocrine cells and suggest that they can be differentiated into pancreatic endocrine cells.

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  694. Establishment of a diabetic mouse model with progressive diabetic nephropathy.

    Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y

    The American journal of pathology   Vol. 167 ( 2 ) page: 327 - 36   2005.8

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    Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER Iγ) in pancreatic β cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Iγ transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER Iγ transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors. Copyright © American Society for Investigative Pathology.

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  695. Establishment of a diabetic mouse model with progressive diabetic nephropathy

    Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 167 ( 2 ) page: 327 - 336   2005.8

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  696. Establishment of a diabetic mouse model with progressive diabetic nephropathy Reviewed

    A Inada, K Nagai, H Arai, J Miyazaki, K Nomura, H Kanamori, S Toyokuni, Y Yamada, S Bonner-Weir, GC Weir, A Fukatsu, Y Seino

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 167 ( 2 ) page: 327 - 336   2005.8

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    Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER I gamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER I gamma transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER I gamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.

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  697. Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells. Reviewed

    Hamahata K, Adachi S, Matsubara H, Okada M, Imai T, Watanabe K, Toyokuni S, Ueno M, Akiba S, Katanosaka Y, Wakabayashi S, Kubota M, Nakahata T

    European Journal of Pharmacology   Vol. 516 ( 3 ) page: 187 - 196   2005.6

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  698. Annexin II overexpression correlates with a poor prognosis in surgically resected non-small-cell lung cancer.

    Ichikawa, M; Mio, T; Toyokuni, S; Tanaka, F; Wada, H; Mishima, M; Yanagihara, K

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 23 ( 16 ) page: 682S - 682S   2005.6

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  699. Annexin II overexpression correlates with a poor prognosis in surgically resected non-small-cell lung cancer. Reviewed International journal

    Ichikawa, M, Mio, T, Toyokuni, S, Tanaka, F, Wada, H, Mishima, M, Yanagihara, K

    JOURNAL OF CLINICAL ONCOLOGY   Vol. 23 ( 16 ) page: 682S - 682S   2005.6

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  700. Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis. Reviewed International journal

    Khokon K Dutta, Yumiko Nishinaka, Hiroshi Masutani, Shinya Akatsuka, Than T Aung, Tomoyuki Shirase, Wen-Hua Lee, Yoshihiro Yamada, Hiroshi Hiai, Junji Yodoi, Shinya Toyokuni

    Laboratory investigation; a journal of technical methods and pathology   Vol. 85 ( 6 ) page: 798 - 807   2005.6

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    Thioredoxin is a major component of thiol-reducing system. Recently, we identified thioredoxin-binding protein-2 (TBP-2) as a negative regulator of thioredoxin. Here, we report the role of TBP-2 in oxidative renal tubular injury and the subsequent carcinogenesis by ferric nitrilotriacetate. TBP-2 was abundantly expressed in the rat kidney. Immunohistochemical analysis revealed that TBP-2 was present in association with nuclei and mitochondrial intermembrane space in the proximal tubular cells and coimmunoprecipitated with cytochrome c. After acute oxidative tubular damage, TBP-2 protein, but not messenger RNA, markedly decreased, demonstrating shortened half-life of this protein. Most cases of the induced renal cell carcinoma showed undetectable levels of TBP-2 protein, which was associated with the methylation of CpG island in the promoter region. Genome sequence analyses identified the poly-A tract in the 3' untranslated region as a mutation hot spot in this rather nonselective environment. Collectively, the amounts of TBP-2 protein were inversely associated with proliferation of tubular cells, as evaluated by proliferating cell nuclear antigen. These results suggest that loss of TBP-2 is essential for proliferation of not only neoplastic but also non-neoplastic renal tubular cells, and that TBP-2 is a target gene in oxidative stress-induced renal carcinogenesis by ferric nitrilotriacetate.

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  701. Transcriptional control of fetal liver hematopoiesis: dominant negative effect of the overexpression of the LIM domain mutants of LMO2. International journal

    Tomo Terano, Yi Zhong, Shinya Toyokuni, Hiroshi Hiai, Yoshihiro Yamada

    Experimental hematology   Vol. 33 ( 6 ) page: 641 - 651   2005.6

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    OBJECTIVE: The LIM-finger protein LMO2 forms a transcription factor complex with other hematopoietic regulator proteins, such as TAL1 (SCL), LDB1, GATA1, 2, and 3, in the promoters of several erythroid genes. To elucidate the functional role of two LIM domains in LMO2, we introduced deletion or mutation in each of the LIM domains and analyzed their phenotypic effects on the hematopoietic system when overexpressed in vivo or in vitro. MATERIALS AND METHODS: Protein interactions of LIM-modified LMO2 constructs with TAL1, LDB1, and GATAs were examined in an immunoprecipitation assay. In vivo hematopoiesis in transgenic mice with wild-type and LIM-modified Lmo2 was studied morphologically and by measuring the progenitor cells in fetal liver. Their effects on the erythroid differentiation of the dimethylsulfoxide (DMSO)-induced murine erythroleukemia (MEL) cells were evaluated. RESULTS: Deletion of the LIM2 domain, but not of the LIM1 domain, abolished its binding of GATA proteins. Overexpression of wild-type LMO2 is known to have dominant negative inhibitory effects on erythropoietic development. Enforced expression of LMO2 constructs with mutant or absent LIM2 but with an intact LIM1 domain resulted in fetal death, small livers and hearts, and decreased hematopoiesis, as well as a hypoplastic thymus. DMSO-induced erythroid differentiation of the MEL cells was inhibited by the overexpressed LMO2 with mutant LIM2 but not by the LMO2 with modified LIM1. CONCLUSION: Overexpression of the LMO2 with modified LIM2 inhibited hematopoiesis probably by interfering with the formation of the physiological complex or by replacing the functional LMO2 with mutants with reduced affinity to GATA proteins. In this experiment, no evident effect of the LMO2 with modified LIM1 could be observed.

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  702. Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice. Reviewed International journal

    Hiroshi Iwakura, Kiminori Hosoda, Choel Son, Junji Fujikura, Tsutomu Tomita, Michio Noguchi, Hiroyuki Ariyasu, Kazuhiko Takaya, Hiroaki Masuzaki, Yoshihiro Ogawa, Tatsuya Hayashi, Gen Inoue, Takashi Akamizu, Hiroshi Hosoda, Masayasu Kojima, Hiroshi Itoh, Shinya Toyokuni, Kenji Kangawa, Kazuwa Nakao

    The Journal of biological chemistry   Vol. 280 ( 15 ) page: 15247 - 15256   2005.4

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    We developed and analyzed two types of transgenic mice: rat insulin II promoter-ghrelin transgenic (RIP-G Tg) and rat glucagon promoter-ghrelin transgenic mice (RGP-G Tg). The pancreatic tissue ghrelin concentration measured by C-terminal radioimmunoassay (RIA) and plasma desacyl ghrelin concentration of RIP-G Tg were about 1000 and 3.4 times higher than those of nontransgenic littermates, respectively. The pancreatic tissue n-octanoylated ghrelin concentration measured by N-terminal RIA and plasma n-octanoylated ghrelin concentration of RIP-G Tg were not distinguishable from those of nontransgenic littermates. RIP-G Tg showed suppression of glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion, pancreatic insulin mRNA and peptide levels, beta cell mass, islet architecture, and GLUT2 and PDX-1 immunoreactivity in RIP-G Tg pancreas were not significantly different from those of nontransgenic littermates. Islet batch incubation study did not show suppression of insulin secretion of RIP-G Tg in vitro. The insulin tolerance test showed lower tendency of blood glucose levels in RIP-G Tg. Taking lower tendency of triglyceride level of RIP-G Tg into consideration, these results may indicate that the suppression of insulin secretion is likely due to the effect of desacyl ghrelin on insulin sensitivity. RGP-G Tg, in which the pancreatic tissue ghrelin concentration measured by C-RIA was about 50 times higher than that of nontransgenic littermates, showed no significant changes in insulin secretion, glucose metabolism, islet mass, and islet architecture. The present study raises the possibility that desacyl ghrelin may have influence on glucose metabolism.

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  703. CYP3A induction more impairs endotoxemic liver injury via reactive oxygen species in rats

    Minamiyama, Y; Takemura, S; Kodai, S; Toyokuni, S; Yoshikawa, T; Okada, S

    GASTROENTEROLOGY   Vol. 128 ( 4 ) page: A709 - A709   2005.4

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  704. Long-term culture of mouse male germline stem cells under serum-or feeder-free conditions. Reviewed International journal

    Mito Kanatsu-Shinohara, Hiromi Miki, Kimiko Inoue, Narumi Ogonuki, Shinya Toyokuni, Atsuo Ogura, Takashi Shinohara

    Biology of reproduction   Vol. 72 ( 4 ) page: 985 - 991   2005.4

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    Spermatogonial stem cells are the only stem cells in the body that transmit genetic information to the next generation. These cells can be cultured for extended periods in the presence of serum and feeder cells. However, little is known about factors that regulate self-renewal division of spermatogonial stem cells. In this investigation we examined the possibility of establishing culture systems for spermatogonial stem cells that lack serum or a feeder cell layer. Spermatogonial stem cells could expand in serum-free conditions on mouse embryonic fibroblasts (MEFs), or were successfully cultivated without feeder cells on a laminin-coated plate. However, they could not expand when both serum and feeder cells were absent. Although the cells cultured on laminin differed phenotypically from those on feeder cells, they grew exponentially for at least 6 mo, and produced normal, fertile progeny following transplantation into infertile mouse testis. This culture system will provide a new opportunity for understanding the regulatory mechanism that governs spermatogonial stem cells.

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  705. CYP3A induction more impairs endotoxemic liver injury via reactive oxygen species in rats

    Minamiyama Y, Takemura S, Kodai S, Toyokuni S, Yoshikawa T, Okada S

    GASTROENTEROLOGY   Vol. 128 ( 4 ) page: A709 - A709   2005.4

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  706. A resected case of multiple early gallbladder carcinomas

    URAI Shunji, HAYAKUMO Takanobu, HABU Yasuki, KAWAMURA Takuji, SHIO Seiji, IKEURA Tsukasa, YOSHINO Takuya, HIRAI Kiyoshi, TOYOKUNI Shinya

    Nippon Shokakibyo Gakkai Zasshi   Vol. 102 ( 3 ) page: 340 - 345   2005.3

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    DOI: 10.11405/nisshoshi.102.340

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  707. Selenium Supplementation Rescues Cardiac Output in Patients with Severe Heart Failure who are Intractable to ACE Inhibitors and β-Blockers(Heart Failure, Clinical 14 (M), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

    Hiraoka Yuuji, Kihara Yasuki, Sarazawa Katsuhiko, Inai Yoshihito, Kitagawa Motoaki, Takahashi Nobuki, Hamanaka Ichirou, Yamazaki Taketoshi, Akagi Tadasu, Hama Norio, Tanabe Masato, Sakurai Hiromu, Toyokuni Shinya, Ueda Kinzou

    Circulation journal : official journal of the Japanese Circulation Society   Vol. 69 ( 0 ) page: 310   2005.3

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  708. Selenium Supplementation Rescues Cardiac Output in Patients with Severe Heart Failure who are Intractable to ACE Inhibitors and β-Blockers(Heart Failure, Clinical 14 (M), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

    Hiraoka Yuuji, Kihara Yasuki, Sarazawa Katsuhiko, Inai Yoshihito, Kitagawa Motoaki, Takahashi Nobuki, Hamanaka Ichirou, Yamazaki Taketoshi, Akagi Tadasu, Hama Norio, Tanabe Masato, Sakurai Hiromu, Toyokuni Shinya, Ueda Kinzou

    Circulation journal : official journal of the Japanese Circulation Society   Vol. 69 ( 0 )   2005.3

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  709. Genetic selection of mouse male germline stem cells in vitro: offspring from single stem cells. Reviewed International journal

    Mito Kanatsu-Shinohara, Shinya Toyokuni, Takashi Shinohara

    Biology of reproduction   Vol. 72 ( 1 ) page: 236 - 240   2005.1

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    Spermatogenesis originates from a small population of spermatogonial stem cells. These cells are believed to divide infinitely and support spermatogenesis throughout life in the male. In this investigation, we examined the possibility of deriving transgenic offspring from single spermatogonial stem cells. Spermatogonial stem cells were transfected in vitro with a plasmid vector containing a drug resistant gene. Stably transfected stem cell clones were isolated by in vitro drug selection; these clones were expanded and used to produce transgenic progeny following spermatogonial transplantation into infertile recipients. An average of 49% of the offspring carried the transgene, and the recipient mice continued to produce monoclonal transgenic progeny a year after transplantation. Thus, a somatic cell-based genetic approach can be used to modify and select clones of spermatogonial stem cells in a manner similar to embryonic stem cells. The feasibility of genetic selection using postnatal spermatogonial stem cells demonstrates their extensive proliferative potential and provides the opportunity to develop new methods for generating stable animal transgenics or for germline gene therapy.

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  710. Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis. Reviewed International journal

    Shinichiro Chuma, Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokuni, Mihoko Hosokawa, Norio Nakatsuji, Atsuo Ogura, Takashi Shinohara

    Development (Cambridge, England)   Vol. 132 ( 1 ) page: 117 - 122   2005.1

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    Primordial germ cells (PGCs) are derived from a population of pluripotent epiblast cells in mice. However, little is known about when and how PGCs acquire the capacity to differentiate into functional germ cells, while keeping the potential to derive pluripotent embryonic germ cells and teratocarcinomas. In this investigation, we show that epiblast cells and PGCs can establish colonies of spermatogenesis after transfer into postnatal seminiferous tubules of surrogate infertile mice. Furthermore, we obtained normal fertile offspring by microinsemination using spermatozoa or spermatids derived from PGCs harvested from fetuses as early as 8.5 days post coitum. Thus, fetal male germ cell development is remarkably flexible, and the maturation process, from epiblast cells through PGCs to postnatal spermatogonia, can occur in the postnatal testicular environment. Primordial germ cell transplantation techniques will also provide a novel tool to assess the developmental potential of PGCs, such as those manipulated in vitro or recovered from embryos harboring lethal mutations.

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  711. Reduction of dibetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice. Reviewed

    Naito Y, Akagiri S, Uchiyama K, Kokura S, Yoshida N, Hasegawa G, Nakamura N, Ichikawa H, Toyokuni S, Ijichi T, Yoshikawa T.

    Biofactors   Vol. 23   page: 85-98   2005

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  712. Genetic and epigenetic properties of mouse male germline stem cells during long-term culture. Reviewed

    Kanatsu-Shinohara M, Ogonuki N, Iwano T, Lee J, Kazuki Y, Inoue K, Miki H, Takehashi M, Toyokuni S, Shinkai Y, Oshimura M, Ishino F, Ogura A, Shinohara T.

    Developmnet   Vol. 132   page: 4155-4163   2005

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  713. Establishment of a diabetic mouse model with progressive diabetic nephropathy. Reviewed

    Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y.

    Am. J. Pathol.   Vol. 167   page: 327-336   2005

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  714. Free radical-induced carcinogenesis: Target genes and fragile genome sites

    Toyokuni, S; Akatsuka, S; Aung, TT; Dutta, KK

    FREE RADICAL RESEARCH   Vol. 39   page: S30 - S30   2005

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  715. Imidapril, an angiotensin-converting enzyme inhibitor, reduces diabetes-induced renal oxidative damage in mice

    Naito Y, Uchiyama K, Akagiri S, Aoi W, Hasegawa G, Nakamura N, Kokura S, Yoshida N, Ichikawa H, Toyokuni S, Yoshikawa T

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 37 ( 1 ) page: 29 - 37   2005

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  716. Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice

    Naito Y, Akagiri S, Uchiyama K, Kokura S, Yoshida N, Hasegawa G, Nakamura N, Ichikawa H, Toyokuni S, Ijichi T, Yoshikawa T

    BIOFACTORS   Vol. 23 ( 2 ) page: 85 - 95   2005

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  717. Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice.

    Naito Y, Akagiri S, Uchiyama K, Kokura S, Yoshida N, Hasegawa G, Nakamura N, Ichikawa H, Toyokuni S, Ijichi T, Yoshikawa T

    BioFactors (Oxford, England)   Vol. 23 ( 2 ) page: 85 - 95   2005

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    Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Oxykine is the cantaloupe melon extract rich in vegetal superoxide dismutase covered by polymeric films of wheat matrix gliadin. In this study, we examined whether chronic oral administration of oxykine could prevent the progression of diabetic nephropathy induced by oxidative stress using preclinical rodent model of type 2 diabetes. We used female db/db mice and their non-diabetic db/m littermates. The mice were divided into the following three groups: non-diabetic db/m; diabetic db/db, and diabetic db/db treated with oxykine. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were preformed on 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the oxykine-treated group and the non-treated db/db group, however both groups kept significantly high levels rather than db/m mice. The relative mesangial area calculated by mesangial area/total glomerular area ratio was significantly ameliorated in the oxykine treated group compared with non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with oxykine. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than that of oxykine-treated db/db mice. In this study, treatment of oxykine ameliorated the progression and acceleration of diabetic nephropathy for rodent model of type 2 diabetes. These results indicated that the oxykine reduced the diabetes-induced oxidative stress and renal mesangial cell injury. In conclusion, oxykine might be a novel approach for the prevention of diabetes nephropathy. © 2005 - IOS Press and the authors. All rights reserved.

    DOI: 10.1002/biof.5520230204

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  718. Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice Reviewed

    Y Naito, S Akagiri, K Uchiyama, S Kokura, N Yoshida, G Hasegawa, N Nakamura, H Ichikawa, S Toyokuni, T Ijichi, T Yoshikawa

    BIOFACTORS   Vol. 23 ( 2 ) page: 85 - 95   2005

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    Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Oxykine is the cantaloupe melon extract rich in vegetal superoxide dismutase covered by polymeric films of wheat matrix gliadin. In this study, we examined whether chronic oral administration of oxykine could prevent the progression of diabetic nephropathy induced by oxidative stress using preclinical rodent model of type 2 diabetes. We used female db/db mice and their non-diabetic db/m littermates. The mice were divided into the following three groups: non-diabetic db/m; diabetic db/db, and diabetic db/db treated with oxykine. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were preformed on 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the oxykine-treated group and the non-treated db/db group, however both groups kept significantly high levels rather than db/m mice. The relative mesangial area calculated by mesangial area/total glomerular area ratio was significantly ameliorated in the oxykine treated group compared with non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with oxykine. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than that of oxykine-treated db /db mice. In this study, treatment of oxykine ameliorated the progression and acceleration of diabetic nephropathy for rodent model of type 2 diabetes. These results indicated that the oxykine reduced the diabetes-induced oxidative stress and renal mesangial cell injury. In conclusion, oxykine might be a novel approach for the prevention of diabetes nephropathy.

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  719. Imidapril, an angiotensin-converting enzyme inhibitor, reduces diabetes-induced renal oxidative damage in mice Reviewed

    Y Naito, K Uchiyama, S Akagiri, W Aoi, G Hasegawa, N Nakamura, S Kokura, N Yoshida, H Ichikawa, S Toyokuni, T Yoshikawa

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 37 ( 1 ) page: 29 - 37   2005

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    The aim of the present study was to determine whether imidapril, an angiotensin-converting enzyme inhibitor, prevents diabetic nephropathy and to determine the effect of imidapril on oxidative damage in the diabetic glomeruli in mice. We used female BKS.cg-m+Lepr(db)/+Lepr(db) (db/db) mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into the following four groups: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with imidapril at doses of 1 mg/kg and 5 mg/kg. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the imidapril-treated group and the non-treated db/db group. The systolic blood pressure was significantly increased in db/db mice compared with db/m mice. The increased blood pressure was significantly reduced by the treatment with imidapril at a dose of 5 mg/kg. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the imidapril-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with imidapril in a dose-dependent manner. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than in the imidapril-treated db/db mice. In conclusion, imidapril prevented the progression of diabetic nephropathy in mice, not only by decreasing the glomerular pressure but also by decreasing the oxidative stress in glomerular cells.

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  720. Control of the peri-operative oxidative stress enables fast recovery from myocardial ischemic damage in cardic surgery. Reviewed

    Takaba K, Matsumura K, Miwa S, Yamazaki K, Nishina K, Nomoto T, Toyokuni S, Hyon SH, Ikeda T, Komeda M

    International Redox Network 2005(2005.11.9-11. kyoto)     2005

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  721. Generation of pluripotent stem cells from neonatal mouse testis. Reviewed International journal

    Mito Kanatsu-Shinohara, Kimiko Inoue, Jiyoung Lee, Momoko Yoshimoto, Narumi Ogonuki, Hiromi Miki, Shiro Baba, Takeo Kato, Yasuhiro Kazuki, Shinya Toyokuni, Megumi Toyoshima, Ohtsura Niwa, Mitsuo Oshimura, Toshio Heike, Tatsutoshi Nakahata, Fumitoshi Ishino, Atsuo Ogura, Takashi Shinohara

    Cell   Vol. 119 ( 7 ) page: 1001 - 12   2004.12

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    Although germline cells can form multipotential embryonic stem (ES)/embryonic germ (EG) cells, these cells can be derived only from embryonic tissues, and such multipotent cells have not been available from neonatal gonads. Here we report the successful establishment of ES-like cells from neonatal mouse testis. These ES-like cells were phenotypically similar to ES/EG cells except in their genomic imprinting pattern. They differentiated into various types of somatic cells in vitro under conditions used to induce the differentiation of ES cells and produced teratomas after inoculation into mice. Furthermore, these ES-like cells formed germline chimeras when injected into blastocysts. Thus, the capacity to form multipotent cells persists in neonatal testis. The ability to derive multipotential stem cells from the neonatal testis has important implications for germ cell biology and opens the possibility of using these cells for biotechnology and medicine.

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  722. Generation of pluripotent stem cells from neonatal mouse testis

    Kanatsu-Shinohara M, Inoue K, Lee J, Yoshimoto M, Ogonuki N, Miki H, Baba S, Kato T, Kazuki Y, Toyokuni S, Toyoshima M, Niwa O, Oshimura M, Heike T, Nakahata T, Ishino F, Ogura A, Shinohara T

    CELL   Vol. 119 ( 7 ) page: 1001 - 1012   2004.12

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  723. オキシカインによる糖尿病性腎症の進展抑制効果 Reviewed

    市川 寛, 赤桐 里美, 内藤 裕二, 内山 和彦, 吉田 憲正, 豊國 伸哉, 吉川 敏一

    日本病態栄養学会誌   Vol. 7 ( 4 ) page: 375 - 375   2004.11

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  724. Novel mechanism of matrix metalloproteinase inhibitor in the treatment of heart failure:: Direct inhibition of myocardial oxidant stress and NF-κB activation in rats

    Takenaka, H; Kihara, Y; Iwanaga, Y; Onozawa, Y; Toyokuni, S; Kita, T

    CIRCULATION   Vol. 110 ( 17 ) page: 514 - 515   2004.10

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  725. Novel mechanism of matrix metalloproteinase inhibitor in the treatment of heart failure: Direct inhibition of myocardial oxidant stress and NF-kappa B activation in rats

    Takenaka H, Kihara Y, Iwanaga Y, Onozawa Y, Toyokuni S, Kita T

    CIRCULATION   Vol. 110 ( 17 ) page: 514 - 515   2004.10

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  726. Transgenic mice produced by retroviral transduction of male germ line stem cells in vivo. International journal

    Mito Kanatsu-Shinohara, Shinya Toyokuni, Takashi Shinohara

    Biology of reproduction   Vol. 71 ( 4 ) page: 1202 - 1207   2004.10

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    Spermatogonial stem cells are the only stem cells in the postnatal body that can transmit parental genetic information to the offspring, making them an attractive target cell population for animal transgenesis. Although transgenic mice and rats were recently produced by retrovirus transduction of these cells in vitro, with transplantation of the transduced cells into infertile recipients, the difficulty of restoring fertility and preparing recipients using spermatogonial transplantation limits practical application of the technique. In this article, we describe a novel approach for producing transgenic animals by transducing spermatogonial stem cells in vivo using a retrovirus vector. Microinjection of retrovirus into immature seminiferous tubules resulted in the direct transduction of spermatogonial stem cells in situ, and the animals produced transgenic offspring after mating with females. Transgenic mice were produced in C57BL/6, BALB/C, A, and C3H backgrounds, with an average efficiency of 2.8%. The transgene was transmitted stably and expressed in the next generation. The technique overcomes the drawback of the in vitro-transduction approach, and will be useful as a novel method for producing transgenic animals as well as providing a means for analyzing the self-renewal and differentiation processes of spermatogonial stem cells in vivo.

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  727. CYP3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats. Reviewed International journal

    Yukiko Minamiyama, Shigekazu Takemura, Shinya Toyokuni, Susumu Imaoka, Yoshihiko Funae, Kazuhiro Hirohashi, Toshikazu Yoshikawa, Shigeru Okada

    Free radical biology & medicine   Vol. 37 ( 5 ) page: 703 - 712   2004.9

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    We carried out this experiment to evaluate the relationship between isoforms of cytochrome P450 (P450) and liver injury in lipopolysaccharide (LPS)-induced endotoxemic rats. Male rats were intraperitoneally administered phenobarbital (PB), a P450 inducer, for 3 days, and 1 day later, they were intravenously given LPS. PB significantly increased P450 levels (200% of control levels) and the activities (300-400% of control) of the specific isoforms (CYP), CYP3A2 and CYP2B1, in male rats. Plasma AST and ALT increased slightly more in PB-treated rats than in PB-nontreated (control) rats with LPS treatment. Furthermore, either troleandomycin or ketoconazole, specific CYP3A inhibitors, significantly inhibited LPS-induced liver injury in control and PB-treated male rats. To evaluate the oxidative stress in LPS-treated rats, in situ superoxide radical detection using dihydroethidium (DHE), hydroxy-2-nonenal (HNE)-modified proteins in liver microsomes and 8-hydroxydeoxyguanosine (8-OHdG) in liver nuclei were measured in control and PB-treated rats. DHE signal intensity, levels of HNE-modified proteins, and 8-OHdG increased significantly in PB-treated rats. LPS further increased DHE intensity, HNE-modified proteins, and 8-OHdG levels in normal and PB-treated groups. CYP3A inhibitors also inhibited the increases in these items. Our results indicate that the induction or preservation of CYP isoforms further promotes LPS-induced liver injury through mechanisms related to oxidative stress. In particular, CYP3A2 of P450 isoforms made an important contribution to this LPS-induced liver injury.

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  728. Gastric inhibitory polypeptide is the major insulinotropic factor in K-ATP null mice Reviewed International journal

    Tsukiyama K, Yamada Y, Miyawaki K, Hamasaki A, Nagashima K, Hosokawa M, Fujimoto S, Takahashi A, Toyoda K, Toyokuni S, Oiso Y, Seino Y

    EUROPEAN JOURNAL OF ENDOCRINOLOGY   Vol. 151 ( 3 ) page: 407 - 412   2004.9

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  729. Gastric inhibitory polypeptide is the major insulinotropic factor in K(ATP) null mice.

    Tsukiyama K, Yamada Y, Miyawaki K, Hamasaki A, Nagashima K, Hosokawa M, Fujimoto S, Takahashi A, Toyoda K, Toyokuni S, Oiso Y, Seino Y

    European journal of endocrinology   Vol. 151 ( 3 ) page: 407 - 12   2004.9

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    Objective: ATP-sensitive K+ (KATP) channels in pancreatic β-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, KATP channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of KATP channels, but the mice still showed a significant insulin response after oral glucose loading in vivo. Gastric inhibitory polypeptide (GIP) is a physiological incretin that stimulates insulin release upon ingestion of nutrients. To determine if GIP is the insulinotropic factor in insulin secretion in KATP channel-deficient mice, we generated double-knockout Kir6.2 and GIP receptor null mice and compared them with Kir6.2 knockout mice. Methods: Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice. An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice. Results: Fasting glucose and insulin levels were similar in both groups. After oral glucose loading, blood glucose levels of double-knockout mice became elevated compared with Kir6.2-knockout mice, especially at 15min (345±10mg/dl vs 294±20mg/dl, P<0.05 and 30min (453±20 mg/dl vs 381 ± 26 mg/dl, P < 0.05). The insulin response was almost completely lost in double-knockout mice, although insulin secretion from isolated islets was stimulated by another incretin, glucagon-like peptide-1 in the double-knockout mice. Double-knockout mice and Kir6.2-knockout mice were similarly insulin sensitive as assessed by the insulin tolerance test. Conclusion: GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in KATP channel-deficient mice. © 2004 Society of the European Journal of Endocrinology.

    DOI: 10.1530/eje.0.1510407

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  730. Gastric inhibitory polypeptide is the major insulinotropic factor in K(ATP) null mice. Reviewed International journal

    Katsushi Tsukiyama, Yuichiro Yamada, Kazumasa Miyawaki, Akihiro Hamasaki, Kazuaki Nagashima, Masaya Hosokawa, Shimpei Fujimoto, Akira Takahashi, Kentaro Toyoda, Shinya Toyokuni, Yutaka Oiso, Yutaka Seino

    European journal of endocrinology   Vol. 151 ( 3 ) page: 407 - 12   2004.9

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    OBJECTIVE: ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, K(ATP) channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of K(ATP) channels, but the mice still showed a significant insulin response after oral glucose loading in vivo. Gastric inhibitory polypeptide (GIP) is a physiological incretin that stimulates insulin release upon ingestion of nutrients. To determine if GIP is the insulinotropic factor in insulin secretion in K(ATP) channel-deficient mice, we generated double-knockout Kir6.2 and GIP receptor null mice and compared them with Kir6.2 knockout mice. METHODS: Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice. An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice. RESULTS: Fasting glucose and insulin levels were similar in both groups. After oral glucose loading, blood glucose levels of double-knockout mice became elevated compared with Kir6.2-knockout mice, especially at 15 min (345+/-10 mg/dl vs 294+/-20 mg/dl, P<0.05) and 30 min (453+/-20 mg/dl vs 381+/-26 mg/dl, P<0.05). The insulin response was almost completely lost in double-knockout mice, although insulin secretion from isolated islets was stimulated by another incretin, glucagon-like peptide-1 in the double-knockout mice. Double-knockout mice and Kir6.2-knockout mice were similarly insulin sensitive as assessed by the insulin tolerance test. CONCLUSION: GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in K(ATP) channel-deficient mice.

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  731. Prevention of myocardial reperfusion injury by poly(ADP-ribose) synthetase inhibitor, 3-aminobenzamide, in cardioplegic solution: in vitro study of isolated rat heart model. International journal

    Kazuhiro Yamazaki, Senri Miwa, Kunihiro Ueda, Seigo Tanaka, Shinya Toyokuni, Oriyanhan Unimonh, Kazunobu Nishimura, Masashi Komeda

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery   Vol. 26 ( 2 ) page: 270 - 275   2004.8

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    OBJECTIVE: Cardioplegic arrest remains the method of choice for myocardial protection in cardiac surgery. Poly(adenosine 5'-diphosphate-ribose) synthetase (PARS) inhibitor has been suggested to attenuate the ischemia-reperfusion injury in myocardial infarction by preventing energy depletion associated with oxidative stress. We investigated the efficacy of a cardioplegic solution containing a PARS inhibitor, 3-aminobenzamide (3-AB), for myocardial protection against ischemia-reperfusion injury caused by cardioplegic arrest. METHODS: Isolated hearts were set on a Langendorff apparatus and perfused. The hearts were arrested for 90 min with a cardioplegic solution given at 30-min intervals and then reperfused for 20 min. The hearts of rat in the 3-AB(-) group (n = 8) were perfused with a standard cardioplegic solution and terminal warm cardoplegia, whereas the 3-AB(+) group (n = 8) received these solutions supplemented with 3-AB (100 microM). Left ventricular function and release of cardiac enzymes were monitored before and after cardioplegic arrest. After reperfusion, NAD+ (nicotinamide-adenine dinucleotide) levels were assessed, and the tissues were examined immunohistochemically for oxidative stress and apoptosis. RESULTS: During reperfusion, the 3-AB(+) group showed significantly higher (P = 0.005)dp/dt and lower creatine phosphokinase (CPK) level and glucotamic-oxaloacetic transaminase (GOT) in the effluent (CPK; P = 0.003 GOT; P < 0.001) The cardiomyocytes of the 3-AB(+) group also preserved a higher NAD+ level (P < 0.001). Immunohistochemical study of oxidative stress revealed a lesser extent (P = 0.007) of nuclear staining and a lower fraction of apoptosis in the 3-AB(+) group. CONCLUSION: Cardioplegic solution supplemented with 3-AB provides efficient myocardial protection in cardioplegic ischemic reperfusion by suppressing oxidative stress and overactivation of PARS.

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  732. Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro Reviewed

    Y. Satou, K. Nosaka, Y. Koya, J.-I. Yasunaga, S. Toyokuni, M. Matsuoka

    Leukemia   Vol. 18 ( 8 ) page: 1357 - 1363   2004.8

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    Other Link: http://orcid.org/0000-0002-7939-2080

  733. Regulation of mouse spermatogonial stem cell self-renewing division by the pituitary gland. Reviewed International journal

    Mito Kanatsu-Shinohara, Takeshi Morimoto, Shinya Toyokuni, Takashi Shinohara

    Biology of reproduction   Vol. 70 ( 6 ) page: 1731 - 1737   2004.6

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    Spermatogenesis originates in spermatogonial stem cells, which have the unique mode of replication. It is considered that a single stem cell can produce two stem cells (self-renewing division), one stem and one differentiating (asymmetric division), or two differentiating cells (differentiating division). However, little is known regarding how each type of division is regulated. In this investigation, we focused on the analysis of self- renewing division and examined the effect of the pituitary gland using two models of stem cell self-renewing division. In the first experiment using newborn mice, the administration of GnRH- analogue, which represses the release of gonadotropin, reduced the number of stem cells during postnatal testicular development, suggesting that the pituitary gland enhances stem cell self- renewing division. In the second experiment, however, the number of stem cells increased dramatically in hypophysectomized adult recipients after spermatogonial transplantation. Thus, the pituitary gland affects the self-renewing division of stem cells, but these contradictory results suggest that its role may be different depending on the stage of the testicular development.

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  734. PAX6 regulates islet β-cell function

    Hamasaki, A; Yamada, Y; Nagashima, K; Fujimoto, S; Ban, N; Toyokuni, S; Kurose, T; Seino, Y

    DIABETES   Vol. 53   page: A394 - A394   2004.6

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  735. Role of reactive oxygen species in skin carcinogenesis

    Nishigori C, Hattori Y, Toyokuni S

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 6 ( 3 ) page: 561 - 570   2004.6

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  736. Redox control of carcinogenesis and tumor biology

    Toyokuni S

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 6 ( 3 ) page: 481 - 482   2004.6

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  737. Role of reactive oxygen species in skin carcinogenesis.

    Nishigori C, Hattori Y, Toyokuni S

    Antioxidants & redox signaling   Vol. 6 ( 3 ) page: 561 - 70   2004.6

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    Reactive oxygen species (ROS) are associated not only with initiation, but also with promotion and progression in the multistage carcinogenesis model. In the present review, we will focus on the involvement of ROS in skin carcinogenesis, especially that induced by ultraviolet (UV) radiation. UV-specific DNA damage has been well studied thus far. However, recent reports have revealed the previously unknown participation of oxidative stress in UV-induced skin carcinogenesis. Indeed, in addition to transition-type mutations at dipyrimidine sites, G:C to T:A transversions, which may be induced by the presence of 8-oxoguanine during DNA replication, are frequently observed in the ras oncogene and p53 tumor suppressor gene in human skin cancers of sun-exposed areas and in UV-induced mouse skin cancers. Recent studies have shown that not only UV-B, but also UV-A is involved in UV-induced carcinogenesis. A wide variety of biological phenomena other than direct influence by UV, such as inflammatory and immunological responses and oxidative modifications of DNA and proteins, appear to play roles in UV-induced skin carcinogenesis. Furthermore, it has become clear that genetic diseases such as xeroderma pigmentosum show deficient repair of oxidatively modified DNA lesions. The involvement of ROS in skin carcinogeneisis caused by arsenic and chemical carcinogens will also be discussed.

    DOI: 10.1089/152308604773934314

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  738. Redox control of carcinogenesis and tumor biology.

    Toyokuni S

    Antioxidants & redox signaling   Vol. 6 ( 3 ) page: 481 - 2   2004.6

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    DOI: 10.1089/152308604773934233

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  739. Role of reactive oxygen species in skin carcinogenesis. International journal

    Chikako Nishigori, Yukari Hattori, Shinya Toyokuni

    Antioxidants & redox signaling   Vol. 6 ( 3 ) page: 561 - 70   2004.6

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    Reactive oxygen species (ROS) are associated not only with initiation, but also with promotion and progression in the multistage carcinogenesis model. In the present review, we will focus on the involvement of ROS in skin carcinogenesis, especially that induced by ultraviolet (UV) radiation. UV-specific DNA damage has been well studied thus far. However, recent reports have revealed the previously unknown participation of oxidative stress in UV-induced skin carcinogenesis. Indeed, in addition to transition-type mutations at dipyrimidine sites, G:C to T:A transversions, which may be induced by the presence of 8-oxoguanine during DNA replication, are frequently observed in the ras oncogene and p53 tumor suppressor gene in human skin cancers of sun-exposed areas and in UV-induced mouse skin cancers. Recent studies have shown that not only UV-B, but also UV-A is involved in UV-induced carcinogenesis. A wide variety of biological phenomena other than direct influence by UV, such as inflammatory and immunological responses and oxidative modifications of DNA and proteins, appear to play roles in UV-induced skin carcinogenesis. Furthermore, it has become clear that genetic diseases such as xeroderma pigmentosum show deficient repair of oxidatively modified DNA lesions. The involvement of ROS in skin carcinogeneisis caused by arsenic and chemical carcinogens will also be discussed.

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  740. PAX6 regulates islet beta-cell function

    Hamasaki A, Yamada Y, Nagashima K, Fujimoto S, Ban N, Toyokuni S, Kurose T, Seino Y

    DIABETES   Vol. 53   page: A394 - A394   2004.6

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  741. Analysis of ghrelin transgenic mice driven by rat insulin II promoter and transgenic mice driven by rat glucagon promoter

    Iwakura, H; Hosoda, K; Son, C; Fujikura, J; Tomita, T; Noguchi, M; Takaya, K; Masuzaki, H; Ogawa, Y; Hayashi, T; Inoue, G; Akamizu, T; Hosoda, H; Kojima, M; Itoh, H; Toyokuni, S; Kangawa, K; Nakao, K

    DIABETES   Vol. 53   page: A357 - A357   2004.6

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  742. Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. International journal

    Tomoyuki Tanaka, Shinya Akatsuka, Munetaka Ozeki, Tomoyuki Shirase, Hiroshi Hiai, Shinya Toyokuni

    Oncogene   Vol. 23 ( 22 ) page: 3980 - 9   2004.5

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    Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal damage leading to a high incidence of renal cell carcinoma (RCC) in rats. Differential display analysis of such RCCs revealed elevated expression of annexin 2 (Anx2), a substrate for kinases and a receptor for tissue-type plasminogen activator and plasminogen. We conducted this study to clarify the significance of Anx2 in Fenton reaction-based carcinogenesis. Messenger RNA and protein levels of Anx2 were increased time-dependently in the rat kidney after Fe-NTA administration as well as in LLC-PK1 cells after exposure to H2O2. The latter was inhibited by pretreatment with N-acetylcysteine, pyrrolidine dithiocarbamate or catalase. Immunohistochemistry revealed negligible staining in the normal renal proximal tubules, but strong staining in regenerating proximal tubules, karyomegalic cells and RCCs. Metastasizing RCCs showed higher Anx2 protein levels. Anx2 was phosphorylated at serine and tyrosine residues in these cells and coimmunoprecipitated with phosphorylated actin. Overexpression of Anx2 induced a higher cell proliferation rate in LLC-PK1 cells. In contrast, a decrease in proliferation leading to apoptosis was observed after Anx2 antisense treatment to cell lines established from Fe-NTA-induced RCCs. These results suggest that Anx2 is regulated by redox status, and that persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer.

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  743. Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis

    Tanaka T, Akatsuka S, Ozeki M, Shirase T, Hiai H, Toyokuni S

    ONCOGENE   Vol. 23 ( 22 ) page: 3980 - 3989   2004.5

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    Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal damage leading to a high incidence of renal cell carcinoma (RCC) in rats. Differential display analysis of such RCCs revealed elevated expression of annexin 2 (Anx2), a substrate for kinases and a receptor for tissue-type plasminogen activator and plasminogen. We conducted this study to clarify the significance of Anx2 in Fenton reaction-based carcinogenesis. Messenger RNA and protein levels of Anx2 were increased time-dependently in the rat kidney after Fe-NTA administration as well as in LLC-PK1 cells after exposure to H2O2. The latter was inhibited by pretreatment with N-acetylcysteine, pyrrolidine dithiocarbamate or catalase. Immunohistochemistry revealed negligible staining in the normal renal proximal tubules, but strong staining in regenerating proximal tubules, karyomegalic cells and RCCs. Metastasizing RCCs showed higher Anx2 protein levels. Anx2 was phosphorylated at serine and tyrosine residues in these cells and coimmunoprecipitated with phosphorylated actin. Overexpression of Anx2 induced a higher cell proliferation rate in LLC-PK1 cells. In contrast, a decrease in proliferation leading to apoptosis was observed after Anx2 antisense treatment to cell lines established from Fe-NTA-induced RCCs. These results suggest that Anx2 is regulated by redox status, and that persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer.

    DOI: 10.1038/sj.onc.1207555

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  744. Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI. International journal

    Wolf-Ruediger Schäbitz, Holger Schade, Sabine Heiland, Rainer Kollmar, Jürgen Bardutzky, Nils Henninger, Harald Müller, Ulrich Carl, Shinya Toyokuni, Clemens Sommer, Stefan Schwab

    Stroke   Vol. 35 ( 5 ) page: 1175 - 9   2004.5

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    BACKGROUND: Hyperbaric oxygenation (HBO) after focal cerebral ischemia reduces infarct size and improves outcome when applied early after stroke. Here, we evaluated effects of HBO on permanent focal cerebral ischemia and applied magnetic resonance imaging (MRI) monitoring to study lesion evolution. METHODS: Rats underwent permanent middle cerebral artery occlusion (MCAO). Two hours later, animals were treated with HBO (100% O(2)/2 atm; n=17) for 1 hour or treated with room air (n=17). Animals underwent serial MRI studies (DWI, PI, T2) beginning 90 minutes after MCAO. Neuroscore was assessed (5-point rating scale). Animals were euthanized and brains were 2,3,5-triphenyltetrazolium chloride (TTC)-stained for infarct volume calculation 120 hours after MCAO. Immunohistochemistry was performed with antibodies against c-FOS and 4-hydroxy-2-nonenal-modified proteins (HNE) to check for effects of oxidative stress caused by HBO treatment. RESULTS: HBO reduced infarct volume by 38% (P<0.001). As shown by MRI, neuroprotection began 5 hours after ischemia and remained effective for 5 days. The relative regional cerebral blood flow was not different between groups at 3.5 and 5 hours after occlusion. There was less neurological deficit in HBO-treated animals compared with controls (P<0.05). Lipid peroxidation of cerebral vessels after HBO treatment as measured by HNE staining and pattern of c-FOS induction were not significantly different between groups at 3.5 and 8 hours after ischemia. CONCLUSIONS: As monitored by MRI HBO treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage.

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  745. Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI

    Schabitz WR, Schade H, Heiland S, Kollmar R, Bardutzky J, Henninger N, Muller H, Carl U, Toyokuni S, Sommer C, Schwab S

    STROKE   Vol. 35 ( 5 ) page: 1175 - 1179   2004.5

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    Background - Hyperbaric oxygenation (HBO) after focal cerebral ischemia reduces infarct size and improves outcome when applied early after stroke. Here, we evaluated effects of HBO on permanent focal cerebral ischemia and applied magnetic resonance imaging (MRI) monitoring to study lesion evolution. Methods - Rats underwent permanent middle cerebral artery occlusion (MCAO). Two hours later, animals were treated with HBO (100% O2/2 atm; n=17) for 1 hour or treated with room air (n=17). Animals underwent serial MRI studies (DWI, PI, T2) beginning 90 minutes after MCAO. Neuroscore was assessed (5-point rating scale). Animals were euthanized and brains were 2,3,5-triphenyltetrazolium chloride (TTC)-stained for infarct volume calculation 120 hours after MCAO. Immunohistochemistry was performed with antibodies against c-FOS and 4-hydroxy-2-nonenal-modified proteins (HNE) to check for effects of oxidative stress caused by HBO treatment. Results - HBO reduced infarct volume by 38% (P<0.001). As shown by MRI, neuroprotection began 5 hours after ischemia and remained effective for 5 days. The relative regional cerebral blood flow was not different between groups at 3.5 and 5 hours after occlusion. There was less neurological deficit in HBO-treated animals compared with controls (P<0.05). Lipid peroxidation of cerebral vessels after HBO treatment as measured by HNE staining and pattern of c-FOS induction were not significantly different between groups at 3.5 and 8 hours after ischemia. Conclusion - As monitored by MRIHBO treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage.

    DOI: 10.1161/01.STR.0000125868.86298.8e

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  746. Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens

    HIROYASU Makoto, AKATSUKA Shinya, SHIRASE Tomoyuki, TODA Yoshinobu, HIAI Hiroshi, TOYOKUNI Shinya

      Vol. 54 ( 4 ) page: 251 - 255   2004.4

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  747. Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens. International journal

    Makoto Hiroyasu, Shinya Akatsuka, Tomoyuki Shirase, Yoshinobu Toda, Hiroshi Hiai, Shinya Toyokuni

    Pathology international   Vol. 54 ( 4 ) page: 251 - 5   2004.4

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    Although the human genome project has been completed, the functions of many genes remain undetermined. In situ hybridization (ISH) is a key method for identifying cells in which a given messenger RNA is transcribed. Paraffin-embedded specimens remain precious materials for research, but preservation of high-quality RNA in these specimens is not expected unless ample caution was taken during fixation. Peptide nucleic acid (PNA) is a recently developed hybrid molecule with genetic information that has high stability and high affinity to the complementary DNA or RNA. We applied a PNA probe to mRNA ISH of liver specimens obtained by autopsy and embedded in paraffin 28-48 years ago. An 18-mer PNA probe for glyceraldehyde 3-phosphate dehydrogenase was used. Staining was then analyzed in association with morphology by hematoxylin and eosin staining, and with the time between death of the patient and tissue fixation. Notably, specimens fixed with formalin and embedded in paraffin 48 years ago yielded excellent results if the time before fixation was short enough (<8 h). There was a significant inverse correlation between the intensity of ISH staining and the time before fixation. Oligonucleotide PNA probe, albeit at high cost, would increase the value of paraffin-embedded specimens in storage for use in human medical research.

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  748. Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic beta cells. International journal

    Akari Inada, Yoshiyuki Hamamoto, Yoshiyuki Tsuura, Jun-ichi Miyazaki, Shinya Toyokuni, Yu Ihara, Koichiro Nagai, Yuichiro Yamada, Susan Bonner-Weir, Yutaka Seino

    Molecular and cellular biology   Vol. 24 ( 7 ) page: 2831 - 2841   2004.4

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    Transcriptional control mediated by the cyclic AMP-responsive element (CRE) represents an important mechanism of gene regulation. To test our hypothesis that increased inducible cyclic AMP early repressor (ICER) Igamma inhibits function of CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic beta cells, we generated transgenic mice with beta-cell-directed expression of ICER Igamma, a powerful repressor that is greatly increased in diabetes. Three transgenic lines clearly show that increased ICER Igamma expression in beta cells results in early severe diabetes. From birth islets were severely disorganized with a significantly increased proportion of alpha cells throughout the islet. Diabetes results from the combined effects of impaired insulin expression and a decreased number of beta cells. The decrease in beta cells appears to result from impaired proliferation rather than from increased apoptosis after birth. Cyclin A gene expression is impaired by the strong inhibition of ICER; the suppression of cyclin A results in a substantially decreased proliferation of beta cells in the postnatal period. These results suggest that CRE and CRE-binding factors have an important role in pancreatic beta-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of beta-cell mass.

    DOI: 10.1128/MCB.24.7.2831-2841.2004

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  749. Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens.

    Hiroyasu M, Akatsuka S, Shirase T, Toda Y, Hiai H, Toyokuni S

    Pathology international   Vol. 54 ( 4 ) page: 251 - 5   2004.4

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    Although the human genome project has been completed, the functions of many genes remain undetermined. In situ hybridization (ISH) is a key method for identifying cells in which a given messenger RNA is transcribed. Paraffin-embedded specimens remain precious materials for research, but preservation of high-quality RNA in these specimens is not expected unless ample caution was taken during fixation. Peptide nucleic acid (PNA) is a recently developed hybrid molecule with genetic information that has high stability and high affinity to the complementary DNA or RNA. We applied a PNA probe to mRNA ISH of liver specimens obtained by autopsy and embedded in paraffin 28-48 years ago. An 18-mer PNA probe for glyceraldehyde 3-phosphate dehydrogenase was used. Staining was then analyzed in association with morphology by hematoxylin and eosin staining, and with the time between death of the patient and tissue fixation. Notably, specimens fixed with formalin and embedded in paraffin 48 years ago yielded excellent results if the time before fixation was short enough (<8 h). There was a significant inverse correlation between the intensity of ISH staining and the time before fixation. Oligonucleotide PNA probe, albeit at high cost, would increase the value of paraffin-embedded specimens in storage for use in human medical research.

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  750. Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens

    Hiroyasu M, Akatsuka S, Shirase T, Toda Y, Hiai H, Toyokuni S

    PATHOLOGY INTERNATIONAL   Vol. 54 ( 4 ) page: 251 - 255   2004.4

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  751. A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL positive human leukemic cells - caspase-independent, necrosis-like programmed cell death mediated by serine protease activity. Reviewed

    Okada M, Adachi S, Imai T, Watanabe K, Toyokuni S, Ueno M, Zervos AS, Kroemer G, Nakahata T

    Blood   Vol. 103 ( 6 ) page: 2299 - 2307   2004.3

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    DOI: 10.1182/blood-2003-05-1605

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  752. A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

    Okada M, Adachi S, Imai T, Watanabe K, Toyokuni SY, Ueno M, Zervos AS, Kroemer G, Nakahata T

    BLOOD   Vol. 103 ( 6 ) page: 2299 - 2307   2004.3

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  753. PJ-628 Oxidant Stress-Mediated Myocardial Cell Injury in Selenium-Deficient Mice : Age-Dependent Roles of Glutathion Peroxidase Inhibition(Cardiomyopathy, Basic and Clinical 2 (M) : PJ105)(Poster Session (Japanese))

    Hiraoka Yuuji, Okada Ikutaro, Tamura Takashi, Akagi Tadasu, Hama Norio, Tanabe Masato, Suzuki Joji, Fujimori Mariko, Takahashi Nobuki, Shimizu Takayuki, Sarazawa Katsuhiko, Shinnmura Tetuo, Toyokuni Shinya, Kihara Yasuki, Nakajima Hisayoshi, Inoue Hiroshi

    Circulation journal : official journal of the Japanese Circulation Society   Vol. 68 ( 0 ) page: 634   2004.3

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  754. Target Genes in Free Radical-Induced Carcinogenesis

    TOYOKUNI Shinya

      Vol. 59 ( 2 ) page: 105   2004.3

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  755. PJ-628 Oxidant Stress-Mediated Myocardial Cell Injury in Selenium-Deficient Mice : Age-Dependent Roles of Glutathion Peroxidase Inhibition(Cardiomyopathy, Basic and Clinical 2 (M) : PJ105)(Poster Session (Japanese))

    Hiraoka Yuuji, Okada Ikutaro, Tamura Takashi, Akagi Tadasu, Hama Norio, Tanabe Masato, Suzuki Joji, Fujimori Mariko, Takahashi Nobuki, Shimizu Takayuki, Sarazawa Katsuhiko, Shinnmura Tetuo, Toyokuni Shinya, Kihara Yasuki, Nakajima Hisayoshi, Inoue Hiroshi

    Circulation journal : official journal of the Japanese Circulation Society   Vol. 68 ( 0 )   2004.3

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  756. Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation. Reviewed International journal

    Susumu Imaoka, Mayuko Osada, Yukiko Minamiyama, Tokihito Yukimura, Shinya Toyokuni, Shigekazu Takemura, Toyoko Hiroi, Yoshihiko Funae

    Cancer letters   Vol. 203 ( 2 ) page: 117 - 125   2004.1

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    We investigated the biological effects of the active oxygen produced by P450s. First, we identified which isoforms of P450 efficiently produced active oxygen using electron spin resonance. Eight forms of P450 purified from rat liver were used. Of these, CYP1A2, 2B1, 2C11 and 3A2 produced hydroxyl radicals efficiently. Phenobarbital (PB) which is a typical inducer of CYP2B1 and 3A2 induced production of hydroxyl radicals by rat liver and ketoconazole, an inhibitor of P450, inhibited production of hydroxyl radicals in vitro. PB is a tumor promoter as well as the P450-inducer. We investigated oxidation of the genomic DNA by the hydroxyl radicals produced by PB-inducible P450 in vitro and in vivo. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation in vivo was assayed by HPLC. PB strongly induced the production of 8-OHdG in the rat liver. While ketoconazole inhibited the production of 8-OHdG in vivo. These results suggest that active oxygen produced by P450 oxidized genomic DNA and induction of P450 increased oxidative stress that may contribute to tumor initiation and promotion.

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  757. Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway. International journal

    Hiroyuki Okumura, Noritoshi Nagaya, Takefumi Itoh, Ichiro Okano, Jun Hino, Kenji Mori, Yoshitane Tsukamoto, Hatsue Ishibashi-Ueda, Senri Miwa, Keiichi Tambara, Shinya Toyokuni, Chikao Yutani, Kenji Kangawa

    Circulation   Vol. 109 ( 2 ) page: 242 - 8   2004.1

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    BACKGROUND: Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown. METHODS AND RESULTS: Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28+/-4% to 16+/-1%, P<0.01), left ventricular end-diastolic pressure (19+/-2 to 8+/-2 mm Hg, P<0.05), and myocardial apoptotic death (19+/-2% to 9+/-4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphorylation in cardiac tissues and that pretreatment with wortmannin significantly attenuated AM-induced Akt phosphorylation. Moreover, pretreatment with wortmannin abolished the beneficial effects of AM: a reduction of infarct size, a decrease in left ventricular end-diastolic pressure, and inhibition of myocardial apoptosis after ischemia/reperfusion. CONCLUSIONS: Short-term infusion of AM significantly attenuated myocardial ischemia/reperfusion injury. These cardioprotective effects are attributed mainly to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway.

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  758. Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway

    Okumura H, Nagaya N, Itoh T, Okano I, Hino J, Mori K, Tsukamoto Y, Ishibashi-Ueda H, Miwa S, Tambara K, Toyokuni S, Yutani C, Kangawa K

    CIRCULATION   Vol. 109 ( 2 ) page: 242 - 248   2004.1

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    Background-Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown. Methods and Results-Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28±4% to 16±1%, P<0.01), left ventricular end-diastolic pressure (19±2 to 8±2 mm Hg, P<0.05), and myocardial apoptotic death (19±2% to 9±4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphorylation in cardiac tissues and that pretreatment with wortmannin significantly attenuated AM-induced Akt phosphorylation. Moreover, pretreatment with wortmannin abolished the beneficial effects of AM: a reduction of infarct size, a decrease in left ventricular end-diastolic pressure, and inhibition of myocardial apoptosis after ischemia/reperfusion. Conclusions-Short-term infusion of AM significantly attenuated myocardial ischemia/reperfusion injury. These cardioprotective effects are attributed mainly to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway.

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  759. CD9 is a surface marker on mouse and rat male germline stem cells. Reviewed International journal

    Mito Kanatsu-Shinohara, Shinya Toyokuni, Takashi Shinohara

    Biology of reproduction   Vol. 70 ( 1 ) page: 70 - 75   2004.1

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    Spermatogenesis is dependent on a small population of stem cells. Despite the biological significance of spermatogonial stem cells, their analysis has been hampered by their scarcity. However, spermatogonial stem cells can be enriched by selection with an antibody against cell-surface molecules. In this investigation, we searched for new antigens expressed on spermatogonial stem cells. Using the spermatogonial transplantation technique, we examined expression of the CD9 molecule, which is commonly expressed on stem cells of other tissues. Selection of both mouse and rat testis cells with anti-CD9 antibody resulted in 5- to 7-fold enrichment of spermatogonial stem cells from intact testis cells, indicating that CD9 is commonly expressed on spermatogonial stem cells of both species. Therefore, CD9 may be involved in the common machinery in stem cells of many self-renewing tissues, and the identification of a common surface antigen on spermatogonial stem cells of different species has important implications for the development of a technique to enrich stem cells from other mammalian species.

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  760. Target genes in free radical-induced carcinogenesis

    Toyokuni S

    SFRR: PROCEEDINGS OF THE XII BIENNIAL MEETING OF THE SOCIETY FOR FREE RADICAL RESEARCH INTERNATIONAL     page: 181 - 185   2004

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  761. Target genes and genomic areas in free radical-induced carcinogenesis

    Toyokuni, S; Akatsuka, S; Shirase, T; Than, TA

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 36   page: S29 - S29   2004

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  762. Target genes in free radical-induced carcinogenesis Reviewed

    S Toyokuni

    SFRR: PROCEEDINGS OF THE XII BIENNIAL MEETING OF THE SOCIETY FOR FREE RADICAL RESEARCH INTERNATIONAL     page: 181 - 185   2004

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    Ferric nitrilotriacetate-induced renal carcinogenesis presents an intriguing model demonstrating what happens if repeated Fenton reaction occurs in vivo. We have asked a question whether there is any target gene in this carcinogenesis model. With a genetic approach, we found that p15 and p16 tumor suppressor genes are one of the major targets. Furthermore, allelic loss of p16 was present as early as three weeks after the start of the experiments. In this model, alterations in expressional levels of several genes were also observed by differential display analysis. Among them, annexin 2 was overexpressed in renal cell carcinoma, and was regulated by oxidative stress. Persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer.

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  763. Formation of acrolein-derived 2'-deoxyadenosine adduct in an iron-induced carcinogenesis model. Reviewed International journal

    Yoshichika Kawai, Atsunori Furuhata, Shinya Toyokuni, Yasuaki Aratani, Koji Uchida

    The Journal of biological chemistry   Vol. 278 ( 50 ) page: 50346 - 50354   2003.12

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    Acrolein is a representative carcinogenic aldehyde found ubiquitously in the environment and formed endogenously through oxidation reactions, such as lipid peroxidation and myeloperoxidase-catalyzed amino acid oxidation. It shows facile reactivity toward DNA to form an exocyclic DNA adduct. To verify the formation of acrolein-derived DNA adduct under oxidative stress in vivo, we raised a novel monoclonal antibody (mAb21) against the acrolein-modified DNA and found that the antibody most significantly recognized an acrolein-modified 2' -deoxyadenosine. On the basis of chemical and spectroscopic evidence, the major antigenic product of mAb21 was the 1,N6-propano-2' -deoxyadenosine adduct. The exposure of rat liver epithelial RL34 cells to acrolein resulted in a significant accumulation of the acrolein-2' -deoxyadenosine adduct in the nuclei. Formation of this adduct under oxidative stress in vivo was immunohistochemically examined in rats exposed to ferric nitrilotriacetate, a carcinogenic iron chelate that specifically induces oxidative stress in the kidneys of rodents. It was observed that the acrolein-2' -deoxyadenosine adduct was formed in the nuclei of the proximal tubular cells, the target cells of this carcinogenesis model. The same cells were stained with a monoclonal antibody 5F6 that recognizes an acrolein-lysine adduct, by which cytosolic accumulation of acrolein-modified proteins appeared. Similar results were also obtained from myeloperoxidase knockout mice exposed to the iron complex, suggesting that the myeloperoxidase-catalyzed oxidation system might not be essential for the generation of acrolein in this experimental animal carcinogenesis model. The data obtained in this study suggest that the formation of a carcinogenic aldehyde through lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.

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  764. Restoration of fertility in infertile mice by transplantation of cryopreserved male germline stem cells Reviewed

    M Kanatsu-Shinohara, N Ogonuki, K Inoue, A Ogura, S Toyokuni, T Shinohara

    HUMAN REPRODUCTION   Vol. 18 ( 12 ) page: 2660 - 2667   2003.12

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    BACKGROUND: The development of a spermatogonial transplantation technique has provided new possibilities for the treatment of male infertility. Previous studies have shown that spermatogonial stem cells could reinitiate spermatogenesis after cryopreservation and reintroduction into the seminiferous tubules of infertile recipient males, and this raised the possibility of banking frozen stem cells for male infertility treatment. It remains unknown, however, whether germ cells from freeze-thawed stem cells are fertile, leaving the possibility that the procedure compromises the integrity of the stem cells. METHODS AND RESULTS: Dissociated mouse testis cells were cryopreserved and transplanted into infertile recipient testes. The freeze-thawed testis cell populations contained higher concentrations of stem cells than fresh testis cell populations. Offspring were obtained from freeze-thawed stem cells transplanted into infertile males, and fertility restoration was more efficient in immature (5-10 days old) than in mature (6-12 weeks old) recipients. However, offspring were also obtained from infertile adult recipients using in-vitro microinsemination. CONCLUSIONS: This first successful application of frozen stem cell technology in the production of offspring by spermatogonial transplantation suggests the superiority of immature recipients for clinical applications. Thus, the combination of cryopreservation and transplantation of stem cells is a promising approach to overcome male infertility.

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  765. Edaravone, a novel free radical scavenger, protects myocardium against oxidative stress after cardioplegic arrest

    Yamazaki, K; Miwa, S; Toyokuni, S; Horii, T; Unimonh, O; Sasahashi, N; Takaba, K; Komeda, M

    CIRCULATION   Vol. 108 ( 17 ) page: 175 - 175   2003.10

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  766. Edaravone, a novel free radical scavenger, protects myocardium against oxidative stress after cardioplegic arrest

    Yamazaki K, Miwa S, Toyokuni S, Horii T, Unimonh O, Sasahashi N, Takaba K, Komeda M

    CIRCULATION   Vol. 108 ( 17 ) page: 175 - 175   2003.10

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  767. Novel aspects in free radical chemistry and biology

    Toyokuni, S

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 417 ( 1 ) page: 2 - 2   2003.9

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  768. Effects of the phenolic contents of Mauritian endemic plant extracts on promoter activities of antioxidant enzymes. Reviewed International journal

    Shinya Toyokuni, Tomoyuki Tanaka, Waka Kawaguchi, Neil Ryan Lai Fang, Munetaka Ozeki, Shinya Akatsuka, Hiroshi Hiai, Okezie I Aruoma, Theeshan Bahorun

    Free radical research   Vol. 37 ( 11 ) page: 1215 - 1224   2003.9

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    Oxidative stress has been associated with a variety of pathologic conditions in humans. Increasing the transcriptional activities of antioxidant enzymes might be a strategy to prevent oxidative stress-associated diseases such as atherosclerosis and cancer. In the present paper, we studied the effects of extracts from 12 Mauritian endemic plants on the promoter activities of antioxidant enzymes; Cu, Zn-superoxide dismutase (Cu,Zn-SOD), Mn-superoxide dismutase (Mn-SOD), catalase, and glutathione dismutase (GPx). The levels of total phenolic compounds, total flavonoids, and proanthocyanidins were measured. Four luciferase expression vectors (pGL3-Basic) with promoter region of each enzyme were constructed, transfected to COS7 cells followed by an exposure to each extract (25 mug/ml, 24 h, non-toxic dose). Thereafter, luciferase activities were evaluated in comparison with a control luciferase vector with a herpes simplex virus thymidine kinase promoter. Mauritian endemic plants contained high amounts of total phenols, flavonoids and proanthocyanidins. Total phenols and flavonoids were proportionally associated with Cu,Zn-SOD promoter activity, whereas they were inversely correlated with catalase promoter activity. These results suggest that the chemopreventive potentials of the extracts might reside in their abilities to modulate the expression of the antioxidant enzyme genes.

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  769. Long-term proliferation in culture and germline transmission of mouse male germline stem cells. Reviewed International journal

    Mito Kanatsu-Shinohara, Narumi Ogonuki, Kimiko Inoue, Hiromi Miki, Atsuo Ogura, Shinya Toyokuni, Takashi Shinohara

    Biology of reproduction   Vol. 69 ( 2 ) page: 612 - 6   2003.8

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    Spermatogenesis is a complex process that originates in a small population of spermatogonial stem cells. Here we report the in vitro culture of spermatogonial stem cells that proliferate for long periods of time. In the presence of glial cell line-derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, and leukemia inhibitory factor, gonocytes isolated from neonatal mouse testis proliferated over a 5-month period (&gt;10(14)-fold)and restored fertility to congenitally infertile recipient mice following transplantation into seminiferous tubules. Long-term spermatogonial stem cell culture will be useful for studying spermatogenesis mechanism and has important implications for developing new technology in transgenesis or medicine.

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  770. Long-term proliferation in culture and germline transmission of mouse male germline stem cells

    Kanatsu-Shinohara M, Ogonuki N, Inoue K, Miki H, Ogura A, Toyokuni S, Shinohara T

    BIOLOGY OF REPRODUCTION   Vol. 69 ( 2 ) page: 612 - 616   2003.8

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    Spermatogenesis is a complex process that originates in a small population of spermatogonial stem cells. Here we report the in vitro culture of spermatogonial stem cells that proliferate for long periods of time. In the presence of glial cell line-derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, and leukemia inhibitory factor, gonocytes isolated from neonatal mouse testis proliferated over a 5-month period (>1014-fold) and restored fertility to congenitally infertile recipient mice following transplantation into seminiferous tubules. Long-term spermatogonial stem cell culture will be useful for studying spermatogenesis mechanism and has important implications for developing new technology in transgenesis or medicine.

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  771. Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice. Reviewed International journal

    Sakata S, Sakamaki K, Watanabe K, Nakamura N, Toyokuni S, Nishimune Y, Mori C, Yonehara S

    Cell death and differentiation   Vol. 10 ( 6 ) page: 676 - 686   2003.6

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  772. Evidence for oxidative stress in NSAID-induced colitis in IL10-/- mice. International journal

    Seiko Narushima, Douglas R Spitz, Larry W Oberley, Shinya Toyokuni, Toshio Miyata, Carol A Gunnett, Garry R Buettner, Juan Zhang, Hanan Ismail, Richard G Lynch, Daniel J Berg

    Free radical biology & medicine   Vol. 34 ( 9 ) page: 1153 - 66   2003.5

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    The goal of this study was to evaluate for evidence of oxidative stress in colonic inflammation in a novel model of inflammatory bowel disease, nonsteroidal anti-inflammatory drug- (NSAID-) treated interleukin-10-deficient (IL10(-/-)) mice. IL10(-/-) and wild-type (wt) mice were treated with a nonselective NSAID (piroxicam, 200 ppm in the diet) for 2 weeks to induce colitis, and parameters for oxidative stress in the colonic tissues were evaluated. Mean chemiluminescence enhanced with lucigenin in the colons from IL10(-/-) mice treated with piroxicam was more than 5-fold higher than that of the control wt group. Chemiluminescence was inhibited with diphenylethylene iodinium, but not allopurinol, indomethacin, or N-omega-nitro-L-arginine, indicating that flavin-containing enzymes were the source of the reactive oxygen species. Colonic aconitase activity in NSAID-treated IL10(-/-) mice decreased to 50% of the activity of control mice. There was no difference in the total glutathione levels in the colonic mucosa among the groups; however, glutathione disulfide levels were approximately 2-fold greater in the colon of NSAID-treated IL10(-/-) mice as compared with control groups. Immunohistochemistry studies of colons from NSAID-treated IL10(-/-) mice demonstrated intense staining with two antibodies that recognize advanced glycation endproducts formed through glycation and oxidation: anticarboxymethylysine and antipentosidine. The epithelial cells and lamina propria cells in the colons of NSAID-treated IL10(-/-) mice showed immunostaining with antinitrotyrosine, indicating the presence of reactive nitrogen species. Colonic epithelium of IL10(-/-) mice with colitis showed moderate immunostaining for 8-hydroxy-2'-deoxyguanosine in the nuclei. NSAID-treated IL10(-/-) mice treated with diphenylene idodonium chloride (DPI), an irreversible inhibitor of flavoprotein enzymes, experienced significantly reduced inflammation. Taken together, these results strongly indicate the presence of oxidative stress in the inflammatory bowel disease in NSAID-treated IL10(-/-) mice and suggests a role for oxidative stress in the pathophysiology of this model of inflammatory bowel disease.

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  773. Evidence for oxidative stress in NSAID-induced colitis in IL10(-/-) mice

    Narushima S, Spitz DR, Oberley LW, Toyckuni S, Miyata T, Gunnett CA, Buettner GR, Zhang J, Ismail H, Lynch RG, Berg DJ

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 34 ( 9 ) page: 1153 - 1166   2003.5

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    The goal of this study was to evaluate for evidence of oxidative stress in colonic inflammation in a novel model of inflammatory bowel disease, nonsteroidal anti-inflammatory drug- (NSAID-) treated interleukin-10-deficient (IL10-/-) mice. IL10-/- and wild-type (wt) mice were treated with a nonselective NSAID (piroxicam, 200 ppm in the diet) for 2 weeks to induce colitis, and parameters for oxidative stress in the colonic tissues were evaluated. Mean chemiluminescence enhanced with lucigenin in the colons from IL10-/- mice treated with piroxicam was more than 5-fold higher than that of the control wt group. Chemiluminescence was inhibited with diphenylethylene iodinium, but not allopurinol, indomethacin, or N-ω-nitro-L-arginine, indicating that flavin-containing enzymes were the source of the reactive oxygen species. Colonic aconitase activity in NSAID-treated IL10-/- mice decreased to 50% of the activity of control mice. There was no difference in the total glutathione levels in the colonic mucosa among the groups; however, glutathione disulfide levels were approximately 2-fold greater in the colon of NSAID-treated IL10-/- mice as compared with control groups. Immunohistochemistry studies of colons from NSAID-treated IL10-/- mice demonstrated intense staining with two antibodies that recognize advanced glycation endproducts formed through glycation and oxidation: anticarboxymethylysine and antipentosidine. The epithelial cells and lamina propria cells in the colons of NSAID-treated IL10-/- mice showed immunostaining with antinitrotyrosine, indicating the presence of reactive nitrogen species. Colonic epithelium of IL10-/- mice with colitis showed moderate immunostaining for 8-hydroxy-2′-deoxyguanosine in the nuclei. NSAID-treated IL10-/- mice treated with diphenylene idodonium chloride (DPI), an irreversible inhibitor of flavoprotein enzymes, experienced significantly reduced inflammation. Taken together, these results strongly indicate the presence of oxidative stress in the inflammatory bowel disease in NSAID-treated IL10-/- mice and suggests a role for oxidative stress in the pathophysiology of this model of inflammatory bowel disease. © 2003 Elsevier Inc.

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  774. Functional assessment of self-renewal activity of male germline stem cells following cytotoxic damage and serial transplantation. Reviewed International journal

    Mito Kanatsu-Shinohara, Shinya Toyokuni, Takeshi Morimoto, Shigeyuki Matsui, Tasuku Honjo, Takashi Shinohara

    Biology of reproduction   Vol. 68 ( 5 ) page: 1801 - 1807   2003.5

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    Spermatogenesis is dependent on a small population of stem cells. Although stem cells are believed to expand infinitely, there is little functional evidence regarding whether spermatogonial stem cells can increase in their number. Using the spermatogonial transplantation technique, we evaluated the proliferative potential of spermatogonial stem cells in two models of regeneration. After busulfan injection to deplete stem cells, the surviving stem cells were able to expand by at least 15.8-fold within 2 mo. On the other hand, a serial transplantation study indicated that one transplanted stem cell was able to expand by 3.8- and 12-fold within 2 and 4 mo, respectively. These results provide direct functional evidence for the expansion of stem cells and establish the basis for further characterization of the stem cell self-renewal process.

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  775. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis

    TOYOKUNI Shinya, KAWAGUCHI Waka, AKATSUKA Shinya, HIROYASU Makoto, HIAI Hiroshi

    Pathol Int   Vol. 53 ( 4 ) page: 259 - 261   2003.4

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  776. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis

    TOYOKUNI Shinya, KAWAGUCHI Waka, AKATSUKA Shinya, HIROYASU Makoto, HIAI Hiroshi

    Pathology international   Vol. 53 ( 4 ) page: 259 - 261   2003.4

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  777. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis

    Toyokuni S, Kawaguchi W, Akatsuka S, Hiroyasu M, Hiai H

    PATHOLOGY INTERNATIONAL   Vol. 53 ( 4 ) page: 259 - 261   2003.4

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  778. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis.

    Toyokuni S, Kawaguchi W, Akatsuka S, Hiroyasu M, Hiai H

    Pathology international   Vol. 53 ( 4 ) page: 259 - 61   2003.4

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  779. Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis. International journal

    Shinya Toyokuni, Waka Kawaguchi, Shinya Akatsuka, Makoto Hiroyasu, Hiroshi Hiai

    Pathology international   Vol. 53 ( 4 ) page: 259 - 61   2003.4

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  780. Glycine ameriorates lung reprefusion injury after cold preservation in an ex vivo rat lung model.

    Omasa M, Fukuse T, Toyokuni S, Mizutani Y, Yoshida H, Ikeyama K, Hasegawa S, Wada H

    TRANSPLANTATION   Vol. 75 ( 5 ) page: 591 - 598   2003.3

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    Background. The role of glycine has not been investigated in lung ischemia-reperfusion injury after cold preservation. Furthermore, the role of apoptosis after reperfusion following cold preservation has not been fully understood. Methods. Lewis rats were divided into three groups (n=6 each). In the GLY(-) and GLY(+) groups, isolated lungs were preserved for 15 hr at 4°C after a pulmonary artery (PA) flush using our previously developed preservation solution (ET-K; extracellular-type trehalose containing Kyoto), with or without the addition of glycine (5 mM). In the Fresh group, isolated lungs were reperfused immediately after a PA flush with ET-K. They were reperfused for 60 min with an ex vivo perfusion model. Pulmonary function, oxidative stress, apoptosis, and tumor necrosis factor (TNF)-α expression were assessed after reperfusion. Results. Shunt fraction and peak inspiratory pressure after reperfusion in the GLY(-) group were significantly higher than those in the GLY(+) and Fresh groups. Oxidative damage and apoptosis in the alveolar epithelial cells of the GLY(-) group, assessed by immunohistochemical staining and quantification of 8-hydroxy-2′-deoxyguanosine and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method, were significantly higher than those of the GLY(+) and Fresh groups. There were correlations among shunt fraction, oxidative damage, and apoptosis. There was no expression of TNF-α messenger RNA in all groups evaluated by the reverse transcription-polymerase chain reaction. Conclusions. Glycine attenuates ischemia/reperfusion injury after cold preservation by reducing oxidative damage and suppressing apoptosis independent of TNF-α in this model. The suppression of apoptosis might ameliorate lung function after reperfusion.

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  781. Glycine ameliorates lung reperfusion injury after cold preservation in an ex vivo rat lung model. International journal

    Mitsugu Omasa, Tatsuo Fukuse, Shinya Toyokuni, Yoichi Mizutani, Hiroshi Yoshida, Kazuyuki Ikeyama, Seiki Hasegawa, Hiromi Wada

    Transplantation   Vol. 75 ( 5 ) page: 591 - 8   2003.3

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    BACKGROUND: The role of glycine has not been investigated in lung ischemia-reperfusion injury after cold preservation. Furthermore, the role of apoptosis after reperfusion following cold preservation has not been fully understood. METHODS: Lewis rats were divided into three groups (n=6 each). In the GLY(-) and GLY(+) groups, isolated lungs were preserved for 15 hr at 4 degrees C after a pulmonary artery (PA) flush using our previously developed preservation solution (ET-K; extracellular-type trehalose containing Kyoto), with or without the addition of glycine (5 mM). In the Fresh group, isolated lungs were reperfused immediately after a PA flush with ET-K. They were reperfused for 60 min with an ex vivo perfusion model. Pulmonary function, oxidative stress, apoptosis, and tumor necrosis factor (TNF)-alpha expression were assessed after reperfusion. RESULTS: Shunt fraction and peak inspiratory pressure after reperfusion in the GLY(-) group were significantly higher than those in the GLY(+) and Fresh groups. Oxidative damage and apoptosis in the alveolar epithelial cells of the GLY(-) group, assessed by immunohistochemical staining and quantification of 8-hydroxy-2'-deoxyguanosine and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method, were significantly higher than those of the GLY(+) and Fresh groups. There were correlations among shunt fraction, oxidative damage, and apoptosis. There was no expression of TNF-alpha messenger RNA in all groups evaluated by the reverse transcription-polymerase chain reaction. CONCLUSIONS: Glycine attenuates ischemia/reperfusion injury after cold preservation by reducing oxidative damage and suppressing apoptosis independent of TNF-alpha in this model. The suppression of apoptosis might ameliorate lung function after reperfusion.

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  782. Tumor initiating activity of Helicobacter pylori water extract on mouse skin carcinogenesis. Reviewed International journal

    Takeshi Ishikawa, Norimasa Yoshida, Harukuni Tokuda, Eiichiro Ichiishi, Masashi Kuchide, Satoshi Kokura, Yuji Naito, Shinya Toyokuni, Hoyoku Nishino, Toshikazu Yoshikawa

    Cancer letters   Vol. 191 ( 1 ) page: 41 - 47   2003.2

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    Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis, but responsible and detail mechanisms are insufficient by the absence of adequate data. To obtain direct evidence regarding the carcinogenicity of H. pylori, we investigated the initiating and promoting activity of H. pylori water extract (HPE) in two-stage mouse skin carcinogenesis model. HPE treatment, as an initiation, significantly enhanced tumor formation compared with control group. Moreover, HPE treatment increased production of 8-hydroxydeoxyguanosine in epidermal cells and HPE-initiated/TPA-promoted papillomas demonstrated a point mutation of the Ha-ras gene. These results suggest an initiating activity of HPE on two-stage mouse skin carcinogenesis.

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  783. Structural basis of protein-bound endogenous aldehydes - Chemical and immunochemical characterizations of configurational isomers of a 4-hydroxy-2-nonenal-histidine adduct International journal

    Hashimoto, M; Sibata, T; Wasada, H; Toyokuni, S; Uchida, K

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 278 ( 7 ) page: 5044 - 5051   2003.2

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    4-Hydroxy-2-nonenal (HNE), a major racemic product of lipid peroxidation, reacts with histidine to form a stable HNE-histidine Michael addition-type adduct possessing three chiral centers in the cyclic hemiacetal structure. In the present study, we characterized configurational isomers of a HNE-Nα-acetylhistidine adduct by NMR spectroscopy and by molecular orbital calculations. In addition, we raised monoclonal antibodies against (R)-HNE-histidine and (S)-HNE-histidine adducts, characterized their specificities, and examined in vivo localizations of each adduct under oxidative stress. To facilitate structural characterization of the configurational isomers of an HNE-histidine adduct, we prepared the (R)-HNE-histidine and (S)-HNE-histidine adducts by incubating Nα-acetylhistidine with each HNE enantiomer, both of which provided two peaks (Ra and Rb from (R)-HNE-histidine and Sa and Sb from (S)-HNE-histidine adducts) in reversed-phase high-performance liquid chromatography. The NMR analysis showed that each peak was a mixture of two diastereomers. In addition, the analysis of the nuclear Overhauser effect enabled the determination of configurations of the eight isomers. The relative amounts of these isomers in the NMR analysis correlated with the relative energies calculated by molecular orbital methods. On the other hand, using (R)-HNE-modified and (S)-HNE-modified keyhole limpet hemocyanins as the antigens, we raised the monoclonal antibodies, mAbR310 and mAbS412, which enantioselectively recognized the (R)-HNE-histidine and (S)-HNE-histidine adducts, respectively. Among the mixtures (Ra, Rb, Sa, and Sb) of diastereomers, mAbR310 showed the highest immunoreactivity to Rb (the mixture of 2R,4S,5R and 2S,4S,5R isomers), whereas mAbS412 preferentially recognized Sa (the mixture of 2R,4S,5S and 2S,4S,5S isomers). The presence of (R)-HNE and (S)-HNE epitopes in vivo was immunohistochemically examined in the kidney of rats exposed to the renal carcinogen, ferric nitrilotriacetate, by which nuclear and cytosolic stainings with mAbR310 and mAbS412, respectively, were detected.

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  784. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway.

    Kuroda K, Han H, Tani S, Tanigaki K, Tun T, Furukawa T, Taniguchi Y, Kurooka H, Hamada Y, Toyokuni S, Honjo T

    Immunity   Vol. 18 ( 2 ) page: 301 - 12   2003.2

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    We found that Msx2-interacting nuclear target protein (MINT) competed with the intracellular region of Notch for binding to a DNA binding protein RBP-J and suppressed the transactivation activity of Notch signaling. Although MINT null mutant mice were embryonic lethal, MINT-deficient splenic B cells differentiated about three times more efficiently into marginal zone B cells with a concomitant reduction of follicular B cells. MINT is expressed in a cell-specific manner: high in follicular B cells and low in marginal zone B cells. Since Notch signaling directs differentiation of marginal zone B lymphocytes and suppresses that of follicular B lymphocytes in mouse spleen, the results indicate that high levels of MINT negatively regulate Notch signaling and block differentiation of precursor B cells into marginal zone B cells. MINT may serve as a functional homolog of Drosophila Hairless.

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  785. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway

    Kuroda K, Han H, Tani S, Tanigaki K, Tun T, Furukawa T, Taniguchi Y, Kurooka H, Hamada Y, Toyokuni S, Honjo T

    IMMUNITY   Vol. 18 ( 2 ) page: 301 - 312   2003.2

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  786. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. International journal

    Kazuki Kuroda, Hua Han, Shoichi Tani, Kenji Tanigaki, Tin Tun, Takahisa Furukawa, Yoshihito Taniguchi, Hisanori Kurooka, Yoshio Hamada, Shinya Toyokuni, Tasuku Honjo

    Immunity   Vol. 18 ( 2 ) page: 301 - 12   2003.2

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    We found that Msx2-interacting nuclear target protein (MINT) competed with the intracellular region of Notch for binding to a DNA binding protein RBP-J and suppressed the transactivation activity of Notch signaling. Although MINT null mutant mice were embryonic lethal, MINT-deficient splenic B cells differentiated about three times more efficiently into marginal zone B cells with a concomitant reduction of follicular B cells. MINT is expressed in a cell-specific manner: high in follicular B cells and low in marginal zone B cells. Since Notch signaling directs differentiation of marginal zone B lymphocytes and suppresses that of follicular B lymphocytes in mouse spleen, the results indicate that high levels of MINT negatively regulate Notch signaling and block differentiation of precursor B cells into marginal zone B cells. MINT may serve as a functional homolog of Drosophila Hairless.

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  787. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Reviewed International journal

    Wataru Aoi, Yuji Naito, Kunihiro Sakuma, Masashi Kuchide, Harukuni Tokuda, Takashi Maoka, Shinya Toyokuni, Shigenori Oka, Masahiro Yasuhara, Toshikazu Yoshikawa

    Antioxidants & redox signaling   Vol. 5 ( 1 ) page: 139 - 44   2003.2

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    Dietary antioxidants may attenuate oxidative damage from strenuous exercise in various tissues. Beneficial effects of the antioxidant astaxanthin have been demonstrated in vitro, but not yet in vivo. We investigated the effect of dietary supplementation with astaxanthin on oxidative damage induced by strenuous exercise in mouse gastrocnemius and heart. C57BL/6 mice (7 weeks old) were divided into groups: rested control, intense exercise, and exercise with astaxanthin supplementation. After 3 weeks of exercise acclimation, both exercise groups ran on a treadmill at 28 m/min until exhaustion. Exercise-increased 4-hydroxy-2-nonenal-modified protein and 8-hydroxy-2'-deoxyguanosine in gastrocnemius and heart were blunted in the astaxanthin group. Increases in plasma creatine kinase activity, and in myeloperoxidase activity in gastrocnemius and heart, also were lessened by astaxanthin. Astaxanthin showed accumulation in gastrocnemius and heart from the 3 week supplementation. Astaxanthin can attenuate exercise-induced damage in mouse skeletal muscle and heart, including an associated neutrophil infiltration that induces further damage.

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  788. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice

    Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Maoka T, Toyokuni S, Oka S, Yasuhara M, Yoshikawa T

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 5 ( 1 ) page: 139 - 144   2003.2

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  789. Allogeneic offspring produced by male germ line stem cell transplantation into infertile mouse testis. Reviewed International journal

    Mito Kanatsu-Shinohara, Narumi Ogonuki, Kimiko Inoue, Atsuo Ogura, Shinya Toyokuni, Tasuku Honjo, Takashi Shinohara

    Biology of reproduction   Vol. 68 ( 1 ) page: 167 - 173   2003.1

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    The testis is one of several immune-privileged organs and is known for its unique ability to support allogeneic or xenogeneic tissue transplants. We investigated the possibility of deriving offspring from mice that underwent transplantation with allogeneic male germ line stem cells in the testis. Although mature adult mice rejected allogeneic germ cells and were infertile, offspring were obtained by intracytoplasmic germ cell injection using partially differentiated donor cells. In contrast, complete spermatogenesis occurred when allogeneic germ cells were transplanted into immature pup testes. Tolerance induction by monoclonal antibody administration allowed the pup transplant recipients to produce allogeneic offspring by natural mating, whereas no spermatozoa were found in the epididymis of untreated recipients. Thus, these results, indicate that a histoincompatible recipient can serve as a "surrogate father" to propagate the genetic information of heterologous male donors.

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  790. Birth of offspring following transplantation of cyropreserved immature testicular pieces and in-vitro microinsemination

    Shinohara T., Inoue K., Ogonuki N., Kanatsu-Shinohara M., Miki H., Nakata K., Kurome M., Nagashima H., Toyokuni S., Kogishi K., Honjo T., Ogura A.

    Human Reproduction   Vol. 17 ( 12 ) page: 3039 - 3045   2002.12

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    Background: Fertility protection is an urgent clinical problem for prepubertal male oncology patients who undergo either chemotherapy or radiotherapy. As these patients do not have mature sperm to be frozen, there is as yet no effective method to preserve their fertility. Methods and results: Single pieces of immature mouse (1.5 × 1.5 × 1.5 mm) or rabbit (2.0 × 2.0 × ≃3.0 mm) testis were cryopreserved, thawed and transplanted into mouse testes. Histological techniques were used to determine the presence of spermatogenesis, which was restored in both mouse and rabbit testicular pieces, and led to the production of mature sperm after both cryopreservation and syngeneic or xenogeneic transplantation into mouse testes. Using sperm developed in the frozen-thawed transplants, mouse offspring were born after in-vitro microinsemination. Furthermore, rabbit offspring were obtained using rabbit sperm that developed in fresh transplants in a xenogeneic surrogate mouse. Conclusions: This approach of 'testicular tissue banking' is a promising technique for the preservation of fertility in prepubertal male oncology patients. Xenogeneic transplantation into immunodeficient mice may provide a system for study spermatogenic failure in infertile men.

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  791. Birth of offspring following transplantation of cryopreserved immature testicular pieces and in-vitro microinsemination

    Shinohara, T; Inoue, K; Ogonuki, N; Kanatsu-Shinohara, M; Miki, H; Nakata, K; Kurome, M; Nagashima, H; Toyokuni, S; Kogishi, K; Honjo, T; Ogura, A

    HUMAN REPRODUCTION   Vol. 17 ( 12 ) page: 3039 - 3045   2002.12

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  792. A novel method of "preparative" myocardial protection using green tea polyphenol in oral uptake

    Miwa, S; Saito, M; Yamazaki, K; Toyokuni, S; Hyon, SH; Fujita, M; Komeda, M

    CIRCULATION   Vol. 106 ( 19 ) page: 345 - 345   2002.11

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  793. Oxydative stress persists in nearby LV area after myocardial infarction (MI) and shows two peaks

    Miwa, S; Toyokuni, S; Tanaka, S; Nishina, T; Nomoto, T; Yamazaki, K; Ueda, K; Nishimura, K

    CIRCULATION   Vol. 106 ( 19 ) page: 312 - 312   2002.11

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  794. Oxydative stress persists in nearby LV area after myocardial infarction (MI) and shows two peaks

    Miwa S, Toyokuni S, Tanaka S, Nishina T, Nomoto T, Yamazaki K, Ueda K, Nishimura K

    CIRCULATION   Vol. 106 ( 19 ) page: 312 - 312   2002.11

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  795. A novel method of "preparative" myocardial protection using green tea polyphenol in oral uptake Reviewed International journal

    Miwa, S, Saito, M, Yamazaki, K, Toyokuni, S, Hyon, SH, Fujita, M, Komeda, M

    CIRCULATION   Vol. 106 ( 19 ) page: 345 - 345   2002.11

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  796. Ex vivo whole-embryo culture of caspase-8-dificient embryos normalize their aberrant phenotypes in the developing neural tube and heart Reviewed

    Sakamaki K, Inoue T, Asano M, Sudo K, Kazama H, Sakagami J, Sakata S, Ozaki M, Nakamura S, Toyokuni S, Osumi N, Yonehara S

    Cell Death and Differentiation   Vol. 9 ( 11 ) page: 1196 - 1206   2002.11

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    Other Link: http://orcid.org/0000-0003-0548-6452

  797. Comparison between high-performance liquid chromatography and enzyme-linked Immunosorbent assay for the determination of 8-hydroxy-2 '-deoxyguanosine in human urine

    Shimoi K, Kasai H, Yokota N, Toyokuni S, Kinae N

    CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION   Vol. 11 ( 8 ) page: 767 - 770   2002.8

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  798. Spaciotemporal alteration of 8-hydroxy-2'-deoxyguanosine levels in cardiomyocytes after myocardial infarction in rats. Reviewed International journal

    Senri Miwa, Shinya Toyokuni, Takeshi Nishina, Takuya Nomoto, Makoto Hiroyasu, Kazunobu Nishimura, Masashi Komeda

    Free radical research   Vol. 36 ( 8 ) page: 853 - 858   2002.8

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    Temporary or persistent heart failure is one of the major complications after myocardial infarction (MI). In order to elucidate the pathogenesis of MI, we studied the spaciotemporal alteration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in cardiomyocytes in a rat model of ligation of the left anterior descending branch of the coronary artery The lethality in this model was 18%. Hearts were dissected at 0, 3, 6, 12, 24, 48 h, and 1, 2, 4, 6 weeks after the operation. The cardiac level of 8-OHdG was evaluated biochemically as well as by immunohistochemistry with monoclonal antibody N45.1. Three to 6h after ligation, the 8-OHdG levels were increased in the cardiomyocytes of MI (six-fold) and peri-MI (four-fold) areas. After 24h, the myocardium in the MI area was necrotized, and thereafter the 8-OHdG level decreased. 8-OHdG levels in the myocardium of peri-MI areas returned once to a normal level, but were significantly increased at 2-4 weeks along with the appearance of apoptotic cardiomyocytes in this area. The heart after MI has been generally considered as clinically stable after four weeks. However, cardiomyocytes near the infarcted area were oxidatively stressed even after four weeks when the affected lesion was extensive. The present data support the use of supplementary antioxidant therapies to save functional myocardium after MI. (213 words).

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  799. Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress

    Kallay E, Bareis P, Bajna E, Kriwanek S, Bonner E, Toyokuni S, Cross HS

    FOOD AND CHEMICAL TOXICOLOGY   Vol. 40 ( 8 ) page: 1191 - 1196   2002.8

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  800. Protective effect of colored rice over white rice on fenton reaction-based renal lipid peroxidation in rats (vol 36, pg 583, 2002)

    Toyokuni, S; Itani, T; Morimitsu, Y; Okada, K; Ozeki, M; Kondo, S; Uchida, K; Osawa, T; Hiai, H; Tashiro, T

    FREE RADICAL RESEARCH   Vol. 36 ( 8 )   2002.8

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  801. Comparison between high-performance liquid chromatography and enzyme-linked immunosorbent assay for the determination of 8-hydroxy-2'-deoxyguanosine in human urine. International journal

    Kayoko Shimoi, Hiroshi Kasai, Naoko Yokota, Shinya Toyokuni, Naohide Kinae

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology   Vol. 11 ( 8 ) page: 767 - 70   2002.8

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    8-Hydroxy-2'-deoxyguanosine (8-OH-dG), which has been regarded as a potential marker of oxidative DNA damage induced by reactive oxygen species, was measured in human urine by a commercial ELISA using a monoclonal antibody N45.1 and by high-performance liquid chromatography (HPLC) coupled to an electrochemical detector (HPLC-ECD) to evaluate whether the ELISA system is applicable to human monitoring studies. The urine samples were collected from 120 healthy men ages 18-58 in a steel-manufacturing company. A good correlation (r = 0.833; P < 0.0001) was observed between the two methods on HPLC-purified 8-OH-dG fractions from 23 urine samples. The mean value (+/-SD) of 8-OH-dG (microg/g creatinine) was 5.47 (+/-2.97) by HPLC-ECD assay and 5.50 (+/-2.36) by ELISA. However, the correlation (r) between the two methods on 120 original urine samples was 0.460 [P < 0.001; mean value (+/-SD) of 8-OH-dG (microg/g creatinine) was 4.46 (+/-2.03) by the HPLC assay and 9.33 (+/-3.23) by ELISA]. ELISA estimates were about 2-fold higher than the HPLC estimates on original urine. For an unknown reason, 10% of the urine samples showed more than a 4-fold increase in value by ELISA. It is suggested that the ELISA system is applicable for comparative human monitoring studies. Prepurification of 'samples is required to determine the absolute value of 8-OH-dG in individual urine samples by ELISA.

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  802. Comparison between high-performance liquid chromatography and enzyme-linked immunosorbent assay for the determination of 8-hydroxy-2'-deoxyguanosine in human urine.

    Shimoi K, Kasai H, Yokota N, Toyokuni S, Kinae N

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology   Vol. 11 ( 8 ) page: 767 - 70   2002.8

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  803. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Reviewed International journal

    Kazumasa Miyawaki, Yuichiro Yamada, Nobuhiro Ban, Yu Ihara, Katsushi Tsukiyama, Heying Zhou, Shimpei Fujimoto, Akira Oku, Kinsuke Tsuda, Shinya Toyokuni, Hiroshi Hiai, Wataru Mizunoya, Tohru Fushiki, Jens Juul Holst, Mitsuhiro Makino, Akira Tashita, Yukari Kobara, Yoshiharu Tsubamoto, Takayoshi Jinnouchi, Takahito Jomori, Yutaka Seino

    Nature medicine   Vol. 8 ( 7 ) page: 738 - 742   2002.7

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    Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr(-/-)) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) mice. The Gipr(-/-) mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.

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  804. Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress

    Kállay E., Bareis P., Bajna E., Kriwanek S., Bonner E., Toyokuni S., Cross H.

    Food and Chemical Toxicology   Vol. 40 ( 8 ) page: 1191 - 1196   2002.6

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    Unimpaired vitamin D action has been implicated in human cancer prevention. We have previously demonstrated the effectiveness of 1α-dihydroxyvitamin D3 (1,25-D3) to reduce proliferation and increase differentiation in human colon cancer cells. The aim of this study was to investigate, on the one hand, expression of the vitamin D receptor (VDR) and of 25-hydroxyvitamin D3-1α-hydroxylase (1α-hydroxylase) in human normal and malignant colonic tissue and, on the other hand, to determine consequences of reduced or lacking VDR action in a VDR knockout mouse model. In low-grade malignancies of the human colon we found increased VDR and 1α-hydroxylase mRNA expression. However, in late-stage high-grade tumors the vitamin D system is severely compromised. In the mouse colon we found an inverse relationship between VDR levels and proliferation in colon descendens, a tissue known to be specifically affected by nutrients during carcinogenesis. Expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, was significantly augmented with complete loss of VDR. These data suggest that genomic 1,25-D3 action is necessary to protect against nutrition-linked hyperproliferation and oxidative DNA damage. © 2002 Elsevier Science Ltd. All rights reserved.

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  805. Carvedilol decreases elevated oxidative stress in human failing myocardium

    Nakamura, K; Kusano, K; Nakamura, Y; Kakishita, M; Ohta, K; Nagase, S; Yamamoto, M; Miyaji, K; Saito, H; Morita, H; Emori, T; Matsubara, H; Toyokuni, S; Ohe, T

    CIRCULATION   Vol. 105 ( 24 ) page: 2867 - 2871   2002.6

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  806. Peroxynitrite-mediated stress is associated with proliferation of human metastatic colorectal carcinoma in the liver

    Kondo S, Toyokuni S, Tsuruyama T, Ozeki M, Tachibana T, Echizenya M, Hiai H, Onodera H, Imamura M

    CANCER LETTERS   Vol. 179 ( 1 ) page: 87 - 93   2002.5

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  807. Peroxynitrite-mediated stress is associated with proliferation of human metastatic colorectal carcinoma in the liver.

    Kondo S, Toyokuni S, Tsuruyama T, Ozeki M, Tachibana T, Echizenya M, Hiai H, Onodera H, Imamura M

    Cancer letters   Vol. 179 ( 1 ) page: 87 - 93   2002.5

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    3-Nitrotyrosine (3-NT), a product of peroxynitrite reaction, is abundantly observed in hepatocytes adjacent to human metastatic colorectal carcinoma. To elucidate its biological significance, we undertook to identify nitric oxide (NO)-producing cells and apoptosis under oxidative stress. We observed strong inducible NO-synthase (iNOS) immunoreactivity in the hepatocytes adjacent to metastatic tumor, revealing an identical pattern to 3-NT immunostaining. Furthermore, intense 3-NT immunostaining of hepatocytes was associated with apoptosis whereas carcinoma cells near those hepatocytes presented high proliferating-cell nuclear antigen. Our results suggest that contact of metastatic tumor induces apoptosis in adjacent hepatocytes through peroxynitrite, thus permitting the proliferation of cancer cells. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

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  808. Peroxynitrite-mediated stress is associated with proliferation of human metastatic colorectal carcinoma in the liver. International journal

    Shohei Kondo, Shinya Toyokuni, Tatsuaki Tsuruyama, Munetaka Ozeki, Tsuyoshi Tachibana, Michiko Echizenya, Hiroshi Hiai, Hisashi Onodera, Masayuki Imamura

    Cancer letters   Vol. 179 ( 1 ) page: 87 - 93   2002.5

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    3-Nitrotyrosine (3-NT), a product of peroxynitrite reaction, is abundantly observed in hepatocytes adjacent to human metastatic colorectal carcinoma. To elucidate its biological significance, we undertook to identify nitric oxide (NO)-producing cells and apoptosis under oxidative stress. We observed strong inducible NO-synthase (iNOS) immunoreactivity in the hepatocytes adjacent to metastatic tumor, revealing an identical pattern to 3-NT immunostaining. Furthermore, intense 3-NT immunostaining of hepatocytes was associated with apoptosis whereas carcinoma cells near those hepatocytes presented high proliferating-cell nuclear antigen. Our results suggest that contact of metastatic tumor induces apoptosis in adjacent hepatocytes through peroxynitrite, thus permitting the proliferation of cancer cells.

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  809. Isolation and characterization of annexin 2 pseudogene in Rattus norvegicus

    Ozeki M, Hoshino S, Hiai H, Toyokuni S

    GENE   Vol. 289 ( 1-2 ) page: 185 - 190   2002.5

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  810. Isolation and characterization of annexin 2 pseudogene in Rattus norvegicus.

    Ozeki M, Hoshino S, Hiai H, Toyokuni S

    Gene   Vol. 289 ( 1-2 ) page: 185 - 90   2002.5

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    Annexin 2 is a calcium-regulated, phospholipid-binding protein present in endothelial cells, macrophages and some tumor cells. Annexin 2 is a substrate for a variety of protein kinases, and plays roles in the regulation of endocytosis, exocytosis and thrombolysis. We have determined the nucleotide sequence of a rat genomic DNA fragment that hybridized to a rat annexin 2 DNA complementary to RNA (cDNA) probe. Sequence analysis revealed that it was an intronless rat annexin 2, consisting of a start-to-stop-codon-length copy of the processed transcript. This pseudogene contained 33 point mutations and two deletion sites in the coding region as compared with the cDNA, and thus displayed typical features of a retroposon. Transitions were more frequent than transversions, and the most frequent type of mutation was G to A transition. We isolated a phage clone that contained a functional rat annexin 2 genomic fragment including coding exons 3 and 4. Polymerase chain reaction and subsequent sequence analysis revealed an intron of approximately 4 kbp at the same site as in humans and mice. Whereas the annexin 2 gene or its cDNA homologues have been detected in various species from Xenopus to humans, its pseudogene has been reported only in humans. In the present study, we demonstrated the presence of an annexin 2 pseudogene in rats. © 2002 Elsevier Science B.V. All rights reserved.

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  811. Isolation and characterization of annexin 2 pseudogene in Rattus norvegicus. International journal

    Munetaka Ozeki, Shinsuke Hoshino, Hiroshi Hiai, Shinya Toyokuni

    Gene   Vol. 289 ( 1-2 ) page: 185 - 90   2002.5

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    Annexin 2 is a calcium-regulated, phospholipid-binding protein present in endothelial cells, macrophages and some tumor cells. Annexin 2 is a substrate for a variety of protein kinases, and plays roles in the regulation of endocytosis, exocytosis and thrombolysis. We have determined the nucleotide sequence of a rat genomic DNA fragment that hybridized to a rat annexin 2 DNA complementary to RNA (cDNA) probe. Sequence analysis revealed that it was an intronless rat annexin 2, consisting of a start-to-stop-codon-length copy of the processed transcript. This pseudogene contained 33 point mutations and two deletion sites in the coding region as compared with the cDNA, and thus displayed typical features of a retroposon. Transitions were more frequent than transversions, and the most frequent type of mutation was G to A transition. We isolated a phage clone that contained a functional rat annexin 2 genomic fragment including coding exons 3 and 4. Polymerase chain reaction and subsequent sequence analysis revealed an intron of approximately 4 kbp at the same site as in humans and mice. Whereas the annexin 2 gene or its cDNA homologues have been detected in various species from Xenopus to humans, its pseudogene has been reported only in humans. In the present study, we demonstrated the presence of an annexin 2 pseudogene in rats.

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  812. Hepatocyte nuclear factor-1 alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter

    Ban N, Yamada Y, Someya Y, Miyawaki K, Ihara Y, Hosokawa M, Toyokuni S, Tsuda K, Seino Y

    DIABETES   Vol. 51 ( 5 ) page: 1409 - 1418   2002.5

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  813. Inhibitory effect of a novel water-soluble vitamin E derivative on atherosclerosis in rabbits

    Yoshida N, Murase H, Kunieda T, Toyokuni S, Tanaka T, Terao J, Naito Y, Tanigawa T, Yoshikawa T

    ATHEROSCLEROSIS   Vol. 162 ( 1 ) page: 111 - 117   2002.5

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  814. Protective effect of colored rice over white rice on Fenton reaction-based renal lipid peroxidation in rats. International journal

    Shinya Toyokuni, Tomio Itani, Yasujiro Morimitsu, Kunihiko Okada, Munetaka Ozeki, Shohei Kondo, Koji Uchida, Toshihiko Osawa, Hiroshi Hiai, Toru Tashiro

    Free radical research   Vol. 36 ( 5 ) page: 583 - 92   2002.5

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    Rice has been one of the most important grains. While polished white rice is favored, colored strains of rice, red, or black, have been maintained for religious purposes in Japan. We studied whether feeding of unpolished colored rice instead of white rice ameliorates oxidative renal tubular damage in rats induced by ferric nitrilotriacetate. Whereas renal lipid peroxidation was exacerbated in white rice-fed group in comparison with standard chow group, this exacerbation was not observed in red or black rice-fed groups. These changes were dependent on the proportion of colored rice to standard chow in the diet. Cyanidin 3-O-beta-D-glucoside was detectable neither in the serum nor kidney after one week of colored rice diet, but serum protocatechuic acid was significantly increased after black rice diet. There was a generalized decrease in the renal glutathione peroxidase activity in rice diet groups. Renal enzymatic activities of superoxide dismutase, glutathione S-transferase and NAD(P)H quinone reductase were not associated with the levels of lipid peroxidation. However, renal catalase activity was significantly increased in black rice-fed groups. These may partly explain the antioxidative effect. Furthermore, colored strains of rice are rich in proteins. Thus, our data warrants further investigation of the antioxidative effect of colored rice.

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  815. Protective effect of colored rice over white rice on Fenton reaction-based renal lipid peroxidation in rats

    Toyokuni S, Itani T, Morimitsu Y, Okada K, Ozeki M, Kondo S, Uchida K, Osawa T, Hiai H, Tashiro T

    FREE RADICAL RESEARCH   Vol. 36 ( 5 ) page: 583 - 592   2002.5

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    Rice has been one of the most important grains. While polished white rice is favored, colored strains of rice, red, or black, have been maintained for religious purposes in Japan. We studied whether feeding of unpolished colored rice instead of white rice ameliorates oxidative renal tubular damage in rats induced by ferric nitrilotriacetate. Whereas renal lipid peroxidation was exacerbated in white rice-fed group in comparison with standard chow group, this exacerbation was not observed in red or black rice-fed groups. These changes were dependent on the proportion of colored rice to standard chow in the diet. Cyanidin 3-O-β-D-glucoside was detectable neither in the serum nor kidney after one week of colored rice diet, but serum protocatechuic acid was significantly increased after black rice diet. There was a generalized decrease in the renal glutathione peroxidase activity in rice diet groups. Renal enzymatic activities of superoxide dismutase, glutathione S-transferase and NAD(P)H quinone reductase were not associated with the levels of lipid peroxidation. However, renal catalase activity was significantly increased in black rice-fed groups. These may partly explain the antioxidative effect. Furthermore, colored strains of rice are rich in proteins. Thus, our data warrants further investigation of the antioxidative effect of colored rice.

    DOI: 10.1080/10715760290025960

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  816. Inhibitory effect of a novel water-soluble vitamin E derivative on atherosclerosis in rabbits.

    Yoshida N, Murase H, Kunieda T, Toyokuni S, Tanaka T, Terao J, Naito Y, Tanigawa T, Yoshikawa T

    Atherosclerosis   Vol. 162 ( 1 ) page: 111 - 7   2002.5

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    A novel vitamin E derivative that is freely soluble in water, 2-(α-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), was evaluated for ability to inhibit development of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits or cholesterol-loaded New Zealand White rabbits. Although TMG rapidly entered the circulation blood after oral administration, the blood TMG concentration remained low, while neither TMG nor its metabolites appeared in the low-density lipoprotein (LDL) fraction. TMG did not decrease serum total cholesterol and the various lipoprotein-associated cholesterol fractions (very LDL-, or high-density lipoprotein- (HDL) cholesterol). TMG reduced the serum concentration of thiobarbituric acid-reactive substances (TBARS; an index of lipid peroxidation) in cholesterol-loaded rabbits but not WHHL rabbits. Nonetheless, TMG inhibited aortic atherosclerosis as effectively as probucol in both models. Our results indicate that TMG opposes progression of atherosclerosis not only by preventing oxidation of LDL, but also by presently unknown mechanisms. Even an antioxidant with no uptake by LDL apparently can inhibit development of atherosclerosis despite a very low serum concentration. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/s0021-9150(01)00702-x

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  817. Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter. International journal

    Nobuhiro Ban, Yuichiro Yamada, Yoshimichi Someya, Kazumasa Miyawaki, Yu Ihara, Masaya Hosokawa, Shinya Toyokuni, Kinsuke Tsuda, Yutaka Seino

    Diabetes   Vol. 51 ( 5 ) page: 1409 - 18   2002.5

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    Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene have been linked to subtype 3 of maturity-onset diabetes of the young (MODY), a disease characterized by a primary defect in insulin secretion. Here we show that the human GLUT2 gene is closely regulated by HNF-1alpha via sequences downstream of the transcriptional start site by interaction with transcriptional co-activator p300. The promoter region of the human GLUT2 gene was subcloned into luciferase expression plasmids that were transfected together with HNF-1alpha expression plasmid into a pancreatic beta-cell line, HIT-T15, to evaluate transcriptional activities. HNF-1alpha enhanced human GLUT2 promoter activity sixfold. Site-direct mutagenesis and footprint analyses showed that the HNF-1alpha binding site (+200 to +218) is critical in human GLUT2 gene expression. Furthermore, mammalian two-hybrid and immunoprecipitation studies revealed the transactivation domain of HNF-1alpha (amino acids 391-540) to interact with both the NH(2)-terminal region (amino acids 180-662) and the COOH-terminal region (amino acids 1,818-2,079) of p300. These findings demonstrated that HNF-1alpha binds to the 5'-untranslated region of GLUT2 and that p300 acts as a transcriptional co-activator for HNF-1alpha. In addition, these results provided new insight into the regulatory function of HNF-1alpha by suggesting a molecular basis for human GLUT2 gene expression.

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  818. Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter.

    Ban N, Yamada Y, Someya Y, Miyawaki K, Ihara Y, Hosokawa M, Toyokuni S, Tsuda K, Seino Y

    Diabetes   Vol. 51 ( 5 ) page: 1409 - 18   2002.5

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    Mutations in the hepatocyte nuclear factor (HNF)-1α gene have been linked to subtype 3 of maturity-onset diabetes of the young (MODY), a disease characterized by a primary defect in insulin secretion. Here we show that the human GLUT2 gene is closely regulated by HNF-1α via sequences downstream of the transcriptional start site by interaction with transcriptional co-activator p300. The promoter region of the human GLUT2 gene was subcloned into luciferase expression plasmids that were transfected together with HNF-1α expression plasmid into a pancreatic β-cell line, HIT-T15, to evaluate transcriptional activities. HNF-1α enhanced human GLUT2 promoter activity sixfold. Site-direct mutagenesis and footprint analyses showed that the HNF-1α binding site (+200 to +218) is critical in human GLUT2 gene expression. Furthermore, mammalian two-hybrid and immunoprecipitation studies revealed the transactivation domain of HNF-1α (amino acids 391-540) to interact with both the NH2-terminal region (amino acids 180-662) and the COOH-terminal region (amino acids 1,818-2,079) of p300. These findings demonstrated that HNF-1α binds to the 5′-untranslated region of GLUT2 and that p300 acts as a transcriptional co-activator for HNF-1α. In addition, these results provided new insight into the regulatory function of HNF-1α by suggesting a molecular basis for human GLUT2 gene expression.

    DOI: 10.2337/diabetes.51.5.1409

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  819. Inhibitory effect of a novel water-soluble vitamin E derivative on atherosclerosis in rabbits. International journal

    Norimasa Yoshida, Hironobu Murase, Tsutomu Kunieda, Shinya Toyokuni, Tomoyuki Tanaka, Junji Terao, Yuji Naito, Toru Tanigawa, Toshikazu Yoshikawa

    Atherosclerosis   Vol. 162 ( 1 ) page: 111 - 7   2002.5

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    A novel vitamin E derivative that is freely soluble in water, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), was evaluated for ability to inhibit development of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits or cholesterol-loaded New Zealand White rabbits. Although TMG rapidly entered the circulation blood after oral administration, the blood TMG concentration remained low, while neither TMG nor its metabolites appeared in the low-density lipoprotein (LDL) fraction. TMG did not decrease serum total cholesterol and the various lipoprotein-associated cholesterol fractions (very LDL-, or high-density lipoprotein- (HDL) cholesterol). TMG reduced the serum concentration of thiobarbituric acid-reactive substances (TBARS; an index of lipid peroxidation) in cholesterol-loaded rabbits but not WHHL rabbits. Nonetheless, TMG inhibited aortic atherosclerosis as effectively as probucol in both models. Our results indicate that TMG opposes progression of atherosclerosis not only by preventing oxidation of LDL, but also by presently unknown mechanisms. Even an antioxidant with no uptake by LDL apparently can inhibit development of atherosclerosis despite a very low serum concentration.

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  820. Increase in oxidative stress in kidneys of diabetic Akita mice Reviewed International journal

    Ueno Y, Horio F, Uchida K, Naito M, Nomura H, Kato Y, Tsuda T, Toyokuni S, Osawa T

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY   Vol. 66 ( 4 ) page: 869 - 872   2002.4

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  821. Increase in Oxidative Stress in Kidneys of Diabetic Akita Mice. International journal

    UENO Yuki, HORIO Fumihiko, UCHIDA Koji, NAITO Michitaka, NOMURA Hideki, KATO Yoji, TSUDA Takanori, TOYOKUNI Shinya, OSAWA Toshihiko

    Bioscience, Biotechnology, and Biochemistry   Vol. 66 ( 4 ) page: 869 - 72   2002.4

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      New biomarkers for oxidative damage, were used to identify whether hyperglycemia caused oxidative stress in diabetic Akita mice. At 13 weeks of age, the tissues of these mice were obtained, and the levels of <i>N</i><sup>ε</sup>-(hexanonyl)lysine (HEL) and dityrosine (DT) were measured, these being related to lipid peroxide-derived protein covalent modification and protein cross-linking. The levels of HEL and DT in the kidneys of Akita mice were significantly increased compared with the control mice without any accumulation of thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified protein. Immunopositive staining was clearly observed in the kidneys of the Akita mice when using the anti-HEL antibody or anti-DT antibody. These results suggest that hyperglycemia in Akita mice induced oxidative stress and increased these markers in the kidneys.<br>

    DOI: 10.1271/bbb.66.869

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  822. Increase in oxidative stress in kidneys of diabetic Akita mice Reviewed International journal

    Ueno Y, Horio F, Uchida K, Naito M, Nomura H, Kato Y, Tsuda T, Toyokuni S, Osawa T

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY   Vol. 66 ( 4 ) page: 869 - 872   2002.4

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  823. Analysis of suspicious endometrial cytology : based on architectural atypia

    SHIMIZU Keiko, OGURA Seiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, NORIMATU Yoshiaki, MORIYA Takuya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 41 ( 2 ) page: 89 - 97   2002.3

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  824. Analysis of suspicious endometrial cytology : based on architectural atypia

    SHIMIZU Keiko, OGURA Seiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, NORIMATU Yoshiaki, MORIYA Takuya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 41 ( 2 ) page: 89 - 97   2002.3

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  825. Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice. Reviewed International journal

    Mito Kanatsu-Shinohara, Atsuo Ogura, Masaya Ikegawa, Kimiko Inoue, Narumi Ogonuki, Kei Tashiro, Shinya Toyokuni, Tasuku Honjo, Takashi Shinohara

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 99 ( 3 ) page: 1383 - 8   2002.2

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    Sertoli cells play a pivotal role in spermatogenesis through their interactions with germ cells. To set up a strategy for treating male infertility caused by Sertoli cell dysfunction, we developed a Sertoli cell gene transfer system by using an adenovirus vector, which maintained long-term transgene expression in the testes of infertile mice. Introduction of an adenovirus carrying the mouse Steel (Sl) gene into Sertoli cells restored partial spermatogenesis in infertile Steel/Steel(dickie) (Sl/Sl(d)) mutant mouse testes. Although these males remained infertile, round spermatids and spermatozoa from the testes produced normal fertile offspring after intracytoplasmic injection into oocytes. None of the offspring showed evidence of germ line transmission of adenoviral DNA. Thus, we demonstrate a successful treatment for infertility by using a gene therapy vector. Therefore, adenovirus-mediated gene delivery into Sertoli cells not only provides an efficient and convenient means for studying germ cell-Sertoli cell interactions through manipulation of the germ cell microenvironment in vivo, but also is a useful method to treat male infertility resulting from a Sertoli cell defect.

    DOI: 10.1073/pnas.022646399

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  826. Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice

    Kanatsu-Shinohara M, Ogura A, Ikegawa M, Inoue K, Ogonuki N, Tashiro K, Toyokuni S, Honjo T, Shinohara T

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 99 ( 3 ) page: 1383 - 1388   2002.2

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  827. Specific allelic loss of p16(INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis

    Hiroyasu M, Ozeki M, Kohda H, Echizenya M, Tanaka T, Hiai H, Toyokuni S

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 160 ( 2 ) page: 419 - 424   2002.2

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  828. Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis

    Jikimoto T, Nishikubo Y, Koshiba M, Kanagawa S, Morinobu S, Morinobu A, Saura R, Mizuno K, Kondo S, Toyokuni S, Nakamura H, Yodoi J, Kumagai S

    MOLECULAR IMMUNOLOGY   Vol. 38 ( 10 ) page: 765 - 772   2002.2

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  829. Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis.

    Jikimoto T, Nishikubo Y, Koshiba M, Kanagawa S, Morinobu S, Morinobu A, Saura R, Mizuno K, Kondo S, Toyokuni S, Nakamura H, Yodoi J, Kumagai S

    Molecular immunology   Vol. 38 ( 10 ) page: 765 - 72   2002.2

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    There is no doubt that oxidative stress occurs in patients with rheumatoid arthritis (RA) and play an important role in both inflammation and destruction of RA joints. Thioredoxin (TRX) is a ubiquitous redox-active protein and is known to be induced in several cells against oxidative stress and to be secreted extracellularly. To clarify whether plasma thioredoxin levels could be a marker for oxidative stress in patients with RA, we measured plasma TRX levels in patients with RA using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) and investigated its relationship to TRX concentrations in the inflammatory joints. We have found that the plasma TRX levels of RA patients were significantly higher than those of normal subjects (86.8 ± 54.1 ng/ml versus 38.6 ± 18.5 ng/ml, P <0.0001). The plasma levels were correlated with the disease activity of RA and also with serum C-reactive protein (CRP) values (P <0.01). The concentration of TRX in synovial fluid (SF) from RA was 353.3 ± 220.1 ng/ml (mean ± S.D.) which was significantly higher than that in SF from osteoarthritis patients (70.6 ± 31.0 ng/ml, P <0.0001). The SF TRX concentration was significantly correlated with the number of leukocytes infiltrating in SF and with the serum CRP levels. The serum TRX levels were significantly positively correlated with the SF TRX concentrations in RA patients (P <0.05). By the histological examination for synovial tissue of RA patients, TRX was shown to be present on the surface of synovial lining layer as well as in the leukocytes. Moreover, urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage by endogenously generated oxygen radicals, was significantly higher in RA patients than in healthy subjects (11.55 ± 4.71 versus 7.76 ± 2.26 ng/mg creatinine, P <0.0001). Plasma TRX levels were significantly correlated with urinary excretion of 8-OHdG (P <0.005). We concluded that plasma TRX level is a new biomarker for the disease activity of RA and may reflect higher levels of oxidative stress in RA patients. © 2002 Elsevier Science Ltd. All rights reserved.

    DOI: 10.1016/s0161-5890(01)00113-4

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  830. Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis. International journal

    Takumi Jikimoto, Yuko Nishikubo, Masahiro Koshiba, Sugayo Kanagawa, Sahoko Morinobu, Akio Morinobu, Ryuichi Saura, Kosaku Mizuno, Shohei Kondo, Shinya Toyokuni, Hajime Nakamura, Junji Yodoi, Shunichi Kumagai

    Molecular immunology   Vol. 38 ( 10 ) page: 765 - 72   2002.2

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    There is no doubt that oxidative stress occurs in patients with rheumatoid arthritis (RA) and play an important role in both inflammation and destruction of RA joints. Thioredoxin (TRX) is a ubiquitous redox-active protein and is known to be induced in several cells against oxidative stress and to be secreted extracellularly. To clarify whether plasma thioredoxin levels could be a marker for oxidative stress in patients with RA, we measured plasma TRX levels in patients with RA using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) and investigated its relationship to TRX concentrations in the inflammatory joints. We have found that the plasma TRX levels of RA patients were significantly higher than those of normal subjects (86.8 +/-54.1 ng/ml versus 38.6 +/-18.5 ng/ml, P<0.0001). The plasma levels were correlated with the disease activity of RA and also with serum C-reactive protein (CRP) values (P<0.01). The concentration of TRX in synovial fluid (SF) from RA was 353.3 +/- 220.1 ng/ml (mean +/- S.D.) which was significantly higher than that in SF from osteoarthritis patients (70.6 +/- 31.0 ng/ml, P<0.0001). The SF TRX concentration was significantly correlated with the number of leukocytes infiltrating in SF and with the serum CRP levels. The serum TRX levels were significantly positively correlated with the SF TRX concentrations in RA patients (P<0.05). By the histological examination for synovial tissue of RA patients, TRX was shown to be present on the surface of synovial lining layer as well as in the leukocytes.Moreover, urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage by endogenously generated oxygen radicals, was significantly higher in RA patients than in healthy subjects (11.55 +/- 4.71 versus 7.76 +/- 2.26 ng/mg creatinine, P<0.0001). Plasma TRX levels were significantly correlated with urinary excretion of 8-OHdG (P<0.005). We concluded that plasma TRX level is a new biomarker for the disease activity of RA and may reflect higher levels of oxidative stress in RA patients.

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  831. Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis.

    Hiroyasu M, Ozeki M, Kohda H, Echizenya M, Tanaka T, Hiai H, Toyokuni S

    The American journal of pathology   Vol. 160 ( 2 ) page: 419 - 24   2002.2

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    Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16INK4A is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16INK4A. By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the p16INK4A locus was significantly and specifically increased (1 week, 37.2 ± 2.3%; 3 weeks, 37.8 ± 1.3% vs control, 22.5 ± 1.9%; mean ± SE, N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16INK4A locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.

    DOI: 10.1016/S0002-9440(10)64860-2

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  832. Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis. International journal

    Makoto Hiroyasu, Munetaka Ozeki, Haruyasu Kohda, Michiko Echizenya, Tomoyuki Tanaka, Hiroshi Hiai, Shinya Toyokuni

    The American journal of pathology   Vol. 160 ( 2 ) page: 419 - 24   2002.2

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    Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16(INK4A) is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16 (INK4A). By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the p16(INK4A) locus was significantly and specifically increased (1 week, 37.2 +/- 2.3%; 3 weeks, 37.8 +/- 1.3% vs control, 22.5 +/- 1.9%; mean +/- SE, N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16 (INK4A) locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.

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  833. Heat shock preconditioning reduces the formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal modified proteins in ischemia-reperfused liver of rats. Reviewed International journal

    Kazuhiko Yamagami, Yuzo Yamamoto, Shinya Toyokuni, Koichiro Hata, Yoshio Yamaoka

    Free radical research   Vol. 36 ( 2 ) page: 169 - 176   2002.2

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    Heat shock preconditioning (HSPC) is a promising strategy for providing ischemic tolerance. The objective of this study is to investigate the effectiveness of HSPC in preventing oxidative damage of cellular proteins and DNA during ischemia-reperfusion of the liver. Male Wistar rats were divided into a heat shock group (group HS) and control (group C). Forty-eight hours prior to ischemia, rats in group HS received HSPC at 42degreesC for 15 min. All rats received hepatic warm ischemia for 30 min and subsequent reperfusion. The formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE) modified proteins in liver tissue, survival rate of the animals, and changes in biochemical and histological parameters were compared between groups. Heat shock protein 72 was produced only in group HS. The 7-day survival of rats was significantly better in group HS (10/10) than in group C (5/10) (p&lt;0.01). The serum release of alanine aminotransferase (n=10, p&lt;0.01) and the concentration of adenosine triphosphate in liver tissue (n=10, p&lt;0.01) 40 min after reperfusion was significantly better in group HS than in group C. The formation of 8-OHdG in liver tissue measured by high-performance liquid chromatography was suppressed in group HS (p&lt;0.01). The production of HNE-modified proteins as determined by Western-blot analysis was also decreased in group HS. These results were also confirmed by immunohistochemical analysis. As determined by levels of 8-OHdG and HNE-modified proteins produced during ischemia-reperfusion of the liver, HSPC reduced the oxidative injury of cellular proteins and DNA in the liver tissue.

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  834. Amelioration of cisplatin toxicity by a fermented grain food product

    Minamiyama Y, Takemura S, Toyokuni S, Nishino Y, Yamasaki K, Hai S, Yamamoto S, Okada S

    BIOFACTORS   Vol. 16 ( 3-4 ) page: 105 - 115   2002

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  835. Iron and carcinogenesis: from Fenton reaction to target genes. International journal

    Shinya Toyokuni

    Redox report : communications in free radical research   Vol. 7 ( 4 ) page: 189 - 197   2002

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    Reactive oxygen species (ROS) have been shown to be associated with a wide variety of pathological phenomena such as carcinogenesis, inflammation, radiation and reperfusion injury. Iron, the most abundant transition metal ion in our body, may work as a catalyst for the generation of ROS in pathological conditions. In the past few years, there have been great advances in the understanding of iron metabolism. These include the discoveries of iron transporters and the gene responsible for hereditary hemochromatosis. Iron overload has been shown to be associated with carcinogenesis. We recently identified the major target genes (p16(INK4A) and p15(INK4B) tumor suppressor genes, which encode cyclin-dependent kinase inhibitors) in a ferric nitrilotriacetate-induced rat renal carcinogenesis model, in which the Fenton reaction is induced in the renal proximal tubules. Allelic loss of the p16 gene occurs early in carcinogenesis and specifically at the p16 loci as compared with other tumor suppressor genes. This led to the novel concept of 'genomic sites vulnerable to the Fenton reaction'. Here, recent new findings on iron metabolism are reviewed and the concept of the vulnerable sites explored. More effort to link iron metabolism with human carcinogenesis is anticipated.

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  836. Radiation-induced kidney injury: a role for chronic oxidative stress?

    Robbins MEC, Zhao WL, Davis CS, Toyokuni S, Bonsib SM

    MICRON   Vol. 33 ( 2 ) page: 133 - 141   2002

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  837. Target genes in fenton reaction-induced carcinogenisis: A novel concept

    Toyokuni, S; Hiroyasu, M; Ozeki, M; Hiai, H

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 33   page: S177 - S177   2002

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  838. Target genes in Fenton reaction-induced carcinogenesis: A novel concept

    Toyokuni, S; Hiroyasu, M; Ozeki, M; Hiai, H

    XI BIENNIAL MEETING OF THE SOCIETY FOR FREE RADICAL RESEARCH INTERNATIONAL     page: 459 - 462   2002

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  839. Novel surrogate end-point biomarker to evaluate agents for use in the chemoprevention of reactive oxygen species-associated cancer. Reviewed International journal

    Makoto Hiroyasu, Munetaka Ozeki, Aya Miyagawa-Hayashino, Yoshie Fujiwara, Hiroshi Hiai, Shinya Toyokuni

    Redox report : communications in free radical research   Vol. 7 ( 5 ) page: 335 - 338   2002

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    Cancer chemoprevention is the use of chemical agents to inhibit, delay or reverse carcinogenesis. We established a novel method to evaluate agents for use in the chemoprevention of reactive oxygen species (ROS)-associated cancer. Induction of renal cell carcinoma in rats by ferric nitrilotriacetate (Fe-NTA) is an established model of ROS-associated cancer. We recently identified the p16INK4A tumor suppressor gene as one of the major target genes in this model, and showed by the use of in situ hybridization that allelic loss of p16IK4A occurs in the increased fraction of renal tubular cells within a few weeks. In the present study, we tested whether diets including green tea powder or a processed grain food are effective chemopreventive agents in this animal model. Consumption of these modified diets led to a significant decrease in the fraction of aneuploid cells after 1 week of repeated Fe-NTA administration. A decrease in renal lipid peroxidation after a single administration of Fe-NTA was also observed. Therefore, intake of green tea or processed grain foods stabilizes p16INK4A in the genome, at least in this model, and might be helpful for the prevention of ROS-associated cancer. This novel method is versatile, and may work as a surrogate end-point biomarker for screening the usefulness of agents for cancer chemoprevention.

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  840. Analysis of suspicious endometrial cytology. Based on architectural atypia.:based on architectural atypia

    SHIMIZU Keiko, OGURA Seiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, NORIMATSU Yoshiaki, MORIYA Takuya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 41 ( 2 ) page: 89 - 94   2002

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    <B><I>Objective</I>:</B> To increase the accuracy of endometrial cytology, we evaluated the use of architectural atypia as a possible diagnostic criterion and the use of cell culture medium to decrease the frequency of insufficient materials.<BR><B><I>Study Design</I>:</B> We selected 84 cytologically suspicious cases for which histological diagnoses were available, dividing them into 2 groups-51 in group A diagnosed with cellular atypia, and 33 in group B with architectural atypia and an additional washing smear.<BR><B><I>Results</I>:</B> Histological findings of group A cases showed 23 (45.1%) that were benign, 21 (41.2%) with endometrial hyperplasia, and 7 (13.7%) with endometrioid adenocarcinoma, grade 1. In group B, 11 (33.3%) cases were benign, 21 (63.7%) were endometrial hyperplasia, and 1 (3.0%) was endometrioid adenocarcinoma, grade 1. The percentage of cases with insufficient material for diagnosis was 32.9% in group A and 20.0% in group B.<BR><B><I>Conclusion</I>:</B> Focusing on architectural atypia effectively raises the accuracy of endometrial cytological diagnosis for endometrial hyperplasia. The additional washing smear was useful in endometrial cytology.

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  841. Target genes in fenton reaction-induced carcinogenisis: A novel concept

    Toyokuni S, Hiroyasu M, Ozeki M, Hiai H

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 33   page: S177 - S177   2002

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  842. Radiation-induced kidney injury: a role for chronic oxidative stress? International journal

    Mike E Robbins, Weiling Zhao, Charles S Davis, Shinya Toyokuni, Stephen M Bonsib

    Micron (Oxford, England : 1993)   Vol. 33 ( 2 ) page: 133 - 41   2002

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    Kidney irradiation clearly leads to a progressive reduction in function associated with concomitant glomerulosclerosis and/or tubulointerstitial fibrosis. However, the particular cell types, mediators and/or mechanisms involved in the development and progression of radiation nephropathy remain ill defined. Angiotensin II (Ang II) plays a major pathogenic role; administration of Ang II blockers markedly abrogates the severity of radiation nephropathy in experimental models. Both ionizing radiation and Ang II signal via generation of reactive oxygen species (ROS). Thus, we hypothesized that localized kidney irradiation might lead to a chronic oxidative stress. In view of the difficulty in measuring ROS in vivo we adopted an indirect immunohistochemical approach in which we used a monoclonal antibody specific for 8-hydroxy-2'-deoxyguanosine (8-OHdG), one of the most commonly used markers of DNA oxidation. The right kidney of 7-8 week-old male Sprague-Dawley rats was removed. Five to 6 weeks later the remaining hypertrophied kidney was irradiated with single doses of 0-20.0 Gy X-rays. Groups of rats, three per dose, were killed at 4, 8, 16 and 24 weeks post-irradiation, their kidneys fixed, and sections stained with the 8-OHdG-specific antibody N45.1. For quantitation of glomerular DNA oxidation with the N45.1 antibody stained sections, 50 glomeruli/animal were counted. The presence of any intensely stained nuclei within the glomerular tuft was scored as positive. Quantitation of tubular DNA oxidation employed a 10 x 10 point ocular grid. Sections were examined at 400 magnification; 250 tubular profiles were counted. All tubules with any nuclear staining were scored as positive.Sham-irradiated kidneys showed little evidence of DNA oxidation over the experimental period. In contrast, localized kidney irradiation led to a marked, dose-independent increase in glomerular and tubular cell nuclear DNA oxidation. This increase was evident at the first time point studied, i.e. 4 weeks after irradiation, and persisted for up to 24 weeks postirradiation. DNA oxidation in the irradiated kidney was only seen in apparently viable glomerular and tubular cells. Thus, while from 16 to 24 weeks post-irradiation structural alterations had progressed to glomerular sclerosis and tubular atrophy, positive staining for 8-OHdG was not observed in severely atrophic tubules. Similarly, fewer positive staining cells were noted in glomeruli undergoing sclerosis, while none were seen in totally sclerotic glomeruli. These data support the hypothesis that renal irradiation is associated with a chronic and persistent oxidative stress.

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  843. Radiation-induced kidney injury: a role for chronic oxidative stress?

    Robbins ME, Zhao W, Davis CS, Toyokuni S, Bonsib SM

    Micron (Oxford, England : 1993)   Vol. 33 ( 2 ) page: 133 - 41   2002

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    Kidney irradiation clearly leads to a progressive reduction in function associated with concomitant glomerulosclerosis and/or tubulointerstitial fibrosis. However, the particular cell types, mediators and/or mechanisms involved in the development and progression of radiation nephropathy remain ill defined. Angiotensin II (Ang II) plays a major pathogenic role; administration of Ang II blockers markedly abrogates the severity of radiation nephropathy in experimental models. Both ionizing radiation and Ang II signal via generation of reactive oxygen species (ROS). Thus, we hypothesized that localized kidney irradiation might lead to a chronic oxidative stress. In view of the difficulty in measuring ROS in vivo we adopted an indirect immunohistochemical approach in which we used a monoclonal antibody specific for 8hydroxy-2′-deoxyguanosine (8-OHdG), one of the most commonly used markers of DNA oxidation. The right kidney of 7-8 week-old male Sprague-Dawley rats was removed. Five to 6 weeks later the remaining hypertrophied kidney was irradiated with single doses of 0-20.0 Gy X-rays. Groups of rats, three per dose, were killed at 4, 8, 16 and 24 weeks post-irradiation, their kidneys fixed, and sections stained with the 8-OHdG-specific antibody N45.1. For quantitation of glomerular DNA oxidation with the N45.1 antibody stained sections, 50 glomeruli/animal were counted. The presence of any intensely stained nuclei within the glomerular tuft was scored as positive. Quantitation of tubular DNA oxidation employed a 10 × 10 point ocular grid. Sections were examined at 400 magnification; 250 tubular profiles were counted. All tubules with any nuclear staining were scored as positive. Sham-irradiated kidneys showed little evidence of DNA oxidation over the experimental period. In contrast, localized kidney irradiation led to a marked, dose-independent increase in glomerular and tubular cell nuclear DNA oxidation. This increase was evident at the first time point studied, i.e. 4 weeks after irradiation, and persisted for up to 24 weeks postirradiation. DNA oxidation in the irradiated kidney was only seen in apparently viable glomerular and tubular cells. Thus, while from 16 to 24 weeks post-irradiation structural alterations had progressed to glomerular sclerosis and tubular atrophy, positive staining for 8-OHdG was not observed in severely atrophic tubules. Similarly, fewer positive staining cells were noted in glomeruli undergoing sclerosis, while none were seen in totally sclerotic glomeruli. These data support the hypothesis that renal irradiation is associated with a chronic and persistent oxidative stress. © 2001 Elsevier Science Ltd. All rights reserved.

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  844. Target genes in Fenton reaction-induced carcinogenesis: A novel concept

    Toyokuni S, Hiroyasu M, Ozeki M, Hiai H

    XI BIENNIAL MEETING OF THE SOCIETY FOR FREE RADICAL RESEARCH INTERNATIONAL     page: 459 - 462   2002

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  845. Comparison between high-performance liquid chromatography and enzyme-linked immunosorbent assay for the determination of 8-hydroxy-2′-deoxyguanosine in human urine

    Shimoi K., Kasai H., Yokota N., Toyokuni S., Kinae N.

    Cancer Epidemiology Biomarkers and Prevention   Vol. 11 ( 8 ) page: 767 - 770   2002

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    8-Hydroxy-2′-deoxyguanosine (8-OH-dG), which has been regarded as a potential marker of oxidative DNA damage induced by reactive oxygen species, was measured in human urine by a commercial ELISA using a monoclonal antibody N45.1 and by high-performance liquid chromatography (HPLC) coupled to an electrochemical detector (HPLCECD) to evaluate whether the ELISA system is applicable to human monitoring studies. The urine samples were collected from 120 healthy men ages 18-58 in a steel-manufacturing company. A good correlation (r = 0.833; P < 0.0001) was observed between the two methods on HPLC-purified 8- OH-dG fractions from 23 urine samples. The mean value (±SD) of 8-OH-dG (μg/g creatinine) was 5.47 (±2.97) by HPLC-ECD assay and 5.50 (±2.36) by ELISA. However, the correlation (r) between the two methods on 120 original urine samples was 0.460 [P < 0.001; mean value (±SD) of 8-OH-dG (μg/g creatinine) was 4.46 (±2.03) by the HPLC assay and 9.33 (±3.23) by ELISA]. ELISA estimates were about 2-fold higher than the HPLC estimates on original urine. For an unknown reason, 10% of the urine samples showed more than a 4-fold increase in value by ELISA. It is suggested that the ELISA system is applicable for comparative human monitoring studies. Prepurification of 'samples is required to determine the absolute value of 8-OH-dG in individual urine samples by ELISA.

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  846. Birth of offspring transplantation of cryopreserved immature testicular pieces and in-vitro microinsemination

    Shinohara, T, Inoue, K, Ogonuki, N, Kanatsu-Shinohara, M, Miki, H, Nakata, K, Kurome, M, Nagashima, H, Toyokuni, S, Kogishi, K, Honjo, T, Ogura, A

    Human Reproduction   Vol. 17   page: 3039-3045 - 3045   2002

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  847. Amelioration of cisplatin toxicity by a fermented grain food product.

    Minamiyama Y, Takemura S, Toyokuni S, Nishino Y, Yamasaki K, Hai S, Yamamoto S, Okada S

    BioFactors (Oxford, England)   Vol. 16 ( 3-4 ) page: 105 - 15   2002

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    The most noticeable hypothesis regarding the pathogenesis of cisplatin toxicity, seen mainly in kidney and intestine, is oxidative stress, an imbalance between free-radical generating cisplatin and radical scavenging systems. This paper describes the role of the antioxidant system in cisplatin-induced toxicity and the protective effect by a processed grain food (Antioxidant Biofactor: AOB®), which has been shown to exhibit strong antioxidant activity. Male Fischer 344 rats were used. They were pre-fed either a basal diet (control, 15 g/day) or the diet supplemented with AOB® to provide 6.5% or 20% of total diet throughout the experiment. Cisplatin (5 mg/kg, i.v.) was administered at the start of the experiment, and the animals were sacrificed 5 days later. Blood urea nitrogen (BUN) and plasma creatinine, NO2- and NO3- (NOx) were determined from the plasma. The levels of 4-hydroxy-2-nonenal (a lipid peroxidation product), 8-hydroxy-deoxyguanosine (8-OHdG, an oxidatively modified DNA adduct) and nitrotyrosine were histologically analyzed. The cisplatin administration resulted in a loss of body weight and elevations of BUN, serum creatinine and NOx levels, whereas AOB supplement reversed these effects. The severe morphological damages induced in the kidney and intestine by the cisplatin administration were markedly improved in the AOB group. The levels of lipid peroxidation, 8-OHdG, and nitrotyrosine all paralleled the morphological damage. The AOB effect was dose dependent. In conclusion, the present study suggests that certain food additives like AOB may be of benefit against the side effects of cisplatin.

    DOI: 10.1002/biof.5520160306

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  848. Amelioration of cisplatin toxicity by a fermented grain food product. Reviewed International journal

    Yukiko Minamiyama, Shigekazu Takemura, Shinya Toyokuni, Yoshihiro Nishino, Keiichi Yamasaki, Seikan Hai, Satoshi Yamamoto, Shigeru Okada

    BioFactors (Oxford, England)   Vol. 16 ( 3-4 ) page: 105 - 15   2002

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    The most noticeable hypothesis regarding the pathogenesis of cisplatin toxicity, seen mainly in kidney and intestine, is oxidative stress, an imbalance between free-radical generating cisplatin and radical scavenging systems. This paper describes the role of the antioxidant system in cisplatin-induced toxicity and the protective effect by a processed grain food (Antioxidant Biofactor: AOB), which has been shown to exhibit strong antioxidant activity. Male Fischer 344 rats were used. They were pre-fed either a basal diet (control, 15 g/day) or the diet supplemented with AOB to provide 6.5% or 20% of total diet throughout the experiment. Cisplatin (5 mg/kg, i.v.) was administered at the start of the experiment, and the animals were sacrificed 5 days later. Blood urea nitrogen (BUN) and plasma creatinine, NO2(-) and NO3(-) (NOx) were determined from the plasma. The levels of 4-hydroxy-2-nonenal (a lipid peroxidation product), 8-hydroxy-deoxyguanosine (8-OHdG, an oxidatively modified DNA adduct) and nitrotyrosine were histologically analyzed. The cisplatin administration resulted in a loss of body weight and elevations of BUN, serum creatinine and NOx levels, whereas AOB supplement reversed these effects. The severe morphological damages induced in the kidney and intestine by the cisplatin administration were markedly improved in the AOB group. The levels of lipid peroxidation, 8-OHdG, and nitrotyrosine all paralleled the morphological damage. The AOB effect was dose dependent. In conclusion, the present study suggests that certain food additives like AOB may be of benefit against the side effects of cisplatin.

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  849. Target genes in oxystress-induced carcinogenesis and its molecular mechanisms

    TOYOKUNI Shinya

    Environmental mutagen research communications   Vol. 23 ( 3 ) page: 177 - 182   2001.12

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    Oxidative stress has been associated with carcinogenesis. In 1982, our laboratory established an oxys-tress-induced carcinogenesis model of rodent kidney by the use of an iron chelate, ferric nitrilotriacetate. This model is unique in that 1) only carcinoma, not sarcoma, is induced, 2) the induced tumor is of high malignant potential to kill the animal by pulmonary metastasis, peritoneal invasion or rupture of the primary tumor, and, 3) increase in a variety of covalently modified products including 8-oxoguanine, thymine-tyrosine cross-link, 4-hydroxy-2-nonenal and its modified proteins are demonstrated in its early stage. Since in general free radicals are not considered to react with specific target molecules in contrast with immune reaction, we undertook to answer the question whether there is any specific target gene (s) in this carcinogenesis model. By genetically analyzing F_1 hybrid rats, we found two chromosomal areas that showed a high incidence of loss of heterozygosity, which lead to a finding that p15^<INK4B>/p16^<INK4A> tumor suppressor genes are one of the major pathways responsible for this oxystress-induced cancer. Furthermore, by screening 84,000 transcripts by differential display techniques, we found that at least 15 genes associated with stress-response or cellular proliferation are differentially expressed in this model. We believe that not only genetic changes but also epigenetic changes play a role in oxidative stress-induced carcinogenesis.

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  850. Target genes in oxystress-induced carcinogenesis and its molecular mechanisms

    TOYOKUNI Shinya

    Environmental mutagen research communications   Vol. 23 ( 3 ) page: 177 - 182   2001.12

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    Oxidative stress has been associated with carcinogenesis. In 1982, our laboratory established an oxys-tress-induced carcinogenesis model of rodent kidney by the use of an iron chelate, ferric nitrilotriacetate. This model is unique in that 1) only carcinoma, not sarcoma, is induced, 2) the induced tumor is of high malignant potential to kill the animal by pulmonary metastasis, peritoneal invasion or rupture of the primary tumor, and, 3) increase in a variety of covalently modified products including 8-oxoguanine, thymine-tyrosine cross-link, 4-hydroxy-2-nonenal and its modified proteins are demonstrated in its early stage. Since in general free radicals are not considered to react with specific target molecules in contrast with immune reaction, we undertook to answer the question whether there is any specific target gene (s) in this carcinogenesis model. By genetically analyzing F_1 hybrid rats, we found two chromosomal areas that showed a high incidence of loss of heterozygosity, which lead to a finding that p15^<INK4B>/p16^<INK4A> tumor suppressor genes are one of the major pathways responsible for this oxystress-induced cancer. Furthermore, by screening 84,000 transcripts by differential display techniques, we found that at least 15 genes associated with stress-response or cellular proliferation are differentially expressed in this model. We believe that not only genetic changes but also epigenetic changes play a role in oxidative stress-induced carcinogenesis.

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  851. Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes

    Iwai-Kanai E., Hasegawa K., Sawamura T., Fujita M., Yanazume T., Toyokuni S., Adachi S., Kihara Y., Sasayama S.

    Circulation   Vol. 104 ( 24 ) page: 2948 - 2954   2001.12

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    Background - Lectin-like oxidized LDL receptor-1 (LOX-1) was originally identified as a receptor expressed predominantly in endothelial cells. LOX-1 can also be expressed in other cell types, and the activation of the LOX-1 pathway has been implicated in apoptosis. There have been no reports, however, about LOX-1 expression in cardiac myocytes or regulation of myocardial cell apoptosis by LOX-1. Methods and Results - In primary cardiac myocytes from neonatal rats, immunohistochemical analyses using a specific monoclonal antibody against LOX-1 demonstrated that LOX-1 expression was markedly induced by stimulation with norepinephrine and endothelin-1. LOX-1 expression was upregulated in cardiac myocytes as well as in vessel walls of failing rat hearts in vivo. In the presence of a low concentration of oxidized LDL that did not induce apoptosis by itself, artificial overexpression of LOX-1 in cardiac myocytes in culture resulted in apoptosis. LOX-1 overexpression induced activation of p38 mitogen-activated protein kinase (MAPK) and oxidative stress in cardiac myocytes, as demonstrated by an increase in positive immunostaining for 8-hydroxy-2′-deoxyguanosine. Inhibition of p38 MAPK by cotransfection of a dominant-negative form of MKK6 as well as by administration of a specific inhibitor, SB203580 or FR167653, almost completely blocked the induction of apoptosis by LOX-1 activation. Antioxidant catalase also blocked LOX-1-induced apoptosis as well as activation of p38 MAPK. Conclusions - These findings demonstrate that LOX-1 expression in cardiac myocytes is induced by neurohormonal factors activated in heart failure and that LOX-1-dependent apoptosis in these cells requires p38 MAPK, a component of oxidant stress-sensitive signaling pathways.

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  852. Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes

    Iwai-Kanai E, Hasegawa K, Sawamura T, Fujita M, Yanazume T, Toyokuni S, Adachi S, Kihara Y, Sasayama S

    CIRCULATION   Vol. 104 ( 24 ) page: 2948 - 2954   2001.12

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  853. Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes Reviewed

    Iwai-Kanai E, Hasegawa K, Sawamura T, Fujita M, Araki M, Yanazume T, Toyokuni S, Adachi S, Kihara Y, Sasayama S

    Circulation   Vol. 104 ( 24 ) page: 2948 - 2954   2001.12

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  854. A case of cervical adenocarcinoma in situ with difficulty in cytological differentiation from recurrent ovarian tumor of borderline malignancy

    OGURA Seiko, SHIMIZU Keiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 40 ( 6 ) page: 636 - 640   2001.11

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  855. A case of cervical adenocarcinoma in situ with difficulty in cytological differentiation from recurrent ovarian tumor of borderline malignancy

    OGURA Seiko, SHIMIZU Keiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 40 ( 6 ) page: 636 - 640   2001.11

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  856. A novel selectin blocker alleviates oxidative stress of lung reperfusion injury Reviewed International journal

    Yoshimura, T; Kawashima, M; Nakamura, T; Isowa, N; Bando, T; Hasegawa, S; Kondo, H; Toyokuni, S; Wada, H

    JOURNAL OF SURGICAL RESEARCH   Vol. 101 ( 1 ) page: 91 - 98   2001.11

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    Background. The importance of reactive oxygen species released through interaction of leukocyte/endothelial cell in ischemia-reperfusion injury of the lung is not yet fully understood. A novel selectin blocker, OJ-R9188, which inhibits the interaction, may alleviate oxidative stress and pulmonary dysfunction after warm ischemia-reperfusion. Materials and methods. Rat lungs were reperfused at 37°C for 60 min with an ex vivo model and were divided into three groups (n = 10). In the fresh group, lungs were reperfused immediately after harvest. In the OJ-R (-) and OJ-R (+) groups, lungs were reperfused after warm ischemia at 37°C for 90 min. In the OJ-R (+) group, rats received 100 μg per body of OJ-R9188 intravenously 10 min before the harvest. The electron spin resonance method was used to assess the direct scavenging activity of OJ-R9188. Results. Both shunt fractions and wet/dry weight ratios of the lung tissue after reperfusion in the OJ-R (+) group were significantly lower than those in the OJ-R (-) group. Oxidative DNA damage in the alveolar wall of the OJ-R (+) group, assessed by immunohistochemical quantitation of 8-hydroxy-2′-deoxyguanosine, was significantly lower than that of the OJ-R (-) group. Immunostaining of 3-nitro-L-tyrosine, which represents nitric oxide-mediated oxidative damage, was also more intense in the OJ-R (-) group than in the OJ-R (+) group. Direct scavenging activity of OJ-R9188 was not observed, and the number of leukocytes infiltrated to the lung tissue as seen by myeloperoxidase activity was not different between the OJ-R (-) and OJ-R (+) groups. Conclusions. A novel selectin blocker, OJ-R9188, improves pulmonary function after warm ischemia-reperfusion and alleviates reperfusion-induced oxidative alveolar damage. © 2001 Academic Press.

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  857. Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage

    Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K, Bieglmayer C, Kato S, Cross HS

    CARCINOGENESIS   Vol. 22 ( 9 ) page: 1429 - 1435   2001.9

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  858. Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage

    Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K, Bieglmayer C, Kato S, Cross HS

    CARCINOGENESIS   Vol. 22 ( 9 ) page: 1429 - 1435   2001.9

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  859. Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice Reviewed International journal

    Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K, Osawa T

    JOURNAL OF NUTRITION   Vol. 131 ( 8 ) page: 2090 - 2095   2001.8

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  860. Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice Reviewed International journal

    Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K, Osawa T

    JOURNAL OF NUTRITION   Vol. 131 ( 8 ) page: 2090 - 2095   2001.8

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  861. Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds

    Kawanishi S, Inoue S, Oikawa S, Yamashita N, Toyokuni S, Kawanishi M, Nishino K

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 31 ( 1 ) page: 108 - 116   2001.7

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  862. Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds

    Kawanishi S., Inoue S., Oikawa S., Yamashita N., Toyokuni S., Kawanishi M., Nishino K.

    Free Radical Biology and Medicine   Vol. 31 ( 1 ) page: 108 - 116   2001.7

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    DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. DNA strand breaks in cultured cells exposed to nickel compounds were measured by using a pulsed field gel electrophoresis technique. Among nickel compounds (Ni3S2, NiO (black), NiO (green), and NiSO4), only Ni3S2, which is highly carcinogenic, induced lesions of both double- and single-stranded DNA in cultured human cells (Raji and HeLa cells). Treatment of cultured HeLa cells with Ni3S2 (10 μg/ml) induced a 1.5-fold increase in 8-hydroxy-2′-deoxyguanosine (8-OH-dG) compared with control, whereas NiO (black), NiO (green), and NiSO4 did not enhance the generation of 8-OH-dG. Intratracheal instillation of Ni3S2, NiO(black), and NiO(green) to Wistar rats increased 8-OH-dG in the lungs significantly. NiSO4 induced a smaller but significant increase in 8-OH-dG. Histological studies showed that all the nickel compounds used induced inflammation in lungs of the rats. Nitric oxide (NO) generation in phagocytic cells induced by Ni3S2, NiO(black), and NiO(green) was examined using macrophage cell line RAW 264.7 cells. NO generation in RAW 264.7 cells stimulated with lipopolysaccharide was enhanced by all nickel particles. Two mechanisms for nickel-induced oxidative DNA damage have been proposed as follows: all the nickel compounds used induced indirect damage through inflammation, and Ni3S2 also showed direct oxidative DNA damage through H2O2 formation. This double action may explain relatively high carcinogenic risk of Ni3S2. © 2001 Elsevier Science Inc.

    DOI: 10.1016/S0891-5849(01)00558-5

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  863. Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds Reviewed

    S Kawanishi, S Inoue, S Oikawa, N Yamashita, S Toyokuni, M Kawanishi, K Nishino

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 31 ( 1 ) page: 108 - 116   2001.7

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    DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. DNA strand breaks in cultured cells exposed to nickel compounds were measured by using a pulsed held gel electrophoresis technique. Among nickel compounds (Ni3S2, NiO (black), NiO (green), and NiSO4), only Ni3S2, which is highly carcinogenic, induced lesions of both double- and single-stranded DNA in cultured human cells (Raji and HeLa cells). Treatment of cultured HeLa cells with Ni3S2 (10 mug/ml) induced a 1.5-fold increase in 8-hydroxy-2'-deoxyguanosine (8-OH-dG) compared with control, whereas NiO (black), NiO (green), and NiSO4 did not enhance the generation of 8-OH-dG. Intratracheal instillation of Ni3S2, NiO(black), and NiO(green) to Wistar rats increased 8-OH-dG in the lungs significantly. NiSO4 induced a smaller but significant increase in 8-OH-dG. Histological studies showed that all the nickel compounds used induced inflammation in lungs of the rats. Nitric oxide (NO) generation in phagocytic cells induced by Ni3S2, NiO(black). and NiO(green) was examined using macrophage cell line RAW 264.7 cells. NO generation in RAW 264.7 cells stimulated with lipopolysaccharide was enhanced by all nickel particles. Two mechanisms for nickel-induced oxidative DNA damage have been proposed as follows: all the nickel compounds used induced indirect damage through inflammation, and Ni3S2 also showed direct oxidative DNA damage through H2O2 formation. This double action may explain relatively high carcinogenic risk of Ni3S2. (C) 2001 Elsevier Science Inc.

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  864. Endogenous formation of protein adducts with carcinogenic aldehydes - Implications for oxidative stress Reviewed International journal

    Ichihashi K, Osawa T, Toyokuni S, Uchida K

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 276 ( 26 ) page: 23903 - 23913   2001.6

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  865. Endogenous formation of protein adducts with carcinogenic aldehydes: Implications for oxidative stress

    Ichihashi K., Osawa T., Toyokuni S., Uchida K.

    Journal of Biological Chemistry   Vol. 276 ( 26 ) page: 23903 - 23913   2001.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Journal of Biological Chemistry  

    In the present study, we characterize the covalent modification of a protein by crotonaldehyde, a representative carcinogenic aldehyde, and describe the endogenous production of this aldehyde in vivo. The crotonaldehyde preferentially reacted with the lysine and histidine residues of bovine serum albumin and generated a protein-linked carbonyl derivative. Upon incubation with the histidine and lysine derivatives, crotonaldehyde predominantly generated β-substituted butanal adducts of histidine and lysine and N ε-(2,5-dimethyl-3-formyl-3,4-dehydropiperidino)lysine (dimethyl-FDP-lysine) as the putative carbonyl derivatives generated in the crotonaldehyde-modified protein. To verify the endogenous formation of crotonaldehyde in vivo, we raised the monoclonal antibody (mAb82D3) against the crotonaldehyde-modified protein and found that it cross-reacted with the protein-bound 2-alkenals, such as crotonaldehyde, 2-pentenal, and 2-hexenal. The anti-2-alkenal antibody recognized multiple crotonaldehyde-lysine adducts, including dimethyl-FDP-lysine and an unknown product, which showed the greatest immunoreactivity with the antibody. On the basis of the chemical and spectroscopic evidence, the major antigenic product was determined to be a novel Schiff base-derived crotonaldehyde-lysine adduct, Nε -(5-ethyl-2-methylpyridinium)lysine (EMP-lysine). It was found that the lysine residues that had disappeared in the protein treated with crotonaldehyde were partially recovered by EMP-lysine. The presence of immunoreactive materials with mAb82D3 in vivo was demonstrated in the kidney of rats exposed to the renal carcinogen, ferric nitrilotriacetate. In addition, the observations that the metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of proteins resulted in an increase in the antigenicity of the protein indicated that lipid peroxidation represents a potential pathway for the formation of crotonaldehyde/2-alkenals in vivo. These data suggest that the formation of carcinogenic aldehydes during lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.

    DOI: 10.1074/jbc.M101947200

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  866. Difference in thioredoxin expression in viral myocarditis in inbred strains of mice

    Miyamoto M, Kishimoto C, Shioji K, Nakamura H, Toyokuni S, Nakayama Y, Kita M, Yodoi J, Sasayama S

    JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION   Vol. 65 ( 6 ) page: 561 - 564   2001.6

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  867. Helicobacter pylori eradication attenuates oxidative stress in human gastric mucosa

    Pignatelli B, Bancel B, Plummer M, Toyokuni S, Patricot LM, Ohshima H

    AMERICAN JOURNAL OF GASTROENTEROLOGY   Vol. 96 ( 6 ) page: 1758 - 1766   2001.6

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  868. Difference in thioredoxin expression in viral myocarditis in inbred strains of mice

    Miyamoto M, Kishimoto C, Shioji K, Nakamura H, Toyokuni S, Nakayama Y, Kita M, Yodoi J, Sasayama S

    JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION   Vol. 65 ( 6 ) page: 561 - 564   2001.6

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  869. Difference in Thioredoxin Expression in Viral Myocarditis in Inbred Strains of Mice

    MIYAMOTO Miki, KISHIMOTO Chiharu, SHIOJI Keisuke, NAKAMURA Hajime, TOYOKUNI Shinya, NAKAYAMA Yukie, KITA Masakazu, YODOI Junji, SASAYAMA Shigetake

    Japanese circulation journal   Vol. 65 ( 6 ) page: 561 - 564   2001.5

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    Redox regulating mechanisms may be involved in the pathogenesis of viral myocarditis and thioredoxin (TRX) is a small multifunctional protein that contains a redox active sequence. The present study investigated the histopathology and characteristics of TRX expression in acute coxsackievirus B3 myocarditis in inbred strains of mice (severe myocarditis in DBA/2 mice, moderate myocarditis in BALB/c mice and mild myocarditis in C57BL/6 mice). Thioredoxin was upregulated and its expression correlated with the severity of the disease. In addition, 8-hydroxy-2'-deoxyguanosine, which is an established marker for oxidative stress, was concominantly positive in damaged myocytes. Thus, TRX may be specifically induced by the acute inflammatory stimuli in murine viral myocarditis, and the severity and development of acute viral myocarditis may be regulated by the cellular redox state. (Jpn Circ J 2001; 65: 561-564)

  870. Difference in Thioredoxin Expression in Viral Myocarditis in Inbred Strains of Mice

    MIYAMOTO Miki, KISHIMOTO Chiharu, SHIOJI Keisuke, NAKAMURA Hajime, TOYOKUNI Shinya, NAKAYAMA Yukie, KITA Masakazu, YODOI Junji, SASAYAMA Shigetake

    Japanese circulation journal   Vol. 65 ( 6 ) page: 561 - 564   2001.5

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    Redox regulating mechanisms may be involved in the pathogenesis of viral myocarditis and thioredoxin (TRX) is a small multifunctional protein that contains a redox active sequence. The present study investigated the histopathology and characteristics of TRX expression in acute coxsackievirus B3 myocarditis in inbred strains of mice (severe myocarditis in DBA/2 mice, moderate myocarditis in BALB/c mice and mild myocarditis in C57BL/6 mice). Thioredoxin was upregulated and its expression correlated with the severity of the disease. In addition, 8-hydroxy-2'-deoxyguanosine, which is an established marker for oxidative stress, was concominantly positive in damaged myocytes. Thus, TRX may be specifically induced by the acute inflammatory stimuli in murine viral myocarditis, and the severity and development of acute viral myocarditis may be regulated by the cellular redox state. (Jpn Circ J 2001; 65: 561-564)

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  871. Spontaneous loss-of-function mutations of the 8-oxoguanine DNA glycosylase gene in mice and exploration of the possible implication of the gene in senescence

    Mori M., Toyokuni S., Kondo S., Kasai H., Naiki H., Toichi E., Hosokawa M., Higuchi K.

    Free Radical Biology and Medicine   Vol. 30 ( 10 ) page: 1130 - 1136   2001.5

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    8-Oxoguanine is one of the major premutagenic oxidative base legions in vivo and is suspected to play a crucial role in various pathophysiological processes, such as cancer and aging. Mammalian 8-oxoguanine DNA glycosylase (OGG1) is thought to play a major role in the removal of 8-oxoguanine adducts in vivo. We have identified several inbred mouse strains with a spontaneous mutation, OGG1-R336H or double mutations, OGG1-R304W/R336H. R304W mutation caused a complete loss of OGG1 activity, while the R336H mutation led to disruption of nuclear localization of the enzyme although the activity remained normal. Among the double mutants was SAMP1, which exhibits accelerated senescence and short lifespan. We assessed the possible implication of the mutant OGG1 and 8-oxoguanine in aging utilizing SAMP1 mice. SAMP1 retained 1.5- to 1.9-fold increase in 8-oxoguanine level of hepatic nuclear DNA as compared with normal mice, until at least 12 months of age. A genetic association study, however, indicated that the mutant Ogg1 gene per se is not responsible for the accelerated senescence and short lifespan of SAMP1. Mutant OGG1 may be associated with pathologic conditions in other mouse strains. © 2001 Elsevier Science Inc.

    DOI: 10.1016/S0891-5849(01)00511-1

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  872. Spontaneous loss-of-function mutations of the 8-oxoguanine DNA glycosylase gene in mice and exploration of the possible implication of the gene in senescence

    Mori M, Toyokuni S, Kondo S, Kasai H, Naiki H, Toichi E, Hosokawa M, Higuchi K

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 30 ( 10 ) page: 1130 - 1136   2001.5

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  873. Angiosarcoma of the scalp: Absence of vascular endothelial cadherin in primary and metastatic lesions

    Tanioka M., Ikoma A., Morita K., Fujii H., Toda K.I., Takahashi K., Tanaka T., Nishigori C., Jin G., Higashi S., Toyokuni S., Miyachi Y.

    British Journal of Dermatology   Vol. 144 ( 2 ) page: 380 - 383   2001.3

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    A 73-year-old man with angiosarcoma of the scalp died about 1 year after disease onset, despite systemic and topical administration of recombinant interleukin-2. Histopathology showed typical changes of endothelial cells with very sparse lymphocytic infiltration into the tumour. An autopsy revealed that the primary site penetrated cranial bone and invaded vertically into the subarachnoid space. Multiple metastases to lung, chest wall, vertebrae and ribs were also found. On immunofluorescence staining, the expression of vascular endothelial cadherin, which is present in normal endothelium, was absent from both primary and metastatic sites. This may have promoted local invasion and metastasis.

    DOI: 10.1046/j.1365-2133.2001.04032.x

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  874. Pericardial fluid from patients with ischemic heart disease induces myocardial cell apoptotis via an oxidant stress-sensitive p38 mitogen-activated protein kinase pathway

    Iwakura, A; Fujita, M; Hasegawa, K; Toyokuni, S; Sawamura, T; Nohara, R; Sasayama, S; Komeda, M

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   Vol. 33 ( 3 ) page: 419 - 430   2001.3

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    Factors produced by the heart are accumulated at high concentrations in pericardial fluid. We recently reported that pericardial fluid from patients with ischemic heart disease induces apoptosis in an F2 cell line. To characterize factors in pericardial fluid from patients with ischemic heart disease, we investigated signaling pathways by which this pericardial fluid induces apoptosis in cardiac myocytes. Pericardial fluid from patients with ischemic heart disease markedly increased the percentage of TUNEL-positive myocytes compared with fetal bovine serum. Apoptosis was also confirmed by ladder formation and morphologic features. Apoptosis mediated by this pericardial fluid occurs as readily in cardiac myocytes prepared from neonatal mice nullizygous for p53 as in wild-type littermates. This indicates that p53 is not required for this process. We have found that pericardial fluid from ischemic heart disease elicits a robust increase in phosphorylation of p38 mitogen-activated protein kinase. Specific inhibition of the p38 mitogen-activated protein kinase pathway with SB 203580 almost completely blocked apoptosis mediated by pericardial fluid from ischemic heart disease. Activation of p38 mitogen-activated protein kinase is caused by cellular stress, including oxidants. We have also found that anti-oxidant catalase inhibited pericardial fluid-induced activation of p38 mitogen-activated protein kinase and apoptosis. These findings demonstrate that myocardial cell apoptosis induced by pericardial fluid from patients with ischemic heart disease is mediated by an oxidant stress-sensitive p38 mitogen-activated protein kinase pathway. A possible application of SB 203580 to preserve cardiac function in patients with ischemic heart disease should be discussed.

    DOI: 10.1006/jmcc.2000.1314

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  875. Angiosarcoma of the scalp: absence of vascular endothelial cadherin in primary and metastatic lesions

    Tanioka M, Ikoma A, Morita K, Fujii H, Toda KI, Takahashi K, Tanaka T, Nishigori C, Jin G, Higashi S, Toyokuni S, Miyachi Y

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 144 ( 2 ) page: 380 - 383   2001.2

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  876. Angiosarcoma of the scalp: absence of vascular endothelial cadherin in primary and metastatic lesions

    Tanioka M, Ikoma A, Morita K, Fujii H, Toda KI, Takahashi K, Tanaka T, Nishigori C, Jin G, Higashi S, Toyokuni S, Miyachi Y

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 144 ( 2 ) page: 380 - 383   2001.2

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  877. An electron spin resonance study on alkylperoxyl radical in thin-sliced renal tissues from ferric nitrilotriacetate-treated rats: the effect of alpha-tocopherol feeding

    Toyokuni S, Masumizu T, Ozeki M, Kondo S, Hiroyasu M, Kohno M, Hiai H

    FREE RADICAL RESEARCH   Vol. 35 ( 3 ) page: 245 - 255   2001

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  878. Difference in Thioredoxin Expression in Viral Myocarditis in Inbred Strains of Mice

    Miyamoto Miki, Kishimoto Chiharu, Shioji Keisuke, Nakamura Hajime, Toyokuni Shinya, Nakayama Yukie, Kita Masakazu, Yodoi Junji, Sasayama Shigetake

    Japanese Circulation Journal   Vol. 65 ( 6 ) page: 561 - 564   2001

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:The Japanese Circulation Society  

    Redox regulating mechanisms may be involved in the pathogenesis of viral myocarditis and thioredoxin (TRX) is a small multifunctional protein that contains a redox active sequence. The present study investigated the histopathology and characteristics of TRX expression in acute coxsackievirus B3 myocarditis in inbred strains of mice (severe myocarditis in DBA/2 mice, moderate myocarditis in BALB/c mice and mild myocarditis in C57BL/6 mice). Thioredoxin was upregulated and its expression correlated with the severity of the disease. In addition, 8-hydroxy-2'-deoxyguanosine, which is an established marker for oxidative stress, was concominantly positive in damaged myocytes. Thus, TRX may be specifically induced by the acute inflammatory stimuli in murine viral myocarditis, and the severity and development of acute viral myocarditis may be regulated by the cellular redox state. (<i>Jpn Circ J</i> 2001; <b>65:</b> 561 - 564)

    DOI: 10.1253/jcj.65.561

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  879. A case of cevical adenocarcinoma in situ with difficulty in cytological differentiation from recurrent ovarian tumor of borderline malignancy.

    OGURA Seiko, SHIMIZU Keiko, KOBAYASHI Hachiro, TOYOKUNI Shinya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 40 ( 6 ) page: 636 - 640   2001

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    <B><I>Background</I>:</B> The incidence of multiple primary cancers of the female genital tract is increaseing, but these are difficult to correctly diagnose by cytological smear. We report a case of heterochronous double cancer consisting of adenocarcinoma <I>in situ</I> of the uterine cervix and mucinous cystic tumor with borderline malignancy of the ovary.<BR><B><I>Case</I>:</B> A 55-year-old woman with a ruptured right ovarian tumor had right salping000phorectomy 3 years earlier. The histological diagnosis of her ovarian tumor was mucinous cystic tumor with borderline malignancy. Atypical glandular cells were later found in a uterine cervical smear, but no abnormal findings were seen in clinical examination. Total hysterectomy combined with left salpingooophorectomy was done. The histological examination proved to be adenocarcinoma <I>in situ</I> of the uterine cervix. No malignancy was found in the uterine corpus or left adnexa.<BR><B><I>Conclusion</I>:</B> Multiple malignancies of the female genital tract should be made combining cytology, clinical data, and diagnostic imaging.

    DOI: 10.5795/jjscc.40.636

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  880. Iron-induced oxidative damage in colon carcinoma (Caco-2) cells

    Núñez M., Tapia V., Toyokuni S., Okada S.

    Free Radical Research   Vol. 34 ( 1 ) page: 57 - 68   2001

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    Intestinal epithelial cells have an active apical iron uptake system that is involved in the regulated absorption of iron. By the action of this system, intestinal cells acquire increasing amounts of iron with time. Since intracellular reactive iron is a source of free radicals and a possible cause of colon carcinoma, this study analyzed the oxidative damages generated by iron accumulation in Caco-2 cells. Cells cultured with increasing concentrations of iron increased both total intracellular iron and the reactive iron pool, despite an active IRE/IRP system, which regulates intracellular iron levels. Increasing concentrations of iron resulted in increased protein oxidative damage, as shown by the immunoreactivity for 4-hydroxy-2-nonenal-modified proteins, and markedly induced DNA oxidation determined by 8-hydroxy-2′-deoxyguanidine production. Iron also impaired cell viability, resulting in increased cell death after 6 days of culture. In summary, iron accumulation by intestinal Caco-2 cells correlated with oxidative damage to proteins and DNA. Oxidative damage finally resulted in loss of cell viability. The Fe-induced oxidative damage observed may be relevant in understanding the cascade of events associated with iron-mediated colon carcinogenesis.

    DOI: 10.1080/10715760100300061

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  881. Helicobacter pylori eradication attenuates oxidative stress in human gastric mucosa

    Pignatelli B., Bancel B., Plummer M., Toyokuni S., Patricot L.M., Ohshima H.

    American Journal of Gastroenterology   Vol. 96 ( 6 ) page: 1758 - 1766   2001

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    OBJECTIVE: Helicobacter pylori infection causes gastric diseases, but the responsible mechanisms are not completely understood. They can involve DNA and tissue damage induced by reactive oxygen and nitrogen species. Our aim is to investigate the effects of bacterial eradication on oxidative stress by measuring changes of relevant markers. METHODS: Antral biopsies were obtained from 34 patients with chronic atrophic gastritis and peptic ulcer disease before and after bacterial eradication. The expression of inducible nitric oxide synthase (iNOS) and levels of nitrotyrosine (NTYR) and 8-hydroxy-2′-deoxyguanosine were assessed immunohistochemically as markers of nitric oxide (NO) production and of damage to proteins and DNA, respectively. RESULTS: Before treatment, the percentages of patients with staining were: 56 for iNOS in inflammatory cells, 79 and 61 for NTYR and 8-hydroxy-2′-deoxyguanosine in foveolar cells, respectively, and 82 for 8-hydroxy-2′-deoxyguanosine in lymphoid follicles. NTYR staining was associated with the intensity of inflammation (p = 0.04) and gastritis activity (p = 0.07). The prevalence of 8-hydroxy-2′-deoxyguanosine tended to be associated with that of NTYR. After successful H. pylori eradication, the prevalence of iNOS and NTYR (in mild gastritis) staining decreased (p < 0.001 and p < 0.06, respectively). 8-Hydroxy-2′-deoxyguanosine staining disappeared in 24% of cases but appeared in 18% of previously negative cases despite eradication. CONCLUSION: Targets of oxidative stress associated with H. pylori infection are inflammatory and deep foveolar cells and lymphoid follicles. This is the first report of 8-hydroxy-2′-deoxyguanosine localization in gastric mucosa. Oxidative stress is reduced by bacterial eradication in the first stages of mild gastritis. Moderate-severe gastritis may be a step that is reversible for iNOS, but partly irreversible for NTYR and 8-hydroxy-2′-deoxyguanosine. © 2001 Am. Coll. of Gastroenterology.

    DOI: 10.1016/S0002-9270(01)02432-7

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  882. Helicobacter pylori eradication attenuates oxidative stress in human gastric mucosa

    Pignatelli B., Bancel B., Plummer M., Toyokuni S., Patricot L., Ohshima H.

    American Journal of Gastroenterology   Vol. 96 ( 6 ) page: 1758 - 1766   2001

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    OBJECTIVE: Helicobacter pylori infection causes gastric diseases, but the responsible mechanisms are not completely understood. They can involve DNA and tissue damage induced by reactive oxygen and nitrogen species. Our aim is to investigate the effects of bacterial eradication on oxidative stress by measuring changes of relevant markers. METHODS: Antral biopsies were obtained from 34 patients with chronic atrophic gastritis and peptic ulcer disease before and after bacterial eradication. The expression of inducible nitric oxide synthase (iNOS) and levels of nitrotyrosine (NTYR) and 8-hydroxy-2′-deoxyguanosine were assessed immunohistochemically as markers of nitric oxide (NO) production and of damage to proteins and DNA, respectively. RESULTS: Before treatment, the percentages of patients with staining were: 56 for iNOS in inflammatory cells, 79 and 61 for NTYR and 8-hydroxy-2′-deoxyguanosine in foveolar cells, respectively, and 82 for 8-hydroxy-2′-deoxyguanosine in lymphoid follicles. NTYR staining was associated with the intensity of inflammation (p = 0.04) and gastritis activity (p = 0.07). The prevalence of 8-hydroxy-2′-deoxyguanosine tended to be associated with that of NTYR. After successful H. pylori eradication, the prevalence of iNOS and NTYR (in mild gastritis) staining decreased (p < 0.001 and p < 0.06, respectively). 8-Hydroxy-2′-deoxyguanosine staining disappeared in 24% of cases but appeared in 18% of previously negative cases despite eradication. CONCLUSION: Targets of oxidative stress associated with H. pylori infection are inflammatory and deep foveolar cells and lymphoid follicles. This is the first report of 8-hydroxy-2′-deoxyguanosine localization in gastric mucosa. Oxidative stress is reduced by bacterial eradication in the first stages of mild gastritis. Moderate-severe gastritis may be a step that is reversible for iNOS, but partly irreversible for NTYR and 8-hydroxy-2′-deoxyguanosine. © 2001 Am. Coll. of Gastroenterology.

    DOI: 10.1111/j.1572-0241.2001.03869.x

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  883. Iron-induced oxidative damage in colon carcinoma (Caco-2) cells Reviewed

    MT Nunez, Tapia, V, S Toyokuni, S Okada

    FREE RADICAL RESEARCH   Vol. 34 ( 1 ) page: 57 - +   2001

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:HARWOOD ACAD PUBL GMBH  

    Intestinal epithelial cells have an active apical iron uptake system that is involved in the regulated absorption of iron. By the action of this system, intestinal cells acquire increasing amounts of iron with time. Since intracellular reactive iron is a source of free radicals and a possible cause of colon carcinoma, this study analyzed the oxidative damages generated by iron accumulation in Caco-2 cells. Cells cultured with increasing concentrations of iron increased both total intracellular iron and the reactive iron pool, despite an active IRE/IRP system, which regulates intracellular iron levels. Increasing concentrations of iron resulted in increased protein oxidative damage, as shown by the immunoreactivity for 4-hydroxy-2-nonenal-modified proteins, and markedly induced DNA oxidation determined by 8-hydroxy-2'-deoxyguanidine production. Iron also impaired cell viability, resulting in increased cell death after 6 days of culture. In summary, iron accumulation by intestinal Caco-2 cells correlated with oxidative damage to proteins and DNA. Oxidative damage finally resulted in loss of cell viability. The Fe-induced oxidative damage observed may be relevant in understanding the cascade of events associated with iron-mediated colon carcinogenesis.

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  884. Iron-induced oxidative damage in colon carcinoma (Caco-2) cells

    Nunez MT, Tapia V, Toyokuni S, Okada S

    FREE RADICAL RESEARCH   Vol. 34 ( 1 ) page: 57 - +   2001

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  885. Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice

    Okada K., Wangpoengtrakul C., Tanaka T., Toyokuni S., Uchida K., Osawa T.

    Journal of Nutrition   Vol. 131 ( 8 ) page: 2090 - 2095   2001

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    Protective effects of curcumin (U1), one of the major yellow pigments in turmeric and its derivative, tetrahydrocurcumin (THU1), against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage were studied in male ddY mice. Single Fe-NTA treatment (5 mg Fe/kg body intraperitoneally) transiently causes oxidative stress, as shown by the accumulation of lipid peroxidation products and 8-hydroxy-2′-deoxyguanosine in the kidney. Mice were fed with a diet containing 0.5 g/100 g U1 or THU1 for 4 wk. THU1 significantly inhibited 2-thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2′-deoxyguanosine formation in the kidney; U1 inhibited only 4-hydroxy-2-nonenal-modified protein formation. To elucidate the mechanisms of protection by U1 and THU1, the pharmacokinetics and radical-scavenging capacities of U1 and THU1 were investigated by HPLC and electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide, respectively. Induction of antioxidant enzymes was also investigated. The amounts of THU1 and its conjugates (as sulfates and glucuronides) in the liver and serum were larger in the THU1 group than in the U1 group. The amounts of U1 and its conjugates were small even in the U1 group. These results suggest that THU1 is more easily absorbed from the gastrointestinal tract than U1. Furthermore, THU1 induced antioxidant enzymes, such as glutathione peroxidase, glutathione S-transferase and NADPH: quinone reductase, as well as or better than U1 and scavenged Fe-NTA-induced free radicals in vitro better than U1. These results suggest that U1 is converted to THU1 in vivo and that THU1 is a more promising chemopreventive agent.

    DOI: 10.1093/jn/131.8.2090

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  886. Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage

    Kallay E., Pietschmann P., Toyokuni S., Bajna E., Hahn P., Mazzucco K., Bieglmayer C., Kato S., Cross H.S.

    Carcinogenesis   Vol. 22 ( 9 ) page: 1429 - 1435   2001

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    The vitamin D receptor knockout (VDR-KO) mouse presents with a skeletal phenotype typical for complete lack of genomic 1,25-dihydroxycholecalciferol effects. Our previous data from human colorectal tissue suggest that the steroid hormone and its receptor may have protective function against tumour progression. In order to investigate the relevance of the vitamin D system for pre-malignant site-directed changes in the colon, we characterized the amount and site-specific distribution of the VDR along the large intestine in wild-type (WT), heterozygote (HT) and KO mice. We also evaluated expression of proliferating cell nuclear antigen (PCNA), of cyclin D1 and the levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative stress. In colon ascendens, proliferative cells were dispersed all along the crypt and expression levels of all three markers were high in WT mice. A decrease of VDR expression did not affect expression significantly. In colon descendens, however, fewer proliferative cells were solely located in the lower third of the crypt, and an inverse relationship between VDR reduction, PCNA positivity and cyclin D1 expression was found in HT and KO mice. In parallel to enhanced proliferation a highly significant increase of 8-OHdG positivity occurred. Therefore, the sigmoid colon of VDR-KO mice, fed on an appropriate lactose/calcium-enriched diet to alleviate impaired calcium homeostasis-related phenotypic changes, is an excellent model for investigating induction and prevention of pre-malignant changes in one of the hotspots for human colorectal cancer incidence.

    DOI: 10.1093/carcin/22.9.1429

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  887. An electron spin resonance study on alkylperoxyl radical in thin-sliced renal tissues from ferric nitrilotriacetate-treated rats: The effect of α-tocopherol feeding

    Toyokuni S., Masumizu T., Ozeki M., Kondo S., Hiroyasu M., Kohno M., Hiai H.

    Free Radical Research   Vol. 35 ( 3 ) page: 245 - 255   2001

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    Formation of excess free radical causes cellular oxidative stress, which has been shown to be associated with a variety of pathologic conditions. While electron spin resonance (ESR) spectroscopy has been the only method to demonstrate the presence of free radicals, its application to tissue samples has been challenging. We report here the successful ESR detection in thin-sliced fresh tissues or frozen sections in a rat model. Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal tubular damage that ultimately leads to high incidence of renal carcinoma in rodents. Twenty minutes after administration of 5 mg iron/kg Fe-NTA to rats, a thin-slice of the kidney was mounted on a tissue-type cell and analyzed by ESR spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). An ESR signal from alkylperoxyl radical adduct was obtained, and the signal was inversely proportional to renal α-tocopherol content which was modulated through diet. Furthermore, we undertook ex vivo study using frozen sections. Fe-NTA (1mM) was added to a rat kidney frozen section for 10 min. After washing the specimen was mounted on a tissue-type cell and analyzed with ESR spin trapping using DMPO. Alkylperoxyl radical signal was dependent on thickness, incubation time and renal tissue levels of α-tocopherol, and was reduced by preincubation with catalase or dimethyl sulfoxide but not with α-tocopherol outside tissue. This versatile method facilitates identification of free radicals in pathologic conditions, and may be useful for selection of antioxidants.

    DOI: 10.1080/10715760100300781

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  888. An electron spin resonance study on alkylperoxyl radical in thin-sliced renal tissues from ferric nitrilotriacetatetreated rats : the effect of alpha-tocopherol feeding

    TOYOKUNI S

    Free Radic Res   Vol. 35 ( 3 ) page: 245 - 255   2001

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  889. Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis International journal

    Kawamura, K; Kobayashi, Y; Kageyama, F; Kawasaki, T; Nagasawa, M; Toyokuni, S; Uchida, K; Nakamura, H

    AMERICAN JOURNAL OF GASTROENTEROLOGY   Vol. 95 ( 12 ) page: 3596 - 3601   2000.12

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  890. Enchanced hepatic lipid peroxidation in patients with primary biliary cirrhosis Reviewed International journal

    KAWAMURA K

    Am J Gastroenterol   Vol. 95 ( 12 ) page: 3596 - 3601   2000.12

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    DOI: 10.1111/j.1572-0241.2000.03300.x

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  891. Activating transcripton factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression

    Ban N., Yamada Y., Someya Y., Ihara Y., Adachi T., Kubota A., Watanabe R., Kuroe A., Inada A., Miyawaki K., Sunaga Y., Shen Z.P., Iwakura T., Tsukiyama K., Toyokuni S., Tsuda K., Seino Y.

    Diabetes   Vol. 49 ( 7 ) page: 1142 - 1148   2000.7

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    Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity o the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV- induced ATF-2 transcriptional activity was not altered by activation of c-Jun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic β- cells, with the transcriptional activity of ATF2 being increased by an elevated concentration of calcium ions.

    DOI: 10.2337/diabetes.49.7.1142

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  892. Activating transcription factor-2 is a positive regulator in CaM kinase IV - Induced human insulin gene expression

    Ban N, Yamada Y, Someya Y, Ihara Y, Adachi T, Kubota A, Watanabe R, Kuroe A, Inada A, Miyawaki K, Sunaga Y, Shen ZP, Iwakura T, Tsukiyama K, Toyokuni S, Tsuda K, Seino Y

    DIABETES   Vol. 49 ( 7 ) page: 1142 - 1148   2000.7

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  893. Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression. International journal

    N Ban, Y Yamada, Y Someya, Y Ihara, T Adachi, A Kubota, R Watanabe, A Kuroe, A Inada, K Miyawaki, Y Sunaga, Z P Shen, T Iwakura, K Tsukiyama, S Toyokuni, K Tsuda, Y Seino

    Diabetes   Vol. 49 ( 7 ) page: 1142 - 8   2000.7

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    Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity of the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of cJun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic beta-cells, with the transcriptional activity of ATF-2 being increased by an elevated concentration of calcium ions.

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  894. Heat-shock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats Reviewed International journal

    Yamamoto H, Yamamoto Y, Yamagami K, Kume M, Kimoto S, Toyokuni S, Uchida K, Fukumoto M, Yamaoka Y

    RESEARCH IN EXPERIMENTAL MEDICINE   Vol. 199 ( 6 ) page: 309 - 318   2000.6

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  895. Expression of stress-response and cell proliferation genes in renal cell carcinoma induced by oxidative stress

    Tanaka T, Kondo S, Iwasa Y, Hiai H, Toyokuni S

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 156 ( 6 ) page: 2149 - 2157   2000.6

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  896. Heat-shock preconditioning reduces oxidative protein denaturation andameliorates liver injury by carbon tetrachloride in rats Reviewed International journal

    YAMAMOTO H.

    Res. Exp. Med.   Vol. 199 ( 6 ) page: 309 - 318   2000.6

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  897. Expression of stress-response and cell proliferation genes in renal cell carcinoma induced by oxidative stress

    TANAKA T.

    Am. J. Pathol.   Vol. 156 ( 6 ) page: 2149 - 2157   2000.6

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    CiNii Books

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  898. Effects of geranyl-geranyl-acetone administration before heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers

    Yamagami K, Yamamoto Y, Ishikawa Y, Yonezawa K, Toyokuni S, Yamaoka Y

    JOURNAL OF LABORATORY AND CLINICAL MEDICINE   Vol. 135 ( 6 ) page: 465 - 475   2000.6

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  899. Detection of lipofuscin-like fluorophore in oxidized human low-density lipoprotein. 4-Hydroxy-2-nonenal as a potential source of fluorescent chromophore

    Itakura K., Oya-Ito T., Osawa T., Yamada S., Toyokuni S., Shibata N., Kobayashi M., Uchida K.

    FEBS Letters   Vol. 473 ( 2 ) page: 249 - 253   2000.5

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    It has recently been shown that the lipid peroxidation product 4- hydroxy-2-nonenal (HNE) forms a fluorescent hydroxyiminodihydropyrrole derivative with the ε-amino group of lysine residue. In this study, we raised a monoclonal antibody (mAb2C12) directed to the fluorophore-protein conjugate and found that the antibody was specific to the chromophore structure of the compound. Immunohistochemical analysis of atherosclerotic lesions from the human aorta showed that the fluorophore was indeed present in the lesions, in which intense positivity was primarily associated with macrophage-derived foam cells and thickening of the neointima of the arterial walls. Antigenic materials were also detected in the oxidatively modified low-density lipoprotein (LDL) with Cu2+ and in the oxidatively modified bovine serum albumin with an iron/linoleic acid autoxidation system, indicating that the HNE, which originated from the peroxidation of polyunsaturated fatty acids, could be a potential source of the fluorescent chromophore in oxidized LDL. (C) 2000 Federation of European Biochemical Societies.

    DOI: 10.1016/S0014-5793(00)01539-8

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  900. Detection of lipofuscin-like fluorophore in oxidized human low-density lipoprotein - 4-Hydroxy-2-nonenal as a potential source of fluorescent chromophore

    Itakura K, Oya-Ito T, Osawa T, Yamada S, Toyokuni S, Shibata N, Kobayashi M, Uchida K

    FEBS LETTERS   Vol. 473 ( 2 ) page: 249 - 253   2000.5

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  901. Antioxidant α-tocopherol ameliorates glycemic control of GK rats, a model of type 2 diabetes

    Ihara, Y; Yamada, Y; Toyokuni, S; Miyawaki, K; Ban, N; Adachi, T; Kuroe, A; Iwakura, T; Kubota, A; Hiai, H; Seino, Y

    FEBS LETTERS   Vol. 473 ( 1 ) page: 24 - 26   2000.5

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    DOI: 10.1016/S0014-5793(00)01489-7

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  902. Antioxidant α-tocopherol improves glycemic control of GK rats, a model of type 2 diabetes

    Ihara, Y; Yamada, Y; Toyokuni, S; Ban, N; Kuroe, A; Seino, Y

    DIABETES   Vol. 49   page: A429 - A429   2000.5

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  903. Upregulation of thioredoxin (TRX) expression in giant cell myocarditis in rats

    Shioji, K; Kishimoto, C; Nakamura, H; Toyokuni, S; Nakayama, Y; Yodoi, J; Sasayama, S

    FEBS LETTERS   Vol. 472 ( 1 ) page: 109 - 113   2000.4

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    DOI: 10.1016/S0014-5793(00)01446-0

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  904. Upregulation of thioredoxin (TRX) expression in giant cell myocarditis in rats

    SHIOJI K

    FEBS Lett   Vol. 472 ( 1 ) page: 109 - 113   2000.4

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  905. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C International journal

    Kageyama, F; Kobayashi, Y; Kawasaki, T; Toyokuni, S; Uchida, K; Nakamura, H

    AMERICAN JOURNAL OF GASTROENTEROLOGY   Vol. 95 ( 4 ) page: 1041 - 1050   2000.4

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  906. Overexpression of the hOGG1 gene and high 8-hydroxy-2 '-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: Regulation mechanism of the 8-OHdG level in DNA

    Kondo S, Toyokuni S, Tanaka T, Hiai H, Onodera H, Kasai H, Imamura M

    CLINICAL CANCER RESEARCH   Vol. 6 ( 4 ) page: 1394 - 1400   2000.4

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  907. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C

    Kageyama F., Kobayashi Y., Kawasaki T., Toyokuni S., Uchida K., Nakamura H.

    American Journal of Gastroenterology   Vol. 95 ( 4 ) page: 1041 - 1050   2000.4

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    OBJECTIVES: Hepatic iron deposition has been reported in chronic hepatitis C (CH-C), and iron-induced lipid peroxidation may be involved in the pathogenesis of CH-C. The aims of the present study were: 1) to determine whether patients with CH-C have evidence of enhanced hepatic lipid peroxidation and to evaluate its relation to iron status, compared with that in patients with chronic hepatitis B (CH-B); and 2) to assess the effect of interferon (IFN) therapy on hepatic iron and lipid peroxidation. METHODS: In the liver biopsies of 40 patients with CH-C and 26 patients with CH-B, immunohistochemical detection of 4-hydroxy-2-nonenal (HNE)-protein adducts for evaluation of lipid peroxidation was performed, and hepatic iron status was biochemically and histologically assessed. In 16 CH-C patients with normal serum transaminases and undetectable serum HCV-RNA >6 months after the end of IFN treatment (responders) and in 11 nonresponders, hepatic HNE- protein adducts and siderosis were evaluated in pre- and posttreatment liver biopsies. RESULTS: Hepatocytic HNE-protein adducts and iron deposits were more abundant in the patients with CH-C than in those with CH-B. No correlation was found between the levels of hepatocytic HNE-protein adducts and hepatic iron status in either of the two groups. In the responders to IFN treatment for CH-C, hepatocytic HNE-protein adducts disappeared or attenuated with improvement of hepatic siderosis after the treatment, whereas IFN treatment did not improve hepatocytic expression of HNE-protein adducts and hepatic siderosis in the nonresponders. CONCLUSIONS: Patients with CH-C have evidence of enhanced hepatic iron accumulation and lipid peroxidation compared to those with CH-B. In CH-C, hepatic siderosis and lipid peroxidation are improved with successful IFN treatment. These results suggest that hepatic lipid peroxidation and iron may potentially play contributory roles in the pathogenesis of CH-C. (C) 2000 by Am. Coll. of Gastroenterology.

    DOI: 10.1016/S0002-9270(00)00771-1

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  908. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C Reviewed International journal

    Kageyama F, Kobayashi Y, Kawasaki T, Toyokuni S, Uchida K, Nakamura H

    AMERICAN JOURNAL OF GASTROENTEROLOGY   Vol. 95 ( 4 ) page: 1041 - 1050   2000.4

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  909. Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: Regulation mechanism of the 8-OHdG level in DNA

    Kondo S., Toyokuni S., Tanaka T., Hiai H., Onodera H., Kasai H., Imamura M.

    Clinical Cancer Research   Vol. 6 ( 4 ) page: 1394 - 1400   2000.4

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    8-Hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidatively modified lesions in DNA. Our previous study (Kondo et al., Free Radic. Biol. Med., 27: 401-410, 1999) revealed that human colorectal carcinoma cells are oxidatively stressed based on 8-OHdG determination. To elucidate 8-OHdG metabolism and its clinical significance in colorectal carcinoma, we studied the 8-OHdG repair system in DNA by measuring specific lyase activity and hOGG1 expression using quantitative-competitive reverse transcription-PCR. In addition, we searched for the presence of mutations and single nucleotide polymorphisms of the hOGG1 gene by single-strand conformational polymorphism and sequencing analyses. It was found that 8- OHdG-specific lyase activity and hOGG1 expression were significantly up- regulated in carcinoma, and a proportional association between 8-OHdG levels and either 8-OHdG lyase activity (r = 0.641, P < 0.05) or hOGG1 expression (r = 0.702, P < 0.05) was present. Whereas no difference was detected in the 8- OHdG level between early- and advanced-stage cancer, lyase activity (1.2- fold) and hOGG1 expression (1.6-fold) were significantly increased in advanced-stage cancer. No mutation was found in the 25 tumors examined. Three kinds of single nucleotide polymorphism were observed, including that of codon 326 (Ser/Cys) in exon 7. However, there was no correlation between any of the three polymorphic patterns and either 8-OHdG level or lyase activity. These results suggest that increased 8-OHdG levels in colorectal carcinoma are attributed to increased formation and are maintained by induced 8-OHdG repair activity at appropriate high levels. Our results may offer a unique approach in the development of preventive and therapeutic interventions as well as new insights into the pathogenesis of colorectal carcinoma.

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  910. Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma : regulation mechanism of the 8-OHdG level in DNA

    KONDO S

    Clin Cancer Res   Vol. 6 ( 4 ) page: 1394 - 1400   2000.4

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  911. Overexpression of the hOGG1 gene and high 8-hydroxy-2'-deoxyguanosine (8-OHdG) lyase activity in human colorectal carcinoma: regulation mechanism of the 8-OHdG level in DNA.

    Kondo S, Toyokuni S, Tanaka T, Hiai H, Onodera H, Kasai H, Imamura M

    Clinical cancer research : an official journal of the American Association for Cancer Research   Vol. 6 ( 4 ) page: 1394 - 400   2000.4

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  912. Cytoprotective effects of nitroglycerin in ischemia-reperfusion-induced lung injury

    Kawashima M, Bando T, Nakamura T, Isowa N, Liu MY, Toyokuni S, Hitomi S, Wada H

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   Vol. 161 ( 3 ) page: 935 - 943   2000.3

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  913. Formation of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in rat liver after ischemia-reperfusion : distinct localization of the two oxidatively modified products

    YAMAGAMI K

    Antioxid Redox Signal   Vol. 2 ( 1 ) page: 127 - 136   2000.1

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    DOI: 10.1089/ars.2000.2.1-127

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  914. Serum 4-Hydroxy-2-Nonenal-Modified Albumin Is Elevated in Patients with Type 2 Diabetes Mellitus Reviewed International journal

    Toyokuni Shinya, Yamada Satoshi, Kashima Minoru, Ihara Yu, Yamada Yuichiro, Tanaka Tomoyuki, Hiai Hiroshi, Seino Yutaka, Uchida Koji

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 2 ( 4 ) page: 681 - U65   2000

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  915. Formation of 8-Hydroxy-2 '-Deoxyguanosine and 4-Hydroxy-2-Nonenal-Modified Proteins in Rat Liver after Ischemia-Reperfusion: Distinct Localization of the Two Oxidatively Modified Products

    Yamagami Kazuhiko, Yamamoto Yuzo, Kume Makoto, Ishikawa Yasuhide, Yamaoka Yoshio, Hiai Hiroshi, Toyokuni Shinya

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 2 ( 1 ) page: 127 - 136   2000

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  916. Serum 4-hydroxy-2-nonenal-modified albumin is elevated in patients with type 2 diabetes mellitus Reviewed International journal

    TOYOKUNI S

    Antioxid Redox Signal   Vol. 2 ( 4 ) page: 681 - 685   2000

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    DOI: 10.1089/ars.2000.2.4-681

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  917. Expression of stress-response and cell proliferation genes in renal cell carcinoma induced by oxidative stress

    Tanaka T., Kondo S., Iwasa Y., Hiai H., Toyokuni S.

    American Journal of Pathology   Vol. 156 ( 6 ) page: 2149 - 2157   2000

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    Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In search of genes specifically involved in oxystress-induced carcinogenesis, we have applied a modified fluorescent differential display technique to the tumors and an established cell line as well as their non- neoplastic counterparts. We screened approximately 84,000 products. Reverse Northern blotting confirmed differential expression of 20 transcripts, which showed either significant increase, decrease or lack of expression in the RCCs. Five cDNA clones encoded novel products of unknown function. Fifteen cDNA clones were identified by homology search, which included annexin II, Y- box binding protein, ribosomal proteins, heat shock proteins, DNA polymerase, nonmuscle caldesmon (increased); protein tyrosine phosphatase (decreased); selenoprotein P, stromal cell-derived factor 1, intestinal trefoil protein, nicotinamide adenine dinucleotide, reduced form (NADH) dehydrogenase, and insulin-like growth factor binding protein 7 (deleted). Most of the identified genes were associated with stress-response or cellular proliferation. These results suggest that multiple, interactive genetic pathways are involved in carcinogenesis induced by oxidative stress.

    DOI: 10.1016/S0002-9440(10)65085-7

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  918. Effects of geranyl-geranyl-acetone administration before heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers

    Yamagami K., Yamamoto Y., Ishikawa Y., Yonezawa K., Toyokuni S., Yamaoka Y.

    Journal of Laboratory and Clinical Medicine   Vol. 135 ( 6 ) page: 465 - 475   2000

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    The effect of geranyl-geranyl-acetone (GGA) administration before heat shock preconditioning on heat shock protein (HSP) 72 induction and on the acquisition of tolerance against ischemia-reperfusion injury was studied in rat livers. Male Wistar rats were divided into four groups: a control group (group C); a GGA group (group G); a simple heat shock group (group VH); and a heat shock with GGA premedication group (group GH). Five-, 10-, and 15-minute periods of heat shock preconditioning at 42°C were performed in groups VH and GH. Subgroups were determined according to the period of heat shock exposure. After a 48-hour recovery, rats in groups C, VH5, VH15, and GH5 received a 30-minute period of hepatic ischemia. Induction of HSP72, survival rates, and changes in biochemical and histologic parameters were compared among the groups. Five-minute heat shock preconditioning was not enough to induce HSP72. However, livers in group GH5 expressed approximately the same amount of HSP72 as those in group VH15. The expression of HSP72 in group GH15 was stronger than that found in group VH15. The degree and location of HSP72 expression were not different between groups GH5 and VH15. Seven-day survival was significantly better in groups GH5 (16/16) and VH15 (15/16) than in group C (8/16) or VH5 (9/16). The recovery of adenosine triphosphate in liver tissue was faster, and the release of liver-related enzymes during reperfusion was lower in groups GH5 and VH15 than in group C or VH5. Administration of GGA before heat shock preconditioning augmented the induction of HSP72 by decreasing the threshold for triggering the stress response.

    DOI: 10.1067/mlc.2000.106806

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  919. Cytoprotective effects of nitroglycerin in ischemia-reperfusion-induced lung injury

    Kawashima M., Bando T., Nakamura T., Isowa N., Liu M., Toyokuni S., Hitomi S., Wada H.

    American Journal of Respiratory and Critical Care Medicine   Vol. 161 ( 3 I ) page: 935 - 943   2000

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    Prevention of ischemia-reperfusion (IR) injury is crucial for successful lung transplantation. We investigated whether a nitric oxide donor, nitroglycerin (NTG), could suppress the oxidative stress of IR injury and improve pulmonary function after reperfusion in an ex vivo rat lung perfusion model. In Fresh group of animals, the lungs were flushed with perfusate, followed immediately by reperfusion, and no lung injury was observed. In NTG- and NTG+ groups of animals, the lungs were flushed with perfusate alone or perfusate containing NTG, respectively. Harvested lung and heart blocks from these latter two groups were immersed in the corresponding perfusate at 4°C for 15 h, and were then reperfused for 60 min. Reperfusion induced pulmonary edema in the NTG- group, but not in the NTG + group. Shunt fractions in NTG+ group were significantly lower than in the NTG- group throughout reperfusion. NTG had no effect on pulmonary arterial pressure or myeloperoxidase activity. In contrast, oxidative DNA damage assessed immunohistochemically with a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine (8-OHdG) was significantly increased in the NTG- group, in the order alveolar epithelium > pulmonary endothelium > bronchial epithelium. NTG treatment significantly decreased staining with the anti-8-OHdG antibody in all three areas Of tissue. Therefore, administration of NTG attenuates the oxidative stress of IR injury, and may improve pulmonary function after reperfusion.

    DOI: 10.1164/ajrccm.161.3.9905003

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  920. Fine-needle aspiration cytology of malignant hemangiopericytoma of the salivary gland: A case report

    Shimizu K., Ogura S., Kobayashi T.K., Kushima R., Toyokuni S., Iwasa Y., Sakurai M.

    Diagnostic Cytopathology   Vol. 21 ( 6 ) page: 398 - 401   1999.12

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    A 79-yr-old woman presented with a 5-yr history of swelling of the left cheek. The fine-needle aspiration (FNA) smear showed a spindle-cell neoplasm with capillaries and benign endothelial cells. The spindle cells possessed pleomorphic, hyperchromatic elongated nuclei and a moderate amount of ill- defined cytoplasm. They also showed papillary arcades surrounded and encased by relatively small ovoid to short spindle cells. Subsequent surgical excision confirmed the presence of malignant hemangiopericytoma (HP). Immunohistochemical studies on the histologic section using vimentin were strongly positive, consistent with HP. To the best of our knowledge, this is the second published report of FNA cellular features of malignant HP of the salivary gland. Besides delineating the FNA cellular features of HP of the salivary gland, the present case illustrates the value of using immunohistochemical approaches.

    DOI: 10.1002/(SICI)1097-0339(199912)21:6<398::AID-DC6>3.0.CO;2-V

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  921. Fine-needle aspiration cytology of malignant hemangiopericytoma of the salivary gland: A case report

    Shimizu K, Ogura S, Kobayashi TK, Kushima R, Toyokuni S, Iwasa Y, Sakurai M

    DIAGNOSTIC CYTOPATHOLOGY   Vol. 21 ( 6 ) page: 398 - 401   1999.12

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  922. Fine-needle aspiration cytology of malignant hemangiopericytoma of the salivary gland: A case report Reviewed

    K Shimizu, S Ogura, TK Kobayashi, R Kushima, S Toyokuni, Y Iwasa, M Sakurai

    DIAGNOSTIC CYTOPATHOLOGY   Vol. 21 ( 6 ) page: 398 - 401   1999.12

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    A 79-yr-old woman presented with a 5-yr history of swelling of the left cheek. The fine-needle aspiration (FNA) smear show ed a spindle-cell neoplasm with capillaries and benign endothelial cells. The spindle cells possessed pleomorphic, hyperchromatic elongated nuclei and a moderate amount of ill-defined cytoplasm. They also showed papillary arcades surrounded and encased by relatively: small ovoid to short spindle cells. Subsequent surgical excision confirmed the presence of malignant hemangiopericytoma (HP). Immunohistochemical studies on the histologic section casing vimentin were strongly positive, consistent with HP To the best of our knowledge, this is the second published report of FNA cellular features of malignant HP of the salivary gland. Besides delineating the FNA cellular of HP of the salivary gland the present case illustrates the value of using immunohistochemical approaches.

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  923. Heat-shock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats

    Yamamoto H., Yamamoto Y., Yamagami K., Kume M., Kimoto S., Toyokuni S., Uchida K., Fukumoto M., Yamaoka Y.

    Research in Experimental Medicine   Vol. 199 ( 6 ) page: 309 - 318   1999.11

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    Membrane lipids and cytosolic proteins are major targets of oxidative injury. This study examined the effect of heat-shock preconditioning associated with the induction of heat-shock protein 72 on liver injury, from the aspect of lipid peroxidation and protein denaturation after carbon tetrachloride (CCl4) administration in rats - one of the representative oxidative injuries. Male Wistar rats were divided into two groups, group HS (preconditioned by heat exposure) and group C (not preconditioned). Expression of HSP72 in the liver tissue was confirmed by Western blot analysis. After a 48-h recovery period, all rats were given CCl4 intragastrically. Liver damage was assessed by measuring serum liver-related enzyme levels and adenine nucleotide concentration in the liver tissue. Lipid peroxidation and protein denaturation were evaluated by measuring tiobarbituric acid reactive substances (TBARS) and by immunohistochemical staining of 4-hydroxy-2-nonenal(HNE)-modified proteins in the liver. Survival rates of the rats after CCl4 administration were also compared. Expression of HSP72 was clearly detected in group HS, but not in group C. Heat-shock preconditioning significantly improved the survival rate, suppressed the increase in liver-related enzyme levels and maintained adenosine triphosphate levels (P < 0.01 each). HNE-modified proteins - denatured proteins by free radical attack - were significantly less stained in group HS than in group C (P < 0.05). However, TBARS levels did not differ between groups. Because heat-shock preconditioning did not alter TBARS levels but reduced HNE-modified proteins in association with the expression of HSP72, it is suggested that HSP72 did not prevent lipid peroxidation but decreased the lipid peroxidation-induced denaturation of proteins. This seemed to be a mechanism of heat-shock preconditioning to ameliorate oxidative liver injury.

    DOI: 10.1007/s004339900040

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  924. Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis. International journal

    Kawamura, K; Kageyama, F; Kobayashi, Y; Kawasaki, T; Toyokuni, S; Uchida, K

    HEPATOLOGY   Vol. 30 ( 4 ) page: 543A - 543A   1999.10

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  925. Enhanced hepatic lipid peroxidation in patients with primary biliary cirrhosis. Reviewed International journal

    Kawamura K, Kageyama F, Kobayashi Y, Kawasaki T, Toyokuni S, Uchida K

    HEPATOLOGY   Vol. 30 ( 4 ) page: 543A - 543A   1999.10

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  926. P-58 Ontogenesis of Anti-Oxidative Enzymes and Effects of Oxygen Stress on Developing Mouse Embryos.

    KOBAYASHI M., NAKAMURA H., YODOI J., TOYOKUNI S., SHIOTA K.

    Congenital anomalies   Vol. 39 ( 3 ) page: 175   1999.9

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  927. P-58 Ontogenesis of Anti-Oxidative Enzymes and Effects of Oxygen Stress on Developing Mouse Embryos.

    KOBAYASHI M, NAKAMURA H, YODOI J, TOYOKUNI S, SHIOTA K

    Congenital anomalies   Vol. 39 ( 3 )   1999.9

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  928. Iron chelators modulate the production of DNA strand breaks and 8-hydroxy-2'-deoxyguanosine

    Toyokuni S., Sagripanti J.

    Free Radical Research   Vol. 31 ( 2 ) page: 123 - 128   1999.9

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    The interaction of chelators and reducing agents is of particular importance in understanding iron-associated pathology since catalytic iron undergoes cyclic reduction and oxidation in vivo. Therefore, we treated plasmid DNA with free or chelated Fe(III) in the presence of biological reductants, and simultaneously measured the number of single strand breaks (SSBs) and oxidative base modification (8-hydroxy-2'-deoxyguanosine; 8-OHdG) by quantitative gel electrophoresis and HPLC with electrochemical detection, respectively. Production of SSBs and 8-OHdG was linearly correlated suggesting that these true different lesions share a common chemical mechanism. The levels of both lesions were enhanced when Fe(III) was chelated to citrate or nitrilotriacetic acid. Reducing agents showed different potency in inducing DNA damage catalyzed by chelated iron (L-ascorbate > L-cysteine > H2O2). Chelation increased SSB formation by ~ 8-fold and 8-OHdG production by ~ 4-fold. The ratio of SSB/8-OHdG catalyzed by chelated iron, which is twice as high as by unchelated iron, indicates that chelation affects iron-catalyzed oxidative DNA damage in a specific way favoring strand breakage over base modification. Since iron is mostly chelated in biological systems, the production of genomic and mitochondrial DNA damage, particularly strand breaks, in diseases involving iron overload is likely to be higher than previously predicted from studies using unchelated iron.

    DOI: 10.1080/10715769900301631

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  929. Localization of hydroxynonenal protein adducts in normal human kidney and selected human kidney cancers

    Oberley TD, Toyokuni S, Szweda LI

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27 ( 5-6 ) page: 695 - 703   1999.9

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    DOI: 10.1016/S0891-5849(99)00117-3

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  930. Localization of hydroxynonenal protein adducts in normal human kidney and selected human kidney cancers Reviewed

    TD Oberley, S Toyokuni, LI Szweda

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27 ( 5-6 ) page: 695 - 703   1999.9

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    Both polyclonal and monoclonal antibodies to 4-hydroxy-2-nonenal (HNE) protein adducts were used to identify lipid peroxidation products in normal human kidney and in selected human kidney cancers using immunoperoxidase techniques at the light microscopic level and immunogold techniques at the ultrastructural level. HNE protein adducts were detected in most cell types in normal kidney, although in highly variable amounts. All six morphologic types of renal tumors examined showed some staining with antibodies to HNE protein adducts, although the intensity of staining Varied considerably depending on tumor type. Renal oncocytoma and the granular cell variant of renal adenocarcinoma both showed greater cytoplasmic staining for HNE protein adducts than the other tumors examined; these tumors both contain high numbers of mitochondria and suggest that mitochondria are a major source of lipid peroxidation products. To test this possibility, immunogold ultrastructural analysis was performed. HNE protein adducts were identified in nuclei and mitochondria in both normal proximal tubule and three types of renal carcinoma examined; these results localize oxidative damage at the subcellular level in both benign and malignant epithelium to nuclei and mitochondria. In conclusion, HNE protein adducts occur in kidneys in both normal and tumor cells, although immunomorphologic analyses suggest less HNE protein adducts in tumor cells. (C) 1999 Elsevier Science Inc.

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  931. Association between M/L55-polymorphism of paraoxonase enzyme and oxidative DNA damage in patients with type 2 diabetes mellitus and in control subjects

    Malin R., Rantalaiho V., Huang X.H., Wirta O., Pasternack A., Leinonen J.S., Alho H., Jokela H., Koivula T., Tanaka T., Okada K., Ochi H., Toyokuni S., Lehtimäki T.

    Human Genetics   Vol. 105 ( 1-2 ) page: 179 - 180   1999.9

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    The paraoxonase enzyme (PON) gene polymorphism causes a change of methionine (M-allele) to leucine (L-allele). PON may reduce low density lipoprotein oxidation and prevent atherosclerosis. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a sensitive index of oxidative DNA damage. We have studied the association between the PON genotypes and the urinary excretion of 8-OHdG. The study population consisted of 93 Finnish type 2 diabetes patients and 106 non-diabetic control subjects. The 24-h excretion of 8-OHdG was significantly higher in diabetic patients than in control subjects (P < 0.001). In control subjects, the ratio of the 8-OHdG/glomerular filtration rate increased in order of genotype from MM to ML to LL (P < 0.0412). These results suggest that lipid peroxidation may have an effect on DNA oxidation.

    DOI: 10.1007/s004399900074

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  932. 4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress - Identification of proteasomes as target molecules Reviewed International journal

    Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 274 ( 34 ) page: 23787 - 23793   1999.8

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  933. 4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules

    Okada K., Wangpoengtrakul C., Osawa T., Toyokuni S., Tanaka K., Uchida K.

    Journal of Biological Chemistry   Vol. 274 ( 34 ) page: 23787 - 23793   1999.8

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    Oxidative stress is associated with important pathophysiological events in a variety of diseases. It has been postulated that free radicals and lipid peroxidation products generated during the process may be responsible for these effects because of their ability to damage cellular components such as membranes, proteins, and DNA. In the present study, we provide evidence that oxidative stress causes a transient impairment of intracellular proteolysis via covalent binding of 4-hydroxy-2-nonenal (HNE), a major end product of lipid peroxidation, to proteasomes. A single intraperitoneal treatment with the renal carcinogen, ferric nitrilotriacetate, caused oxidative stress, as monitored by accumulation of lipid peroxidation products and 8-hydroxy-2'- deoxyguanosine, in the kidney of mice. In addition, transient accumulation of HNE-modified proteins in the kidney was also found by competitive enzyme- linked immunosorbent assay and immunohistochemical analyses. This and the observation that the HNE-modified proteins were significantly ubiquitinated suggested a crucial role of proteasomes in the metabolism of HNE-modified proteins. In vitro incubation of the kidney homogenates with HNE indeed resulted in a transient accumulation of HNE-modified proteins, whereas the proteasome inhibitor significantly suppressed the time-dependent elimination of HNE-modified proteins. We found that, among three proteolytic activities (trypsin, chymotrypsin, and peptidylglutamyl peptide hydrolase activities) of proteasomes, both trypsin and peptidylglutamyl peptide hydrolase activities in the kidney were transiently diminished in accordance with the accumulation of HNE-modified proteins during oxidative stress. The loss of proteasome activities was partially ascribed to the direct attachment of HNE to the protein, based on the detection of HNE-proteasome conjugates by an immunoprecipitation technique. These results suggest that HNE may contribute to the enhanced accumulation of oxidatively modified proteins via an impairment of ubiquitin/proteasome-dependent intracellular proteolysis.

    DOI: 10.1074/jbc.274.34.23787

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  934. Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

    Kondo S, Toyokuni S, Iwasa Y, Tanaka T, Onodera H, Hiai H, Imamura M

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27 ( 3-4 ) page: 401 - 410   1999.8

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  935. Persistent oxidative stress in human colorectal carcinoma, but not in adenoma

    Kondo S., Toyokuni S., Iwasa Y., Tanaka T., Onodera H., Hiai H., Imamura M.

    Free Radical Biology and Medicine   Vol. 27 ( 3-4 ) page: 401 - 410   1999.8

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    Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'- deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3- nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.

    DOI: 10.1016/S0891-5849(99)00087-8

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  936. The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2 '-deoxyguanosine in arsenic-related Bowen's disease

    Matsui M, Nishigori C, Toyokuni S, Takada J, Akaboshi M, Ishikawa M, Imamura S, Miyachi Y

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 113 ( 1 ) page: 26 - 31   1999.7

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  937. The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2 '-deoxyguanosine in arsenic-related Bowen's disease

    Matsui M, Nishigori C, Toyokuni S, Takada J, Akaboshi M, Ishikawa M, Imamura S, Miyachi Y

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 113 ( 1 ) page: 26 - 31   1999.7

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  938. High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

    Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S

    ONCOGENE   Vol. 18 ( 25 ) page: 3793 - 3797   1999.6

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  939. High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

    Tanaka T., Iwasa Y., Kondo S., Hiai H., Toyokuni S.

    Oncogene   Vol. 18 ( 25 ) page: 3793 - 3797   1999.6

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    Ferric nitrilotriacetate induces oxidative damage in renal proximal tubules, a consequence of Fenton-like reaction, that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. In order to find common genetic alterations in this oxystress-induced carcinogengesis model, RCCs were produced in F1 hybrid rats between Wistar and Long-Evans strains and genomes were screened for loss of heterozygosity (LOH) with microsatellite polymorphic markers by PCR. Five consecutive markers on chromosome 5 (D5Mgh5, D5Mit9, D5Mgh6, D5Mit11 and D5Mit6) showed LOH in ≥ 40% of the RCCs. As possible candidate tumor suppressor genes on chromosome 5, p15(INK4B) and p16(INK4A) were investigated for genetic alteration and aberrant methylation by Southern blot, PCR/SSCP/sequencing and methylation-specific PCR. Genetic alteration (homozygous or hemizygous deletion with or without point mutation) or aberrant methylation were found in 30.7 and 53.8% of the RCC cases, respectively, which was proportionally associated with the histological nuclear grade and metastatic activity. Our data suggest that inactivation of p15 and p16 genes could be one of the major pathways responsible for oxystress-induced carcinogenesis.

    DOI: 10.1038/sj.onc.1202707

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  940. High incidence of allelic loss on chromosome 5 and inactivation of p15(INK4B) and p16(INK4A) tumor suppressor genes in oxystress-induced renal cell carcinoma of rats

    Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S

    ONCOGENE   Vol. 18 ( 25 ) page: 3793 - 3797   1999.6

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  941. A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method Reviewed International journal

    Satoh K, Yamada S, Koike Y, Igarashi Y, Toyokuni S, Kumano T, Takahata T, Hayakari M, Tsuchida S, Uchida K

    ANALYTICAL BIOCHEMISTRY   Vol. 270 ( 2 ) page: 323 - 328   1999.6

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  942. A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method

    Satoh K., Yamada S., Koike Y., Igarashi Y., Toyokuni S., Kumano T., Takahata T., Hayakari M., Tsuchida S., Uchida K.

    Analytical Biochemistry   Vol. 270 ( 2 ) page: 323 - 328   1999.6

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    A simple and rapid enzyme-linked immunosorbent assay (ELISA) method for quantitation of acrolein and 4-hydroxy-2-nonenal (HNE)-modified proteins was developed. Microtiter plate wells were precoated and blocked simultaneously with epitope-bound bovine caseins as matrix proteins, and aldehyde-modified proteins were quantitated by a competition assay with a monoclonal antibody specific for acrolein-modified lysine or HNE-modified histidine epitopes. Minimal reaction times required for the coating/blocking; first monoclonal antibody and the peroxidase-conjugated second antibody binding steps were 3, 3, and 7 min, respectively, the former two steps being found to be or akin to diffusion-rate-limiting reactions. The convenient ELISA should find an application for analyses of the intricate processes involved in oxidative stress and carcinogenic insult. The epitope-attachment methodology may also be advantageous for the quantitation of various other biologically important haptenic molecules.

    DOI: 10.1006/abio.1999.4073

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  943. A 1-hour enzyme-linked immunosorbent assay for quantitation of acrolein- and hydroxynonenal-modified proteins by epitope-bound casein matrix method Reviewed International journal

    Satoh K, Yamada S, Koike Y, Igarashi Y, Toyokuni S, Kumano T, Takahata T, Hayakari M, Tsuchida S, Uchida K

    ANALYTICAL BIOCHEMISTRY   Vol. 270 ( 2 ) page: 323 - 328   1999.6

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  944. Intranuclear distribution of 8-hydroxy-2 '-deoxyguanosine: An immunocytochemical study

    Toyokuni S, Iwasa Y, Kondo S, Tanaka T, Ochi H, Hiai H

    JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY   Vol. 47 ( 6 ) page: 833 - 835   1999.6

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  945. Intranuclear distribution of 8-hydroxy-2'-deoxyguanosine: An immunocytochemical study

    Toyokuni S., Iwasa Y., Kondo S., Tanaka T., Ochi H., Hiai H.

    Journal of Histochemistry and Cytochemistry   Vol. 47 ( 6 ) page: 833 - 835   1999.6

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    We used immunofluorescence staining (monoclonal antibody N45.1) with cytological imprinting to study changes in the intranuclear distribution of 8-hydroxy-2'-deoxyguanosine in renal cells of male Wistar rats after oxidative stress by ferric nitrilotriacetate. In the control proximal tubule cells, small spherical signals were uniformly distributed throughout the nuclei. Under oxidative stress, immunofluorescence intensity was increased, especially near nuclear membrane. In cells with nuclear shrinkage or deformity, intense, diffuse signals throughout the nuclei were observed. Our results suggest that specific nuclear sites are vulnerable to oxidative DNA damage and that diffuse intense signals precede cell death after oxidative stress.

    DOI: 10.1177/002215549904700613

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  946. Intranuclear distribution of 8-hydroxy-2'-deoxyguanosine. An immunocytochemical study

    TOYOKUNI S.

    J Histochem Cytochem   Vol. 47 ( 6 ) page: 833 - 835   1999.6

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  947. Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes Reviewed International journal

    Ihara Y, Toyokuni S, Uchida K, Odaka H, Tanaka T, Ikeda H, Hiai H, Seino Y, Yamada Y

    DIABETES   Vol. 48 ( 4 ) page: 927 - 932   1999.4

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  948. Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes Reviewed International journal

    IHARA Y

    Diabetes   Vol. 48 ( 4 ) page: 927 - 932   1999.4

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  949. Reactive oxygen species-induced molecular damage and its application in pathology

    Toyokuni S.

    Pathology International   Vol. 49 ( 2 ) page: 91 - 102   1999.3

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    Recent studies have clarified that reactive oxygen species (ROS) are involved in a diversity of biological phenomena including radiation damage, carcinogenesis, ischemia-reperfusion injury, diabetes mellitus and neurodegenerative diseases. The breakthrough of these fruitful accomplishments was the discovery of an enzyme, superoxide dismutase, by McCord and Fridovich in 1968. In the 1970s and 80s, biochemists and radiation biologists were attracted by the role of ROS in its irreversible damage to biological molecules. In the 1990s, ROS were further found to be a reversible modulator of protein structure as well, and this led to a recent rapid data accumulation on the association of ROS and transcription factors. At the same time, methods to localize ROS-induced damage in paraffin-embedded tissues have been established. This owes to a successful production of antibodies against covalently modified structures specific for ROS-induced damage. The epitopes include 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins. The present article reviews histochemical and immunohistochemical methods to localize ROS-induced damage in tissues and cells, further comments on the association of ROS with transcription factors, and shows a prospective view of ROS-induced carcinogenesis.

    DOI: 10.1046/j.1440-1827.1999.00829.x

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  950. Formation of 4-hydroxy-2-nonenal-modified proteins and 3-nitro-L-tyrosine in rat island skin flaps during and after ischemia Reviewed International journal

    Um SC, Suzuki S, Toyokuni S, Uchida K, Hiai H, Nishimura Y

    ANNALS OF PLASTIC SURGERY   Vol. 42 ( 3 ) page: 293 - 298   1999.3

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  951. Protection of ischemia-reperfusion lung against oxidative stress by nitroglycerin.

    Kawashima, M; Bando, T; Nakamura, T; Yoshimura, T; Hanaoka, N; Hirata, T; Fukuse, T; Hasegawa, S; Toyokuni, S; Hitomi, S; Wada, H

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   Vol. 159 ( 3 ) page: A543 - A543   1999.3

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  952. Protection of ischemia-reperfusion lung against oxidative stress by nitroglycerin.

    Kawashima M, Bando T, Nakamura T, Yoshimura T, Hanaoka N, Hirata T, Fukuse T, Hasegawa S, Toyokuni S, Hitomi S, Wada H

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   Vol. 159 ( 3 ) page: A543 - A543   1999.3

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  953. Formation of 4-hydroxy-2-nonenal-modified proteins and 3-nitro-L-tyrosine in rat island skin flaps during and after ischemia Reviewed International journal

    UM S. C.

    Ann. Plast. Surg.   Vol. 42 ( 3 ) page: 293 - 298   1999.3

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    DOI: 10.1097/00000637-199903000-00011

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  954. Reactive oxygen species-induced molecular damage and its application in pathology

    TOYOKUNI Shinya

    Pathology International   Vol. 49 ( 2 ) page: 91 - 102   1999.2

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  955. Reactive oxygen species-induced molecular damage and its application in pathology

    Toyokuni S

    PATHOLOGY INTERNATIONAL   Vol. 49 ( 2 ) page: 91 - 102   1999.2

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  956. The 4-hydroxy-2-nonenal-derived fluorescent pigment International journal

    Uchida, K; Itakura, K; Oya-Ito, T; Toyokuni, S

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27   page: S100 - S100   1999

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  957. The malondialdehyde-derived fluorescent pigment International journal

    Uchida, K; Sakamoto, S; Itakura, K; Kumazawa, S; Nakayama, T; Toyokuni, S; Osawa, T

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27   page: S100 - S100   1999

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  958. Detection of 8-hydroxy-2′-deoxyguanosine by a monoclonal antibody N45.1 and its application

    Toyokuni, S

    ADVANCES IN DNA DAMAGE AND REPAIR   Vol. 302   page: 395 - 405   1999

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  959. Iron chelators modulate the production of DNA strand breaks and 8-hydroxy-2 '-deoxyguanosine

    Toyokuni S, Sagripanti JL

    FREE RADICAL RESEARCH   Vol. 31 ( 2 ) page: 123 - 128   1999

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  960. hOGG1 overexpression and high 8-Oxo-2'-deoxyguanosine lyase activity in human colorectal carcinoma

    Toyokuni, S; Kondo, S; Tanaka, T; Hiai, H; Onodera, H; Imamura, M

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27   page: S149 - S149   1999

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  961. Oxidative stress in the human stomach infected with <i>Helicobacter pylori</i>:: effect of bacterial eradication

    Pignatelli, B; Li, CQ; Bancel, B; Toyokuni, S; Ohshima, H

    2ND INTERNATIONAL CONGRESS ON GASTROENTEROLOGICAL CARCINOGENESIS     page: 39 - 42   1999

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  962. Association between M/L55-polymorphism of paraoxonase enzyme and oxidative DNA damage in patients with type 2 diabetes mellitus and in control subjects

    Malin R, Rantalaiho V, Huang XH, Wirta O, Pasternack A, Leinonen JS, Alho H, Jokela H, Koivula T, Tanaka T, Okada K, Ochi H, Toyokuni S, Lehtimaki T

    HUMAN GENETICS   Vol. 105 ( 1-2 ) page: 179 - 180   1999

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    DOI: 10.1007/s004390051085

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  963. Spuamous Cell Carcinoma in Thyroid Papillary Carcinoma

    MINAMINO Masayuki, TSUJI Hiroyuki, NAKAMURA Akihiko, INOUE Toshiya, OHNISHI Sumio, HUJISAWA Takuo, YAMASHITA Toshio, TOYOKUNI Shinya

    Practica Oto-Rhino-Laryngologica   Vol. 92 ( 3 ) page: 283 - 286   1999

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    We report the case of a 62-year-old man with a Squamous cell carcinoma of the thyroid gland which had invaded the hypopharynx. Primary squamous cell carcinoma of the thyroid gland is extremely rare. Its clinical course is very aggressive and the prognosis is poor. The patient underwent a radical resection of the thyroid, hypopharynx, larynx and resection of the trachea and esophagus was conducted concomitantly with bilateral neck dissection. Reconstruction of the terminal tracheostomy in the anterior mediastinum was created using a pectoralis major muscle flap.

    DOI: 10.5631/jibirin.92.283

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  964. The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-hydroxy-2'-deoxyguanosine in arsenic-related Bowen's disease

    Matsui M., Nishigori C., Toyokuni S., Takada J., Akaboshi M., Ishikawa M., Imamura S., Miyachi Y.

    Journal of Investigative Dermatology   Vol. 113 ( 1 ) page: 26 - 31   1999

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    Arsenic is widely distributed in nature in the form of either metalloids or chemical compounds, which cause a variety of pathologic conditions including cutaneous and visceral malignancies. Recently, reactive oxygen species have been hypothesized to be one of the causes of arsenic-induced carcinogenesis. 8-Hydroxy-2'-deoxyguanosine is one of the major reactive oxygen species-induced DNA base-modified products that is widely accepted as a sensitive marker of oxidative DNA damage. We studied the presence of 8- hydroxy-2'-deoxyguanosine by immunohistochemistry using N45.1 monoclonal antibody in 28 cases of arsenic-related skin neoplasms and arsenic keratosis as well as in 11 cases of arsenic-unrelated Bowen's diseases. The frequency of 8-hydroxy-2'-deoxyguanosine positive cases was significantly higher in arsenic-related skin neoplasms (22 of 28; 78%) than in arsenic-unrelated Bowen's disease (one of 11; 9%) (p < 0.001 by χ2 test). 8-Hydroxy-2'- deoxyguanosine was also detected in normal tissue adjacent to the arsenic- related Bowen's disease lesions. Furthermore, arsenic was detected by neutron activation analysis in the deparaffined skin tumor samples of arsenic- related disease (four of five; 80%), whereas arsenic was not detected in control samples. Our results strongly suggest the involvement of reactive oxygen species in arsenic-induced human skin cancer.

    DOI: 10.1046/j.1523-1747.1999.00630.x

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  965. The 4-hydroxy-2-nonenal-derived fluorescent pigment Reviewed International journal

    Uchida K, Itakura K, Oya-Ito T, Toyokuni S

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27   page: S100 - S100   1999

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  966. The malondialdehyde-derived fluorescent pigment Reviewed International journal

    Uchida K, Sakamoto S, Itakura K, Kumazawa S, Nakayama T, Toyokuni S, Osawa T

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27   page: S100 - S100   1999

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  967. Oxidative stress in the human stomach infected with Helicobacter pylori: effect of bacterial eradication

    Pignatelli B, Li CQ, Bancel B, Toyokuni S, Ohshima H

    2ND INTERNATIONAL CONGRESS ON GASTROENTEROLOGICAL CARCINOGENESIS     page: 39 - 42   1999

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  968. Iron chelators modulate the production of DNA strand breaks and 8-hydroxy-2 '-deoxyguanosine

    Toyokuni S, Sagripanti JL

    FREE RADICAL RESEARCH   Vol. 31 ( 2 ) page: 123 - 128   1999

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  969. hOGG1 overexpression and high 8-Oxo-2'-deoxyguanosine lyase activity in human colorectal carcinoma

    Toyokuni S, Kondo S, Tanaka T, Hiai H, Onodera H, Imamura M

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 27   page: S149 - S149   1999

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  970. Hyperglycemia causes oxidative stress in pancreatic β-cells of GK rats, a model of type 2 diabetes

    Ihara Y., Toyokuni S., Uchida K., Odaka H., Tanaka T., Ikeda H., Hiai H., Seino Y., Yamada Y.

    Diabetes   Vol. 48 ( 4 ) page: 927 - 932   1999

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    Reactive oxygen species are involved in a diversity of biological phenomena such as inflammation, carcinogenesis, aging, and atherosclerosis. We and other investigators have shown that the level of 8-hydroxy-2'- deoxyguanosine (8-OHdG), a marker for oxidative stress, is increased in either the urine or the mononuclear cells of the blood of type 2 diabetic patients. However, the association between type 2 diabetes and oxidative stress in the pancreatic β-cells has not been previously described. We measured the levels of 8-OHdG and 4-hydroxy-2-nonenal (HNE)-modified proteins in the pancreatic β-cells of GK rats, a model of nonobese type 2 diabetes. Quantitative immunohistochemical analyses with specific antibodies revealed higher levels of 8-OHdG and HNE-modified proteins in the pancreatic β-cells of GK rats than in the control Wistar rats, with the levels increasing proportionally with age and fibrosis of the pancreatic islets. We further investigated whether the levels of 8-OHdG and HNE-modified proteins would be modified in the pancreatic β-cells of GK rats fed with 30% sucrose solution or 50 ppm of voglibose (α-glucosidase inhibitor). In the GK rats, the levels of 8-OHdG and HNE-modified proteins, as well as islet fibrosis, were increased by sucrose treatment but reduced by voglibose treatment. These results indicate that the pancreatic β-cells of GK rats are oxidatively stressed, and that chronic hyperglycemia might be responsible for the oxidative stress observed in the pancreatic β-cells.

    DOI: 10.2337/diabetes.48.4.927

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  971. Detection of 8-hydroxy-2 '-deoxyguanosine by a monoclonal antibody N45.1 and its application

    Toyokuni S

    ADVANCES IN DNA DAMAGE AND REPAIR   Vol. 302   page: 395 - 405   1999

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  972. Association between M/L55-polymorphism of paraoxonase enzyme and oxidative DNA damage in patients with type 2 diabetes mellitus and in control subjects

    Malin R, Rantalaiho V, Huang XH, Wirta O, Pasternack A, Leinonen JS, Alho H, Jokela H, Koivula T, Tanaka T, Okada K, Ochi H, Toyokuni S, Lehtimaki T

    HUMAN GENETICS   Vol. 105 ( 1-2 ) page: 179 - 180   1999

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  973. A study of imprint smear cytology during surgery of mucinous cystic tumor of ovary : A special reference to borderline malignancy

    SHIMIZU Keiko, OGURA Seiko, MURATA Masayoshi, TAKAO Yumi, TOYOKUNI Shinya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 37 ( 6 ) page: 583 - 590   1998.11

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  974. A study of imprint smear cytology during surgery of mucinous cystic tumor of ovary : A special reference to borderline malignancy

    SHIMIZU Keiko, OGURA Seiko, MURATA Masayoshi, TAKAO Yumi, TOYOKUNI Shinya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 37 ( 6 ) page: 583 - 590   1998.11

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  975. Improvement in hepatic lipid peroxidation in patients with complete response to interferon-α treatment for chronic hepatitis C. International journal

    Kageyama, F; Kobayashi, Y; Kawasaki, T; Toyokuni, S; Uchida, K; Nakamura, H

    HEPATOLOGY   Vol. 28 ( 4 ) page: 250A - 250A   1998.10

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  976. Role of cytochrome P450 isoforms and free radicals in endotoxemic liver injury.

    Minamiyama, Y; Takemura, S; Imaoka, S; Toyokuni, S; Funae, Y; Kinoshita, H; Inoue, M

    HEPATOLOGY   Vol. 28 ( 4 ) page: 251A - 251A   1998.10

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  977. Role of cytochrome P450 isoforms and free radicals in endotoxemic liver injury. Reviewed

    Minamiyama Y, Takemura S, Imaoka S, Toyokuni S, Funae Y, Kinoshita H, Inoue M

    HEPATOLOGY   Vol. 28 ( 4 ) page: 251A - 251A   1998.10

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  978. Improvement in hepatic lipid peroxidation in patients with complete response to interferon-alpha treatment for chronic hepatitis C. Reviewed International journal

    Kageyama F, Kobayashi Y, Kawasaki T, Toyokuni S, Uchida K, Nakamura H

    HEPATOLOGY   Vol. 28 ( 4 ) page: 250A - 250A   1998.10

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  979. Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in steatotic rat livers

    Yamagami K, Yamamoto Y, Kume M, Kimoto S, Yamamoto H, Ozaki N, Yamamoto M, Shimahara Y, Toyokuni S, Yamaoka Y

    JOURNAL OF SURGICAL RESEARCH   Vol. 79 ( 1 ) page: 47 - 53   1998.9

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  980. Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in steatotic rat livers

    YAMAGAMI K

    J Surg Res   Vol. 79 ( 1 ) page: 47 - 53   1998.9

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    DOI: 10.1006/jsre.1998.5403

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  981. Development of High-grade Renal Cell Carcinomas in Rats Independently of Somatic Mutations in the Tsc2 and VHL Tumor Suppressor Genes

    TOYOKUNI Shinya, OKADA Kunihiko, KONDO Shohei, NISHIOKA Hiroaki, TANAKA Tomoyuki, NISHIYAMA Yasuyuki, HINO Okio, HIAI Hiroshi

      Vol. 89 ( 8 ) page: 814 - 820   1998.8

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  982. Development of High-grade Renal Cell Carcinomas in Rats Independently of Somatic Mutations in the Tsc2 and VHL Tumor Suppressor Genes

    TOYOKUNI Shinya, OKADA Kunihiko, KONDO Shohei, NISHIOKA Hiroaki, TANAKA Tomoyuki, NISHIYAMA Yasuyuki, HINO Okio, HIAI Hiroshi

    Japanese journal of cancer research : gann   Vol. 89 ( 8 ) page: 814 - 820   1998.8

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  983. Development of high-grade renal cell carcinomas in rats independently of somatic mutations in the Tsc2 and VHL tumor suppressor genes

    Toyokuni S, Okada K, Kondo S, Nishioka H, Tanaka T, Nishiyama Y, Hino O, Hiai H

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 89 ( 8 ) page: 814 - 820   1998.8

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  984. A processed grain food inhibits hepatic injury in endotoxemic rats

    Minamiyama Y, Takemura S, Toyokuni S, Tanimoto Y, Sato EF, Inoue M

    JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY   Vol. 44 ( 4 ) page: 547 - 559   1998.8

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  985. Development of high-grade renal cell carcinomas in rats independently of somatic mutations in the Tsc2 and VHL tumor suppressor genes

    Toyokuni S., Okada K., Kondo S., Nishioka H., Tanaka T., Nishiyama Y., Hino O., Hiai H.

    Japanese Journal of Cancer Research   Vol. 89 ( 8 ) page: 814 - 820   1998.8

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    Ferric nitrilotriacetate (Fe-NTA) induces renal proximal tubular damage that ultimately leads to a high incidence of renal cell carcinoma (RCC) in rats. The RCCs are characterized by 1) high incidence of pulmonary metastasis and peritoneal invasion, 2) high incidence of tumor-associated mortality and 3) possible involvement of reactive oxygen species in carcinogenesis. The present study investigated the possible role of Tsc2 and VHL tumor suppressor genes in this model. Thirty-four Fe-NTA-induced primary RCCs and 20 other primary or metastatic tumors of rats were searched for genetic alteration in all the coding exons of both genes by polymerase chain reaction-single-strand-conformation polymorphism analysis and sequencing in conjunction with morphological evaluation. In the Fe-NTA-induced RCCs, frequency of metastasis or invasion was proportionally associated with the nuclear grade of the tumor (grades 1-3). Only one Fe-NTA-induced RCC of grade 1 revealed missense mutations with loss of heterozygosity in exon 10 of the Tsc2 gene (codons 334, GTG (Val) to GCG (Ala), and 336, TAT (Tyr) to CAT (His)). No mutation was found in the VHL gene. The results suggest that 1) high-grade RCCs can develop in the absence of mutations in the Tsc2 and VHL genes in rats, and that 2) Tsc2 gene somatic mutation can nonetheless be one of the causes of non-Eker rat RCCs.

    DOI: 10.1111/j.1349-7006.1998.tb00633.x

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  986. Development of high-grade renal cell carcinomas in rats independently of somatic mutations in the Tsc2 and VHL tumor suppressor genes

    Toyokuni S, Okada K, Kondo S, Nishioka H, Tanaka T, Nishiyama Y, Hino O, Hiai H

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 89 ( 8 ) page: 814 - 820   1998.8

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  987. Oxidative stress and cancer: The role of redox regulation

    Toyokuni S.

    Biotherapy   Vol. 11 ( 2-3 ) page: 147 - 154   1998.7

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    DOI: 10.1023/A:1007934229968

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  988. Over-expression of glutathione S-transferase Yp isozyme and concomitant down-regulation of Ya isozyme in renal cell carcinoma of rats induced by ferric nitrilotriacetate Reviewed International journal

    Tanaka T, Nishiyama Y, Okada K, Satoh K, Fukuda A, Uchida K, Osawa T, Hiai H, Toyokuni S

    CARCINOGENESIS   Vol. 19 ( 5 ) page: 897 - 903   1998.5

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  989. Oxidative stress in pancreatic β-cells of GK rat, a model of non-obese NIDDM

    Ihara, Y; Yamada, Y; Uchida, K; Toyokuni, S; Seino, Y

    DIABETES   Vol. 47   page: A263 - A263   1998.5

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  990. Oxidative stress in pancreatic beta-cells of GK rat, a model of non-obese NIDDM

    Ihara Y, Yamada Y, Uchida K, Toyokuni S, Seino Y

    DIABETES   Vol. 47   page: A263 - A263   1998.5

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  991. Over-expression of glutathione S-transferase Yp isozyme and concomitant down-regulation of Ya isozyme in renal cell carcinoma of rats induced by ferric nitrilotriacetate

    Tanaka T., Nishiyama Y., Okada K., Satoh K., Fukuda A., Uchida K., Osawa T., Hiai H., Toyokuni S.

    Carcinogenesis   Vol. 19 ( 5 ) page: 897 - 903   1998.5

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular damage, a consequence of iron-catalysed Fenton-like reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Glutathione S-transferase (GST) is a family of enzymes that play an important role in detoxification of hydrophobic and electrophilic molecules, and has been associated with putative preneoplastic foci of rat hepatocarcinogenesis and chemotherapy-resistance of human cancers. Our previous study revealed an induction of π-class glutathione S-transferase (Yp) mRNA in the kidney 3 h after administration of Fe-NTA. In the present study, expression of GST isozymes were further investigated in the Fe-NTA-induced RCCs of rats which are characterized by (1) high incidence of metastasis and invasion, (2) high incidence of tumour-associated mortality, and (3) possible involvement of reactive oxygen species in carcinogenesis. In the Fe-NTA-induced RCCs, the levels of α-class GST (Ya) mRNA and proteins were markedly decreased with no apparent change in the copy number of the gene. In contrast, GST-Yp mRNA and proteins were significantly increased in the RCCs while the total GST enzymatic activity was decreased. Immunohistochemical analysis revealed intense staining of GST-Yp not only in the primary RCCs and its metastatic sites, but also in their non-tumorous part of proximal tubules. The contrastive expression of GST isozymes in this renal carcinogenesis model suggests an alteration of its transcription mechanisms and warrants further investigation of this particular detoxifying enzyme from the viewpoint of reactive oxygen species-induced carcinogenesis.

    DOI: 10.1093/carcin/19.5.897

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  992. Immunohistochemical detection of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver diseases

    Ohhira M, Ohtake T, Matsumoto A, Saito H, Ikuta K, Fujimoto Y, Ono M, Toyokuni S, Kohgo Y

    ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH   Vol. 22 ( 3 ) page: 145S - 149S   1998.5

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  993. Immunohistochemical detection of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver diseases Reviewed

    M Ohhira, T Ohtake, A Matsumoto, H Saito, K Ikuta, Y Fujimoto, M Ono, S Toyokuni, Y Kohgo

    ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH   Vol. 22 ( 3 ) page: 145S - 149S   1998.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:LIPPINCOTT WILLIAMS & WILKINS  

    4-Hydroxy-2-nonenal (HNE) is one of the major components of lipid peroxidation product and has been shown to react with proteins to form HNE-protein adducts. HNE-protein adducts are relatively stable and can be used as a marker of radical-mediated cellular damage. We report herein the immunohistochemical analysis of HNE-protein adducts in human alcoholic liver diseases using a specific monoclonal antibody HNEJ-2. Cytoplasm of hepatocytes and bile duct epithelia was positively stained for HNE-protein adducts, and the nucleus was negligibly stained. The immunohistochemical intensity of hepatocytes was classified into three groups: strong, moderate, and faint staining. Strong staining was found in 43% of alcoholic liver diseases and in 4% of viral liver diseases. Hepatocytes of alcoholic liver diseases contained a higher amount of HNE-protein adducts than those of viral liver diseases, and the difference was statistically significant (p = 0.005; chi(2) test). Semiquantitative analysis of the histological intensities of HNE-protein adducts and iron indicated a significant positive correlation (p = 0.084; Spearman's rank correlation). The localization of HNE-protein adducts and iron in hepatocytes appeared to be identical. These data suggested the correlation between HNE-protein adducts and iron. Our results indicate that HNE-protein adducts, a marker of oxidative stress-induced damage, are increased in human alcoholic liver damage, and that hepatic siderosis may act on the production of free radicals.

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  994. Significant deposition of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver disease; Positive correlation with parenchymal iron.

    Ohhira, M; Ohtake, T; Matsumoto, A; Saito, H; Kawashima, T; Ikuta, K; Tanaka, K; Fujimoto, Y; Ono, M; Toyokuni, S; Kohgo, Y

    GASTROENTEROLOGY   Vol. 114 ( 4 ) page: A1315 - A1315   1998.4

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    DOI: 10.1016/S0016-5085(98)85337-7

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  995. The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-OHdG in arsenic related Bowen's disease.

    Matsui, M; Nishigori, C; Toyokuni, S; Takada, J; Akaboshi, M; Ochi, H; Ishikawa, M; Imamura, S

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 110 ( 4 ) page: 526 - 526   1998.4

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  996. The role of oxidative DNA damage in human arsenic carcinogenesis: Detection of 8-OHdG in arsenic related Bowen's disease.

    Matsui M, Nishigori C, Toyokuni S, Takada J, Akaboshi M, Ochi H, Ishikawa M, Imamura S

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 110 ( 4 ) page: 526 - 526   1998.4

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  997. Enhanced hepatic lipid peroxidation in chronic hepatitis C

    Kageyama F., Kobayashi Y., Koide S., Murohisa G., Otake M., Shimizu E., Sasada Y., Suzuki F., Kawasaki T., Nakamura H., Toyokuni S., Uchida K.

    Japanese Pharmacology and Therapeutics   Vol. 26 ( SUPPL. 2 ) page: 149 - 152   1998.4

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  998. Involvement of nitric oxide in survival of random pattern skin flap

    Um SC, Suzuki S, Toyokuni S, Kim BM, Tanaka T, Hiai H, Nishimura Y

    PLASTIC AND RECONSTRUCTIVE SURGERY   Vol. 101 ( 3 ) page: 785 - 792   1998.3

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  999. Involvement of nitric oxide in survival of random pattern skin flap

    UM SC

    Plast Reconstr Surg   Vol. 101 ( 3 ) page: 785 - 792   1998.3

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    DOI: 10.1097/00006534-199803000-00030

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  1000. Major targets of ROS-induced cancer in rats are p15/p16 oncosuppressor genes

    Toyokuni, S; Tanaka, T; Iwasa, Y; Kondo, S; Hiai, H

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 25   page: S119 - S119   1998

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    DOI: 10.1016/S0891-5849(98)90367-7

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  1001. A processed grain food AOB inhibits hepatic injury in endotoxemic rats

    Minamiyama, Y; Takemura, S; Toyokuni, S; Tanimoto, Y; Sato, EF; Inoue, M

    BIOLOGICAL OXIDANTS AND ANTIOXIDANTS: MOLECULAR MECHANISMS AND HEALTH EFFECTS     page: 349 - 357   1998

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  1002. A processed grain food inhibits hepatic injury in endotoxemic rats Reviewed

    Minamiyama Y, Takemura S, Toyokuni S, Tanimoto Y, Sato EF, Inoue M

    JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY   Vol. 44 ( 4 ) page: 547 - 559   1998

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    Although various antioxidants have been tested as therapeutics for endotoxemic subjects, the results of their efficacy are conflicting. Antioxidant biofactor (AOB) is a unique processed grain food that exhibits strong antioxidant activity (Minamiyama et al, J Nutr Sci Vitaminol, 40: 467-477, 1994). The present study was carried out to test the effect of AOB on hepatic injury in rats induced by lipopolysaccharide (LPS). Intravenous administration of LPS induced liver injury with a concomitant increase in hepatic generation of nitric oxide (NO) and 4-hydroxy-2nonenal (HNE) modified proteins in the control group. The administration of AOB significantly inhibited the LPS-induced hepatic injury and generation of HNE-modified proteins and increased the survival rate of endotoxemic rats without affecting NO generation and plasma levels of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). AOB scavenged superoxide radicals without affecting NO production by LPS-stimulated macrophage cell line J 774.2 cells. AOB also inhibited lipid peroxidation induced by LPS in the cells. These results suggested that AOB might scavenge superoxide radicals and decrease toxic metabolites including HNE, thereby inhibiting liver injury in endotoxemic rats.

    DOI: 10.3177/jnsv.44.547

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  1003. Oxidative stress and cancer: The role of redox regulation

    Toyokuni S

    BIOTHERAPY   Vol. 11 ( 2-3 ) page: 147 - 154   1998

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  1004. A study of imprint smear cytology during surgery of mucinous cystic tumor of ovary. A special reference to borderline malignancy.:A special reference to borderline malignancy

    SHIMIZU Keiko, OGURA Seiko, MURATA Masayoshi, TAKAO Yumi, TOYOKUNI Shinya, SAKURAI Masami

    The Journal of the Japanese Society of Clinical Cytology   Vol. 37 ( 6 ) page: 583 - 590   1998

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    <B><I>Objective</I>:</B> Preoperative diagnosis of ovarian tumors is often difficult. Additional squashed smear cytology during surgery was undertaken for the correct diagnosis of mucinous cystic tumors of the ovary.<BR><B><I>Study Design</I>:</B> We reviewed the cytological findings of imprint smear during surgery of 34 cases with mucinous cystic tumors of the ovary, especially borderline malignant cases, that we have experienced over an 8 year period (1990-1997). Additional squashed smears were applied in some recent cases and compared with the routine imprint smears.<BR><B><I>Results</I>:</B> Characteristic cytological findings of mucinous cystic tumors of borderline malignancy were relatively clear background, crowded clumps of cells, and papillary and ball-like architectures.<BR>In some cases, an additinal squashed smear technique was useful for the correctdiagnosis, because the structure of cell clusters became more apparent.<BR><B><I>Conclusion</I>:</B> It was possible to differentiate borderline cases from malignancies, but was difficult to differentiate borderline cases from benign cases by cytological examinations.<BR>The additional of the squashed smear technique was useful for correct cytological diagnosis.

    DOI: 10.5795/jjscc.37.583

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  1005. Oxidative stress and cancer: The role of redox regulation Reviewed

    S Toyokuni

    BIOTHERAPY   Vol. 11 ( 2-3 ) page: 147 - 154   1998

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  1006. Immunohistochemical detection of 4-hydroxy-2-nonenal-modified-protein adducts in human alcoholic liver diseases

    Ohhira M., Ohtake T., Matsumoto A., Saito H., Ikuta K., Fujimoto Y., Ono M., Toyokuni S., Kohgo Y.

    Alcoholism: Clinical and Experimental Research   Vol. 22 ( 3 SUPPL. 1 )   1998

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    4-Hydroxy-2-nonenal (HNE) is one of the major components of lipid peroxidation product and has been shown to react with proteins to form HNE-protein adducts. HNE-protein adducts are relatively stable and can be used as a marker of radical-mediated cellular damage. We report herein the immunohistochemical analysis of HNE-protein adducts in human alcoholic liver diseases using a specific monoclonal antibody HNEJ-2. Cytoplasm of hepatocytes and bile duct epithelia was positively stained for HNE-protein adducts, and the nucleus was negligibly stained. The immunohistochemical intensity of hepatocytes was classified into three groups: strong, moderate, and faint staining. Strong staining was found in 43% of alcoholic liver diseases and in 4% of viral liver diseases. Hepatocytes of alcoholic liver diseases contained a higher amount of HNE-protein adducts than those of viral liver diseases, and the difference was statistically significant (p = 0.005; χ2 test). Semiquantitative analysis of the histological intensities of HNE-protein adducts and iron indicated a significant positive correlation (p = 0.084; Spearman's rank correlation). The localization of HNE-protein adducts and iron in hepatocytes appeared to be identical. These data suggested the correlation between HNE-protein adducts and iron. Our results indicate that HNE-protein adducts, a marker of oxidative stress-induced damage, are increased in human alcoholic liver damage, and that hepatic siderosis may act on the production of free radicals. Copyright © 1998 by The Research Society on Alcoholism.

    DOI: 10.1111/acer.1998.22.s3_part1.145s

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  1007. A processed grain food AOB inhibits hepatic injury in endotoxemic rats Reviewed International journal

    Minamiyama, Y, Takemura, S, Toyokuni, S, Tanimoto, Y, Sato, EF, Inoue, M

    BIOLOGICAL OXIDANTS AND ANTIOXIDANTS: MOLECULAR MECHANISMS AND HEALTH EFFECTS     page: 349 - 357   1998

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  1008. New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus

    Leinonen J., Lehtimäki T., Toyokuni S., Okada K., Tanaka T., Hiai H., Ochi H., Laippala P., Rantalaiho V., Wirta O., Pasternack A., Alho H.

    FEBS Letters   Vol. 417 ( 1 ) page: 150 - 152   1997.11

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    Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. We have investigated oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus (NIDDM) by urinary 8-OHdG assessments. We determined the total urinary excretion of and OHdG from 24 h urine samples of 81 NIDDM patients 9 years after the initial diagnosis and of 100 non-diabetic control subjects matched for age and gender. The total 24 h urinary excretion of 8-OHdG was markedly higher in NIDDM patients than in control subjects (68.2 ± 39.4 μg vs, 49.6 ± 37.7 μg, P= 0.001). High glycosylated hemoglobin was associated with a high level of urinary 8-OHdG. The increased excretion of urinary and OHdG is seen as indicating an increased systemic level of oxidative DNA damage in NIDDM patients.

    DOI: 10.1016/S0014-5793(97)01273-8

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  1009. New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus

    Leinonen J, Lehtimaki T, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, Laippala P, Rantalaiho V, Wirta O, Pasternack A, Alho H

    FEBS LETTERS   Vol. 417 ( 1 ) page: 150 - 152   1997.11

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  1010. Protein modification by lipid peroxidation products: Formation of malondialdehyde-derived N epsilon-(2-propenal)lysine in proteins Reviewed International journal

    Uchida K, Sakai K, Itakura K, Osawa T, Toyokuni S

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 346 ( 1 ) page: 45 - 52   1997.10

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  1011. Protein modification by lipid peroxidation products: Formation of malondialdehyde-derived N(ε)(2-propenal)lysine in proteins

    Uchida K., Sakai K., Itakura K., Osawa T., Toyokuni S.

    Archives of Biochemistry and Biophysics   Vol. 346 ( 1 ) page: 45 - 52   1997.10

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    Malondialdehyde (MDA), a naturally occurring dialdehyde produced in the membrane lipid peroxidation, is known to react with lysine residues of proteins, but the MDA-lysine adducts generated in the proteins have not been characterized adequately. In the present study, we provide evidence that the enaminal-type MDA-lysine adduct, N(ε)-(2-propenal)lysine, is formed in human low-density lipoprotein (LDL) upon reaction with MDA or Cu2+. We found that the incubation of N(α)acetyllysine with MDA generated N(α)-acetyl-N(ε)- (2-propenal)lysine as the predominant product. In addition, a polyclonal antiserum raised against the MDA-modified protein was found to contain antibody populations that could be purified by affinity gel prepared by covalent attachment of N(α)-acetyl-N(ε)-(2-propenal)lysine. It was concluded that the affinity-purified anti-N(ε)-(2-propenal) lysine antibody was highly specific to the enaminal derivative of both lysine residues and phosphatidylethanolamine, based on the observations that (i) MDA was the only aldehyde which generated immunoreactive materials in proteins; (ii) among structurally defined MDA-lysine adducts tested, the antibody recognized the enaminal adduct only; and (iii) immunoreactivity to N(2-propenal)serine was still significant but much weaker than its reactivity to N-(2- propenal)ethanol- amine. Furthermore, analysis of antibody recognition sites with a variety of N-(2-propenal)alkylamines revealed that the mono-specific antibody recognized the N-2-propenal-N-ethyl moiety [-(CH2)2-NH-CH=CH - CHO] of enaminal adducts. Determination by a competitive enzyme-linked immunosorbent assay demonstrated that N(ε)-(2-propenal)lysine accounted for 33.7 and 3.1% of the lysine residues that disappeared during in vitro incubation of LDL with MDA and Cu2+, respectively. These results suggest that N(ε)-(2-propenal)lysine represents a major form of MDA covalently attached to proteins.

    DOI: 10.1006/abbi.1997.0266

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  1012. Enhanced hepatic lipid peroxidation in chronic hepatitis C. International journal

    Kageyama, F; Kobayashi, Y; Kawasaki, T; Nakamura, H; Toyokuni, S; Uchida, K

    HEPATOLOGY   Vol. 26 ( 4 ) page: 79 - 79   1997.10

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  1013. Impact of the protection from free radical injury in heat shock preconditioning against ischemia-reperfusion injury in steatotic rat livers.

    Yamagami, K; Yamamoto, Y; Kume, M; Kimoto, S; Ozaki, N; Toyokuni, S; Yamaoka, Y

    HEPATOLOGY   Vol. 26 ( 4 ) page: 844 - 844   1997.10

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  1014. Impact of the protection from free radical injury in heat shock preconditioning against ischemia-reperfusion injury in steatotic rat livers.

    Yamagami K, Yamamoto Y, Kume M, Kimoto S, Ozaki N, Toyokuni S, Yamaoka Y

    HEPATOLOGY   Vol. 26 ( 4 ) page: 844 - 844   1997.10

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  1015. Enhanced hepatic lipid peroxidation in chronic hepatitis C [abstract]. Reviewed International journal

    KAGEYAMA F.

    Hepatology   Vol. 26 ( 4 ) page: 79 - 79   1997.10

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  1016. Induction and nuclear translocation of thioredoxin by oxidative damage in the mouse kidney: Independence of tubular necrosis and sulfhydryl depletion

    Tanaka T., Nishiyama Y., Okada K., Hirota K., Matsui M., Yodoi J., Hiai H., Toyokuni S.

    Laboratory Investigation   Vol. 77 ( 2 ) page: 145 - 155   1997.8

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    Adult T-cell leukemia-derived factor (ADF), originally defined as an interleukin-2 receptor inducer, is a human thioredoxin (TRX). ADF/TRX is a conserved multifunctional reductant presumably associated with redox regulation of the cellular environment; it works in vitro as a cytokine, free radical scavenger, activator of transcription factors, and substrate for several enzymes. In the present series of experiments, we studied the expression and intracellular localization of ADF/TRX in mouse kidney from two different renal tubular injury models: a free radical-associated model with ferric nitrilotriacetate (Fe-NTA) and a free radical-independent model with HgCI2. Markers of oxidative damage, such as 8-hydroxy-2'-deoxyguanosine, thiobarbituric acid-reactive substances, and 4-hydroxy-2-nonenal-modified proteins, were significantly increased in kidney from male C57BL/6 mice 1 hour after a single intraperitoneal injection of Fe-NTA (5 mg iron/kg). However, in kidney from mice given a subcutaneous injection of HgCI2 (5 mg Hg/kg), none of these markers were increased, despite tubular necrosis with sulfhydryl depletion. In the Fe-NTA model only, Northern and Western blot analyses of the kidney revealed induction of ADF/TRX (> 2.5-fold) after 16 hours and translocation of ADF/TRX from the cytoplasmic to nuclear fraction (> 3.5-fold) after 24 hours. Immunohistochemistry showed a catchy distribution of ADF/TRX in the normal renal proximal tubules. In ex vivo experiments using serial normal kidney frozen sections, it was found mat renal proximal tubules with low expression of ADF/FRX were more vulnerable to oxidative stress mediated by Fe-NTA. Collectively, these data suggest that: (a) ADF/TRX is induced and translocated to nuclei by oxidative damage mediated by Fe-NTA in the renal proximal tubules: (b) induction of ADF/TRX is independent of tubular necrosis or sulfhydryl depletion; and (c) ADF/TRX is involved in the cellular defense mechanisms in vive against oxidative damage.

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  1017. Induction and nuclear translocation of thioredoxin by oxidative damage in the mouse kidney: Independence of tubular necrosis and sulfhydryl depletion

    Tanaka T, Nishiyama Y, Okada K, Hirota K, Matsui M, Yodoi J, Hiai H, Toyokuni S

    LABORATORY INVESTIGATION   Vol. 77 ( 2 ) page: 145 - 155   1997.8

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  1018. Induction and nuclear translocation of thioredoxin by oxidative damage in the mouse kidney: independence of tubular necrosis and sulfhydryl depletion.

    Tanaka T, Nishiyama Y, Okada K, Hirota K, Matsui M, Yodoi J, Hiai H, Toyokuni S

    Laboratory investigation; a journal of technical methods and pathology   Vol. 77 ( 2 ) page: 145 - 55   1997.8

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    PubMed

  1019. Biomarker evidence of DNA oxidation in lung cancer patients: Association of urinary 8-hydroxy-2'-deoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment

    Erhola M., Toyokuni S., Okada K., Tanaka T., Hiai H., Ochi H., Uchida K., Osawa T., Nieminen M.M., Alho H., Kellokumpu-Lehtinen P.

    FEBS Letters   Vol. 409 ( 2 ) page: 287 - 291   1997.6

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    Ratios of urinary 8-hydroxy-2'-deoxyguanosine to urinary creatinine (8-OHdG/creatinine) have been considered as a good biological indicator of DNA oxidation. Urinary 8-OHdG/creatinine levels of lung cancer patients were evaluated by enzyme-linked immunosorbent assay using a monoclonal antibody N45.1 during radiotherapy and chemotherapy. An increase in urinary 8-OHdG/creatinine was found in non-small-cell carcinoma (non-SCC) patients during the course of radiotherapy. SCC patients showed higher levels of urinary 8-OHdG/creatinine than the controls. Furthermore, SCC patients with complete or partial response to the chemotherapy showed a significant decrease in urinary 8-OHdG/creatinine while patients with no change or progressive disease showed an increase.

    DOI: 10.1016/S0014-5793(97)00523-1

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  1020. Biomarker evidence of DNA oxidation in lung cancer patients: Association of urinary 8-hydroxy-2'-deoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment

    Erhola M, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, Uchida K, Osawa T, Nieminen MM, Alho H, KellokumpuLehtinen P

    FEBS LETTERS   Vol. 409 ( 2 ) page: 287 - 291   1997.6

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  1021. Biomarker evidence of DNA oxidation in lung cancer patients: Association of urinary 8-hydroxy-2'-deoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment Reviewed International coauthorship International journal

    Erhola M, Toyokuni S, Okada K, Tanaka T, Hiai H, Ochi H, Uchida K, Osawa T, Nieminen MM, Alho H, KellokumpuLehtinen P

    FEBS LETTERS   Vol. 409 ( 2 ) page: 287 - 291   1997.6

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  1022. Protection by αG-Rutin, a Water-soluble Antioxidant Flavonoid, against Renal Damage in Mice Treated with Ferric Nitrilotriacetate

    SHIMOI Kayoko, SHEN Bingrong, TOYOKUNI Shinya, MOCHIZUKI Rika, FURUGORI Michiyo, KINAE Naohide

    Jpn. J. Cancer Res.   Vol. 88 ( 5 ) page: 453 - 460   1997.5

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  1023. Protection by αG-Rutin, a Water-soluble Antioxidant Flavonoid, against Renal Damage in Mice Treated with Ferric Nitrilotriacetate

    SHIMOI Kayoko, SHEN Bingrong, TOYOKUNI Shinya, MOCHIZUKI Rika, FURUGORI Michiyo, KINAE Naohide

    Japanese journal of cancer research : gann   Vol. 88 ( 5 ) page: 453 - 460   1997.5

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  1024. Protection by alpha G-rutin, a water-soluble antioxidant flavonoid, against renal damage in mice treated with ferric nitrilotriacetate

    Shimoi K, Shen BR, Toyokuni S, Mochizuki R, Furugori M, Kinae N

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 88 ( 5 ) page: 453 - 460   1997.5

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  1025. Protection by αG-Rutin, a water-soluble antioxidant flavonoid, against renal damage in mice treated with ferric nitrilotriacetate

    Shimoi K., Shen B., Toyokuni S., Mochizuki R., Furugori M., Kinae N.

    Japanese Journal of Cancer Research   Vol. 88 ( 5 ) page: 453 - 460   1997.5

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    The protective effect of αG-Rutin against ferric nitrilotriacetate (Fe-NTA)-induced renal damage was studied in male ICR mice. Fe-NTA induces renal lipid peroxidation, leading to a high incidence of renal cell carcinoma in rodents. Administration of αG-Rutin (50 μmol as rutin/kg) by gastric intubation 30 min after i.p. injection of Fe-NTA (7 mg Fe/kg) most effectively suppressed renal lipid peroxidation. Repeated i.p. injection of Fe-NTA (2 mg Fe/kg/day for the first 3 days and 3 mg Fe/kg/day for 12 days, 5 days a week) causes subacute nephrotoxicity as revealed by induction of karyomegalic cells in renal proximal tubules. A protective effect was observed in mice given αG-Rutin 30 min after each Fe-NTA treatment. To elucidate the mechanism of protection by αG-Rutin, the pharmacokinetics and hydroxyl radical-scavenging effect of αG-Rutin were investigated by HPLC analysis and by electron spin resonance (ESR) spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), respectively. When mice were given αG-Rutin (50 μmol as rutin/kg) by gastric intubation, rapid absorption into the circulation was observed. The plasma concentration of αG-Rutin reached the highest level 30 min after oral administration and then decreased to the control level within 60 min. αG-Rutin inhibited the formation of DMPO-OH in a concentration-dependent manner. Further, chelating activity of αG-Rutin to ferric ions was shown by spectrophotometric analysis. These results suggest that absorbed αG-Rutin works as an antioxidant in vivo either by scavenging reactive oxygen species or by chelating ferric ions and this serves to prevent oxidative renal damage in mice treated with Fe-NTA.

    DOI: 10.1111/j.1349-7006.1997.tb00403.x

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  1026. Protection by alpha G-rutin, a water-soluble antioxidant flavonoid, against renal damage in mice treated with ferric nitrilotriacetate

    Shimoi K, Shen BR, Toyokuni S, Mochizuki R, Furugori M, Kinae N

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 88 ( 5 ) page: 453 - 460   1997.5

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  1027. Copper and iron-induced oxidative damage in non-tumor bearing LEC rats Reviewed International journal

    Ma YX, Zhang DX, Kawabata T, Kiriu T, Toyokuni S, Uchida K, Okada S

    PATHOLOGY INTERNATIONAL   Vol. 47 ( 4 ) page: 203 - 208   1997.4

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  1028. Copper and iron-induced oxidative damage in non-tumor bearing LEC rats

    MA Yuxiang, ZHANG Daxian, KAWABATA Teruyuki, KIRIU Takahiro, TOYOKUNI Shinya, UCHIDA Koji, OKADA Shigeru

    Pathology International   Vol. 47 ( 4 ) page: 203 - 208   1997.4

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  1029. Copper and iron-induced oxidative damage in non-tumor bearing LEC rats Reviewed

    YX Ma, DX Zhang, T Kawabata, T Kiriu, S Toyokuni, K Uchida, S Okada

    PATHOLOGY INTERNATIONAL   Vol. 47 ( 4 ) page: 203 - 208   1997.4

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    The copper and iron status in the liver of non-tumor bearing Long-Evans Cinnamon (LEC) rats (average age 17 months) was investigated. A direct quantitation of loosely-bound copper anti iron was also investigated by using a chelating agent, nitrilotriacetic acid (NTA-chelatable free copper and iron). Besides the total copper and iron contents, the level of NTA-chelatable free copper was also higher in LEC rats than in LEA rats (P&lt;0.05). But for the free iron level there was no significant difference between the two rat groups (P&gt;0.05). The formation of thiobarbituric acid-reactive substances was higher in LEC rats than in LEA mts (P&lt;0.01). The 4-hydroxy-2-nonenal (HNE)-modified proteins were also clearly demonstrated in LEC rat liver. The copper and iron which produced the most important effect in the process of oxidative damage in LEC rats could not be distinguished. Even though free copper, which could induce free radical injuries, was increased in LEC rats, neither tumor-induction nor preneoplastic lesions in the experimental LEC rats were observed. therefore it is speculated that the elevation of a free iron is another important factor. Copper and iron, both important transition metals In the body, may participate in the induction of DNA damage and oncogenesis.

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  1030. Quantitative immunohistochemical determination of 8-hydroxy-2'-deoxyguanosine by a monoclonal antibody N45.1: Its application to ferric nitrilotriacetate-induced renal carcinogenesis model Reviewed International journal

    Toyokuni S, Tanaka T, Hatton Y, Nishiyama Y, Yoshida A, Uchida K, Hiai H, Ochi H, Osawa T

    LABORATORY INVESTIGATION   Vol. 76 ( 3 ) page: 365 - 374   1997.3

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  1031. Quantitative immunohistochemical determination of 8-hydroxy-2'-deoxyguanosine by a monoclonal antibody N45.1: Its application to ferric nitrilotriacetate-induced renal carcinogenesis model Reviewed International journal

    Toyokuni S, Tanaka T, Hatton Y, Nishiyama Y, Yoshida A, Uchida K, Hiai H, Ochi H, Osawa T

    LABORATORY INVESTIGATION   Vol. 76 ( 3 ) page: 365 - 374   1997.3

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  1032. Quantitative immunohistochemical determination of 8-hydroxy-2'- deoxyguanosine by a monoclonal antibody N45.1: Its application to ferric nitrilotriacetate-induced renal carcinogenesis model

    Toyokuni S., Tanaka T., Hattori Y., Nishiyama Y., Yoshida A., Uchida K., Hiai H., Ochi H., Osawa T.

    Laboratory Investigation   Vol. 76 ( 3 ) page: 365 - 374   1997.3

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    The DNA base-modified product 8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most commonly used markers for the evaluation of oxidative DNA damage. A monoclonal antibody specific for 8-OHdG (N45.1) was characterized end applied in quantitative immunohistochemistry. N45.1 recognized both the modified base and deoxyribose structure of 8-OHdG and required a concentration two orders higher of 8-hydroxyguanosine as a competitor in the ELISA. In addition, N45.1 did not cross-react with the original four deoxyribonucleosides, other DNA base-modified products such as 8-hydroxy-2'- deoxyadenosine and O6-methyl-2'-deoxyguanosine, or urine components such as uric acid, creatine, and creatinine. A ferric nitrilotriacetate-induced rat renal carcinogenesis model was used for the evaluation of quantitative immunohistochemistry. The 8-OHdG index of quantitative immunohistochemistry, as analyzed by NIH Image freeware, correlated reasonably well with the 8- OHdG amount determined by high-performance liquid chromatography with an electrochemical detector-except for a difference in peak time, which could be attributed to the selection of target location. The present method has advantages over the high-performance liquid chromatography/electrochemical detector, gas chromatography/mass spectrometry, and 32P-postlabeling methods in that it allows localization of 8-OHdG to be specified without the risk of artifactual production of 8-OHdG during the DNA extraction and hydrolytic processes.

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  1033. Quantitative immunohistochemical determination of 8-hydroxy-2'-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model.

    Toyokuni S, Tanaka T, Hattori Y, Nishiyama Y, Yoshida A, Uchida K, Hiai H, Ochi H, Osawa T

    Laboratory investigation; a journal of technical methods and pathology   Vol. 76 ( 3 ) page: 365 - 74   1997.3

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  1034. Overexpression of Integrin-associated Protein (CD47) in Rat Kidney Treated with a Renal Carcinogen, Ferric Nitrilotriacetate

    NISHIYAMA Yasuyuki, TANAKA Tomoyuki, NAITOH Hiroshi, MORI Chisato, FUKUMOTO Manabu, HIAI Hiroshi, TOYOKUNI Shinya

    Jpn, J. Cancer Res.   Vol. 88 ( 2 ) page: 120 - 128   1997.2

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  1035. Overexpression of Integrin-associated Protein (CD47) in Rat Kidney Treated with a Renal Carcinogen, Ferric Nitrilotriacetate

    NISHIYAMA Yasuyuki, TANAKA Tomoyuki, NAITOH Hiroshi, MORI Chisato, FUKUMOTO Manabu, HIAI Hiroshi, TOYOKUNI Shinya

    Japanese journal of cancer research : gann   Vol. 88 ( 2 ) page: 120 - 128   1997.2

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  1036. Induction of a wide range of C<inf>2-12</inf> aldehydes and C<inf>7-12</inf> acyloins in the kidney of wistar rats after treatment with a renal carcinogen, ferric nitrilotriacetate

    Toyokuni S., Luo X.P., Tanaka T., Uchida K., Hiai H., Lehotay D.C.

    Free Radical Biology and Medicine   Vol. 22 ( 6 ) page: 1019 - 1027   1997.2

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis associated with lipid peroxidation and oxidative DNA damage that finally leads to a high incidence of renal cell carcinoma in rodents. In the present study, we investigated what kinds of C2-12 saturated and unsaturated aldehydes and C7-12 acyloins, metabolites of saturated aldehydes, are produced in the kidney and liver within 24 h after single ip administration of 15 mg Fe/kg of Fe-NTA, or after repeated (1 or 3 wk) ip administration of 5-10 mg Fe/kg of Fe-NTA. Amounts of twenty one aldehydes and five acyloins were determined by capillary column gas chromatography-negative-ion chemical ionization mass spectrometry with ammonia as reagent gas. Most of the aldehydes and all the acyloins measured revealed a significant dose-dependent increase 1 to 3 h after single administration in the kidney, among which 4-hydroxy-2-nonenal (HNE) showed the highest increase (27.3-fold) and malondialdehyde (MDA) was the most abundant aldehyde (2.40 nmol/100 mg wet tissue). In the liver, however, the increase in aldehydes and acyloins was less prominent. After repeated administration of Fe-NTA, only 9 aldehydes (ethanal; furfural; trans, trans- 2,4-heptadienal; nonanal; trans-2, cis-6 nonadienal; HNE; decanal; trans-4, cis-4-decenal; MDA) and 4 acyloins (3-hydroxyheptan-2-one; 3-hydroxyoctan-2- one; 3-hydroxynonan-2-one; 3-hydroxydodecan-2-one) showed a significant increase. Immunohistochemistry further demonstrated an increased amount of HNE-modified and MDA-modified proteins in the renal proximal tubules after repeated Fe-NTA administration. Some of the aldehydes measured such as HNE and MDA are reportedly cytotoxic, genotoxic and mutagenic. Accumulation of these aldehydes may play a role in this renal carcinogenesis model.

    DOI: 10.1016/S0891-5849(96)00489-3

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  1037. 8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure (vol 107, pg 733, 1996)

    Hattori, Y; Nishigori, C; Tanaka, T; Uchida, K; Nikaido, O; Osawa, T; Hiai, H; Imamura, S; Toyokuni, S

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 108 ( 2 ) page: 237 - 237   1997.2

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  1038. Overexpression of integrin-associated protein (CD47) in rat kidney treated with a renal carcinogen, ferric nitrilotriacetate

    Nishiyama Y, Tanaka T, Naitoh H, Mori C, Fukumoto M, Hiai H, Toyokuni S

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 88 ( 2 ) page: 120 - 128   1997.2

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  1039. Induction of a wide range of C-2-12 aldehydes and C-7-12 acyloins in the kidney of Wistar rats after treatment with a renal carcinogen, ferric nitrilotriacetate Reviewed International journal

    Toyokuni S, Luo XP, Tanaka T, Uchida K, Hiai H, Lehotay DC

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 22 ( 6 ) page: 1019 - 1027   1997

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  1040. A case of malignant myoenithelioma in the hard palate

    KITA Jun, IWAI Hiroshi, TOYOKUNI Shinya, YANAGIDA Masahiro, KAWASAKI Eiko, MINAMINO Masayuki, NAKASHIMA Yasuaki, YAMASHITA Toshio

    OTOLOGIA FUKUOKA   Vol. 43 ( 1 ) page: 30 - 33   1997

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    A rare case of low grade malignant myoepithelioma arising from the hard palate is reported. The CT findings indicated a defect of the hard palate due to the tumor. Surgery combined with postoperative irradiation therapy was performed. A histopathological examination indicated that the tumor originated in the myoepithelial cells, invaded the hard palate, and also showed cellular atypia with rare mitoses. Malignant myoepithelioma clinically shows a low sensitivity to both radiation therapy and chemotherapy. Surgery should thus be the first choice of treatment.

    DOI: 10.11334/jibi1954.43.1_30

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  1041. Overexpression of integrin-associated protein (CD47) in rat kidney treated with renal carcinogen, ferric nitrilotriacetate

    Nishiyama Y., Tanaka T., Naitoh H., Mori C., Fukumoto M., Hiai H., Toyokuni S.

    Japanese Journal of Cancer Research   Vol. 88 ( 2 ) page: 120 - 128   1997

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis, a consequence of free radical-associated damage, that ultimately leads to a polycystic change of the renal cortex and a high incidence of renal cell carcinoma (RCC) in rodents. The differential display technique was used to search for inducible genes in the kidney of male Wistar rats treated with Fe-NTA and in the induced RCCs. Six fragments were selected that showed specific quantitative changes in mRNA. Two of them exhibited similar patterns in northern blots as well. One fragment showed a high homology (89%) to murine integrin-associated protein (IAP; CD47). We thus cloned rat IAP cDNA including the entire coding region for use in further analysis. Rat IAP cDNA showed a 21-amino-acid deletion that was also observed in human, but not in mouse. Northern blots revealed that IAP was consistently overexpressed in non-tumorous parts of the kidney (2.4-fold increase, n = 9, P < 0.0001) as compared with matched controls 1 to 2 years after Fe-NTA treatment. IAP overexpression of more than 2.9-fold was found in 25% (2/8) of RCCs studied, and was limited to cases of a high histological grade and lung metastasis. Unexpectedly, IAP expression was higher in the non-tumorous part of the kidney after Fe-NTA treatment (2.8-fold) than in RCC (1.5-fold) in each case (n = 4, P < 0.05). Abundant expression of IAP mRNA in the renal tubular epithelium after Fe-NTA treatment and RCC cells was observed by in situ hybridization. The results suggest that IAP overexpression may be associated with Fe-NTA-induced renal cortical tubular damage and regeneration that lead to a polycystic state, and with tumor progression and metastasis of the induced RCCs.

    DOI: 10.1111/j.1349-7006.1997.tb00356.x

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  1042. Induction of a wide range of C-2-12 aldehydes and C-7-12 acyloins in the kidney of Wistar rats after treatment with a renal carcinogen, ferric nitrilotriacetate Reviewed

    S Toyokuni, XP Luo, T Tanaka, K Uchida, H Hiai, DC Lehotay

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 22 ( 6 ) page: 1019 - 1027   1997

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis associated with lipid peroxidation and oxidative DNA damage that finally leads to a high incidence of renal cell carcinoma in rodents. In the present study, we investigated what kinds of C-2-12 saturated and unsaturated aldehydes and C-7-12 acyloins, metabolites of saturated aldehydes, are produced in the kidney and liver within 24 h after single ip administration of 15 mg Fe/kg of Fe-NTA, or after repeated (1 or 3 wk) ip administration of 5-10 mg Fe/kg of Fe-NTA. Amounts of twenty one aldehydes and five acyloins were determined by capillary column gas chromatography-negative-ion chemical ionization mass spectrometry with ammonia as reagent gas. Most of the aldehydes and all the acyloins measured revealed a significant dose-dependent increase 1 to 3 h after single administration in the kidney, among which 4-hydroxy-2-nonenal (HNE) showed the highest increase (27.3-fold) and malondialdehyde (MDA) was the most abundant aldehyde (2.40 nmol/100 mg wet tissue). In the liver, however, the increase in aldehydes and acyloins was less prominent. After repeated administration of Fe-NTA, only 9 aldehydes (ethanal; furfural; trans,trans-2,4-heptadienal; nonanal; trans-2,cis-6-nonadienal; HNE; decanal; trans-4,cis-4-decenal; MDA) and 4 acyloins (3-hydroxyheptan-2-one; 3-hydroxyoctan-2-one; 3-hydroxynonan-2-one; 3-hydroxydodecan-2-one) showed a significant increase. Immunohistochemistry further demonstrated an increased amount of HNE-modified and MDA-modified proteins in the renal proximal tubules after repeated Fe-NTA administration. Some of the aldehydes measured such as HNE and MDA are reportedly cytotoxic, genotoxic and mutagenic. Accumulation of these aldehydes may play a role in this renal carcinogenesis model. Copyright (C) 1997 Elsevier Science Inc.

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  1043. Induction and nuclear translocation of thioredoxin by oxidative damage in the mouse kidney: Independence of tubular necrosis and sulfhydryl depletion Reviewed

    Tanaka T, Nishiyama Y, Okada K, Hirota K, Matsui M, Yodoi J, Hiai H, Toyokuni S

    Laboratory Investigation   Vol. 77 ( 2 ) page: 145 - 155   1997

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  1044. Copper and iron-induced oxidative damage in non-tumor bearing LEC rats

    Ma Y., Zhang D., Kawabata T., Kiriu T., Toyokuni S., Uchida K., Okada S.

    Pathology International   Vol. 47 ( 4 ) page: 203 - 208   1997

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    The copper and iron status in the liver of non-tumor bearing Long-Evans Cinnamon (LEC) rats (average age 17 months) was investigated. A direct quantitation of loosely-bound copper and iron was also investigated by using a chelating agent, nitrilotriacetic acid (NTA-chelatable free copper and iron). Besides the total copper and iron contents, the level of NTA- chelatable free copper was also higher in LEC rats than in LEA rats (P<0.05). But for the free iron level there was no significant difference between the two rat groups (P>0.05). The formation of thiobarbituric acid-reactive substances was higher in LEC rate than in LEA rats (P<0.01). The 4-hydroxy- 2-nonenal (HNE)-modified proteins were also clearly demonstrated In LEC rat liver. The copper and iron which produced the most important effect in the process of oxidative damage in LEC rats could not be distinguished. Even though free copper, which could induce free radical injuries, was increased in LEC rats, neither tumor-induction nor preneoplastic lesions in the experimental LEC rats were observed. Therefore it is speculated that the elevation of s free iron is another important factor. Copper and iron, both important transition metals in the body, may participate in the induction of DNA damage and oncogenesis.

    DOI: 10.1111/j.1440-1827.1997.tb04481.x

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  1045. 8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure Reviewed International journal

    Hattori Y, Nishigori C, Tanaka T, Uchida K, Nikaido O, Osawa T, Hiai H, Imamura S, Toyokuni S

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 107 ( 5 ) page: 733 - 737   1996.11

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  1046. 8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure Reviewed International journal

    Hattori Y, Nishigori C, Tanaka T, Uchida K, Nikaido O, Osawa T, Hiai H, Imamura S, Toyokuni S

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 107 ( 5 ) page: 733 - 737   1996.11

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  1047. Prevention by 2-Mercaptoethane Sulfonate and N-Acetylcysteine of Renal Oxidative Damage in Rats Treated with Ferric Nitrilotriacetate

    UMEMURA Takashi, HASEGAWA Ryuichi, SAI-KATO Kimie, NISHIKAWA Akiyoshi, FURUKAWA Fumio, TOYOKUNI Shinya, UCHIDA Koji, INOUE Tohru, KUROKAWA Yuji

    Jpn J Cancer Res   Vol. 87 ( 9 ) page: 882 - 886   1996.9

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  1048. Prevention by 2-Mercaptoethane Sulfonate and N-Acetylcysteine of Renal Oxidative Damage in Rats Treated with Ferric Nitrilotriacetate

    UMEMURA Takashi, HASEGAWA Ryuichi, SAI-KATO Kimie, NISHIKAWA Akiyoshi, FURUKAWA Fumio, TOYOKUNI Shinya, UCHIDA Koji, INOUE Tohru, KUROKAWA Yuji

    Japanese journal of cancer research : gann   Vol. 87 ( 9 ) page: 882 - 886   1996.9

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  1049. Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate Reviewed International journal

    Umemura T, Hasegawa R, SaiKato K, Nishikawa A, Furukawa F, Toyokuni S, Uchida K, Inoue T, Kurokawa Y

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 87 ( 9 ) page: 882 - 886   1996.9

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  1050. Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate

    Umemura T., Hasegawa R., Sai-Kato K., Nishikawa A., Furukawa F., Toyokuni S., Uchida K., Inoue T., Kurokawa Y.

    Japanese Journal of Cancer Research   Vol. 87 ( 9 ) page: 882 - 886   1996.9

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    Ferric nitrilotriacetate (Fe-NTA) is a renal toxicant and carcinogen in rats and mice. We found that its administration results in formation of 4-hydroxy-2-nonenal (HNE) in the renal proximal tubule cells of rats, and 8-hydroxydeoxyguanosine (8-OHdG) adducts in their DNA, suggesting a role for oxidative stress. Since 2-mercaptoethane sulfonate (MESNA) and N-acetylcysteine (NAC), administered orally, have been shown to increase the kidney levels of free thiol groups, their influence on the renal toxicity and carcinogenicity induced by Fe-NTA was examined in the present study. Male Wistar rats were intraperitoneally injected with Fe-NTA (12 mg Fe/kg), and MESNA (100 mg/kg) or NAC (200 mg/kg) was given orally 1 h before and 1 h after this treatment. The animals were killed for tissue analyses 3 h after the Fe-NTA exposure. In accord with our previous reports, HNE-modified protein was detected in the proximal tubules of Fe-NTA-treated rats by means of immunohistochemistry. Likewise, levels of 8-OHdG in the renal nuclear DNA, lipid peroxides as thiobarbituric acid-reactive substances in the kidneys, and blood urea nitrogen and creatinine in the serum were significantly increased by the Fe-NTA treatment. All of these changes were completely inhibited by oral administration of MESNA or NAG. These results suggest that both of these compounds can prevent the oxidative stress induced by Fe-NTA.

    DOI: 10.1111/j.1349-7006.1996.tb02115.x

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  1051. Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate Reviewed International journal

    Umemura T, Hasegawa R, SaiKato K, Nishikawa A, Furukawa F, Toyokuni S, Uchida K, Inoue T, Kurokawa Y

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 87 ( 9 ) page: 882 - 886   1996.9

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  1052. Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate

    Toyokuni S, Tanaka T, Nishiyama Y, Okamoto K, Nakashima Y, Hamazaki S, Okada S, Hiai H

    LABORATORY INVESTIGATION   Vol. 75 ( 2 ) page: 239 - 248   1996.8

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  1053. Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate

    Toyokuni S., Tanaka T., Nishiyama Y., Okamoto K., Nakashima Y., Hamazaki S., Okada S., Hiai H.

    Laboratory Investigation   Vol. 75 ( 2 ) page: 239 - 248   1996.8

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    Systemic administration of copper, an essential trace metal in the human body, has never been reported to be carcinogenic in animals. We investigated the induction of tumors by the cupric complex of nitrilotriacetic acid (Cu- NTA) in male Wistar rats. Thirty-two animals received ip injections of Cu- NTA, 3 to 5 mg of copper/kg body weight 5 days a week for 12 weeks, and were kept under close observation. For comparison, 31 animals received ip injections of ferric nitrilotriacetate (Fe-NTA), 5 to 10 mg of iron/kg body weight, and 16 animals received nitrilotriacetic acid (NTA) alone at the molar dose equivalent to Cu-NTA for the same period of time. Sixteen animals were left untreated as controls. Fourteen animals in the Cu-NTA group died of hepatic failure during the treatment period, and renal cell carcinoma (RCC) was induced in eight animals (25%). Of these, four animals died of either pulmonary metastasis or intraperitoneal hemorrhage. A total of 12 RCC were obtained, of which six tumors were ≤5 mm. The Cu-NTA group yielded fewer RCC and required a longer latent period for their incubation than the Fe-NTA group. Furthermore, the Cu-NTA group showed one hepatocellular carcinoma and one high-grade sarcoma of hepatic origin. No renal or hepatic tumor was observed in the NTA or control groups. The nontumorous part of the kidney treated with Cu-NTA presented hemosiderosis caused by copper-induced hemolytic anemia. This is the first report that systemic administration of copper compounds can induce malignant tumors in animals. Not only copper but also iron may play a role in the Cu-NTA-induced renal carcinogenesis model.

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  1054. Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate

    Toyokuni S, Tanaka T, Nishiyama Y, Okamoto K, Nakashima Y, Hamazaki S, Okada S, Hiai H

    LABORATORY INVESTIGATION   Vol. 75 ( 2 ) page: 239 - 248   1996.8

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  1055. Induction of renal cell carcinoma in male Wistar rats treated with cupric nitrilotriacetate.

    Toyokuni S, Tanaka T, Nishiyama Y, Okamoto K, Nakashima Y, Hamazaki S, Okada S, Hiai H

    Laboratory investigation; a journal of technical methods and pathology   Vol. 75 ( 2 ) page: 239 - 48   1996.8

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  1056. Oxidative stress response in iron-induced renal carcinogenesis: Acute nephrotoxicity mediates the enhanced expression of glutathione S-transferase Yp isozyme Reviewed International journal

    Fukuda A, Osawa T, Oda H, Toyokuni S, Satoh K, Uchida K

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 329 ( 1 ) page: 39 - 46   1996.5

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  1057. Oxidative stress response in iron-induced renal carcinogenesis: Acute nephrotoxicity mediates the enhanced expression of glutathione S-transferase Yp isozyme

    Fukuda A., Osawa T., Oda H., Toyokuni S., Satoh K., Uchida K.

    Archives of Biochemistry and Biophysics   Vol. 329 ( 1 ) page: 39 - 46   1996.5

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces acute renal proximal tubular necrosis, a consequence of free radical-mediated oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we investigated the free radical-induced oxidative stress response in this carcinogenesis model, focusing on the expression of glutathione S-transferases (GSTs) which catalyze the conjugation of reactive chemicals with glutathione and play an important role in protecting cells. A single intraperitoneal Fe-NTA treatment (15 mg Fe/kg body weight) induced a rapid oxidative stress, which was monitored by the accumulation of lipid peroxidation products and the loss of sulfhydryl contents in the kidneys, resulting in a 30% reduction of GST activity 1 h after an Fe-NTA treatment. The enzyme activity returned to the control level after 16 h. The immunoblot analysis of GST isozymes demonstrated that the level of α-class GSTs (GST-Ya and GST-Yc) and π- class GST (GST-Yp), major GST isozymes constitutively produced in the kidney, decreased immediately within 1 h of the Fe-NTA treatment. The onset of the recovery of GST-Yp protein levels was detected 3 h after the Fe-NTA treatment. The enhanced production of GST-Yp in gene expression was evident in the drastic elevation of mRNA levels and these increases coincided with a substantial rise in the GST activity and protein levels. The α-class GSTs were not inducible by treatment with Fe-NTA. The immunohistochemical analysis demonstrated that the expression of GST-Yp was strongly induced in the regenerating proximal tubular cells. A steady accumulation of GST-Yp protein was observed in the subacute toxicity experiments with multiple injections of Fe-NTA. These results suggest that the enhanced expression of GST-Yp is important in mediating cell repairs or increasing the resistance to subsequent injury.

    DOI: 10.1006/abbi.1996.0189

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  1058. Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer

    Okamoto K, Toyokuni S, Kim WJ, Ogawa O, Kakehi Y, Arao S, Hiai H, Yoshida O

    INTERNATIONAL JOURNAL OF CANCER   Vol. 65 ( 4 ) page: 437 - 441   1996.2

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  1059. Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer

    Okamoto K., Toyokuni S., Kim W., Ogawa O., Kakehi Y., Arao S., Hiai H., Yoshida O.

    International Journal of Cancer   Vol. 65 ( 4 ) page: 437 - 441   1996.2

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    Data regarding oxidatively modified DNA bases suggest that cancer cells are more exposed to oxidative stress than adjacent non-tumorous tissue. This novel concept may contribute to the understanding of certain aspects of tumor biology such as activated transcription factors, genetic instability, chemotherapy resistance and metastasis. We therefore tested this concept in human renal-cell carcinomas (RCCs) by evaluating the expression of hMTHI, an enzyme preventing the misincorporation into DNA of 8-oxo-dGTP (8-oxo-7,8 -dihydrodeoxyguanosine triphosphate), an oxidized form of dGTP in the nucleotide pool. The expression of hMTHI messenger RNA (mRNA) in RCC was significantly higher than that in adjacent nontumorous kidney. Moreover, advanced-stage tumors showed significantly higher hMTHI mRNA expression than early-stage tumors, and there was a modest linear correlation between hMTHI expression and c-myc expression. The results provide logical support for the concept of 'persistent oxidative stress in cancer' and suggest a role of hMTHI mRNA level as prognostic marker.

    DOI: 10.1002/(SICI)1097-0215(19960208)65:4<437::AID-IJC7>3.0.CO;2-Y

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  1060. Overexpression of human mutt homologue gene messenger RNA in renal-cell carcinoma : evidence of persistent oxidative stress in cancer

    OKAMOTO K.

    Int. J. Cancer   Vol. 65 ( 4 ) page: 437 - 441   1996.2

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  1061. Oxidative stress response in iron-induced acute nephrotoxicity: Enhanced expression of heat shock protein 90 Reviewed International journal

    Fukuda A, Osawa T, Oda H, Tanaka T, Toyokuni S, Uchida K

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 219 ( 1 ) page: 76 - 81   1996.2

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  1062. Oxidative stress response in iron-induced acute nephrotoxicity: Enhanced expression of heat shock protein 90

    Fukuda A., Osawa T., Oda H., Tanaka T., Toyokuni S., Uchida K.

    Biochemical and Biophysical Research Communications   Vol. 219 ( 1 ) page: 76 - 81   1996.2

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    Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we determined the proteins preferentially produced in response to the Fe-NTA-induced oxidative injury. A single intraperitoneal Fe-NTA treatment led to the enhanced production of a number of proteins with molecular masses of 85-95 kDa. These included heat shock protein 90 (HSP90) as determined by immunoprecipitation. The enhanced production of HSP90 was prominent in the renal tubular cells. Steady accumulation of HSP90 was observed in the subacute toxicity experiments with multiple injections of Fe-NTA, suggesting that the enhanced production of HSP90 is important in increasing resistance to subsequent injury caused by the Fe-NTA-induced oxidative stress.

    DOI: 10.1006/bbrc.1996.0184

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  1063. Association between 8-hydroxy-2'-deoxyguanosine formation and DNA strand breaks mediated by copper and iron

    Toyokuni S, Sagripanti JL

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 20 ( 6 ) page: 859 - 864   1996

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  1064. Iron-induced carcinogenesis: The role of redox regulation

    Toyokuni S

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 20 ( 4 ) page: 553 - 566   1996

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  1065. Iron-induced carcinogenesis: The role of redox regulation

    Toyokuni S.

    Free Radical Biology and Medicine   Vol. 20 ( 4 ) page: 553 - 566   1996

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    Redox cycling is a characteristic of transition metals such as iron. Iron is hypothesized to have been actively involved in the birth of primitive life on earth through the generation of reducing equivalents in the presence of UV light. Iron is an essential metal in mammals for oxygen transport by hemoglobin and for the function of many enzymes including catalase and cytochromes. However, the 'free' or 'catalytic' form of iron mediates the production of reactive oxygen species via the Fenton reaction and induces oxidative stress. Serum 'free' iron is observed in rare situations such as in severe hemochromatosis in which serum transferrin is saturated. However, it is known that superoxide can release 'free' iron from ferritin and hemosiderin in the cell. 'Free' iron is quite cytotoxic as well as mutagenic and carcinogenic. Iron compounds were first reported to induce sarcomas in rats by Richmond in 1959. Thereafter, several iron-induced carcinogenesis models were established, including the ferric nitrilotriacetate model by Okada and colleagues. Iron may have a role in the carcinogenic process of other transition metals such as copper and nickel, or other kinds of carcinogens such as nitrosamine and even virus-induced carcinogenesis. In humans, genetic hemochromatosis and asbestosis are two major diseases associated with iron-induced carcinogenesis. There is an increasing number of reports of an association between increased body iron stores and increased risk of cancer. Iron-induced oxidative stress results in two possible consequences: (1) redox regulation failure that leads to lipid peroxidation and oxidative DNA and protein damage; (2) redox regulation that activates a variety of reducing and oxystress-protective mechanisms via signal transduction. Both consequences appear to play a role in iron-induced carcinogenesis.

    DOI: 10.1016/0891-5849(95)02111-6

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  1066. Association between 8-hydroxy-2'-deoxyguanosine formation and DNA strand breaks mediated by copper and iron

    TOYOKUNI S.

    Free Radic. Biol. Med.   Vol. 20 ( 6 ) page: 859 - 864   1996

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    DOI: 10.1016/0891-5849(95)02184-1

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  1067. 8-Hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure

    Hattori Y., Nishigori C., Tanaka T., Uchida K., Nikaido O., Osawa T., Hiai H., Imamura S., Toyokuni S.

    Journal of Investigative Dermatology   Vol. 107 ( 5 ) page: 733 - 737   1996

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    8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a mutation-prone (G:C to T:A transverion) DNA base-modified product generated by reactive oxygen species or photodynamic action. G:C to T:A transversions are observed in the p53 and ras genes of UVB-induced skin cancers of mice and in squamous and basal cell carcinomas of human skin exposed to sun-light. In the current study, 8-OHdG formation was evaluated in the epidermis of hairless mice after repeated exposure to UVB, and possible mechanisms involved were studied. Exposure of hairless mice to either 3.4 [2 minimal erythema dose (MED)] or 16.8 (10 MED) kJ/m2 of UVB three times a week for 2 wk induced a 2.5- or 6.1-fold increase, respectively, in the levels of 8-OHdG in DNA, compared to the unexposed controls. An immunohistochemical method using a monoclonal antibody specific for 8-OHdG showed stronger and more extensive staining in the nuclei of UV-irradiated epidermal cells than in those of nonirradiated cells. Western blots probed with antibodies against 4-hydroxy-2-nonenal-modified proteins confirmed the involvement of reactive oxygen species in the epidermal damage induced by chronic UVB exposure. 3-Nitro-L-tyrosine was detected in western blots in a concentration-dependent manner, suggesting that peroxynitrite derived from the reaction of nitric oxide and superoxide, both of which were probably released from inflammatory cells, was involved in modifying the DNA bases. Therefore, the formation of 8-OHdG after UVB exposure appears to be regulated by at least three pathways: photodynamic action, lipid peroxidation, and inflammation and may play a role in sunlight-induced skin carcinogenesis.

    DOI: 10.1111/1523-1747.ep12365625

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  1068. Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies Reviewed International journal

    Uchida K, Itakura K, Kawakishi S, Hiai H, Toyokuni S, Stadtman ER

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 324 ( 2 ) page: 241 - 248   1995.12

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  1069. Characterization of epitopes recognized by 4-Hydroxy-2-nonenal specific antibodies

    Uchida K., Itakura K., Kawakishi S., Hiai H., Toyokuni S., Stadtman E.

    Archives of Biochemistry and Biophysics   Vol. 324 ( 2 ) page: 241 - 248   1995.12

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    In the present study, we have raised anti-peptide antibodies directed to the major membrane lipid peroxidation product 4-hydroxy-2-nonenal (HNE) attached covalently to histidine, and their specificities were compared with those of the polyclonal antibodies (anti-HNE-protein antibodies) raised against HNE-treated keyhole limpet hemocyanin (K. Uchidaet al.(1993)Proc. Natl. Acad. Sci. USA90, 8742-8746). The anti-HNE-histidyl peptide antibodies (anti-HNE-histidine antibodies) were prepared by immunizing rabbits with a HNE-conjugated heptapeptide (Gly3-His-Gly3amide) coupled to the carrier protein. The antisera were purified on an affinity gel prepared by covalent attachment of a HNE-conjugated heptapeptide (Ala3-His-Ala3amide). Among the structurally defined 4-hydroxy-2-alkenal-amino acid adducts tested, binding of anti-HNE-histidine antibodies to the HNE-treated protein was not only inhibited by HNE-histidine, HNE-cysteine, and HNE-lysine, but also by 4-hydroxy-2-octenal-histidine and 4-hydroxy-2-decenal-histidine adducts. Cross-reactivity studies revealed that both anti-HNE-protein antibodies had the highest affinity for the HNE-treated protein and that neither of the antibodies cross-reacted with the protein treated with aldehydes including malondialdehyde, 1-hexanal, 2-hexenal, or 2-nonenal. These results suggest that the dominant epitope recognized by antibodies is the 2-CH3(CH2)n-5-hydroxytetrahydrofuran (n≥ 3) moiety of the Michael adducts. The immunohistochemical analysis of atherosclerotic lesions of human aorta demonstrated that these antibodies reacted strongly with granular cytoplasmic elements of foam cells and weakly with elements in the surrounding sclerotic stroma. © 1995 Academic Press. All rights reserved.

    DOI: 10.1006/abbi.1995.0036

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  1070. Characterization of epitopes recognized by 4-hydroxy-2-nonenal specific antibodies Reviewed International journal

    Uchida K, Itakura K, Kawakishi S, Hiai H, Toyokuni S, Stadtman ER

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 324 ( 2 ) page: 241 - 248   1995.12

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  1071. Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of Wistar rats induced by ferric nitrilotriacetate

    Nishiyama Y, Suwa H, Okamoto K, Fukumoto M, Hiai H, Toyokuni S

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 86 ( 12 ) page: 1150 - 1158   1995.12

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  1072. Low Incidence of Point Mutations in H- ,K- and N-ras Oncogenes and p53 Tumor Suppressor Gene in Renal Cell Carcinoma and Peritoneal Mesothelioma of Wistar Rats Induced by Ferric Nitrilotriacetate

    NISHIYAMA Yasuyuki, SUWA Hirofumi, OKAMOTO Keisei, FUKUMOTO Manabu, HIAI Hiroshi, TOYOKUNI Shinya

    Jpn J Cancer Res   Vol. 86 ( 12 ) page: 1150 - 1158   1995.12

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    DOI: 10.1111/j.1349-7006.1995.tb03308.x

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  1073. Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of wistar rats induced by ferric nitrilotriacetate

    Nishiyama Y., Suwa H., Okamoto K., Fukumoto M., Hiai H., Toyokuni S.

    Japanese Journal of Cancer Research   Vol. 86 ( 12 ) page: 1150 - 1158   1995.12

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular damage, a consequence of iron-catalyzed free radical reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Previous studies have identified, within 24 h after administration of Fe-NTA, lipid peroxidation products, aldehyde-modified proteins and a variety of modified DNA bases such as 8-hydroxyguanine that may be mutagenic in vivo. In the present study, pathological features of the RCCs were studied, and, in an effort to correlate them with carcinogen-specific molecular events in Fe-NTA-induced carcinogenesis, the H-, K- and N-ras oncogenes and the p53 tumor suppressor gene were investigated for the presence of mutations. Fe-NTA-induced RCCs showed similarity to human RCCs in that they are often invasive, metastatic and fatal. None (0 of 12) of the tumors had mutation in codons 12,13 and 61 of the H-, K- and N-ras genes by direct sequencing. Only one (1 of 12) tumor with high grade histology revealed a CGC-to-CTC (Arg to Leu) transversion in codon 246 of the p53 gene by the use of single strand conformation polymorphism (SSCP) analysis and direct sequencing. High expression of mutant p53 protein was confirmed by Western blotting and immunohistochemistry. Study of three peritoneal mesotheliomas induced by Fe-NTA revealed no mutation in ras and p53 genes. These results suggest that the ras and p53 genes are not the major targets of mutation in Fe-NTA-induced carcinogenesis of kidney and mesothelium. Instead, p53 mutation may work for potentiation of malignant character in Fe-NTA-induced renal carcinogenesis. © 1995.

    DOI: 10.1016/0910-5050(96)85255-0

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  1074. Low incidence of point mutations in H-, K- and N-ras oncogenes and p53 tumor suppressor gene in renal cell carcinoma and peritoneal mesothelioma of Wistar rats induced by ferric nitrilotriacetate

    Nishiyama Y, Suwa H, Okamoto K, Fukumoto M, Hiai H, Toyokuni S

    JAPANESE JOURNAL OF CANCER RESEARCH   Vol. 86 ( 12 ) page: 1150 - 1158   1995.12

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  1075. TREATMENT OF WISTAR RATS WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE, CAUSES DNA-PROTEIN CROSS-LINKING BETWEEN THYMINE AND TYROSINE IN THEIR RENAL CHROMATIN

    TOYOKUNI S, MORI T, HIAI H, DIZDAROGLU M

    INTERNATIONAL JOURNAL OF CANCER   Vol. 62 ( 3 ) page: 309 - 313   1995.7

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  1076. Treatment of wistar rats with a renal carcinogen, ferric nitrilotriacetate, causes dna‐protein cross‐linking between thymine and tyrosine in their renal chromatin

    Toyokuni S., Mori T., Hiai H., Dizdaroglu M.

    International Journal of Cancer   Vol. 62 ( 3 ) page: 309 - 313   1995.7

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    Ferric nitrilotriacetate (Fe‐NTA) induces renal proximal tubular damage associated with lipid peroxidation and oxidative DNA base modifications that finally leads to a high incidence of renal adenocarcinoma in rodents. In the present study, we report on the in vivo formation of DNA‐protein cross‐links (DPCs) involving thymine and tyrosine in the renal chromatin of Wistar rats treated with single or repeated i.p. administration of Fe‐NTA. Analyses of chromatin samples by gas chromatography/mass spectrometry revealed a significant increase in the amount of 3‐[(1, 3‐dihydro‐2, 4‐dioxopyrimidin‐5‐yl)‐methyl]‐L‐tyrosine (Thy‐Tyr cross‐link) 24 and 48 hr after the administration of Fe‐NTA. At 19th day of Fe‐NTA treatment, the amount of Thy‐Tyr cross‐link decreased to the control level, indicating the presence of cellular repair activity. Thy‐Tyr cross‐link may play a role in the genetic alteration of this renal carcinogenesis model, since mitoses for regeneration of renal proximal tubules were closely associated with the increase in DPCs. © 1995 Wiley‐Liss Inc. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Company

    DOI: 10.1002/ijc.2910620313

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  1077. Treatment of Wistar rats with a renal carcinogen, ferric nitrilotriacetate, causes DNA-protein cross-linking between thymine and tyrosine in their renal chromatin

    TOYOKUNI S.

    Int J Cancer.   Vol. 62 ( 3 ) page: 309 - 313   1995.7

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  1078. 4-HYDROXY-2-NONENAL-TRAPPING ELISA - DIRECT EVIDENCE FOR THE RELEASE OF A CYTOTOXIC ALDEHYDE FROM OXIDIZED LOW-DENSITY LIPOPROTEINS Reviewed International journal

    UCHIDA K, OSAWA T, HIAI H, TOYOKUNI S

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 212 ( 3 ) page: 1068 - 1073   1995.7

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  1079. DEGRADATION OF DNA IN DRIED TISSUES BY ATMOSPHERIC OXYGEN

    MATSUO S, TOYOKUNI S, OSAKA M, HAMAZAKI S, SUGIYAMA T

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 208 ( 3 ) page: 1021 - 1027   1995.3

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  1080. Degradation of DNA in dried tissues by atmospheric oxygen

    Matsuo S., Toyokuni S., Osaka M., Hamazaki S., Sugiyama T.

    Biochemical and Biophysical Research Communications   Vol. 208 ( 3 ) page: 1021 - 1027   1995.3

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    Recently, DNA of extinct creatures have been brought into analyses. The difficulty in this field of research is DNA degradation. Oxidative damage is considered to be one of the causes of the DNA degradation. We studied how DNA in dried tissue was affected by atmospheric oxygen using freeze-dried rat liver as a model. In tissues exposed to oxygen, DNA degradation occurred within several months and the amount of 8-hydroxy-2′-deoxyguanosine in DNA rapidly increased. The DNA degradation was inhibited by lipid extraction prior to the exposure to atmospheric oxygen. Purified lambda phage DNA was not affected by oxygen. Cellular DNA and RNA were degraded slowly in nitrogen air. These results suggest that both atmospheric and endogenous oxygens play a role in DNA degradation in dried tissues. © 1995 Academic Press, Inc.

    DOI: 10.1006/bbrc.1995.1436

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  1081. Degradation of DNA in dried tissues by atmospheric oxygen

    MATSUO S.

    Biochem Biophys Res Commun   Vol. 208 ( 3 ) page: 1021 - 1027   1995.3

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  1082. A RENAL CARCINOGEN FERRIC NITRILOTRIACETATE MEDIATES A TEMPORARY ACCUMULATION OF ALDEHYDE-MODIFIED PROTEINS WITHIN CYTOSOLIC COMPARTMENT OF RAT-KIDNEY Reviewed International journal

    UCHIDA K, FUKUDA A, KAWAKISHI S, HIAI H, TOYOKUNI S

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 317 ( 2 ) page: 405 - 411   1995.3

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  1083. A Renal carcinogen ferric nitrilotriacetate mediates a temporary accumulation of aldehyde-modified proteins within cytosolic compartment of rat-Kidney

    Uchida K., Fukuda A., Kawakishi S., Hiai H., Toyokuni S.

    Archives of Biochemistry and Biophysics   Vol. 317 ( 2 ) page: 405 - 411   1995.3

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    Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. A recent immunohistochemical study has revealed that the materials immunoreactive to the antibody against the aldehyde (4-hydroxy-2-nonenal)-modified proteins are generated in the renal proximal tubules of rats treated with Fe-NTA (S. Toyokuni et al. (1994) Proc. Natl. Acad. Sci. USA 91, 2616-2620). Here we present further evidences that cytosolic proteins modified with lipid peroxidation-derived aldehydes (4-hydroxy-2-nonenal and malondialdehyde) are indeed accumulated in the kidney of rats treated with Fe-NTA. A single intraperitoneaI Fe-NTA treatment (15 or 30 mg Fe/kg body wt) induced a rapid accumulation of thiobarbituric acid-reactive substances, a direct consequence of membrane lipid peroxidation, mostly within the cytosolic compartment of rat kidney. The accumulation of lipid peroxidation-derived aldehydes was associated with an apparent accumulation (from 67.9 nmol in untreated controls to 83.3 nmol/mg protein in Fe-NTA-treated rats at 3 h after treatment) and subsequent elimination of aberrant proteins as assessed by a 2, 4-dinitrophenylhydrazine postlabeling assay. Immunoblot analysis with two different polyclonal antibodies against 4-hydroxy-2-nonenal-modified and malondialdehyde-modified proteins detected a temporary accumulation of aldehyde-modified proteins in the cytosol. An immunohistochemical technique with serial sectioning revealed that immunoreactivities of these antibodies were observed in the identical portion of the renal proximal tubules. The implications of these data in relation to the nephrotoxicity of Fe-NTA-are discussed. © 1995 Academic Press. All rights reserved.

    DOI: 10.1006/abbi.1995.1181

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  1084. A RENAL CARCINOGEN FERRIC NITRILOTRIACETATE MEDIATES A TEMPORARY ACCUMULATION OF ALDEHYDE-MODIFIED PROTEINS WITHIN CYTOSOLIC COMPARTMENT OF RAT-KIDNEY Reviewed

    K UCHIDA, A FUKUDA, S KAWAKISHI, H HIAI, S TOYOKUNI

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 317 ( 2 ) page: 405 - 411   1995.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    Iron overload with ferric nitrilotriacetate (Fe-NTA) induces acute renal proximal tubular necrosis, a consequence of oxidative tissue damage, that eventually leads to a high incidence of renal adenocarcinoma in rodents. A recent immunohistochemical study has revealed that the materials immunoreactive to the antibody against the aldehyde (4-hydroxy-2-nonenal)-modified proteins are generated in the renal proximal tubules of rats treated with Fe-NTA (S. Toyokuni et al. (1994) Proc. Natl. Acad. Sci. USA 91, 2616-2620). Here we present further evidences that cytosolic proteins modified with lipid peroxidation-derived aldehydes (4-hydroxy-2-nonenal and malondialdehyde) are indeed accumulated in the kidney of rats treated with Fe-NTA. A single intraperitoneaI Fe-NTA treatment (15 or 30 mg Fe/kg body wt) induced a rapid accumulation of thiobarbituric acid-reactive substances, a direct consequence of membrane lipid peroxidation, mostly within the cytosolic compartment of rat kidney. The accumulation of lipid peroxidation-derived aldehydes was associated with an apparent accumulation (from 67.9 nmol in untreated controls to 83.3 nmol/mg protein in Fe-NTA-treated rats at 3 h after treatment) and subsequent elimination of aberrant proteins as assessed by a 2,4-dinitrophenylhydrazine postlabeling assay. Immunoblot analysis with two different polyclonal antibodies against 4-hydroxy-2-nonenal-modified and malondialdehyde-modified proteins detected a temporary accumulation of aldehyde-modified proteins in the cytosol. An immunohistochemical technique with serial sectioning revealed that immunoreactivities of these antibodies were observed in the identical portion of the renal proximal tubules. The implications of these data in relation to the nephrotoxicity of Fe-NTA-are discussed. (C) 1995 Academic Press, Inc.

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  1085. THE MONOCLONAL-ANTIBODY SPECIFIC FOR THE 4-HYDROXY-2-NONENAL HISTIDINE ADDUCT Reviewed International journal

    TOYOKUNI S, MIYAKE N, HIAI H, HAGIWARA M, KAWAKISHI S, OSAWA T, UCHIDA K

    FEBS LETTERS   Vol. 359 ( 2-3 ) page: 189 - 191   1995.2

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  1086. The monoclonal antibody specific for the 4-hydroxy-2-nonenal histidine adduct

    Toyokuni S., Miyake N., Hiai H., Hagiwara M., Kawakishi S., Osawa T., Uchida K.

    FEBS Letters   Vol. 359 ( 2-3 ) page: 189 - 191   1995.2

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    Monoclonal antibodies directed against proteins modified with the major membrane lipid peroxidation product, 4-hydroxy-2-nonenal, have been established and characterized. The monoclonal antibodies specific for HNE-modified proteins were raised by immunizing mice with a HNE-keyhole limpet hemocyanin conjugate. The resulting five monoclonal antibodies (mAbs HNEJ-1-5) recognized HNE-modified bovine serum albumin (BSA), but not native BSA in Western blot studies. Of the five mAbs, HNEJ-2 exhibited the highest affinity for HNE-modified proteins and a much higher affinity for the HNE-histidine adduct than the HNE-lysine or HNE-cysteine adducts. mAb HNEJ-2 did not cross-react with proteins that had been treated with other aldehydes, such as 1-hexenal, 2-hexenal, 4-hydroxy-2-hexenal, 2-nonenal, formaldehyde, or glutaraldehyde. These results suggest that the major epitope recognized by mAb HNEJ-2 is the Michael addition-type HNE-histidine adduct. © 1995.

    DOI: 10.1016/0014-5793(95)00033-6

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  1087. CYTOTOXIC AND MUTAGENIC EFFECTS OF FERRIC NITRILOTRIACETATE ON L5178Y MOUSE LYMPHOMA-CELLS

    TOYOKUNI S, SAGRIPANTI JL, HITCHINS VM

    CANCER LETTERS   Vol. 88 ( 2 ) page: 157 - 162   1995.1

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  1088. Cytotoxic and mutagenic effects of ferric nitrilotriacetate on L5178Y mouse lymphoma cells

    TOYOKUNI S.

    Cancer Lett.   Vol. 88 ( 2 ) page: 157 - 162   1995.1

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  1089. Cytotoxic and mutagenic effects of ferric nitrilotriacetate on L5178Y mouse lymphoma cells

    Toyokuni S., Sagripanti J., Hitchins V.

    Cancer Letters   Vol. 88 ( 2 ) page: 157 - 162   1995.1

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular necrosis that leads to a high incidence of renal adenocarcinoma in rodents. Others have shown that Fe-NTA induces modified DNA base products both in vitro and in vivo. However, Fe-NTA is negative in the Ames Salmonella test with or without S9 activation. The goal of this project was to determine if Fe-NTA is cytotoxic and mutagenic using the L5178Y (TK+/-) mouse lymphoma assay. Our experiments showed a relationship between the concentration of Fe-NTA (0 to 1 mM) and the decrease in relative survival. An exposure-dependent increase in the number of mutations was observed with increasing concentrations of Fe-NTA. At 14% relative survival, there was about a 4-fold increase in mutations (trifluorothymidine resistance) over unexposed, control cells. Ferric nitrate or nitrilotriacetic acid alone induced a relatively tow 1.5- or 1.1-fold increase in mutation, respectively. Our results establish that Fe-NTA is mutagenic in the L5178Y mouse lymphoma assay system. © 1995.

    DOI: 10.1016/0304-3835(94)03641-U

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  1090. PERSISTENT OXIDATIVE STRESS IN CANCER

    TOYOKUNI S, OKAMOTO K, YODOI J, HIAI H

    FEBS LETTERS   Vol. 358 ( 1 ) page: 1 - 3   1995.1

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  1091. Persistent oxidative stress in cancer

    Toyokuni S., Okamoto K., Yodoi J., Hiai H.

    FEBS Letters   Vol. 358 ( 1 ) page: 1 - 3   1995.1

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    DNA of cancers such as renal cell carcinoma and mammary invasive ductal carcinoma, is persistently exposed to more oxidative stress than that of adjacent nornal tissue. We suggest that the concept of 'persistent oxidative stress in cancer' may open up a new research area, explaining part of the characteristic tumor biology of cancer such as activated transcription factors and proto-oncogenes, genomic instability, chemotherapy-resistance, invasion and metastasis. © 1995.

    DOI: 10.1016/0014-5793(94)01368-B

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  1092. Persistent oxidative stress in cancer

    TOYOKUNI S.

    FEBS Lett.   Vol. 358 ( 1 ) page: 1 - 3   1995.1

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  1093. ACUTE NEPHROTOXICITY OF A CARCINOGENIC IRON CHELATE - SELECTIVE-INHIBITION OF A PROTEOLYTIC CONVERSION OF ALPHA(2U)-GLOBULIN TO THE KIDNEY FATTY-ACID-BINDING PROTEIN Reviewed International journal

    UCHIDA K, FUKUDA A, KAWAKISHI S, TOYOKUNI S, HIAI H, IKEDA S, HORIO F

    FEBS LETTERS   Vol. 357 ( 2 ) page: 165 - 167   1995.1

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  1094. Acute nephrotoxicity of a carcinogenic iron chelate Selective inhibition of a proteolytic conversion of α<inf>2U</inf>-globulin to the kidney fatty acid-binding protein

    Uchida K., Fukuda A., Kawakishi S., Toyokuni S., Hiai H., Ikeda S., Horio F.

    FEBS Letters   Vol. 357 ( 2 ) page: 165 - 167   1995.1

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    The mechanism of acute nephrotoxicity of an iron chelate in vivo has been investigated. Administration of a renal carcinogen ferric nitrolotriacetate (Fe-NTA) (15 mg Fe/kg body weight, intraperitoneally) led to selective loss of a renal protein with an apparent molecular mass of 17 kDa. Analysis of the 17 kDa protein by NH2-terminal sequence demonstrated its identity over 16 NH2-terminal residues as a kidney fatty acid-binding protein (k-FABP) that is a proteolytically modified form of α2U-globulin, a major urinary protein of adult male rats. An immunochemical study using anti-α2U-globulin polyclonal antibodies confirmed that a single injection of Fe-NTA led to a decrease in k-FABP levels. However, a 19-kDa protein identical to the α2U-globulin progressively appeared in the kidney, suggesting that the proteolytic processing of α2U-globulin in the renal proximal tubules was suppressed by the treatment with Fe-NTA. By monitoring k-FABP and its precursor α2U-globulin, it was determined that repeated exposure to Fe-NTA caused suppression of both proteolytic and endocytotic activity of the kidney. The implications of these data in relation to the nephrotoxicity of Fe-NTA are discussed. © 1995.

    DOI: 10.1016/0014-5793(94)01330-4

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  1095. 4-Hydroxy-2-nonenal-trapping elisa: Direct evidence for the release of a cytotoxic aldehyde from oxidized low density lipoproteins

    Uchida K., Osawa T., Hiai H., Toyokuni S.

    Biochemical and Biophysical Research Communications   Vol. 212 ( 3 ) page: 1068 - 1073   1995

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    Among the aldehydes that originate from the peroxidation of cellular membrane lipids, 4-hydroxy-2-nonenal (HNE) is thought to be largely responsible for cytopathological effects observed during oxidative stress. Taking advantage of the fact that HNE is very reactive with proteins and forms stable Michael addition-type adducts, a novel immunochemical procedure for quantifying “free” HNE has been developed. The method designated as “HNE-trapping ELISA” is based on the detection of HNE trapped by a protein that has been coated in the immunoplate. The HNE-derived epitopes generated in the coating protein are then detected by the ELISA using a monoclonal antibody (mAbHNEJ-2) specific to the haptenic groups of the HNE-protein conjugates. Using this method, we determined that a considerable amount of HNE was released from human plasma low density lipoproteins (LDL) treated with copper ions or endothelial cells. © 1995 by Academic Press, Inc.

    DOI: 10.1006/bbrc.1995.2078

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  1096. MICHAEL ADDITION-TYPE 4-HYDROXY-2-NONENAL ADDUCTS IN MODIFIED LOW-DENSITY LIPOPROTEINS - MARKERS FOR ATHEROSCLEROSIS Reviewed International journal

    UCHIDA K, TOYOKUNI S, NISHIKAWA K, KAWAKISHI S, ODA H, HIAI H, STADTMAN ER

    BIOCHEMISTRY   Vol. 33 ( 41 ) page: 12487 - 12494   1994.10

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  1097. Michael addition type 4-hydroxy-2-nonenal adducts in modified low density lipoproteins : markers for atherosclerosi Reviewed International journal

    UCHIDA K.

    Biochemistry.   Vol. 33 ( 41 ) page: 12487 - 12494   1994.10

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  1098. Michael Addition-Type 4-Hydroxy-2-nonenal Adducts in Modified Low-Density Lipoproteins: Markers for Atherosclerosis

    Uchida K., Toyokuni S., Nishikawa K., Kawakishi S., Oda H., Hiai H., Stadtman E.

    Biochemistry   Vol. 33 ( 41 ) page: 12487 - 12494   1994.10

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    It has been proposed that plasma low-density lipoprotein (Lall-trans-bRDL) undergoes oxidative modification before it can give rise to foam cells in atherosclerosis. Oxidation of LDL generates a variety of reactive aldehyde products including 4-hydroxy-2-nonenal (HNE), which may covalently attach to the LDL apolipoproteins. We here present direct evidence that HNE derivatization of LDL forms Michael additiontype adducts of HNE with histidine and lysine residues of apolipoprotein B-100 (apo B) and also demonstrate the utility of an antibody specific to the HNE adducts generated in the LDL treated with HNE or oxidatively modified by Cu2+ or cultured endothelial cells. HNE adducts present in the LDL that had been treated with HNE were attested to be Michael addition-type adducts on the basis of the fact that incubation of LDL with 1 mM HNE (2 h, 37 °C) resulted primarily in the formation of Michael addition-type HNE-histidine (39.9 mol/mol of LDL) and HNE-lysine (19.3 mol/mol of LDL) adducts. An enzyme-linked immunosorbent assay (ELISA) and an SDS-polyacrylamide gel electrophoresis (SDS-PAGE)/immunoblot analysis of HNE-modified LDL demonstrated that these HNE adducts were detectable with the HNE-specific antibody affinity-purified with the Michael adduct (HNE-histidine) as a ligand. The following lines of evidence indicated the presence of Michael addition-type HNE adducts in the oxidatively modified LDL in vitro: (i) Amino acid analysis of LDL that had been treated with Cu2+ (24 h, 37 °C) demonstrated the presence of a Michael addition-type HNE-histidine adduct (7-9 mol/mol of LDL). (ii) Competitive ELISA demonstrated the inhibition of antibody binding to HNE-modified LDL by the addition of Cu2+- oxidized LDL. (iii) SDS-PAGE/immunoblot analysis of the Cu2+-oxidized LDL demonstrated the appearance of HNE adducts, which were abolished by the addition of a HNE-modified histidyl peptide. Furthermore, HNE adducts were detected in the LDL that had been treated with cultured bovine aortic endothelial cells (24 h, 37 °C). Taken together, this evidence suggests that the Michael addition-type HNE adducts may be reliable markers for atherosclerosis. © 1994, American Chemical Society. All rights reserved.

    DOI: 10.1021/bi00207a016

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  1099. FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE AND 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN HUMAN RENAL-CELL CARCINOMA Reviewed International journal

    OKAMOTO K, TOYOKUNI S, UCHIDA K, OGAWA O, TAKENEWA J, KAKEHI Y, KINOSHITA H, HATTORINAKAKUKI Y, HIAI H, YOSHIDA O

    INTERNATIONAL JOURNAL OF CANCER   Vol. 58 ( 6 ) page: 825 - 829   1994.9

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  1100. Formation of 8‐hydroxy‐2′‐deoxyguanosine and 4‐hydroxy‐2‐nonenal‐modified proteins in human renal‐cell carcinoma

    Okamoto K., Toyokuni S., Uchida K., Ogawa O., Takenewa J., Kakehi Y., Kinoshita H., Hattori‐Nakakuki Y., Hiai H., Yoshida O.

    International Journal of Cancer   Vol. 58 ( 6 ) page: 825 - 829   1994.9

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    To study the possible involvement of reactive oxygen species (ROS) in the tumor biology of human renal‐cell carcinoma (RCC), we analvzed 35 cases of RCC for 2 parameters of oxidative damage: 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), a mutation‐prone DNA‐ base ‐modified product, was measured by means of high‐performance liquid chromatography (HPLC) with an electrochemical (EC) detector, and 4‐hydroxy‐2‐nonenal (HNE)‐modified proteins were measured with a poly‐clonal antibody against HNE‐modified proteins. A 54% higher content of 8‐OHdG was found in RCC than in the corresponding non‐tumorous kidney, suggesting that the DNA of RCC is more exposed to ROS than is the DNA of non‐tumorous kidneys. Immunohistochemistry for HNE‐modified proteins showed a distinct staining pattern of fine to coarse granularity in the cytoplasm of RCC (n = 15), implying that lipid peroxidation products are located in cytoplasmic organelles. These results suggest that RCC constitutionally elaborates more ROS than is produced by the non‐tumorous parts of kidneys. No correlation was found between clinical stage, histology, age or sex and the 2 parameters examined. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

    DOI: 10.1002/ijc.2910580613

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  1101. FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE AND 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN HUMAN RENAL-CELL CARCINOMA Reviewed International journal

    OKAMOTO K, TOYOKUNI S, UCHIDA K, OGAWA O, TAKENEWA J, KAKEHI Y, KINOSHITA H, HATTORINAKAKUKI Y, HIAI H, YOSHIDA O

    INTERNATIONAL JOURNAL OF CANCER   Vol. 58 ( 6 ) page: 825 - 829   1994.9

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  1102. FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE IN EPIDERMIS OF HAIRLESS MICE EXPOSED TO NEAR-UV

    HATTORINAKAKUKI Y, NISHIGORI C, OKAMOTO K, IMAMURA S, HIAI H, TOYOKUNI S

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 201 ( 3 ) page: 1132 - 1139   1994.6

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  1103. Formation of 8-Hydroxy-2′-Deoxyguanosine in epidermis of hairless mice exposed to near-UV

    Hattori-Nakakuki Y., Nishigori C., Okamoto K., Imamura S., Hiai H., Toyokuni S.

    Biochemical and Biophysical Research Communications   Vol. 201 ( 3 ) page: 1132 - 1139   1994.6

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    Six-week-old male albino hairless mice (Hos: Hr-1) were exposed to a near-ultraviolet (UV) fluorescent sun lamp (33.5 kJ/m2/hr; wave length > 270 nm with a peak at 312.5 nm) to investigate the induction of oxidative DNA damage in epidermal cells. Significantly higher levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) were detected in a dose-dependent manner in epidermis of mice exposed to near-UV than in those of control animals. The ratio of 8-OHdG in near-UV-exposed/unexposed control was 2.08 ± 0.19 after 168 kJ/m2 exposure, P < 0.01; 3.49 ± 0.36 after 335 kJ/m2 exposure, P < 0.01 (means ± SE). The levels of 8-OHdG decreased with time after near-UV exposure, suggesting the presence of removal and/or repair mechanisms. This is the first report that oxidative DNA base modification is induced in vivo in epidermal cells by near-UV exposure. Oxidative DNA base modification may be one of the causes of sunlight-induced skin carcinogenesis. © 1994 Academic Press, Inc.

    DOI: 10.1006/bbrc.1994.1823

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  1104. FORMATION OF 8-HYDROXY-2'-DEOXYGUANOSINE IN EPIDERMIS OF HAIRLESS MICE EXPOSED TO NEAR-UV

    HATTORINAKAKUKI Y, NISHIGORI C, OKAMOTO K, IMAMURA S, HIAI H, TOYOKUNI S

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 201 ( 3 ) page: 1132 - 1139   1994.6

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  1105. INCREASED 8-HYDROXYDEOXYGUANOSINE IN KIDNEY AND LIVER OF RATS CONTINUOUSLY EXPOSED TO COPPER

    TOYOKUNI S, SAGRIPANTI JL

    TOXICOLOGY AND APPLIED PHARMACOLOGY   Vol. 126 ( 1 ) page: 91 - 97   1994.5

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  1106. Increased 8-hydroxydeoxyguanosine in kidney and liver of rats continuously exposed to copper

    Toyokuni S., Sagripanti J.

    Toxicology and Applied Pharmacology   Vol. 126 ( 1 ) page: 91 - 97   1994.5

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    Copper is a ubiquitous metal in the environment, it is a component of dental casting gold alloys and dental amalgams, and it is a main component in some intrauterine contraceptive devices (IUDs). Since copper materials implanted in the human body corrode and release ions into the surrounding tissue, the potential toxicity caused by contact of this metal with bodily fluids needs to be evaluated. We implanted male Wistar rats with osmotic mini pumps that continuously administered saline, CuCl2, or a copper chelate, cupric nitrilotriacetate (Cu-NTA), at a rate of 4 mg copper/kg body wt/day. This experimental design maintained serum copper concentrations at a level 30-70% (CuCl2) or 100-120% (Cu-NTA) higher than in untreated controls. At different times postimplantation, we measured the levels of 8-hydroxydeoxyguanosine (8-OHdG) in DNA of kidney, liver, and tissue surrounding the pump implant, since production of 8-OHdG has been associated with mutagenesis and carcinogenesis. Hepatic and renal levels of 8-OHdG in CuCl2- or Cu-NTA-treated animals were significantly higher than in control animals. In contrast, histopathologic changes in kidneys and livers of rats exposed to CuCl2 and Cu-NTA were limited to mild changes involving hepatic focal necrosis and slightly increased mitotic activity in the renal proximal tubules. These observations suggest that levels of 8-OHdG could be an early marker of copper toxicity. It is unlikely that the high levels of copper at which we observed DNA modification will be encountered after occupational or environmental exposure. A different situation could be found around medical devices that include copper, particularly IUDs, where the amount of copper administered in our experiments could be released in the uterus of women after a few months of continued IUD use. © 1994 Academic Press, Inc.

    DOI: 10.1006/taap.1994.1094

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  1107. INCREASED 8-HYDROXYDEOXYGUANOSINE IN KIDNEY AND LIVER OF RATS CONTINUOUSLY EXPOSED TO COPPER

    TOYOKUNI S, SAGRIPANTI JL

    TOXICOLOGY AND APPLIED PHARMACOLOGY   Vol. 126 ( 1 ) page: 91 - 97   1994.5

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  1108. DNA-BASE MODIFICATIONS IN RENAL CHROMATIN OF WISTAR RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE

    TOYOKUNI S, MORI T, DIZDAROGLU M

    INTERNATIONAL JOURNAL OF CANCER   Vol. 57 ( 1 ) page: 123 - 128   1994.4

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  1109. DNA base modification in renal chromatin of wister rats trea, ed with a renal carcinogen, ferric nitrilotriacetate

    TOYOKUNI S.

    Int. J. Cancer   Vol. 57 ( 1 ) page: 123 - 128   1994.4

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  1110. DNA base modifications in renal chromatin of wistar rats treated with a renal carcinogen, ferric nitrilotriacetate

    Toyokuni S., Mori T., Dizdaroglu M.

    International Journal of Cancer   Vol. 57 ( 1 ) page: 123 - 128   1994.4

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    Ferric nitrilotriacetate (Fe‐NTA) causes renal proximal tubular necrosis, a consequence of iron ion‐mediated free‐radical‐associated damage, that finally leads to a high incidence of renal ad en oca re in dm a in male rats and mice. We have investigated the levels of typical hydroxyl radical‐induced DNA base modifications in renal chromatin of male Wistar rats treated with a single or repeated administrations of Fe‐NTA. Five pyrimidine‐derived and 5 purine‐derived modified DNA bases were identified and quantified by gas chromatography/mass spectrometry with selected‐ion monitoring. The modified bases were 5‐hydroxy‐5‐methylhydantoin, 5‐(hydroxymethyl)uracil, 5‐hydroxy‐cytosine, thymine glycol, 5,6‐dihydroxyuraril, 4,6‐diamino‐5‐form‐amidopyrimidine, 8‐hydroxyadenine, xanthine, 2‐hydroxyadenine and 8‐hydroxyguanine. The amounts of most of these compounds were significantly increased over control levels in renal chromatin of Fe‐NTA‐treated rats as measured 3 and 24 hr after treatment. Elevated levels of modified bases were accompanied by proximal tubular necrosis. On the 19th day, however, accumulation of modified DNA bases was not observed. Morphologically, scattered karyomegaiic cells were seen in the proximal tubules, but necrosis was rarely found. Some of the identified DNA base lesions are known to be promutagenic., although others have not been investigated. Presence of modified DNA bases concomitant with necrosis and regeneration of the renal proximal tubules may be a critical step in Fe‐NTA‐induced carcinogenesis. © Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

    DOI: 10.1002/ijc.2910570122

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  1111. FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE Reviewed International journal

    TOYOKUNI S, UCHIDA K, OKAMOTO K, HATTORINAKAKUKI Y, HIAI H, STADTMAN ER

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 91 ( 7 ) page: 2616 - 2620   1994.3

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  1112. Formation of 4-hydroxy-2-nonenal-modified proteins in the renal proximal tubules of rats treated with a renal carcinogen, ferric nitrilotriacetate

    Toyokuni S., Uchida K., Okamoto K., Hattori-Nakakuki Y., Hiai H., Stadtman E.

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 91 ( 7 ) page: 2616 - 2620   1994.3

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    An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces proximal tubular necrosis, a consequence of lipid peroxidation, that finally leads to a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation as monitored by formation of thiobarbituric acid-reactive substances and free 4- hydroxy-2-nonenal (HNE) was observed in the kidney homogenates of rats treated with Fe-NTA. Based on the fact that HNE is capable of reacting with cellular proteins, we attempted to detect the localization of HNE-modified proteins in rat kidney tissues with an immunohistochemical procedure. By means of an immunohistochemical technique using polyclonal antibody against the HNE-modified proteins, it was shown that HNE-modified proteins are formed in the target cells of this carcinogenesis model. HNE-modified proteins were detected in the renal proximal tubules 1 hr after i.p. administration of Fe- NTA (15 mg of iron per kg). Intense positivity was found in the cells with degeneration. After 6 hr, the level of HNE-protein conjugates decreased due to the subsequent necrosis. The intensity of the immunochemical reaction with HNE-modified proteins increased in parallel with an increase in the amounts of thiobartituric acid-reactive substances and free HNE that were found. Furthermore, histochemical detection of aldehydes by cold Schiff's reagent demonstrated that location of aldehydes was identical to that of the HNE- modified proteins determined by immunohistochemical procedures. It would thus appear that the production of HNE, a genotoxic and mutagenic aldehyde, and its reaction with proteins may play a role in Fe-NTA-induced renal carcinogenesis.

    DOI: 10.1073/pnas.91.7.2616

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  1113. FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE Reviewed International journal

    TOYOKUNI S, UCHIDA K, OKAMOTO K, HATTORINAKAKUKI Y, HIAI H, STADTMAN ER

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   Vol. 91 ( 7 ) page: 2616 - 2620   1994.3

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  1114. ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL KH MICE

    OKAMOTO K, YAMADA Y, OGAWA MS, TOYOKUNI S, NAKAKUKI Y, IKEDA H, YOSHIDA O, HIAI H

    CANCER RESEARCH   Vol. 54 ( 2 ) page: 399 - 402   1994.1

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  1115. GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL KH STRAIN MICE

    YAMADA Y, MATSUSHIRO H, OGAWA MS, OKAMOTO K, NAKAKUKI Y, TOYOKUNI S, FUKUMOTO M, HIAI H

    CANCER RESEARCH   Vol. 54 ( 2 ) page: 403 - 407   1994.1

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  1116. GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL KH STRAIN MICE

    YAMADA Y, MATSUSHIRO H, OGAWA MS, OKAMOTO K, NAKAKUKI Y, TOYOKUNI S, FUKUMOTO M, HIAI H

    CANCER RESEARCH   Vol. 54 ( 2 ) page: 403 - 407   1994.1

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  1117. Abnormal bone marrow B-cell differentiation in pre-B lymphoma-prone SL/Kh mice

    OKAMOTO K

    Cancer Res   Vol. 54 ( 2 ) page: 399 - 402   1994.1

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  1118. Genetic predisposition to pre-B lymphomas in SL/Kh strain mice.

    Yamada Y, Matsushiro H, Ogawa MS, Okamoto K, Nakakuki Y, Toyokuni S, Fukumoto M, Hiai H

    Cancer research   Vol. 54 ( 2 ) page: 403 - 7   1994.1

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  1119. Abnormal bone marrow B-cell differentiation in pre-B lymphoma-prone SL/Kh mice.

    Okamoto K, Yamada Y, Ogawa MS, Toyokuni S, Nakakuki Y, Ikeda H, Yoshida O, Hiai H

    Cancer research   Vol. 54 ( 2 ) page: 399 - 402   1994.1

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  1120. Genetic Predisposition to Pre-B Lymphomas in SL/Kh Strain Mice

    Yamada Y., Matsushiro H., Ogawa M.S., Okamoto K., Nakakuki Y., Toyokuni S., Fukumoto M., Hiai H.

    Cancer Research   Vol. 54 ( 2 ) page: 403 - 407   1994.1

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    Genetic predisposition of SL/Kh mice to spontaneous pre-B lymphomas was investigated in crosses between SL/Kh and NFS/N, another inbred strain of mice lacking endogenous ecotropic provirus and spontaneous lymphoma. (SL/Kh x NFS/N) F! hybrids developed lymphomas similar to those in SL/Kh but at a lower frequency and with a longer latent period. Of 83 backcross mice to NFS/N, 22 developed hemopoietic tumors: 8 were diffuse lymphoblastic lymphomas; 2 were myeloid leukemias arising by 12 months of age; and 12 were follicular center cell lymphomas found later in life. Of 6 endogenous ecotropic proviruses in SL/Kh, 2 were expressed in (SL/Kh x NFS) Fx backcrossed to NFS. One, encoded by a 27-kilobase EcoSl fragment, was closely linked to Gpi-1” on chromosome 7 and its expression seemed to be a prerequisite for the occurrence of all types of hemopoietic tumors. Microsatellite analysis of the backcross generation revealed multiple host genetic factors determining susceptibility to tumors. An allele derived from SL/Kh, mapped in the major histocompatibility locus on chromosome 17, was essential for development of early onset tumors. This locus was designated as Esl-1 (early lymphoma of SL-1). On the other hand, follicular center cell lymphomas developed mostly in the backcross mice homozygous for the NFS/N derived allele at the D4MIT17-linked locus, designated as foc-1 (follicular center cell lymphoma-1), on chromosome 4. © 1994, American Association for Cancer Research. All rights reserved.

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  1121. Abnormal Bone Marrow B-Cell Differentiation in Pre-B Lymphoma-prone SL/Kh Mice

    Okamoto K., Yamada Y., Ogawa M.S., Toyokuni S., Nakakuki Y., Ikeda H.

    Cancer Research   Vol. 54 ( 2 ) page: 399 - 402   1994.1

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    SL/Kh mice spontaneously develop pre-B lymphomas with surface phenotypes of B220+, BP-1+, Thy-1-, and surface immunoglobulin negative. The immunoglobulin heavy chain of lymphoma is clonally rearranged but the light chain gene remains in germline configuration. Studying prelymphoma stage SL/Kh bone marrow (BM), we found unusual multiclonal expansion of BP-1+ pre-B cells [34.8 + 5.8% (mean - SD)] by 4 weeks of age, whereas there were far fewer of such cells in most other laboratory strains (8 - 5%). The BP-1+ cells did not express surface immunoglobulin, Thy-1.1, or c-kit. Therefore, they seemed to belong to the pre-B II category. Increased numbers of BP-1+ cells were seen in Fx hybrids between SL/Kh and NFS/N; thus it was apparently a dominant heritable property of SL/Kh mice. Emergence of this population was independent of expression of endogenous ecotropic virus, since they were present in BMs of the Yt hybrid to C4W (Fv-4r) and were not inhibited by neonatal injection of maternal resistance factor. In the radiation chimeras SL/Kh - BALB/c, BP-1+ cells appeared abundantly (29.0 - 3.8%), whereas in the reciprocal chimeras BALB/c - SL/Kh, for fewer (5.5 - 2.3%) appeared. Therefore, expansion of BP-1+ cells in prelymphomatous BM is a property of SL/Kh stem cells rather than BM microenvironments. © 1994, American Association for Cancer Research. All rights reserved.

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  1122. ALTERATION OF THE DEOXYGUANINE NUCLEOTIDES TO 8-HYDROXYDEOXYGUANOSINE IN HUMAN RENAL-CELL CARCINOMA

    OKAMOTO, K; YOSHIDA, O; HATTORINAKAKUKI, Y; HIAI, H; TOYOKUNI, S

    FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE   Vol. 1058   page: 447 - 448   1994

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  1123. FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE

    TOYOKUNI, S; UCHIDA, K; OKAMOTO, K; HATTORINAKAKUKI, Y; HIAI, H; STADTMAN, ER

    FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE   Vol. 1058   page: 171 - 172   1994

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  1124. FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE

    TOYOKUNI S, UCHIDA K, OKAMOTO K, HATTORINAKAKUKI Y, HIAI H, STADTMAN ER

    FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE   Vol. 1058   page: 171 - 172   1994

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  1125. ALTERATION OF THE DEOXYGUANINE NUCLEOTIDES TO 8-HYDROXYDEOXYGUANOSINE IN HUMAN RENAL-CELL CARCINOMA Reviewed International journal

    OKAMOTO, K, YOSHIDA, O, HATTORINAKAKUKI, Y, HIAI, H, TOYOKUNI, S

    FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE   Vol. 1058   page: 447 - 448   1994

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  1126. ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL/KH MICE

    OKAMOTO, K; YAMADA, Y; SHIMADA, M; TOYOKUNI, S; NAKAKUKI, Y; HIAI, H

    EXPERIMENTAL HEMATOLOGY   Vol. 21 ( 8 ) page: 1126 - 1126   1993.8

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  1127. GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL/KH STRAIN MICE

    YAMADA, Y; SHIMADA, M; OKAMOTO, K; TOYOKUNI, S; NAKAKUKI, Y; FUKUMOTO, M; HIAI, H

    EXPERIMENTAL HEMATOLOGY   Vol. 21 ( 8 ) page: 1118 - 1118   1993.8

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  1128. INDUCTION OF OXIDATIVE SINGLE-STRAND AND DOUBLE-STRAND BREAKS IN DNA BY FERRIC CITRATE

    TOYOKUNI S, SAGRIPANTI JL

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 15 ( 2 ) page: 117 - 123   1993.8

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  1129. INDUCTION OF OXIDATIVE SINGLE-STRAND AND DOUBLE-STRAND BREAKS IN DNA BY FERRIC CITRATE Reviewed

    S TOYOKUNI, JL SAGRIPANTI

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 15 ( 2 ) page: 117 - 123   1993.8

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    The relative risk of primary hepatocellular carcinoma in genetic hemochromatosis (GH) is estimated at over 200 times as that of control populations. Recently, ferric ion chelated to citrate (Fe-citrate) was identified as the major non-transferrin-bound iron in the serum of GH patients. We investigated whether low concentration of Fe-citrate plus reductant could damage supercoiled plasmid DNA under physiological pH and ionic strength. Incubation of Fe-citrate with either H2O2, L-ascorbate, or L-cysteine induced single- and double-strand breaks in supercoiled plasmid pZ189 in a concentration- and time-dependent fashion. DNA strand breaks produced by Fe-citrate plus H2O2 increased at reduced pH (less-than-or-equal-to 6.9). Catalase and free radical scavengers inhibited the DNA breakage produced by Fe-citrate in combination with each reductant, suggesting that H2O2 and finally .OH are responsible DNA damaging species. The catalytic ability of Fe-citrate to induce DNA strand breaks, particularly double-strand breaks (DSBs), may contribute to the carcinogenic processes observed in GH.

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  1130. Induction of oxidative single- and double-strand breaks in DNA by ferric citrate

    Toyokuni S., Sagripanti J.

    Free Radical Biology and Medicine   Vol. 15 ( 2 ) page: 117 - 123   1993.8

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    The relative risk of primary hepatocellular carcinoma in genetic hemochromatosis (GH) is estimated at over 200 times as that of control populations. Recently, ferric ion chelated to citrate (Fe-citrate) was identified as the major non-transferrin-bound iron in the serum of GH patients. We investigated whether low concentration of Fe-citrate plus reductant could damage supercoiled plasmid DNA under physiological pH and ionic strength. Incubation of Fe-citrate with either H2O2, l-ascorbate, or l-cysteine induced single- and double-strand breaksin supercoiled plasmid pZ189 in a concentration- and time-dependent fashion. DNA strand breaks produced by Fe-citrate plus H2O2 increased at reduced pH (≤ 6.9). Catalase and free radical scavengers inhibited the DNA breakage produced by Fe-citrate in combination with each reductant, suggesting that H2O2 and finally .OH are responsible DNA damaging species. The catalytic ability of Fe-citrate to induce DNA strand breaks, particularly double-strand breaks (DSBs), may contribute to the carcinogenic processes observed in GH. © 1993.

    DOI: 10.1016/0891-5849(93)90050-5

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  1131. GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL/KH STRAIN MICE

    YAMADA Y, SHIMADA M, OKAMOTO K, TOYOKUNI S, NAKAKUKI Y, FUKUMOTO M, HIAI H

    EXPERIMENTAL HEMATOLOGY   Vol. 21 ( 8 ) page: 1118 - 1118   1993.8

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  1132. ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL/KH MICE Reviewed International journal

    OKAMOTO, K, YAMADA, Y, SHIMADA, M, TOYOKUNI, S, NAKAKUKI, Y, HIAI, H

    EXPERIMENTAL HEMATOLOGY   Vol. 21 ( 8 ) page: 1126 - 1126   1993.8

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  1133. GLUTATHIONE CYCLE DEPENDENCY OF FERRIC NITRILOTRIACETATE-INDUCED LIPID-PEROXIDATION IN MOUSE PROXIMAL RENAL TUBULES

    OKADA S, MINAMIYAMA Y, HAMAZAKI S, TOYOKUNI S, SOTOMATSU A

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 301 ( 1 ) page: 138 - 142   1993.2

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  1134. GLUTATHIONE CYCLE DEPENDENCY OF FERRIC NITRILOTRIACETATE-INDUCED LIPID-PEROXIDATION IN MOUSE PROXIMAL RENAL TUBULES

    OKADA S, MINAMIYAMA Y, HAMAZAKI S, TOYOKUNI S, SOTOMATSU A

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 301 ( 1 ) page: 138 - 142   1993.2

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  1135. Glutathione cycle dependency of ferric nitrilotriacetate-induced lipid peroxidation in mouse proximal renal tubules

    Okada S., Minamiyama Y., Hamazaki S., Toyokuni S., Sotomatsu A.

    Archives of Biochemistry and Biophysics   Vol. 301 ( 1 ) page: 138 - 142   1993.2

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    Parenteral administration of ferric nitrilotriacetate (Fe-NTA), a known carcinogen in mouse and rat kidneys, enhances iron-dependent lipid peroxidation (LP) and causes acute renal tubular necrosis. We assume that filtered Fe-NTA in vivo is rapidly reduced by cysteine, a component of glutathione which is hydrolyzed by γ-GTP and dipeptidase, and that this reduced iron initiates lipid peroxidation in the lumen. In addition, the fatty acid composition of phospholipids between the cortex and the medulla may differ, because only the proximal tubules (which are located mainly in the cortex) are known to be vulnerable to LP. We tested these assumptions in the present study. Gas chromatographic determination of fatty acid composition in five male and five female 6-week-old normal ddY mice showed the ratio of polyunsaturated fatty acids to saturated fatty acids plus C18:1, a single double-bond fatty acid, to be 0.98 ± 0.08 (av ± SD) in the male cortex and 1.00 ± 0.08 in the female cortex. In the male and female medulla, however, it was 0.78 ± 0.09 (P < 0.05, vs cortex) and 0.68 ± 0.04 (P < 0.01, vs cortex), respectively. Pretreatment of the animals with buthionine sulfoximine, a glutathione synthetase inhibitor, and a procedure that reduces total glutathione content in the kidneys, suppressed LP. Reduced thiobarbituric acid reactive substances were also observed in animals treated with AT-125, a γ-GTP inhibitor, and in animals with immature γ-GTP activity. These results are consistent with our assumptions. © 1993 Academic Press, Inc.

    DOI: 10.1006/abbi.1993.1125

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  1136. DNA SINGLE-STRAND AND DOUBLE-STRAND BREAKS PRODUCED BY FERRIC NITRILOTRIACETATE IN RELATION TO RENAL TUBULAR CARCINOGENESIS

    TOYOKUNI S, SAGRIPANTI JL

    CARCINOGENESIS   Vol. 14 ( 2 ) page: 223 - 227   1993.2

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  1137. DNA single- and double-strand breaks produced by ferric nitrilotriacetate in relation to renal tubular carcinogenesis

    TOYOKUNI S.

    Carcinogenesis   Vol. 14 ( 2 ) page: 223 - 227   1993.2

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  1138. DNA single- and double-strand breaks produced by ferric nitrilotriacetate in relation to renal tubular carcinogenesis

    Toyokuni S., Sagripanti J.

    Carcinogenesis   Vol. 14 ( 2 ) page: 223 - 227   1993.2

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    Fe(III) bound to a chelator, nitrilotriacetate (NTA), has been reported to induce a high frequency of adenocarcinoma localized to the proximal tubules of the kidney in rodents. In order to examine possible mechanisms for the carcinogenic activity, we investigated the in vitro production of single- and double-strand breaks in DNA mediated by iron alone or Fe-NTA chelate using supercoiled plasmid pZ189. Neither Fe(III) nor NTA alone broke DNA. Fe(III) plus NTA together mediated the efficient oxidative production of DNA single-and double-strand breaks in the presence of reducing agents (ascorbate » H2O2 > cysteine). The Fe(III): NTA ratio (1:4) that was found to be optimal for DNA strand breakage was similar to the ratio that produced adenocarcinomas in rodents. Maximal Fe-NTA-mediated DNA damage in vitro was induced under conditions of neutral pH, low ionic strength, presence of reducing agent and absence of albumin. These conditions are present exclusively in the cortical proximal tubules of the kidney, the only location where toxicity and carcinogenicity of Fe-NTA has been observed. Thus, localized DNA damage may explain the anatomic site preferred by Fe-NTA-induced carcinogenesis. © 1993 Oxford University Press.

    DOI: 10.1093/carcin/14.2.223

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  1139. CHARACTERIZATION OF IMMORTALIZED CELL-LINES ISOLATED FROM A SOFT-TISSUE TUMOR-DERIVED FROM A RABBIT SUBCHRONICALLY EXPOSED TO 60HZ MAGNETIC-FIELDS AT 1-G

    NING, JT; BUSHAR, G; LI, L; TOYOKUNI, S; THOMAS, D; CRESS, L; CZERSKA, EM; SWICORD, ML; ELSON, E; DAVIS, CC

    ELECTRICITY AND MAGNETISM IN BIOLOGY AND MEDICINE     page: 405 - 408   1993

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  1140. DOSE-DEPENDENT HEALTH-EFFECTS EXHIBITED IN RABBITS EXPOSED TO 60HZ MAGNETIC-FIELDS AT 1 G AND 5 G

    NING, JT; CZERSKA, EM; CASAMENTO, J; TOYOKUNI, S; SWICORD, ML; STCHARLES, C; EINSMANN, FE; PERRY, B; ELSON, E; DAVIS, CC

    ELECTRICITY AND MAGNETISM IN BIOLOGY AND MEDICINE     page: 845 - 848   1993

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  1141. PATHOLOGICAL EVALUATION OF RABBITS SUBCHRONICALLY EXPOSED TO 60HZ MAGNETIC-FIELDS AT 1 G AND 5 G

    NING, JT; TOYOKUNI, S; THOMAS, D; CZERSKA, EM; CASAMENTO, J; SWICORD, ML; DAVIS, CC; ELSON, E

    ELECTRICITY AND MAGNETISM IN BIOLOGY AND MEDICINE     page: 835 - 838   1993

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  1142. PATHOLOGICAL EVALUATION OF RABBITS SUBCHRONICALLY EXPOSED TO 60HZ MAGNETIC-FIELDS AT 1 G AND 5 G

    NING JT, TOYOKUNI S, THOMAS D, CZERSKA EM, CASAMENTO J, SWICORD ML, DAVIS CC, ELSON E

    ELECTRICITY AND MAGNETISM IN BIOLOGY AND MEDICINE     page: 835 - 838   1993

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  1143. DOSE-DEPENDENT HEALTH-EFFECTS EXHIBITED IN RABBITS EXPOSED TO 60HZ MAGNETIC-FIELDS AT 1 G AND 5 G

    NING JT, CZERSKA EM, CASAMENTO J, TOYOKUNI S, SWICORD ML, STCHARLES C, EINSMANN FE, PERRY B, ELSON E, DAVIS CC

    ELECTRICITY AND MAGNETISM IN BIOLOGY AND MEDICINE     page: 845 - 848   1993

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  1144. CHARACTERIZATION OF IMMORTALIZED CELL-LINES ISOLATED FROM A SOFT-TISSUE TUMOR-DERIVED FROM A RABBIT SUBCHRONICALLY EXPOSED TO 60HZ MAGNETIC-FIELDS AT 1-G Reviewed International coauthorship International journal

    NING, JT, BUSHAR, G, LI, L, TOYOKUNI, S, THOMAS, D, CRESS, L, CZERSKA, EM, SWICORD, ML, ELSON, E, DAVIS, CC

    ELECTRICITY AND MAGNETISM IN BIOLOGY AND MEDICINE     page: 405 - 408   1993

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  1145. IRON-MEDIATED DNA DAMAGE - SENSITIVE DETECTION OF DNA STRAND BREAKAGE CATALYZED BY IRON

    TOYOKUNI S, SAGRIPANTI JL

    JOURNAL OF INORGANIC BIOCHEMISTRY   Vol. 47 ( 3-4 ) page: 241 - 248   1992.8

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  1146. REPORT OF A PATIENT WITH POEMS-TAKATSUKI-CROW-FUKASE SYNDROME ASSOCIATED WITH FOCAL SPINAL PACHYMENINGEAL AMYLOIDOSIS

    TOYOKUNI S, EBINA Y, OKADA S, YAMABE H, ISHIKAWA T, UCHIYAMA T, YODOI J, UCHINO H, TAKATSUKI K

    CANCER   Vol. 70 ( 4 ) page: 882 - 886   1992.8

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  1147. Report of a patient with POEMS/takatsuki/crow‐fukase syndrome associated with focal spinal pachymeningeal amyloidosis

    Toyokuni S., Ebina Y., Okada S., Yamabe H., Ishikawa T., Uchiyama T., Yodoi J., Uchino H., Takatsuki K.

    Cancer   Vol. 70 ( 4 ) page: 882 - 886   1992.8

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    The authors present the results of an autopsy of a 67‐year‐old Japanese man with POEMS/Takatsuki/Crow‐Fukase syndrome (P/T/CFS) diagnosed in 1972. Each component of the syndrome was gradually recognized after the resection of lumbar vertebral solitary plasma‐cytoma in 1967. The patient died in 1989 of generalized infection and renal failure. Autopsy revealed in the vertebral canal between the fifth and seventh thoracic vertebrae dorsal pachymeningeal fibrosis, with prominent amyloid deposition that oppressed the spinal cord. This condition was consistent with the final neurologic manifestation of the patient, bilateral motor and sensory disturbance below the sixth thoracic level. Myelopathy remained clinically unnoticed because neurologic disturbance had begun as peripheral polyneuropathy. Normo‐cellular marrow with heterogeneously scattered lambda light chain‐positive plasma cells and degeneration of the myelinated fibers of sciatic nerve also were observed. This is the first report of focal spinal amyloidosis associated with P/T/CFS. Cancer 1992; 70:882–886. Copyright © 1992 American Cancer Society

    DOI: 10.1002/1097-0142(19920815)70:4<882::AID-CNCR2820700426>3.0.CO;2-R

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  1148. Peport of a patient with POEMS/Takatsuki/Crow-Fukase syndrome associated with focal spinal pachymeningeal amyloidsis.

    TOYOKUNI S.

    Cancer   Vol. 70 ( 4 ) page: 882 - 886   1992.8

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  1149. Iron-mediated DNA damage : sensitive detection of DNA strand breakage catalyzed by iron

    TOYOKUNI S

    J. Inorg. Biochem.   Vol. 47 ( 3-4 ) page: 241 - 248   1992.8

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  1150. A case of undifferentiated sarcoma of the liver

    OKUYAMA Takazo, TOYOKUNI Shinya, OKADA Shigeru, NAKASHIMA Yasuaki, YAMABE Hirohiko, KAN Shugen, MORI Keiichiro, OZAWA Kazue

    The Journal of the Japanese Society of Clinical Cytology   Vol. 31   page: 89 - 90   1992

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  1151. A case of undifferentiated sarcoma of the liver.

    OKUYAMA Takazo, TOYOKUNI Shinya, OKADA Shigeru, NAKASHIMA Yasuaki, YAMABE Hirohiko, KAN Shugen, MORI Keiichiro, OZAWA Kazue

    The Journal of the Japanese Society of Clinical Cytology   Vol. 31 ( 1 ) page: 89 - 90   1992

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    DOI: 10.5795/jjscc.31.89

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  1152. A case of undifferentiated sarcoma of the liver

    OKUYAMA Takazo, TOYOKUNI Shinya, OKADA Shigeru, NAKASHIMA Yasuaki, YAMABE Hirohiko, KAN Shugen, MORI Keiichiro, OZAWA Kazue

    The Journal of the Japanese Society of Clinical Cytology   Vol. 31   page: 89 - 90   1992

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  1153. Iron-mediated DNA damage: Sensitive detection of DNA strand breakage catalyzed by iron

    Toyokuni S., Sagripanti J.

    Journal of Inorganic Biochemistry   Vol. 47 ( 1 ) page: 241 - 248   1992

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    Oxidative DNA damage is involved in mutagenesis, carcinogenesis, aging, radiation effects, and the action of several anticancer drugs. Accumulated evidence indicates that iron may play an important role in those processes. We studied the in vitro effect of low concentrations of Fe(II) alone or Fe(III) in the presence of reducing agents on supercoiled plasmid DNA. The assay, based on the relaxation and linearization of supercoiled DNA, is simple yet sensitive and quantitative. Iron mediated the production of single and double strand breaks in supercoiled DNA. Iron chelators, free radical scavengers, and enzymes of the oxygen reduction pathways modulated the DNA damage. Fe(III)-nitrilotriacetate (NTA) plus either H2O2, L-ascorbate, or L-cysteine produced single and double strand breaks as a function of reductant concentration. A combination of 0.1 μM Fe(III)-NTA and 100 μM L-ascorbate induced detectable DNA strand breaks after 30 min at 24°C. Whereas superoxide dismutase was inhibitory only in systems containing H2O2 as reductant, catalase inhibited DNA breakage in all the iron-mediated systems studied. The effect of scavengers and enzymes indicates that H2O2 and .OH are involved in the DNA damaging process. These reactions may account for the toxicity and carcinogenicity associated with iron overload. © 1992.

    DOI: 10.1016/0162-0134(92)84069-Y

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  1154. Histochemical detection of burn-induced lipid peroxidation in sebaceous glands of rat skin.

    Kitajima T, Hamanaka H, Miyachi Y, Ono Y, Moriguchi T, Toyokuni S, Imamura S

    The Journal of dermatology   Vol. 18 ( 7 ) page: 393 - 6   1991.7

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    Increased lipid peroxide levels both in skin and serum have been reported after cutaneous thermal injury. However, it still remains unclear where lipid peroxides are produced at the site of burned skin. In the present study, a histochemical method using cold Schiff's reagent was applied in order to detect the localization of lipid peroxide. Schiff positivity was detected in sebaceous glands, and the extent of positivity seemed to correlate with the serum lipid peroxide levels. These results may suggest that lipid peroxides produced in sebaceous glands after thermal injury enter the blood stream and are partially responsible for the elevated serum lipid peroxide levels.

    DOI: 10.1111/j.1346-8138.1991.tb03104.x

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  1155. SEX-DIFFERENCES IN THE LOCALIZATION AND SEVERITY OF FERRIC NITRILOTRIACETATE-INDUCED LIPID-PEROXIDATION IN THE MOUSE KIDNEY

    OKADA, S; FUKUNAGA, Y; HAMAZAKI, S; YAMADA, Y; TOYOKUNI, S

    ACTA PATHOLOGICA JAPONICA   Vol. 41 ( 3 ) page: 221 - 226   1991.3

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  1156. Sex differences in the localization and severity of ferric nitrilotriacetate-induced lipid peroxidation in the mouse kidney

    OKADA S.

    Acta Pathol. Jpn.   Vol. 41 ( 3 ) page: 221 - 226   1991.3

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  1157. Sex Differences in the Localization and Severity of Ferric Nitrilotriacetate‐induced Lipid Peroxidation in the Mouse Kidney

    Okada S., Fukunaga Y., Hamazaki S., Yamada Y., Toyokuni S.

    Pathology International   Vol. 41 ( 3 ) page: 221 - 226   1991.3

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    Male mice are much more susceptible than female mice to acute renal proximal tubular necrosis as well as the carcinogenic effect induced by an iron chelate, ferric nitrilotriacetate (Fe‐NTA). In the present study, iron‐promoted lipid peroxidation was analyzed histochemically in frozen kidney sections using cold Schiffs reagent and biochemically by measuring thiobarbituric acid‐reactive substance in the kidney. When untreated mouse frozen kidney sections were exposed to ascorbic acid‐Fe‐NTA (0.8 mM, 0.2 mM and 0.4 mM) in vitro for 40 min and washed, diffuse Schiff positivity was obtained along the proximal tubules, and no sex differences were evident. When non‐reduced Fe‐NTA (0.2 mM and 0.4 mM) was layered on untreated kidney sections from males, about half of the cortical proximal tubules showed a positive reaction with Schiffs reagent, whereas in females the proximal tubules of the outer stripe of the outer medulla were positive. In an ex vivo study, 30 to 40 min after i.p. injection of Fe‐NTA (5 mg Fe/kg), Schiff‐positive areas corresponded to those observed in the in vitro non‐reduced Fe‐NTA study in each sex. However, in males, the positive tubular cells gradually became necrotic, whereas in females the positivity disappeared with time and there was no tubular necrosis. Results of the thiobarbituric acid test were correlated with the above findings. In conclusion, the localization and severity of FeNTA induced lipid peroxidation in the tubules differed between the sexes. We suspect that these results reflect functional heterogeneity in the ability of the tubules to reduce iron. Copyright © 1991, Wiley Blackwell. All rights reserved

    DOI: 10.1111/j.1440-1827.1991.tb01651.x

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  1158. CONGENITAL MYOTONIC-DYSTROPHY WITH PROGRESSIVE EDEMA AND HYPOPROTEINEMIA

    FUJII T, YORIFUJI T, OKUNO T, TOYOKUNI S, OKADA S, MIKAWA H

    BRAIN & DEVELOPMENT   Vol. 13 ( 1 ) page: 58 - 60   1991

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  1159. Congenital myotonic dystrophy with progressive edema and hypoproteinemia

    FUJI T

    Brain Develop   Vol. 13 ( 1 ) page: 58 - 60   1991

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  1160. Congenital myotonic dystrophy with progressive edema and hypoproteinemia

    Fujii T., Yorifuji T., Okuno T., Toyokuni S., Okada S., Mikawa H.

    Brain and Development   Vol. 13 ( 1 ) page: 58 - 60   1991

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    We report a patient with congenital myotonic dystrophy who had progressive edema and hypoproteinemia. An atrioseptal defect and patent ductus arteriosus were noted and were considered to be the cause of the right heart failure and edema. Although urinary protein levels were minimal, infusion of albumin did not improve the hypoproteinemia. Administration of dexamethasone increased the serum protein level, but the edema was not ameliorated. Autopsy revealed a slight lymphatic dilatation in the small intestine, suggesting protein-losing enteropathy. © 1991, All rights reserved.

    DOI: 10.1016/S0387-7604(12)80300-7

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  1161. A CASE OF BIOPSY-PROVEN MYOCARDITIS PROGRESSING TO AUTOPSY-PROVEN DILATED CARDIOMYOPATHY

    MATOBA Y, MATSUMORI A, OHTANI H, TOMINAGA M, FUJIWARA H, TOYOKUNI S, TAKAHASHI K, MIDORIKAWA O, KAWAI C

    CLINICAL CARDIOLOGY   Vol. 13 ( 10 ) page: 732 - 737   1990.10

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  1162. A case of biopsy‐proven myocarditis progressing to autopsy‐proven dilated cardiomyopathy

    Matoba Y., Matsumori A., Ohtani H., Tominaga M., Fujiwara H., Kawai C., Toyokuni S., Midorikawa O., Takahashi K.

    Clinical Cardiology   Vol. 13 ( 10 ) page: 732 - 737   1990.10

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    A 22‐year‐old man presented with congestive heart failure following flulike symptoms. The diagnosis of acute myocarditis was confirmed by endomyocardial biopsy, which revealed mild infiltration of inflammatory cells. A favorable response to beta‐adrenergic receptor blockade was seen, and the patient was discharged without symptoms. Five months later, however, congestive heart failure recurred, and intracardiac thrombi were demonstrated. The patient died after two months. Postmortem examination revealed left ventricular dilatation with slight interstitial fibrosis; the diagnosis was dilated cardiomyopathy. Thus, progression of biopsy‐proven myocarditis to dilated cardiomyopathy 10 months after the onset of disease was documented. Copyright © 1990 Wiley Periodicals, Inc.

    DOI: 10.1002/clc.4960131013

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  1163. A case of biopsy-proven myocarditis progressing to autopsy-proven dilated cardiomyopathy

    MATOBA Y.

    Clinical Cardiol   Vol. 13 ( 10 ) page: 732 - 737   1990.10

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  1164. COMBINED HISTOCHEMICAL AND BIOCHEMICAL-ANALYSIS OF SEX-HORMONE DEPENDENCE OF FERRIC NITRILOTRIACETATE-INDUCED RENAL LIPID-PEROXIDATION IN DDY-MICE

    TOYOKUNI S, OKADA S, HAMAZAKI S, MINAMIYAMA Y, YAMADA Y, LIANG P, FUKUNAGA Y, MIDORIKAWA O

    CANCER RESEARCH   Vol. 50 ( 17 ) page: 5574 - 5580   1990.9

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  1165. Combined histochemical and biochemical analysis of sex hormone dependence of ferric nitrilotriacetate-induced renal lipid peroxidation in ddY mice

    TOYOKUNI S.

    Cancer Res   Vol. 50 ( 17 ) page: 5574 - 5580   1990.9

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  1166. Combined Histochemical and Biochemical Analysis of Sex Hormone Dependence of Ferric Nitrilotriacetate-induced Renal Lipid Peroxidation in ddY Mice

    Toyokuni S., Okada S., Hamazaki S., Minamiyama Y., Yamada Y., Liang P., Fukunaga Y., Midorikawa O.

    Cancer Research   Vol. 50 ( 17 ) page: 5574 - 5580   1990.9

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    Ferric nitrilotriacetate (Fe-NTA) induces renal proximal tubular necrosis, a consequence of lipid peroxidation, that finally leads to a high incidence of renal adenocarcinoma in rats and mice. Male animals are much more susceptible than female animals to both effects. Moreover, the distribution of the susceptible proximal tubules is different between male and female animals. The present study investigated the effects of castration and sex hormones on Fe-NTA-induced renal lipid peroxidation. Male and female ddY mice were either left untreated, castrated, and/or treated with testosterone or estriol. Histochemical (reactivity to cold SchifTs reagent) and biochemical (thiobarbSturic acid-reactive substance) evaluations were performed 1 h after the i.p. injection of Fe-NTA (5 mg iron/kg). Testosterone treatment and/or oophorectomy increased the Schiff pos-itivity of the renal cortical proximal tubules and the amount of thiobar-bituric acid-reactive substance (testosterone-treated female > intact female, P < 0.005; castrated female > intact female, P < 0.1; castrated and testosterone-treated female >intact female, P < 0.005). In contrast, estriol treatment and/or orchiectomy decreased the Schiff positivity of the renal cortical proximal tubules and the amount of thiobarbituric acid-reactive substance (estriol-treated male < intact male, P < 0.01; castrated male < intact male, P < 0.01; castrated and estriol-treated male < intact male, P < 0.005). Estradiol treatment produced similar results to estriol treatment (estradiol-treated male <intact male, P < 0.005). Castration and/or administration of the opposite sex hormone reversed the sex difference in the distribution of proximal tubules susceptible to lipid peroxidation. However, the i.v. injection to male mice, 5 min prior to the Fe-NTA treatment, of conjugated estrogen that is promptly excreted via the urine produced no significant effect. Thus, altered metabolic pathways rather than the direct scavenging activity of estrogens seem to be involved in the sex hormone-dependent difference of lipid peroxidation. Genetically determined sex hormone status appears to have influenced the incidence of Fe-NTA-induced renal adenocarcinoma in intact animals. © 1990, American Association for Cancer Research. All rights reserved.

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  1167. Combined histochemical and biochemical analysis of sex hormone dependence of ferric nitrilotriacetate-induced renal lipid peroxidation in ddY mice.

    Toyokuni S, Okada S, Hamazaki S, Minamiyama Y, Yamada Y, Liang P, Fukunaga Y, Midorikawa O

    Cancer research   Vol. 50 ( 17 ) page: 5574 - 80   1990.9

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  1168. THIOBARBITURIC ACID-REACTIVE SUBSTANCE FORMATION OF RAT-KIDNEY BRUSH-BORDER MEMBRANE-VESICLES INDUCED BY FERRIC NITRILOTRIACETATE

    HAMAZAKI S, OKADA S, TOYOKUNI S, MIDORIKAWA O

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 274 ( 2 ) page: 348 - 354   1989.11

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  1169. Thiobarbituric acid-reactive substance formation of rat kidney brush border membrane vesicles induced by ferric nitrilotriacetate

    Hamazaki S., Okada S., Toyokuni S., Midorikawa O.

    Archives of Biochemistry and Biophysics   Vol. 274 ( 2 ) page: 348 - 354   1989.11

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    An iron chelate, ferric nitrilotriacetate (Fe3+-NTA), is nephrotoxic and also carcinogenic to the kidney in experimental animals. Iron-promoted lipid peroxidation in the proximal tubules is thought to be responsible for the pathologic process. In the present study, iron-promoted lipid peroxidation, with thiobarbituric acid (TBA) formation as an indication, in the tubular surface was simulated in vitro using rat kidney brush border membrane vesicles and the results were compared with those using linoleate micelles and rat liver microsomal lipid liposomes. Addition of ascorbate, cysteine, or dithiothreitol to the Fe3+-NTA solution resulted in consumption of dissolved oxygen and promoted the lipid peroxidation in the micelles and in the liposomes. In contrast, addition of glutathione to the Fe3+-NTA solution caused only sluggish oxygen consumption and far less peroxidation in these lipid systems. When the brush border membrane vesicles were used for the peroxidation substrate, Fe3+-NTA and glutathione could promote TBA formation at a rate comparable to that elicited by Fe3+-NTA with cysteine or dithiothreitol. Acivicin, a γ-glutamyl transpeptidase inhibitor, suppressed the peroxidation of the brush border membrane vesicles promoted by Fe3+-NTA and glutathione. These results suggest the following mechanism of proximal tubular cell lipid peroxidation promoted by Fe-NTA: Fe3+-NTA filtered through glomeruli is rapidly reduced by cysteine and Fe2+-NTA starts lipid peroxidation at the site, leading to proximal tubular necrosis. Cysteine is amply supplied by the decomposition of glutathione within the lumen by the action of γ-glutamyl transpeptidase and dipeptidase situated at the proximal tubular brush border membrane. © 1989.

    DOI: 10.1016/0003-9861(89)90448-7

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  1170. INDUCTION OF MESOTHELIOMA BY INTRAPERITONEAL INJECTIONS OF FERRIC SACCHARATE IN MALE WISTAR RATS

    OKADA S, HAMAZAKI S, TOYOKUNI S, MIDORIKAWA O

    BRITISH JOURNAL OF CANCER   Vol. 60 ( 5 ) page: 708 - 711   1989.11

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  1171. THIOBARBITURIC ACID-REACTIVE SUBSTANCE FORMATION OF RAT-KIDNEY BRUSH-BORDER MEMBRANE-VESICLES INDUCED BY FERRIC NITRILOTRIACETATE Reviewed

    S HAMAZAKI, S OKADA, S TOYOKUNI, O MIDORIKAWA

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 274 ( 2 ) page: 348 - 354   1989.11

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  1172. Induction of mesothelioma by intraperitoneal injections of ferric saccharate in male wistar rats

    Okada S., Hamazaki S., Toyokuni S., Midorikawa O.

    British Journal of Cancer   Vol. 60 ( 5 ) page: 708 - 711   1989.11

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    Iron appears to play a major role in catalysing free radical production, leading to lipid peroxidation and DNA damage. We, therefore, investigated the effect of colloidal iron deposited in the peritoneum. Wistar male rats were given either ferric saccharate, ferric saccharate and nitrilotriacetic acid (NTA), NTA or saline. NTA was shown previously to ‘free’ iron to promote lipid peroxidation and an iron chelate of NTA is known to be carcinogenic to the kidney. Iron at a dose of 5 mg kg-1 day-1, and saline at a dose of 0.5 ml day-1 were injected i.p. for 3 months. NTA at a dose of 83.5 mg kg-1 day1 was give i.p for 5 months. All the rats were killed about a year later for histological examination. In nine of the 19 rats treated with ferric saccharate, mesothelial tumors were induced in the serosa of the tunica vaginalis or the length of the spermatic cord. Among rats treated with ferric saccharate and NTA, seven had localised mesotheliomas in the above locations and six had wide-spread peritoneal mesotheliomas. No mesothelial tumors developed in either NTA treated or saline treated rats. No pleural mesotheliomas were found in any group. These findings add to the evidence that iron is involved in some carcinogenic processes. © The Macmillan Press Ltd., 1989.

    DOI: 10.1038/bjc.1989.344

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  1173. Induction of mesothelioma by intraperitoneal injections of ferric saccharate in male Wistar rats

    OKADA S.

    Br J Cancer   Vol. 60 ( 5 ) page: 708 - 711   1989.11

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  1174. OXYGEN REDUCTION AND LIPID-PEROXIDATION BY IRON CHELATES WITH SPECIAL REFERENCE TO FERRIC NITRILOTRIACETATE

    HAMAZAKI S, OKADA S, LI JL, TOYOKUNI S, MIDORIKAWA O

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 272 ( 1 ) page: 10 - 17   1989.7

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  1175. OXYGEN REDUCTION AND LIPID-PEROXIDATION BY IRON CHELATES WITH SPECIAL REFERENCE TO FERRIC NITRILOTRIACETATE Reviewed

    S HAMAZAKI, S OKADA, JL LI, S TOYOKUNI, O MIDORIKAWA

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 272 ( 1 ) page: 10 - 17   1989.7

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  1176. Oxygen reduction and lipid peroxidation by iron chelates with special reference to ferric nitrilotriacetate

    Hamazaki S., Okada S., Li J., Toyokuni S., Midorikawa O.

    Archives of Biochemistry and Biophysics   Vol. 272 ( 1 ) page: 10 - 17   1989.7

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    A certain iron chelate, ferric nitrilotriacetate (Fe3+-NTA) is nephrotoxic and also carcinogenic to the kidney in mice and rats, a distinguishing feature not shared by other iron chelates tested so far. Iron-promoted lipid peroxidation is thought to be responsible for the initial events. We examined its ability to initiate lipid peroxidation in vitro in comparison with that of other ferric chelates. Chelation of Fe2+ by nitrilotriacetate (NTA) enhanced the autoxidation of Fe2+. In the presence of Fe2+-NTA, lipid peroxidation occurred as measured by the formation of conjugated diene in detergent-dispersed linoleate micelles, and by the formation of thiobarbituric acid-reactive substances in the liposomes of rat liver microsomal lipids. Addition of ascorbic acid to Fe3+-NTA solution promoted dose-dependent consumption of dissolved oxygen, which indicates temporary reduction of iron. On reduction, Fe3+-NTA initiated lipid peroxidation both in the linoleate micelles and in the liposomes. Fe3+-NTA also initiated NADPH-dependent lipid peroxidation in rat liver microsomes. Although other chelators used (deferoxamine, EDTA, diethylenetriaminepentaacetic acid, ADP) enhanced autoxidation, reduction by ascorbic acid, or in vitro lipid peroxidation of linoleate micelles or liposomal lipids, NTA was the sole chelator that enhanced all the reactions. © 1989.

    DOI: 10.1016/0003-9861(89)90188-4

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  1177. CIRRHOSIS OF THE LIVER INDUCED BY CUPRIC NITRILOTRIACETATE IN WISTAR RATS - AN EXPERIMENTAL-MODEL OF COPPER TOXICOSIS

    TOYOKUNI S, OKADA S, HAMAZAKI S, FUJIOKA M, LI JL, MIDORIKAWA O

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 134 ( 6 ) page: 1263 - 1274   1989.6

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  1178. CIRRHOSIS OF THE LIVER INDUCED BY CUPRIC NITRILOTRIACETATE IN WISTAR RATS - AN EXPERIMENTAL-MODEL OF COPPER TOXICOSIS Reviewed

    S TOYOKUNI, S OKADA, S HAMAZAKI, M FUJIOKA, JL LI, O MIDORIKAWA

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 134 ( 6 ) page: 1263 - 1274   1989.6

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  1179. Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats. An experimental model of copper toxicosis.

    Toyokuni S, Okada S, Hamazaki S, Fujioka M, Li JL, Midorikawa O

    The American journal of pathology   Vol. 134 ( 6 ) page: 1263 - 74   1989.6

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  1180. Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats: an experimental model of copper toxicosis. Reviewed

    Toyokuni S, Okada S, Hamazaki S, Fujioka M, Li J-L and Midorikawa O.

    Am. J. Pathol.   Vol. 134   page: 1263-1274   1989

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  1181. Oxygen reduction and lipid peroxidation by iron chelates with special reference to ferric nitrilotriacetate. Reviewed

    Hamazaki S, Okada S, Li J-L, Toyokuni S and Midorikawa O.

    Arch. Biochem. Biophys.   Vol. 272   page: 10-17   1989

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  1182. Nasal T-cell lymphoma associated with double gammopathy; A case report.

    Omori Koichi, Kojima Hisayoshi, Nonomura Mitsuharu, Kanaji Myojo, Toyokuno Shinya

    Practica Oto-Rhino-Laryngologica   Vol. 82 ( 12 ) page: 1739 - 1744   1989

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    Nasal T-cell lymphoma associated with double gammopathy (IgG and IgA) was found in a 78-year-old man with a necrotic tumor in his right nasal cavity. He was treated with radiotherapy and CVP chemotherapy but the lymphoma relapsed in his left nasal cavity 1 year later. He was treated again with the same therapy and is now alive and tumor-free.<br>Two serum M-components (IgG and IgA) were detected through his clinical course. To our knowledge, this is the first report of T-cell lymphoma associated with double gammopathy. The significance of M-components in T-cell lymphocytic proliferation remains unclear, but it may be that the M-components appear because of the inappropriate regulation of the T-B immune-response system in the presence of T-cell lymphoma.<br>Histology in this case is also noteworthy. The first nasal tumor showed granulation and necrotic tissue with plasma cell infiltration; it was diagnosed as non-Hodgkin diffuse lymphoma, mixed type, by surface marker analysis. This indicates that immunohistochemical study is indispensable for the diagnosis of nasal non-healing granuloma with necrosis.

    DOI: 10.5631/jibirin.82.1739

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  1183. Renal changes induced by chronic oral administration of potassium bromate of ferric nitrilotriacetate in Wistar rats

    K. Nakano, S. Okada, S. Toyokuni, O. Midorikawa

    Japanese Archives of Internal Medicine   Vol. 36 ( 2 ) page: 41 - 47   1989

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  1184. Cirrhosis of the liver induced by cupric nitrilotriacetate in Wistar rats. An experimental model of copper toxicosis

    Toyokuni S., Okada S., Hamazaki S., Fujioka M., Li J.L., Midorikawa O.

    American Journal of Pathology   Vol. 134 ( 6 ) page: 1263 - 1274   1989

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    Rats intraperitoneally injected with a daily dose of cupric nitrilotriacetate (Cu-NTA), which contained 4 to 7 mg of copper/kg body weight, showed submassive liver necrosis, hemolytic anemia, and acute renal tubular necrosis at the beginning of the experiment and intermittently after 4 weeks of injections. All rats that survived over 8 weeks exhibited liver fibrosis with portal-portal, portal-central, and central-central bridging. In all rats that survived over 16 weeks, micronodular cirrhosis of the liver or extensive liver fibrosis was observed. The copper content of the cirrhotic/fibrotic liver was above 250 μg/g dry weight. Electron-microscopic x-ray analysis at day 93 revealed that copper stored in secondary lysosomes was always accompanied by a proportional amount of sulfur (correlation coefficient, 0.98; P < 0.005). An experimental model of copper toxicosis in terms of copper-induced cirrhosis of the liver was established with exogenous copper chelated by nitrilotriacetate.

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Books 35

  1. 酸化ストレスの医学

    内藤 裕二, 豐國 伸哉, 赤池 孝章, 半田 修, 日本酸化ストレス学会( Role: Sole author)

    診断と治療社  2024  ( ISBN:9784787826206

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  2. 慢性腎臓病・透析患者の酸化ストレス-最新の知見と治療展開 臨床透析

    豊國伸哉( Role: Contributor ,  3:慢性腎臓病の病態と酸化ストレス (2)腎発がんにおける酸化ストレス )

    日本メディカルセンター  2020.11 

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    Responsible for pages:36(12), 1558-1564   Language:Japanese Book type:Scholarly book

  3. 慢性腎臓病・透析患者の酸化ストレス-最新の知見と治療展開 臨床透析

    豊國伸哉( Role: Contributor ,  3:慢性腎臓病の病態と酸化ストレス (2)腎発がんにおける酸化ストレス)

    日本メディカルセンター  2020.11 

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    Responsible for pages:36(12), 1558-1564   Language:Japanese Book type:Scholarly book

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  4. 実験医学 特集 環境因子と発がん

    豊國伸哉( Role: Contributor ,  豊國伸哉 アスベスト・線維性ナノ物質による発がんメカニズム:なぜ特定の鉱物はヒトにがんを発生させるのか?)

    羊土社  2020.7 

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    Total pages:538   Responsible for pages:第38巻第11号、1835-1841   Language:Japanese Book type:Scholarly book

  5. 実験医学 特集 環境因子と発がん

    豊國伸哉( Role: Contributor ,  豊國伸哉 アスベスト・線維性ナノ物質による発がんメカニズム:なぜ特定の鉱物はヒトにがんを発生させるのか?)

    羊土社  2020.7 

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    Total pages:538   Responsible for pages:第38巻第11号、1835-1841   Language:Japanese Book type:Scholarly book

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  6. マウス・ラットモデル作製・解析プロフェッショナル 編集:先端モデル動物支援プラットフォーム(AdAMS)

    豊國伸哉、伊藤文哉、本岡大社、蒋 麗( Role: Contributor ,  使いたくなる病理解析新技術 第2章 病理形態の解析)

    羊土社  2020.3 

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    Total pages:317   Responsible for pages:147-160   Language:Japanese Book type:Scholarly book

  7. マウス・ラットモデル作製・解析プロフェッショナル 編集:先端モデル動物支援プラットフォーム(AdAMS)

    豊國伸哉, 伊藤文哉, 本岡大社, 蒋 麗( Role: Contributor ,  使いたくなる病理解析新技術 第2章 病理形態の解析)

    羊土社  2020.3 

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    Total pages:317   Responsible for pages:147-160   Language:Japanese Book type:Scholarly book

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  8. 腎臓内科 特集 特集:微量元素と腎 微量元素・総論② 

    豊國伸哉( Role: Contributor ,  微量元素の欠乏と過剰によって生じる病態)

    科学評論社  2020 

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    Total pages:122   Responsible for pages:11(2): 1-8   Language:Japanese Book type:Scholarly book

  9. 腎臓内科 特集 特集:微量元素と腎 微量元素・総論②

    豊國伸哉( Role: Contributor ,  微量元素の欠乏と過剰によって生じる病態)

    科学評論社  2020 

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    Total pages:122   Responsible for pages:11(2): 1-8   Language:Japanese Book type:Scholarly book

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  10. Cancer and Excess Iron

    Toyokuni S.( Role: Sole author)

    Human Pathobiochemistry: From Clinical Studies to Molecular Mechanisms  2019.1  ( ISBN:9789811329760

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    A 62-year-old male presented transient loss of consciousness during dialysis and was transferred to the emergency room. Chest X-ray and computed tomography revealed prominent right pleural effusion with large tumor mass surrounding the contour of the right lung. The patient had been involved in demolition work of old buildings and water pipes for more than 25 years, where he was often exposed to asbestos fibers in the air. The patient suffered from diabetes mellitus for 18 years and started dialysis three times a week since 7 years ago due to diabetic nephropathy.

    DOI: 10.1007/978-981-13-2977-7_19

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  11. Plasma medical science

    Toyokuni S., Ikehara Y., Kikkawa F., Hori M.( Role: Sole author)

    Plasma Medical Science  2018.1  ( ISBN:9780128150054

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    Plasma Medical Science describes the progress that has been made in the field over the past five years, illustrating what readers must know to be successful. As non-thermal, atmospheric pressure plasma has been applied for a wide variety of medical fields, including wound healing, blood coagulation, and cancer therapy, this book is a timely resource on the topics discussed.

    DOI: 10.1016/C2017-0-01916-X

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  12. Plasma medical science

    Toyokuni S( Role: Joint author)

    Plasma Medical Science  2018.1  ( ISBN:9780128150054

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    DOI: 10.1016/C2017-0-01916-X

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  13. ロビンス基礎病理学

    Kumar Vinay, Abbas Abul K, Aster Jon C, Robbins Stanley L, Stanley Leonard, 豐國 伸哉, 高橋 雅英( Role: Joint author)

    エルゼビア・ジャパン  2018  ( ISBN:9784621301982

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    Total pages:xxiii, 1030p   Language:Japanese

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  14. Plasma medical science

    豐國, 伸哉( Role: Joint author)

    Academic Press, imprint of Elsevier  2018  ( ISBN:9780128150047

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    Total pages:xix, 438 p.   Language:English

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  15. はじめの一歩の病理学

    深山 正久, 田中 伸哉, 豐國 伸哉, 伊藤 彰彦, 宮崎 龍彦, 宇於崎 宏, 田中 文彦, 林 祥剛, 大澤 佳代, 酒々井 眞澄, 小田 義直, 前田 大地, 川村 公一, 後藤 明輝( Role: Joint author)

    羊土社  2017  ( ISBN:9784758120845

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    Total pages:278, 1p   Language:Japanese

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  16. 酸化ストレスの医学 改訂第2版

    内藤裕二、豊國伸哉(編集)( Role: Joint author)

    診断と治療社  2014.9 

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  17. 酸化ストレスの医学 改訂第2版

    内藤裕二, 豊國伸哉( Role: Joint author)

    診断と治療社  2014.9 

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    Responsible for pages:1-444   Language:Japanese

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  18. ロビンス基礎病理学 原書9版

    豊國伸哉、高橋雅英(監訳)( Role: Joint author)

    エルゼビア・ジャパン(丸善出版)  2014.8 

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  19. ロビンス基礎病理学 原書9版

    豊國伸哉, 高橋雅英( Role: Joint author)

    エルゼビア・ジャパン(丸善出版)  2014.8 

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    Responsible for pages:1-1087   Language:Japanese

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  20. 酸化ストレスの医学

    内藤 裕二, 豐國 伸哉, 吉川 敏一( Role: Joint author)

    診断と治療社  2014  ( ISBN:9784787821188

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    Total pages:ix, 444p   Responsible for pages:155-163   Language:Japanese

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  21. ロビンス基礎病理学

    Kumar Vinay, Abbas Abul K, Aster Jon C, Robbins Stanley L, Stanley Leonard, 豐國 伸哉, 高橋 雅英( Role: Joint author)

    エルゼビア・ジャパン  2014  ( ISBN:9784621086988

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    Total pages:xiv, 1087p   Language:Japanese

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  22. ロビンス基礎病理学 原書8版

    豊國伸哉、高橋雅英(監訳)( Role: Joint author)

    丸善出版  2011.9 

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  23. ロビンス基礎病理学 原書8版

    豊國伸哉, 高橋雅英( Role: Joint author)

    丸善出版  2011.9 

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    Responsible for pages:1-1106   Language:Japanese

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  24. ロビンス基礎病理学

    Kumar Vinay, Abbas Abul K, Fausto Nelson, Mitchell Richard N, Robbins Stanley L, Stanley Leonard, 豐國 伸哉, 高橋 雅英( Role: Joint author)

    エルゼビア・ジャパン  2011  ( ISBN:9784621084250

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    Total pages:xiv, 1106p   Language:Japanese

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  25. Oxidative DNA damage and carcinogenesis

    Jiang L., Toyokuni S.( Role: Sole author)

    Free Radical Biology in Digestive Diseases  2010.12  ( ISBN:9783805596091

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    Carcinogenesis follows multi-step processes involving both genetic alteration and increased cell proliferation. Oxidative stress can occur via overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Oxidative stress is always associated with inflammation, radiation, reperfusion, and iron overload. Epidemiological observations have shown that oxidative stress is one of the major pathologic mechanisms for cancer, the top-ranked cause of human mortality worldwide. During carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation through generation of oxidative DNA damage. Furthermore, signal transduction pathways are activated by reactive species, and they lead to the transcription of genes involved in cellular growth regulatory and stress protection pathways. This review examines the involvement of oxidative stress in the carcinogenic process starting from its history, and presents future perspectives.

    DOI: 10.1159/000319941

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  26. 酸化ストレスの医学

    豊國伸哉、内藤裕二 編( Role: Joint author)

    診断と医療社  2008.6 

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  27. 酸化ストレスの医学

    内藤 裕二, 豐國 伸哉, 吉川 敏一 ( Role: Sole author)

    診断と治療社  2008  ( ISBN:9784787816566

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    CiNii Books

  28. Iron-induced carcinogenesis

    Toyokuni S.( Role: Sole author)

    Oxidative Stress, Disease and Cancer  2006.1  ( ISBN:9781860946097

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    DOI: 10.1142/9781860948046_0027

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  29. Helicobacter pylori and gastric cancer

    Toyokuni S.( Role: Sole author)

    Phytopharmaceuticals in Cancer Chemoprevention  2004.1  ( ISBN:9780849315602

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    A few years after the discovery of Helicobacter pylori (H. pylori), fundamental revision had to be made at the sections of gastritis and gastric cancer in the textbooks of pathology and gastroenterology. Nobody had imagined such a high incidence of H. pylori infection in humans, since it was thought that no bacteria could survive such a high pH in the gastric cavity. Almost 20 years have passed since the report of Marshall and Warren in 1984. 1 Now it is clear that there is a category of gastritis associated with H. pylori infection, leading to high incidence of gastric cancer and malignant lymphoma. There was a great impact in the report that removal of the bacteria by antibiotics cures longstanding uncontrollable gastric ulcer. The International Agency for Research on Cancer (IARC) has defined H. pylori as a Group 1 carcinogen.

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  30. 酸化ストレスの病理的意義の追究とその病理診断への応用

    豐國, 伸哉, 京都大学大学院医学研究科( Role: Joint author)

    [豊國伸哉]  2004 

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    Total pages:298p   Language:Japanese

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  31. Free radicals in chemistry, biology and medicine

    吉川 敏一 , Toyokuni Shinya, 山本 順寛 , Naito Yuji( Role: Sole author)

    Oica International  2000  ( ISBN:1903063043

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  32. Free radicals in chemistry, biology and medicine

    吉川 敏一, Toyokuni Shinya, 山本 順寛, Naito Yuji( Role: Joint author)

    Oica International  2000  ( ISBN:1903063043

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  33. 活性酸素のエフェクター分子の同定とその生物学的意義の追求

    豐國, 伸哉( Role: Joint author)

    [豐國伸哉]  1999 

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    Total pages:1冊   Language:Japanese

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  34. フリーラジカルによるDNA・蛋白の損傷・修飾が発癌過程で果たす意義

    豊國 伸哉( Role: Joint author)

    [豊國伸哉]  1997 

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  35. フリーラジカルによるDNA・蛋白の損傷・修飾が発癌過程で果たす意義

    豊國 伸哉( Role: Joint author)

    [豊國伸哉]  1997 

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MISC 379

  1. CD63 is post-transcriptionally regulated by iron via the IRE-IRP system and is important for ferritin secretion.

    簗取いずみ, 豊國伸哉

    月刊血液内科   Vol. 84 ( 3 )   2022

  2. 疾患における生命金属動態の破綻と創薬 がんとフェロトーシス抵抗性

    豊國 伸哉

    日本生化学会大会プログラム・講演要旨集   Vol. 94回   page: [1S04m - 05]   2021.11

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  3. プラズマ活性化リンゲル液による悪性中皮腫細胞のフェロトーシスにはライソゾームの一酸化窒素が関与する

    豊國 伸哉, 蒋 麗, 鄭 好, 中村 香江, 田中 宏昌, 堀 勝

    Biomedical Research on Trace Elements   Vol. 32 ( 2 ) page: 91 - 91   2021.10

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  4. 生理的フェロトーシスの可視化のため、バイオマーカーの開発

    鄭 好, 豊國 伸哉

    日本癌学会総会記事   Vol. 80回   page: [P8 - 5]   2021.9

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  5. 女性器へのタルクの曝露は鉄過剰環境を形成し卵巣がんの発がんに関わる

    本岡 大社, 伊藤 文哉, 田代 浩徳, 片渕 秀隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 80回   page: [E1 - 6]   2021.9

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  6. 変革する病理学:形態診断から普遍的研究プラットフォームへ 実験病理学に起源を持つがんのフェロトーシス抵抗性

    豊國 伸哉, Zheng Hao, Kong Yingyi, Yaguang Luo, 本岡 大社

    日本癌学会総会記事   Vol. 80回   page: [S10 - 6]   2021.9

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  7. 外因性細胞外微粒子としてのタバコと電子タバコ抽出液の生物学的作用の相違に関する検討

    呂 沁穎, 豊國 伸哉

    日本癌学会総会記事   Vol. 80回   page: [P23/24/26 - 2]   2021.9

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  8. BRCA1欠損は腎臓における鉄代謝の変化と酸化ストレスによる腎発がんに関わる

    孔 穎怡, 本岡 大社, 赤塚 慎也, 真下 知士, 今岡 達彦, 豊國 伸哉

    日本癌学会総会記事   Vol. 80回   page: [P2 - 1]   2021.9

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  9. カーボンナノチューブによる毒性発現機構

    山口 慎一朗, 守田 匡伸, 伊藤 文哉, 謝 祺琳, 豊國 伸哉, 中山 勝文

    The Journal of Toxicological Sciences   Vol. 46 ( Suppl. ) page: S71 - S71   2021.7

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  10. メタロミクスと抗加齢医学〜命と健康の源泉となる「生命金属」の最前線から〜 フェロトーシス抵抗性と発がん

    豊國 伸哉

    日本抗加齢医学会総会プログラム・抄録集   Vol. 21回   page: 103 - 103   2021.6

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  11. マウス腎ゲノムにおける酸化的DNA損傷分布の高解像度解析

    北山 拓郎, 赤塚 慎也, 程 真, 豊國 伸哉

    日本病理学会会誌   Vol. 110 ( 1 ) page: 377 - 377   2021.3

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  12. シリコーンオイルによる網膜フェロトーシス(Silicone oil induces retinal ferroptosis)

    兼子 裕規, 清水 英幸, 南波 里奈, 田中 寛, 原 英彰, 安川 力, 鈴間 潔, 豊國 伸哉, 寺崎 浩子

    日本眼科学会雑誌   Vol. 125 ( 臨増 ) page: 166 - 166   2021.3

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  13. Cigarette smoke extractが口腔組織のACE2およびTMPRSS2発現に及ぼす影響

    藤井 皓基, 佐藤 康太郎, 豊國 伸哉

    日本病理学会会誌   Vol. 110 ( 1 ) page: 370 - 370   2021.3

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  14. Chlamydia pneumoniaeのエフェクター分子CPj0034とCPj0524の宿主細胞内における作用の解析

    久米 海豊, 豊國 伸哉

    日本病理学会会誌   Vol. 110 ( 1 ) page: 371 - 371   2021.3

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  15. 【慢性腎臓病・透析患者の酸化ストレス-最新知見と治療展開】慢性腎臓病の病態と酸化ストレス 腎発がんにおける酸化ストレス

    豊國 伸哉

    臨床透析   Vol. 36 ( 12 ) page: 1558 - 1564   2020.11

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    <文献概要>透析は腎細胞癌のリスクであり,嚢胞性変化に伴うものと終末期腎に伴うものがある.慢性腎障害に伴う腎性貧血もよく臨床的な問題となるが,これはエリスロポエチン産生不全に伴い鉄過剰を誘導する鉄代謝の異常があることを意味する.筆者らは1980年代から過剰鉄と腎癌の関係を動物モデルで考究してきた.鉄ニトリロ三酢酸という中性で可溶性かつ触媒性を保有する低分子鉄を雄ラットに投与すると,近位尿細管特異的な酸化ストレスを誘発し,その反復投与によりほぼ全例で転移まで起こす高悪性度腎細胞癌を発症する.高率にp16Ink4aがん抑制遺伝子の不活化が観察されるが,これは発がん自体が鉄依存性を維持しながらフェロトーシス抵抗性を獲得する過程であることを示唆する.

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  16. 「生命金属科学」分野の創成による生体内金属動態の統合的研究:生命金属研究のさらなる発展に向けて 発がんにおけるフェロトーシスの意義

    豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 31 ( 2 ) page: 39 - 39   2020.11

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  17. レドックス活性鉄の制御不全を介したアスベストによる発がん機構

    伊藤 文哉, 豊國 伸哉

    日本癌学会総会記事   Vol. 79回   page: IS8 - 5   2020.10

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  18. アスベスト誘発ラット中皮腫におけるゲノム変異の特徴

    赤塚 慎也, 蒋 麗, エルザワハリ・アスマ, 加藤 護, 戸塚 ゆ加里, 柴田 龍弘, 豊國 伸哉

    日本癌学会総会記事   Vol. 79回   page: PJ2 - 6   2020.10

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  19. 【環境因子と発がん】アスベスト・繊維性ナノ物質による発がんメカニズム なぜ特定の鉱物はヒトにがんを発生させるのか?

    豊國 伸哉

    実験医学   Vol. 38 ( 11 ) page: 1835 - 1841   2020.7

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    経済優先の社会が構築され、多くの新規マテリアルが発見・開発されてきた。そのなかにはアスベストのように予想外にがんを引き起こすものもあった。繊維性鉱物がなぜヒトに悪性中皮腫を引き起こすのかは長年の謎であったが、その分子メカニズムが明らかになってきた。長さ・直径などの物理的因子、生体内非分解性に加えてヘモグロビン・ヒストンをはじめとする特異的タンパク質の吸着、さらに中皮細胞の貪食性が重要であることが判明した。過剰鉄環境下でフェロトーシス抵抗性が獲得されたのである。同様の現象は直径が50nmの多層カーボンナノチューブでも報告された。感染症が克服され寿命が延びた今、環境因子の重要性が再認識される。(著者抄録)

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  20. 生理的フェロトーシスの可視化のため、バイオマーカーの開発(Visualization of physiological ferroptosis)

    鄭 好, 蒋 麗, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 454 - 454   2020.3

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  21. 生体金属が関与する疾患メカニズムと治療戦略の新機軸 がん研究におけるフェロトーシスの意義

    豊國 伸哉

    日本薬学会年会要旨集   Vol. 140年会   page: S32 - 2   2020.3

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  22. 低温プラズマ活性化培養液を用いた悪性中皮腫の治療方法の開発

    蒋 麗, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 451 - 451   2020.3

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  23. 中皮オルガノイドの創出

    井上 桃花, 伊藤 文哉, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 506 - 506   2020.3

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  24. 低温プラズマにより生じるヒドロキシルラジカルはアスコルビン酸により効果的に消去される

    石津 裕梨, 岡崎 泰昌, 田中 宏昌, 堀 勝, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 505 - 505   2020.3

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  25. マウス系統間における腎酸化ストレス応答の差異に関わる遺伝子の解析

    平野 龍一, 程 真, 赤塚 慎也, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 505 - 505   2020.3

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  26. アスベスト誘発ラット中皮腫におけるゲノム変異の特徴解析

    赤塚 慎也, 蒋 麗, 戸塚 ゆ加里, 加藤 護, エルザワハリ・アスマ, 柴田 龍弘, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 423 - 423   2020.3

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  27. BRCA1欠損は鉄代謝と鉄ニトリロ三酢酸誘発性腎癌発症に変化をもたらす(BRCA1 deficiency modifies iron metabolism and ferric nitrilotriacetate-induced renal carcinogenesis)

    孔 穎怡, 蒋 麗, 豊國 伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 438 - 438   2020.3

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  28. 【微量元素と腎】微量元素・総論 微量元素の欠乏と過剰によって生じる病態

    豊國 伸哉

    腎臓内科   Vol. 11 ( 2 ) page: 99 - 106   2020.2

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  29. Asbestos contribute to ovarian carcinogenesis via iron overload in ovarian surface epithelia

    本岡大社, 伊藤文哉, 豊國伸哉

    日本病理学会会誌   Vol. 109 ( 1 ) page: 314 - 314   2020

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  30. Asbestos and talc contribute to ovarian carcinogenesis via iron overload

    本岡大社, 本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

    日本癌学会学術総会抄録集(Web)   Vol. 79th   page: OJ1 - 1   2020

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  31. 発がん過程におけるゲノムと環境因子の相互作用 鉄を介した酸化ストレスによる動物発がんモデルとゲノム変化(Interactions between genomic and environmental factors during carcinogenesis Genomic alterations in animal carcinogenesis associated with iron-mediated oxidative stress)

    赤塚 慎也, 蒋 麗, 伊藤 文哉, 豊國 伸哉

    日本癌学会総会記事   Vol. 78回   page: S21 - 2   2019.9

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  32. マウスモデルを用いた発がん研究を再考する 発がん実験から確立されたフェロトーシスのコンセプト(Carcinogenesis experiments revisited Emergence of the concept of ferroptosis through carcinogenesis experiments)

    豊國 伸哉

    日本癌学会総会記事   Vol. 78回   page: S7 - 6   2019.9

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  33. Txn1遺伝子変異ラットのてんかんの表現型

    大守 伊織, 真下 知士, 大内田 守, 豊國 伸哉

    てんかん研究   Vol. 37 ( 2 ) page: 647 - 647   2019.9

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  34. Carbonic anhydrase 9によるヒト悪性中皮腫細胞における鉄代謝とレドックス恒常性の維持(Carbonic anhydrase 9 maintains iron-metabolism and redox homeostasis in human malignant mesothelioma cells Carbonic anhydrase 9 maintains iron-metabolism and redox homeostasis in human malignant mesothelioma cells)

    李 贊, 蒋 麗, 豊國 伸哉

    日本癌学会総会記事   Vol. 78回   page: E - 3107   2019.9

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  35. 生体微量金属が関与する疾患メカニズムと治療戦略の新機軸 がん研究におけるフェロトーシス

    豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 30 ( 2 ) page: 48 - 48   2019.6

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  36. 尿細管障害と糸球体障害に対する新規バイオマーカーとしての血中microRNAの検討(A scrutiny of circulating microRNA biomarkers for tubular and glomerular injury in rats)

    香川 匠, Zarybnicky Tomas, 大見 貴尚, 白井 勇司, 豊國 伸哉, 織田 進吾, 横井 毅

    The Journal of Toxicological Sciences   Vol. 44 ( Suppl. ) page: S352 - S352   2019.6

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  37. がん研究におけるフェロトーシス

    豊國 伸哉

    昭和学士会雑誌   Vol. 79 ( 3 ) page: 428 - 428   2019.6

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  38. Txn1遺伝子ミスセンス変異をもつ新規CKDモデルラット

    大守 伊織, 真下 知士, 大内田 守, 豊國 伸哉

    日本腎臓学会誌   Vol. 61 ( 3 ) page: 399 - 399   2019.5

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  39. 酸化ストレス・生活習慣病の病理 フェロトーシス抵抗性と発がん(Ferroptosis resistance and carcinogenesis)

    豊國 伸哉

    日本病理学会会誌   Vol. 108 ( 1 ) page: 201 - 201   2019.4

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  40. 繊維状物質誘導性の炎症におけるCD163の役割

    前田 勇貴, 伊藤 文哉, 豊國 伸哉

    日本病理学会会誌   Vol. 108 ( 1 ) page: 463 - 463   2019.4

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  41. 悪性中皮腫における癌関連線維芽細胞の解析(Analysis of the involvement of cancer-associated fibroblasts in the progression of mesothelioma)

    大原 悠紀, 榎本 篤, 露木 悠太, 佐藤 康太郎, 高橋 雅英, 豊國 伸哉

    日本病理学会会誌   Vol. 108 ( 1 ) page: 363 - 363   2019.4

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  42. 低温プラズマ活性化培養液は悪性中皮腫の増殖と浸潤を阻害する(Non-Thermal Plasma-Activated Medium Inhibits Proliferation and Invasion of Malignant Mesothelioma)

    石田 萌, 蒋 麗, 豊國 伸哉

    日本病理学会会誌   Vol. 108 ( 1 ) page: 461 - 461   2019.4

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  43. マウス系統間における腎酸化ストレス応答の差異に関わる遺伝子の解析

    金谷 和樹, 程 真, 赤塚 慎也, 豊國 伸哉

    日本病理学会会誌   Vol. 108 ( 1 ) page: 461 - 461   2019.4

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  44. Asbestos contributes to ovarian carcinogenesis via iron overload

    本岡大社, 本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

    日本癌学会学術総会抄録集(Web)   Vol. 78th   page: E - 1077   2019

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  45. アスベストの曝露は上皮性悪性卵巣腫瘍の発癌に関与する

    水野勇太, 本岡大社, 豊國伸哉

    日本病理学会会誌   Vol. 108 ( 1 ) page: 460 - 461   2019

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  46. アスベストの曝露は上皮性悪性卵巣腫瘍の発癌に関与する

    豊國伸哉, 本岡大社, 本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆

    がん予防学術大会プログラム・抄録集     2019

  47. 悪性中皮腫の進展を制御する癌関連線維芽細胞の解析(Analysis of the involvement of cancer-associated fibroblasts in the progression of malignant mesothelioma)

    大原 悠紀, 榎本 篤, 高橋 雅英, 豊國 伸哉

    日本癌学会総会記事   Vol. 77回   page: 681 - 681   2018.9

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  48. アスベストの形成する炎症性微小環境は再生中皮細胞に対し変異原性を増大する(Inflammatory microenvironment derived from asbestos increases mutagenesis to repairing mesothelial cell)

    伊藤 文哉, 豊國 伸哉

    日本癌学会総会記事   Vol. 77回   page: 1282 - 1282   2018.9

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  49. がん細胞と正常細胞の代謝機構 がん研究におけるフェロトーシスの意義(Metabolic mechanisms in cancer and normal cells Ferroptosis in Cancer Research)

    豊國 伸哉

    日本癌学会総会記事   Vol. 77回   page: 16 - 16   2018.9

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  50. Ptger2を分子標的とした中皮腫治療と予防(Multifaceted roles of Ptger2 (Prostaglandin E receptor 2) in asbestos-induced inflammation and malignant mesothelioma)

    蒋 麗, 赤塚 慎也, 豊國 伸哉

    日本癌学会総会記事   Vol. 77回   page: 1281 - 1281   2018.9

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  51. Development of a novel monoclonal antibody against 4-hydroxy-2E,6Z-dodecadienal (4-HDDE)-protein adducts: Immunochemical application in quantitative and qualitative analyses of lipid peroxidation in vitro and ex vivo

    Koji Uchida, Takahiro Shibata, Shinya Toyokuni, Bareket Daniel, Kamelija Zarkovic, Neven Zarkovic, Shlomo Sasson

    Free Radical Biology and Medicine   Vol. 124   page: 12 - 20   2018.8

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    Non-enzymatic peroxidation of polyunsaturated fatty acids (PUFA) results in the formation of various α,β-unsaturated aldehydes, of which 4-hydroxyalkenals are abundant. The propensity of n-6 PUFA, such as linoleic acid, γ-linolenic acid and arachidonic acid, to undergo radical-induced peroxidation and generate 4-hydroxy-2E-nonenal (4-HNE) has been widely demonstrated. The ability of the latter to form covalent adducts with macromolecules and modify cellular functions has been linked to numerous pathological processes. Concomitantly, evidence has accumulated on specific signaling properties of low concentrations of 4-HNE that may induce hormetic and protective responses to peroxidation stress in cells. It has long been known that peroxidation of PUFA, and particularly arachidonic acid, also give rise to 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), which is more chemically reactive than 4-HNE. Few studies on 4-HDDE revealed its ability to avidly interact covalently with electronegative moieties in macromolecules and to its ability to selectively activate the transcriptional regulator Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ. The research on 4-HDDE has been impeded due to the lack of available pure 4-HDDE and antibodies that recognize 4-HDDE-modified epitopes in proteins. The purpose of this study was to employ an established procedure to synthesize 4-HDDE and use it to create and characterize a monoclonal antibody against 4-HDDE-modified proteins and establish its application for ELISA and immunohistochemical analysis of cells and tissues and further expand lipid peroxidation research.

    DOI: 10.1016/j.freeradbiomed.2018.05.079

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  52. New hopes for plasma-based cancer treatment Reviewed

    Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Shinya Toyokuni, Hiroaki Kajiyama, Fumitaka Kikkawa, Masaru Hori

    Plasma 2018   Vol. 1   page: 150-155   2018.8

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    DOI: 10.3390/plasma1010014

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  53. Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model. International journal

    Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Tomoko Nakano, Takafumi Ushida, Akira Iwase, Taku Nagai, Shinya Toyokuni, Akio Suzumura, Fumitaka Kikkawa

    Scientific reports   Vol. 8 ( 1 ) page: 9221 - 9221   2018.6

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    The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H2) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H2 attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H2 administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H2 on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H2-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H2 administration. Overall, these findings indicate that maternal H2 administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.

    DOI: 10.1038/s41598-018-27626-4

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  54. Acute fulminant invasive pulmonary aspergillosis in an immunocompetent host: An autopsy case report. International journal

    Yuuki Ohara, Takahiko Ito, Makoto Ito, Kyoko Yamashita, Shinya Toyokuni

    Medical mycology case reports   Vol. 20   page: 39 - 42   2018.6

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    A 62-year-old previously healthy male who was a welder/smoker/drinker was admitted to Kani Tono Hospital for severe hypoxemia (Day 0). Initial physical and radiological examinations suggested an acute exacerbation of chronic obstructive pulmonary disease. However, respiratory failure developed rapidly, and he died on Day + 4. Aspergillus fumigatus was identified after his death, and he was diagnosed with invasive pulmonary aspergillosis. The clinical and pathological features are precisely described with pathogenetic considerations.

    DOI: 10.1016/j.mmcr.2018.02.002

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  55. 悪性中皮腫の発がん過程における2価鉄トランスポーターの役割の解析

    舟橋 諭美, 岡崎 泰昌, 赤塚 慎也, 豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 29 ( 1 ) page: 70 - 70   2018.6

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  56. 先天性横隔膜ヘルニアモデルにおける鉄代謝

    三浦 麻世, 平光 志麻, 津田 弘之, 伊藤 文哉, 岡崎 泰昌, 平山 祐, 永澤 秀子, 森山 佳則, 牛田 貴文, 中野 知子, 今井 健史, 小谷 友美, 吉川 史隆, 豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 29 ( 1 ) page: 72 - 73   2018.6

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  57. 妊娠中の酸化鉄摂取と神経芽腫の発生に関する研究

    林 祥太郎, 石田 千晴, 中村 智子, 豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 29 ( 1 ) page: 75 - 75   2018.6

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  58. がんの起源をフェロトーシスとレドックス制御から考える

    豊國 伸哉

    昭和学士会雑誌   Vol. 78 ( 3 ) page: 301 - 301   2018.6

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  59. An autopsy case report: Differences in radiological images correlate with histology in Erdheim-Chester disease. International journal

    Yuuki Ohara, Seiichi Kato, Daisuke Yamashita, Akira Satou, Yoshie Shimoyama, Chie Hamaie, Motoki Sato, Nobutaro Ban, Koji Yamamoto, Takehiro Yamada, Hisashi Kawai, Koichi Ohshima, Shigeo Nakamura, Shinya Toyokuni

    Pathology international   Vol. 68 ( 6 ) page: 374 - 381   2018.6

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    p16 activation caused by oncogenic mutations may represent oncogene-induced senescence (OIS), a protective mechanism against oncogenic events. However, OIS can contribute to tumor development via tissue remodeling in some tumors. Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is one such tumor. Its clinical and histological features vary, making it difficult to diagnose. Herein, we describe an autopsy of an ECD patient. The patient underwent radiological examinations, including 18 F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS-induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio-histological correlation can help further both the understanding and diagnosis of ECD.

    DOI: 10.1111/pin.12663

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  60. Ferroptosis in carcinogenesis and tumor biology

    Toyokuni Shinya

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 120   page: S19-S19   2018.5

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    DOI: 10.1016/j.freeradbiomed.2018.04.081

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  61. Expression of P-REX2a is associated with poor prognosis in endometrial malignancies. International journal

    Sho Takeshita, Yoriko Yamashita, Kosuke Shiomi, Nako Suzuki, Jun Yoshida, Aya Naiki-Ito, Shugo Suzuki, Shinya Akatsuka, Shinya Toyokuni, Takashi Takahashi, Shoko Mase, Atsushi Arakawa, Mayumi Sugiura-Ogasawara, Satoru Takahashi

    Oncotarget   Vol. 9 ( 37 ) page: 24778 - 24786   2018.5

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    P-REX2a is a PTEN inhibitor that also activates Rac 1. No associations with P-REX2a and human endometrial cancers have been reported to date. In this study, we immunohistochemically analyzed 155 uterine endometrial malignancies for P-REX2a expression. The P-REX2a-positive tumors displayed worse prognosis independent of PTEN expression. Then, we transduced either P-REX2a expression vector or short hairpin RNAs targeting P-REX2a into 2 uterine endometrioid carcinoma cell lines, OMC-2 and JHUEM-14. Ectopic expression of P-REX2a led to increased cell proliferation only in the PTEN-expressing OMC-2 cells but did not show any change in the PTEN-negative JHUEM-14 cells or the P-REX2a-knockdown cells. Induction of P-REX2a increased and knockdown of P-REX2a decreased cell migration in both cell lines. Then, we performed expression microarray analysis using these cells, and pathway analysis revealed that the expression of members of the GPCR downstream pathway displayed the most significant changes induced by the knockdown of P-REX2a. Immunohistochemical analysis revealed that Vav1, a member of the GPCR downstream pathway, was expressed in 139 of the 155 endometrial tumors, and the expression levels of Vav1 and P-REX2a showed a positive correlation (r = 0.44, p < 0.001). In conclusion, P-REX2a enhanced cell motility via the GPCR downstream pathway independently of PTEN leading to progression of uterine endometrioid malignancies and poor prognosis of the patients.

    DOI: 10.18632/oncotarget.25349

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  62. Effect of molecular hydrogen on uterine inflammation during preterm labour. International journal

    Tomoko Nakano, Tomomi Kotani, Kenji Imai, Yukako Iitani, Takafumi Ushida, Hiroyuki Tsuda, Hua Li, Akira Iwase, Shinya Toyokuni, Fumitaka Kikkawa

    Biomedical reports   Vol. 8 ( 5 ) page: 454 - 460   2018.5

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    Intrauterine inflammation causes preterm birth and is associated with complications in preterm neonates. Thus, strategies aimed at suppressing inflammation are expected to be effective for reducing the risk of preterm birth and associated complications. Our previous studies demonstrated that molecular hydrogen (H2), an anti-inflammatory agent, prevented inflammation-induced impairment in foetal brain and lung tissues in lipopolysaccharide (LPS)-induced rodent models. However, it remains unclear whether H2 is capable of inhibiting preterm labour. The aim of the current study was therefore to investigate the effect of H2 on inflammation-induced preterm labour. Pregnant ICR (CD-1) mice were divided into three groups: Control, LPS and H2 water (HW) + LPS. In the control and LPS groups, vehicle and LPS, respectively, were intraperitoneally injected on embryonic day 15.5. In the HW + LPS group, HW was administered 24 h prior to LPS injection. The time from LPS administration to parturition was compared between the LPS and HW + LPS groups. Maternal uterus was collected 6 h after LPS injection and the transcript levels of pro-inflammatory cytokines, contractile-associated proteins (CAPs), matrix metalloproteinase-3 (Mmp3) and endothelin-1 (Et1) were assessed by reverse transcription-quantitative polymerase chain reaction. The protein levels of cyclooxygenase-2 (Cox2) were also evaluated by immunohistochemistry. The time from LPS administration to parturition in the HW + LPS group was significantly increased compared with that in the LPS group (33.5±3.4 vs. 18.3±8.8 h, respectively, P=0.020). H2 administration also resulted in significantly higher progesterone levels compared with LPS treatment alone (P=0.002). The transcript levels of pro-inflammatory cytokines, CAPs, Mmp3 and Et1 in the uteri of the LPS group were significantly higher than those in the control group (all P&lt
    0.05). In turn, all these levels with the exception of interleukin-8 and Mmp3 were significantly lower in the HW + LPS group compared with those in the LPS group (all P&lt
    0.05). The protein levels of Cox2 in the LPS group were also significantly increased compared with those in the control (P&lt
    0.001) and HW + LPS (P=0.003) groups. These results suggest that inflammation-induced changes in the uterus may be ameliorated through maternal H2 administration. Preventive H2 administration may therefore represent an effective strategy for the suppression of inflammation during preterm labour.

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  63. Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model. International journal

    Yuuki Ohara, Shan Hwu Chew, Nobuaki Misawa, Shenqi Wang, Daiki Somiya, Kae Nakamura, Hiroaki Kajiyama, Fumitaka Kikkawa, Yuta Tsuyuki, Li Jiang, Kyoko Yamashita, Yoshitaka Sekido, Kenneth E Lipson, Shinya Toyokuni

    Oncotarget   Vol. 9 ( 26 ) page: 18494 - 18509   2018.4

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    Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

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  64. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. International journal

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Takeaki Ishii, Yoshihiro Nishida, Hiroshi Urakawa, Ichiro Ito, Mitsuru Takahashi, Takeshi Inoue, Masafumi Ito, Yuuki Ohara, Yoshinao Oda, Shinya Toyokuni

    Histopathology   Vol. 72 ( 5 ) page: 729 - 738   2018.4

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    Aims: Ossification is found occasionally in dedifferentiated liposarcoma (DDLPS). The aims of this study were to elucidate whether the formed bone tissue is usually produced by tumour cells or by reactive non-neoplastic cells, and to reveal the clinicopathological characteristics of DDLPS with ossification. Methods and results: We examined 36 cases of ossified DDLPS by comparing them to 31 cases of non-ossified DDLPS. MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all but one ossified DDLPS cases (27 of 28) using fluorescence in-situ hybridisation, although the morphological impression of ossification appeared to be mainly metaplastic (27 of 36) or high-grade osteosarcoma-like (six of 36). The bone tissue was often formed predominantly at the periphery of the DDLPS area near the well-differentiated liposarcoma component (18 of 36), and an organised structure such as bone marrow-like differentiation was not uncommon (12 of 36). According to a modified French Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, ossified DDLPS tended to be lower grade than non-ossified DDLPS (mean grade: 1.88 and 2.15, respectively). Ossification in DDLPS was associated significantly with shorter local recurrence-free survival by multivariate analysis (P = 0.02347), but metaplastic-appearing ossification tended to be associated with longer overall survival (P = 0.1400). Conclusions: The bone tissue formed in DDLPS was mainly neoplastic regardless of its morphology and maturity, which highlighted the osteogenic differentiation of the tumour cells. DDLPS patients with osteogenic differentiation tended to suffer from earlier local recurrences, which did not necessarily lead to poor life outcomes.

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  65. 脱分化型脂肪肉腫に寄与するゲノム変化についての検討

    横山 翔大, 山下 享子, 豊國 伸哉

    日本病理学会会誌   Vol. 107 ( 1 ) page: 521 - 522   2018.4

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  66. アスベストによる酸化ストレス傷害は鉄過剰を介して再生中皮細胞優位に生じる

    前田 勇貴, 伊藤 文哉, 豊國 伸哉

    日本病理学会会誌   Vol. 107 ( 1 ) page: 517 - 517   2018.4

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  67. びまん性胸膜肥厚を伴う肺炎の一剖検例

    佐々木 香菜子, 岡崎 泰昌, 大原 悠紀, 豊國 伸哉

    日本病理学会会誌   Vol. 107 ( 1 ) page: 529 - 529   2018.4

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  68. DNA合成期に生じる鉄依存的な酸化ストレスはゲノム傷害に至りやすい

    二村 健太, 伊藤 文哉, 豊國 伸哉

    日本病理学会会誌   Vol. 107 ( 1 ) page: 520 - 520   2018.4

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  69. C型肝炎ウイルス排除後に生じた肝癌ゲノム変異の解析

    岩田 侑也, 赤塚 慎也, 豊國 伸哉

    日本病理学会会誌   Vol. 107 ( 1 ) page: 519 - 519   2018.4

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  70. 【レドックス疾患学 酸素・窒素・硫黄活性種はどう作用するのか、どこまで健康・疾患と関わるのか?】(第2章)レドックスと疾患 フェロトーシスとレドックス生物学・疾患とのかかわり

    豊國 伸哉

    実験医学   Vol. 36 ( 5 ) page: 803 - 808   2018.3

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    フェロトーシスとは2012年に提唱された制御された壊死に関する新概念であり、鉄依存性の脂質過酸化が細胞致死的なレベルまで上昇するのが特徴である。細胞膜に不飽和脂肪酸を取り込むようになったのがその起源とされる。フェロトーシスへの感受性は種々の因子が関連しており、アミノ酸・鉄・不飽和脂肪酸代謝やグルタチオン・リン脂質・NADPH・コエンザイムQなどを含む。フェロトーシスは、神経変性疾患・発がん・脳卒中・再灌流傷害・腎障害における細胞死と深く関連するとされ、腫瘍抑制機能が提唱されている。したがって、うまく利用することによりがん治療として利用できる可能性もある。(著者抄録)

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  71. Similarities And Differences In The Cellular Resposnses Between Plasma-Activated Medium-Treated Glioblastomas And Plasma-Activated Ringer's Lactate Solution-Treated Glioblastomas Reviewed

    Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Keigo Takeda, Hiroki Kondo, Makoto Sekine, Hiroshi Hashizume, Kae Nakamura, Hiroaki Kajiyama, Yasumasa Okazaki, Shinya Toyokuni, Shinichi Akiyama, Shoichi Maruyama, Fumitaka Kikkawa, Masaru Hori

    Clinical Plasma Medicine   Vol. 9   page: 42-43   2018.2

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  72. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. International journal

    Yuuki Ohara, Shan-Hwu Chew, Takahiro Shibata, Yasumasa Okazaki, Kyoko Yamashita, Shinya Toyokuni

    Cancer science   Vol. 109 ( 2 ) page: 330 - 339   2018.2

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    Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial–mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

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  73. Plasma-Activated Medium Inhibites Metastatic Activities Of Ovarian Cancer Cells In Vitro Via Repressing Mapk Pathway Reviewed

    Yang Peng, Hiroaki Kajiyama, Kae Nakamura, Fumi Utsumi, Nobuhisa Yoshikawa, Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa

    Clinical Plasma Medicine   Vol. 9   page: 41-42   2018.2

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  74. Intraperitoneal Treatment With Plasma-Activated Liquid Inhibits Peritoneal Metastasis In Ovarian Cancer Mouse Model Reviewed

    Kae Nakamura, Hiroaki Kajiyama, Yang Peng, Fumi Utsumi, Nobuhisa Yoshikawa, Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa

    Clinical Plasma Medicine   Vol. 9   page: 47-48   2018.2

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  75. 若手pathologistsのための文書作成講座(第5回) 基礎研究論文の書き方

    豊國 伸哉

    病理と臨床   Vol. 36 ( 2 ) page: 165 - 169   2018.2

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  76. Plasma medical science

    Shinya Toyokuni, Yuzuru Ikehara, Fumitaka Kikkawa, Masaru Hori

    Plasma Medical Science     page: 1 - 423   2018.1

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    © 2018 Elsevier Inc. All rights reserved. Plasma Medical Science describes the progress that has been made in the field over the past five years, illustrating what readers must know to be successful. As non-thermal, atmospheric pressure plasma has been applied for a wide variety of medical fields, including wound healing, blood coagulation, and cancer therapy, this book is a timely resource on the topics discussed.

    DOI: 10.1016/C2017-0-01916-X

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  77. Phlebotomy attenuates the growth of malignant mesothelioma on rat model International journal

    Ohara Yuuki, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 781-781   2018.1

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  78. Molecular mechanisms in oxidative stress-induced carcinogenesis International journal

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 163-163   2018.1

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  79. Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice International journal

    Akatsuka Shinya, Li Guang-Hua, Sakumi Kunihiko, Nakabeppu Yusaku, Futakuchi Mitsuru, Suzuki Hiromu, Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 167-167   2018.1

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  80. タルクへの曝露は卵巣表層上皮細胞内の2価鉄イオンの増加に寄与し卵巣癌の発癌に関わる

    本岡大社, 本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

    Biomedical Research on Trace Elements   Vol. 29 ( 1 )   2018

  81. 本気でがんを予防する 鉄と酸素からがん予防を考える

    豊國 伸哉

    生命科学系学会合同年次大会   Vol. 2017年度   page: [2PW20 - 1]   2017.12

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  82. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. Reviewed

    Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S

    Cancer Science     2017.11

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  83. Role of catalytic iron and oxidative stress in nitrofen-induced congenital diaphragmatic hernia and its amelioration by Saireito (TJ-114).

    Shima Hirako, Hiroyuki Tsuda, Fumiya Ito, Yasumasa Okazaki, Tasuku Hirayama, Hideko Nagasawa, Tomoko Nakano, Kenji Imai, Tomomi Kotani, Fumitaka Kikkawa, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 61 ( 3 ) page: 176 - 182   2017.11

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    Congenital diaphragmatic hernia (CDH) is a life-threatening neonatal disease that leads to lung hypoplasia and pulmonary hypertension. We recently found that maternal prenatal administration of Saireito (TJ-114) ameliorates fetal CDH in a nitrofen-induced rat model. Here, we studied the role of iron and oxidative stress in neonates of this model and in lung fibroblasts IMR90-SV in association with nitrofen and Saireito. We observed increased immunostaining of 8-hydroxy-2'-deoxyguanosine in the lungs of neonates with CDH, which was ameliorated by maternal Saireito intake. Pulmonary transferrin receptor expression was significantly decreased in both CDH and CDH after Saireito in comparison to normal controls, indicating functional lung immaturity, whereas catalytic Fe(II) and pulmonary DMT1/ferroportin expression remained constant among the three groups. Saireito revealed a dose-dependent scavenging capacity with electron spin resonance spin trapping in vitro against hydroxyl radicals but not against superoxide. Finally, nitrofen revealed dose-dependent cytotoxicity to IMR90-SV cells, accompanied by an increase in oxidative stress, as seen by 5(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and catalytic Fe(II). Saireito ameliorated all of these in IMR90-SV cells. In conclusion, catalytic Fe(II)-dependent oxidative stress by nitrofen may be the pathogenic cause of CDH, and the antioxidative activity of Saireito is at least partially responsible for improving nitrofen-induced CDH.

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  84. Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. Reviewed International journal

    Guang Hua Li, Shinya Akatsuka, Shan Hwu Chew, Li Jiang, Takahiro Nishiyama, Akihiko Sakamoto, Takashi Takahashi, Mitsuru Futakuchi, Hiromu Suzuki, Kunihiko Sakumi, Yusaku Nakabeppu, Shinya Toyokuni

    Pathology international   Vol. 67 ( 11 ) page: 564 - 574   2017.11

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    Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P=0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16(INKA) inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.

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  85. Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model

    Guang Hua Li, Shinya Akatsuka, Shan Hwu Chew, Li Jiang, Takahiro Nishiyama, Akihiko Sakamoto, Takashi Takahashi, Mitsuru Futakuchi, Hiromu Suzuki, Kunihiko Sakumi, Yusaku Nakabeppu, Shinya Toyokuni

    PATHOLOGY INTERNATIONAL   Vol. 67 ( 11 ) page: 564 - 574   2017.11

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    Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P=0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16(INKA) inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.

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  86. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. Reviewed

    Yamashita K, Kohashi K, Yamada Y, Ishii T, Nishida Y, Urakawa H, Ito I, Takahashi M, Inoue T, Ito M, Ohara Y, Oda Y, Toyokuni S

    Histopathology     2017.10

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  87. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

    Brent R. Stockwell, Jose Pedro Friedmann Angeli, Hulya Bayir, Ashley I. Bush, Marcus Conrad, Scott J. Dixon, Simone Fulda, Sergio Gascon, Stavroula K. Hatzios, Valerian E. Kagan, Kay Noel, Xuejun Jiang, Andreas Linkermann, Maureen E. Murphy, Michael Overholtzer, Atsushi Oyagi, Gabriela C. Pagnussat, Jason Park, Qitao Ran, Craig S. Rosenfeld, Konstantin Salnikow, Daolin Tang, Frank M. Torti, Suzy V. Torti, Shinya Toyokuni, K. A. Woerpel, Donna D. Zhang

    CELL   Vol. 171 ( 2 ) page: 273 - 285   2017.10

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    Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q(10). Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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  88. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease Invited Reviewed

    Brent R. Stockwell, Jose Pedro Friedmann Angeli, Hulya Bayir, Ashley I. Bush, Marcus Conrad, Scott J. Dixon, Simone Fulda, Sergio Gascon, Stavroula K. Hatzios, Valerian E. Kagan, Kay Noel, Xuejun Jiang, Andreas Linkermann, Maureen E. Murphy, Michael Overholtzer, Atsushi Oyagi, Gabriela C. Pagnussat, Jason Park, Qitao Ran, Craig S. Rosenfeld, Konstantin Salnikow, Daolin Tang, Frank M. Torti, Suzy V. Torti, Shinya Toyokuni, K. A. Woerpel, Donna D. Zhang

    CELL   Vol. 171 ( 2 ) page: 273 - 285   2017.10

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    Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q(10). Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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  89. 環境要因から考える発がんリスク 酸化ストレスによる発がんの分子メカニズム

    豊國 伸哉

    日本癌学会総会記事   Vol. 76回   page: S8 - 1   2017.9

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  90. 瀉血療法はラットモデルにおける悪性中皮腫の発育を減弱する

    大原 悠紀, 豊國 伸哉

    日本癌学会総会記事   Vol. 76回   page: P - 2416   2017.9

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  91. MUTYH欠損マウスにおける鉄ニトリロ三酢酸誘発腎発がん

    赤塚 慎也, 李 光華, 作見 邦彦, 中別府 雄作, 二口 充, 鈴木 拓, 豊國 伸哉

    日本癌学会総会記事   Vol. 76回   page: P - 1004   2017.9

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  92. The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. International journal

    Izumi Yanatori, Des R Richardson, Shinya Toyokuni, Fumio Kishi

    The Journal of biological chemistry   Vol. 292 ( 32 ) page: 13205 - 13229   2017.8

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    Mammals incorporate a major proportion of absorbed iron as heme, which is catabolized by the heme oxygenase 1 (HO1)-NADPH-cytochrome P450 reductase (CPR) complex into biliverdin, carbon monoxide, and ferrous iron. Moreover, intestinal iron is incorporated as ferrous iron, which is transported via the iron importer, divalent metal transporter 1 (DMT1). Recently, we demonstrated that the iron chaperone poly(rC)-binding protein 2 (PCBP2) can directly receive ferrous iron from DMT1 or transfer iron to the iron exporter, ferroportin 1. To promote intracellular iron flux, an iron chaperone may be essential for receiving iron generated by heme catabolism, but this hypothesis is untested so far. Herein, we demonstrate that HO1 binds to PCBP2, but not to other PCBP family members, namely PCBP1, PCBP3, or PCBP4. Interestingly, HO1 formed a complex with either CPR or PCBP2, and it was demonstrated that PCBP2 competes with CPR for HO1 binding. Using PCBP2-deletion mutants, we demonstrated that the PCBP2 K homology 3 domain is important for the HO1/PCBP2 interaction. In heme-loaded cells, heme prompted HO1-CPR complex formation and decreased the HO1/PCBP2 interaction. Furthermore, in vitro reconstitution experiments with purified recombinant proteins indicated that HO1 could bind to PCBP2 in the presence of heme, whereas loading of PCBP2 with ferrous iron caused PCBP2 to lose its affinity for HO1. These results indicate that ferrous iron released from heme can be bound by PCBP2 and suggest a model for an integrated heme catabolism and iron transport metabolon.

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  93. 【消化吸収からみた微量元素の最新情報】鉄の代謝と機能に関する最近の話題

    赤塚 慎也, 豊國 伸哉

    消化と吸収   Vol. 39 ( 3 ) page: 171 - 174   2017.8

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  94. The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer Reviewed

    Izumi Yanatori, Des R. Richardson, Shinya Toyokuni, Fumio Kishi

    JOURNAL OF BIOLOGICAL CHEMISTRY   Vol. 292 ( 32 ) page: 13205 - 13229   2017.8

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    Mammals incorporate a major proportion of absorbed iron as heme, which is catabolized by the heme oxygenase 1 (HO1)-NADPH-cytochrome P450 reductase (CPR) complex into biliverdin, carbon monoxide, and ferrous iron. Moreover, intestinal iron is incorporated as ferrous iron, which is transported via the iron importer, divalent metal transporter 1 (DMT1). Recently, we demonstrated that the iron chaperone poly(rC)-binding protein 2 (PCBP2) can directly receive ferrous iron from DMT1 or transfer iron to the iron exporter, ferroportin 1. To promote intracellular iron flux, an iron chaperone may be essential for receiving iron generated by heme catabolism, but this hypothesis is untested so far. Herein, we demonstrate that HO1 binds to PCBP2, but not to other PCBP family members, namely PCBP1, PCBP3, or PCBP4. Interestingly, HO1 formed a complex with either CPR or PCBP2, and it was demonstrated that PCBP2 competes with CPR for HO1 binding. Using PCBP2-deletion mutants, we demonstrated that the PCBP2 K homology 3 domain is important for the HO1/PCBP2 interaction. In heme-loaded cells, heme prompted HO1-CPR complex formation and decreased the HO1/PCBP2 interaction. Furthermore, in vitro reconstitution experiments with purified recombinant proteins indicated that HO1 could bind to PCBP2 in the presence of heme, whereas loading of PCBP2 with ferrous iron caused PCBP2 to lose its affinity for HO1. These results indicate that ferrous iron released from heme can be bound by PCBP2 and suggest a model for an integrated heme catabolism and iron transport metabolon.

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  95. IRON OVERLOAD ENHANCED CELL DEATH INDUCED BY CARCINOGENIC FIBROUS MATERIALS

    Fumiya Ito, Lei Shi, Shinya Toyokuni

    AMERICAN JOURNAL OF HEMATOLOGY   Vol. 92 ( 8 ) page: E365 - E365   2017.8

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  96. State of the art in medical applications using non-thermal atmospheric pressure plasma Reviewed

    Hiromasa Tanaka, Kenji Ishikawa, Masaaki Mizuno, Shinya Toyokuni, Hiroaki Kajiyama, Fumitaka Kikkawa, Hans-Robert Metelmann, Masaru Hori

    Plasma Physics, Association of Asia Pacific Physical Societies 2017   Vol. 1   2017.7

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  97. 微量元素とヒトの疾患 鉄と発がん

    豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 28 ( 2 ) page: 85 - 85   2017.7

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  98. Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells Reviewed

    Kae Nakamura, Yang Peng, Fumi Utsumi, Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa, Hiroaki Kajiyama

    SCIENTIFIC REPORTS   Vol. 7 ( 1 ) page: 6085   2017.7

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    Non-thermal atmospheric pressure plasma has been proposed as a new therapeutic tool for cancer treatment. Recently, plasma-activated medium (PAM) has been widely studied in various cancer types. However, there are only few reports demonstrating the anti-tumour effects of PAM in an animal model reflecting pathological conditions and the accompanying mechanism. Here we investigated the inhibitory effect of PAM on the metastasis of ovarian cancer ES2 cells in vitro and in vivo. We demonstrated that ES2 cell migration, invasion and adhesion were suppressed by PAM at a certain PAM dilution ratio, whereas cell viability remained unaffected. In an in vivo mouse model of intraperitoneal metastasis, PAM inhibited peritoneal dissemination of ES2 cells, resulting in prolonged survival. Moreover, we assessed the molecular mechanism and found that MMP-9 was decreased by PAM. On further investigation, we also found that PAM prevented the activation of the MAPK pathway by inhibiting the phosphorylation of JNK1/2 and p38 MAPK. These findings indicate that PAM inhibits the metastasis of ovarian cancer cells through reduction of MMP-9 secretion, which is critical for cancer cell motility. Our findings suggest that PAM intraperitoneal therapy may be a promising treatment option for ovarian cancer.

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  99. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. International journal

    Shinya Toyokuni, Fumiya Ito, Kyoko Yamashita, Yasumasa Okazaki, Shinya Akatsuka

    Free radical biology & medicine   Vol. 108   page: 610 - 626   2017.7

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    Epidemiological data indicate a constant worldwide increase in cancer mortality, although the age of onset is increasing. Recent accumulation of genomic data on human cancer via next-generation sequencing confirmed that cancer is a disease of genome alteration. In many cancers, the Nrf2 transcription system is activated via mutations either in Nrf2 or Keap1 ubiquitin ligase, leading to persistent activation of the genes with antioxidative functions. Furthermore, deep sequencing of passenger mutations is clarifying responsible cancer causative agent (s) in each case, including aging, APOBEC activation, smoking and UV. Therefore, it is most likely that oxidative stress is the principal initiating factor in carcinogenesis, with the involvement of two essential molecules for life, iron and oxygen. There is evidence based on epidemiological and animal studies that excess iron is a major risk for carcinogenesis, suggesting the importance of ferroptosis-resistance. Microscopic visualization of catalytic Fe (II) has recently become available. Although catalytic Fe(II) is largely present in lysosomes, proliferating cells harbor catalytic Fe(II) also in the cytosol and mitochondria. Oxidative stress catalyzed by Fe(II) is counteracted by thiol systems at different functional levels. Nitric oxide, carbon monoxide and hydrogen (per) sulfide modulate these reactions. Mitochondria generate not only energy but also heme/iron sulfur cluster cofactors and remain mostly dysfunctional in cancer cells, leading to Warburg effects. Cancer cells are under persistent oxidative stress with a delicate balance between catalytic iron and thiols, thereby escaping ferroptosis. Thus, high-dose L-ascorbate and non-thermal plasma as well as glucose/glutamine deprivation may provide additional benefits as cancer therapies over preexisting therapeutics.

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  100. Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy

    Lei Shi, Fumiya Ito, Yue Wang, Yasumasa Okazaki, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Tasuku Hirayama, Hideko Nagasawa, Des R. Richardson, Shinya Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 108   page: 904 - 917   2017.7

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    Non-thermal plasma (NTP) is a potential new therapeutic modality for cancer. However, its mechanism of action remains unclear. Herein, we studied the effect of NTP on mesothelioma cells and fibroblasts to understand its anti-proliferative efficacy. Interestingly, NTP demonstrated greater selective anti-proliferative activity against mesothelioma cells relative to fibroblasts than cisplatin, which is used for mesothelioma treatment. The anti-proliferative effect of NTP was enhanced by pre-incubation with the cellular iron donor, ferric ammonium citrate (FAC), and inhibited by iron chelation using desferrioxamine (DFO). Three oxidative stress probes (CM-H2DCFDA, MitoSOX and C11-BODIPY) demonstrated reactive oxygen species (ROS) generation by NTP, which was inhibited by DFO. Moreover, NTP decreased transferrin receptor-1 and increased ferritin-H and -L chain expression that was correlated with decreased iron-regulatory protein expression and RNA-binding activity. This regulation was potentially due to increased intracellular iron in lysosomes, which was demonstrated via the Fe (II)-selective probe, HMRhoNox-M, and was consistent with autophagic-induction. Immunofluorescence using LysoTracker and Pepstatin A probes demonstrated increased cellular lysosome content, which was confirmed by elevated LAMP1 expression. The enhanced lysosomal biogenesis after NTP could be due to the observed increase in fluid-phase endocytosis and early endosome formation. These results suggest NTP acts as a stressor, which results in increased endocytosis, lysosome content and autophagy. In fact, NTP rapidly increased autophagosome formation, as judged by increased LC3B-II expression, which co-localized with LAMP1, indicating autophagolysosome formation. Autophagic-induction by NTP was confirmed using electron microscopy. In summary, NTP acts as a cellular stressor to rapidly induce fluid-phase endocytosis, lysosome biogenesis and autophagy.

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  101. Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy. Reviewed International journal

    Lei Shi, Fumiya Ito, Yue Wang, Yasumasa Okazaki, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Tasuku Hirayama, Hideko Nagasawa, Des R Richardson, Shinya Toyokuni

    Free radical biology & medicine   Vol. 108   page: 904 - 917   2017.7

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    Non-thermal plasma (NTP) is a potential new therapeutic modality for cancer. However, its mechanism of action remains unclear. Herein, we studied the effect of NTP on mesothelioma cells and fibroblasts to understand its anti-proliferative efficacy. Interestingly, NTP demonstrated greater selective anti-proliferative activity against mesothelioma cells relative to fibroblasts than cisplatin, which is used for mesothelioma treatment. The anti-proliferative effect of NTP was enhanced by pre-incubation with the cellular iron donor, ferric ammonium citrate (FAC), and inhibited by iron chelation using desferrioxamine (DFO). Three oxidative stress probes (CM-H2DCFDA, MitoSOX and C11-BODIPY) demonstrated reactive oxygen species (ROS) generation by NTP, which was inhibited by DFO. Moreover, NTP decreased transferrin receptor-1 and increased ferritin-H and -L chain expression that was correlated with decreased iron-regulatory protein expression and RNA-binding activity. This regulation was potentially due to increased intracellular iron in lysosomes, which was demonstrated via the Fe (II)-selective probe, HMRhoNox-M, and was consistent with autophagic-induction. Immunofluorescence using LysoTracker and Pepstatin A probes demonstrated increased cellular lysosome content, which was confirmed by elevated LAMP1 expression. The enhanced lysosomal biogenesis after NTP could be due to the observed increase in fluid-phase endocytosis and early endosome formation. These results suggest NTP acts as a stressor, which results in increased endocytosis, lysosome content and autophagy. In fact, NTP rapidly increased autophagosome formation, as judged by increased LC3B-II expression, which co-localized with LAMP1, indicating autophagolysosome formation. Autophagic-induction by NTP was confirmed using electron microscopy. In summary, NTP acts as a cellular stressor to rapidly induce fluid-phase endocytosis, lysosome biogenesis and autophagy.

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  102. Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells

    Kae Nakamura, Yang Peng, Fumi Utsumi, Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa, Hiroaki Kajiyama

    SCIENTIFIC REPORTS   Vol. 7 ( 1 ) page: 6085   2017.7

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    Non-thermal atmospheric pressure plasma has been proposed as a new therapeutic tool for cancer treatment. Recently, plasma-activated medium (PAM) has been widely studied in various cancer types. However, there are only few reports demonstrating the anti-tumour effects of PAM in an animal model reflecting pathological conditions and the accompanying mechanism. Here we investigated the inhibitory effect of PAM on the metastasis of ovarian cancer ES2 cells in vitro and in vivo. We demonstrated that ES2 cell migration, invasion and adhesion were suppressed by PAM at a certain PAM dilution ratio, whereas cell viability remained unaffected. In an in vivo mouse model of intraperitoneal metastasis, PAM inhibited peritoneal dissemination of ES2 cells, resulting in prolonged survival. Moreover, we assessed the molecular mechanism and found that MMP-9 was decreased by PAM. On further investigation, we also found that PAM prevented the activation of the MAPK pathway by inhibiting the phosphorylation of JNK1/2 and p38 MAPK. These findings indicate that PAM inhibits the metastasis of ovarian cancer cells through reduction of MMP-9 secretion, which is critical for cancer cell motility. Our findings suggest that PAM intraperitoneal therapy may be a promising treatment option for ovarian cancer.

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  103. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats

    Yasumasa Okazaki, Shigeru Okada, Shinya Toyokuni

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 61 ( 1 ) page: 18 - 24   2017.7

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    Daily intake of vegetables can reduce the risk of cancer and lifestyle-related diseases. However, supplementary intake of 13 carotene alone has been reported to increase the risk of lung cancer in male cigarette smokers and people who were exposed to asbestos. The mechanism of the antioxidative properties of carotenoids in vivo, especially under oxidative stress conditions, still remains unclear. To investigate the antioxidant properties of dietary compounds, we examined the effects of chemically modified astaxanthin (Ax-C-8) using a rat model of ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative injury. Ax-C-8 demonstrated lethally toxic effects on the rats in a dose-dependent manner. Following supplementation with Ax-C-8 (0.02%, w/w) for 30 days, the rats were euthanized 1, 4 and 24 h after injection of Fe-NTA. After 4 h, Ax-C-8 pretreatment suppressed the elevation of creatinine and blood urea nitrogen and protected the rats from renal tubular necrosis and the formation of 4-hydroxy-2-nonenal-modified proteins. After 24 h, pretreatment with Ax-C-8 maintained the renal antioxidant enzyme levels and renal tubules. Here, we demonstrate the antioxidant effects of Ax-C-8 against Fe-NTA-induced oxidative injury in rats receiving a regular diet. These data suggest that dietary intake of astaxanthin may be useful for the prevention of renal tubular oxidative damage.

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  104. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats Reviewed

    Yasumasa Okazaki, Shigeru Okada, Shinya Toyokuni

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 61 ( 1 ) page: 18 - 24   2017.7

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    Daily intake of vegetables can reduce the risk of cancer and lifestyle-related diseases. However, supplementary intake of 13 carotene alone has been reported to increase the risk of lung cancer in male cigarette smokers and people who were exposed to asbestos. The mechanism of the antioxidative properties of carotenoids in vivo, especially under oxidative stress conditions, still remains unclear. To investigate the antioxidant properties of dietary compounds, we examined the effects of chemically modified astaxanthin (Ax-C-8) using a rat model of ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative injury. Ax-C-8 demonstrated lethally toxic effects on the rats in a dose-dependent manner. Following supplementation with Ax-C-8 (0.02%, w/w) for 30 days, the rats were euthanized 1, 4 and 24 h after injection of Fe-NTA. After 4 h, Ax-C-8 pretreatment suppressed the elevation of creatinine and blood urea nitrogen and protected the rats from renal tubular necrosis and the formation of 4-hydroxy-2-nonenal-modified proteins. After 24 h, pretreatment with Ax-C-8 maintained the renal antioxidant enzyme levels and renal tubules. Here, we demonstrate the antioxidant effects of Ax-C-8 against Fe-NTA-induced oxidative injury in rats receiving a regular diet. These data suggest that dietary intake of astaxanthin may be useful for the prevention of renal tubular oxidative damage.

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  105. 微量金属が操る健康と疾患 鉄が操る生体反応と発がん

    豊國 伸哉

    日本抗加齢医学会総会プログラム・抄録集   Vol. 17回   page: 98 - 98   2017.6

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  106. Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics. International journal

    Tetsuro Yoshimaru, Keisuke Aihara, Masato Komatsu, Yosuke Matsushita, Yasumasa Okazaki, Shinya Toyokuni, Junko Honda, Mitsunori Sasa, Yasuo Miyoshi, Akira Otaka, Toyomasa Katagiri

    Scientific reports   Vol. 7 ( 1 ) page: 1821 - 1821   2017.5

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    Estradiol (E2) and the oestrogen receptor-alpha (ER alpha) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ER alpha signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERa activity-regulator synthetic peptide (ERAP: 165-177 amino acids), derived from a-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable a-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.

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  107. Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells. Reviewed International journal

    Yi-Peng Han, Atsushi Enomoto, Yukihiro Shiraki, Shen-Qi Wang, Xiaoze Wang, Shinya Toyokuni, Naoya Asai, Kaori Ushida, Hosne Ara, Fumiharu Ohka, Toshihiko Wakabayashi, Jie Ma, Atsushi Natsume, Masahide Takahashi

    Neuro-oncology   Vol. 19 ( 5 ) page: 636 - 647   2017.5

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    The significance of mammalian target of rapamycin complex 1 (mTORC1) activity in the maintenance of cancer stem cells (CSCs) remains controversial. Previous findings showed that mTORC1 activation depleted the population of leukemia stem cells in leukemia, while maintaining the stemness in pancreatic CSCs. The purpose of this study was to examine the currently unknown role and significance of mTORC1 activity in brain tumor stem cells (BTSCs).
    Basal mTORC1 activity and its kinetics were investigated in BTSC clones isolated from patients with glioblastoma and their differentiated progenies (DIFFs). The effects of nutrient deprivation and the mTORC1 inhibitors on cell proliferation were compared between the BTSCs and DIFFs. Tissue sections from patients with brain gliomas were examined for expression of BTSC markers and mTORC1 activity by immunohistochemistry.
    BTSCs presented lower basal mTORC1 activity under each culture condition tested and a more rapid decline of mTORC1 activity after nutrient deprivation than observed in DIFFs. The self-renewal capacity of BTSCs was unaffected by mTORC1 inhibition, whereas it effectively suppressed DIFF proliferation. In agreement, immunohistochemical staining of glioma tissues revealed low mTORC1 activity in tumor cells positive for BTSC markers. In in vitro culture, BTSCs exhibited resistance to the antitumor agent temozolomide.
    Our findings indicated the importance of low mTORC1 activity in maintaining the undifferentiated state of BTSCs, implicating the relevance of manipulating mTORC1 activity when developing future strategies that target BTSCs.

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  108. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. International journal

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Yoshihiro Nishida, Hiroshi Urakawa, Yoshinao Oda, Shinya Toyokuni

    Human pathology   Vol. 63   page: 63 - 69   2017.5

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    Extraskeletal osteosarcoma (ESOS) is an uncommon malignant neoplasm. Most ESOSs are high grade, although some low-grade cases have been reported. A few cases of ESOS with MDM2 amplification have also been reported, suggesting some similarity to skeletal low-grade osteosarcoma such as parosteal osteosarcoma, where MDM2 is often amplified. However, the frequency of low-grade cases and cases with MDM2 amplification among ESOSs remains unknown, and their relationship is unclear. To clarify this, we examined 18 primary ESOS cases clinically, pathologically, and genetically, focusing on their MDM2 amplification status. Our cases comprised 10 men and 8 women whose mean age was 58.6 years
    the most common site of the lesion was the thigh and buttock. There were one histologically low-grade case evaluated by biopsy specimen with an aggressive course and 2 relatively low-grade cases whose lesions were of low grade for the most part. MDM2 amplification status was revealed by fluorescence in situ hybridization in all 18 cases
    2 patients—histologically intermediate- and high-grade cases—were found to have MDM2 amplification. In conclusion, this study indicates that histologically low-grade and relatively low-grade cases of ESOS are not always associated with MDM2 amplification. The ESOS case with MDM2 amplification could be high grade, although MDM2-amplified dedifferentiated liposarcoma with osteogenic differentiation should be ruled out in making the diagnosis.

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  109. Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics Reviewed

    Tetsuro Yoshimaru, Keisuke Aihara, Masato Komatsu, Yosuke Matsushita, Yasumasa Okazaki, Shinya Toyokuni, Junko Honda, Mitsunori Sasa, Yasuo Miyoshi, Akira Otaka, Toyomasa Katagiri

    SCIENTIFIC REPORTS   Vol. 7 ( 1 ) page: 1821   2017.5

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    Estradiol (E2) and the oestrogen receptor-alpha (ER alpha) signalling pathway play pivotal roles in the proliferative activity of breast cancer cells. Recent findings show that the brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex plays a crucial role in E2/ER alpha signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERa activity-regulator synthetic peptide (ERAP: 165-177 amino acids), derived from a-helical BIG3 sequence, resulted in a significant anti-tumour effect. However, the duration of this effect was very short for viable clinical application. We developed the chemically modified ERAP using stapling methods (stapledERAP) to improve the duration of its antitumour effects. The stapledERAP specifically inhibited the BIG3-PHB2 interaction and exhibited long-lasting suppressive activity. Its intracellular localization without the membrane-permeable polyarginine sequence was possible via the formation of a stable a-helix structure by stapling. Tumour bearing-mice treated daily or weekly with stapledERAP effectively prevented the BIG3-PHB2 interaction, leading to complete regression of E2-dependent tumours in vivo. Most importantly, combination of stapledERAP with tamoxifen, fulvestrant, and everolimus caused synergistic inhibitory effects on growth of breast cancer cells. Our findings suggested that the stapled ERAP may be a promising anti-tumour drug to suppress luminal-type breast cancer growth.

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  110. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma

    Shan Hwu Chew, Yasumasa Okazaki, Shinya Akatsuka, Shenqi Wang, Li Jiang, Yuuki Ohara, Fumiya Ito, Hideyuki Saya, Yoshitaka Sekido, Shinya Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 106   page: 91 - 99   2017.5

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    CD44 exists as a standard (CD44s) isoform and different variant isoforms (CD44v) due to alternative splicing. While the complex nature of these different isoforms has not been fully elucidated, CD44v expression has been shown to exert oncogenic effects by promoting tumor progression, metastasis and resistance of tumor cells to chemotherapy. One of the CD44v isoforms, CD44v8-10, was recently shown to protect cancer cells from oxidative stress by increasing the synthesis of glutathione (GSH). However, data regarding CD44 isoform expression in malignant mesothelioma (MM) are still lacking. Here, we show that most of the MM cell lines express both the CD44s and CD44v isoforms, in contrast to non-tumorigenic mesothelial cells, which express only CD44s. Moreover, we show here that these MM cell lines are positive for CD44 variable axon 9, with CD44v8-10 among the variant isoforms expressed. The expression of CD44 variable axon 9 was found to be statistically associated with NF2 inactivation, a common occurrence in MM. Knockdown of CD44 reduced the protein level of xCT, a cystine transporter, and increased oxidative stress. However, an increase in GSH was also observed and was associated with enhanced chemoresistance in CD44-knockdown cells. Increased GSH was mediated by the Nrf2/AP-1-induced upregulation of GCLC, a subunit of the enzyme catalyzing GSH synthesis. Our results thus suggest that the response to CD44 depletion is cell type-dependent and, in cases such as MM cells, compensatory pathway(s) might be activated rheostatically to account for the loss of CD44 and counteract enhanced oxidative stress.

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  111. Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells

    Yi-Peng Han, Atsushi Enomoto, Yukihiro Shiraki, Shen-Qi Wang, Xiaoze Wang, Shinya Toyokuni, Naoya Asai, Kaori Ushida, Hosne Ara, Fumiharu Ohka, Toshihiko Wakabayashi, Jie Ma, Atsushi Natsume, Masahide Takahashi

    NEURO-ONCOLOGY   Vol. 19 ( 5 ) page: 636 - 647   2017.5

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    The significance of mammalian target of rapamycin complex 1 (mTORC1) activity in the maintenance of cancer stem cells (CSCs) remains controversial. Previous findings showed that mTORC1 activation depleted the population of leukemia stem cells in leukemia, while maintaining the stemness in pancreatic CSCs. The purpose of this study was to examine the currently unknown role and significance of mTORC1 activity in brain tumor stem cells (BTSCs).
    Basal mTORC1 activity and its kinetics were investigated in BTSC clones isolated from patients with glioblastoma and their differentiated progenies (DIFFs). The effects of nutrient deprivation and the mTORC1 inhibitors on cell proliferation were compared between the BTSCs and DIFFs. Tissue sections from patients with brain gliomas were examined for expression of BTSC markers and mTORC1 activity by immunohistochemistry.
    BTSCs presented lower basal mTORC1 activity under each culture condition tested and a more rapid decline of mTORC1 activity after nutrient deprivation than observed in DIFFs. The self-renewal capacity of BTSCs was unaffected by mTORC1 inhibition, whereas it effectively suppressed DIFF proliferation. In agreement, immunohistochemical staining of glioma tissues revealed low mTORC1 activity in tumor cells positive for BTSC markers. In in vitro culture, BTSCs exhibited resistance to the antitumor agent temozolomide.
    Our findings indicated the importance of low mTORC1 activity in maintaining the undifferentiated state of BTSCs, implicating the relevance of manipulating mTORC1 activity when developing future strategies that target BTSCs.

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  112. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. Reviewed

    Toyokuni S, Ito F, Yamashita K, Okazaki Y, Akatsuka S

    Free Radical Biology & Medicine   Vol. 108   page: 610-626   2017.4

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  113. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor Reviewed

    Yuki Shikata, Tetsuro Yoshimaru, Masato Komatsu, Hiroto Katoh, Reiko Sato, Shuhei Kanagaki, Yasumasa Okazaki, Shinya Toyokuni, Etsu Tashiro, Shumpei Ishikawa, Toyomasa Katagiri, Masaya Imoto

    CANCER SCIENCE   Vol. 108 ( 4 ) page: 785 - 794   2017.4

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    Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.

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  114. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor

    Yuki Shikata, Tetsuro Yoshimaru, Masato Komatsu, Hiroto Katoh, Reiko Sato, Shuhei Kanagaki, Yasumasa Okazaki, Shinya Toyokuni, Etsu Tashiro, Shumpei Ishikawa, Toyomasa Katagiri, Masaya Imoto

    CANCER SCIENCE   Vol. 108 ( 4 ) page: 785 - 794   2017.4

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    Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.

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  115. 鉄ニトリロ三酢酸誘発腎発がんにおけるMUTYH発現の意義

    落合 晴菜, 赤塚 慎也, 李 光華, 豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 505 - 505   2017.3

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  116. 脱分化型脂肪肉腫における組織所見と予後との関連

    佐々木 和磨, 山下 享子, 孝橋 賢一, 豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 523 - 523   2017.3

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  117. 悪性中皮腫細胞への低温プラズマ照射による鉄の代謝

    丹下 恵里花, 石 蕾, 豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 521 - 521   2017.3

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  118. 環境発がん 環境がおよぼす細胞・組織・臓器・個体レベルでの病理学的変化 酸化ストレスと発がん

    豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 199 - 199   2017.3

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  119. 繊維状物質は鉄過剰を介した炎症細胞の細胞死を誘導する

    前田 勇貴, 伊藤 文哉, 豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 520 - 520   2017.3

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  120. 中皮腫診断の最前線 中皮腫発生のメカニズム

    豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 577 - 577   2017.3

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  121. ラットモデルにおいて瀉血は悪性中皮腫の増殖を抑制する(Phlebotomy attenuates the growth of malignant mesothelioma on rat model)

    大原 悠紀, 宗宮 大輝, 柴田 崇宏, 豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 410 - 410   2017.3

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  122. アスベストによる細胞死は鉄過剰依存的に増強する

    伊藤 文哉, 前田 勇貴, 石 蕾, 豊國 伸哉

    日本病理学会会誌   Vol. 106 ( 1 ) page: 289 - 289   2017.3

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  123. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. Reviewed

    Yamashita K, Kohashi K, Yamada Y, Nishida Y, Urakawa H, Oda Y, Toyokuni S

    Human Pathology   Vol. 63   page: 63-69   2017.2

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    DOI: 10.1016/j.humpath.2017.02.007.

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  124. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. Reviewed

    Chew SH, Okazaki Y, Akatsuka S, Wang S, Jiang L, Ohara Y, Ito F, Saya H, Sekido Y, Toyokuni S

    Free Radical Biology & Medicine   Vol. 106   page: 91-99   2017.2

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    DOI: 10.1016/j.freeradbiomed.2017.02.011.

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  125. 【微量金属元素と生体機能-メタロミクス研究から臨床検査へ】がんと微量金属元素

    伊藤 文哉, 豊國 伸哉

    臨床検査   Vol. 61 ( 2 ) page: 168 - 173   2017.2

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    <Point>微量金属元素のなかでも,鉄は発がんとの関連性が強い.がんのなかで,特に悪性中皮腫,慢性ウイルス性肝炎,ヘモクロマトーシスによる肝がん,卵巣がん,骨髄異形成症候群(MDS)が鉄過剰との関わりが強い.ヘプシジンと非トランスフェリン結合鉄(NTBI)が検査データとして新規に有用視されている.(著者抄録)

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  126. Clinicopathological and Molecular Features of Dedifferentiated Liposarcoma with Ossification: A Comparative Study with Dedifferentiated Liposarcoma without Ossification and Extraskeletal Osteosarcoma

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Yoshinao Oda, Shinya Toyokuni

    MODERN PATHOLOGY   Vol. 30   page: 27A - 27A   2017.2

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  127. Clinicopathological and Molecular Features of Dedifferentiated Liposarcoma with Ossification: A Comparative Study with Dedifferentiated Liposarcoma without Ossification and Extraskeletal Osteosarcoma

    Kyoko Yamashita, Kenichi Kohashi, Yuichi Yamada, Yoshinao Oda, Shinya Toyokuni

    LABORATORY INVESTIGATION   Vol. 97   page: 27A - 27A   2017.2

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  128. 環境化学物質の毒性影響とリスク評価-生活環境病から発がん影響まで- 発がんの根源的原因 毒性病理学にできること

    豊國 伸哉

    日本毒性病理学会講演要旨集   Vol. 33回   page: 45 - 45   2017.1

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  129. Future perspective of strategic non-thermal plasma therapy for cancer treatment

    Hiroaki Kajiyama, Fumi Utsumi, Kae Nakamura, Hiromasa Tanaka, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 60 ( 1 ) page: 33 - 38   2017.1

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    The therapeutic effects of non-thermal plasma are expected in the medical fields, including hemostasis, vascularization, prevention of organ adhesion, and cell proliferation. Cancer is an internal enemy arising from normal tissue in the body. The prognosis of metastatic and recurrent cancers is still poor despite advances in medicine. To apply non-thermal plasma in cancer treatment is now on going. The mechanism of the proliferation-inhibitory effect of plasma is reactive nitrogen oxide species/reactive oxygen species production in cells. There are a number of problems to be overcome, such as existence of intrinsic reactive oxygen species/reactive nitrogen species scavengers and the shallow infiltration of plasma on tumor surface. The current reviews makes referral to the study results of plasma therapy clarified so far, the possibility of its application in the future.

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  130. Future perspective of strategic non-thermal plasma therapy for cancer treatment. Reviewed

    Kajiyama H, Utsumi F, Nakamura K, Tanaka H, Toyokuni S, Hori M, Kikkawa F

    Journal of Clinical Biochemistry and Nutrition   Vol. 60 ( 1 ) page: 33-38   2016.12

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  131. 悪性中皮腫に対するCTGF特異抗体の前臨床研究

    大原 悠紀, 伊藤 文哉, 豊國 伸哉

    日本癌学会総会記事   Vol. 75回   page: J - 2038   2016.10

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  132. 内分泌療法耐性乳がんに対するBIG3-PHB2相互作用阻害ペプチドの開発

    吉丸 哲郎, 松下 洋輔, 小松 正人, 岡崎 泰昌, 豊國 伸哉, 笹 三徳, 三好 康雄

    日本癌学会総会記事   Vol. 75回   page: J - 3045   2016.10

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  133. Non-thermal plasma prevents progression of endometriosis in mice. Reviewed International journal

    Chiharu Ishida, Masahiko Mori, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Akira Iwase, Fumitaka Kikkawa, Shinya Toyokuni

    Free radical research   Vol. 50 ( 10 ) page: 1131 - 1139   2016.10

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    Endometriosis is observed in approximate to 10% of reproductive age women. Ovarian endometriosis not only causes dysmenorrhea but also causes infertility and a high risk of adenocarcinoma. Due to its scattered nature, complete surgical resection is difficult. Endometriosis consists of glandular and stromal cells. Previously, we showed that endometrial stromal cells (ESCs) play a role in the protection against pathologic events caused by monthly repeated hemorrhage. Here, we undertook a preclinical study of non-thermal plasma (NTP) as a surgical treatment of endometriosis. Epithelial cells were most sensitive to NTP-activated medium in vitro, whereas ectopic ESCs were most resistant. We then transplanted excised uteruses into BALB/c mice from donors of the same strain with estradiol supplementation. Four weeks after the transplantation, we exposed NTP to each endometriotic lesion after laparotomy. Immunohistochemical analysis revealed that immediately after NTP exposure, epithelial cells exhibited significantly higher levels of nuclear immunostaining for 8-hydroxy-2-deoxyguanosine than did stromal cells. Four weeks after NTP exposure, the total surface area consisting of endometriotic cysts was significantly smaller with less epithelial proliferative activity than the helium-exposed control, whereas the number of endometriotic lesions had not changed. Therefore, NTP exposure may be useful to prevent the progression and recurrence of endometriosis.

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  134. Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. Reviewed International journal

    Cai Zong, C Edwin Garner, Chinyen Huang, Xiao Zhang, Lingyi Zhang, Jie Chang, Shinya Toyokuni, Hidenori Ito, Masashi Kato, Toshihiro Sakurai, Sahoko Ichihara, Gaku Ichihara

    Toxicology letters   Vol. 258   page: 249 - 258   2016.9

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    Neurotoxicity of 1-bromopropane (1-BP) has been reported in both human cases and animal studies. To date, neurotoxicity of 1-BP has been induced in rats but not in mice due to the lethal hepatotoxicity of 1-BP. Oxidization by cytochromes P450 and conjugation with glutathione (GSH) are two critical metabolism pathways of 1-BP and play important roles in toxicity of 1-BP. The aim of the present study was to establish a murine model of 1-BP neurotoxicity, by reducing the hepatotoxicity of 1-BP with 1-aminobenzotriazole (1-ABT); a commonly used nonspecific P450s inhibitor. The results showed that subcutaneous or intraperitoneal injection of 1-ABT at 50mg/kg body weight BID (100mg/kg BW/day) for 3days, inhibited about 92-96% of hepatic microsomal CYP2E1 activity, but only inhibited about 62-64% of CYP2E1 activity in brain microsomes. Mice treated with 1-ABT survived even after exposure to 1200ppm 1-BP for 4 weeks and histopathological studies showed that treatment with 1-ABT protected mice from 1-BP-induced hepatic necrosis, hepatocyte degeneration, and hemorrhage. After 4-week exposure to 1-BP, the brain weight of 1-ABT(+)/1200ppm 1-BP group was decreased significantly. In 1-ABT-treated groups, expression of hippocampal Ran protein and cerebral cortical GRP78 was dose-dependently increased by exposure to 1-BP. We conclude that the control of hepatic P450 activity allows the observation of effects of 1-BP on the murine brain at a higher concentration by reduction of hepatotoxicity. The study suggests that further experiments with liver-specific control of P450 activity using gene technology might provide better murine models for 1-bromopropane-induced neurotoxicity.

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  135. Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells. Reviewed International journal

    Lei Shi, Yue Wang, Fumiya Ito, Yasumasa Okazaki, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Des R Richardson, Shinya Toyokuni

    Archives of biochemistry and biophysics   Vol. 605   page: 109 - 16   2016.9

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    Non-thermal plasma (NTP) is a recently developed technology that elicits a variety of biological effects. This includes cancer cell-specific cytotoxicity, which is mainly attributed to the regional generation of reactive oxygen species (ROS). We studied the effects of NTP on malignant mesothelioma (MM) and its modulation by L-ascorbate. L-ascorbate is a major water-soluble anti-oxidant in vivo, but its pro-oxidant activity in vitro has been well recognized. Thus, the effects of ascorbate on the efficacy of NTP is important to examine. NTP exposure dose-dependently killed MM cells, whereas MM cells tolerated 1 mM L-ascorbate. However, brief pre-treatment with a pharmacological dose (250-750 mu M) of L-ascorbate immediately prior to NTP exposure significantly increased its cytotoxicity in a dose-dependent manner, which was inhibited by the iron chelator, deferoxamine. However, paradoxically, this potentiating effect of L-ascorbate was completely abolished by a prolonged 4 h pre-incubation with L-ascorbate (500 mu M). MM cytotoxicity induced by NTP was associated with immediate oxidative stress evaluated by 2',7'-dichlorodihydrofluorecein diacetate, which was followed by an increase in the expression of the autophagosome marker, LC3B-II. In conclusion, MM can be a target for NTP treatment and L-ascorbate can increase or decrease its efficacy depending on the length of the pre-incubation period. (C) 2016 Elsevier Inc. All rights reserved.

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  136. 鉄代謝異常 疾患と病態 発がんにおける鉄の役割

    豊國 伸哉

    日本生化学会大会プログラム・講演要旨集   Vol. 89回   page: [3S02 - 2]   2016.9

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  137. Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia Reviewed

    Shima Hirako, Hiroyuki Tsuda, Tomomi Kotani, Seiji Sumigama, Yukio Mano, Tomoko Nakano, Kenji Imai, Hua Li, Shinya Toyokuni, Fumitaka Kikkawa

    PHYTOTHERAPY RESEARCH   Vol. 30 ( 9 ) page: 1474 - 1480   2016.9

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    Congenital diaphragmatic hernia (CDH) can induce lung hypoplasia and pulmonary hypertension and is associated with high mortality. The purpose of this study is to examine the efficacy and safety of antenatal Saireito (TJ-114), a traditional Japanese herbal medicine, in a rat CDH model. Sprague-Dawley rats were exposed to an herbicide (nitrofen, 100 mg) on embryonic day 9 (E9) to induce CDH, and antenatal Saireito (2000 mg/kg/day) was orally administered from E10 to E20. On E21, fetuses were delivered. Antenatal Saireito significantly decreased the incidence of CDH (p &lt; 0.01), increased lung volume (p &lt; 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p &lt; 0.05, and PCO2; p &lt; 0.01). In addition, antenatal Saireito significantly decreased endothelin-1 and endothelin receptor A expression in the pulmonary arteries. Taken together, our results demonstrated that antenatal Saireito can improve fetal pulmonary hypoplasia and pulmonary vascular remodeling and, as a result, can improve respiratory function in a rat CDH model. Copyright (C) 2016 John Wiley & Sons, Ltd.

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  138. Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis Reviewed

    Fumiya Ito, Takahiro Nishiyama, Lei Shi, Masahiko Mori, Tasuku Hirayama, Hideko Nagasawa, Hiroyuki Yasui, Shinya Toyokuni

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 476 ( 4 ) page: 600 - 606   2016.8

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    Iron is an essential nutrient for every type of life on earth. However, excess iron is cytotoxic and can lead to an increased cancer risk in humans. Catalytic ferrous iron [Fe(II)] is an initiator of the Fenton reaction, which causes oxidative stress by generating hydroxyl radicals. Recently, it became possible to localize catalytic Fe(II) in situ with a turn-on fluorescent probe, RhoNox-1. Here, we screened each organ/cell of rats to globally evaluate the distribution of catalytic Fe(II) and found that eosinophils showed the highest abundance. In various cells, lysosomes were the major organelle, sharing 40-80% of RhoNox-1 fluorescence. We then used an ovalbumin-induced allergic peritonitis model to study the dynamics of catalytic Fe(II). Peritoneal lavage revealed that the total iron contents per cell were significantly decreased, whereas an increase in the number of inflammatory cells (macrophages, neutrophils, eosinophils and lymphocytes) resulted in an increased total iron content of the peritoneal inflammatory cells. Notably, macrophages, eosinophils and neutrophils exhibited significantly increased catalytic Fe(II) with increased DMT1 expression and decreased ferritin expression, though catalytic Fe(II) was significantly decreased in the peritoneal lavage fluid. In conclusion, catalytic Fe(II) in situ more directly reflects cellular activity and the accompanying pathology than total iron does. (C) 2016 Elsevier Inc. All rights reserved.

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  139. 【微量元素の生体機能と疾患-基礎・臨床研究の最新知見-】微量元素の機能と疾患 鉄機能と発がん

    赤塚 慎也, 豊國 伸哉

    日本臨床   Vol. 74 ( 7 ) page: 1168 - 1175   2016.7

  140. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. Reviewed

    Cahill MA, Jazayeri JA, Catalano SM, Toyokuni S, Kovacevic Z, Richardson DR

    Biochim Biophys Acta. 2016 Jul 22.   Vol. pii: S0304-419X ( 16 ) page: 30049-X.   2016.7

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  141. 各種病態における微量元素の関わり 過剰鉄と発がん

    豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 27 ( 2 ) page: 68 - 68   2016.6

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  142. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium Reviewed

    Fumi Utsumi, Hiroaki Kajiyama, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Shinnya Toyokuni, Masaru Hori, Fumitaka Kikkawa

    ONCOLOGY REPORTS   Vol. 35 ( 6 ) page: 3169 - 3177   2016.6

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    Non-thermal atmospheric pressure plasma has been widely studied in recent years in many fields, including cancer treatment. However, its efficiency for inducing apoptosis sometimes varies depending on the cell species and experimental conditions. The aim of this study was to elucidate what causes these differences in responses to plasma treatment. Using four ovarian cancer cell lines, the cell density had a markedly negative impact on the proliferation inhibition rate (PIR) and it was more obvious in OVCAR-3 and NOS2 cells. Furthermore, TOV21G and ES-2 cells were drastically sensitive to plasma-activated medium (PAM) compared with the other two cell lines. We demonstrated that the proportion of reactive oxygen species and cell number had a marked impact on the effect of PAM against ovarian cancer cells. Additionally it was suggested that the morphological features of cells were also closely related to the sensitivity of cancer cells to the plasma treatment.

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  143. 骨外性骨肉腫との比較における骨軟骨形成性脱分化型脂肪肉腫の臨床病理学的検討

    山下 享子, 孝橋 賢一, 山田 裕一, 小田 義直, 豊國 伸哉

    日本病理学会会誌   Vol. 105 ( 1 ) page: 461 - 461   2016.4

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  144. 触媒性二価鉄と細胞周期や細胞分化との関連

    伊藤 理樹, 伊藤 文哉, 石 蕾, 豊國 伸哉

    日本病理学会会誌   Vol. 105 ( 1 ) page: 596 - 596   2016.4

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  145. 悪性中皮腫治療のためのCTGF特異的単クローン抗体の前臨床的使用(Preclinical use of CTGF-specific monoclonal antibody for the treatment of malignant mesothelioma)

    大原 悠紀, 豊國 伸哉

    日本病理学会会誌   Vol. 105 ( 1 ) page: 440 - 440   2016.4

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  146. 線維芽細胞はConnective tissue growth factorを介して悪性中皮腫細胞増殖を促進する

    宗宮 大輝, 大原 悠紀, 豊國 伸哉

    日本病理学会会誌   Vol. 105 ( 1 ) page: 590 - 591   2016.4

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  147. 巨大な脱分化型脂肪肉腫の一剖検例

    尾崎 航太郎, 大原 悠紀, 亀山 祐行, 山下 享子, 豊國 伸哉

    日本病理学会会誌   Vol. 105 ( 1 ) page: 582 - 582   2016.4

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  148. ラット悪性中皮腫におけるGalectinの発現とその意義

    太田 和樹, 赤塚 慎也, 豊國 伸哉

    日本病理学会会誌   Vol. 105 ( 1 ) page: 593 - 593   2016.4

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  149. 中皮細胞傷害と発がん性はトレモライトに強く、アンソフィライトに弱い(Mesothelial injury and carcinogenesis are induced by tremolite, but not anthophyllite)

    岡崎 泰昌, 周 珊瑚, 酒井 晃太, Arken Dilnur, 王 越, 永井 裕崇, 三澤 伸明, 神山 宣彦, 豊國 伸哉

    日本病理学会会誌   Vol. 105 ( 1 ) page: 440 - 440   2016.4

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  150. Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics

    Danuta S. Kalinowski, Christian Stefani, Shinya Toyokuni, Tomas Ganz, Gregory J. Anderson, Nathan V. Subramaniam, Debbie Trinder, John K. Olynyk, Anita Chua, Patric J. Jansson, Sumit Sahni, Darius J. R. Lane, Angelica M. Merlot, Zaklina Kovacevic, Michael L. H. Huang, C. Soon Lee, Des R. Richardson

    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH   Vol. 1863 ( 4 ) page: 727 - 748   2016.4

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    Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics. (C) 2016 Elsevier B.V. All rights reserved.

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  151. Mutyh欠損マウスにおける鉄ニトリロ三酢酸誘発腎発がんの解析

    李 光華, 赤塚 慎也, 豊國 伸哉, 二口 充, 中別府 雄作

    日本病理学会会誌   Vol. 105 ( 1 ) page: 435 - 435   2016.4

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  152. Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis Reviewed

    Yue Wang, Yasumasa Okazaki, Lei Shi, Hiro Kohda, Minoru Tanaka, Kentaro Taki, Tomoki Nishioka, Tasuku Hirayama, Hideko Nagasawa, Yoriko Yamashita, Shinya Toyokuni

    CANCER SCIENCE   Vol. 107 ( 3 ) page: 250 - 257   2016.3

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    Multi-wall carbon nanotubes (MWCNT) are a form of flexible fibrous nanomaterial with high electrical and thermal conductivity. However, 50-nm MWCNT in diameter causes malignant mesothelioma (MM) in rodents and, thus, the International Agency of Research on Cancer has designated them as a possible human carcinogen. Little is known about the molecular mechanism through which MWCNT causes MM. To elucidate the carcinogenic mechanisms of MWCNT in mesothelial cells, we used a variety of lysates to comprehensively identify proteins specifically adsorbed on pristine MWCNT of different diameters (50 nm, NT50; 100 nm, NT100; 150 nm, NT150; and 15 nm/tangled, NTtngl) using mass spectrometry. We identified &gt;400 proteins, which included hemoglobin, histone, transferrin and various proteins associated with oxidative stress, among which we selected hemoglobin and transferrin for coating MWCNT to further evaluate cytotoxicity, wound healing, intracellular catalytic ferrous iron and oxidative stress in rat peritoneal mesothelial cells (RPMC). Cytotoxicity to RPMC was observed with pristine NT50 but not with NTtngl. Coating NT50 with hemoglobin or transferrin significantly aggravated cytotoxicity to RPMC, with an increase in cellular catalytic ferrous iron and DNA damage also observed. Knockdown of transferrin receptor with ferristatin II decreased not only NT50 uptake but also cellular catalytic ferrous iron. Our results suggest that adsorption of hemoglobin and transferrin on the surface of NT50 play a role in causing mesothelial iron overload, contributing to oxidative damage and possibly subsequent carcinogenesis in mesothelial cells. Uptake of NT50 at least partially depends on transferrin receptor 1. Modifications of NT50 surface may decrease this human risk.

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  153. Pain-reducing anesthesia prevents oxidative stress in human term placenta. Reviewed

    Yoko Tsuzuki, Yoriko Yamashita, Yuka Hattori, Guang Hua Li, Shinya Akatsuka, Tomomi Kotani, Fumitaka Kikkawa, Aya Naiki-Ito, Satoru Takahashi, Kimitoshi Nishiwaki, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 58 ( 2 ) page: 156 - 60   2016.3

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    Anesthesia is sometimes used for the reduction of maternal pain in normal human term labor, but whether the drugs affect oxidative stress remains unclear. The placenta serves as an interface between the maternal and fetal vasculature. In this study, we immunohistochemically analyzed two markers for oxidative stress, namely 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-modified proteins (HNE), using placentas from 21 cases of normal tansvaginal delivery (V group), 20 Caesarean sections (C group), and 17 normal transvaginal deliveries with epidural anesthesia (E group). 8-OHdG staining in the nuclei of trophoblasts lining the chorionic villi was significantly stronger in the V group either compared with the C or E group (p<0.001), without significant differences in the C and E groups (p = 0.792). Moderate to intense staining by HNE of the intravascular serum of chorionic villi vasculature was frequently observed in the placentas from the V group, but less frequently of those in either C or E groups (p<0.001), nor the p value comparing the C and E groups was significant (p = 0.128) for HNE staining. Our results suggest that although the role of oxidative stress and its influences on fetal state in the placenta in labor remains unclear, it seems to be lessened by epidural anesthesia.

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  154. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. Reviewed International journal

    Kenji Imai, Tomomi Kotani, Hiroyuki Tsuda, Yukio Mano, Tomoko Nakano, Takafumi Ushida, Hua Li, Rika Miki, Seiji Sumigama, Akira Iwase, Akihiro Hirakawa, Kinji Ohno, Shinya Toyokuni, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura, Fumitaka Kikkawa

    Free radical biology & medicine   Vol. 91   page: 154 - 63   2016.2

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    Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H-2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H-2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H-2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H-2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H-2, involved in the process of activating microglia. These results suggested that H-2 holds promise for the prevention of inflammation related to perinatal brain injury. (C) 2015 Elsevier Inc. All rights reserved.

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  155. Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma Reviewed

    Shenqi Wang, Li Jiang, Yipeng Han, Shan Hwu Chew, Yuuki Ohara, Shinya Akatsuka, Liang Weng, Koji Kawaguchi, Takayuki Fukui, Yoshitaka Sekido, Kohei Yokoi, Shinya Toyokuni

    Oncotarget   Vol. 7 ( 43 ) page: 69565 - 69578   2016

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    Malignant mesothelioma (MM) is a rare neoplasm associated with asbestos exposure. The prognosis of MM is poor because it is aggressive and highly resistant to chemotherapy. Using a rat model of asbestos-induced MM, we found elevated urokinase-type plasminogen activator receptor (uPAR
    Plaur) expression in rat tissues, which was associated with poor prognosis. The proliferation, migration and invasion of MM cells were suppressed by uPAR knockdown and increased by overexpression experiments, irrespective of urokinase-type plasminogen activator (uPA
    Plau) levels. More importantly, we found that uPAR expression is associated with sensitivity to cisplatin in MM through the PI3K/AKT pathway, which was demonstrated with specific inhibitors, LY294002 and Akti-1/2. uPAR knockdown significantly increased sensitivity to cisplatin whereas its overexpression significantly decreased cisplatin sensitivity. Furthermore, sera and tissues from MM patients showed significantly high uPAR levels, which suggested the pathogenic role of uPAR in the tumor biology of human MM. In conclusion, our findings indicate that uPAR levels are associated with malignant characteristics and cisplatin sensitivity of MM. In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM.

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  156. 酸化ストレスの発生と制御 発がんと老化の抑制をめざして 酸化ストレスによる発がんとゲノム変化

    赤塚 慎也, 李 光華, 豊國 伸哉

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   Vol. 88回・38回   page: [2W6 - 4]   2015.12

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  157. Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. Reviewed International journal

    Masahiko Mori, Fumiya Ito, Lei Shi, Yue Wang, Chiharu Ishida, Yuka Hattori, Masato Niwa, Tasuku Hirayama, Hideko Nagasawa, Akira Iwase, Fumitaka Kikkawa, Shinya Toyokuni

    Redox biology   Vol. 6   page: 578 - 586   2015.12

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    Ovarian endometriosis is a recognized risk for infertility and epithelial ovarian cancer, presumably due to iron overload resulting from repeated hemorrhage. To find a clue for early detection and prevention of ovarian endometriosis-associated cancer, it is mandatory to evaluate catalytic (labile) ferrous iron (catalytic Fe(II)) and to study iron manipulation in ovarian endometriotic lesions. By the use of tissues from women of ovarian endometriosis as well as endometrial tissue from women with and without endometriosis, we for the first time performed histological analysis and cellular detection of catalytic Fe(II) with a specific fluorescent probe (HMRhoNox-M), and further evaluated iron transport proteins in the human specimens and in co-culture experiments using immortalized human eutopic/ectopic endometrial stromal cells (ESCs) in the presence or absence of epithelial cells (EpCs). The amounts of catalytic Fe(II) were higher in ectopic endometrial stromal cells (ecESCs) than in normal eutopic endometrial stromal cells (n-euESCs) both in the tissues and in the corresponding immortalized ESCs. ecESCs exhibited higher transferrin receptor 1 expression both in vivo and in vitro and lower ferroportin expression in vivo than n-euESCs, leading to sustained iron uptake. In co-culture experiments of ESCs with iron-loaded EpCs, ecESCs received catalytic ferrous iron from EpCs, but n-euESCs did not. These data suggest that ecESC play a protective role for cancer-target epithelial cells by collecting excess iron, and that these characteristics are retained in the immortalized ecESCs. (C) 2015 The Authors. Published by Elsevier B.V.

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  158. P450を阻害して肝臓毒性を減弱させることでマウス神経毒性モデルを確立する

    宗 才, エドウィン・ガーナー, 黄 晋彦, 張 霊逸, 張 堯, 豊國 伸哉, 市原 佐保子, 櫻井 敏博, 市原 学

    産業衛生学雑誌   Vol. 57 ( 6 ) page: 326 - 326   2015.11

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  159. 鉄を介した酸化ストレスによるゲノム変化と発がん

    赤塚 慎也, 李 光華, 豊國 伸哉

    日本癌学会総会記事   Vol. 74回   page: IS4 - 3   2015.10

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  160. 中皮細胞傷害と発がん性はトレモライトに強く、アンソフィライトに弱い

    岡崎 泰昌, 周 珊瑚, 酒井 晃太, Dilnur Arken, 王 越, 永井 裕崇, 三澤 伸明, 神山 宣彦, 豊國 伸哉

    日本癌学会総会記事   Vol. 74回   page: P - 1058   2015.10

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  161. ライブセルイメージングを用いた癌細胞の鉄代謝の解明

    伊藤 文哉, 豊國 伸哉, 大原 悠紀, 森 正彦, 石 蕾, 西山 崇浩

    日本癌学会総会記事   Vol. 74回   page: P - 3154   2015.10

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  162. 中皮細胞の傷害及び発がんにおいてカーボンナノチューブの表面性質によるタンパク質吸着は重要因子である

    王 越, 岡崎 泰昌, 石 蕾, 神田 容, 豊國 伸哉

    日本癌学会総会記事   Vol. 74回   page: P - 1021   2015.10

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  163. エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がんの治療法

    吉丸 哲郎, 小松 正人, 田代 悦, 長田 裕之, 井本 正哉, 豊國 伸哉, 三好 康雄, 笹 三徳, 片桐 豊雅

    日本癌学会総会記事   Vol. 74回   page: J - 1207   2015.10

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  164. アスベスト繊維による中皮腫発生機構

    豊國 伸哉

    日本臨床細胞学会雑誌   Vol. 54 ( Suppl.2 ) page: 463 - 463   2015.10

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  165. アネキシンA2は中皮細胞によるアスベスト取り込みにおいて受容体として働く

    山下 享子, 永井 裕崇, 豊國 伸哉

    日本癌学会総会記事   Vol. 74回   page: P - 1094   2015.10

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  166. CPC解説(第75回) 肺動脈血栓内膜摘除術後に体外循環から離脱できずに死亡した慢性血栓塞栓性肺高血圧症の一例

    山下 享子, 榎本 篤, 大島 英揮, 安藤 太三, 平敷 安希博, 近藤 隆久, 全 陽, 中村 栄男, 豊國 伸哉

    病理と臨床   Vol. 33 ( 10 ) page: 1135 - 1140   2015.10

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  167. 印刷会社で集団発生した胆管癌の最近の知見 職業性胆管癌の原因物質解明のための動物実験

    市原 学, 張 霊逸, 豊國 伸哉, 熊谷 信二

    産業医学レビュー   Vol. 28 ( 2 ) page: 151 - 156   2015.9

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  168. Malignant mesothelioma as an oxidative stress-induced cancer: An update Reviewed

    Shan Hwu Chew, Shinya Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 86   page: 166 - 178   2015.9

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    Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. On fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasomes in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and TGF-beta pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP] as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still similar to 8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by beta-catenin, has been recognized as a hopeful target for therapy, especially in sarcomatoid subtype. Recent research outcomes related to microRNAs and cancer stem cells also offer additional novel targets for the treatment of MM. Iron reduction as chemoprevention of mesothelioma is helpful at least in an animal preclinical study. Integrated approaches to fiber-induced oxidative stress would be necessary to overcome this currently fatal disease. (C) 2015 Elsevier Inc. All rights reserved.

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  169. Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin. Reviewed International journal

    Shinya Toyokuni, Li Jiang, Shenqi Wang, Ayaka Hirao, Tamae Wada, Chieko Soh, Kazumi Toyama, Akira Kawada

    Pathology international   Vol. 65 ( 8 ) page: 415 - 9   2015.8

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    Sunlight exposure and aging are two major factors in the deterioration of skin function. In the present study, we used eighty formalin-fixed human skin samples from sun-exposed and unexposed areas from old and young individuals to evaluate the presence of miR-125b-positive epidermal stem cells (ESCs) by in situ hybridization. miR-125b-positive ESCs were detected in the basal layer of the epidermis. The density of miR-125b-positive ESCs was significantly associated with age rather than sun exposure, whereas the density of miR-125b-positive ESCs tended to decrease in the sun-exposed area. These data suggest the potential use of miR-125b as a surrogate marker for the quality of epidermal cells.

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  170. 晩期乳癌再発症例の穿刺吸引細胞診プレパラートを用いたHER2蛋白検索

    安部 まこと, 豊國 伸哉

    日本乳癌学会総会プログラム抄録集   Vol. 23回   page: 551 - 551   2015.7

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  171. グルタチオンS-トランスフェラーゼの肝臓内における分布は、1,2-ジクロロプロパン曝露による胆管癌誘導作用におけるヒトとげっ歯類の違いを説明できない(Hepatic distribution of GST cannot explain the gap between human and rodents for induction of cholangiocarcioma following exposure to dichloropropane)

    Zhang Lingyi, Zong Cai, 市原 佐保子, 内藤 久雄, 豊國 伸哉, 熊谷 信二, 市原 学

    The Journal of Toxicological Sciences   Vol. 40 ( Suppl. ) page: S279 - S279   2015.6

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  172. プラズマ活性溶液:作用機序解明と臨床応用・産業化を目指して

    田中宏昌, 水野正明, 豊國伸哉, 丸山彰一, 小寺泰弘, 吉川史隆, 堀勝

    福岡医学雑誌   Vol. 106 ( 4 ) page: 71-76 - 76   2015.4

  173. 増加する悪性中皮腫診断のスキルアップを目指して 中皮細胞の機能と形態から診断のカギを探る アスベストによる中皮腫発生機構

    豊國 伸哉

    日本臨床細胞学会雑誌   Vol. 54 ( Suppl.1 ) page: 102 - 102   2015.4

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  174. 非平衡大気圧プラズマは酸化ストレスを生じる

    岡崎 泰昌, 王 越, 田中 宏昌, 水野 正明, 中村 香江, 梶山 広明, 加納 浩之, 吉川 史隆, 堀 勝, 豊國 伸哉

    日本病理学会会誌   Vol. 104 ( 1 ) page: 377 - 377   2015.3

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  175. 鉄ニトリロ三酢酸誘発腎発癌モデルにおける酸化的DNA損傷のゲノム内分布

    赤塚 慎也, 李 光華, 川口 真一, 豊國 伸哉

    日本病理学会会誌   Vol. 104 ( 1 ) page: 459 - 459   2015.3

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  176. 酸化ストレス病理学の確立とその疾患予防への展望

    豊國 伸哉

    日本病理学会会誌   Vol. 104 ( 1 ) page: 147 - 147   2015.3

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  177. 蛍光プローブを用いた全身の細胞における触媒性二価鉄の局在解析

    伊藤 文哉, 三澤 信明, 豊國 伸哉

    日本病理学会会誌   Vol. 104 ( 1 ) page: 376 - 376   2015.3

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  178. 悪性中皮腫におけるウロキナーゼ型プラスミノーゲンアクティベーターレセプターの発現(Increased expression of urokinase-type plasminogen activator receptor in malignant mesothelioma)

    王 申奇, 蒋 麗, 鈴木 浩二, 北川 崇, 豊國 伸哉

    日本病理学会会誌   Vol. 104 ( 1 ) page: 376 - 376   2015.3

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  179. タンパク質を吸着することはカーボンナノチューブの中皮細胞毒性を増強させる

    神田 容, 王 越, 豊國 伸哉

    日本病理学会会誌   Vol. 104 ( 1 ) page: 508 - 508   2015.3

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  180. 【鉄代謝制御機構と鉄過剰症】鉄過剰症による発がんの分子機構

    豊國 伸哉

    血液内科   Vol. 70 ( 3 ) page: 337 - 342   2015.3

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  181. Mutyh欠損マウスにおける鉄ニトリロ三酢酸誘発腎発がんの解析

    李 光華, 赤塚 慎也, 西山 誉大, 中別府 雄作, 豊國 伸哉

    日本病理学会会誌   Vol. 104 ( 1 ) page: 459 - 459   2015.3

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  182. Erdheim-Chester diseaseの1剖検例

    大原 悠紀, 加藤 省一, 山下 大祐, 豊國 伸哉, 中村 栄男

    日本病理学会会誌   Vol. 104 ( 1 ) page: 398 - 398   2015.3

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  183. Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells. Reviewed

    Satomi Funahashi, Yasumasa Okazaki, Daiki Ito, Atsushi Asakawa, Hirotaka Nagai, Masafumi Tajima, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 56 ( 2 ) page: 111 - 7   2015.3

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    Asbestos exposure is considered a social burden by causing mesothelioma. Despite the use of synthetic materials, multi-walled carbon nanotubes (MWCNTs) are similar in dimension to asbestos and produce mesothelioma in animals. The role of inflammatory cells in mesothelial carcinogenesis remains unclear. Here, we evaluated the differences in inflammatory cell responses following exposure to these fibrous materials using a luminometer and L-012 (8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H) dione) to detect reactive oxygen species (ROS). Rat peripheral blood or RAW264.7 cells were used to assess the effects on neutrophils and macrophages, respectively. Crocidolite and amosite induced significant ROS generation by neutrophils with a peak at 10 min, whereas that of chrysotile was similar to 25% of the crocidolite/amosite response. MWCNTs with different diameters (similar to 15, 50, 115 and 145 nm) and different carcinogenicity did not induce significant ROS in peripheral blood. However, the MWCNTs induced a comparable amount of ROS in RAW264.7 cells to that following asbestos treatment. The peaks for MWCNTs (0.5-1.5 h) were observed earlier than those for asbestos (1-5 h). Apocynin and superoxide dismutase significantly inhibited ROS generation for each fiber, suggesting an involvement of NADPH oxidase and superoxide. Thus, asbestos and MWCNTs induce different oxidative responses in inflammatory cells, indicating the importance of mesothelial cell evaluation for carcinogenesis.

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  184. Possible involvement of iron-induced oxidative insults in neurodegeneration. Reviewed International journal

    Takeshi Asano, Masato Koike, Shin-ichi Sakata, Yukiko Takeda, Tomoko Nakagawa, Taku Hatano, Satoshi Ohashi, Manabu Funayama, Kenji Yoshimi, Masato Asanuma, Shinya Toyokuni, Hideki Mochizuki, Yasuo Uchiyama, Nobutaka Hattori, Kazuhiro Iwai

    Neuroscience letters   Vol. 588   page: 29 - 35   2015.2

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    Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  185. MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES Reviewed

    Shinya Toyokuni, Li Jiang, Ryo Kitaura, Hisanori Shinohara

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 77 ( 1-2 ) page: 195 - 202   2015.2

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    Carbon nanotubes (CNTs) are a novel synthetic material comprising only carbon atoms. Based on its rigidity, its electrical and heat conductivity and its applicability to surface manufacturing, this material is expected to have numerous applications in industry. However, due to the material's dimensional similarity to asbestos fibers, its carcinogenicity was hypothesized during the last decade, and indeed, we have shown that multi- wall CNTs (MWCNTs) of 50 nm in diameter are potently carcinogenic to mesothelial cells after intraperitoneal injection. Additionally, we suggested that inflammogenicity after intraperitoneal injection can predict mesothelial carcinogenesis. However, few data have been published on the intraperitoneal inflammogenicity of single-wall CNTs (SWCNTs). Here, we conducted a series of studies on SWCNTs using both intraperitoneal injection into rats and MeT5A mesothelial cells. Intraperitoneal injection of 10 mg SWCNTs caused no remarkable inflammation in the abdominal cavity, and the exposure of MeT5A cells to up to 25 mu g/cm(2) SWCNTs did not alter proliferation. MWCNTs of 50 nm in diameter were used as a positive control, and tangled MWCNTs of 15 nm in diameter were used as a negative control. The results suggest that SWCNTs are a low- risk material with respect to mesothelial carcinogenesis.

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  186. Napsin A is a specific marker for ovarian clear cell adenocarcinoma. Reviewed

    Yamashita Y, Nagasaka T, Naiki-Ito A, Sato S, Suzuki S, Toyokuni S, Ito M, Takahashi S

    Mod Pathol   Vol. 28   page: 111-117   2015.1

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  187. Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders. Reviewed

    Yuka Hattori, Takahiro Mukaide, Li Jiang, Tomomi Kotani, Hiroyuki Tsuda, Yukio Mano, Seiji Sumigama, Tasuku Hirayama, Hideko Nagasawa, Fumitaka Kikkawa, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 56 ( 1 ) page: 57 - 63   2015.1

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    Amniotic fluid contains numerous biomolecules derived from fetus and mother, thus providing precious information on pregnancy. Here, we evaluated oxidative stress of human amniotic fluid and measured the concentration of catalytic Fe(II). Amniotic fluid samples were collected with consent from a total of 89 subjects in Nagoya University Hospital, under necessary medical interventions: normal pregnancy at term, normal pregnancy at the 2nd trimester, preterm delivery with maternal disorders but without fetal disorders, congenital diaphragmatic hernia, fetal growth restriction, pregnancy-induced hypertension, gestational diabetes mellitus, Down syndrome and trisomy 18. Catalytic Fe(II) and oxidative stress markers (8-hydroxy-2'-deoxyguanosine, 8-OHdG; dityrosine) were determined with RhoNox-1 and specific antibodies, respectively, using plate assays. Levels of 8-OHdG and dityrosine were higher in the 3rd trimester compared with the 2nd trimester in normal subjects, and the abnormal groups generally showed lower levels than the controls, thus suggesting that they represent fetal metabolic activities. In contrast, catalytic Fe(II) was higher in the 2nd trimester than the 3rd trimester in the normal subjects, and overall the abnormal groups showed higher levels than the controls, suggesting that high catalytic Fe(II) at late gestation reflects fetal pathologic alterations. Notably, products of H2O2 and catalytic Fe(II) remained almost constant in amniotic fluid.

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  188. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury Reviewed

    Y. Hattori, T. Kotani, H. Tsuda, Y. Mano, L. Tu, H. Li, S. Hirako, T. Ushida, K. Imai, T. Nakano, Y. Sato, R. Miki, S. Sumigama, A. Iwase, S. Toyokuni, F. Kikkawa

    FREE RADICAL RESEARCH   Vol. 49 ( 8 ) page: 1026 - 1037   2015

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    Maternal inflammation is associated with spontaneous preterm birth and respiratory impairment among premature infants. Recently, molecular hydrogen (H-2) has been reported to have a suppressive effect on oxidative stress and infl ammation. The aim of this study was to evaluate the effects of H-2 on fetal lung injury caused by maternal infl ammation. Cell viability and the production of interleukin-6 (IL-6) and reactive oxygen species (ROS) were examined by treatment with lipopolysaccharide (LPS) contained in ordinal or H-2-rich medium (HM) using a human lung epithelial cell line, A549. Pregnant Sprague Dawley rats were divided into three groups: Control, LPS, and HW + LPS groups. Rats were injected with phosphate-buffered saline (Control) or LPS intraperitoneally (LPS) on gestational day 19 and provided H-2 water (HW) ad libitum for 24 h before LPS injection (HW + LPS). Fetal lung samples were collected on day 20, and the levels of apoptosis, oxidative damage, IL-6, and vascular endothelial growth factor (VEGF) were evaluated using immunohistochemistry. The number of apoptotic cells, and levels of ROS and IL-6 were significantly increased by LPS treatment, and repressed following cultured with HM in A549 cells. In the rat models, the population positive for cleaved caspase-3, 8-hydroxy-2'-deoxyguanosine, IL-6, and VEGF was significantly increased in the LPS group compared with that observed in the Control group and significantly decreased in the HW + LPS group. In this study, LPS administration induced apoptosis and oxidative damage in fetal lung cells that was ameliorated by maternal H-2 intake. Antenatal H-2 administration may decrease the pulmonary mobility associated with infl ammation in premature infants.

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  189. A trial to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases. Reviewed International journal

    Lingyi Zhang, Cai Zong, Sahoko Ichihara, Hisao Naito, Shinya Toyokuni, Shinji Kumagai, Gaku Ichihara

    Journal of occupational health   Vol. 57 ( 6 ) page: 548 - 54   2015

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    OBJECTIVES: It has been reported that 1,2-Dichloropropane (DCP) induced cholangiocarcinoma (CCA) in offset color proof-printing workers. However, exposure to DCP by inhalation or gavage for 2 year did not induce CCA in mice and rats. The present study mapped the hepatic distribution of GST, which is known to activate dihalogenated alkanes, and proliferative and fibrotic changes in bile ducts in various species to find the most appropriate animal model of DCP-induced CCA. METHODS: First, 12 each of C57BL/6J mice, Balb/cA mice, F344 rats, Syrian hamsters, and guinea pigs were divided into four equal groups and exposed to DCP at 0, 300, 1,000, or 3,000 ppm 8 hours/day for 7 days. Second, 32 Balb/cA mice and 32 Syrian hamsters were each divided into four equal groups and exposed to DCP at 0, 200, 400, and 800 ppm 6 hours/day for 14 days. After the last exposure, the animals were decapitated, and the livers were dissected out for histopathological evaluation. Immunostaining was conducted to determine the distribution of GSTT1, GSTM1, and GSTPi, as well as the expression of proliferation marker Ki67. RESULTS: GSTT1, GSTM1, and GSTPi were expressed in both hepatocytes and bile duct cells in all control and exposed animals. There was no clear difference in the expression of Ki67 between the exposed groups and the control. No fibrotic changes were observed in any species or strains examined. CONCLUSIONS: Expression of GSTT1 or other GST isozymes might not explain the difference in sensitivity of hepatocytes and the bile duct to DCP between humans and rodents.

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  190. Plasma Medical Science for Cancer Therapy: Toward Cancer Therapy Using Nonthermal Atmospheric Pressure Plasma Reviewed

    Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Keigo Takeda, Kae Nakamura, Fumi Utsumi, Hiroaki Kajiyama, Hiroyuki Kano, Yasumasa Okazaki, Shinnya Toyokuni, Shoichi Maruyama, Fumitaka Kikkawa, Masaru Hori

    IEEE TRANSACTIONS ON PLASMA SCIENCE   Vol. 42 ( 12 ) page: 3760 - 3764   2014.12

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    We have been developing novel ultrahigh density atmospheric pressure plasma sources and succeeded in the selective killing ovarian cancer cells against normal ones. Furthermore, we have found out the plasma- activated medium (PAM) also killed glioblastoma brain tumor cells selectively against normal ones and the chemical products in the PAM have long lifetime healing effects. To clarify the mechanism, interactions of plasma with the organism and the medium where the organism belongs were investigated on the viewpoint of intracellular molecular mechanism.

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  191. Genome-wide Profiling of 8-Oxoguanine Reveals Its Association with Spatial Positioning in Nucleus Reviewed

    Minako Yoshihara, Li Jiang, Shinya Akatsuka, Mikita Suyama, Shinya Toyokuni

    DNA RESEARCH   Vol. 21 ( 6 ) page: 603 - 612   2014.12

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    8-Oxoguanine (8-oxoG) is one of the most common DNA lesions generated by reactive oxygen species. In this study, we analysed the genome-wide distribution profile of 8-oxoG by combining immunoprecipitation by antibodies specific for the DNA fragments containing 8-oxoG with a microarray that covers rat genome. Genome-wide mapping of 8-oxoG in normal rat kidney revealed that 8-oxoG is preferentially located at gene deserts. We did not observe differences in 8-oxoG levels between groups of genes with high and low expression, possibly because of the generally low 8-oxoG levels in genic regions compared with gene deserts. The distribution of 8-oxoG and lamina-associated domains (LADs) were strongly correlated, suggesting that the spatial location of genomic DNA in the nucleus determines the susceptibility to oxidative modifications. One possible explanation for high 8-oxoG levels in LADs is that the nuclear periphery is more susceptible to the oxidative damage caused by the extra-nuclear factors. Moreover, LADs have a rather compact conformation, which may limit the recruitment of repair components to the modified bases.

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  192. Direct exposure of non-equilibrium atmospheric pressure plasma confers simultaneous oxidative and ultraviolet modifications in biomolecules. Reviewed

    Yasumasa Okazaki, Yue Wang, Hiromasa Tanaka, Masaaki Mizuno, Kae Nakamura, Hiroaki Kajiyama, Hiroyuki Kano, Koji Uchida, Fumitaka Kikkawa, Masaru Hori, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 55 ( 3 ) page: 207 - 15   2014.11

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    Thermal plasmas and lasers are used in medicine to cut and ablate tissues and for coagulation. Non-equilibrium atmospheric pressure plasma (NEAPP) is a recently developed, non-thermal technique with possible biomedical applications. Although NEAPP reportedly generates reactive oxygen/nitrogen species, electrons, positive ions, and ultraviolet radiation, little research has been done into the use of this technique for conventional free radical biology. Recently, we developed a NEAPP device with high electron density. Electron spin resonance spin-trapping revealed (OH)-O-center dot as a major product. To obtain evidence of NEAPP-induced oxidative modifications in biomolecules and standardize them, we evaluated lipid peroxidation and DNA modifications in various in vitro and ex vivo experiments. Conjugated dienes increased after exposure to linoleic and a-linolenic acids. An increase in 2-thiobarbituric acid-reactive substances was also observed after exposure to phosphatidylcholine, liposomes or liver homogenate. Direct exposure to rat liver in saline produced immunohistochemical evidence of 4-hydroxy-2-nonenal- and acrolein-modified proteins. Exposure to plasmid DNA induced dose-dependent single/double strand breaks and increased the amounts of 8-hydroxy-2'-deoxyguanosine and cyclobutane pyrimidine dimers. These results indicate that oxidative biomolecular damage by NEAPP is dose-dependent and thus can be controlled in a site-specific manner. Simultaneous oxidative and UV-specific DNA damage may be useful in cancer treatment.

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  193. 非平衡大気圧プラズマは酸化ストレス傷害を起こす(Non-equilibrium atmospheric pressure plasma (NEAPP) generates oxidative injury)

    岡崎 泰昌, 王 越, 田中 宏昌, 水野 正明, 中村 香江, 梶山 広明, 加納 浩之, 内田 浩二, 吉川 史隆, 堀 勝, 豊國 伸哉

    日本癌学会総会記事   Vol. 73回   page: P - 1445   2014.9

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  194. 環境発がんのリスク評価における病理学の貢献 アスベストによる中皮腫発がん機構の解明からナノマテリアルのリスク評価へ

    豊國 伸哉

    日本病理学会会誌   Vol. 103 ( 2 ) page: 25 - 25   2014.9

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  195. 中皮細胞に発がん性があるカーボンナノチューブに特異的に吸着するタンパク質の同定(Identification of proteins specifically adsorbed on carcinogenic carbon nanotubes to mesothelial cells)

    王 越, 岡崎 泰昌, 永井 裕崇, 豊國 伸哉

    日本癌学会総会記事   Vol. 73回   page: P - 2010   2014.9

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  196. マウス腎発がん過程における酸化的DNA損傷のゲノム内分布(Genomic distribution of oxidative DNA damages at the initial process of mouse renal carcinogenesis)

    赤塚 慎也, 豊國 伸哉

    日本癌学会総会記事   Vol. 73回   page: P - 2009   2014.9

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  197. ラット中皮腫細胞において低温プラズマへの感受性は鉄の細胞内局在と関連する(Association of iron localization with sensitivity to non-thermal plasma in rat malignant mesothelioma cells)

    石 蕾, 蒋 麗, 王 越, 岡崎 泰昌, 豊國 伸哉

    日本癌学会総会記事   Vol. 73回   page: P - 3028   2014.9

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  198. ゲノム制御変異から見た環境発がん 中皮腫発がん機構解明とその予防への挑戦(Environmental carcinogenesis from the view of genomic change Elucidation of asbestos-induced carcinogenesis and its application to prevention)

    豊國 伸哉

    日本癌学会総会記事   Vol. 73回   page: S10 - 2   2014.9

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  199. Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model. Reviewed International journal

    T Mukaide, Y Hattori, N Misawa, S Funahashi, L Jiang, T Hirayama, H Nagasawa, S Toyokuni

    Free radical research   Vol. 48 ( 9 ) page: 990 - 5   2014.9

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    Iron overload of a chronic nature has been associated with a wide variety of human diseases, including infection, carcinogenesis, and atherosclerosis. Recently, a highly specific turn-on fluorescent probe (RhoNox-1) specific to labile ferrous iron [Fe(II)], but not to labile ferric iron [Fe(III)], was developed. The evaluation of Fe(II) is more important than Fe(III) in vivo in that Fe(II) is an initiating component of the Fenton reaction. In this study, we applied this probe to frozen sections of an established Fenton reaction-based rat renal carcinogenesis model with an iron chelate, ferric nitrilotriacetate (Fe-NTA), in which catalytic iron induces the Fenton reaction specifically in the renal proximal tubules, presumably after iron reduction. Notably, this probe reacted with Fe(II) but with neither Fe(II)-NTA, Fe(III) nor Fe(III)-NTA in vitro. Prominent red fluorescent color was explicitly observed in and around the lumina of renal proximal tubules 1 h after an intraperitoneal injection of 10-35 mg iron/kg Fe-NTA, which was dose-dependent, according to semiquantitative analysis. The RhoNox-1 signal colocalized with the generation of hydroxyl radicals, as detected by hydroxyphenyl fluorescein (HPF). The results demonstrate the transformation of Fe(III)-NTA to Fe(II) in vivo in the Fe-NTA-induced renal carcinogenesis model. Therefore, this probe would be useful for localizing catalytic Fe(II) in studies using tissues.

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  200. FREE FERROUS IRON IN AMNIOTIC FLUID AS A PREDICTIVE MARKER OF FETAL DISORDERS IN PREGNANCY

    Yuka Hattori, Tomomi Kotani, Tomoko Nakano, Yukio Mano, Seiji Sumigama, Hiroyuki Tsuda, Takafumi Usida, Hideko Nagasawa, Shinya Toyokuni, Fumitaka Kikkawa

    PLACENTA   Vol. 35 ( 9 ) page: A71 - A71   2014.9

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  201. Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. Reviewed International journal

    Li Jiang, Yoriko Yamashita, Shan-Hwu Chew, Shinya Akatsuka, Shun Ukai, Shenqi Wang, Hirotaka Nagai, Yasumasa Okazaki, Takashi Takahashi, Shinya Toyokuni

    The Journal of pathology   Vol. 233 ( 4 ) page: 402 - 14   2014.8

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    Due to the formerly widespread use of asbestos, malignant mesothelioma (MM) is increasingly frequent worldwide. MM is classified into epithelioid (EM), sarcomatoid (SM), and biphasic subtypes. SM is less common than EM but is recognized as the most aggressive type of MM, and these patients have a poor prognosis. To identify genes responsible for the aggressiveness of SM, we induced EM and SM in rats, using asbestos, and compared their transcriptomes. Based on the results, we focused on connective tissue growth factor (Ctgf), whose expression was significantly increased in SM compared with EM; EM itself exhibited an increased expression of Ctgf compared with normal mesothelium. Particularly in SM, Ctgf was a major regulator of MM proliferation and invasion through activation of the beta-catenin-TCF-LEF signalling pathway, which is autocrine and formed a positive feedback loop via LRP6 as a receptor for secreted Ctgf. High Ctgf expression also played a role in the epithelial-mesenchymal transition in MM. Furthermore, Ctgf is a novel serum biomarker for both early diagnosis and determining the MM prognosis in rats. These data link Ctgf to SM through the LRP6-GSK3 beta-beta-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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  202. Lack of presence of the human cytomegalovirus in human glioblastoma. Reviewed International journal

    Yoriko Yamashita, Yoshinori Ito, Hiroki Isomura, Naoaki Takemura, Akira Okamoto, Kazuya Motomura, Takashi Tsujiuchi, Atsushi Natsume, Toshihiko Wakabayashi, Shinya Toyokuni, Tatsuya Tsurumi

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   Vol. 27 ( 7 ) page: 922 - 9   2014.7

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    Recent reports have indicated human cytomegalovirus (HCMV) to be associated with human glioblastoma carcinogenesis. In established examples of viral carcinogenesis, viral DNA and one or more of its products have been detected in most tumor cells of biopsies in the majority of cases. To test whether HCMV is associated with human glioblastoma based on this criterion, we measured the number of viral DNA molecules per cell in both frozen and paraffin-embedded tumor biopsies from 58 patients using real-time quantitative PCR (QPCR). Immunohistochemical and fluorescence in situ hybridization (FISH) to detect HCMV proteins and genome was performed in 10 cases using formalin-fixed paraffin-embedded glioblastoma tissues. Southern blotting using DNA extracted from four glioblastoma cell lines together with immunoblotting using the four cell lines and five glioblastoma tissue samples were also performed. We further confirmed the immunoblot bands using liquid chromatography-tandem mass spectrometry assay. As a result, HCMV DNA was not detected in the tumor cells from any of the glioblastoma cases by QPCR detecting two different HCMV genes, in clear contrast to samples from patients with HCMV infection. Southern blotting and immunoblotting of cell lines and FISH using paraffin sections were all negative. However, immunoblotting and immunohistochemistry using tissue samples were partly positive, but HCMV proteins were not detected by proteomic analysis, suggesting false positivity of the analyses. As our QPCR analysis could detect 10 copies of HCMV DNA mixed with DNA extracted from 10(4) HCMV-negative cells, we conclude that HCMV is not persistent, at least in the tumor cells, of developed human glioblastoma.

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  203. 【職業・環境発がん:メカニズムと病理】繊維性ナノマテリアルの発がん機構

    豊國 伸哉

    病理と臨床   Vol. 32 ( 6 ) page: 632 - 637   2014.6

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  204. アスベスト問題 予防・診断・治療を科学する アスベスト発がんと過剰鉄 動物発がんから発症予防へ

    豊國 伸哉

    日本衛生学雑誌   Vol. 69 ( Suppl. ) page: S115 - S115   2014.5

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  205. Dexamethasone Palmitate Ameliorates Macrophages-Rich Graft-versus-Host Disease by Inhibiting Macrophage Functions Reviewed

    Satoshi Nishiwaki, Takayuki Nakayama, Makoto Murata, Tetsuya Nishida, Seitaro Terakura, Shigeki Saito, Tomonori Kato, Hiroki Mizuno, Nobuhiko Imahashi, Aika Seto, Yukiyasu Ozawa, Koichi Miyamura, Masafumi Ito, Kyosuke Takeshita, Hidefumi Kato, Shinya Toyokuni, Keisuke Nagao, Ryuzo Ueda, Tomoki Naoe

    PLOS ONE   Vol. 9 ( 5 ) page: e96252   2014.5

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    Macrophage infiltration of skin GVHD lesions correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear and GVHD with many macrophages is a therapeutic challenge. Here, we characterize the macrophages involved in GVHD and report that dexamethasone palmitate (DP), a liposteroid, can ameliorate such GVHD by inhibiting macrophage functions. We found that host-derived macrophages could exacerbate GVHD in a mouse model through expression of higher levels of pro-inflammatory TNF-alpha and IFN-gamma, and lower levels of anti-inflammatory IL-10 than resident macrophages in mice without GVHD. DP significantly decreased the viability and migration capacity of primary mouse macrophages compared to conventional dexamethasone in vitro. DP treatment on day 7 and day 14 decreased macrophage number, and attenuated GVHD score and subsequent mortality in a murine model. This is the first study to provide evidence that therapy for GVHD should be changed on the basis of infiltrating cell type.

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  206. Ovarian mucinous tumors arising from mature cystic teratomas--a molecular genetic approach for understanding the cellular origin. Reviewed International journal

    Kaho Fujii, Yoriko Yamashita, Toshimichi Yamamoto, Koji Takahashi, Katsunori Hashimoto, Tomoko Miyata, Kumi Kawai, Fumitaka Kikkawa, Shinya Toyokuni, Tetsuro Nagasaka

    Human pathology   Vol. 45 ( 4 ) page: 717 - 24   2014.4

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    Mucinous tumors of the ovary are frequently associated with mature cystic teratomas, and it has been speculated that the mucinous tumors arise from teratoma components. The cellular origins of mature cystic teratomas are believed to be post-meiotic ovarian germ cells, and the analysis of microsatellite markers such as short tandem repeats is suitable for determining the cellular origin of tumors. In this study, we analyzed 3 ovarian mature cystic teratomas, all of which were associated with simultaneous ovarian mucinous tumors within the same ovary. Two of the 3 mucinous tumors were intestinal-type and the other was endocervical type. A laser capture microdissection technique was used to separate the epithelial component of the mucinous tumor, the components of the mature cystic teratoma, and control ovarian somatic tissue. Using short tandem repeat analysis based on 6 markers (D20S480, D6S2439, D6S1056, D9S1118, D4S2639, and D17S1290), we could distinguish the germ cell (homozygous) or somatic (heterozygous) origin of a given component in each sample. The epithelial components of the intestinal-type mucinous tumors in cases 1 and 2 were homozygous, and the epithelial component in case 3 (endocervical type) was heterozygous. All teratomatous components were homozygous, and the control components were heterozygous. In addition, we analyzed 3 mature cystic teratomas without mucinous tumors, and all 3 were homozygous in the tumor component. Our data suggest that the origin of mucinous tumors in the ovary may differ among histological subtypes, and intestinal-type mucinous tumors may arise from mature cystic teratomas, although endocervical-type mucinous tumors may not. (C) 2014 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.humpath.2013.10.031

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  207. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion Reviewed

    Yukio Mano, Tomomi Kotani, Mikako Ito, Taku Nagai, Yuko Ichinohashi, Kiyofumi Yamada, Kinji Ohno, Fumitaka Kikkawa, Shinya Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 69   page: 324 - 330   2014.4

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    Molecular hydrogen (H-2) scavenges hydroxyl radicals. Recently, H-2 has been reported to prevent a variety of diseases associated with oxidative stress in model systems and in humans. Here, we studied the effects of H-2 on rat fetal hippocampal damage caused by ischemia and reperfusion (IR) on day 16 of pregnancy with the transient occlusion of the bilateral utero-ovarian arteries. Starting 2 days before the operation, we provided the mothers with hydrogen-saturated water ad libitum until vaginal delivery. We observed a significant increase in the concentration of H-2 in the placenta after the oral administration of hydrogen-saturated water to the mothers, with less placental oxidative damage after IR in the presence of H-2. Neonatal growth retardation was observed in the IR group, which was alleviated by the H-2 administration. We analyzed the neuronal cell damage in the CA1 and CA3 areas of the hippocampus at day 7 after birth by immunohistochemical analysis of the 8-oxo-7,8-dihydro-2 '-deoxyguanosine- and 4-hydroxy-2-nonenal-modified proteins. Both oxidative stress markers were significantly increased in the IR group, which was again ameliorated by the H-2 intake. Last, 8-week-old rats were subjected to a Morris water maze test. Maternal H-2 administration improved the reference memory of the offspring to the sham level after IR injury during pregnancy. Overall, the present results support the idea that maternal H-2 intake helps prevent the hippocampal impairment of offspring induced by IR during pregnancy. (C) 2014 Elsevier Inc. All rights reserved.

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  208. 腫瘍病理学の真髄 発がん要因としての酸化ストレス

    豊國 伸哉

    日本病理学会会誌   Vol. 103 ( 1 ) page: 159 - 159   2014.3

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  209. 私にとっての病理学の魅力と病理医・研究医の育成とリクルート委員会の取組み

    豊國 伸哉

    日本病理学会会誌   Vol. 103 ( 1 ) page: 141 - 141   2014.3

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  210. 卵巣粘液性腫瘍は成熟奇形種より発生する 分子遺伝学的アプローチによる組織起源の解明

    山下 依子, 藤井 佳穂, 高橋 智, 豊國 伸哉, 長坂 徹朗

    日本病理学会会誌   Vol. 103 ( 1 ) page: 214 - 214   2014.3

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  211. 分子病理診断に関する英論文の書き方

    豊國 伸哉

    日本病理学会会誌   Vol. 103 ( 1 ) page: 197 - 197   2014.3

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  212. 病理医の疫学 2013

    佐々木 毅, 伊藤 智雄, 宇於崎 宏, 大橋 健一, 小田 義直, 金井 弥栄, 豊国 伸哉, 豊澤 悟, 日本病理学会将来構想検討委員会

    日本病理学会会誌   Vol. 103 ( 1 ) page: 307 - 307   2014.3

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  213. 科学論文出版のしくみに関する最新事情

    豊國 伸哉

    病理と臨床   Vol. 32 ( 2 ) page: 202 - 204   2014.2

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  214. RAT MODEL DEMONSTRATES A HIGH RISK OF TREMOLITE BUT A LOW RISK OF ANTHOPHYLLITE FOR MESOTHELIAL CARCINOGENESIS Reviewed

    Dilinuer Aierken, Yasumasa Okazaki, Shan Hwu Chew, Akihiro Sakai, Yue Wang, Hirotaka Nagai, Nobuaki Misawa, Norihiko Kohyama, Shinya Toyokuni

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 76 ( 1-2 ) page: 149 - 160   2014.2

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    Asbestos was abundantly used in industry during the last century. Currently, asbestos confers a heavy social burden due to an increasing number of patients with malignant mesothelioma ( MM), which develops after a long incubation period. Many studies have been conducted on the effects of the asbestos types that were most commonly used for commercial applications. However, there are few studies describing the effects of the less common types, or minor asbestos. We performed a rat carcinogenesis study using Japanese tremolite and Afghan anthophyllite. Whereas more than 50% of tremolite fibers had a diameter of &lt; 500 nm, only a small fraction of anthophyllite fibers had a diameter of &lt; 500 nm. We intraperitoneally injected 1 or 10 mg of asbestos into F1 Fischer-344/Brown-Norway rats. In half of the animals, repeated intraperitoneal injections of nitrilotriacetate (NTA), an iron chelator to promote Fenton reaction, were performed to evaluate the potential involvement of iron overload. Tremolite induced MM with a high incidence (96% with 10 mg; 52% with 1 mg), and males were more susceptible than females. Histology was confirmed using immunohistochemistry, and most MMs were characterized as the sarcomatoid or biphasic subtype. Unexpectedly NTA showed an inhibitory effect in females. In contrast, anthophyllite induced no MM after an observation period of 550 days. The results suggest that the carcinogenicity of anthophyllite is weaker than formerly reported, whereas that of tremolite is as potent as major asbestos as compared with our previous data.

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  215. Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production. Reviewed International journal

    Shan Hwu Chew, Yasumasa Okazaki, Hirotaka Nagai, Nobuaki Misawa, Shinya Akatsuka, Kyoko Yamashita, Li Jiang, Yoriko Yamashita, Michio Noguchi, Kiminori Hosoda, Yoshitaka Sekido, Takashi Takahashi, Shinya Toyokuni

    Carcinogenesis   Vol. 35 ( 1 ) page: 164 - 72   2014.1

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    Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos-induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse transcriptionPCR revealed that adipocytes respond directly to asbestos exposure with an increased production of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y-MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.

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  216. 中皮細胞によるアスベスト取り込みに関わるタンパク質についての解析

    山下享子, 永井裕崇, 豊国伸哉

    臨床フリーラジカル会議   Vol. 31st   2014

  217. Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. Reviewed International journal

    Takashi Tsujiuchi, Atsushi Natsume, Kazuya Motomura, Goro Kondo, Melissa Ranjit, Rei Hachisu, Itsuro Sugimura, Shinpei Tomita, Isao Takehara, Max Woolley, Neil U Barua, Steven S Gill, Alison S Bienemann, Yoriko Yamashita, Shinya Toyokuni, Toshihiko Wakabayashi

    American journal of translational research   Vol. 6 ( 2 ) page: 169 - 78   2014

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    The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O-6-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O-6-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

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  218. Iron as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis. Reviewed

    Toyokuni, S

    Redox Rep.   Vol. 19   page: 1-7   2014

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    DOI: 10.1179/1351000213Y.0000000075.

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  219. 中皮細胞によるアスベスト取り込みに関わるタンパクについての解析

    山下享子, 永井裕崇, 豊国伸哉

    日本病理学会会誌   Vol. 103 ( 1 )   2014

  220. 【活性酸素-基礎から病態解明・制御まで】疾患病態・臨床編 炎症・酸化ストレスと発がん 鉄と炎症のあらたなリンク

    豊國 伸哉

    医学のあゆみ   Vol. 247 ( 9 ) page: 969 - 975   2013.11

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    がんは1981年以降日本人の死因の第1位を占めており、年齢調整死亡率はやや低下傾向にあるものの、死亡数は増加の一途をたどっている。こういう状況においては、がんの原因として万人に共通の基盤があると考えざるをえない。われわれは酸素なしで生きることはできず、それに伴って活性酸素が発生しており、また、その活性酸素を殺菌などにも利用している。こうした活性酸素のなかでもヒドロキシラジカルやその類縁化学種は反応性がきわめて高く、ゲノムの情報改変の原動力となる。感染性あるいは非感染性の炎症は酸化ストレスを増強する。また、体内過剰鉄はフェントン反応の触媒となるという意味から重要であり、しかも炎症と局所の鉄過剰はリンクすることがわかってきた。年2回の瀉血ががん予防となるという趣旨の論文報告もあり、この領域におけるさらなる研究発展が望まれる。(著者抄録)

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00060&link_issn=&doc_id=20131204010039&doc_link_id=%2Faa7ayuma%2F2013%2F024709%2F040%2F0969-0975%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2013%2F024709%2F040%2F0969-0975%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  221. 【最新肺癌学-基礎と臨床の最新研究動向-】肺癌の分子生物学と発癌機序 発癌の分子機序 アスベスト発がんの分子機序

    豊國 伸哉

    日本臨床   Vol. 71 ( 増刊6 最新肺癌学 ) page: 150 - 155   2013.11

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  222. Deferasirox induces mesenchymal-epithelial transition in crocidolite-induced mesothelial carcinogenesis in rats. Reviewed International journal

    Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Hiroyuki Yasui, Shinya Toyokuni

    Cancer prevention research (Philadelphia, Pa.)   Vol. 6 ( 11 ) page: 1222 - 30   2013.11

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    Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction.

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  223. 卵巣奇形腫に合併する粘液性腫瘍の遺伝学的解析(Ovarian Mucinous Tumors Arising from Mature Cystic Teratoma: A Molecular Genetic Approach)

    山下 依子, 藤井 佳穂, 梶山 広明, 吉川 史隆, 高橋 智, 豊國 伸哉, 長坂 徹朗

    日本癌学会総会記事   Vol. 72回   page: 390 - 390   2013.10

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  224. マウス腎発がん過程における酸化的DNA損傷のゲノム内分布(Genomic distribution of oxidative DNA damages at the initial process of mouse renal carcinogenesis)

    赤塚 慎也, 豊國 伸哉

    日本癌学会総会記事   Vol. 72回   page: 220 - 220   2013.10

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  225. ヒト口腔扁平上皮癌に関して、Lewis y抗原の発現と進行期における消失(Lewis y antigen is expressed in human oral squamous cell carcinomas, but disappears in the advanced stage)

    堀田 宏司, 浜村 和紀, 豊國 伸哉, 古川 圭子, 山本 憲幸, 服部 宇, 上田 実, 古川 鋼一

    日本癌学会総会記事   Vol. 72回   page: 352 - 352   2013.10

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  226. がん研究とモデル動物 モデル動物から明らかになった過剰鉄と発がんの親和性(Animal models in cancer research Affinity of iron overload with carcinogenesis: what we have learned from animal studies toward its prevention)

    豊國 伸哉

    日本癌学会総会記事   Vol. 72回   page: 53 - 53   2013.10

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  227. Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15 nm in diameter does not induce mesothelial carcinogenesis in rats. Reviewed International journal

    Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Yasumitsu Miyata, Hisanori Shinohara, Shinya Toyokuni

    Pathology international   Vol. 63 ( 9 ) page: 457 - 62   2013.9

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    Multiwalled carbon nanotubes (MWCNTs) have attracted public attention not only for their potential applications in engineering and materials science but also for possible environmental risks. MWCNTs share similar properties with asbestos, a definite human carcinogen causing malignant mesothelioma (MM), in that they are both biopersistent thin fibers with a high aspect ratio. Certain types of MWCNTs do induce MM in animal experiments. Though there are many different types of MWCNTs awaiting use in industry, there is little evidence about what types of MWCNTs present a high risk for MMin vivo. We have previously shown that the diameter of MWCNTs is one of the critical factors for mesothelial injury, which eventually leads to MM. Because of the extensive commercial use of MWCNTs, the properties of MWCNTs that determine carcinogenic activity should be clarified. Here we report that a high dose (10mg) of a tangled form of pristine MWCNT (with a diameter of 15nm) did not induce MM after intraperitoneal administration in rats, which were followed for up to 3 years after injection. This observation strengthens our previous finding that the rigidity, diameter, length and surface properties of MWCNTs are important factors in MM induction in vivo. © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

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  228. Lewis y antigen is expressed in oral squamous cell carcinoma cell lines and tissues, but disappears in the invasive regions leading to the enhanced malignant properties irrespective of sialyl-Lewis x. Reviewed International journal

    Hiroshi Hotta, Kazunori Hamamura, Kyoko Yamashita, Hidenobu Shibuya, Noriyo Tokuda, Noboru Hashimoto, Keiko Furukawa, Noriyuki Yamamoto, Hisashi Hattori, Shinya Toyokuni, Minoru Ueda, Koichi Furukawa

    Glycoconjugate journal   Vol. 30 ( 6 ) page: 585 - 97   2013.8

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    Expression and implication of carbohydrate antigens in squamous cell carcinomas (SCCs) in oral cavity was examined. In the cell lines, type 2H and Lewis y antigens were markedly expressed. In the tissues from SCC patients and benign disorders, type 2H was highly expressed in hyperplasia (96.4 %), displasia (92.9 %) and SCC (100 %). Lewis y was, in turn, expressed mainly in cancer tissues (91.3 %), suggesting that Lewis y is a cancer-associated antigen. Normal oral mucosa showed no expression of these blood group antigens. Surprisingly, Lewis y antigen disappeared in the invasion sites where Ki-67 was definitely stained. Over-expression of Lewis y with manipulation of a fucosyltransferase cDNA resulted in suppression of cell growth and invasion, and knockdown of Lewis y also brought about increased cell growth and invasion. In either situations, no changes in the expression of sialyl-Lewis x could be found. Lowered tumor growth and invasion into surrounding tissues were also shown in Lewis y-positive SCC grafts in nu/nu mice. All these results together with alternative staining between Lewis y and Ki-67 in cancer tissues and FUT1 transfectants suggested that loss of Lewis y is a crucial event for the late stage of SCCs.

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  229. CD146 and insulin-like growth factor 2 mRNA-binding protein 3 predict prognosis of asbestos-induced rat mesothelioma. Reviewed International journal

    Yasumasa Okazaki, Hirotaka Nagai, Shan H Chew, Jiang Li, Satomi Funahashi, Tohru Tsujimura, Shinya Toyokuni

    Cancer science   Vol. 104 ( 8 ) page: 989 - 95   2013.8

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    Malignant mesothelioma (MM), which is associated with asbestos exposure, is one of the most deadly tumors in humans. Early MM is concealed in the serosal cavities and lacks specific clinical symptoms. For better treatment, early detection and prognostic markers are necessary. Recently, CD146 and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) were reported as possible positive markers of MM to distinguish from reactive mesothelia in humans. However, their application on MM of different species and its impact on survival remain to be elucidated. To disclose the utility of these molecules as early detection and prognostic markers of MM, we injected chrysotile or crocidolite intraperitoneally to rats, thus obtaining 26 peritoneal MM and establishing 11 cell lines. We immunostained CD146 and IMP3 using paraffin-embedded tissues and cell blocks and found CD146 and IMP3 expression in 58% (15/26) and 65% (17/26) of MM, respectively, but not in reactive mesothelia. There was no significant difference in both immunostainings for overexpression among the three histological subtypes of MM and the expression of CD146 and IMP3 was proportionally associated. Furthermore, the overexpression of CD146 and/or IMP3 was proportionally correlated with shortened survival. These results suggest that CD146 and IMP3 are useful diagnostic and prognostic markers of MM.

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  230. Repeated short-term daily exercise ameliorates oxidative cerebral damage and the resultant motor dysfunction after transient ischemia in rats Reviewed

    Michiru Hamakawa, Akimasa Ishida, Keigo Tamakoshi, Haruka Shimada, Hiroki Nakashima, Taiji Noguchi, Shinya Toyokuni, Kazuto Ishida

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 53 ( 1 ) page: 8 - 14   2013.7

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    Long-term exercise prior to brain ischemia enhances the activities of antioxidant enzymes and leads to a significant reduction in brain damage and neurological deficits in rats subjected to transient middle cerebral artery occlusion. However, it has not been established whether relatively short-term exercise generates similar results following middle cerebral artery occlusion. We aimed to determine whether short-term exercise could reduce oxidative damage and prevent sensori-motor dysfunction. Male Wistar rats were subjected to perform daily exercise on a treadmill for 30 min at a speed of 15 m/min for 3 weeks, followed by a 90-mm middle cerebral artery occlusion. Animals were assessed after middle cerebral artery occlusion for neurological deficits and sensori-motor function. Brain tissues were processed to evaluate infarct volume and oxidative damage. Oxidative stress was assessed using immunohistochemistry for 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Antioxidant enzymes were evaluated using immunohistochemistry for thioredoxin and activity assay for superoxide dismutase. Exercise for 3 weeks decreased the severity of paralysis and impairment in forelimb motor coordination. Furthermore, exercise had effect on superoxide dismutase and reduced the infarct volume and the number of cells immunopositive for 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Our results suggest that pre-conditioning treadmill exercise for 3 weeks is useful for ameliorating ischemia-induced brain injury.

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  231. Evaluation of two distinct methods to quantify the uptake of crocidolite fibers by mesothelial cells. Reviewed

    Kyoko Yamashita, Hirotaka Nagai, Yuji Kondo, Nobuaki Misawa, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 53 ( 1 ) page: 27 - 35   2013.7

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    Exposure to asbestos fibers increases the risk of mesothelioma in humans. One hypothetical carcinogenic mechanism is that asbestos fibers may directly induce mutations in mesothelial cells. Although the uptake of asbestos fibers by mesothelial cells is recognized, methods for the quantification of the uptake have not been well established. In the present study, we evaluated two distinct methods, using crocidolite fibers and MeT5A mesothelial cells. One method is histological evaluation using the cell-block technique, which allows for the direct cross-sectional observation of cells and fibers. We found the bright field observation with x1000 magnification (oil-immersion) of the sample with Kernechtrot staining was most suitable for this purpose. The other method is flow cytometric analysis, which permits the evaluation of a much larger number of cells. We observed that the side scatter (SSC) increased with the intracellular fibers, and that the "mean SSC ratio (treated/control)" was useful for quantification. We could collect the cells with abundant internalized crocidolite fibers by sorting. Results of the two methodologies were correlated well in the experiments. The quantities of internalized fibers increased with incubation time and loaded dosage, but they were inversely associated with cellular density in culture.

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  232. ナノマテリアルの評価手法開発における今後の課題 ナノ材料(CNT)の物性と発がん性

    豊國 伸哉

    The Journal of Toxicological Sciences   Vol. 38 ( Suppl. ) page: S132 - S132   2013.6

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  233. Multispecificity of immunoglobulin M antibodies raised against advanced glycation end products: involvement of electronegative potential of antigens. Reviewed International journal

    Miho Chikazawa, Natsuki Otaki, Takahiro Shibata, Hiroaki Miyashita, Yoshichika Kawai, Shoichi Maruyama, Shinya Toyokuni, Yasuyuki Kitaura, Tsukasa Matsuda, Koji Uchida

    The Journal of biological chemistry   Vol. 288 ( 19 ) page: 13204 - 14   2013.5

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    BACKGROUND: Advanced glycation end products (AGEs) can act as neoantigens to trigger immune responses. RESULTS: Natural IgM antibodies against AGEs recognize multiple molecules, including DNA and chemically modified proteins. CONCLUSION: There is a close relationship between the formation of AGEs and innate immune responses. SIGNIFICANCE: Our findings highlight AGEs and related modified proteins as a source of multispecific natural antibodies Advanced glycation end products (AGEs) are a heterogeneous and complex group of compounds that are formed when reducing sugars, such as dehydroascorbic acid, react in a nonenzymatic way with amino acids in proteins and other macromolecules. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect the extracellular and intracellular structure and function. In the present study, we studied the immune response to the dehydroascorbic acid-derived AGEs and provide multiple lines of evidence suggesting that the AGEs could be an endogenous source of innate epitopes recognized by natural IgM antibodies. Prominent IgM titers to the AGEs were detected in the sera of normal mice and were significantly accelerated by the immunization with the AGEs. Patients with systemic lupus erythematosus (SLE), a potentially fatal systemic autoimmune disease characterized by the increased production of autoantibodies, showed significantly higher serum levels of the IgM titer against the AGEs than healthy individuals. A progressive increase in the IgM response against the AGEs was also observed in the SLE-prone mice. Strikingly, a subset of monoclonal antibodies, showing a specificity toward the AGEs, prepared from normal mice immunized with the AGEs and from the SLE mice cross-reacted with the double-stranded DNA. Moreover, they also cross-reacted with several other modified proteins, including the acetylated proteins, suggesting that the multiple specificity of the antibodies might be ascribed, at least in part, to the increased electronegative potential of the proteins. These findings suggest that the protein modification by the endogenous carbonyl compounds, generating electronegative proteins, could be a source of multispecific natural antibodies.

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  234. 脳梗塞発症前の運動による脳梗塞障害軽減効果及びその作用機序の検討 酸化ストレスに着目して

    野口 泰司, 濱川 みちる, 玉越 敬悟, 戸田 拓弥, 豊國 伸哉, 石田 和人

    理学療法学   Vol. 40 ( 大会特別号3 ) page: P - 183   2013.5

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  235. 細胞ストレス応答の破綻と病態 酸化ストレスによるゲノム変化と発がん

    豊國 伸哉, 蒋 麗, 岡崎 泰昌, 山下 依子, 赤塚 慎也

    日本病理学会会誌   Vol. 102 ( 1 ) page: 177 - 177   2013.4

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  236. 悪性中皮腫におけるuPARの発現とその影響、および治療標的としての可能性の検討

    鈴木 浩二, 蒋 麗, 豊國 伸哉

    日本病理学会会誌   Vol. 102 ( 1 ) page: 497 - 497   2013.4

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  237. 卵巣明細胞腺癌におけるポリコーム蛋白CBX7の役割の解析

    山下 依子, 新城 加奈子, 赤塚 慎也, 豊國 伸哉

    日本病理学会会誌   Vol. 102 ( 1 ) page: 295 - 295   2013.4

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  238. Desferalの中皮腫発生に対する効果の検討

    中村 公亮, 蒋 麗, 豊國 伸哉

    日本病理学会会誌   Vol. 102 ( 1 ) page: 501 - 501   2013.4

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  239. CTGFはアスベスト誘導性悪性中皮腫において過剰発現しβ-カテニンシグナル伝達を増強する(CTGF is overexpression in asbestos-induced malignant mesothelioma and promotes β-catenin signaling)

    蒋 麗, 山下 依子, 周 珊瑚, 赤塚 慎也, 岡崎 泰昌, 豊國 伸哉

    日本病理学会会誌   Vol. 102 ( 1 ) page: 420 - 420   2013.4

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  240. Met Is the Most Frequently Amplified Gene in Endometriosis-Associated Ovarian Clear Cell Adenocarcinoma and Correlates with Worsened Prognosis Reviewed

    Yoriko Yamashita, Shinya Akatsuka, Kanako Shinjo, Yasushi Yatabe, Hiroharu Kobayashi, Hiroshi Seko, Hiroaki Kajiyama, Fumitaka Kikkawa, Takashi Takahashi, Shinya Toyokuni

    PLoS ONE   Vol. 8 ( 3 ) page: e57724   2013.3

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    Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR
    37.0% demonstrated Met gene amplification (&gt
    4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p&lt
    0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC. © 2013 Yamashita et al.

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  241. Protective effect of cardioplegia with poly (ADP-ribose) polymerase-1 inhibitor against myocardial ischemia-reperfusion injury: in vitro study of isolated rat heart model. Reviewed International journal

    Kazuhiro Yamazaki, Seigo Tanaka, Ryuzo Sakata, Senri Miwa, Wnimonk Oriyanhan, Kiyoaki Takaba, Kenji Minakata, Akira Marui, Tadashi Ikeda, Shinya Toyokuni, Masashi Komeda, Kunihiro Ueda

    Journal of enzyme inhibition and medicinal chemistry   Vol. 28 ( 1 ) page: 143 - 7   2013.2

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    Poly(ADP-ribose) polymerase (PARP)-1 inhibitor has been suggested to attenuate the ischemia-reperfusion injury. We investigated the protective effect of the cardioplegia with a PARP-1 inhibitor, 4-hydoxyquinazoline (4-HQ), against myocardial ischemia-reperfusion injury. Isolated rat hearts were perfused on a Langendorff apparatus and cardioplegically arrested for 90 min by perfusion with St. Thomas' Hospital solution (ST-solution). In the Group ST (n = 8), the hearts were arrested with the ST-solution alone. The Group HQ (n = 8) were treated with the ST-solution containing 4-HQ (10 mu M) for cardioplegia. During reperfusion, the Group HQ showed significantly greater functional recovery of +dp/dt(max) (p = 0.005) and lower enzymatic leakage (p &lt; 0.01). NAD(+) levels were also preserved higher in the Group HQ (p &lt; 0.01). Immunohistochemical study revealed lesser extents of oxidative stress and apoptosis, in the Group HQ. Thus, addition of 4-HQ in the cardioplegia may provide a new intervention for myocardial protection against ischemia-reperfusion injury by decreasing NAD+ consumption and suppressing oxidative stress.

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  242. Metamorphosis of mesothelial cells with active horizontal motility in tissue culture. Reviewed International journal

    Hirotaka Nagai, Shan Hwu Chew, Yasumasa Okazaki, Satomi Funahashi, Takashi Namba, Takuya Kato, Atsushi Enomoto, Li Jiang, Shinya Akatsuka, Shinya Toyokuni

    Scientific reports   Vol. 3   page: 1144 - 1144   2013.1

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    Mesothelial cells, which have diverse roles in physiology and pathology, constitute the mesothelium along with connective tissue and the basement membrane; the mesothelium serves to shield the somatic cavities. After mesothelial injury, mesothelial cells undergo tissue recovery. However, the mechanism of mesothelial regeneration remains poorly understood. In this study, we used confocal time-lapse microscopy to demonstrate that transformed mesothelial cells (MeT5A) and mouse peritoneal mesothelial cells can randomly migrate between cells in cell culture and in ex vivo tissue culture, respectively. Moreover, peritoneal mesothelial cells changed their morphology from a flattened shape to a cuboidal one prior to the migration. Conversely, MDCKII epithelial cells forming tight cell-cell contacts with one another do not alter the arrangement of adjacent cells during movement. Our evidence complements the current hypotheses of mesothelial regeneration and suggests that certain types of differentiated mesothelial cells undergo morphological changes before initiating migration to repair injured sites.

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  243. がんモデルマウス・ラットライブラリ(第7回)中皮腫モデル

    豊國 伸哉, 蒋 麗

    細胞工学   Vol. 32 ( 2 ) page: 220 - 224   2013

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    Other Link: http://search.jamas.or.jp/link/ui/2013120513

  244. グリケーションタンパク質(AGEs)を認識する自然抗体に関する研究

    近澤未歩, 宮下宙士, 大瀧菜月, 柴田貴広, 河合慶親, 丸山彰一, 豊國伸哉, 松田幹, 内田浩二

    日本農芸化学会大会講演要旨集(Web)   Vol. 2013   2013

  245. 中皮細胞によるクロシドライト取り込みの定量的評価

    山下享子, 永井裕崇, 豊国伸哉

    日本病理学会会誌   Vol. 102 ( 1 )   2013

  246. 過剰鉄と発がんの親和性

    豊國 伸哉

    病理と臨床   Vol. 30 ( 12 ) page: 1396 - 1398   2012.12

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  247. 最終糖化産物(AGEs)を認識する多重交差性抗体

    近澤 未歩, 宮下 宙士, 大瀧 菜月, 柴田 貴広, 河合 慶親, 丸山 彰一, 豊國 伸哉, 松田 幹, 内田 浩二

    日本生化学会大会プログラム・講演要旨集   Vol. 85回   page: 2P - 896   2012.12

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  248. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes Reviewed

    T. Mizuno, H. Murakami, M. Fujii, F. Ishiguro, I. Tanaka, Y. Kondo, S. Akatsuka, S. Toyokuni, K. Yokoi, H. Osada, Y. Sekido

    ONCOGENE   Vol. 31 ( 49 ) page: 5117 - 5122   2012.12

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    Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 (NF2) -tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2, LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro. We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1, in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells. Oncogene (2012) 31, 5117-5122; doi:10.1038/onc.2012.5; published online 30 January 2012

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  249. The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma Reviewed

    Momen Elshazley, Mitsuo Sato, Tetsunari Hase, Ryo Yamashita, Kenya Yoshida, Shinya Toyokuni, Futoshi Ishiguro, Hirotaka Osada, Yoshitaka Sekido, Kohei Yokoi, Noriyasu Usami, David S. Shames, Masashi Kondo, Adi F. Gazdar, John D. Minna, Yoshinori Hasegawa

    INTERNATIONAL JOURNAL OF CANCER   Vol. 131 ( 12 ) page: 2820 - 2831   2012.12

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    Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21(WAF1/CIP1) and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.

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  250. 【活性酸素・ガス状分子による恒常性制御と疾患 酸化ストレス応答と低酸素センシングの最新知見からがん、免疫、代謝・呼吸・循環異常、神経変性との関わりまで】(第3章)酸化ストレス・低酸素応答と制御破綻 発がん、がん進展と酸化ストレス・低酸素応答 酸化ストレスによるゲノム変化と発がん

    赤塚 慎也, 豊國 伸哉

    実験医学   Vol. 30 ( 17 ) page: 2779 - 2785   2012.11

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    慢性的な酸化ストレス状態による生体分子への酸化的な損傷の蓄積が、発がんを誘発する一因と考えられている。発がんの原因として重要となるのは、特にゲノムDNAに対する傷害である。われわれが確立した酸化ストレス誘発発がんモデルである鉄ニトリロ三酢酸誘発腎がんでは、Cdkn2aがん抑制遺伝子が主要な標的遺伝子であることがLOH解析により判明した。アレイCGHを用いてゲノム網羅的に染色体コピー数変化を解析することにより、酸化ストレスによる発がん促進の様式がさらに詳細に理解された。(著者抄録)

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  251. Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. Invited Reviewed

    Yurika Kubo, Hiroyuki Takenaka, Hirotaka Nagai, Shinya Toyokuni

    Journal of clinical biochemistry and nutrition   Vol. 51 ( 3 ) page: 221 - 6   2012.11

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    The inhalation of asbestos is a risk factor for the development of malignant mesothelioma and lung cancer. Based on the broad surface area of asbestos fibers and their ability to enter the cytoplasm and nuclei of cells, it was hypothesized that proteins that adsorb onto the fiber surface play a role in the cytotoxicity and carcinogenesis of asbestos fibers. However, little is known about which proteins adsorb onto asbestos. Previously, we systematically identified asbestos-interacting proteins and classified them into eight sub-categories: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. Here, we report an adsorption profile of proteins for the three commercially used asbestos compounds: chrysotile, crocidolite and amosite. We quantified the amounts of adsorbed proteins by analyzing the silver-stained gels of sodium dodecyl sulfate-polyacrylamide gel electrophoresis with ImageJ software, using the bands for amosite as a standard. We found that histones were most adsorptive to crocidolite and that chromatin-binding proteins were most adsorptive to chrysotile. The results suggest that chrysotile and crocidolite directly interact with chromatin structure through different mechanisms. Furthermore, RNA-binding proteins preferably interacted with chrysotile, suggesting that chrysotile may interfere with transcription and translation. Our results provide novel evidence demonstrating that the specific molecular interactions leading to carcinogenesis are different between chrysotile and crocidolite.

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  252. 【がんと代謝 何故がん細胞が好んで解糖系を使うのか?メタボローム解析が明かすがん細胞の本質から代謝研究がもたらす創薬・診断まで】(第3章)低酸素、酸化ストレス 発がんの隠れた主役鉄代謝

    豊國 伸哉

    実験医学   Vol. 30 ( 15 ) page: 2448 - 2454   2012.9

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    ヒトは進化の過程で、酸素を利用することを学び、その運搬ベクターとして鉄を採用した。しかし、鉄は両刃の剣であり、過剰になると活性酸素発生の触媒作用を発揮することにより発がんのリスクを上げる。この病態の明らかなヒトの疾患には、遺伝性ヘモクロマトーシス、B型・C型ウイルス性肝炎、アスベスト曝露、子宮内膜症がある。動物モデルの精緻な検討により、鉄を介したゲノム傷害はランダムではなく、また鉄誘発発がんには標的となる遺伝子が存在することがわかってきた。ヒトで定期的除鉄を行うとがん発生が抑制されるという報告もあり、発がんに関した鉄代謝研究はホットになってきている。(著者抄録)

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  253. Bovine lactoferrin ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats Reviewed

    Yasumasa Okazaki, Isato Kono, Takayoshi Kuriki, Satomi Funahashi, Soichiro Fushimi, Mohammad Iqbal, Shigeru Okada, Shinya Toyokuni

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 51 ( 2 ) page: 84 - 90   2012.9

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    Milk provides a well-balanced source of amino acids and other ingredients. One of the functional ingredients in milk is lactoferrin (LF). LF presents a wide variety of bioactivities and functions as a radical scavenger in models using iron-ascorbate complexes and asbestos. Human clinical trials of oral LF administration for the prevention of colon polyps have been successful and demonstrated that dietary compounds exhibit direct interactions. However, antioxidative properties of IF in distant organs require further investigation. To study the antioxidant property of LF, we employed bovine lactoferrin (bLF) using the rat model of ferric nitrilotriacetate (Fe-NTA)-induced renal tubular oxidative injury. We fed rats with bLF (0.05%, w/w) in basal chow for 4 weeks and sacrificed them after Fe-NTA treatment. After intraperitoneal administration of 9.0 mg iron/kg Fe-NTA for 4 and 24 h, bLF pretreatment suppressed elevation of serum creatinine and blood urea nitrogen levels. In addition, we observed protective effects against renal oxidative tubular damage and maintenance of antioxidant enzyme activities in the bLF-pretreated group. We thus demonstrated the antioxidative effect of bLF against Fe-NTA-induced renal oxidative injury. These results suggest that LF intake is useful for the prevention of renal tubular oxidative damage mediated by iron.

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  254. Iron overload signature in chrysotile-induced malignant mesothelioma. Reviewed

    Jiang L, Akatsuka S, Nagai H, Chew SH, Ohara H, Okazaki Y, Yamashita Y, Yoshikawa Y, Yasui H, Ikuta K, Sasaki K, Kohgo Y, Hirano S, Shinohara Y, Kohyama N, Takahashi T, Toyokuni S

    J Pathol   Vol. 228   page: 366-377   2012.8

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  255. 脂肪細胞はアディポサイトカインの異常調節でアスベスト暴露に誘導される炎症反応に関与する(Adipocytes contribute to inflammatory response induced by asbestos exposure through dysregulated adipocytokines)

    周 珊瑚, 岡崎 泰昌, 永井 裕崇, 赤塚 慎也, 山下 依子, 蒋 麗, 高橋 隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 71回   page: 198 - 198   2012.8

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  256. 発がん過程における鉄の役割(Role of iron in carcinogenesis)

    豊國 伸哉

    日本癌学会総会記事   Vol. 71回   page: 58 - 58   2012.8

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  257. 卵巣明細胞腺癌においてCBX7の発現は予後不良因子である(Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma(OCCA))

    新城 加奈子, 山下 依子, 豊國 伸哉, 吉川 史隆

    日本癌学会総会記事   Vol. 71回   page: 513 - 513   2012.8

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  258. マウス腎発がん過程における酸化的DNA損傷のゲノム内分布(Intragenomic distribution of oxidative DNA damages at the initial process of mouse renal carcinogenesis)

    赤塚 慎也, 豊國 伸哉

    日本癌学会総会記事   Vol. 71回   page: 192 - 192   2012.8

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  259. アスベストによる悪性中皮腫においてはCTGFの増幅と高発現によりbeta-catenin-T-cell factor/Lef経路が活性化される(CTGF is overexpressed in asbestos-induced malignant mesothelioma and promotes beta-catenin-T-cell factor/Lefsignaling)

    蒋 麗, 赤塚 慎也, 山下 依子, 周 珊瑚, 豊國 伸哉

    日本癌学会総会記事   Vol. 71回   page: 206 - 206   2012.8

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  260. The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis Reviewed

    Hiroharu Kobayashi, Yoriko Yamashita, Akira Iwase, Yutaka Yoshikawa, Hiroyuki Yasui, Yoshichika Kawai, Koji Uchida, Nozomi Uno, Shinya Akatsuka, Takashi Takahashi, Fumitaka Kikkawa, Shinya Toyokuni

    FERTILITY AND STERILITY   Vol. 98 ( 2 ) page: 415 - +   2012.8

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    Objective: To understand the role of ectopic endometriotic stromal cells in ovarian endometriosis (OEM) and the associated risks for infertility and carcinogenesis.
    Design: Analyses of secreted proteins and gene expression using immortalized eutopic/ectopic endometrial(-otic) stromal cells from OEM.
    Setting: University.
    Patient(s): Women with and without OEM.
    Intervention(s): Samples of endometrial(-otic) tissue from women with or without OEM.
    Main Outcome Measure(s): Immunohistochemical analysis of oxidative stress in OEM, gene expression profiles, and the identification of secreted proteins by mass spectrometry in immortalized endometrial(-otic) stromal cells.
    Result(s): 4-Hydroxy-2-nonenal-modified proteins and carboxymethyllysine were abundant in the stroma, rather than epithelia, of OEM patients, indicating the presence of oxidative stress. Immortalized ectopic endometriotic stromal cells exhibited high IRP1/IRP2/HIF-1 beta expression and contained lower amounts of iron and copper than their eutopic counterparts. Expression profiles, in combination with protein identification, revealed that complement component 3 (C3) and pentraxin-3 (PTX3) are the major proteins secreted from immortalized ectopic endometriotic stromal cells. Complement-3/PTX3 promoted the secretion of various cytokines by THP1 macrophage cells and thus supported M1 differentiation.
    Conclusion(s): Immortalized ectopic endometriotic stromal cells in OEM predominantly secrete C3 and PTX3 and exhibit a differential regulation of iron metabolism. (Fertil Steril (R) 2012;98:415-22. (C) 2012 by American Society for Reproductive Medicine.)

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  261. Mitochondria and free radical studies on health, disease and pollution Invited

    Hideyuki J. Majima, Shinya Toyokuni

    FREE RADICAL RESEARCH   Vol. 46 ( 8 ) page: 925 - 926   2012.8

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    DOI: 10.3109/10715762.2012.700784

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  262. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer. Reviewed International journal

    Shinya Akatsuka, Yoriko Yamashita, Hiroki Ohara, Yu-Ting Liu, Masashi Izumiya, Koichiro Abe, Masako Ochiai, Li Jiang, Hirotaka Nagai, Yasumasa Okazaki, Hideki Murakami, Yoshitaka Sekido, Eri Arai, Yae Kanai, Okio Hino, Takashi Takahashi, Hitoshi Nakagama, Shinya Toyokuni

    PloS one   Vol. 7 ( 8 ) page: e43403   2012.8

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    Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

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  263. DAPはDMT1(IRE)の発現制御を介して、細胞増殖を調節する(AP (DMT1 Associated Protein) regulates cell proliferation through the regulation of DMT1 (IRE))

    岡崎 泰昌, 永井 裕崇, 舟橋 諭美, 周 珊瑚, 葉 淑彬, 葉 國義, Glass Jonathan, 豊國 伸哉

    日本癌学会総会記事   Vol. 71回   page: 308 - 308   2012.8

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  264. Transient but Not Stable ZEB1 Knockdown Dramatically Inhibits Growth of Malignant Pleural Mesothelioma Cells Reviewed

    Mihoko Horio, Mitsuo Sato, Yoshihiro Takeyama, Momen Elshazley, Ryo Yamashita, Tetsunari Hase, Kenya Yoshida, Noriyasu Usami, Kohei Yokoi, Yoshitaka Sekido, Masashi Kondo, Shinya Toyokuni, Adi F. Gazdar, John D. Minna, Yoshinori Hasegawa

    ANNALS OF SURGICAL ONCOLOGY   Vol. 19 ( Suppl 3 ) page: S634 - S645   2012.7

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    Background. The role of ZEB1, a master epithelial-to-mesenchymal transition gene, in malignant pleural mesothelioma (MPM) is unclear.
    Methods. The expression of ZEB1, E-cadherin, vimentin, and epithelial cell adhesion molecule (EpCAM) in 18 MPM cell lines and a normal pleural mesothelial cell line MeT-5A was determined by quantitative real-time polymerase chain reaction and Western blot testing. RNA interference-mediated transient and/or stable knockdown of ZEB1 and EpCAM was performed. Microarray expression analysis was performed with a TORAY-3D gene chip. Growth was evaluated by colorimetric proliferation and colony formation assays. Luciferase reporter assay was performed to access the effects of ZEB1 knockdown on EpCAM promoter activity.
    Results. Most MPM cell lines exhibited mesenchymal phenotype and expressed ZEB1. Transient ZEB1 knockdown suppressed growth in all four cell lines studied (ACC-MESO-1, H2052, Y-MESO-8A, Y-MESO-29) while stable ZEB1 knockdown suppressed growth only in Y-MESO-29. Genome-wide gene expression analysis revealed that EpCAM was the most prominently up-regulated gene by both transient and stable ZEB1 knockdown in ACC-MESO-1, with more marked up-regulation in stable knockdown. We hypothesized that EpCAM up-regulation counteracts the stable ZEB1 knockdown-induced growth inhibition in ACC-MESO-1. Transient EpCAM knockdown suppressed growth dramatically in ACC-MESO-1 cells expressing shZEB1 but only modestly in those expressing shGFP, supporting our hypothesis. Luciferase reporter assay showed that ZEB1 knockdown resulted in increased EpCAM promoter activity. EpCAM was also up-regulated in Y-MESO-29 expressing shZEB1, but this EpCAM up-regulation did not counteract ZEB1knockdown-induced growth suppression, suggesting that the counteracting effects of EpCAM may be cellular context dependent.
    Conclusions. RNA interference-mediated ZEB1 knockdown may be a promising therapeutic strategy for MPM, but one has to consider the possibility of diminished growth inhibitory effects of long-term ZEB1 knockdown, possibly as a result of EpCAM up-regulation and/or other gene expression changes resulting from ZEB1 knockdown.

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  265. 鉄代謝と発がん(基礎)

    豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 23 ( 2 ) page: 102 - 102   2012.6

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  266. 【酸化ストレス】酸化ストレスと癌 発癌のメカニズムと癌の進展への関与

    山下 依子, 豊國 伸哉

    HORMONE FRONTIER IN GYNECOLOGY   Vol. 19 ( 2 ) page: 137 - 141   2012.6

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    生体には、エネルギー産生のために必要な酸化システムとその過剰による悪影響を防ぐための抗酸化システムが備わっており、その恒常性が保たれていることが健康の維持に必要である。酸化と抗酸化のバランスが崩れて酸化が過剰になった状態を酸化ストレスと呼ぶ。酸化ストレスはDNAを直接傷害することによって癌の原因となる。過剰鉄による活性酸素種(ROS)の発生による発癌はその代表例である。最近では酸化ストレスの発生に関与する分子の異常が発癌のみならず癌の浸潤や転移など、癌の進展にも深く関わっていることが明らかとなりつつある。今後は癌の予防・治療への応用が期待されるところである。(著者抄録)

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  267. In Vitro Transformation of Mouse Testis Cells by Oncogene Transfection Reviewed

    Hiroko Morimoto, Jiyoung Lee, Takashi Tanaka, Kei Ishii, Shinya Toyokuni, Mito Kanatsu-Shinohara, Takashi Shinohara

    BIOLOGY OF REPRODUCTION   Vol. 86 ( 5 ) page: 1-11   2012.5

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    Germ cell tumors (GCTs) are unique in that they exhibit diverse biological characteristics and pathological features. Although several in vivo GCT models are available, studies on GCTs are hampered because in vivo development of GCTs is time consuming and prevents a detailed molecular analysis of the transformation process. Here we developed a novel strategy to transform mouse testis cells in vitro. Lentivirus-mediated transfection of dominant negative Trp53, Myc, and activated Hras1 into a CD9-expressing testis cells caused tumorigenic conversion in vitro. Although these cells resembled embryonic stem (ES) cells, they were aneuploid and lacked Nanog expression, which is involved in the maintenance of the undifferentiated state in ES cells. Euploid ES-like cells were produced by transfecting the Yamanaka factors (Pou5f1, Myc, Klf4, and Sox2) into the same cell population. Although these cells expressed Nanog, they were distinct from ES cells in that they expressed CD44, a cancer stem cell antigen. Both treatments induced similar changes in the DNA methylation patterns in differentially methylated regions of imprinted genes. Moreover, despite the differences in their phenotype and karyotype, both cell types similarly produced mixed GCTs on transplantation, which were composed of teratomas, seminomas, and embryonal carcinomas. Thus, in vitro testis cell transformation facilitates an analysis of the GCT formation process, and our results also suggest the close similarity between GCT formation and reprogramming.

    DOI: 10.1095/biolreprod.111.095307

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  268. Genome-wide assessment of oxidatively generated DNA damage Reviewed

    Shinya Akatsuka, Shinya Toyokuni

    FREE RADICAL RESEARCH   Vol. 46 ( 4 ) page: 523 - 530   2012.4

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    In the tide of science nouveau after the completion of genome projects of various species, there appeared a movement to understand an organism as a system rather than the sum of cells directed for certain functions. With the advent and spread of microarray techniques, systematic and comprehensive genome-wide approaches have become reasonably possible and more required on the investigation of DNA damage and the subsequent repair. The immunoprecipitation-based technique combined with high-density microarrays or next-generation sequencing is one of the promising methods to provide access to such novel research strategies. Oxygen is necessary for most of the life on earth for electron transport. However, reactive oxygen species are inevitably generated, giving rise to steady-state levels of DNA damage in the genome, that may cause mutations leading to cancer, ageing and degenerative diseases. Previously, we showed that there are many factors involved in the genomic distribution of oxidatively generated DNA damage including chromosome territory, and proposed this sort of research area as oxygenomics. Recently, RNA is also recognized as a target of this kind of modification.

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  269. Age- and sun exposure-dependent differences in 8-hydroxy-2 '-deoxyguanosine and N epsilon-(carboxymethyl)lysine in human epidermis

    Akira Kawada, Akira Date, Shinya Toyokuni

    JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY   Vol. 66 ( 4 ) page: AB174 - AB174   2012.4

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  270. 鉄化合物誘発ラット腹膜中皮腫において、高悪性度を特徴づけるmicroRNAの発現 機能解析への取組み

    酒井 晃太, 岡崎 泰昌, 永井 裕崇, 胡 茜, 赤塚 慎也, 山下 享子, 山下 依子, 蒋 麗, 舟橋 諭美, 周 珊瑚, 高橋 隆, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 435 - 435   2012.3

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  271. 腎尿細管細胞に対するlipocalin-2シグナルの作用

    岩井 貴寛, 赤塚 慎也, 山下 依子, 岡崎 泰昌, 森 潔, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 435 - 435   2012.3

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  272. 統括病理学の現状と展望 酸化ストレス・DNA傷害と発がんにおける統括病理学

    豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 191 - 191   2012.3

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  273. 卵巣明細胞性腺癌におけるnon-cooding RNA 'ANRIL'の発現の検討

    山下 依子, 新城 加奈子, 宇野 希望, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 419 - 419   2012.3

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  274. マウス腎発がん過程における酸化的DNA損傷のゲノム内分布

    赤塚 慎也, 山下 依子, 岡崎 泰昌, 蒋 麗, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 335 - 335   2012.3

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  275. グリオブラストーマとCMVの関係の検討

    竹村 直晃, 山下 依子, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 437 - 437   2012.3

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  276. がん研究における疾患モデル動物とその有用性 アスベスト発がんモデルを用いた発症機構の解明と予防への応用

    豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 203 - 203   2012.3

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  277. アスベスト誘発ラット悪性中皮腫の悪性度にctgf(connective tissue growth factor)が及ぼす影響について

    鵜飼 俊, 蒋 麗, 周 珊瑚, 赤塚 慎也, 山下 依子, 永井 裕崇, 岡崎 泰昌, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 440 - 440   2012.3

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  278. アスベスト誘発性中皮腫においてctgfの上方制御はβ-カテニン経路と関連する(Up-regulated ctgf is associated with beta-catenin pathway in asbestos-induced mesothelioma)

    蒋 麗, 山下 依子, 赤塚 慎也, 周 珊瑚, 永井 裕崇, 鵜飼 俊, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 397 - 397   2012.3

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  279. DMT1(divalent metal transporter 1)を介した鉄利用と細胞増殖機構の解析

    岡崎 泰昌, 永井 裕崇, 舟橋 諭美, 周 珊瑚, 葉 淑彬, 葉 國義, Glass Jonathan, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 291 - 291   2012.3

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  280. CD146の過剰発現は、アスベスト誘発ラット悪性腹膜中皮腫の検出に有用である

    舟橋 諭美, 岡崎 泰昌, 永井 裕崇, 蒋 麗, 周 珊瑚, 辻村 亨, 豊國 伸哉

    日本病理学会会誌   Vol. 101 ( 1 ) page: 396 - 396   2012.3

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  281. ラット乳腺線維腺腫の間質細胞はTWIST-1を発現する

    舟橋 諭美, 岡崎 泰昌, 胡 茜, 周 珊瑚, 永井 裕崇, 豊國 伸哉

    日本毒性病理学会講演要旨集   Vol. 28回   page: 87 - 87   2012.2

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  282. Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary

    Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

    LABORATORY INVESTIGATION   Vol. 92   page: 302A - 302A   2012.2

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  283. Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary

    Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

    MODERN PATHOLOGY   Vol. 25   page: 302A - 302A   2012.2

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  284. Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. Reviewed International journal

    Hirotaka Nagai, Yasumasa Okazaki, Shan Hwu Chew, Nobuaki Misawa, Yoriko Yamashita, Shinya Akatsuka, Toshikazu Ishihara, Kyoko Yamashita, Yutaka Yoshikawa, Hiroyuki Yasui, Li Jiang, Hiroki Ohara, Takashi Takahashi, Gaku Ichihara, Kostas Kostarelos, Yasumitsu Miyata, Hisanori Shinohara, Shinya Toyokuni

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 108 ( 49 ) page: E1330-8 - 101   2011.12

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    Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter ∼ 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammogenicity and mesotheliomagenicity in vivo. In contrast, thick (diameter ∼ 150 nm) or tangled (diameter ∼ 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.

    DOI: 10.1073/pnas.1110013108

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  285. Asbestos surface provides a niche for oxidative modification. Reviewed International journal

    Hirotaka Nagai, Toshikazu Ishihara, Wen-Hua Lee, Hiroki Ohara, Yasumasa Okazaki, Katsuya Okawa, Shinya Toyokuni

    Cancer science   Vol. 102 ( 12 ) page: 2118 - 25   2011.12

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    Asbestos is a potent carcinogen associated with increased risks of malignant mesothelioma and lung cancer in humans. Although the mechanism of carcinogenesis remains elusive, the physicochemical characteristics of asbestos play a role in the progression of asbestos-induced diseases. Among these characteristics, a high capacity to adsorb and accommodate biomolecules on its abundant surface area has been linked to cellular and genetic toxicity. Several previous studies identified asbestos-interacting proteins. Here, with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry, we systematically identified proteins from various lysates that adsorbed to the surface of commercially used asbestos and classified them into the following groups: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. The surfaces of crocidolite and amosite, two iron-rich types of asbestos, caused more protein scissions and oxidative modifications than that of chrysotile by in situ-generated 4-hydroxy-2-nonenal. In contrast, we confirmed the intense hemolytic activity of chrysotile and found that hemoglobin attached to chrysotile, but not silica, can work as a catalyst to induce oxidative DNA damage. This process generates 8-hydroxy-2'-deoxyguanosine and thus corroborates the involvement of iron in the carcinogenicity of chrysotile. This evidence demonstrates that all three types of asbestos adsorb DNA and specific proteins, providing a niche for oxidative modification via catalytic iron. Therefore, considering the affinity of asbestos for histones/DNA and the internalization of asbestos into mesothelial cells, our results suggest a novel hypothetical mechanism causing genetic alterations during asbestos-induced carcinogenesis. (Cancer Sci 2011; 102: 21182125)

    DOI: 10.1111/j.1349-7006.2011.02087.x

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  286. 悪性胸膜中皮腫におけるYAPがん遺伝子の標的遺伝子検索

    水野 鉄也, 村上 秀樹, 石黒 太志, 豊國 伸哉, 横井 香平, 関戸 好孝

    肺癌   Vol. 51 ( 5 ) page: 553 - 553   2011.10

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  287. miR-375 Is Activated by ASH1 and Inhibits YAP1 in a Lineage-Dependent Manner in Lung Cancer Reviewed

    Eri Nishikawa, Hirotaka Osada, Yasumasa Okazaki, Chinatsu Arima, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Yasushi Yatabe, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   Vol. 71 ( 19 ) page: 6165 - 6173   2011.10

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    Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. Cancer Res; 71(19); 6165-73. (C)2011 AACR.

    DOI: 10.1158/0008-5472.CAN-11-1020

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  288. 鉄過剰と発がん

    豊國 伸哉

    日本生化学会大会プログラム・講演要旨集   Vol. 84回   page: 1S16a - 7   2011.9

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  289. 鉄化合物による高悪性度肉腫型中皮腫の表現型に関与するmicroRNAの検出と機能解析(Detection and functional analyses of microRNA in high-grade phenotype of iron-induced sarcomatoid mesothelioma in rats)

    岡崎 泰昌, 胡 茜, 赤塚 慎也, 山下 享子, 舟橋 諭美, 山下 依子, 蒋 麗, 大原 浩貴, 周 珊瑚, 永井 裕崇, 高橋 隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 70回   page: 266 - 267   2011.9

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  290. 酸化ストレス誘発腎発癌モデルにおけるlipocalin-2発現の意義(An implication of lipocalin-2 expression in an oxidative stress-induced renal carcinogenesis model)

    赤塚 慎也, 山下 依子, 岡崎 泰昌, 蒋 麗, 永井 裕崇, 高橋 隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 70回   page: 147 - 148   2011.9

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  291. 環境因子の発がんへのインパクトの未来像 アスベストによる中皮腫発生機構の解明とその予防戦略(Molecular mechanism of asbestos-related mesothelioma development and prevention strategies)

    豊國 伸哉

    日本癌学会総会記事   Vol. 70回   page: 223 - 223   2011.9

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  292. 異所性子宮間質細胞の卵巣明細胞腺癌発生における役割について(The role of ectopic endometrial stromal cells in endometriosis-associated ovarian clear cell adenocarcinoma)

    山下 依子, 小林 浩晴, 赤塚 慎也, 永井 裕崇, 吉川 史隆, 高橋 隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 70回   page: 278 - 279   2011.9

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  293. 悪性中皮腫の発生における脂肪組織の役割(Potential involvement of adipose tissue in malignant mesothelioma development)

    周 珊瑚, 岡崎 泰昌, 永井 裕崇, 山下 依子, 赤塚 慎也, 蒋 麗, 豊國 伸哉

    日本癌学会総会記事   Vol. 70回   page: 485 - 485   2011.9

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  294. 分子標的療法の新展開 過剰鉄と活性酸素を介した発がん機構と治療への展開

    豊國 伸哉

    臨床血液   Vol. 52 ( 9 ) page: 956 - 956   2011.9

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  295. 口腔扁平上皮癌におけるType 2HとLewis y抗原の関与(Implication of type 2H and Lewis y antigens in the oral squamous cell carcinomas)

    堀田 宏司, 浜村 和紀, 豊國 伸哉, 山下 享子, 渋谷 英伸, 小池 達也, 古川 圭子, 山本 憲幸, 服部 宇, 上田 実, 古川 鋼一

    日本癌学会総会記事   Vol. 70回   page: 327 - 327   2011.9

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  296. ヒト悪性中皮腫細胞におけるYAP transcriptional coactivatorのCCND1を介した増殖機構の解析(YAP transcriptional coactivator induces malignant mesothelioma cell proliferation via up-regulating CCND1)

    水野 鉄也, 村上 秀樹, 藤井 万紀子, 石黒 太志, 近藤 豊, 赤塚 慎也, 豊國 伸哉, 横井 香平, 長田 啓隆, 関戸 好孝

    日本癌学会総会記事   Vol. 70回   page: 147 - 147   2011.9

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  297. MET Amplification is a Molecular Hallmark in Endometriosis-associated Ovarian Clear Cell Carcinoma and Correlates With Worse Prognosis

    Y. Yamashita, Y. Yatabe, S. Akatsuka, H. Kajiyama, F. Kikkawa, T. Takahashi, S. Toyokuni

    EUROPEAN JOURNAL OF CANCER   Vol. 47   page: S529 - S529   2011.9

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  298. Age-and sun exposure-dependent differences in 8-hydroxy-2 '-deoxyguanosine and N-epsilon-(carboxymethyl)lysine in human epidermis Reviewed

    Shinya Toyokuni, Ayaka Hirao, Tamae Wada, Ryoji Nagai, Akira Date, Takashi Yoshii, Shinya Akatsuka, Yoriko Yamashita, Akira Kawada

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   Vol. 49 ( 2 ) page: 121 - 124   2011.9

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    Aging and exposure to sunlight are two major factors in the deterioration of skin function. In this study, thirty-six fixed human skin samples from sun-exposed and unexposed areas from young and old individuals were used to evaluate the localization of oxidative stress according to levels and distribution of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine in samples using immunohistochemistry. In the epidermis of the young, negligible amounts of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine were detected in unexposed areas, whereas nuclear 8-hydroxy-2'-deoxyguanosine and cytoplasmic N-epsilon-(carboxymethyl)lysine were increased in the lower epidermis in sun-exposed areas. In contrast, the aged presented prominent nuclear 8-hydroxy-2'-deoxyguanosine and nuclear N-epsilon-(carboxymethyl)lysine in the epidermis of unexposed areas, concomitant with dermal increase in N-epsilon-(carboxymethyl)lysine. However, the immunostaining of 8-hydroxy-2'-deoxyguanosine and N-epsilon-(carboxymethyl)lysine revealed a decrease in the epidermis of sun-exposed areas in the aged. These results suggest an age-dependent difference in the adaptation and protective mechanisms of the epidermis against sunlight-associated oxidative stress, thus necessitating distinct standards for evaluation in each age group. Further investigation is warranted to elucidate underlying molecular mechanisms.

    DOI: 10.3164/jcbn.11-05

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  299. Dietary Fish Oil Promotes Colonic Apoptosis and Mitochondrial Proton Leak in Oxidatively Stressed Mice Reviewed

    Yang-Yi Fan, Qitao Ran, Shinya Toyokuni, Yasumasa Okazaki, Evelyn S. Callaway, Joanne R. Lupton, Robert S. Chapkin

    CANCER PREVENTION RESEARCH   Vol. 4 ( 8 ) page: 1267 - 1274   2011.8

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    An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2(Het), Gpx4(Het), and transgenic Gpx4(Tg) mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4(Het) &gt; SOD2(Het) &gt; Wt &gt; Gpx4(Tg)), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4(Het) and SOD2(Het) mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4(Tg) mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P &lt; 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk. Cancer Prev Res; 4(8); 1267-74. (C) 2011 AACR.

    DOI: 10.1158/1940-6207.CAPR-10-0368

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  300. The human cytomegalovirus gene products essential for late viral gene expression assemble into prereplication complexes before viral DNA replication. Reviewed International journal

    Hiroki Isomura, Mark F Stinski, Takayuki Murata, Yoriko Yamashita, Teru Kanda, Shinya Toyokuni, Tatsuya Tsurumi

    Journal of virology   Vol. 85 ( 13 ) page: 6629 - 44   2011.7

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    The regulation of human cytomegalovirus (HCMV) late gene expression by viral proteins is poorly understood, and these viral proteins could be targets for novel antivirals. HCMV open reading frames (ORFs) UL79, -87, and -95 encode proteins with homology to late gene transcription factors of murine gammaherpesvirus 68 ORFs 18, 24, and 34, respectively. To determine whether these HCMV proteins are also essential for late gene transcription of a betaherpesvirus, we mutated HCMV ORFs UL79, -87, and -95. Cells were infected with the recombinant viruses at high and low multiplicities of infection (MOIs). While viral DNA was detected with the recombinant viruses, infectious virus was not detected unless the wild-type viral proteins were expressed in trans. At a high MOI, mutation of ORF UL79, -87, or -95 had no effect on the level of major immediate-early (MIE) gene expression or viral DNA replication, but late viral gene expression from the UL44, -75, and -99 ORFs was not detected. At a low MOI, preexpression of UL79 or -87, but not UL95, in human fibroblast cells negatively affected the level of MIE viral gene expression and viral DNA replication. The products of ORFs UL79, -87, and -95 were expressed as early viral proteins and recruited to prereplication complexes (pre-RCs), along with UL44, before the initiation of viral DNA replication. All three HCMV ORFs are indispensable for late viral gene expression and viral growth. The roles of UL79, -87, and -95 in pre-RCs for late viral gene expression are discussed.

    DOI: 10.1128/JVI.00384-11

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  301. YAP TRANSCRIPTION COACTIVATOR INDUCES MALIGNANT MESOTHELIOMA CELL PROLIFERATION BY UP-REGULATING CELL CYCLE PROGRESSION

    Tetsuya Mizuno, Hideki Murakami, Makiko Fujii, Futoshi Ishiguro, Yutaka Kondo, Shinya Akatsuka, Shinya Toyokuni, Kohei Yokoi, Hirotaka Osada, Yoshitaka Sekido

    JOURNAL OF THORACIC ONCOLOGY   Vol. 6 ( 6 ) page: S707 - S708   2011.6

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  302. 脳梗塞発症前の運動による脳梗塞障害軽減効果及び作用機序の検討 酸化ストレスに着目して

    濱川 みちる, 石田 章真, 玉越 敬悟, 嶋田 悠, 中島 宏樹, 豊國 伸哉, 石田 和人

    日本基礎理学療法学雑誌   Vol. 15 ( 1 ) page: 20 - 20   2011.5

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  303. 科学技術振興調整費「アスベスト関連疾患への総括的取り組み」班研究 成果報告 班研究の概要と登録事業、中皮腫細胞特性ならびにアスベストの免疫影響について

    大槻 剛巳, 中野 孝司, 長谷川 誠紀, 岡田 守人, 辻村 亨, 関戸 好孝, 豊國 伸哉, 西本 寛, 福岡 和也, 田中 文啓, 熊谷 直子, 前田 恵, 松崎 秀紀, 李 順姫, 西村 泰光, 科学技術振興調整費平成18-22年度「アスベスト関連疾患への総括的取り組み」研究班

    日本衛生学雑誌   Vol. 66 ( 3 ) page: 543 - 552   2011.5

  304. 脳梗塞モデルラット作成前の運動が脳梗塞に及ぼす影響 抗酸化作用に着目して

    濱川 みちる, 嶋田 悠, 中島 宏樹, 石田 章真, 玉越 敬悟, 豊國 伸哉, 石田 和人

    日本生理学雑誌   Vol. 73 ( 5 ) page: 127 - 128   2011.5

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  305. アスベスト誘発中皮腫発がん機構の解明

    豊國 伸哉, 蒋 麗, 胡 茜, 永井 裕崇, 岡崎 泰昌, 赤塚 慎也, 山下 依子

    日本衛生学雑誌   Vol. 66 ( 3 ) page: 562 - 567   2011.5

  306. 【見直されつつある生体鉄】鉄による発がん

    岡崎 泰昌, 豊國 伸哉

    血液フロンティア   Vol. 21 ( 6 ) page: 851 - 864   2011.5

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    鉄は、生体内に最も豊富に含まれている遷移金属であり、酸化還元反応を介して生体の恒常性の維持に寄与している。そのため、体内に鉄を吸収し、貯蔵する仕組みが備わっている。一方、過剰鉄は周囲の蛋白、脂質、核酸に酸化傷害を来す。平均寿命が長く、栄養を十分に摂取することが可能である先進国では、過剰鉄が細胞傷害を惹起し、発がんのリスクとなることが判明してきている。本稿では、鉄と細胞傷害・発がん機構について概説する。(著者抄録)

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  307. XCR1 Expression and Biased V-H Gene Usage Are Distinct Feautres of Diffuse Large B-Cell Lymphoma Initially Manifesting in the Bone Marrow Reviewed

    Yoriko Yamashita, Dai Kajiura, Lee Tang, Yuichi Hasegawa, Tomohiro Kinoshita, Shigeo Nakamura, Shinya Akatsuka, Shinya Toyokuni, Naoyoshi Mori

    AMERICAN JOURNAL OF CLINICAL PATHOLOGY   Vol. 135 ( 4 ) page: 556 - 564   2011.4

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    A total of 29 cases of diffuse large B-cell lymphoma initially manifesting in the bone marrow (BM-DLBCL) were analyzed for V-H gene sequence, and expression microarray of chemokines and chemokine receptors and immunohistochemical analysis were done. Seminested polymerase chain reaction (PCR) and sequencing analyses of 18 cases revealed that the V-H gene usage in 6 cases was restricted to V(H)3-7, in 3 cases to V(H)4-34, and in 2 cases to V(H)4-39, which were all previously reported to be autoreactive. In total, 14 of 18 V-H genes were those associated with autoimmune diseases, including V(H)3-21, V(H)3-23, and V(H)3-48. Furthermore, cDNA microarray analysis specific for chemokine and chemokine receptors revealed that chemokine receptor XCR1 expression was significantly elevated in the BM-DLBCL cases (P &lt; .05), which was confirmed by quantitative reverse transcriptase PCR and immunohistochemical analysis. Expression of the chemokine receptor XCR1 and frequent usage of autoreactive V-H genes seem to be distinct characteristics of BM-DLBCL.

    DOI: 10.1309/AJCPCTDC5PY3LXBP

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  308. 酸化ストレス誘発ラット腎癌は高度な染色体不安定性を示す

    赤塚 慎也, 山下 依子, 岡崎 泰昌, 蒋 麗, 永井 裕崇, 新井 恵吏, 金井 弥栄, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 422 - 422   2011.3

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  309. 腎酸化ストレス傷害におけるシデロフォア結合蛋白の意義

    福岡 香, 赤塚 慎也, 山下 依子, 岡崎 泰昌, 森 潔, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 495 - 495   2011.3

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  310. 子宮内膜症における間質細胞の遺伝子発現と上皮への影響について

    宇野 希望, 山下 依子, 小林 浩晴, 赤塚 慎也, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 497 - 497   2011.3

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  311. 子宮内膜症における発癌メカニズムの解明の試み

    山下 依子, 小林 浩晴, 赤塚 慎也, 宇野 希望, 谷田部 恭, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 340 - 340   2011.3

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  312. アスベスト貪食後に中皮細胞が分泌するタンパク質の機能解析

    有竹 典, 永井 裕崇, 加藤 琢哉, 近藤 裕史, 山下 依子, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 495 - 495   2011.3

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  313. アスベストは表面に特異的なタンパクを結合する

    永井 裕崇, 石原 敏和, 李 文華, 大原 浩貴, 岡崎 泰昌, 大川 克也, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 423 - 423   2011.3

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  314. アスベスト発がんの解明からその予防へ

    豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 289 - 289   2011.3

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  315. アスベスト誘発ラット悪性中皮腫の悪性度とCTGF(Connective Tissue Growth Factor)の関連について

    多田 正幸, 蒋 麗, 周 珊瑚, 山下 依子, 永井 裕崇, 岡崎 泰昌, 赤塚 慎也, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 495 - 495   2011.3

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  316. アスベスト誘発中皮腫の病理解明と予防法の開発

    蒋 麗, 山下 依子, 赤塚 慎也, 永井 裕崇, 多田 正幸, 岡崎 泰昌, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 423 - 423   2011.3

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  317. microRNA 199/214は鉄誘発高悪性度ラット中皮腫の特徴である

    岡崎 泰昌, 胡 茜, 赤塚 慎也, 山下 享子, 山下 依子, 蒋 麗, 大原 浩貴, 永井 裕崇, 高橋 隆, 豊國 伸哉

    日本病理学会会誌   Vol. 100 ( 1 ) page: 311 - 311   2011.3

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  318. 科学技術振興調整費「アスベスト関連疾患への総括的取り組み」班研究の成果と総括 アスベスト発がん機構の解明とその予防への応用

    豊國 伸哉

    日本衛生学雑誌   Vol. 66 ( 2 ) page: 272 - 272   2011.2

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  319. 【癌の代謝 正常組織との代謝特性の違いから見えてくる新たな診断・治療戦略】発癌における鉄代謝とフリーラジカル

    豊國 伸哉

    細胞工学   Vol. 30 ( 1 ) page: 30 - 35   2010.12

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  320. 脳梗塞モデルラット作成前に実施する運動の効果および作用機序の検討 抗酸化作用に着目して

    濱川 みちる, 石田 章真, 玉越 敬悟, 嶋田 悠, 中島 宏樹, 豊國 伸哉, 石田 和人

    東海北陸理学療法学術大会誌   Vol. 26回   page: 72 - 72   2010.11

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  321. 科学技術振興調整費「アスベスト関連疾患への総括的取り組み」班 悪性中皮腫集学的治療に関する安全性確認試験ならびに基礎研究の進捗状況

    大槻 剛巳, 中野 孝司, 長谷川 誠紀, 岡田 守人, 辻村 享, 関戸 好孝, 豊國 伸哉, 西本 寛, 福岡 和也, 田中 文啓

    日本職業・災害医学会会誌   Vol. 58 ( 臨増 ) page: 別179 - 別179   2010.10

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  322. 悪性胸膜中皮腫におけるYAPを介した細胞増殖機構の解析

    水野 鉄也, 村上 秀樹, 石黒 太志, 豊國 伸哉, 横井 香平, 関戸 好孝

    肺癌   Vol. 50 ( 5 ) page: 642 - 642   2010.10

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  323. アスベスト誘発中皮腫発がん機構の解明に基づく予防の試み

    豊國 伸哉, 蒋 麗, 永井 裕崇, 岡崎 泰昌, 赤塚 慎也, 山下 依子

    肺癌   Vol. 50 ( 5 ) page: 559 - 559   2010.10

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  324. ヒト口腔扁平上皮癌におけるマーカーとしてのtype 2HとLewis Y抗原(Type 2H and Lewis y antigens as markers for human oral squamous cell carcinomas)

    堀田 宏司, 浜村 和紀, 豊國 伸哉, 渋谷 英伸, 徳田 典代, 古川 圭子, 山本 憲幸, 服部 宇, 上田 実, 古川 鋼一

    日本癌学会総会記事   Vol. 69回   page: 503 - 504   2010.8

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  325. ヒト中皮細胞はアスベスト貪食後に様々なタンパクを分泌する(Human mesothelial cells secretes various proteins upon phagocytosis of asbestos)

    永井 裕崇, 加藤 琢哉, 山下 依子, 豊國 伸哉

    日本癌学会総会記事   Vol. 69回   page: 140 - 140   2010.8

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  326. アスベストに誘発されたラット悪性中皮腫の病理学の解析(Mechanism implicated in asbestos-induced malignant mesothelioma in rat)

    蒋 麗, 山下 依子, 赤塚 慎也, 岡崎 泰昌, 永井 裕崇, 豊國 伸哉

    日本癌学会総会記事   Vol. 69回   page: 87 - 87   2010.8

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  327. がんの予防・化学予防 アスベスト誘発中皮腫発がん機構の解明に基づく予防の試み(Cancer prevention and chemoprevention Elucidation of asbestos-induced mesothelial carcinogenesis and its application to prevention)

    豊國 伸哉, 蒋 麗, 永井 裕崇, 岡崎 泰昌, 赤塚 慎也, 山下 依子

    日本癌学会総会記事   Vol. 69回   page: 233 - 233   2010.8

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  328. TOWARD A NEW ERA OF THE NAGOYA JOURNAL OF MEDICAL SCIENCE: MESSAGE FROM THE NEW EDITOR-IN-CHIEF Invited

    Shinya Toyokuni

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 72 ( 3-4 ) page: 107 - 109   2010.8

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  329. Suppression of SLC11A2 Expression Is Essential to Maintain Duodenal Integrity During Dietary Iron Overload Reviewed

    Tomoyuki Shirase, Kiyoshi Mori, Yasumasa Okazaki, Ken Itoh, Masayuki Yamamoto, Mitsuaki Tabuchi, Fumio Kishi, Li Jiang, Shinya Akatsuka, Kazuwa Nakao, Shinya Toyokuni

    AMERICAN JOURNAL OF PATHOLOGY   Vol. 177 ( 2 ) page: 677 - 685   2010.8

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    Iron is essential for the survival of mammals, but iron overload causes fibrosis and carcinogenesis. Reduced iron absorption and regulated release into circulation in duodenal mucosa constitute two major mechanisms of protection against dietary iron overload; however, their relative contribution remains elusive. To study the significance of the former process, we generated SLC11A2 transgenic mice (TGs) under the control of the chicken beta-actin promoter. TGs were viable and fertile, and displayed no overt abnormalities up to 20 months. No significant difference in iron concentration was observed in major solid organs between TGs and their wild-type littermates, suggesting that increased number of iron transporters does not lead to increased iron absorption. To test the sensitivity to iron overload, TGs and wild-type mice were fed with an iron-rich diet containing 2% ferric citrate. Iron supplementation caused suppression of endogenous duodenal SLC11A2 expression, down-regulation of duodenal ferroportin, and overexpression of hepatic hepcidin, precluding excessive iron uptake both in the TGs and wild-type mice. However, iron-treated TGs revealed increased mortality, resulting from oxidative mucosal damage leading to hemorrhagic erosion throughout the whole intestinal area. These findings suggest that reduced iron release from duodenal cells into circulation plays a role in mitigating excessive iron uptake from the diet and that finely regulated duodenal absorption is essential to protect intestinal mucosa from iron-induced oxidative damage. (Am J Pathol 2010, 177:677-685; DOI: 10.2353/ajpath.2010.090823)

    DOI: 10.2353/ajpath.2010.090823

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  330. Met遺伝子の増幅は卵巣明細胞性腺癌の予後不良因子である(Met amplification is a prognostic factor in ovarian clear cell adenocarcinoma)

    山下 依子, 赤塚 慎也, 谷田部 恭, 梶山 広明, 吉川 史隆, 中村 栄男, 豊國 伸哉

    日本癌学会総会記事   Vol. 69回   page: 466 - 466   2010.8

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  331. CDKN2A/2Bのホモ欠損は鉄誘発高悪性度ラット中皮腫の特徴である(Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced hieh-grade rat mesothelioma)

    岡崎 泰昌, 胡 茜, 赤塚 慎也, 山下 依子, 大原 浩貴, 蒋 麗, 永井 裕崇, 高橋 隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 69回   page: 218 - 218   2010.8

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  332. 【睡眠時無呼吸症候群 研究と臨床の新時代】基礎医学とのダイアローグ 酸化ストレスと代謝変化

    山下 依子, 豊國 伸哉

    THE LUNG-perspectives   Vol. 18 ( 3 ) page: 282 - 285   2010.7

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    生体にはエネルギー産生のために必要な酸化システムとその過剰による悪影響を防ぐための抗酸化システムが備わっており、その恒常性が保たれていることが健康の維持に必要である。酸化と抗酸化のバランスが崩れて酸化が過剰になった状態を酸化ストレスと呼ぶ。酸化ストレスは糖、タンパク、脂質およびDNAを変性あるいは傷害し、生体にとって有害となる。本稿では、酸化ストレスと代謝について、前半は分子・細胞レベルで、後半は疾患との関連を中心に個体レベルで概説した。今後は酸化ストレスと老化、特に脳の機能的老化についてもより詳細に解明されることが期待される。(著者抄録)

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  333. 鉄研究の新展開 過剰鉄による発がん機構の解明

    豊國 伸哉

    Biomedical Research on Trace Elements   Vol. 21 ( 2 ) page: 84 - 84   2010.6

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  334. Lipid peroxidation generates body odor component trans-2-nonenal covalently bound to protein in vivo. Reviewed International journal

    Kousuke Ishino, Chika Wakita, Takahiro Shibata, Shinya Toyokuni, Sachiko Machida, Shun Matsuda, Tomonari Matsuda, Koji Uchida

    The Journal of biological chemistry   Vol. 285 ( 20 ) page: 15302 - 15313   2010.5

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    trans-2-Nonenal is an unsaturated aldehyde with an unpleasant greasy and grassy odor endogenously generated during the peroxidation of polyunsaturated fatty acids. 2-Nonenal covalently modified human serum albumin through a reaction in which the aldehyde preferentially reacted with the lysine residues. Modified proteins were immunogenic, and a specific monoclonal antibody (mAb) 27Q4 that cross-reacted with the protein covalently modified with 2-nonenal was raised from mouse. To verify the presence of the protein-bound 2-nonenal in vivo, the mAb 27Q4 against the 2-nonenal-modified keyhole limpet hemocyanin was raised. It was found that a novel 2-nonenal-lysine adduct, cis- and trans-N(epsilon)-3-[(hept-1-enyl)-4-hexyl-pyridinium]lysine (HHP-lysine), constitutes an epitope of the antibody. The immunoreactive materials with mAb 27Q4 were detected in the kidney of rats exposed to ferric nitrilotriacetate, an iron chelate that induces free radical-mediated oxidative tissue damage. Using high performance liquid chromatography with on-line electrospray ionization tandem mass spectrometry, we also established a highly sensitive method for detection of the cis- and trans-HHP-lysine and confirmed that the 2-nonenal-lysine adducts were indeed formed during the lipid peroxidation-mediated modification of protein in vitro and in vivo. Furthermore, we examined the involvement of the scavenger receptor lectin-like oxidized low density lipoprotein receptor-1 in the recognition of 2-nonenal-modified proteins and established that the receptor recognized the HHP-lysine adducts as a ligand.

    DOI: 10.1074/jbc.M109.068023

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  335. 【鉄過剰症 その病態と治療】鉄過剰と組織障害

    谷本 光音, 豊國 伸哉, 小澤 敬也, 高後 裕

    日本医師会雑誌   Vol. 139 ( 2 ) page: 269 - 279   2010.5

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  336. 【鉄過剰症 その病態と治療】鉄による酸化ストレスとDNA傷害

    豊國 伸哉

    日本医師会雑誌   Vol. 139 ( 2 ) page: 285 - 289   2010.5

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  337. 腎酸化ストレス傷害に対するlipocalin 2の作用

    高橋 雄太, 赤塚 慎也, 山下 依子, 岡崎 泰昌, 森 潔, 豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 373 - 373   2010.3

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  338. 明日の病理学教育 MD/PhDコースと病理学講座での研究者育成

    豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 172 - 172   2010.3

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  339. 家族性アミロイドポリニューロパチードナーからの全肝ドミノ肝移植後にBurkittリンパ腫を発症した1剖検例

    森田 紗枝, 岡崎 泰昌, 小池 春樹, 安田 貴彦, 山下 依子, 木内 哲也, 祖父江 元, 中村 栄男, 下山 芳江, 豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 372 - 372   2010.3

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  340. 卵巣明細胞腺癌の発癌におけるMetの役割の解析

    山下 依子, 瀬古 浩史, 谷田部 恭, 赤塚 慎也, 岡崎 泰昌, 中村 栄男, 豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 358 - 358   2010.3

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  341. ヒト中皮細胞はアスベストを貪食した後に様々なタンパク質を産生する

    伊藤 裕紀, 永井 裕崇, 加藤 琢哉, 山下 依子, 豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 368 - 368   2010.3

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  342. アスベストは表面に特異的なタンパクを結合する

    永井 裕崇, 李 文華, 大原 浩貴, 大川 克也, 豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 298 - 298   2010.3

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  343. アスベスト誘発中皮腫発がんには酸化ストレスが関与する

    豊國 伸哉, 蒋 麗, 胡 茜, 永井 裕崇, 赤塚 慎也, 岡崎 泰昌, 山下 依子

    日本病理学会会誌   Vol. 99 ( 1 ) page: 207 - 207   2010.3

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  344. CDKN2A/2Bのホモ欠損は鉄誘発高悪性度ラット中皮腫の特徴である

    岡崎 泰昌, 胡 茜, 赤塚 慎也, 山下 依子, 大原 浩貴, 永井 裕崇, 高橋 隆, 豊國 伸哉

    日本病理学会会誌   Vol. 99 ( 1 ) page: 298 - 298   2010.3

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  345. A quantitative trait locus responsible for inducing B-cell lymphoblastic lymphoma is a hotspot for microsatellite instability. Reviewed International journal

    Richard H Kaszynski, Shinya Akatsuka, Takuya Hiratsuka, Guang Jin, Munetaka Ozeki, Tomoko Okuno, Takuro Nakamura, Toshiaki Manabe, Tetsuya Takakuwa, Hiroshi Hiai, Shinya Toyokuni, Keiji Tamaki, Tatsuaki Tsuruyama

    Cancer science   Vol. 101 ( 3 ) page: 800 - 5   2010.3

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    While the molecular mechanisms underlying microsatellite instability (MSI) have been exhaustively investigated, identifying the patterns of MSI distribution within diverse cancer genomes has remained an elusive issue. In the present study, we conducted genome-wide MSI screening in B-cell lymphoblastic lymphomas (B-LBL) which spontaneously develop in the SL/Kh strain of mice. Tumor samples harvested from 16 mice were investigated using a framework map consisting of 150 microsatellite markers spaced at increments of roughly 0.5-3.0 centimorgans, spanning the entirety of mouse chromosomes (mus musculus chromosomes [MMU]) 3-6. MMU3 contains a quantitative trait locus (QTL), Bomb1 (bone marrow pre-B1), known to induce an aberrant expansion of pre-B cells in bone marrow prior to the onset of B-LBL in SL/Kh mice. The remaining chromosomes were selected on the basis of those most closely resembling MMU3 in terms of total estimated length (maximum variance 10 Mb). MSI was confirmed at 2 &lt;= markers in DNA derived from tumor tissues in 15 SL/Kh mice (93.7%), while healthy splenic DNA samples screened in parallel were consistently negative for MSI. The overall MSI incidence was significantly higher on MMU3 compared with MMU4-6 (P = 0.031). Additionally, by applying spatial point pattern analysis combined with a 1-D version of Ripley&apos;s K-function, we successfully demonstrated the predilection of MSI-susceptible loci to structure a massive cluster within the Bomb1 locus. Our study is the first to suggest that a QTL concomitantly serves as a hotspot for MSI-susceptible loci and sheds new light on somatic cancer genetics. (Cancer Sci 2010; 101: 800-805)

    DOI: 10.1111/j.1349-7006.2009.01437.x

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  346. 平成20年度学術大会科学技術振興研究発表「悪性中皮腫」より 概要と基礎研究からのアプローチ

    大槻 剛巳, 中野 孝司, 長谷川 誠紀, 岡田 守人, 辻村 亨, 関戸 好孝, 豊國 伸哉, 西本 寛, 福岡 和也, 田中 文啓

    日本職業・災害医学会会誌   Vol. 58 ( 1 ) page: 1 - 8   2010.1

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    いわゆるクボタ・ショック以来、本邦でもアスベスト被害者に対して、あるいはアスベスト起因性疾患に対して、いくつかの対策が進められている。そのひとつとして、科学技術振興調整費「アスベスト関連疾患への総括的取り組み」研究班では、登録事業、早期診断法の確立、生命予後を改善させるべき臨床試験の試み、そして、これら臨床的事項に貢献できるべき基礎研究の推進に取り組んでいる。日本職業・災害医学会学術大会では、本班研究が開始された平成18年度より「科学技術振興研究発表」として企画をしていただき、それぞれに背景や概要を説明させていただいてきた。平成20年度には、3年度目を迎え、特に登録事業と臨床試験について、これらの開始とエントリーに関しての広報を踏まえて、特別企画を設けていただいた。本稿では、その際に報告した全体の概要を紹介するとともに、基礎研究について報告する。(著者抄録)

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J03464&link_issn=&doc_id=20100414370001&doc_link_id=%2Fdr7jjomt%2F2010%2F005801%2F001%2F0001-0008%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdr7jjomt%2F2010%2F005801%2F001%2F0001-0008%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  347. Homozygous Deletion of CDKN2A/2B is a Hallmark of Iron-induced High-grade Rat Mesothelioma Reviewed

    Yasumasa Okazaki, Quan Hu, Shinya Akatsuka, Hiroki Ohara, Hirotaka Nagai, Takashi Takahashi, Shinya Toyokuni

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 49   page: S67 - S67   2010

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    DOI: 10.1016/j.freeradbiomed.2010.10.162

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  348. 科学技術振興調整費「アスベスト関連疾患への総括的取り組み」班 登録事業の現状と、基礎研究よりアスベストの免疫系への影響について

    大槻 剛巳, 西本 寛, 前田 恵, 熊谷 直子, 林 宏明, 西村 泰光, 長谷川 誠紀, 田中 文啓, 岡田 守人, 福岡 和也, 辻村 亨, 関戸 好孝, 豊國 伸哉, 岸本 卓巳, 中野 孝司, 科学技術振興調整費, アスベスト関連疾患への総括的取り組み

    日本職業・災害医学会会誌   Vol. 57 ( 臨増 ) page: 別149 - 別149   2009.10

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  349. 悪性胸膜中皮腫 アスベスト誘発中皮腫発がん機構の解明に基づく予防の試み

    豊國 伸哉, 蒋 麗, 永井 裕崇, 石原 敏和, 赤塚 慎也, 山下 依子

    肺癌   Vol. 49 ( 5 ) page: 584 - 584   2009.10

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  350. 科学技術振興調整費「アスベスト関連疾患への総括的取り組み」班 悪性中皮腫集学的治療に関する安全性確認試験の進捗状況

    大槻 剛巳, 長谷川 誠紀, 田中 文啓, 岡田 守人, 福岡 和也, 辻村 亨, 西本 寛, 関戸 好孝, 豊國 伸哉, 中野 孝司, 科学技術振興調整費, アスベスト関連疾患への総括的取り組み

    日本職業・災害医学会会誌   Vol. 57 ( 臨増 ) page: 別148 - 別148   2009.10

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  351. アスベスト誘発性悪性中皮腫に関与する新たな病態機構(Novel mechanism implicated in asbestos-induced malignant mesothelioma)

    蒋 麗, 永井 裕崇, 赤塚 慎也, 大原 浩貴, 山下 依子, 豊國 伸哉

    肺癌   Vol. 49 ( 5 ) page: 759 - 759   2009.10

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  352. ITPase-deficient mice show growth retardation and die before weaning Reviewed

    M. Behmanesh, K. Sakumi, N. Abolhassani, S. Toyokuni, S. Oka, Y. N. Ohnishi, D. Tsuchimoto, Y. Nakabeppu

    CELL DEATH AND DIFFERENTIATION   Vol. 16 ( 10 ) page: 1315 - 1322   2009.10

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    Inosine triphosphate pyrophosphatase (ITPase), the enzyme that hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding purine nucleoside monophosphate and pyrophosphate, is encoded by the Itpa gene. In this study, we established Itpa knockout (KO) mice and used them to show that ITPase is required for the normal organization of sarcomeres in the heart. Itpa(-/-) mice died about 2 weeks after birth with features of growth retardation and cardiac myofiber disarray, similar to the phenotype of the cardiac alpha-actin KO mouse. Inosine nucleotides were found to accumulate in both the nucleotide pool and RNA of Itpa(-/-) mice. These data suggest that the role of ITPase in mice is to exclude ITP from the ATP pool, and the main target substrate of this enzyme is rITP. Our data also suggest that cardiomyopathy, which is mainly caused by mutations in sarcomeric protein-encoding genes, is also caused by a defect in maintaining the quality of the ATP pool, which is an essential requirement for sarcomere function.

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  353. 【病態解明に迫る活性酸素シグナルと酸化ストレス 癌、神経変性疾患、循環・代謝異常にかかわるレドックス制御機構と最新の技術開発】酸化ストレスと病態 炎症・発癌と変性疾患 酸化ストレス誘発発癌機構の解明 フリーラジカル傷害に弱いゲノム領域を探る

    大原 浩貴, 豊國 伸哉

    実験医学   Vol. 27 ( 15 ) page: 2427 - 2432   2009.9

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    慢性的な酸化ストレス状態による生体分子への酸化的な傷害の蓄積が、発癌を誘発する一因と考えられている。これまでフリーラジカルによる傷害に選択性は存在しないと考えられてきた。しかし、われわれが確立した酸化ストレス誘発発癌モデルにおいて、癌抑制遺伝子として知られるp16INK4A遺伝子座では欠失とプロモーター領域のメチル化が高頻度に認められ、1つの標的遺伝子となっていることが判明した。フリーラジカルに対して脆弱なゲノム領域の解明という新たな切り口で酸化ストレス誘発発癌機構を眺めることで、その予防・治療法の開発に新たなコンセプトを提示できるだろう。(著者抄録)

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  354. 鉄ニトリロ三酢酸誘発ラット腎癌に見られる高度の染色体不安定性(Ferric nitrilotriacetate-induced rat renal cancer exhibits a considerable degree of chromosomal instability)

    赤塚 慎也, 山下 依子, 蒋 麗, 大原 浩貴, 泉谷 昌志, 阿部 浩一郎, 中釜 斉, 村上 秀樹, 関戸 好孝, 新井 恵吏, 金井 弥栄, 樋野 興夫, 豊國 伸哉

    日本癌学会総会記事   Vol. 68回   page: 118 - 118   2009.8

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  355. 酸化ストレス誘発腎発癌における標的遺伝子の解析(Analysis of a target gene in oxidative stress-induced renal carcinogenesis)

    大原 浩貴, 劉 玉テイ, 永井 裕崇, 赤塚 慎也, 中邨 智之, 豊國 伸哉

    日本癌学会総会記事   Vol. 68回   page: 135 - 135   2009.8

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  356. 鉄の腹腔内反復投与によるラット中皮腫モデルにおけるマイクロアレイ解析(Microarray analysis of mesothelioma induced by intraperitoneal injections of ferric saccharate in rats)

    胡 茜, 赤塚 慎也, 大原 浩貴, 永井 裕崇, 山下 依子, 高橋 隆, 豊國 伸哉

    日本癌学会総会記事   Vol. 68回   page: 117 - 117   2009.8

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  357. 鉄を視点とするアスベスト発がんの解明と予防・診断・治療への応用の可能性

    豊國 伸哉

    肺癌   Vol. 49 ( 4 ) page: 362 - 367   2009.8

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    目的.アスベストの発がん機構を解明する。方法.アスベスト(UICC:クリソタイル、クロシドライト、アモサイト)の物理化学的な性質を再検討する一方、培養細胞や実験動物個体にアスベストの投与を行い、生物学的性質を詳細に評価した。結果.ラジカル発生の触媒能はアモサイト>クロシドライト>>>クリソタイルであり、それは種々のキレート剤の存在で修飾を受けた。貪食細胞以外に、中皮細胞や腺癌細胞もアスベスト繊維を取り込み、核内にいたることを観察した。supercoiled plasmid DNAを使用して、各アスベストの2本鎖DNA切断能を検討した。鉄含量の高いアモサイトとクロシドライトで2本鎖切断を認め、繰り返し配列部位やG:C塩基間で切断しやすいことが判明した。ラット腹腔内に各アスベスト繊維を投与すると、全アスベスト投与グループで、中皮細胞で酸化ストレス増加を認めるとともに特に脾臓において鉄沈着を認めた。結論.クリソタイル腹腔内投与も中皮腫を発生する事実と考えあわせると、アスベスト発がんにはアスベストに含まれる鉄のみならず、他の機序で発生する過剰鉄も重要な役割を演じていることが示唆され、中皮腫発生の予防標的として期待される。(著者抄録)

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  358. 卵巣明細胞腺癌のアレイCGH解析(Array CGH analysis of ovarian clear cell adenocarcinoma)

    山下 依子, 谷田部 恭, 赤塚 慎也, 梶山 広明, 吉川 史隆, 中村 栄男, 豊國 伸哉

    日本癌学会総会記事   Vol. 68回   page: 327 - 327   2009.8

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  359. ヒト口腔扁平上皮癌におけるtype 2HとLewis Y抗原の発現(Expression of type 2H and Lewis Y antigens in human oral squamous cell carcinomas)

    堀田 宏司, 浜村 和紀, 豊國 伸哉, 徳田 典代, 古川 圭子, 服部 宇, 上田 実, 古川 鋼一

    日本癌学会総会記事   Vol. 68回   page: 278 - 278   2009.8

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  360. アスベスト誘発中皮腫発がん機構の解明(Novel mechanism implicated in asbestos-induced malignant mesothelioma)

    蒋 麗, 永井 裕崇, 赤塚 慎也, 大原 浩貴, 山下 依子, 豊國 伸哉

    日本癌学会総会記事   Vol. 68回   page: 117 - 117   2009.8

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  361. Potent antioxidative activity of Vineatrol30 grapevine-shoot extract. Reviewed International journal

    Carsten Müller, Kristina Ullmann, Andrea Wilkens, Peter Winterhalter, Shinya Toyokuni, Pablo Steinberg

    Bioscience, biotechnology, and biochemistry   Vol. 73 ( 8 ) page: 1831 - 6   2009.8

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    The health promoting effects of a grapevine-shoot extract named Vineatrol (R) 30, which contains resveratrol (Resv) as well as considerable amounts of Resv oligomers, have recently been investigated. In the present study, we analyzed the free radical scavenging capacity, the ability to inhibit lipid peroxidation, and the capacity to enhance the human glutathione peroxidase 1 (GPx) and the human superoxide dismutase 1 (SOD) gene promoter activities of Vineatrol (R) 30. Vineatrol (R) 30 was able to scavenge the 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid radical cation and led to concentration-dependent inhibition of lipid peroxidation, Vineatrol (R) 30 not being superior to Resv alone in both cases. Vineatrol (R) 30 also enhanced the gene promoter activities of human GPx and SOD expressed in V79 cells, whereas this effect could not be demonstrated for Resv. In summary, the results presented in this study show that the Vineatrol (R) 30 grapevine-shoot extract is a free radical scavenger and potent antioxidant at non-eytotoxic concentrations.

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  362. Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro by Ras-cyclin D2 activation. Reviewed International journal

    Jiyoung Lee, Mito Kanatsu-Shinohara, Hiroko Morimoto, Yasuhiro Kazuki, Seiji Takashima, Mitsuo Oshimura, Shinya Toyokuni, Takashi Shinohara

    Cell stem cell   Vol. 5 ( 1 ) page: 76 - 86   2009.7

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    Spermatogonial stem cells (SSCs) undergo self-renewal division and support spermatogenesis. Although several cytokines coordinate to drive SSC self-renewal, little is known about the mechanisms underlying this process. We investigated the molecular mechanism by reconstructing SSC self-renewal in vitro without exogenous cytokines. Activation of Ras or overexpression of cyclins D2 and E1, both of which were induced by Ras; enabled long-term self-renewal of cultured spermatogonia. SSCs with activated Ras responded properly to differentiation signals and underwent spermatogenesis, whereas differentiation was abrogated in cyclin transfectants after spermatogonial transplantation. Both Ras- and cyclin-transfected cells produced seminomatous tumors, suggesting that excessive self-renewing stimulus induces oncogenic transformation. In contrast, cells that overexpressed cyclin D1 or D3 failed to make germ cell colonies after transplantation, which indicated that cyclin expression pattern is an important determinant to long-term SSC recolonization. Thus, the Ras-cyclin D2 pathway regulates the balance between tissue maintenance and tumorigenesis in the SSC population.

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  363. Abnormal DNA methyltransferase expression in mouse germline stem cells results in spermatogenic defects. Reviewed International journal

    Seiji Takashima, Masanori Takehashi, Jiyoung Lee, Shinichiro Chuma, Masaki Okano, Kenichiro Hata, Isao Suetake, Norio Nakatsuji, Hiroyuki Miyoshi, Shoji Tajima, Yoriko Tanaka, Shinya Toyokuni, Hiroyuki Sasaki, Mito Kanatsu-Shinohara, Takashi Shinohara

    Biology of reproduction   Vol. 81 ( 1 ) page: 155 - 64   2009.7

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    Although spermatogonial stem cells (SSCs) are committed to spermatogenesis, they may also convert to an embryonic stem cell-like pluripotent state at a low frequency. Because changes in DNA methylation patterns are associated with this conversion, we examined the effect of manipulating DNA methyltransferase (Dnmt) expression on the fate of cultured SSCs, germline stem (GS) cells. Dnmt1 knockdown induced apoptosis in GS cells, which was attenuated by the loss of Trp53. In contrast, GS cells proliferated normally in vitro after Dnmt3a/Dnmt3b ablation or during Dnmt3l overexpression. However, Dnmt3a/Dnmt3b double-mutant cells showed hypomethylation in the SineB1 repetitive sequence, and Dnmt3l-overexpressing cells showed hypermethylation in major and minor satellite sequences; neither cell type formed teratomas and completed spermatogenesis following transplantation into the seminiferous tubules. Although genetic manipulation did not increase the conversion of GS cells to a pluripotent state, these results underscore the important role of DNMTs in survival and spermatogenic differentiation in SSCs.

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  364. Pro-apoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of SOD2 knockout mice. Reviewed

    Fan YY, Zhan Y, Aukema HM, Davidson LA, Zhou L, Callaway E, Tian Y, Weeks BR, Lupton JR, Toyokuni S, Chapkin RS

    J. Nutr.   Vol. 139   page: 1328-1332   2009.5

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  365. Effect of edaravone, a novel free radical scavenger, supplemented to cardioplegia on myocardial function after cardioplegic arrest: in vitro study of isolated rat heart Reviewed

    Kazuhiro Yamazaki, Senri Miwa, Shinya Toyokuni, Shintaro Nemoto, Wnimunk Oriyanhan, Kiyoaki Takaba, Yoshiaki Saji, Akira Marui, Takeshi Nishina, Tadashi Ikeda, Masashi Komeda

    HEART AND VESSELS   Vol. 24 ( 3 ) page: 228 - 235   2009.5

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    Cardioplegic arrest has been the main mechanism of myocardial protection during open-heart surgery; however, it causes myocardial injury during ischemia-reperfusion. Free radical scavengers are widely known to attenuate ischemia-reperfusion injury in various settings. We investigated the effects of edaravone, a novel free radical scavenger that was originally used for cerebral protection, on myocardial function during ischemia-reperfusion after cardioplegic arrest. Rat hearts were excised and perfused using Langendorff apparatus. The hearts were cardioplegically arrested for 90 min using St. Thomas' Hospital cardioplegic solution (ST solution) at 4A degrees C every 45 min and then reperfused for 20 min. The hearts were divided into 4 groups (n = 13 in each group). In Group ST, the hearts were arrested using the ST solution alone. In Groups L, M, and H, the hearts were arrested using the ST solution supplemented with a low-dose (1 mu M), moderate dose (10 mu M), and high dose (100 mu M) of edaravone, respectively. Left ventricular function (+dp/dt (max)) and the levels of the cardiac enzymes released were measured before and after cardioplegic arrest. At the end of the study, the water content and the tissue oxidative stress (8-hydroxy-2'-deoxyguanosine) of the heart were measured. During reperfusion, the edaravone-treated groups showed a greater functional recovery with regard to the +dp/dt (max) (P &lt; 0.05). The lactate level was the lowest (P &lt; 0.01) in Group M. The water content of the hearts in the edaravone-treated groups was significantly lower (P &lt; 0.05) than that in Group ST. Oxidative stress was significantly lower (P &lt; 0.01) in the edaravone-treated hearts than in Group ST, and it was the lowest in Group M. The addition of edaravone to the cardioplegic solution ameliorates the impairment in myocardial function by reducing the oxidative stress after cardioplegic arrest. In this study, the maximum improvement in the myocardial function was achieved by addition of a moderate dose (10 mu M) of edaravone.

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  366. 卵巣明細胞腺癌のアレイCGH解析

    山下 依子, 石原 敏和, 永井 裕崇, 中村 栄男, 豊國 伸哉

    日本病理学会会誌   Vol. 98 ( 1 ) page: 379 - 379   2009.3

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  367. アスベスト関連疾患 病態から治療まで アスベスト発癌機構の解明と予防への応用

    豊國 伸哉

    日本病理学会会誌   Vol. 98 ( 1 ) page: 144 - 144   2009.3

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  368. アスベスト発癌における鉄の関与

    石原 敏和, 永井 裕崇, 蒋 麗, 大川 克也, 豊國 伸哉

    日本病理学会会誌   Vol. 98 ( 1 ) page: 399 - 399   2009.3

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  369. アスベスト繊維は非貪食細胞である中皮細胞株に積極的に取り込まれる

    永井 裕崇, 豊國 伸哉

    日本病理学会会誌   Vol. 98 ( 1 ) page: 399 - 399   2009.3

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  370. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury. Reviewed International journal

    Yoshimi Hiraumi, Eri Iwai-Kanai, Shiro Baba, Yoshihiro Yui, Yuri Kamitsuji, Yasuhiro Mizushima, Hiroshi Matsubara, Motonobu Watanabe, Ken-Ichirou Watanabe, Shinya Toyokuni, Hiroaki Matsubara, Tatsutoshi Nakahata, Souichi Adachi

    American journal of physiology. Heart and circulatory physiology   Vol. 296 ( 3 ) page: H823-32 - H832   2009.3

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    Hiraumi Y, Iwai-Kanai E, Baba S, Yui Y, Kamitsuji Y, Mizushima Y, Matsubara H, Watanabe M, Watanabe K, Toyokuni S, Matsubara H, Nakahata T, Adachi S. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury. Am J Physiol Heart Circ Physiol 296: H823-H832, 2009. First published January 9, 2009; doi:10.1152/ajpheart.00774.2008.-Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.

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  371. 酸化ストレス発がん 動物モデルからアスベスト発がんまで

    豊國 伸哉

    日本体質医学会雑誌   Vol. 71 ( 1 ) page: 26 - 33   2009.2

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    酸化ストレスには種々の病態が存在するが、ほとんどの場合、鉄の関与が想定されている。鉄はヒトにおいて最も多く含まれる重金属である。隕石の成分分析より宇宙には鉄が豊富にあると考えられているが、私たちは進化の過程で酸素の運搬体として鉄を選択した。鉄は、不足すると貧血や筋肉の機能障害をひき起こすが、逆に過剰は種々の実質臓器に傷害を与えるだけでなく発がんのリスクとなることが明らかにされている。鉄吸収が増加する遺伝性疾患のヘモクロマトーシスでは肝癌発生リスクが著しく増加する。昨今、社会的問題となっているアスベストによる中皮腫も、鉄含有量の高いアスベストの発がん性が高いとされている。なぜ鉄が発がんと関連するかに関しては、鉄が遷移金属であり、酸化還元反応の触媒として作用し酸化ストレスを引き起こすこと、ならびに、鉄が多数の酵素の活性部位に含まれており、必須栄養素のひとつでもあるという2つの側面がある。酸化ストレスの発がん機構への関与について最近多くの新事実がわかってきた。鉄はヒトの体質に関しても重要な役割を果たしていると考えられ、コントロールが可能な因子である。年齢に応じた適切なコントロールにより、種々の生活習慣病を遅延できる可能性が示唆される。(著者抄録)

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  372. MECHANISMS OF ASBESTOS-INDUCED CARCINOGENESIS

    Shinya Toyokuni

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 71 ( 1-2 ) page: 1 - 10   2009.2

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    Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM and the development of animal models, the carcinogenic mechanisms of the disease remain unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be summarized as follows: (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of free radicals due to their inability to digest the fibers, and epidemiological studies indicating that iron-containing asbestos fibers appear more carcinogenic; (2) the "chromosome tangling theory" postulates that asbestos fibers damage chromosomes when cells divide; and (3) the "theory of adsorption of many specific proteins as well as carcinogenic molecules" states that asbestos fibers in vivo concentrate proteins or chemicals including the components of cigarette smoke. Elucidation of the major mechanisms underlying DMM would be helpful for the development of novel strategies to prevent DMM induction in people who have already been exposed to asbestos.

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  373. Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma Reviewed

    Yi Zhong, Janice Onuki, Toshinari Yamasaki, Osamu Ogawa, Shinya Akatsuka, Shinya Toyokuni

    CARCINOGENESIS   Vol. 30 ( 1 ) page: 158 - 164   2009.1

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    A growing number of studies indicate a link between oxidative stress and cancer. We previously developed a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Here, we performed a genome-wide analysis to study characteristics of genomic alteration and identify putative genes involved in the development of Fe-NTA-induced RCCs. Array-based comparative genomic hybridization analyses revealed a chromosomal loss spanning chromosome 8 in most of the RCCs studied, with a common deletion at 8q31-32, which was confirmed by loss of heterozygosity (LOH) analysis. Studies of gene expression in RCCs or following Fe-NTA treatment revealed globally decreased transcription levels of 34 genes derived from chromosome 8 that are expressed in the kidney. Among them, the aminoacylase 1 (Acy1) gene, which maps to 8q32 and is highly expressed in the kidney, displayed a significantly decreased level of expression in RCCs. Significant amounts of the Acy1 protein were detected in the cytoplasm as well as in the nuclei of renal proximal tubular cells of untreated rats. Transfection of Acy1 into RCC cell lines inhibited proliferation and colony formation on soft agar. An increased number of apoptotic cells were observed following Acy1 transfection. The rat 8q31-32 chromosomal region corresponds to human 3p21.31-24.1, a hot spot where LOH is frequently found in various human cancers. Thus, Fe-NTA-induced renal tumor model is ideal for studying the link between deletions within this region and tumor formation. Our data demonstrate that Acy1 functions as a tumor suppressor in this rat RCC model.

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  374. Biased Immunoglobulin VH Recombination and Increased Expression of Chemokine Receptor XCR1 Are Distinct Features of Bone Marrow-Derived Diffuse Large B-Cell Lymphoma

    Y. Yamashita, D. Kajiura, S. Nakamura, S. Toyokuni, N. Mori

    MODERN PATHOLOGY   Vol. 22   page: 292A - 292A   2009.1

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  375. Biased Immunoglobulin VH Recombination and Increased Expression of Chemokine Receptor XCR1 Are Distinct Features of Bone Marrow-Derived Diffuse Large B-Cell Lymphoma

    Y. Yamashita, D. Kajiura, S. Nakamura, S. Toyokuni, N. Mori

    LABORATORY INVESTIGATION   Vol. 89   page: 292A - 292A   2009.1

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  376. Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma Reviewed

    Yi Zhong, Janice Onuki, Toshinari Yamasaki, Osamu Ogawa, Shinya Akatsuka, Shinya Toyokuni

    Carcinogenesis   Vol. 30 ( 1 ) page: 158 - 164   2009

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    A growing number of studies indicate a link between oxidative stress and cancer. We previously developed a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Here, we performed a genome-wide analysis to study characteristics of genomic alteration and identify putative genes involved in the development of Fe-NTA-induced RCCs. Array-based comparative genomic hybridization analyses revealed a chromosomal loss spanning chromosome 8 in most of the RCCs studied, with a common deletion at 8q31-32, which was confirmed by loss of heterozygosity (LOH) analysis. Studies of gene expression in RCCs or following Fe-NTA treatment revealed globally decreased transcription levels of 34 genes derived from chromosome 8 that are expressed in the kidney. Among them, the aminoacylase 1 (Acy1) gene, which maps to 8q32 and is highly expressed in the kidney, displayed a significantly decreased level of expression in RCCs. Significant amounts of the Acy1 protein were detected in the cytoplasm as well as in the nuclei of renal proximal tubular cells of untreated rats. Transfection of Acy1 into RCC cell lines inhibited proliferation and colony formation on soft agar. An increased number of apoptotic cells were observed following Acy1 transfection. The rat 8q31-32 chromosomal region corresponds to human 3p21.31-24.1, a hot spot where LOH is frequently found in various human cancers. Thus, Fe-NTA-induced renal tumor model is ideal for studying the link between deletions within this region and tumor formation. Our data demonstrate that Acy1 functions as a tumor suppressor in this rat RCC model. © The Author 2008. Published by Oxford University Press. All rights reserved.

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  377. 鉄と発癌

    豊國 伸哉

    現代医学   Vol. 56 ( 2 ) page: 297 - 306   2008.11

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  378. Characteristics and modifying factors of asbestos-induced oxidative DNA damage. Reviewed International journal

    Li Jiang, Hirotaka Nagai, Hiroki Ohara, Shigeo Hara, Mitsuhiro Tachibana, Seishiro Hirano, Yasushi Shinohara, Norihiko Kohyama, Shinya Akatsuka, Shinya Toyokuni

    Cancer science   Vol. 99 ( 11 ) page: 2142 - 51   2008.11

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    Respiratory exposure to asbestos has been linked with mesothelioma in humans. However, its carcinogenic mechanism is still unclear. Here we studied the ability of chrysotile, crocidolite and amosite fibers to induce oxidative DNA damage and the modifying factors using four distinct approaches. Electron spin resonance analyses revealed that crocidolite and amosite containing high amounts of iron, but not chrysotile, catalyzed hydroxyl radical generation in the presence of H(2)O(2), which was enhanced by an iron chelator, nitrilotriacetic acid, and suppressed by desferal. Natural iron chelators, such as citrate, adenosine 5&apos;-triphosphate and guanosine 5&apos;-triphosphate, did not inhibit this reaction. Second, we used time-lapse video microscopy to evaluate how cells cope with asbestos fibers. RAW264.7 cells, MeT-5 A and HeLa cells engulfed asbestos fibers, which reached not only cytoplasm but also the nucleus. Third, we utilized supercoiled plasmid DNA to evaluate the ability of each asbestos to induce DNA double strand breaks (DSB). Crocidolite and amosite, but not chrysotile, induced DNA DSB in the presence of iron chelators. We cloned the fragments to identify break sites. DSB occurred preferentially within repeat sequences and between two G:C sequences. Finally, i.p. administration of each asbestos to rats induced not only formation of nuclear 8-hydroxy-2&apos;-deoxyguanosine in the mesothelia, spleen, liver and kidney but also significant iron deposits in the spleen. Together with the established carcinogenicity of i.p. chrysotile, our data suggest that asbestos-associated catalytic iron, whether constitutional or induced by other mechanisms, plays an important role in asbestos-induced carcinogenesis and that chemoprevention may be possible through targeting the catalytic iron. (Cancer Sci 2008; 99: 2142-2151).

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  379. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias Reviewed

    Y. Kamitsuji, J. Kuroda, S. Kimura, S. Toyokuni, K. Watanabe, E. Ashihara, H. Tanaka, Y. Yui, M. Watanabe, H. Matsubara, Y. Mizushima, Y. Hiraumi, E. Kawata, T. Yoshikawa, T. Maekawa, T. Nakahata, S. Adachi

    CELL DEATH AND DIFFERENTIATION   Vol. 15 ( 11 ) page: 1712 - 1722   2008.11

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    Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis ( CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.

    DOI: 10.1038/cdd.2008.107

    Web of Science

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Presentations 94

  1. Role of Ferroptosis in carcinogenesis and tumor biology; Symposium 4. Role of Redox-active Metals for the Prevention and Treatment of Cancer in the Era of Precision Medicine Invited International conference

    Shinya Toyokuni

    20th Binennial Meeting of Society for Free Radical Research International  2021.3.16  SFRR Europe/International

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    Event date: 2021.3

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:Online meeting   Country:Spain  

  2. Ferroptosis at the crossroads of aging, infection and camcer: Non-thermal plasma as a ferroptosis inducer for cancer cells Invited International conference

    Shinya Toyokuni

    ISPlasma2021/IC-PLANTS2021 13th International Symposium on Advanced Plasma Science and its Appilcations for Nitrides and Nanomaterials 14th Internaitonal Conference on Plasma-Nano Technilogy & Science  2021.3.8  Meijo University

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    Event date: 2021.3

    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:Nagoya   Country:Japan  

  3. Role of Ferroptosis in carcinogenesis and tumor biology; Symposium 4. Role of Redox-active Metals for the Prevention and Treatment of Cancer in the Era of Precision Medicine Invited International conference

    Shinya Toyokuni

    20th Binennial Meeting of Society for Free Radical Research International  2021.3.16  SFRR Europe/International

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    Event date: 2021.3

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:Online meeting   Country:Spain  

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  4. Ferroptosis at the crossroads of aging, infection and camcer: Non-thermal plasma as a ferroptosis inducer for cancer cells Invited International conference

    Shinya Toyokuni

    ISPlasma2021/IC-PLANTS2021 13th International Symposium on Advanced Plasma Science and its Appilcations for Nitrides and Nanomaterials 14th Internaitonal Conference on Plasma-Nano Technilogy & Science  2021.3.8  Meijo University

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    Event date: 2021.3

    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:Nagoya   Country:Japan  

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  5. 発がんにおけるフェロトーシスの意義 シンポジウム:生命金属科学分野の創成による生体内金属動態の統合的研究:生命金属研究のさらなる発展にむけて  Invited

    豊國伸哉

    第31回日本微量元素学会学術集会  2020.11.27  日本微量元素学会

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    Event date: 2020.11

    Language:Japanese  

    Venue:静岡県静岡市 静岡県立大学   Country:Japan  

  6. 発がんにおけるフェロトーシスの意義 シンポジウム:生命金属科学分野の創成による生体内金属動態の統合的研究:生命金属研究のさらなる発展にむけて Invited

    豊國伸哉

    第31回日本微量元素学会学術集会  2020.11.27  日本微量元素学会

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    Event date: 2020.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:静岡県静岡市 静岡県立大学   Country:Japan  

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  7. International Session: レドックス活性鉄の制御不全を介したアスベストにより発がん機構  Invited International conference

    伊藤文哉、豊國伸哉 

    第79回日本癌学会学術集会  2020.10.2  日本癌学会

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    Event date: 2020.10

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:広島県広島市リーガロイヤルホテル広島・メルパルク広島   Country:Japan  

  8. シンポジウム: アスベスト誘発ラット中皮腫におけるゲノム変異の特徴 Invited International conference

    赤塚慎也、蒋麗、エルザワハリ・アスマ、加藤 護、戸塚ゆ加里、柴田龍弘、豊國伸哉

    第79回日本癌学会学術集会  2020.10.3  日本癌学会

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    Event date: 2020.10

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:広島県広島市リーガロイヤルホテル広島・メルパルク広島   Country:Japan  

  9. シンポジウム: アスベスト誘発ラット中皮腫におけるゲノム変異の特徴 Invited International conference

    赤塚慎也, 蒋麗, エルザワハリ・アスマ, 加藤 護, 戸塚ゆ加里, 柴田龍弘, 豊國伸哉

    第79回日本癌学会学術集会  2020.10.3  日本癌学会

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    Event date: 2020.10

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:広島県広島市リーガロイヤルホテル広島・メルパルク広島   Country:Japan  

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  10. International Session: レドックス活性鉄の制御不全を介したアスベストにより発がん機構 Invited International conference

    伊藤文哉, 豊國伸哉

    第79回日本癌学会学術集会  2020.10.2  日本癌学会

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    Event date: 2020.10

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

    Venue:広島県広島市リーガロイヤルホテル広島・メルパルク広島   Country:Japan  

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  11. 細胞外微粒子の生体応用と発がん シンポジウム:細胞外微粒子の研究を加速する分析化学 Invited

    豊國伸哉

    日本分析化学会 第69年会  2020.9.16  日本分析化学会

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    Event date: 2020.9

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:オンライン開催   Country:Japan  

  12. 細胞外微粒子の生体応用と発がん シンポジウム:細胞外微粒子の研究を加速する分析化学 Invited

    豊國伸哉

    日本分析化学会 第69年会  2020.9.16  日本分析化学会

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    Event date: 2020.9

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:オンライン開催   Country:Japan  

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  13. シンポジウム2:がん予防への新概念 がん予防におけるフェロトーシスの意義 Invited

    豊國伸哉

    がん予防学術大会2020米子 第27回日本がん予防学会総会 第43回日本がん疫学・分子疫学研究会総会  2020.9.15  日本がん予防学会

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    Event date: 2020.9

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:オンライン開催(米子、鳥取県)   Country:Japan  

  14. シンポジウム2:がん予防への新概念 がん予防におけるフェロトーシスの意義 Invited

    豊國伸哉

    がん予防学術大会2020米子 第27回日本がん予防学会総会 第43回日本がん疫学・分子疫学研究会総会  2020.9.15  日本がん予防学会

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    Event date: 2020.9

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

    Venue:オンライン開催(米子、鳥取県)   Country:Japan  

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  15. がんはどうしてできるかのはなし Invited

    豊國伸哉

    名古屋大学オープンレクチャー2021  2020.3.20  名古屋大学

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    Event date: 2020.3

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:ウェブ開催   Country:Japan  

  16. がんはどうしてできるかのはなし Invited

    豊國伸哉

    名古屋大学オープンレクチャー2021  2020.3.20  名古屋大学

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    Event date: 2020.3

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:ウェブ開催   Country:Japan  

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  17. Asbestos-induced carcinogenesis is oxidative stress-dependent. The 4th International Conference on Oxidative/Nitrosative Stress and Disease International conference

    The 4th International Conference on Oxidative/Nitrosative Stress and Disease 

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    Event date: 2009.10

    Language:English   Presentation type:Poster presentation  

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  18. Association of oxidatives stress with carcinogenesis. Invited International conference

    SFRR International Free Radical School in Japan 2009 

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    Event date: 2009.9

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  19. Chronic oxidative stress as a cause of genomic amplification. International conference

    Keystone Symposia: Cancer Genomics and epigenomics 

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    Event date: 2008.2

    Language:English   Presentation type:Oral presentation (general)  

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  20. Chronic oxidative stress as a cause of genomic amplification and deletion. Invited International coauthorship International conference

    4th Joint Meeting of the Society for Free Radical Research Australasia and Japan 

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    Event date: 2007.12

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  21. アスベスト・タルクは卵巣表層上皮において細胞内の鉄および酸化ストレスの上昇を惹起し発がんに関わる 

    本岡大社、伊藤文哉、豊國伸哉 

    日本酸化ストレス学会東海支部第9回学術集会  2021.2.13  日本酸化ストレス学会東海支部

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    Event date: 2021.2

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:ウェブ開催 金城学院大学、愛知県名古屋市   Country:Japan  

  22. アスベスト・タルクは卵巣表層上皮において細胞内の鉄および酸化ストレスの上昇を惹起し発がんに関わる

    本岡大社, 伊藤文哉, 豊國伸哉

    日本酸化ストレス学会東海支部第9回学術集会  2021.2.13  日本酸化ストレス学会東海支部

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    Event date: 2021.2

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:ウェブ開催 金城学院大学、愛知県名古屋市   Country:Japan  

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  23. アスベストとタルクは鉄過剰環境を形成し卵巣癌の発がんに関わる International conference

    本岡大社、伊藤文哉、田代浩德、片渕秀隆、豊國伸哉 

    第79回日本癌学会学術集会  2020.10.1  日本癌学会

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    Event date: 2020.10

    Language:English   Presentation type:Oral presentation (general)  

    Venue:広島県広島市リーガロイヤルホテル広島・メルパルク広島   Country:Japan  

  24. アスベストとタルクは鉄過剰環境を形成し卵巣癌の発がんに関わる International conference

    本岡大社, 伊藤文哉, 田代浩德, 片渕秀隆, 豊國伸哉

    第79回日本癌学会学術集会  2020.10.1  日本癌学会

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    Event date: 2020.10

    Language:English   Presentation type:Oral presentation (general)  

    Venue:広島県広島市リーガロイヤルホテル広島・メルパルク広島   Country:Japan  

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  25. アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣がんの発がんに関わる

    本岡大社、伊藤文哉、豊國伸哉 

    第10回名古屋大学医学系研究科・生理学研究所合同シンポジウム  2020.9.19  名古屋大学医学系研究科

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催   Country:Japan  

  26. アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣がんの発がんに関わる

    本岡大社, 伊藤文哉, 豊國伸哉

    第10回名古屋大学医学系研究科・生理学研究所合同シンポジウム  2020.9.19  名古屋大学医学系研究科

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催   Country:Japan  

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  27. アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣癌の発癌に関わる 

    本岡大社、伊藤文哉、豊國伸哉 

    文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム 若手支援技術講習会  2020.9.11  文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催   Country:Japan  

  28. 卵巣子宮内膜症モデルマウスの作成

    林 祥太郎、豊國伸哉 

    文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム 若手支援技術講習会  2020.9.11  文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催   Country:Japan  

  29. 卵巣子宮内膜症モデルマウスの作成

    林 祥太郎, 豊國伸哉

    文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム 若手支援技術講習会  2020.9.11  文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催   Country:Japan  

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  30. アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣癌の発癌に関わる

    本岡大社, 伊藤文哉, 豊國伸哉

    文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム 若手支援技術講習会  2020.9.11  文部科学省新学術領域研究学術研究支援基盤形成:先端モデル動物支援プラットフォーム

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催   Country:Japan  

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  31. 市民公開講座:病理学研究の楽しみ Invited

    豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:オンライン開催、博多   Country:Japan  

  32. アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣癌の発癌に関わる

    本岡 大社、豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

  33. 中皮オルガノイドの創出

    井上桃花、伊藤文哉、豊國伸哉 

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

  34. 低温プラズマにより生じるヒドロキシラジカルはアスコルビン酸により効果的に消去される

    石津裕梨、岡崎泰昌、豊國伸哉 

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

  35. マウス系統間における腎酸化ストレス応答の際に関わる遺伝子の解析

    平野龍一、赤塚慎也、豊國伸哉 

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

  36. 生理的フェロトーシス可視化のためのバイオマーカーの開発

    鄭好、豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:English   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

  37. 低温プラズマ活性化培養液を用いた悪性中皮腫の治療方法の開発

    蒋麗、豊國伸哉 

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

  38. BRCA1 deficiency modifies iron metabolism and ferric nitrilotriacetate-induced carcinogenesis

    孔穎怡、豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:English   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

  39. 生理的フェロトーシス可視化のためのバイオマーカーの開発

    鄭好, 豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:English   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

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  40. 市民公開講座:病理学研究の楽しみ Invited

    豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Public lecture, seminar, tutorial, course, or other speech  

    Venue:オンライン開催、博多   Country:Japan  

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  41. 低温プラズマ活性化培養液を用いた悪性中皮腫の治療方法の開発

    蒋麗, 豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

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  42. 中皮オルガノイドの創出

    井上桃花, 伊藤文哉, 豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

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  43. 低温プラズマにより生じるヒドロキシラジカルはアスコルビン酸により効果的に消去される

    石津裕梨, 岡崎泰昌, 豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

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  44. マウス系統間における腎酸化ストレス応答の際に関わる遺伝子の解析

    平野龍一, 赤塚慎也, 豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

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  45. アスベストは卵巣表層上皮に鉄過剰状態を形成し卵巣癌の発癌に関わる

    本岡 大社, 豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

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  46. BRCA1 deficiency modifies iron metabolism and ferric nitrilotriacetate-induced carcinogenesis

    孔穎怡, 豊國伸哉

    第109回日本病理学会総会  2020.7.1  日本病理学会

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    Event date: 2020.7

    Language:English   Presentation type:Poster presentation  

    Venue:オンライン開催(博多、福岡)   Country:Japan  

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  47. アスベストによる細胞死依存性EVを介した中皮腫発がん機構の解明 

    伊藤文哉、豊國伸哉

    第20回分子予防環境医学研究会大会  2020.2.22  分子予防環境医学研究会

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    Event date: 2020.2

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:ウェブ開催 東京都品川区、FUKURASHIA品川クリスタル(港南)   Country:Japan  

  48. アスベストによる細胞死依存性EVを介した中皮腫発がん機構の解明

    伊藤文哉, 豊國伸哉

    第20回分子予防環境医学研究会大会  2020.2.22  分子予防環境医学研究会

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    Event date: 2020.2

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:ウェブ開催 東京都品川区、FUKURASHIA品川クリスタル(港南)   Country:Japan  

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  49. 宿題報告3:酸化ストレス病理学の確立とその疾患予防への展望 Invited

    豊國 伸哉

    第104回日本病理学会総会 

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    Event date: 2015.4 - 2015.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:名古屋国際会議場   Country:Japan  

  50. 宿題報告3:酸化ストレス病理学の確立とその疾患予防への展望 Invited

    豊國 伸哉

    第104回日本病理学会総会  2015.4.30  日本病理学会

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    Event date: 2015.4 - 2015.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:名古屋国際会議場   Country:Japan  

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  51. Asbestos-induced carcinogenesis is oxidative stress-dependent. The 4th International Conference on Oxidative/Nitrosative Stress and Disease International conference

    The 4th International Conference on Oxidative/Nitrosative Stress and Disease 

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    Event date: 2009.10

    Language:English   Presentation type:Poster presentation  

  52. Association of oxidatives stress with carcinogenesis. International conference

    SFRR International Free Radical School in Japan 2009 

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    Event date: 2009.9

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  53. Asbestos-induced carcinogenesis is oxidative stress-dependent. International conference

    7th COSTAM/SFRR (Asia/Malaysia) International Workshop 2009 and 4th Biennial Meeting of SFRR Asia 

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    Event date: 2009.7

    Language:English   Presentation type:Oral presentation (invited, special)  

  54. Asbestos-induced carcinogenesis is oxidative stress-dependent. International conference

    7th COSTAM/SFRR (Asia/Malaysia) International Workshop 2009 and 4th Biennial Meeting of SFRR Asia 

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    Event date: 2009.7

    Language:English   Presentation type:Oral presentation (invited, special)  

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  55. アスベスト発癌機構の解明とその予防への応用 シンポジウム:アスベスト関連疾患-病態から治療まで

    豊國伸哉

    第98回日本病理学会総会 

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    Event date: 2009.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  56. アスベスト発癌機構の解明とその予防への応用 シンポジウム:アスベスト関連疾患-病態から治療まで

    豊國伸哉

    第98回日本病理学会総会 

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    Event date: 2009.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  57. アスベスト曝露と中皮腫発生のつながり

    豊國伸哉

    市民公開講座:アスベスト起因性疾患:悪性中皮腫の克服に向けて 

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    Event date: 2009.3

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  58. アスベスト曝露と中皮腫発生のつながり

    豊國伸哉

    市民公開講座:アスベスト起因性疾患:悪性中皮腫の克服に向けて 

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    Event date: 2009.3

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  59. Role of oxidative stress in asbestos-induced carcinogenesis.

    International Workshop at Nagoya University: Recent Progress in Environmental, Health and Safety Research on Manufactured Nanomaterials 

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    Event date: 2008.12

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  60. Role of oxidative stress in asbestos-induced carcinogenesis.

    International Workshop at Nagoya University: Recent Progress in Environmental, Health and Safety Research on Manufactured Nanomaterials 

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    Event date: 2008.12

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  61. Oxygenomics approach to understand chronic oxidative stress as a cause of genomics amplification and deletion. International conference

    The 7th China-Japan Joint Conference for Cancer Research “Infection, inflammation and cancer" 

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    Event date: 2008.12

    Language:English   Presentation type:Oral presentation (invited, special)  

  62. Oxygenomics approach to understand chronic oxidative stress as a cause of genomics amplification and deletion. International conference

    The 7th China-Japan Joint Conference for Cancer Research “Infection, inflammation and cancer" 

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    Event date: 2008.12

    Language:English   Presentation type:Oral presentation (invited, special)  

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  63. 鉄と発癌:動物実験からオキシゲノミクスまで

    豊國伸哉

    第5回酸化ストレスと肝研究会 

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    Event date: 2008.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  64. 鉄と発癌:動物実験からオキシゲノミクスまで

    豊國伸哉

    第5回酸化ストレスと肝研究会 

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    Event date: 2008.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  65. Molecular mechanisms of oxidative stress-induced carcinogenesis: From epidemiology to oxygenomics. International conference

    The 14th Biennial Meeting of the Society for Free Radical Research International (14th SFRRI) 

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    Event date: 2008.10

    Language:English   Presentation type:Oral presentation (invited, special)  

  66. Molecular mechanisms of oxidative stress-induced carcinogenesis: From epidemiology to oxygenomics. International conference

    The 14th Biennial Meeting of the Society for Free Radical Research International (14th SFRRI) 

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    Event date: 2008.10

    Language:English   Presentation type:Oral presentation (invited, special)  

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  67. Oxygenomics approach to undestand chronic oxidative stress as a cause of genomic amplification and deletion.

    Lipid Peroxidation 2008 

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    Event date: 2008.10

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  68. Oxygenomics approach to undestand chronic oxidative stress as a cause of genomic amplification and deletion.

    Lipid Peroxidation 2008 

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    Event date: 2008.10

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  69. 教育講演2 酸化ストレス発がん:動物モデルからアスベスト発がんまで

    豊國伸哉

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    Event date: 2008.9

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  70. 教育講演2 酸化ストレス発がん:動物モデルからアスベスト発がんまで

    豊國伸哉

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    Event date: 2008.9

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  71. 病理の面白さ

    第2回日本病理学会東海支部夏の学校 

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    Event date: 2008.8

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  72. 病理の面白さ

    第2回日本病理学会東海支部夏の学校 

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    Event date: 2008.8

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  73. シンポジウム:酸化的DNA損傷と発がん 酸化ストレス発がんの標的遺伝子へのアプローチ

    豊國伸哉

    第61回日本酸化ストレス学会学術集会 

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    Event date: 2008.6

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  74. シンポジウム:酸化的DNA損傷と発がん 酸化ストレス発がんの標的遺伝子へのアプローチ

    豊國伸哉

    第61回日本酸化ストレス学会学術集会 

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    Event date: 2008.6

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  75. 酸化ストレス発癌の標的遺伝子について 合同シンポジウム(1)酸化ストレスと発がん

    豊國伸哉、赤塚慎也、劉 玉亭

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    Event date: 2008.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  76. 酸化ストレス発癌の標的遺伝子について 合同シンポジウム(1)酸化ストレスと発がん

    豊國伸哉, 赤塚慎也, 劉 玉亭

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    Event date: 2008.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

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  77. 公募シンポジウム:分子予防・環境医学への新たな挑戦 酸化ストレス発がんの標的遺伝子について

    豊國伸哉

    第78回日本衛生学会総会 

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    Event date: 2008.3

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  78. 公募シンポジウム:分子予防・環境医学への新たな挑戦 酸化ストレス発がんの標的遺伝子について

    豊國伸哉

    第78回日本衛生学会総会 

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    Event date: 2008.3

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  79. Chronic oxidative stress as a cause of genomic amplification. International conference

    Keystone Symposia: Cancer Genomics and epigenomics 

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    Event date: 2008.2

    Language:English   Presentation type:Oral presentation (general)  

  80. 胸膜中皮腫とアスベスト・鉄発癌

    豊國伸哉

    BioIron2007京都 フォローアップシンポジウム 

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    Event date: 2008.2

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  81. 胸膜中皮腫とアスベスト・鉄発癌

    豊國伸哉

    BioIron2007京都 フォローアップシンポジウム 

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    Event date: 2008.2

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  82. Oxygenomics: a novel approach to understand oxidative stress-induced carcinogenesis.

    Biomarkers of Oxidative Stress in Health and Diseases 

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    Event date: 2008.1

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  83. Oxygenomics: a novel approach to understand oxidative stress-induced carcinogenesis.

    Biomarkers of Oxidative Stress in Health and Diseases 

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    Event date: 2008.1

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    Country:Japan  

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  84. Chronic oxidative stress as a cause of genomic amplification and deletion. International conference

    4th Joint Meeting of the Society for Free Radical Research Australasia and Japan 

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    Event date: 2007.12

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  85. Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phophatase to activate beta-catenin pathway. International conference

    International Conference on Food Factors and Health Promotion 

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    Event date: 2007.11

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  86. Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phophatase to activate beta-catenin pathway. Invited International conference

    International Conference on Food Factors and Health Promotion 

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    Event date: 2007.11

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  87. シンポジウム「悪性中皮腫の克服に向けて」:鉄を視点とするアスベスト発癌の解明と予防・診断・治療への応用の可能性

    豊國伸哉

    第48回日本肺癌学会総会 

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    Event date: 2007.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  88. シンポジウム「悪性中皮腫の克服に向けて」:鉄を視点とするアスベスト発癌の解明と予防・診断・治療への応用の可能性

    豊國伸哉

    第48回日本肺癌学会総会 

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    Event date: 2007.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

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  89. シンポジウム:Genomic instability: 酸化ストレスによるゲノム傷害と発がん

    豊國伸哉

    第66回日本癌学会学術総会 

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    Event date: 2007.10

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  90. シンポジウム:Genomic instability: 酸化ストレスによるゲノム傷害と発がん

    豊國伸哉

    第66回日本癌学会学術総会 

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    Event date: 2007.10

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    Country:Japan  

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  91. ゲノムからみた鉄発がんを解く鍵

    豊國伸哉

    第31回日本鉄バイオサイエンス学会学術集会:シンポジウム「鉄を起点としてがんを考える」 

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    Event date: 2007.4

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  92. ゲノムからみた鉄発がんを解く鍵

    豊國伸哉

    第31回日本鉄バイオサイエンス学会学術集会:シンポジウム「鉄を起点としてがんを考える」 

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    Event date: 2007.4

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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  93. Novel approach for eluidation of iron-induced carcinogenesis: oxygenomics and microRNA. International conference

    BioIron 2007, the Second Congress of the International BioIron Society 

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    Event date: 2007.4

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

  94. Novel approach for eluidation of iron-induced carcinogenesis: oxygenomics and microRNA. International conference

    BioIron 2007, the Second Congress of the International BioIron Society 

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    Event date: 2007.4

    Language:English   Presentation type:Oral presentation (invited, special)  

    Country:Japan  

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Works 2

  1. 第3回病理学会中部支部「夏の学校」を主催

    2009.8

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    日本病理学会中部支部主催

  2. 第3回病理学会中部支部「夏の学校」を主催

    2009.8

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Research Project for Joint Research, Competitive Funding, etc. 7

  1. 細胞外微粒子への生体応答と発がん・動脈硬化症との関連の解析 International coauthorship

    Grant number:JPMJCR19H4  2019.10

    戦略的創造研究推進事業 

    豊國伸哉

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    Authorship:Principal investigator  Grant type:Competitive

  2. 発がん過程におけるフェロトーシスの意義の追究

    Grant number:19-251  2020.4

    高松宮妃癌研究基金  高松宮妃癌研究基金研究助成 

    豊國伸哉

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000

  3. プラズマ誘起生体活性物質による超バイオ機能の展開 International coauthorship

    Grant number:19H05462  2019.4

    科学研究費  特別推進研究

    豊國伸哉

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    Authorship:Coinvestigator(s)  Grant type:Competitive

  4. フェロトーシスにおける細胞内鉄制御機構の破綻 (公募研究)

    Grant number:20H05502  2019.4

    科学研究費  新学術領域「生命金属科学」

    豊國伸哉

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    Authorship:Principal investigator 

  5. 老化研究推進・支援拠点

    2017.4

    健康・医療戦略の推進に必要となる研究開発  老化メカニズムの解明・制御プロジェクト

    豊國伸哉

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    Authorship:Coinvestigator(s) 

  6. 先端モデル動物支援プラットフォーム International coauthorship

    Grant number:16H06276   2016.4

    科学研究費  新学術領域研究(研究領域提案型)『学術研究支援基盤形成』

    豊國伸哉

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    Authorship:Coinvestigator(s)  Grant type:Competitive

  7. 発がんにおけるDNA損傷・修復ダイナミクスの実像解明

    Grant number:20K07588  2019.4

    科学研究費  基盤研究C

    豊國伸哉

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KAKENHI (Grants-in-Aid for Scientific Research) 70

  1. 先端モデル動物支援プラットフォーム

    Grant number:22H04922  2022.4 - 2028.3

    科学研究費助成事業  学術変革領域研究(学術研究支援基盤形成)

    武川 睦寛, 井上 純一郎, 中村 卓郎, 高田 昌彦, 清宮 啓之, 八尾 良司, 山崎 聡, 荒木 喜美, 阿部 学, 山田 泰広, 伊川 正人, 高橋 智, 真下 知士, 小林 和人, 小林 憲太, 井上 謙一, 豊國 伸哉, 二口 充, 神田 浩明, 上野 正樹, 宮崎 龍彦, 高松 学, 宮川 剛, 高雄 啓三, 池田 和隆, 井手 聡一郎, 新田 淳美, 尾藤 晴彦, 虫明 元, 小山内 実, 旦 慎吾, 馬島 哲夫, 田代 悦, 堂前 直, 松本 健, 川田 学, 田原 栄俊, 掛谷 秀昭, 澤崎 達也, 松浦 正明

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    Authorship:Coinvestigator(s) 

    モデル動物を用いた研究は、ヒトへの応用の前段階として、細胞レベルの研究で得られた成果を高度に組織化された個体において実証するためや、遺伝子改変動物においては個体としてどのような表現型を示すかを検証する上で極めて重要である。本プラットフォームは、遺伝子改変動物を初めとする先進的なモデル動物を作製し、その病理形態解析や生理機能解析を支援する。さらに、これまでに構築した先進的な分子プロファイリング技術・資源を利用し、個体レベルの研究の端緒となる分子・細胞レベルの研究支援を行う。
    1, 総括支援活動:ホームページをリニューアルして情報発信し、キックオフシンポジウム、主要学会ブース出展・ランチョンセミナーなど、積極的広報活動を行った。若手支援技術講習会(8/30-9/1、名古屋、134名参加)を開催して若手の修練・交流を支援し、成果発表会(2/8-9、大津、108名参加)を開催して支援成果を把握・総括した。
    2, モデル動物作成支援活動:年2回の課題公募を行い、109件の応募があった。プレコンサルテーションは64件行った。審査の結果、モデル動物作製支援77件、ウイルス作製支援18件の計95件が採択された。各支援拠点は、課題採択者と綿密な打ち合わせを行い、希望する遺伝子改変動物とウイルスベクターを作製し、提供した。
    3, 病理形態解析支援活動:マウスやラットなど実験動物個体に認める病的所見やその治療効果を、H&E染色や免疫染色など主に光学顕微鏡を使用する解析技術を駆使して表現系を解釈する支援活動を実施した。33件の申請を受け、21件を採択した。解剖、標本作製、レーザーマイクロダイセクションなど多彩な解析を行い、論文の投稿・改訂も支援した。
    4, 生理機能解析支援活動:行動学的解析29件、薬理学的解析23件、光技術による操作解析5件、多機能電極・計測データ解析12件、計69件の課題全てについてプレコンサルテーションを行い計画的支援を実施した。支援は、動物モデルにおける病態・生理学的基盤の解明推進などに寄与し、Mol Psychiat誌などに成果が発表された。
    5, 分子プロファイリング支援活動:171件の申請に対し、化合物評価134件(のべ271点)、分子探索30件(のべ88点)の計164件(のべ359点)を採択した。このうち18件はアドホック支援であった。また、新規導入したマウス(2件)、ゼブラフィッシュ(17件)の化合物評価を実施し、動物モデル研究への起点となった。
    1, 総括支援活動:コロナ禍を注視しつつ、対面回帰のトレンドを捉えて若手支援技術講習会および成果発表会の2大イベントを完全オンサイトとしたことで、若手研究者間、支援担当者および被支援者間の学術交流・情報交換を例年以上に活発化することが出来た。プラットフォーム第1期の実績・ノウハウを継承し、新体制を円滑に軌道に乗せることが出来た。
    2, モデル動物作成支援活動:プラットフォーム第一期の実績とノウハウを継承、効率的に遺伝子改変マウス・ラットを作製し、被支援者に提供することができた。今年度から加わったウイルスベクター作製支援活動では、国内のニーズを把握し、新たな支援メニューとして円滑に軌道に乗せることが出来た。
    3, 病理形態解析支援活動:初年度であったが、33件と十分な数の申請が集まり、21件の支援を実施することができた。外部委員2名を含む審査はウェブで実施しているが、円滑に業務を果たすことができている。班員の専門性に応じて支援の振り分けも問題なく実施できた。2月に開催された成果発表会においても、本支援による興味ある成果が複数披露された。
    4, 生理機能解析支援活動:支援対象者のモデルマウスを対象にした行動解析支援を29課題、依存性薬物や治療薬の感受性に関連する行動解析および規制薬物作用ゲノム関連解析支援を23課題、光遺伝学に関する最新技術を活用した研究支援を5課題、多機能集積化電極による最先端の技術提供を行う多元的生理機能計測操作支援を12課題で実施した。
    5, 分子プロファイリング支援活動:前期からの実績とノウハウを継承した細胞パネル等の化合物評価支援4系、標準阻害剤キット等の分子探索支援2系を継続したことが順調な支援実績に繋がった。また、今年度から新たに加わった分子探索支援3系、動物レベルの化合物評価系2系に関しても、支援担当者の綿密な準備により順調に支援実績を伸ばすことができた。
    1, 総括支援活動:前年度の活動を継続する。各支援活動班長・連絡担当者と緊密な連絡を保ち、ワンストップ窓口の機能を強化することでサービスの向上を図る。若手支援技術講習会および成果発表会については、各実行委員長と連携し、学術的内容のみならず、過去の参加者アンケート結果、コロナ禍の推移なども分析しながら企画・運営に当たる。
    2, モデル動物作成支援活動:先端的な遺伝子改変技術の導入および開発に加え、各支援拠点で独自に開発されたリソースを積極的に活用することにより、国内のモデル動物研究を支援する。また、被支援者のニーズ把握に努め、必要とされる遺伝子改変動物とウイルスベクターを効率的に提供する。作製された遺伝子改変動物は、公共リソースバンクに供出し、学術基盤としての研究リソース整備を推進する。
    3, 病理形態解析支援活動:諸学会や若手支援技術講習会などを通じて、文部科学省科学研究費の受給者に本制度の周知を図ることにより、本支援活動を推進する。内容に関しては、AI技術を取り入れた定量化などの解析に関して、新たに技術提供できるようにしたいと考えている。
    4, 生理機能解析支援活動:6つの拠点への支援申請が何れも安定して多数であることから、引き続きニーズに応えられるように拠点における技術力を維持・向上させ、プレコンサルテーションで有意義な計画を立案し、公正に支援課題を選考し、支援実施体制をハイレベルに保つ。また、支援該当部の論文分担執筆を積極的に進め、成果の公表にも貢献する。
    5, 分子プロファイリング支援活動
    前年度に引き続き、被支援者の要望に応じた解析条件のカスタマイズ対応・支援実施後のフォロー(フィードバックミーティングによる科学的助言・技術指導、高次支援の勧奨など)に努めるとともに、定例班会議とユーザーミーティングで課題を共有し、研究支援から発展した効果的な共同研究の提案・斡旋を進める。

  2. 発がんにおけるDNA損傷・修復ダイナミクスの実像解明

    Grant number:20K07588  2020.4 - 2023.3

    文部科学省  科学研究費  基盤研究C

    赤塚 慎也

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    本研究は、DNA損傷のゲノム内分布動態を確定するための方法として次世代シークエンサーを用いた新たな解析法を確立し、発がん刺激によるDNA損傷分布の変化とその意義を明らかにすることを目的とする。DNA損傷は遺伝子変異の原因となるため、そのゲノム内での分布動態を知ることは、がんの発生経路を確定し、予防の方策を講ずるうえで重要となる。本研究では、損傷DNAに対する免疫沈降産物の網羅的解析を次世代シークエンサーの新たな応用技術として確立し、発がん過程におけるDNA損傷のゲノム分布動態を解明する。さらに、その際の変異の発生頻度を評価することにより、DNA損傷分布変化の発がんにおける意義を明らかにする。

  3. Breakdown of iron regulatory mechanisms in ferroptosis

    Grant number:20H05502  2020.4 - 2022.3

    Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\6370000 ( Direct Cost: \4900000 、 Indirect Cost:\1470000 )

  4. Development of "super-bio-functions" by plasma-activated biological substances

    Grant number:19H05462  2019.4 - 2024.3

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\603330000 ( Direct Cost: \464100000 、 Indirect Cost:\139230000 )

  5. Analyses based on iron dynamics and multiomics to overcome oxidative stress-induced carcinogenesis

    Grant number:17H04064  2017.4 - 2020.3

    Toyokuni Shinya

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\17810000 ( Direct Cost: \13700000 、 Indirect Cost:\4110000 )

    This project was planned to establish a basis for novel cancer prevention by evaluating iron dynamics multidimensionally. We established the concept of ferroptosis, as catalytic Fe(II)-dependent regulated necrosis, based on our experience of iron-induced carcinogenesis. We used phlebotomy to remove excess iron in crocidolite-induced mesothelial carcinogenesis, which significantly prolonged survival and reduced tumor burden. We used knockout (KO) mice of 3 repair genes for 8-oxoguanine (Ogg1, Mutyh and Mth1) and found that Mutyh KO showed a tendency to increase iron-induced renal carcinogenesis whereas Mth1 KO significantly reduced crocidolite-induced malignant mesothelioma (MM) in females. MM induction by crocidolite was delayed in Dmt1 transgenic mice. We also found that carbonic anhydrase 9 (CA9) confers ferroptosis-resistance to MM cells in hypoxia. Thus, CA9 can be another target for cancer therapy. In conclusion, iron metabolism regulates not only carcinogenesis but tumor biology.

  6. Development of combinational therapy of non-thermal plasma and carbon nanotubes

    Grant number:16K15257  2016.4 - 2018.3

    Toyokuni Shinya

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3640000 ( Direct Cost: \2800000 、 Indirect Cost:\840000 )

    We obtained fundamental data for the use of combinational therapy of non-thermal plasma (NTP) and carbon nanotubes. We identified hemoglobin, histones and transferrin as specifically adsorbed proteins on carbon nanotube surface with mass spectrometry. Biological effects of NTP exposure were recognized as oxidative stress with biochemical, FACS and immunostaining studies, which was promoted with preincubation with ferric ammonium citrate and repressed by preincubation with redox-inactive iron chelator, desferal. NTP exposure to mesothelioma cells caused an increase in intracellular catalytic Fe(II), lipid peroxidation with increased ferritin/decreased transferrin receptor, which was accompanied by promoted endocytosis and autophagy (ferritinophagy). These data suggest that NTP can cause ferroptosis in mesothelioma cells. As in vitro experiments we also observed that NTP exposure can directly destroy the ferritin core protein and reduce Fe(III) to Fe(II).

  7. 先端モデル動物支援プラットフォーム

    Grant number:16H06276  2016 - 2021

    文部科学省  科学研究費  新学術領域研究(研究領域提案型)『学術研究支援基盤形成』

    豊國伸哉

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Grant amount:\25818000 ( Direct Cost: \19860000 、 Indirect Cost:\5958000 )

    ①総括支援活動 : ホームページ(HP)に改良を加えながら公募の円滑化をさらに進めた。モデル動物作製解析の講習や若手研究者の交流促進を推進する技術講習会を開催した。また成果発表会を開催、全国から127名の参加があり一般口演ならびにポスター発表など、本活動の支援成果を、より幅広い研究分野にアピールした。
    ②モデル動物作製支援活動 : 利用者の様々な要望に個別に対応し、相同組換えやゲノム編集など先進的な遺伝子改変技術を用いて、遺伝子改変マウスおよびラットを合計83件、迅速に作製し、学術研究を推進するための研究リソースを提供した。
    ③病理形態解析支援活動 : 昨年より多い52件の申請を受け、2回の審査の結果、42件に関して病理形態解析を実施した。研究の方向性を裏付ける多くの成果が得られた。論文の図の作成にもかかわり、論文が受理されるまで支援を実施した。
    ④生理機能解析支援活動 : 行動学的解析では23課題、薬理学的解析では9課題、光技術による操作解析では10課題、多機能電極・計測データ解析では16課題をそれぞれ支援し、動物モデルにおける病態・生理学的基盤の解明推進に関する支援を展開した。
    ⑤分子プロファイリング支援活動 : 依頼化合物の分子プロファイリング308件、阻害剤キット配付102枚、RNA干渉キット配付・siRNAデザイン合成92件、バーコードshRNAライブラリーによる化合物の標的経路探索24件、を実施した。
    ①総括支援活動 : 公募申請と選考作業の効率化が促進された。技術講習会と成果発表会で多くの参加者を得た。参加者対象のアンケートから若手の研究意欲を促進する効果が明らかとなった。参加希望者が前年度よりも増え、参加者の研究分野の多様性が一層顕著になった。
    ②モデル動物作製支援活動 : 研究実施計画に沿った支援を行うことができている。増加傾向にある応募課題に対し、最新技術を導入することにより効率化を図り、予算が許す範囲で可能な課題数を採択し、支援を行なった。遺伝子改変が複雑あるいは技術的に難しいケースは、必要な技術を導入・開発することにより対応している。
    ③病理形態解析支援活動 : 年々申請数が増加しており、審査をより厳格に行っている。現在の予算ならびに班員のエフォートにおいてできる最大限の支援活動を実施しており、成果は確実に上がっている。
    ④生理機能解析支援活動 : 支援対象者のモデルマウスを対象にした感覚・運動・認知機能に関わる「網羅的行動テストバッテリー」を用いた行動解析支援を23課題、依存性薬物等の感受性に関連する行動解析および臨床データと遺伝子多型との関連解析を行う規制薬物作用解析支援を9課題、進展著しい光遺伝学に関する最新技術を活用した研究支援を10課題、多機能集積化電極による最先端の技術提供を行う多元的生理機能計測操作支援を16課題で実施した。
    ⑤分子プロファイリング支援活動 : 応募課題の審査体制が軌道に乗り、採否決定までの所要日数が前年度と比較して最大10日程度短縮された。応募前の技術相談を積極的に受け付けたことで、幅広い分野から新規ユーザーを獲得することができた。前年度までの支援成果を受けて高次評価に進んだ課題については、複数の支援担当者間での連携が功を奏した。shRNAライブラリー探索支援では実験条件をカスタマイズし、被支援者の特殊なニーズにも応えた。
    ①総括支援活動 : 支援により得られた成果の広報にも力を入れるとともに、被支援者にも本支援活動の重要性をアピールしてもらうよう働きかける。技術講習会では4プラットフォームとの連携を推進し、H31年度は先進ゲノム解析研究支援プラットフォームから講師と参加者を受け入れる。
    ②モデル動物作製支援活動 : 先端的なゲノム編集技術や研究リソース等を用いて、支援活動の拡充を図るとともに、革新的な遺伝子改変技術および周辺技術の導入・開発を進めることにより、学術研究の推進に貢献するとともに、学術基盤としての研究リソースを整備する。
    ③病理形態解析支援活動 : 現状で予算ならびに支援を担当する班員の対応状況に関して厳しい状態となっていることから、今後は審査をより厳格に行い、成果につながる可能性が高い申請を選択する。基本姿勢として、一旦開始した病理形態支援は論文が受理されるまでサポートするという方針に変化はない。
    ④生理機能解析支援活動 : 5つの拠点への支援申請が何れも安定して多数あることから、引き続きニーズに応えられるように拠点における技術力を維持・向上させ、支援実施体制をハイレベルに保つ。また、研究者コミュニティーにおける支援事業の認知度を向上させるため、学会等での広報活動を行う。技術支援にとどまらず、支援該当部の論文分担執筆を積極的に進め、成果の公表にも貢献する。
    ⑤分子プロファイリング支援活動 : H30年度に引き続き、広報活動の強化・解析条件のカスタマイズ対応・支援実施後のフォロー(科学的助言、共同究の斡旋、高次支援の勧奨)に努めるとともに、年2回の定例班会議で問題点を洗い出し、常に最善の運用体制で支援を実施する。支援内容の性質上、個体レベルの研究を行わない研究者層が主要な被支援者層と一致しているが、共同研究や他の支援活動班との連絡を通じて、個体レベルの研究にも展開させたい。

  8. Systematic genetic analysis for urethane-induced lung cancer susceptibility loci in mice

    Grant number:26430088  2014.4 - 2018.3

    Ohno Tamio

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    QTL analysis using SMXA・RI strains revealed plumonary adenoma resistance locus 1 (Par1) on Chr.11 and Par3 on Chr.12. However, it could not be confirmed the existence and effects of these loci by using congenic strains developed in this study. We conducted re-mapping by the Chr. 11 congenic strains, and indicated that the other Par locus was located between 27.72Mb and 36.39Mb. The Mpg gene, which encodes a ubiquitous DNA repair enzyme associated with lung cancer, is located within this region. A Sanger sequence analysis of the Mpg gene revealed five polymorphic sites in the A/J genome. One variant, p.Ala132Ser, was suggested the strong candidate mutation with regard to susceptibility to urethan-induced lung cancer.

  9. Targeted therapy for ovarian clear cell carcinoma, focusing on MET amplifcation and oxidative stress.

    Grant number:26460423  2014.4 - 2017.3

    YAMASHITA Yoriko

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    At this moment, we do not have definite data about positive effects of Met inhibitors against transplanted ovarian clear cell carcinoma model. There are multiple reasons, but an important factor is that cell lines of ovarian clear cell carcinoma are slow-growing and difficult to obtain stable grafts in nude mice. We have analyzed tumors other than ovarian clear cell carcinomas, and Met amplification was confirmed in a subpopulation of endometrial cancers. On the other hand, breast cancers mostly had no amplification of the Met gene.

  10. The effects of pre-conditioning intervention induced alleviating of dysfunction and brain damage after cerebral infarction or dementia.

    Grant number:26350610  2014.4 - 2017.3

    ISHIDA KAZUTO

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    "Healthy life expectancy" extension is very important for our super aging society, it is necessary to establish a prevention policy of cerebral infarction and dementia to remarkably limit QOL in particular. We examined protective efficacy by exercise or caloric restriction using cerebral infarction or dementia animal model.
    At first, to prevent an obstacle of the cerebral infarction by the exercise from three weeks before cerebral infarction and showed that the expression of the superoxide dismutase in the brain increased as the mechanism. In addition, using another infarction model, pre-conditioning exercise promoted the astrocytic activity and increased hypoxia-inducible factor-1 alpha expression closed area of infarction which means neuro-protective action increased. Furthermore, we examined the pre-conditioning effects of exercise to apolipoprotein E4 knock in mice, known to leak a dementia-like symptom with aging, the recognitive functions about the spatial memory are prevented.

  11. Animal model for cholangiocarcinoma associated with offset printing process

    Grant number:26670329  2014.4 - 2017.3

    Ichihara Gaku

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    Authorship:Collaborating Investigator(s) (not designated on Grant-in-Aid)  Grant type:Competitive

    Although serial cases of cholangiocarcinoma found in an offset printing factory suggest that 1,2-dichloropropane (DCP) is the causative agent for them, the past bioassay studies did not show cholangiocarcinoma. The present study showed difficulty in explaining the species difference in susceptibility to DCP by distribution of glutathione S-transferase. Moreover the study is the first to demonstrate that exposure to DCP induce proliferation and apoptosis of cholangiocytes, as well as contribution of P450 to such effects. The present study strongly indicates that DCP is the causative agent for cholangiocarcinoma.

  12. 新領域「プラズマ医療科学創成」

    2012.10 - 2017.3

    科学研究費補助金  新領域研究

    堀 勝

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    Authorship:Coinvestigator(s) 

  13. Systematization and development of clinical applications for plasma medicine based on scientific infrastructure

    Grant number:24108008  2012.6 - 2017.3

    Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Kikkawa Fumitaka

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Non-thermal plasma has been focused on as a novel medical practice. There have been a number of reports showing the effect of non-thermal plasma on cell death of various cancers. We have succeeded in selective killing of ovarian cancer and glioblastoma brain tumor cells, which are difficult to achieve complete remission under the present therapies, using not only directly but also indirectly plasma referred to as plasma-activated liquids. We have also elucidated that the effects and mechanisms of non-thermal plasma on biological systems using mesothelioma. We have demonstrated that plasma-activated liquids might be more useful for advanced cancers with metastasis and micro-dissemination. On the other hand, for developing medical applications of non-thermal plasma, we have achieved a certain result for regenerative medicine using human adipose tissue-derived stromal cells we established.
    These discoveries have led to the use of non-thermal plasma for alternative clinical applications.

  14. 中皮細胞の発がん機構解析による予防基盤の形成

    2012.4 - 2015.3

    科学研究費補助金  基盤研究(B)

    豊國伸哉

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    Authorship:Principal investigator 

  15. Establishing preventive strategy for mesothelioma by elucidating its carcinogenic mechanism

    Grant number:24390094  2012.4 - 2015.3

    TOYOKUNI SHINYA

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\18720000 ( Direct Cost: \14400000 、 Indirect Cost:\4320000 )

    We analyzed the molecular carcinogenic mechanisms of mesothelioma by the use of rat model of intraperitoneal asbestos injection. This model revealed a very high incidence of mesothelioma with similar genetic alterations to human counterparts. We recognized that local iron overload is an important pathogenic factor, and showed a significant increase in epithelioid subtype that show favorable prognosis after preventive administration of an iron chelator, deferasirox. Furthermore, we identified connective tissue growth factor as a major responsible gene for sarcomatoid subtype and also for proliferation of mesothelioma cells.

  16. Elucidation of the molecular mechanisms and prognostic perspectives for ovarian cancer induced by iron overload due to endometriosis

    Grant number:23590394  2011 - 2013

    YAMASHITA Yoriko

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Previous reports indicated that ovarian endometrioid and clear cell adenocarcinoma develop in association with oxidative stress due to excess of iron deposit. In this term, we performed array CGH analysis to find Met gene amplification in a certain proportion of ovarian clear cell adenocarcinoma samples correlated with worse prognosis (Yamashita et al. PLoS One 2013). Expression of CBX7, which is known to collaborate with the ANRIL gene reported to be associated with endometriosis, also had relationship with worse prognosis of the patients (Shinjo K, Yamashita Y et al. Int J Cancer 2014). We also analyzed the role of ectopic stromal cells in endometriotic cysts (Kobayashi H, Yamashita Y et al Fertil Steril 2012).

  17. がん研究分野の特性等を踏まえた支援活動

    2010.4 - 2016.3

    科学研究費補助金  新領域研究

    中村 祐輔

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    Authorship:Coinvestigator(s) 

    個体レベルでのがん研究支援活動の中で、病変の組織学的解析を担当する。

  18. Scientific Support Programs for Cancer Research Grant-in-Aid for Scientific Research on Innovative Areas

    Grant number:221S0001  2010.4 - 2016.3

    Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    IMAI Kohzoh

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    We started this project first supporting scientists who aim to overcome cancer, and from 2014 we extended our support to scientists in life sciences. The outcome has been as follows: General Support Group fostered young scientists and those who will be involved in research support in the future, and developed international academic exchanges. Our support services such as providing genetically modified mice and providing bioresources including cancer tissues enabled many scientists to conduct international and cutting-edge researches. All Japan Cohort Group and ATL Study Group (originated in Japan) collected more than 110,000 important samples and contributed for many scientists to produce their results. Chemotherapy Group and Genome and Epigenome Group also achieved more than their original goals. Further, we organized open lectures for general public to inform the importance of scientific support.

  19. Study on oxidative stress and glial activation explaining demyelination in the central nervous system induced by alternative to freons

    Grant number:22390120  2010 - 2012

    ICHIHARA Gaku

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    Exposure to 1-bromopropane (1BP) induced oxidative stress as well as activating astrocyte and microglia in the cerebellum of rats. Exposure to 1BP also promoted carbonylation of various proteins including triosephosphateisomerase (TPI), decreased TPI activity and increased advanced glycation endproduct. The study suggested oxidative stress might be involved in toxicity of 1BP to the central nervous system.

  20. Elucidation of genomic distribution dynamics of DNA damage and repair in carcinogenesis process

    Grant number:22500997  2010 - 2012

    AKATSUKA Shinya

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    We developed a novel method to detectgenomic sites harboring DNA damage comprehensively and verified practical effectiveness of the method. We conducted immunoprecipitations with genomic DNA extracted from target cells of ferric nitrilotriacetate-induced rodent renal carcinogenesis model using antibodies against two types of representative oxidative modified bases, 8-OHdG and acrolein-dA, and analyzed genomic distributions of the oxidative DNA damages by the use of array-CGH.

  21. 転写と染色体領域の視点から見たゲノムDNA損傷位置情報の解析

    2008.4 - 2010.3

    科学研究費補助金  特定領域研究 研究種目コード:034 20012026

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  22. 転写と染色体領域の視点から見たゲノムDNA損傷位置情報の解析

    Grant number:20012026  2008 - 2009

    豊國 伸哉

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\11200000 ( Direct Cost: \11200000 )

    ゲノム情報の変化は発がん過程で重要な役割を果たしている。本研究においては、培養細胞や個体各臓器の細胞のゲノム配列において、紫外線・放射線あるいは鉄を介した酸化ストレスによってDNA塩基への傷害が起こりやすい部位をアレイ技術の応用により網羅的に同定し、その法則性を見いだすことを目的とした。これまでに、私たちは鉄ニトリロ三酢酸(Fe-NTA)腹腔内投与による腎発がんモデルを開発し、その病態に酸化ストレスが関与すること、主要な標的遺伝子にCDKN2Aがん抑制遺伝子やptprz1遺伝子などがあることを示し、ゲノムに酸化ストレスに対して欠損・増幅しやすい領域があることを報告した。今年度は遺伝解析より新たにalninoacylase-1にがん抑制遺伝子としての作用があることを見いだした。昨年度に引き続き、モノクローナル抗体で修飾塩基を含むDNA断片を免疫沈降する技術とマイクロアレイ技術を組み合わせることにより、ゲノム内の酸化ストレスに対する脆弱部位を網羅的に解析した。Fe-NTA腹腔内投与による腎癌モデル初期において代表的な酸化修飾塩基である8-hydroxy-2'-deoxyguanosine(8-OHdG)に対するモノクローナル抗体を使用した実験を反復した。対照のラット腎臓ならびにFe-NTA投与3時間後の腎臓からゲノムDNAを抽出し、制限酵素BmgT120Iで切断後,DNA断片の免疫沈降を行い,8-OHdGを含むDNA断片を回収した。DNA断片を蛍光色素でラベルした後CCGHのアレイにハイブリダイゼーションし解析を行った。すると、8-OHdGは非遺伝子領域に高密度に分布し、遺伝子領域には相対的に低密度に分布することが判明した。ゲノムの遺伝子密度と8-OHdGの存在頻度に有意な負の相関を認めた。分布のパターンそのものは対照と酸化ストレスのかかった状態でほとんど差が見られなかった。CDKN2A部位では酸化ストレス時に8-OHdGの増加を認めた。

  23. 臓器の酸化ストレスを予知する血清検査法の開発

    2006.4 - 2008.3

    科学研究費補助金 

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  24. 転写と染色体領域の視点から見たゲノムDNA損傷位置情報の解析

    2006.4 - 2008.3

    科学研究費補助金  特定領域研究 研究種目コード:034 18012023

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  25. 臓器の酸化ストレスを予知する血清検査法の開発

    Grant number:18659160  2006 - 2007

    萌芽研究

    豊國 伸哉

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    Grant amount:\3300000 ( Direct Cost: \3300000 )

    制限酵素で断片化したゲノムDNAを用いて、特定の修飾塩基を含む断片を特異的に免疫沈降する方法の開発を行った。酸化ストレスにより生成する修飾塩基として、8-hydroxy(oxo)guanine, acrolein-modified adenine, thymine glycolを選出し、それぞれ特異性を確認したモノクローナル抗体を使用した。二本鎖オリゴDNAで修飾塩基をひとつ含む断片を作成し、システムが稼働することを確認した。次に制限酵素で切断したゲノムDNAを使用し、負荷DNA量・修飾塩基の含量と正の量依存性があることを確認した。マウスに鉄キレート化合物を投与し、酸化ストレス傷害を起こした腎臓を使用して以下の実験を行った。対照として、未処置動物腎臓を使用し、ゲノムに存在する8-hydroxyguanineの除去修復を行う酵素OGG1のノックアウト動物も使用した。酸化ストレスを与えると、免疫沈降されたDNA断片量は8-hydroxyguanine, acrolein-modified adenineに関して有意に増加した。回収DNA断片をライブラリーとみなしてクローニングし、未処置コントロール群と酸化ストレス群の両修飾塩基について、各群約300クローンの塩基配列決定を行い、データベースで染色体上の位置を確認し、マッピングを行った。染色体分布に関して検討すると、各群において有意に高頻度・低頻度を示す染色体が存在した。特に、8-hydroxyguanine/controlで多い16番染色体とacrolein-modifiedadenine/oxidative stressで多い15番染色体に注目した。ペインティング・プローブを使用してFISH解析を行うと、15番は核膜の近傍に、16番は核中心部に存在する確率の高いことが判明した。また、ヒト線維芽細胞を使用し紫外線を照射する系においても、thymine glycolに関して同様の方法論の有効性を確認した。また、本法の応用として、免疫沈降したDNA断片を増幅し、注目するゲノム領域でPCR解析ができるプロトコールも開発した。結論として、今回検討したDNA修飾塩基のゲノム内分布はランダムではないことが判明し、新たな血清検査法への基礎となるデータを得ることが出来た。

  26. 転写と染色体領域の視点から見たゲノムDNA損傷位置情報の解析

    Grant number:18012023  2006 - 2007

    豊國 伸哉

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    Grant amount:\10900000 ( Direct Cost: \10900000 )

    新たに開発したDNA断片の免疫沈降法により、酸化ストレスによるゲノムDNA傷害部位がランダムではないことを、ラット鉄ニトリロ三酢酸誘発腎癌モデルを使用して初めて明らかにした。その片寄りを決定する要素は、当該ゲノム部位が遺伝子か否か、その発現量、核内位置(染色体領域)、反応化学種などが想定された。gpt delta transgenic mouseを使用して、酸化ストレス発がんにおける変異スペクトラムを評価した。点突然変異はG:Cを標的とするもの(特にG:C to C:G)が多いことが判明し、1kb以上の欠損を比較的高頻度に認めた。この傾向は放射線や紫外線と異なり、正常の大腸粘膜に類似していた。鉄ニトリロ三酢酸誘発腎癌においてCGH解析を行い、動物モデルとしては初めて、共通した領域で高頻度のアレル損失や、染色体領域の増幅を認めた。ほとんどアレル増減のないEkerラット腎癌や他の発癌モデルと対照を呈した。この結果は染色体レベルの異常が高頻度に見られるヒトの発がんにおいても酸化ストレスが関与していることを示唆する。ヒトの染色体座標ヘデータを変換し種々のヒト癌のデータと比較検討も試みた。更に、アレイCGHと発現マイクロアレイの データから、本発癌モデルにおいて増幅する癌遺伝子を同定した。染色体全領域の中で、ラット染色体4番短腕(ヒト染色体7番)で高頻度の遺伝子増幅を認め、その部位に存在するptprzlに着目し た。これまで、phosphataseは癌抑制遺伝子とみなされる場合が多かったが、今回は転写因子であるβカテニンが分解されないよう核への移行を促進する癌遺伝子としての新たなメカニズムを解明した。

  27. 遺伝的負荷の高い脳血管疾患の遺伝疫学と高リスク者戦略による2次予防

    2005.4 - 2009.3

    科学研究費補助金  基盤研究(S) 研究種目コード:330 17109007

    小泉昭夫

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    我々は、遺伝的負荷のとして家族性脳動脈瘤、家族性もやもや病および家族性の脳動静脈奇形(AVM)について昨年に引き続き検討した。
    1)家族性脳動脈瘤に関する研究:3世代にわたり罹患の証明できる9家系に常染色体優性遺伝形式を仮定し連鎖解析を行なった。その結果19q13.3-19q13.4に、LOD=4.10(HLOD=4.10)連鎖領域を確認した。この領域は、我々が既に報告した領域と一致する。今後、この領域を候補とし候補遺伝子の解析を進める。また、平成18年度には、平成13年に登録した69名の追跡を行い、そのうちSAH発症者を除く46名(未破裂脳動脈瘤5名、前回に脳動脈瘤なし41名)に呼びかけたところ、新規参加者7名と、不参加の6名を除く40名がMRAに参加した。前回なしの36名のうち2名に新たに脳動脈瘤が見出された。今後も引き続き追跡を続ける予定である。
    2)家族性もやもや病:15家系を用いて、affected-member-onlyによるパラメトリック解析を行ったところ、有意な連鎖領域は1領域(LOD>3.6)のみであり、17q25に、LOD Score8.08の強い連鎖領域を認めた。この領域には90遺伝子が存在し、pseudogeneおよびhypothetical geneを除いた62の遺伝子について解析を進めている。
    3)家族性AVM:家族性AVM6家系およびAVMの高発性地域である岐阜県内のT市で症例26例および対照30例の協力を得て行なった。またこの地域から、2組のdiscordant identical twinsが参加した。家系を用いた連鎖の候補領域(p<0.05)と多発地域での相関研究での候補領域(p<5X10-6)の重なりは認められなかった。また、discordant identical twinsの2組を50Kの高密度SNPsでタイピングしたところ、配列の欠失、重複などは認められなかった。

  28. The genetic epidemiology of cerebrovascular disease with high risk genetic factors to establish the secondary prevention program targeting high risk subjects

    Grant number:17109007  2005 - 2009

    KOIZUMI Akio

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    The major goal of the present study is to isolate the susceptibility genes for intracranial aneurysms (IA), cerebral arteriovenous malformation (AVM) and moyamoya disease (MMD). We identified TNFRSF13B as a susceptibility gene for IA. We concluded that any discernible genetic factor is not involved in AVM. The intensive sequencing in IBD revealed a novel gene named "mytserin" as a susceptibility gene for MMD.

  29. 酸化ストレス発がんモデル動物の遺伝学的・分子生物学的解析

    2004.11 - 2006.10

    科学研究費補助金  特別研究員奨励費 研究種目コード:500 04F04494

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    鉄ニトリロ三酢酸(Fe-NTA)腹腔内投与によるラット腎発がんは、転移が高頻度におこること,発がん過程でフリーラジカルによる組織傷害を伴うことに特徴を有する酸化ストレス発がんモデルである。ヒトの発がん過程においても酸化ストレスが炎症,放射線,紫外線など多面的に関わっていると考えられることから、この発がんモデルの詳細な解析を施行した。まず、Fischer344系統とBrown-Norway系統のラットをかけあわせ,F1動物を作成した。そのF1動物の雄にFe-NTAを腹腔内に3ヶ月に渡り投与し、その後1年以上経過観察することにより、50例以上の腎臓癌サンプルを収集した。これまでのマイクロサテライト解析により、ラット染色体5番と8番にアレル揖失が高頻度に発生することが判明していたため、染色体8番について解析を進めた。2系統でpolymorphicな34のマイクロサテライトマーカーを使用して、22の腫瘍についてアレル損失の解析を行った。染色体8番全体に高いアレル損失を認めたが、その中でも70%を越える高率の部位に関して、腎癌のcDNAマイクロアレイ解析による発現が有意に減少する遺伝子を検索した。今回,aminoacylase-1を新たながん抑制遺伝子の候補として見出した。これをRNA,蛋白レベルで確認した。細胞内画分を用意し,この蛋白が細胞のどの部分に存在するのかを検索した。核画分のみにおいてこの蛋白と結合する低分子蛋白の4本の強いバンドが出現した。これを切り抜きマススペクトロメトリーで同定すると、すべてヒストン蛋白であった。また,gpt deltaトランスジェニックマウスを使用して腎臓におけるFe-NTAの変異パタンの解析を行った。G : Cへの点突然変異ならびに1kb以上の欠損が高頻度に起こることが判明した。

  30. ゲノムレベルにおける酸化ストレス病態解析法の開発とその応用

    2004.4 - 2005.3

    科学研究費補助金  特定領域研究 研究種目コード:034 16012234

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    酸化ストレスは動脈硬化、糖尿病などの生活習慣病の発症に関与していると考えられる。これまで私たちはラジカル発がんモデルにおいて、変異の標的となる遺伝子が存在することを報告した。酸化ストレス病態のゲノムへの影響を調べるため、ゲノムDNAで酸化傷害が生じた部位を網羅的に検出する方法を開発した。修飾塩基を含む8-hydroxy-2'-deoxyguanosine (8-OHdG)に対するモノクローナル抗体で免疫沈降することにより、その修飾塩基を含むDNA断片をクローニングする技術を確立した。無処置あるいは鉄ニトリロ三酢酸を投与したマウス腎から抽出したゲノムDNAを材料として、各動物について100個以上の8-OHdGを含有する断片をクローニング、塩基配列を決定し、その断片の染色体上における位置情報・意義をインタネット上のデータベースで検索し、解析した。1)N45.1は8-OHdGを含有する断片を特異的に免疫沈降した。2)このシステムでDNA負荷量と8-OHdG含有量に関して量依存性を認めた。3)「ランダム」という現象を「各染色体の塩基長に比例した断片の分布」と仮定すると、カイ2乗統計量による適合度検定でp=0.07程度の危険率でランダムではない。特に16番はどちらの群でも頻度が高い。5)遺伝子領域からの距離という観点で8-OHdG含有断片を解析すると、遺伝子領域の比率がやや高い。遺伝子領域ならびに遺伝子から数百kb離れた領域の断片の割合が鉄ニトリロ三酢酸投与で増加した。6)遺伝子領域断片のうち、その発現の認められる割合も鉄ニトリロ三酢酸投与で増加した。ゲノムDNAにおける8-OHdGの生成部位はランダムではない。少なくとも、どの染色体上にあるか、遺伝子領域かどうか、遺伝子領域なら発現しているかどうかなどの多因子が関係していることが示唆される。

  31. ゲノムレベルにおける酸化ストレス病態解析法の開発とその応用

    Grant number:16012234  2004

    豊國 伸哉

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    Grant amount:\4000000 ( Direct Cost: \4000000 )

    酸化ストレスは動脈硬化、糖尿病などの生活習慣病の発症に関与していると考えられる。これまで私たちはラジカル発がんモデルにおいて、変異の標的となる遺伝子が存在することを報告した。酸化ストレス病態のゲノムへの影響を調べるため、ゲノムDNAで酸化傷害が生じた部位を網羅的に検出する方法を開発した。修飾塩基を含む8-hydroxy-2'-deoxyguanosine (8-OHdG)に対するモノクローナル抗体で免疫沈降することにより、その修飾塩基を含むDNA断片をクローニングする技術を確立した。無処置あるいは鉄ニトリロ三酢酸を投与したマウス腎から抽出したゲノムDNAを材料として、各動物について100個以上の8-OHdGを含有する断片をクローニング、塩基配列を決定し、その断片の染色体上における位置情報・意義をインタネット上のデータベースで検索し、解析した。1)N45.1は8-OHdGを含有する断片を特異的に免疫沈降した。2)このシステムでDNA負荷量と8-OHdG含有量に関して量依存性を認めた。3)「ランダム」という現象を「各染色体の塩基長に比例した断片の分布」と仮定すると、カイ2乗統計量による適合度検定でp=0.07程度の危険率でランダムではない。特に16番はどちらの群でも頻度が高い。5)遺伝子領域からの距離という観点で8-OHdG含有断片を解析すると、遺伝子領域の比率がやや高い。遺伝子領域ならびに遺伝子から数百kb離れた領域の断片の割合が鉄ニトリロ三酢酸投与で増加した。6)遺伝子領域断片のうち、その発現の認められる割合も鉄ニトリロ三酢酸投与で増加した。ゲノムDNAにおける8-OHdGの生成部位はランダムではない。少なくとも、どの染色体上にあるか、遺伝子領域かどうか、遺伝子領域なら発現しているかどうかなどの多因子が関係していることが示唆される。

  32. 酸化ストレス下における細胞内ゲノム環境の可塑性と破綻

    2003.10 - 2005.9

    科学研究費補助金  特別研究員奨励費 研究種目コード:500 03F03342

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    哺乳類を含む高等動物は酸素をエネルギーに変換して生命活動を行っている。その変換効率は100%ではないため、ミトコンドリアなどで活性酸素が常時発生し、ゲノムに傷害を与えていると考えられる。これまで代表的なDNA修飾塩基である8-oxoguanineに関して、その量の多寡ならびに修復酵素の研究が行われてきた。本研究においては、脂質過酸化物のひとつであるアクロレインと2'-deoxyadenosineの付加体について、ゲノムのどのような部位でできるのかを解析するのを目指して、今年度の6ヶ月に間に方法の確立を図った。これまで、私たちはアクロレインと2'-deoxyadenosineの付加体に対するマウスモノクローナル抗体を共同で開発し、酸化ストレスによる発癌モデルである鉄ニトリロ三酢酸誘発ラット腎発癌モデルに置いて、この付加体が増加していることを確認した。この結果をもとに、ゲノムDNAの免疫沈降の実用化を検討した。ラット腎臓より、ゲノムDNAはよう化ナトリウム法で抽出し、制限酵素処理により平均的1000bpの断片とした。添加DNA量、抗体量、反応時間、洗浄バッファー組成、プロテインAセファロースあるいは2次抗体付加磁気ビーズ量などに関して詳細な検討を行い、最適な条件を見出した。この条件で、免疫沈降を行うと鉄ニトリロ三酢酸投与6時間の腎臓のゲノムDNAにおいて、免疫沈降されるDNA量が有意義に高いことが判明した。
    平成15年度の6ヶ月間において、DNAの免疫沈降の条件の最適化を行うことが出来た。平成16年度においては、この条件を使用してデータの収集を推進した。動物モデルとして、酸化ストレス発がんモデルとして確立された鉄ニトリロ三酢酸をマウスの腹腔内に投与する方法を使用した。コントロールおよび投与後6時間のサンプルを採取し、酸化を起こさない条件でゲノムDNAを抽出後、制限酵素処理で断片として、抗アクロレインデオキシアデノシン付加体(ADA)モノクローナル抗体を使用して免疫沈降を行った。各条件について動物3匹、動物1匹に関して100クローン以上をそれぞれシークエンスし、セレラあるいは公共のデータベースと照合することにより、当該クローンの染色体位置、最も近い遺伝子からの距離などに関して詳細に解析した。鉄ニトリロ三酢酸の投与によりADAは有意に増加した。ADAの生成した各染色体の頻度はほぼ染色体のゲノムの長さに比例したものの、全染色体に予想される頻度に関して、カイ2乗検定を行うと、コント

  33. マウス遺伝的カタラクトの分子生物学的解析

    2003.4 - 2005.3

    科学研究費補助金  基盤研究(B) 研究種目コード:310 15300142

    鶴山 竜昭

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    レンズは解剖学的に簡素な構造ながら、多数の遺伝子群が働いてその発達、光学的特性を維持している。遺伝的カタラクトはレンズの分子解剖を行う上で有力なツールである。松島らが発見したRupture of lens cataract (RLC)はマウスの劣性単一変異遺伝子による遺伝的カタラクトで、生後35日ころからレンズ後縫合のレンズ線維末端部の変性により、線維相互間あるいは線維・カプセル間の結合が失われる結果、レンズの破綻がおこるものである。我々はRLCと野生マウス由来近交系MOMの交配系を遺伝解析し第14染色体の約28.5cMの位置に遺伝子座rlcをマップした。当研究室では理化学研究所林崎研究室と協力し、この遺伝子の本体の検索を行い、これが細胞内シグナル伝達分子DOCK180の9アミノ酸の欠損によるものであることを確定した。ミュータント形質はcrystallin promoterをつないだDock1 cDNAを導入したトランスジェニックマウスを作成することによりレスキューされることを確認した。この欠損はDOCK180下流のRac1の活性化を低下させることにより、細胞接着シグナル細胞骨格系に伝える経路に機能不全をおこす。この結果、発達しつつあるレンズの内部応力に耐えることができず、レンズの破綻をきたすものと考えられた。RLCにみられる分子構造の異常はこれまで全く記載がなく、レンズの生理機能を明らかにするのみならず、DOCK180の生理的機能についても新しい光をあてるものである。

  34. MOLECULAR ANALYSIS OF MOUSE HEREDITARY CATARACT

    Grant number:15300142  2003 - 2004

    TSURUYAMA Tatsuaki

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    Rupture of lens cataract (RLC) is a hereditary cataract in the mouse inherited by single autosomal recessive mutation. At about 35-days of age, degeneration of lens fibers at posterior pole occurs and results in lens rupture by defective binding between lens fibers or between fiber-capsule. We mapped the responsible locus rls at the map position 28.5 cM on chromosome 14. In collaboration with Hayashizaki's laboratory in RIKEN, we investigated the library of full size cDNA and identified a 27 bp nucleotide defect in DOCK180, causing deletion of 8 amino adds. The mutant phenotype was completely rescued in the rlc/rlc mice introduced the wild type Dock180 cDNA driven by crystalline promoter. The rlc mutation of Dock180 reduced activation of Rac, so that intracellular signaling of cell adhesion or cell motility are affected. This functional failure leads to repture of lens during expansive growth of lens. This is the first report of pathogenetilc role of Dock180. This study will shed new light on molecular anatomy of eye lens and also physiological function of Dock180.

  35. 酸化ストレスの病理的意義の追究とその病理診断への応用

    2002.4 - 2004.3

    科学研究費補助金  基盤研究(C) 研究種目コード:320 14570140

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    鉄ニトリロ三酢酸(Fe-NTA)をラットに腹腔内に反復投与すると、高率に腎癌が発生する。この発癌過程では鉄を介したフェントン反応が関与していること、癌の悪性度が高いことが特徴である。このモデルでDifferential Displayによるスクリーニングで得られたAnnexin 2(Anx2)の役割について動物モデル・試験管内の実験で詳細な検討を行い、次にヒトの癌の予後判定に役立つかどうかを手術標本を使用して検討した。ラット腎正常近位尿細管でAnx2蛋白を検出しなかったが、Fe-NTA投与6時間より、残存尿細管で高い発現を検出した。Fe-NTA反復投与後3週間ではkaryomegalic cellの胞体・核に集積を認め、腫瘍では主に細胞表面に陽性像を認めた。Anx2はSerとTyr残基がリン酸化され、リン酸化されたactinと共沈した。転移例の原発巣において高発現を認めた。高発現性Fe-NTA誘発腎がん由来細胞株にanti-sense投与するとapoptosisを起した。LLC-PK1ブタ尿細管細胞に過酸化水素により酸化ストレスをかけると発現が増加し、この誘導は抗酸化剤で抑制された。Anx2はがん遺伝子srcの基質として発見されたが、各種kinaseの基質でもあり、さらに線溶系分子の細胞表面受容体などの役割を担う。今回の実験でAnx2がレドックス制御を受けることを初めて示した。Anx2は、レドックス制御・キナーゼ系・線溶系の要となり、promotion, progressionの過程で重要な役割を果たすと考えられた。更にこの結果を踏まえて、ヒト肺癌の予後の検討を行った。Anx2の発現の高い肺癌は予後の悪いことが判明した。

  36. Pathological significance of oxidative stress and its application to pathologic diagnosis

    Grant number:14570140  2002 - 2003

    TOYOKUNI Shinya

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    Grant amount:\3500000 ( Direct Cost: \3500000 )

    Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal damage leading to a high incidence of renal cell carcinoma (RCC) in rats. Differential display analysis of such RCCs revealed elevated expression of annexin 2 (Anx2), a substrate for kinases and a receptor for tissue-type plasminogen adivator and plasminogen. We conducted this study to clarifythe significance of Anx2 in Fenton reaction-based carcinogenesis. Messenger RNA and protein levels of Anx2 were increased time-dependently in the rat kidney after Fe-NTA administration as well as in LLC-PK1 cells after exposure to H_2O_2. The latter was inhibited by pretreatment with N-acetylcysteine, pyrrolidine dithiocarbamate or catalase. immunohistochemistry revealed negligible staining in the normal renal proximal tubules, but strong staining in regenerating proximal tubules, karyomegalic cells and RCCs. Metastasizing RCCs showed higher Anx2 protein levels. Anx2 was phosphorylated at serine and tyrosine residues in these cells and coimmunoprecipitated with phosphorylated actin. Overexpresison of Anx2 induced a higher cell proliferation rate in LLC-PKI cells. In contrast, a decrease in proliferation leading to apoptosis was observed after Anx2 antisense treatment to cell lines established from Fe-NIA-induced RCCs. These results suggest that Anx2 is regulated by redox status, and that persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer. Furthermore, we demonstrated that peptide nucleic acid (PNA)-based mRNA in situ hybridization is applicable to paraffin-embedded pathologic specimens produced 50 years ago. We have developed an extremely rapid method for Western blot analysis by the use of low dose of microwave radiation. Finally, we have produced diagnostic criteria for the early humoral rejection in ABO-incompatible liver transplantation. This would be important for investigating the involvement of oxidative stress in the rejection of transplanted liver.

  37. 心臓の虚血再灌流障害とフリーラジカルによる酸化障害についての研究

    2001.4 - 2003.3

    科学研究費補助金  基盤研究(C) 研究種目コード:320 13671414

    野島 武久

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    心筋梗塞後の心不全に関して再灌流障害の関与が指摘されておりその際の酸化ストレスの影響が考えられるがその詳細は報告されていない。とくに時間的、空間的な変移については未だ明らかではない。本研究は心筋虚血再灌流時の酸化障害の免疫病理的・定量的評価を行っている。
    平成13年度は心筋梗塞およびそれに引き続いておこるリモデリング、虚血性心筋症において酸化ストレスの時間空間的変化を明らかにした。ランゲンドルフモデルにおいて、再灌流後の酸化傷害は再灌流直後より上昇し、20分灌流後も持続した。灌流後3分ですでに上昇していること、無血下の条件で上昇している事から、細胞内の酸化物質の活性化による障害が示唆された。
    平成14年度は、SDラット66匹に対して心筋梗塞を作成し、この心筋を梗塞後0、3、6、12、24、48時間1、2、4、6週間後に採取。免疫染色にて心筋酸化障害の局在を評価している。さらに高速液体クロマトグラフィー(HPLC)によって核DNA中の8-OHdGを定量し、アポトーシスの程度をTUNEL法にて評価した。免疫染色およびdG/8-OhdG比にて心筋梗塞部の8-OHdGは梗塞後6時間までは梗塞部に高く発現し、健常部は上昇しなかった。しかし12時間以後は梗塞部・周囲部で一度低下するが1週目を過ぎる頃から周囲部・健常部で上昇し、4週後でも周囲部には酸化障害が残存した。アポトーシスの程度は1週間程度まではあまり上昇しないが2週目から上昇しこの変化は心筋梗塞後の心機能の低下と相関があった。心筋梗塞後の酸化ストレスは2峰性の変化を示し1つ目が虚血による心壊死、2つ目がアポトーシスと関連した心機能不全を示していると考えられた。またこの手法は種々の心不全時の心筋細胞の評価に応用できる可能性が示唆された。

  38. 長時間心保存を期待したトレハロースの虚血再灌流障害防止作用に関する研究

    2001.4 - 2003.3

    科学研究費補助金  基盤研究(C) 研究種目コード:320 13671383

    植山 浩二

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    1 トレハロースの指摘濃度の検討と再灌流障害の免疫病理学的検討。
    [方法]SDラット摘出心にたいして灌流法は20分の準備灌流後に上記の液用いて心停止。以後30分に一回追加しながら90虚血とし再灌流する。再灌流後の左心機能を収縮末期圧容積関係(ESPVR)と拡張末期圧容積関係(EDPVR)にて評価した。この際灌流液または灌流血液を肺動脈より採取し生化学的検査(CK・MBなど)を行うとともに心筋標本採取。8-0HdG免疫染色と高速液体クロマトグラフィーにて定量した。
    [結果]1 心筋保護効果の検討;グループA:セントトーマス液、グループB:3%トレハロース付加セントトーマス液の2群で比較検討した。(心収縮能の検討)再灌流後5分における収縮末期圧容量関係にて評価した。その結果トレハロース3%入りのセントトーマス液の方が収縮能をより保つことが示された。(心筋浮腫の程度に関する検討)心筋の浮腫を還流後の心筋重量増加率で比較した。結果トレハロース付加群で有為に浮腫を軽減した。また病理学的な細胞浮腫の検討でもトレハロース付加群で細胞浮腫の軽減される傾向を示した。以上のことからトレハロースは心筋保護液に付加する物質として有用である。
    2 至適濃度の検討
    4%の溶液においてその浸透圧は420前後と高く3%で380前後2%で340前後となる。この点から濃度は2%?3%が至適と考えられた。
    3 保護にかんする作用機序の検討
    1で得たサンプルにTUNEL法を用いてapoptosisを検討した。トレハロース群で有為にapoptosisが軽減した。
    4 他の添加薬剤の検討
    PARS inhibitorである3ABについて同様に検討。心収縮能に関して有効な結果を得た。

  39. OXIDATIVE STRESS AND REPERFUSION INJURY OF HEART

    Grant number:13671414  2001 - 2002

    NOJIMA Takehisa

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    Objective: Heart failure after MI is associated with oxidative stress. We studied spaciotemporal alteration of LV oxidative stress related to cell damage, LV function, and apoptotic change after MI.
    Methods: LAD in SD rats was ligated. Heart was dissected 0, 3, 6, 12, 24, 48 hours, and 1, 2, 4 weeks after ligation. LV function was examined by echocardiography (SONOS 5500【○!R】), in the same time course. Oxidative stress was assessed by immunohistochemistry; determination of 8-hydroxy-2'-deoxyguanosine (8-OHdG) by HPLC-ECD, and cell injury was detected by nicotinamide adenine dinucleotide (NAD) level as coenzyme of ADP-ribose polymerase (PARP). Apoptotic change of the hearts was detected by TUNEL procedure.
    Results: Soon after MI, oxidative stress as shown by 8-OHdG was intense, in 24 hours, cardiomyocytes were necrotized in the MI area. However, oxidative stress reincreased at 2 weeks [8-OHdG/dG×10^5: 0 91±0.04 (p<0.01) in Remote Areas, 1,16+0.19 (p<0.05) in Near Area]; it remained high only in Near Area at 4 weeks [1.18 + 0.76 (p<0.05)](Fig.). The peak of PARP was 6 hour after MI, with no second peak. The second peak had relationship with LV disfunction and enlargement. NAD decreased immediately and 1/10 of normal 12 hour after MI. It was normalized 2 weeks after MI. Three hours after the ligation of the coronary artery, few apoptotic cardiomyocytes were observed in the MI area, and scarcely any were observed in any area from 6 hours to 1 week. However, 2 to 4 weeks after the operation, cardiomyocytes in the peri-MI area showed apoptosis, suggesting that loss of cardiomyocytes occurred due to apoptosis induced by oxidative DNA damage.
    Conclusion: Repair of DMA by PARP was maximal 6-12 hours after MI and so did 8-OHdG. Only 8-OHdG had the second peak 2 weeks after MI, and cardiomyocytes in Near Area remained oxidatively stressed even 4 weeks after MI. The first peak implies acute damage of DNA by ischemia, and the second peak suggests continuing damage of cardiomyocytes in the course of LV remodeling, related to apoptosis of cardiomyocites.

  40. Torehalose can protect myocardium by preventing its edema in ischemic reperfusion

    Grant number:13671383  2001 - 2002

    UEYAMA Koji

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    Background: Trehalose, one of bicarbonate seen in desert plants, has been reported to protect cell membrane after long hours' preservation in lung transplantation. We explored the feasibility and possible usefulness of Trehalose for cardiac preservation. Methods: Hearts were harvested from 14 SD rats and connected to Langendorffs apparatus. After 20 minutes equilibration with Krebs-Henseleit buffer the hearts developed arrest by one of 2 different cardioplegic solution (20ml/kg): St. Thomas solution (n=8, Group A) and St. Thomas solution with 3% Torehalose (n=8, Group B). After 90 minutes' ischemia with intermittent infusion of the solution (10ml/kg) every 30 minutes the hearts had reperfusion. LV function was measured at the end of the equilibration, 5 and 15 minutes after the reperfusion. We also studied edema of the LV myocardium by relationship of weight of isolated hearts at the moment of harvesting and after 15 minutes' reperfusion. Results: LV systolic function was assessed by end-systolic pressure-volume relationship (ESPVR). Group B had better ESPVR than group A 5 minutes after the reperfusion. There was no difference in diastolic function as assessed by end-diastolic pressure-volume relationship (EDPVR) between the two groups. The rate of increase in weight of heart (weight after 15 minutes reperfusion / weight at harvesting) is 1.46±0.71 in Group A, and 1.14±0.37 in Group B (p<0.001). Pathological examinations revealed more edema of the LV myocardium in Group A than Group B. Conclusion: The results suggest that Trehalose can be given safely and it has potential benefits to preserve LV systolic function and to decrease myocardial edema after reperfusion

  41. 呼吸器外科手術における再灌流障害の予防と治療

    1999.4 - 2002.3

    科学研究費補助金  基盤研究(B) 研究種目コード:310 11470270

    和田 洋巳

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    これまでのラットex vivo実験により、selectin blocker(KB-R9188改めOJ-R9188)が肺温虚血再潅流傷害を軽減することが明らかになったが、本年度はその作用機序を明らかにすべく、検討を行った。
    1、Myeloperoxidase(MPO)活性の測定
    ラットex vivo実験から得られた再潅流後肺の一部を用い、白血球組織浸潤の指標となるMPO活性を測定した。しかしその結果は、selectin blocker投与群、非投与群間に有意差を認めなかった。
    2、抗酸化作用機序の検討
    (1)直接的抗酸化作用
    Electron Spin Resonance(ESR)法を用い、OJ-R9188がhydroxyl radicalやsuperoxideに対するradical scavengerとして作用するか否かを検討した。実際には、種々の濃度のOJ-R9188にspin trapping試薬を添加し、ESR spectrometerで抗酸化作用を測定した。
    その結果、OJ-R9188に直接的抗酸化作用は認められなかった。
    (2)一酸化窒素(NO)を介した抗酸化作用
    ラットex vivo実験から得られた再潅流後肺の一部を摘出し、ピクリン酸で固定後スライド標本を作製した。ABC法に準じて3-nitro-L-tyrosine(3-NT)に対するポリクロナル抗体を用い、免疫染色を行い、評価した。その結果、selectin blocker投与群では非投与群に比し、NOを介した酸化傷害を軽減することが示された。

  42. Prevention and treatment for reperfusion injuny in thoracic surgery

    Grant number:11470270  1999 - 2001

    WADA Hiromi

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    Importance of reactive oxygen species released through interaction of leukocyte-endothelial cell in ischemia-reperfusion injury of the lung is not yet fully understood. A novel selectin blocker OJ-R9188, which inhibits the interaction may alleviate oxidative stress and pulmonary dysfunction after warm ischemia reperfusion. Rat lungs were reperfused at 37℃ for 60 min with an ex vivo model, and were divided into three groups (n=10). In Fresh group, lungs were reperfused immediately after harvest. In OJ-R (-) and OJ-R (+) groups, lungs were reperfused after warm ischemia at 37℃ for 90 min. In OJ-R (+) group, rats received 100 μg/body of OJ-R9188 intravenously 10 min before the harvest. Electron spin resonance method was used to assess the direct scavenging activity of OJ-R9188. Both shunt fractions and wet/dry weight ratios of the lung tissue after reperfusion in OJ-R (+) group were significantly lower than those in OJ-R (-) group. Oxidative DNA damage in the alveolar wall of OJ-R (+) group, assessed by immunohistochemical quantitation of 8-hydroxy-2'deoxyguanosine, was significantly lower than that of OJ-R (-) group. Immunostaining of 3-nitro-L-tyrosine, which represents nitric oxide-mediated oxidative damage, was also more intense in OJ-R (-) group than in OJ-R (+) group. Direct scavenging activity of OJ-R9188 was not observed, and the number of leukocytes infiltrated to the lung tissue as seen by myeloperoxidase activity was not different between OJ-R (-) and OJ-R (+) groups. A novel selectin blocker OJ-R9188 improves pulmonary function after warm ischemia-reperfusion and alleviates reperfusion-induced oxidative alveolar damage.

  43. ABO血液型不適合移植における移植肝障害の病理学

    1998.4 - 2000.3

    科学研究費補助金  基盤研究(C) 研究種目コード:320 10670157

    山邉 博彦

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    Authorship:Coinvestigator(s) 

    本研究はABO血液型不適合移植後に発生する肝機能障害の病理学的特徴を解明することを目的とする。京大病院において平成2年6月から平成8年3月の5年9カ月間にタクロリムス免疫抑制下に行った血縁者間生体部分肝移植移植213例中ABO血液型不適合移植症例29例の結果は昨年報告した。
    本年はその後平成8年4月から平成10年末までの2年9ヶ月間に移植された210例のうちのABO血液型不適合移植症例24例について、移植後の肝機能障害時の病理組織学的検討を行い以下の結果を得た。(1)超急性拒絶反応は見られなかった。(2)急性細胞性拒絶反応は54%の症例(13症例)に見られた。(3)慢性拒絶反応の症例はなかった。(4)胆管炎は42%の症例(10例)に見られた。(5)死亡例9例のうち剖検を行った3例ではいずれも循環障害による肝障害が見られた。また、再移植例2例の摘出肝では1例で肝動脈血栓症が、他の1例では肝動脈血栓症を原因とすると考えられる慢性胆管障害が見られた。(6)移植前後の抗血液型抗体価と胆管障害および死亡・再移植との関連が見られた。
    この両年度の結果を総合すると、ABO血液型不適合肝移植においては液性拒絶反応に特有とされる超急性拒絶反応は見られなかったが、特に抗血液型抗体価の高い症例において剖検肝、再移植時摘出肝および肝生検において刊循環障害あるいは胆管障害(慢性胆管炎)がしばしば見られ、また生検で胆管炎がABO血液型適合または一致症例にくらべて高頻度に見られた。
    これらの所見からこの肝循環障害と胆管障害がABO血液型不適合肝移植に特有な障害と考えられ、その組織発生としては、まず血管内皮を標的とする抗原抗体反応性の血管障害が起こり、その結果胆管に虚血を生じて虚血性胆管炎を招来すると推測された。なお、急性拒絶反応もABO血液型適合または一致症例にくらべて高頻度に見られた。

  44. Pathology of ABO-Incompatible Liver Transplants

    Grant number:10670157  1998 - 1999

    YAMABE Hirohiko

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    During the 8 years and 7 months period between June 1990 and December 1998, 412 patients with end-stage liver diseases underwent 423 living related liver transplantation under tacrolimus immunosuppression. Among these, there were 53 ABO incompatible transplants in 51 patients. This report describes the histopathological features of liver dysfunction seen in these ABO-incompatible transplants.
    No hyperacute rejection was found. Hepatic artery thrombosis was seen in 7% of transplants, acute/chronic cholangitis in 38%, acute cellular rejection in 59%, chronic rejection in 2%, preservation and reperfusion injury in 2%, acute hepatitis in 25%, chronic hepatitis in 8% and posttransplant lymphoproliferative disorder in 6%. Hepatic artery thrombosis, acute/chronic cholangitis and acute cellular rejection were more frequently seen in ABO incompatible than in ABO identical and compatible transplants. Hepatic artery thrombosis and acute/chronic cholangitis were more frequently seen in transplants with higher (> x128) pre-and/or post-operative isoagglutinin titers. However, acute cellular rejection was not related to the isoagglutinin titers. Patient death or graft loss occurred in 22 transplants (41.5%). This was more frequent than in ABO identical and compatible transplants (18.6%). Most important causes of transplant failure in these cases were hepatic artery thrombosis and acute/chronic cholangitis. Histopathological analysis of explants that failed due to hepatic artery thrombosis and chronic cholangitis showed that hepatic artery thrombosis is the primary lesion which was followed by large bile duct infarction and acute/chronic cholangitis in the peripheral bile ducts.
    From these data, it is suggested that, in ABO incompatible transplants, hepatic artery thrombosis which is a result of reaction between circulating antibodies and ABO blood group antigens expressed on endothelial cells of large hepatic arteries, and acute/chronic cholangitis which is a result of ischemia due to hepatic thrombosis, are responsible for the transplant failure. It is also suggested that there are no relationship between high incidence of acute cellular rejection and isoagglutinins in ABO-incompatible transplants.

  45. 活性酸素のエフェクター分子の固定とその生物学的意義の追求

    1997.4 - 2000.3

    科学研究費補助金  基盤研究(C) 研究種目コード:320 09670223

    豊國 伸哉

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    鉄ニトリロ三酢酸による腎尿細管傷害・腎発がんのモデルは1982年に当教室で開発されたモデルであり、腎近位尿細管でFenton-like reactionを引き起こす。酸化ストレスの形態学的評価のためには、フリーラジカル反応によるcovalentな修飾を受けた分子に対する抗体を作製するというストラテジーが適切と考え、まず、生体内においてはどのような修飾分子の増加率が高いかを検討した。上記モデルにおいては、DNA修飾塩基として8-hydroxy-2'-deoxyguanosine(8-OHdG)、アルデヒド化合物として4-hydroxy-2-nonenal(HNE)の増加率が最も高いことを見いだした。アルデヒド化合物はフリーの状態でいると、疎水性でありパラフィン包埋の過程で流出し失われてしまう。アルデヒド化合物が蛋白のアミノ酸残基と反応しマイケル反応産物を形成するという化学反応の解明が、抗体作成の過程で重要であった。名古屋大学大学院生命農学研究科、日本老化制御研究所と共同で、上記のエピトープに対するポリクローナル・モノクローナル抗体を作製あるいは評価を行った。そして、幸運にもこれらの抗体は通常のパラフィン包埋の病理標本で使用可能であることが判明した。
    上記鉄ニトリロ三酢酸のモデルだけではなく、糖尿病(Goto-Kakizakiラット)、虚血・再灌流モデル(肺、肝、皮弁)、砒素中毒症、大腸癌、C型肝炎、アルコール性肝炎などにおいて酸化ストレスが関与していることを証明した。特に、糖尿病の膵ランゲルハンス島における酸化ストレスの評価は本手法により初めて可能となったものであり意義深い。

  46. 多因子遺伝病の研究・宿主モディファイヤー遺伝子の探求

    1997.4 - 2000.3

    科学研究費補助金  基盤研究(A) 研究種目コード:300 豊國 伸哉  (トヨクニ シンヤ)  京都大学・大学

    日合 弘

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    これまで取り組んできた仕事の多くで著明な進展がみられた。(1)リンパ腫好発系SL/Khマウスの骨髄Pre-B細胞の一過性増殖は第3染色体上のQTLであるBomb1(Lef1)によることが示された。(2)リンパ腫DNAへのウイルス組込みホットスポットの多くがクローニングされ、Bomb1によるリンパ球分化異常とリンパ腫発生機構の関連に大きな手がかりが得られた。(3)4NQO誘発ラット舌癌については感受性に関与する5つの宿主遺伝子座をマップし遺伝様式を解明した。(4)化学発癌剤抵抗性DRHラットの肝発癌モデルで前癌病変であるGST-P陽性フォーカスの遺伝支配を研究し第1、第4染色体に高度に有意な座位をマップした。(5)遺伝的カタラクトRLCについては責任遺伝子マップ位置からPYK2が候補遺伝子で、RLCレンズで正常マウスを免疫するとPYK2のN端異常ペプチドに対する抗体が作られた。cDNA,genomic DNAについて、遺伝子構造を解析中。(6)NCTカタラクトはNa/Kpumpに対する内因性抑制ペプチドの形成により発生する。1000頭の戻し交配系を解析し、マップ位置からBAC contingを作製中である。カタラクトのタイプ(pin head or diffuse)を決めるmodifier geneを第10染色体にマップした。この位置にNa/K pumpの一部がマップされていた。(7)PNUによるラット白血病の病型決定機構を解析するためF344とLE/Stmの間で育成されたRl系について、白血病を誘発して遺伝解析を行い、数個のQTLが関与している可能性を示した。これら一連の研究から内在性レトロウイルス、化学発癌剤、遺伝的変異による疾患も多くは多因子の宿主修飾遺伝子の影響を受け、発病の有無、重篤度、病型などが決定されることを示した。一部のものについては分子生物学的な理解に肉迫している。

  47. Studies on Polygenic Diseases : Search for Host Modifier Genes

    Grant number:09307004  1997 - 1999

    HIAI Hirosahi

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    We studied effects of genetic background of host on various diseases. Defect in lpr gene causes a spectrum of autoimmunities in MRL mice, but not in C3H mice. Analyzing(MRL-lpr x C3H-lpr)FィイD22ィエD2 mice, we could show several host genes or their combinations to determine the spectrum of autoimmunities. Similar polygenic trait was found in SL/Kh pre-B lymphoma system. Lymphomas were induced by somatic integration of endogenous ecotropic MuLV to Slv1-8 hot spots, their host-junctional fragments were cloned with a modified inverse PCR technique. SL/Kh mice showed a unique pre-B cell expansion in pre-lymphoma BM. Such expansion was induced by Bomb1 host locus on Chr. 3 mapped us. A candidate gene for Bomb1 is Lef1, a transcription factor in Wnt/Frzl pathway, expressed in both T and pre-B cells. SL/Kh thymocytes showed very low responsiveness to Con A. Immunological abnormalities in B-lineage may induce expansion of the target cells for virus integration. We could identify several other host genes affecting type of lymphomas, length of latent period, and resistance to lymphoma development. These studies clearly indicate that lymphomagenesis is tightly bound to host modifying genes that regulate steps of carcinogenesis. In addition to lymphomas, we could map modifier genes for tongue cancer, bladder cancer, lung cancer and liver cancers using quantitative trait mapping. In these studies, we showed that the recombinant inbred strains is a highly useful tool to analyze complicated trait such as cancer susceptibility.

  48. Identification of effetor molecules for reactive oxygen species and its biological significance

    Grant number:09670223  1997 - 1999

    TOYOKUNI Shinya

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3800000 ( Direct Cost: \3800000 )

    Recent studies have clarified that reactive oxygen species(ROS)are involved in a diversity of biological phenomena including radiation damage, carcinogenesis, ischemia-reperfusion injury, diabetes mellitus and neurodegenerative diseases. In this project we have established methods to localize ROS-induced damage in paraffin-embedded specimens. This owes to a successful production of antibodies against covalently modified structures specific for ROS-induced damage. The epitopes include 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins. This technique was applied to animal models of human specimens of diabetes mellitus, reperfusion injury, arsenic intoxication, colon cancer, viral hepatitis as well as oxidative stress-induced cancer model of rats using ferric nitrilotriacetate(Fe-NTA). Then, we have answered a question whether there are target genes in the oxidative stress-induced carcinogenesis by genetic analysis using F1 hybrid rats. This study revealed that chromosome 5 and 8 of rats showed a high incidence of loss of heterozygosity with PCR microsatellite analyses, which finally lead to a conclusion that p15/p16 tumor suppressor gene is one of the major target genes in this oxidative stress-induced carcinogenesis model.

  49. 高発がん性ラットを用いた発がん過程の主要因の解析

    1996.4 - 2000.3

    科学研究費補助金  特定領域研究(A) 研究種目コード:031 08264108

    樋野 興夫

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    1.遺伝性腎癌ラット(Eker rat)の腎癌発生過程に見られる多段階的な病理組織像に対応する遺伝子変化の同定をsubtraction法を用いて試みた。癌抑制遺伝子であるTsc2の不活化とその結果として発現が亢進してくる癌関連遺伝子群を単離を試みた。さらに、本ラットの腎癌細胞の転移系を確立し、転移に関与する遺伝子群の単離をcDNA subtraction法を用いて試みた(樋野)。
    2.ラットゲノムマップの統合を行った。この統合ゲノムマップは、ラットモデルにおける発癌感受性などを含む量的遺伝形質の解析において求められる全ゲノムスキャンを容易にするものである(芹川)。
    3.発がん物質投与後形成される8-hydroxydeoxy-guanosine(8-OHdG)はLECラットがBNラットに比べ有為に高いことを確認した。8-OHdG形成メカニズムには銅の蓄積が関与していることが考えられた。(榎本)。
    4.ラット前立腺に特異的に発現するprobasin遺伝子のプロモ-タ-領域にSV40T抗原遺伝子を連結したtransgenic ratを作製し、生後早期に腹葉に異型過形成を起こす系を確立した(白井)。
    5.BUF/Mna系ラットにおける胸腺腫発生感受性遺伝子Tsr1は第7染色体上のマ-カ-、D7Rat21の近傍に局在することを明らかにした(松山)。
    6.新しいwilms腫瘍遺伝子の探索の為に経胎盤N-ethyl-N-nitrosourea(ENU)発癌とラット腎移植手術を組み合わせたラットモデルの開発を行った(横森)。
    7.(1)コリン欠乏アミノ酸(CDAA)食で誘発した肝発がんでc-myc遺伝子のプロモ-タ-及びexon1の領域におけるメチル化を検討した。(2)ジエチルニトロサミン(DEN)及びCDAA食で誘発した肝細胞癌におけるβ-カテニン遺伝子の異常を検索した(小西)。
    8.鉄を介した活性酸素・フリ-ラジカルによるラット腎癌モデルにおいて(1)グルタチオンSトランスフェラ-ゼが腎癌で高発現しており、中でもπアイソザイムが著明に増加していた。(2)F1動物の腎癌を用いた遺伝解析により、染色体5番に高頻度のLOHを見出し、p15/p16癌抑制遺伝子が主な標的のひとつである(豊國)。

  50. 生体肝移植後の移植肝に発生する慢性肝機能障害の病理学

    Grant number:08670201  1996

    山邊 博彦

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    目的:生体部分肝移植は小児の非可逆性肝疾患末期の肝不全症の唯一の治療法として定着してきている。その移植不成功の最大の原因となる移植肝に発生する慢性の進行性肝機能障害を臨床病理学的に解析した。
    方法:1990年6月から1996年5月の6年間に224例(5再移植例を含む)に生体部分肝移植が行われた。このうち移植後2ヵ月以降に進行性肝機能障害を来した33例の生検材料、手術材料、剖検材料について、免疫組織化学、in situ hybridization法を含む病理組織学的検索を行い、臨床病理学的に解析した。
    結果及び考察:進行性肝機能障害を示した33例中、21例が移植後64日から5年11カ月の間(中央値174日)に移植不成功(死亡16例、再移植5例)となった。そのうち慢性拒絶反応は7例(死亡4例、再移植3例)にみられた。3例が主として血管性、4例が主として胆管消失性拒絶反応であった。また、上記33例中、慢性胆管炎が15例(うち死亡9例、再移植1例)に見られた。うち7例はABO血液型不適合移植例であり、その2例は抗血液型抗体価が高く、胆管吻合部分に問題がないにも拘わらず胆管炎が発生した。また他の1例はリンパ球クロスマッチ試験陽性例であった。これらのことから胆管炎とhumoral mechanismの関連が注目された。移植後リンパ増殖性疾患は4例(うち1例は胆管炎に、1例は慢性拒絶反応に合併、全例死亡)に見られ、Epstein-Barrウイルスの関与が組織学的に証明された。慢性肝炎・肝硬変は8例(うち死亡1例)に見られ、5例はB型、1例はC型の慢性肝炎、他の2例は原因が不明であった。
    結論:生体部分肝移植後の慢性進行性肝機能障害の原因として、慢性拒絶反応、慢性胆管炎、移植後リンパ増殖性疾患及び慢性肝炎・肝硬変が重要であることが判明した。

  51. レドックス制御とシグナル伝達機構

    1995.4 - 1997.3

    科学研究費補助金  国際学術研究 研究種目コード:160 07041160

    淀井 淳司

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    淀井らが報告したATL-derived factor(ADF)は、チオ-ル基を介して強い還元活性を示すthioredoxin(TRX)のヒトホモロ-グであり、レドックス制御に関わる抗酸化ストレス因子である。今年度の成果として以下のことが明らかとなった。1)TRX遺伝子のknock outマウスは胎生致死であり、TRX遺伝子はマウス胎仔の早期分化および形態形成に重要な役割を果たしていたこと。2)TRX遺伝子のプロモ-タ-部位に酸化ストレスに応答する遺伝子配列を同定したこと。3)NF-κBおよびAP1などの転写因子活性化に、TRXやRef-1などのレドックス蛋白が、重要な制御的働きをするが、さらにRef-1がTRXに結合し、AP-1転写活性への役割を果たすこと。3)ステロイドホルモンレセプタ-、PEBP-2の活性化にも、レドックス制御機構の役割が重要であること(田中、重定との共同研究)。また、Chae,Paakによりペルオキシダ-ゼ活性を有するTRX依存性peroxidase(peroxiredoxin)も報告され、抗酸化ストレス機構の解明が進んでいる。一方、酸化ストレスに対する防御因子が生体内レドックスセンサ-機構としての役割も積極的に担うことが明らかにされつつある。淀井などが、酸化ストレスによるtyrosine kinaseの活性化を示したが、MAP kinaseのレドックス制御機構は、Karinらによって進展している。また、山本によりp53の酸化ストレスによる活性化機構の解析がなされた。豊國らは鉄による酸化ストレス下のレドックス制御不全状態で過酸化脂質蛋白複合体が生体内で生じていることを明らかにし、鉄による発癌に関する研究を展開した。今後さらにレドックス関連分子の解析およびその情報伝達における役割、酸化ストレスに対するレドックスセンサ-機構、レドックス制御異常による不可逆的酸化ストレスの病態形成への関与を解析することが必要と思われる。

  52. Tリンパ腫病型決定の遺伝機構

    1995.4 - 1997.3

    科学研究費補助金  基盤研究(B) 研究種目コード:310 07457059

    日合 弘

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    本研究はリンパ腫病型決定の遺伝機構を解明することを目的とし、研究を進めた結果、次の結果を得た。(1)SL/Khマウスとその4系の亜系間の遺伝的相互関係を詳細に解明した。(2)正常の骨髄Pre-B細胞はLECAM-1,LFA-1等の接着因子を発現していないが、SL/Khの自然発生Pre-Bリンパ腫は表現型から正常Pre-B細胞によく似ているにも関わらず、LECAM-1,LFA-1の明瞭な発現があることを示し、変異Pre-B細胞のマ-カ-とみなせることを示した。(3)Tlsm-1の機能を調べるため、胸腺を摘出した(SL/Kh x AKR)F1の腎被膜下にSL/Kh,F1,AKRの胸腺を移植し、発生するリンパ腫の病型、組織由来を検討した。(SL/Kh X AKR/Ms)F1ではDual T and B phenotype lymphomaが多発し、このタイプの腫瘍の発生は胸腺に依存しないが、pure T lymphomはTlms-1陽性の胸腺の存在に依存していることを示した。(4)これまで発見したリンパ腫関連宿主遺伝子のcongenic系を作出した。(5)Tlsm-1の詳細なマッピングのため、AKXD11とAKXD21の間の退交配系を観察中。(6)野生由来近交系MSM/Msマウスの2つの優性リンパ腫抵抗性遺伝子を同定しChr.17,19にマップした。(7)ポリゲニックな癌感受性を解析するマウス(SMXA)、ラット(LEXF)の組み替え近交系を作出し遺伝解析を行った。

  53. フリ-ラジカルによるDNA・蛋白の損傷・装飾が発癌過程で果たす意義

    1995.4 - 1997.3

    科学研究費補助金  基盤研究(C) 研究種目コード:320 07670241

    豊國 伸哉

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    Authorship:Principal investigator 

    活性酸素(フリ-ラジカル)は変異、発癌、虚血・再灌流障害、放射線・紫外線障害など種々の生命現象に深く関与することが認識されるようになっている。私たちはいままで、鉄キレ-ト剤である鉄ニトリロ三酢酸反復投与によるラット腎発癌モデルにおいて、活性酸素がその発癌過程に深く関与することを報告してきた。本研究の最終目標は、上記「活性酸素による発癌モデル」において、rate-limitingとなりうる遺伝子を同定し、その変異や発現機構を解析することおよび活性酸素をひとつの切り口として発癌機構を追及することである。
    発癌の標的遺伝子の同定に関して、私たちは以下のアプロ-チを取った。1)活性酸素の代謝に関与する蛋白・酵素遺伝子の発現の評価、2)p53、rasなど既知遺伝子の変異の解析である。1)では、発癌過程初期よりGSH S-transferase piの特異的な誘導を見いだした。2)では、低頻度のp53遺伝子の変異を認めた。従って、本発癌モデルの主要な標的遺伝子はいまだ同定されていない。
    更に、フリ-ラジカルの攻撃により生成する産物の検討を詳細に行った。フリ-ラジカルの標的は脂質・核酸・蛋白質など多岐に渡り、フリ-ラジカル反応により生成する化合物の報告数は年々増加している。しかしながら、活性酸素のエフェクタ-として実際、要となり働くのはかなり限られた分子であることが予想される。私たちはこのモデルにおいて膜脂質の損傷(過酸化脂質)において炭素鎖が2から12の全飽和・不飽和アルデヒドをガスクロマトグラフィ-と質量検出器を使用する分析法で定量し、4-hydroxy-2-nonenal(HNE)の増加率が最も高いことを見いだし、更にHNE修飾蛋白に対するモノクロ-ナル抗体を作成し、免疫化学的応用を行った。

  54. Bリンパ腫病型決定遺伝子の同定とその作用機序の研究

    1995.4 - 1996.3

    科学研究費補助金  重点領域研究 研究種目コード:030 07272222

    日合 弘

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    Authorship:Coinvestigator(s) 

    本研究はPre-Bリンパ腫好発近交系マウスSL/Khのリンパ腫の発生、病型、潜伏期間の長さなどを支配している宿主遺伝子を同定し、その作用機序を解析することを目的としている。今回はSL/Khと野生マウス由来の近交系MSM/Msの交配系のリンパ腫発生を観察し、遺伝解析を加えた。F1ではリンパ腫の発生はなく、SL/Khへの退交配世代60頭のうち14頭が1年6ケ月の観察期間中にリンパ腫を発生した。この頻度から、MSM/Msは2つの優性抵抗性遺伝子を持つという仮説をたてた。退交配世代をマイクロサテライト法により遺伝解析した結果、第17染色体MHC領域と第14染色体上に優性抵抗性遺伝子がマップされ、それぞれMsmr-1,Msmr-2と命令された。SL/KhのMHC haplotypeはqで、MHC classll分子に欠損がある。SL/Kh系マウスはウイルス、あるいはリンパ腫細胞に対する免疫学的抵抗性を欠如していると考えられる。またMsmr-2はヒトの5q23-31とシンテニックであり、この部位ではヒト造血系腫瘍でしばしば転座、LOHなどが報告されている。

  55. Genetic Mechanism of Determination of Types of Lymphomas

    Grant number:07457059  1995 - 1996

    HIAI Hiroshi

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    This project aimed to elucidate host genetic mechanism to determine types of murine lymphomas. During the period of funding, the followings are progress.
    1.Origin as well genetic relationship among 4 members of SL family mice have been extensively elucidated by means of polymorphic microsatellite Ioci, endogenous retrovirus genome as well as Mx gene. 2.SL/Kh pre-B lymphoma cells were shown to express adhesion molecules ICAM-1 and LFA1, whereas their normal conterpart did not. 3.To investigate the function of Tlsm-1 gene, thymectomized (SL/Kh*AKR) F1 mice were grafted with AKR,F1, SL/Kh newborn thymus under kidney capsule and allowed to lymphomas to develop. Unusual dual T and B phenotype lymphomas developed in normal or thymectomizeed F1 mice. Biphenotypic lymphomas were not thymus-dependent, whereas the minority pure T lymphomas depended on Tlsm-1 positive thymus. Thymectomized F1 mice developed NK1.1 positive CD3+CD4-CD8-lymphomas, possibly derived from the extrathymic NK cell population. 4.Congenic mice for lymphoma susceptible or resistance genes have been developed. 5.To further map Tlsm-1, crosses between AKXD11 and AKXD21 recombinant inbred strains have been under observation. 6.In a wildmice-derived inbred strain MSM/Ms, two dominant resistance gene to SL/Kh lymphomas were identified and mapped on Chr.17 and 19.7.Recombinant inbred mouse SMXA as well as rat LEXF have been established and extensively characterized. These RI strains are powerful tool to analyze polygenic trait such as cancer susceptibility.

  56. Redox Regulation and Cellular Signal Transduction

    Grant number:07041160  1995 - 1996

    Grant-in-Aid for international Scientific Research

    YODOI Junji

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Human thioredoxin (TRX) has a potent thiol reducing activity and plays an important role on the redox regulation. Yodoi and the the members of the international cooperation program of the redox regulation and cellular signal transduction demonstrated the following results : 1) the targeted disruption of the TRX was embryonic lethal, suggesting the essential role of TRX in the mouse embryogenesis and differentiation. 2) the oxidative responsive element in the thioredoxin promoter was identified. 3) TRX and Ref-1 which is important for the activation of the AP-1 was demonstrated to be able to interact physically. 4) the redox regulation was shown to be important for the binding of transcription factors including steroid hormone receptor or PEBP2.5) the thioredoxin-dependent peroxidase (peroxiredoxin) was characterized and indicated to be involved in scavenging reactive oxygen intermediates. 6) Several groups started to analyze the redox sensor mechanism against oxidative stress. 7) Irreversible oxidative stress was indicated to be involved in several disease processes including iron induced carcinogenesis. Analysis of the signal transduction system and redox regulation seems to be an approach to elucidated the pathogenesis of several diseases. In summary, this international program showed the importance of the further study of the molecular mechanism of the redox regulation and the cellular signal transduction system.

  57. SIGNIFICANCE OF FREE RADICAL-INDUCED DNA AND PROTEIN DAMAGE AND MODIFICATIONS ON CARCINOGENESIS

    Grant number:07670241  1995 - 1996

    TOYOKUNI Shinya

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2600000 ( Direct Cost: \2600000 )

    It is established that free radicals are involved in a diversity of biological phenomena such as mutation, carcinogenesis, ischemia-reperfusion injury, and irradiation/ultraviolet damage. We have thus far reported that free radicals are deeply involved in the carcinogenic process of ferric nitrilotriacetate (Fe-NTA) -induced rat renal cell carcinoma model. The purpose of this study is 1) to identify rate-limiting genes for Fe-NTA-induced renal carcinogenesis and further explore the presence of mutations and the expression of the identified genes, and 2) to clarify carcinogenic mechanisms by analyzing modified molecules by free radicals.
    We used two strategies for identifying the target genes : 1) evaluation of genes associated with free radical metabolism ; 2) the analysis of known oncogene or oncosuppressor gene, ras and p53. We have found the specific induction of glutathione S-transferase pi in the early stage of this carcinogenesis model. We also found no incidence of mutations in H,K,and N-ras genes and a low incidence of p53 mutations in the induced renal cell carcinomas.
    Then, we analyzed the products modified by free radical reaction. Main targets for free radicals reactions are lipids, nucleic acids and proteins, and an increasing number of products are reported every year. We suppose, however, limited number of molecules have biological meaning. We have measured using gas chromatography/mass spectrometry the amount of C2-12 saturated and unsaturated aldehydes in the kidney of rats treated with Fe-NTA,and found that 4-hydroxy-2-nonenal (HNE) shows the highest increase. HNE reacts with cysteine, histidine or lysine residues of proteins. We made monoclonal antibodies for HNE-modified proteins, and analyzed renal samples after Fe-NTA treatment by ELISA and immunohistochemistry.

  58. Bリンパ腫病型決定遺伝子の同定とその作用機序の研究

    Grant number:07272222  1995

    日合 弘

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    本研究はPre-Bリンパ腫好発近交系マウスSL/Khのリンパ腫の発生、病型、潜伏期間の長さなどを支配している宿主遺伝子を同定し、その作用機序を解析することを目的としている。今回はSL/Khと野生マウス由来の近交系MSM/Msの交配系のリンパ腫発生を観察し、遺伝解析を加えた。F1ではリンパ腫の発生はなく、SL/Khへの退交配世代60頭のうち14頭が1年6ケ月の観察期間中にリンパ腫を発生した。この頻度から、MSM/Msは2つの優性抵抗性遺伝子を持つという仮説をたてた。退交配世代をマイクロサテライト法により遺伝解析した結果、第17染色体MHC領域と第14染色体上に優性抵抗性遺伝子がマップされ、それぞれMsmr-1,Msmr-2と命令された。SL/KhのMHC haplotypeはqで、MHC classll分子に欠損がある。SL/Kh系マウスはウイルス、あるいはリンパ腫細胞に対する免疫学的抵抗性を欠如していると考えられる。またMsmr-2はヒトの5q23-31とシンテニックであり、この部位ではヒト造血系腫瘍でしばしば転座、LOHなどが報告されている。

  59. 腎がんの進展と予後に関与する宿主側要因の研究

    1994.4 - 1996.3

    科学研究費補助金  一般研究(C) 研究種目コード:090 06671587

    寺地 敏郎

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    本年度の主な実績は以下の通りである。
    1)85例の腎細胞癌および212例の他の泌尿器癌について、PCR-RFLP法を用いてp53遺伝子コドン75の多型(CGC(Arg)またはCCC(Pro))を解析し、ノ-マルコントロ-ル群と比較した。統計学的には有意差を認めなかったが、腎細胞癌ではArg/Argの頻度は比較的低く、Pro/Proの頻度が高くなる傾向が認められた。
    2)97例の腎細胞癌罹患者について、PCRを用いてHLA class II DRB1のアレル頻度を解析し、1216例の日本人ノ-マルコントロ-ル群と比較することにより、臨床パラメ-タ-との相関について検討した。腎細胞癌罹患者ではHLA class II DRB 0101,0405アレル頻度が有意に低く、またこれらのアレルを有する例では他の群に比べlow grade, low stageのが有意に多かった。
    3)25例の腎細胞癌について、ウエスタンブロッティングおよびカイネ-スアッセイを用いてMAP、MEK、Raf-1の活性化について検討した。約半数の症例でMAPの恒常的活性化を認めた。
    4)55例の腎細胞癌についてマイクロサテライトを用いた9p21-22のLOH、サザンブロッティング、SSCP、ダイレクトシ-クエンスを用い、p16の欠失、変異について解析した。p16の欠失、mutationの頻度は極めてひくかったが、55例を手術時の転移の有無により2群に分けた場合、9p21-22のLOHは転移を有する群で有意に高かった。
    以上より、P53コドン75の多型、HLAクラスII抗原の違いは、宿主側の要因であるが、腎癌の発生に大きく関与し、健常人の腎癌罹患の危険因子とみなしうる可能性が示唆された。MAPは腎癌の発生、進展を生物学的に解析する上で極めて意義のある蛋白であると考えられた。さらに、HLAクラスII抗原、染色体9p21-22の欠失は腎癌罹患者の予後を予測するマ-カ-となりうることが示された。以上の分子生物学的なパラメ-タ-のさらに詳細な解析は臨床上の治療指針の確立に大きく寄与するものと思われる。

  60. 鉄ニトリロ三酢酸によるrasおよびp53遺伝子の突然変異と腎発癌

    1994.4 - 1995.3

    科学研究費補助金  奨励研究(A) 研究種目コード:210 06770151

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    Authorship:Principal investigator 

    フリ-ラジカルによる生体高分子損傷は変異、発癌、老化、放射線効果、坑癌剤活性等の種々の生物学的過程で重要な役割を果たす。低分子鉄キレ-ト化合物である鉄ニトリロ三酢酸の投与はラットやマウスに高率に腎癌を誘発する。本研究代表者はこれまでに脂質過酸化物の測定等により、この発癌系でフリ-ラジカルが深く関与することを示してきた。今回新たに腎クロマチンにおいてヒドロキシラジカルに特徴的なDNA修飾塩基の生成をガスクロマトグラフィ-・マススペクトロメトリ-による測定で証明し、また変異原性の確立された過酸化脂質である4-hydroxy-2-nonenal修飾蛋白に対する抗体を使用しその存在を証明した。更に誘発された腎原発腫瘍12例において癌遺伝子であるrasおよび癌抑制遺伝子であるp53の突然変異の検索を行った。rasについてはH-ras,K-ras,n-rasいずれにおいてもcodon12,13,61において変異を認めなかった。p53は1例においてcodon246で変異を認め(CGC to CTC;Arg to Leu)、蛋白レベルでその異常蛋白の発現が高いことを確認した。この変異パタ-ンはヒドロキシラジカルに特徴的な修飾塩基である8-hydroxyguanineにより引き起こされたものとして矛盾しない。本研究では、この腎発癌モデルにおいてはras,p53はフリ-ラジカルによる変異の主要な標的となっていないことが明らかとなった。これはヒト腎癌の報告とも一致し、臓器特異的な事実である可能性もあり、現在新たな標的遺伝子を検索している。

  61. The Factors contributing to the Progression and Prognosis of Renal cell Carcinomas ; In the aspect of the Hosts

    Grant number:06671587  1994 - 1995

    Grant-in-Aid for General Scientific Research (C)

    TERACHI Toshiro

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Our results in the studies supported by Grants-in Aid from Ministry of Education, Science, and Culture of Japan are the followings :
    1, The biological characteristics of renal cell carcinoma (RCC). 1) 'Persistent oxidative stress' was correlated with the carcinogenesis in RCCs. 2) The expression levels of the mdr1, MRP,and topoisomerase II were different among histopathologic subtypes of RCCs. In papillary subtype, MRP gene was much less expressed compared with other subtypes. 3) RCC cells which resisted to CDDP showed the increase of the sensitivity to CDDP,when these cells were treated with the antibody of Interleukin 6, or its receptor. 4) The expression levels of the E-cadherin were different among histopathologic subtypes of RCCs. In papillary and chromophobe subtypes, the expression of the E-cadherin was maintained. 5) Approximately 80% of the RCCs showed enhanced-expression of the c-met gene. 6) Constitutive Activation of Mitogen-Activated Protein (MAP) Kinases was demonstrated in almost half of Human RCCs. 7) The LOH on chromosome 9P21-22 was strongly correlated with the progression and metastasis of Human RCCs.
    2, The factors contributed to the tumorigenesis or tumor development of renal cell carcinomas : In the aspects of the affected patients. 8) Allelic Frequency of p53 Gene Codon 72 Polymorphism was correlated with the carcinogenesis in Human RCCs. In the patients, the frequency of the Arg/Arg was lower, and that of the Pro/Pro was higher than the normal Japanese population. 9) In the patients affected RCCs, the frequency of the 0404 or the 0120 allele on the HLA class II DRB 1 was significantly low when compared with the normal Japanese population.
    We could obtain so many systemic data of the tumorigenesis and development of human renal call carcinoma.

  62. 鉄ニトリロ三酢酸によるrasおよびp53遺伝子の突然変異と腎発癌

    Grant number:06770151  1994

    奨励研究(A)

    豊國 伸哉

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\900000 ( Direct Cost: \900000 )

    フリーラジカルによる生体高分子損傷は変異、発癌、老化、放射線効果、坑癌剤活性等の種々の生物学的過程で重要な役割を果たす。低分子鉄キレート化合物である鉄ニトリロ三酢酸の投与はラットやマウスに高率に腎癌を誘発する。本研究代表者はこれまでに脂質過酸化物の測定等により、この発癌系でフリーラジカルが深く関与することを示してきた。今回新たに腎クロマチンにおいてヒドロキシラジカルに特徴的なDNA修飾塩基の生成をガスクロマトグラフィー・マススペクトロメトリーによる測定で証明し、また変異原性の確立された過酸化脂質である4-hydroxy-2-nonenal修飾蛋白に対する抗体を使用しその存在を証明した。更に誘発された腎原発腫瘍12例において癌遺伝子であるrasおよび癌抑制遺伝子であるp53の突然変異の検索を行った。rasについてはH-ras,K-ras,n-rasいずれにおいてもcodon12,13,61において変異を認めなかった。p53は1例においてcodon246で変異を認め(CGC to CTC;Arg to Leu)、蛋白レベルでその異常蛋白の発現が高いことを確認した。この変異パターンはヒドロキシラジカルに特徴的な修飾塩基である8-hydroxyguanineにより引き起こされたものとして矛盾しない。本研究では、この腎発癌モデルにおいてはras,p53はフリーラジカルによる変異の主要な標的となっていないことが明らかとなった。これはヒト腎癌の報告とも一致し、臓器特異的な事実である可能性もあり、現在新たな標的遺伝子を検索している。

  63. 食品因子による生体防御を目的としたDNA障害マ-カ-の開発と応用

    1993.4 - 1996.3

    科学研究費補助金  試験研究(B) 研究種目コード:122 05556021

    大澤 俊彦

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    Authorship:Coinvestigator(s) 

    最近、がんの発生におけるフリ-ラジカルの役割については多くの注目を集めてきているが科学的な根拠については未知の点も多い。特に、防御機構が正常に機能しない状態に陥ったときに生体内では過剰な活性酸素が生成し、フリ-ラジカル連鎖反応が誘発される。その結果、生体膜での障害や生体重要物質での損傷にもとずく機能障害の蓄積と共に遺伝子レベルにおける障害が「遺伝毒性」を発現し、「がんの発生」を誘発したり「がん化の促進」に大きな役割をはたしているのではないかと考えられてきている。このような遺伝子レベルにおける酸化的障害を抑制すること、特に食品成分が抑制因子となりうるかについてを評価するために、老化に関連した疾病のマ-カ-として酸化修飾塩基の代表である8-デオキシグアノシンのモノクロ-ナル抗体よる検出法の応用を日本老化制御研究所(越智)との共同研究で開発することができた。そこで本年度は、まず、ゴマ種子中に大量に含まれている新規な抗酸化前駆体であるリグナン配糖体の持つ酸化障害予防効果の検討を行った。方法は、ゴマ脱脂粕をビタミンE欠乏飼料中に10%加えてラットに2ヵ月間投与し、四塩化炭素で過酸化障害を与えた。その結果、ビタミンE欠乏食だけの場合に較べてゴマ脱脂粕の場合は肝臓や血液中の過酸化度と共に尿中での過酸化度、さらに8-デオキシクアノシン量を有意に低下させた。これらの結果より、セサミノ-ル配糖体が腸内細菌により加水分解を受けた後に生体内に吸収され抗酸化的な防御効果を示すという新しい機構を提出することができた。また、本年は、生体膜の酸化的障害物質として代表的な4-ヒドロキシノネナ-ルのモノクロ-ナル抗体の作製に成功し、さらに最近マロンジアルデヒドにより修飾されたタンパク質に対するポリクロ-ナル抗体の作製にも成功している。これらの抗体による組織染色、特に酸化障害により生じた腎臓がん部位での検出への応用にも成功している。さらに、培養細胞系、特に、チャイニ-ズハムスタ-や大腸由来の細胞で過酸化水素を中心とした酸化的障害の保護効果についても、新しい機構を提出することができた。また、ゴマ油中の抗酸化成分として抗酸化的な防御効果の検討を行ったセサミノ-ルについては、ビタミンEに対して強い相乗的な効果が見られるという新しいメカニズムを明らかにすることができたので、これらのリグナンを食品因子として代謝も含めた新しい研究へのアプロ-

  64. 鉄によるDNA損傷とその癌遺伝子、癌抑制遺伝子への影響

    1993.4 - 1994.3

    科学研究費補助金  奨励研究(A) 研究種目コード:210 05770149

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    Authorship:Principal investigator 

    ヒトにおいて体内の鉄貯蔵量増加は発癌のリスクとなることが明らかとなったため、鉄による発癌機構の分子病理学的解明をめざした。この際、中性で自由鉄でありうる鉄キレ-ト化合物が重要となる。鉄ニトリロ三酢酸の反復投与はラット、マウスで高率に胃癌を発生させる。また、鉄クエン酸はヒトのヘモクロマト-シスにおける血中の自由鉄である。両鉄キレ-ト化合物は本研究者らの開発したsupercoiled plasmidを使用したin vitroの系でDNAを切断し修飾塩基を生成した。この反応は、温度、還元剤、pH、鉄とキレ-ト剤の比率に依存した。次に、鉄ニトリロ三酢酸を投与したラット腎において、ガスクロマトグラフィ-/マススぺクトロメトリ-によりDNA修飾塩基を検討し、癌遺伝子であるc-fos、c-junの蛋白について酵素抗体法により解析を加えた。投与後1-3hrsをピ-クとして、8-hydroxyguanine(8-OH-Gua)をはじめとする7種のDNA修飾塩基の増加を認めた。8-OH-GuaはG:C to T:A transversionの原因として注目されるが、生成修飾塩基の中には変異原性に関するデ-タがいまだ報告のないものもある。近位尿細管の変性壊死再生に伴い、修飾塩基が存在することは変異を誘発し固定するという意味において発癌過程で重要な役割を果たしていると考えられる。投与後16hrs以後再生上皮にc-fos、c-jun蛋白の増加がみられ、これらの蛋白の発癌過程への関与が示唆された。

  65. リンパ腫発生に先立つ骨髄内pre-B細胞の異常分化

    1993.4 - 1994.3

    科学研究費補助金  がん特別研究 研究種目コード:021 05152060

    日合 弘

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    Authorship:Coinvestigator(s) 

    リンパ腫好発系近交系マウスSL/Kh系の前リンパ腫期骨髄におけるB細胞分化を検討した。BP-1抗原陽性前B細胞が生後4-6週を中心に著明にポリクロ-ナルに増殖し15-18週令ころより急速にモノクロ-ナル増殖に転化した。他の大部分の近交系マウスでは前B細胞のレベルははるかに低かった。SL/KhとのF1では前B細胞の増殖がみられこの形質は遺伝的に優性とみなされた。SL/Khのリンパ腫発生には内在性レトロウイルスが必要であるが、前リンパ腫期の前B細胞の増殖にはウイルスは関与していないことがウイルス抵抗性遺伝子FV-4^Rcongenic C4WとのF1においても前B細胞の増殖があること、母系抵抗因子の投与によっても減少しないことから証明された。一方、放射線キメラを作成したところ、骨髄細胞ドナ-によって前B細胞のレベルは決定されており、SL/Kh系の幹細胞の性質に基づくものと思われた。これらの所見から、SL/Kh系の前Bリンパ腫の発生は多段階過程を経て発生することが示された。
    自然発生リンパ腫をみないNFS/N系とのF1、退交配系についてリンパ腫の発生、病型を観察し、プロウイルスとその発現、生化学的遺伝子マ-カ-、マイクロサテライトマ-カ-を全個体について解析した。すべてのリンパ腫の発生には内在性ウイルスのうちAkv-1(第7染色体)の存在と発現が必要であった。リンパ腫の発生は遺伝的に優性であるが、MHCと連関したEsl-1座位がSL/Kh由来のアレルを持つ場合には急性の前Bリンパ腫が発生し、第4染色体上のfoc-1座位がNFS/N由来の劣性アレルのホモの場合にはより成熟したB細胞腫瘍であるろ胞中心細胞リンパ腫が発生した。これらの所見はウイルスによる腫瘍の病型は宿主の遺伝的感受性により決定されていることを示すものである。

  66. Development of Damaged DNA Markers for Prevention by Food Factors

    Grant number:05556021  1993 - 1995

    Grant-in-Aid for Developmental Scientific Research (B)

    OSAWA Toshihiko

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Free radical has been associated with important pathophysiological events in a variety of diseases, drug toxicities, and traumatic or ischemic injuries. It has been postulated that free radicals generated during the process may be responsible for these effects because of their ability to damage cellular membranes, proteins, and DNA.We have developed a unique immunochemical procedure for quantifying 8-oxodeoxyguanosine (8-OH-dG) generated in the oxidized DNA.Using this method, we found that sesamisol glucoside decreased the level of 8-OH-dG and considerably inhibits the hepatotoxicity of rats treated with carbon tetrachloride. Furthermore, we developed another immunochemical procedure for quantifying a cytotoxic aldehyde 4-hydroxy-2-nonenal (HNE) originated from the peroxidation of polyunsaturated fatty acide. We characterize the specificity of this assay and found that considerable amount of HNE is generated in the kidney of rats treated with a renal carcinogen ferric nitrilotriacetate. Recently, we have obtained a direct evidence that oxidatively modified low density lipoproteins (LDL) also possess a considerable amount of HNE that is capable of reacting with other molecules.

  67. リンパ腫発生に先立つ骨髄内pre-B細胞の異常分化

    Grant number:05152060  1993

    がん特別研究

    日合 弘

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    リンパ腫好発系近交系マウスSL/Kh系の前リンパ腫期骨髄におけるB細胞分化を検討した。BP-1抗原陽性前B細胞が生後4-6週を中心に著明にポリクローナルに増殖し15-18週令ころより急速にモノクローナル増殖に転化した。他の大部分の近交系マウスでは前B細胞のレベルははるかに低かった。SL/KhとのF1では前B細胞の増殖がみられこの形質は遺伝的に優性とみなされた。SL/Khのリンパ腫発生には内在性レトロウイルスが必要であるが、前リンパ腫期の前B細胞の増殖にはウイルスは関与していないことがウイルス抵抗性遺伝子FV-4^Rcongenic C4WとのF1においても前B細胞の増殖があること、母系抵抗因子の投与によっても減少しないことから証明された。一方、放射線キメラを作成したところ、骨髄細胞ドナーによって前B細胞のレベルは決定されており、SL/Kh系の幹細胞の性質に基づくものと思われた。これらの所見から、SL/Kh系の前Bリンパ腫の発生は多段階過程を経て発生することが示された。
    自然発生リンパ腫をみないNFS/N系とのF1、退交配系についてリンパ腫の発生、病型を観察し、プロウイルスとその発現、生化学的遺伝子マーカー、マイクロサテライトマーカーを全個体について解析した。すべてのリンパ腫の発生には内在性ウイルスのうちAkv-1(第7染色体)の存在と発現が必要であった。リンパ腫の発生は遺伝的に優性であるが、MHCと連関したEsl-1座位がSL/Kh由来のアレルを持つ場合には急性の前Bリンパ腫が発生し、第4染色体上のfoc-1座位がNFS/N由来の劣性アレルのホモの場合にはより成熟したB細胞腫瘍であるろ胞中心細胞リンパ腫が発生した。これらの所見はウイルスによる腫瘍の病型は宿主の遺伝的感受性により決定されていることを示すものである。

  68. 鉄によるDNA損傷とその癌遺伝子、癌抑制遺伝子への影響

    Grant number:05770149  1993

    奨励研究(A)

    豊國 伸哉

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\900000 ( Direct Cost: \900000 )

    ヒトにおいて体内の鉄貯蔵量増加は発癌のリスクとなることが明らかとなったため、鉄による発癌機構の分子病理学的解明をめざした。この際、中性で自由鉄でありうる鉄キレート化合物が重要となる。鉄ニトリロ三酢酸の反復投与はラット、マウスで高率に胃癌を発生させる。また、鉄クエン酸はヒトのヘモクロマトーシスにおける血中の自由鉄である。両鉄キレート化合物は本研究者らの開発したsupercoiled plasmidを使用したin vitroの系でDNAを切断し修飾塩基を生成した。この反応は、温度、還元剤、pH、鉄とキレート剤の比率に依存した。次に、鉄ニトリロ三酢酸を投与したラット腎において、ガスクロマトグラフィー/マススぺクトロメトリーによりDNA修飾塩基を検討し、癌遺伝子であるc-fos、c-junの蛋白について酵素抗体法により解析を加えた。投与後1-3hrsをピークとして、8-hydroxyguanine(8-OH-Gua)をはじめとする7種のDNA修飾塩基の増加を認めた。8-OH-GuaはG:C to T:A transversionの原因として注目されるが、生成修飾塩基の中には変異原性に関するデータがいまだ報告のないものもある。近位尿細管の変性壊死再生に伴い、修飾塩基が存在することは変異を誘発し固定するという意味において発癌過程で重要な役割を果たしていると考えられる。投与後16hrs以後再生上皮にc-fos、c-jun蛋白の増加がみられ、これらの蛋白の発癌過程への関与が示唆された。

  69. 非胸腺リンパ腫実験モデル系によるウイルス-宿主相互関係の解析

    1992.4 - 1995.3

    科学研究費補助金  一般研究(B) 研究種目コード:080 04454187

    日合 弘

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    Authorship:Coinvestigator(s) 

    リンパ腫の発生はマウスでは内在性レトロウイルスによるが、多くの宿主要因の関与する多段階過程で、いわば多因子遺伝病のモデルともみなされる。当研究室で樹立したPre-Bリンパ腫好発系SL/Khを材料として詳細な宿主遺伝要因の解析を行ってきた。まず、ウイルスゲノムを持たずリンパ腫の自然発生のないNFS/N系との交配実験から、SL/KhマウスのPre-Bリンパ腫に対する遺伝的感受性はプロウイルスEmv-11の存在に依存し、SL/Kh由来MHCをもつ場合はPre-Bリンパ腫を、これをもたず第4染色体上のfoc-1座位がNFS/N由来アレルのホモである場合には濾胞中心細胞リンパ腫を発生することを発見し報告した。本年度は、標的細胞の異なるTリンパ腫好発系AKR/Msとの交配実験を行い、SL/Khへの退交配、F2世代ではTリンパ腫の発生は常染色体単一優性遺伝子Tlsm-1 により決定されていること、同遺伝子はマイクロサテライト法による解析から第7染色体のセントロメアより62cMにマップされることを明らかにした。AKRとDBA/2との組み替え近交系AKXDの第7染色体を精査し、Tリンパ腫発生はこの系でもTlsm-1と相同な遺伝子によって決定されていることを示した。この部位にはラットの化学発癌剤誘発Tリンパ腫の感受性遺伝子も我々の手でマップされている。これらの一連の知見はリンパ腫病型は宿主遺伝子型の組み合わせにより決定されることを示唆し、ヒトのリンパ腫についても相同遺伝子を中心にこの考えを拡大適用できる可能性を示すものである。

  70. VIRUS-HOST INTERACTIONS IN A NON-THYMIC LYMPHOMA MOUSE MODEL

    Grant number:04454187  1992 - 1994

    Grant-in-Aid for General Scientific Research (B)

    HIAI Hisoshi

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Lymphomagenesis in mice is dependent on endogenous retrovirus. It is, however, a multi-step phenomenon involving numerous host factors, thus assumed to be a model of multifactorial genetic diseases. We have studied genetic basis of the pre-B lymphomas in SL/Kh strain mice. In crosses with NFS/N strain, lacking endogenous ecotropic virus and spontaneous lymphomas, all lymphomas developed only when Emv-11 provirus was expressed. In the backcross mice to NFS/N,pre-B lymphomas developed only in the mice with SL/Kh-derived MHC allele, and follicular center cell lymphomas occured only in the homezygotes for NFS-derived allele both at MHC and foc-1 locus on Chr.4. We further examined the cross between SL/Kh and AKR/Ms strain. T-lymphoma-prone mice. In the backcross to AKR,development of T-lymphomas was determined by a single dominant gene Tlsm-1 (T-lymphoma susceptible mouse-1) and Tlsm-1 was mapped at map position 62 cM on Chr.7. Similar gene was identified in AKXD RI strains as wellas in chemical-induced T-lymphomas in F344 rats in the homologous region of Chr.7. These findings clearly indicate that the types of lymphomas are determined by a combination of host genes and may suggest that this hypothesis could be extended to human lymphomas.

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Industrial property rights 7

  1. 抗腫瘍水溶液の製造方法

    堀 勝, 水野 正明, 吉川 史隆, 豊國 伸哉, 丸山 彰一, 田中 宏昌, 加納 浩之

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    Applicant:国立大学法人東海国立大学機構

    Application no:特願2016-517578  Date applied:2015.9

    Patent/Registration no:特許第6755491号  Date registered:2020.8 

    J-GLOBAL

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  2. 酸化ストレス傷害を受けたDNA断片の収集法

    豊國伸哉 外2名

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    Application no:特許出願2004-021493  Date applied:2004.1

    Announcement no:WO2005/073373 

    Date registered:2005.8 

    Country of applicant:Domestic  

    本発明は、DNAを含む試料中の酸化ストレスにより傷害された領域のDNA断片を選択的に収集する方法であって、試料からDNAを抽出し、断片化した後、傷害により修飾された修飾ヌクレオシドまたは該修飾ヌクレオシドを含むポリヌクレオチドに特異的な一次抗体とインキュベートし、沈降した複合体を回収し、該複合体から傷害されたDNA断片を回収することを特徴とする方法を提供する。

  3. 酸化ストレス傷害を受けたDNA断片の収集法

    豊國伸哉

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    Application no:特許出願2004-021493  Date applied:2004.1

    Announcement no:WO2005/073373 

    Date registered:2005.8  Date issued:2005.8

    Country of applicant:Domestic  

    本発明は、DNAを含む試料中の酸化ストレスにより傷害された領域のDNA断片を選択的に収集する方法であって、試料からDNAを抽出し、断片化した後、傷害により修飾された修飾ヌクレオシドまたは該修飾ヌクレオシドを含むポリヌクレオチドに特異的な一次抗体とインキュベートし、沈降した複合体を回収し、該複合体から傷害されたDNA断片を回収することを特徴とする方法を提供する。

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  4. 抗血清およびその製造方法

    内田浩二、豊國伸哉 外3名

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    Applicant:日本油脂株式会社

    Application no:特許出願平9-251395  Date applied:1997.9

    Announcement no:特許公開平11-80023 

    Date registered:1999.3 

    Country of applicant:Domestic  

    【課題】 アクロレインと蛋白質あるいはペプチドの構成アミノ酸の1つであるリジンの付加体に関して着目し、このアクロレイン付加体が有するホルミルデヒドロピペリジン-リジン構造に対して認識特異性の高い抗血清と、その製造方法を提供する。
    【解決手段】 (1)アクロレインで修飾したカギアナカサガイから得たヘモシアニンを抗原とし、(2)恒温動物に免疫して、次式:【化1】
    〔式中、R1 、R2 は蛋白質残基、ペプチド残基、もしくはR1 =R2 =Hを示す。〕で示されるホルミルデヒドロピペリジン-リジン構造を特異的に認識する抗血清を採取する。

  5. 抗血清およびその製造方法

    内田浩二、豊國伸哉 外3名

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    Applicant:日本油脂株式会社

    Application no:特許出願平9-247632  Date applied:1997.8

    Announcement no:特許公開平11-71400 

    Date registered:1999.3 

    Country of applicant:Domestic  

    【課題】 リノレン酸やエイコサペンタエン酸等のω-3系高度不飽和脂肪酸の過酸化分解によって生ずる4-ヒドロキシ-2-ヘキセナール(略語:4-HHE)が蛋白質と反応してなるマイケル付加体構造を特異的に認識する抗血清を提供し、且つモノクローナル抗体のような複雑多岐な製造工程を経ることなく、該抗血清の効率的な製造方法を提供する。
    【解決手段】 4-ヒドロキシ-2-ヘキセナールで修飾したカギアナカサガイから得たヘモシアニンを抗原とし、恒温動物に免疫して、次式:【化1】
    [式中、Y-CH2 -X-は、アミノ酸残基、ペプチド残基、蛋白質残基を示し、Xは、システイン、ヒスチジンあるいはリジン側鎖を示す。]で示されるマイケル付加体構造を特異的に認識する抗血清を採取する。

  6. ポリクローナル抗体および製造方法

    内田浩二、豊國伸哉 外4名

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    Applicant:日本油脂株式会社

    Application no:特許出願平8-245725  Date applied:1996.8

    Announcement no: 特許公開平10-72499 

    Date registered:1998.3 

    Country of applicant:Domestic  

    【課題】 動脈硬化症に相関する抗体であって、特異的認識部位が分子構造レベルで特定されており、臨床診断、分析等において有用な抗体を提供し、且つ該抗体の効率的な製造方法を提供する。
    【解決手段】 マロンジアルデヒド(略語:MDA)で修飾した蛋白質、例えば、MDAで修飾されたカギアナカサガイから得たヘモシアニンを抗原とし、恒温動物に免疫して抗血清を得、該抗血清を、N-ε-プロペナール-リジン構造を有するリガンドが固定化されたアフィニテイーゲルを用いて精製する。得られたポリクローナル抗体はN-ε-プロペナール-リジン構造を特異的に認識し、生体中の過酸化脂質の分析への可能性が期待される。

  7. 4-ヒドロキシ-2-ノネナール修飾蛋白質に対するモノクローナル抗体とその製造法及びこれを生産するハイブリッド細胞並びに4-ヒドロキシ-2-ノネナール定量用免疫測定キット

    豊國伸哉 外1名

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    Applicant:日研フード株式会社

    Application no: 特許出願平6-313652  Date applied:1994.12

    Announcement no: 特許公開平8-168394 

    Date registered:1996.7 

    Country of applicant:Domestic  

    【目的】 この発明は工業用油脂、食品および生体において発生する脂質の過酸化物である4-ヒドロキシ-2-ノネナールを指標とし、これを免疫化学的に迅速・微量定量することにより、工業用油脂や食品の劣化あるいは生体の酸化的ストレスを評価することを可能ならしめることを目的としたものである。
    【構成】 4-ヒドロキシ-2-ノネナール(HNE)による修飾を受けたカギアナカサガイのヘモシアニンを抗原とし、免疫されたマウスの脾臓細胞とマウスミエローマ細胞よりなることを特徴とした抗HNE修飾蛋白抗体を産生するハイブリッド細胞。4-ヒドロキシ-2-ノネナール(HNE)による修飾をうけたカギアナカサガイのヘモシアニンを抗原とし、免疫されたマウスの脾臓細胞とマウスミエローマ細胞とのハイブリッド細胞を作製し、前記ハイブリッド細胞の増殖により生産することを特徴とした抗HNE修飾蛋白に対するモノクローナル抗体。

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Teaching Experience (On-campus) 5

  1. 病因と病態(病理学総論・各論)

    2021

  2. 基礎セミナーA

    2021

  3. 病理学(修士課程)

    2020

  4. 病因と病態学(病理学)

    2015

  5. First Year Seminar A

    2015

Teaching Experience (Off-campus) 9

  1. 環境健康学入門・概論:アスベスト曝露と中皮腫

    2009.4 - 2010.3 東京大学大学院医学系研究科)

  2. 病理学総論:活性酸素の病理学

    2010.4 - 2011.3 京都大学医学部)

  3. 病理学総論:活性酸素の病理学

    2009.4 - 2010.3 愛媛大学医学部)

  4. 病理学総論:活性酸素の病理学

    2010.4 - 2011.3 島根大学医学部)

  5. 病理学総論:活性酸素の病理学

    2010.4 - 2011.3 福井大学医学部)

  6. 病理学総論:活性酸素の病理学

    2009.4 - 2010.3 琉球大学医学部)

  7. 基礎セミナーA

    2021 Nagoya University)

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    Level:Undergraduate (liberal arts) 

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  8. 領域統合型先端科学特論「生命・環境科学領域」

    2010.4 - 2011.3 大阪薬科大学)

  9. 大学院講義「医学工学特論Ⅰ」

    2010.4 - 2011.3 名古屋工業大学)

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Social Contribution 9

  1. 日本病理学会 病理医・研究医の育成とリクルート委員会 委員長

    2010.4

  2. シドニー大学 客員教授

    Role(s):Lecturer

    2016.1

  3. Pathologogy International, deputy editor

    2014.10

  4. Free Radical Research, associate editor

    2012.4

  5. Archives of Biochemistry and Biophysics, associate editor

    2013.1

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    Archives of Biochemistry and Biophysics誌のassociate editor

  6. Cancer Science, associate editor

    2012.4

  7. Journal of Clinical Biochemistry and Nutrition, executive editor

    2012.4

  8. Nagoya Journal of Medical Science, editor-in-chief

    2010.4

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    Nagoya Journal of Medical Science誌の編集長

  9. 市民公開講座:アスベスト起因性疾患:悪性中皮腫の克服に向けて を主催

    2009.3

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    5人の演者が、それぞれの立場よりアスベスト誘発悪性中皮腫に関して最新の情報を一般市民に提供した。
    総論、豊國伸哉;内科、中野孝司;外科、横井香平;行政、福本 怜;研究、関戸好孝

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