Updated on 2024/04/03

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 1173

  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

    Web of Science

  9. 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     page: 1 - 34   2024.3

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

    DOI: 10.1080/15548627.2024.2319901

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  10. Protocol for the isolation of GFP-expressing ferroptosis-dependent extracellular vesicles in in vitro cell culture models.

    Ito F, Yanatori I, Kato K, Toyokuni S

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

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:STAR Protocols  

    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

    DOI: 10.1016/j.xpro.2024.102892

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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.

    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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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Free Radical Biology and Medicine  

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

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

    Free radical research     page: 1 - 14   2024.2

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    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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  13. A guideline on the molecular ecosystem regulating ferroptosis.

    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     2024.2

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

    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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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PLoS Pathogens  

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

    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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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Laboratory Investigation  

    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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  16. 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     2023.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Oral Diseases  

    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.

    DOI: 10.1111/odi.14827

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

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

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

    Ishikawa K, Takeda K, Yoshimura S, Kondo T, Tanaka H, Toyokuni S, Nakamura K, Kajiyama H, Mizuno M, Hori M

    Free radical research   Vol. 57 ( 3 ) page: 239 - 270   2023.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Free Radical Research  

    This review provides a description of the historical background of the development of biological applications of low-temperature plasmas. The generation of plasma, methods and devices, plasma sources, and measurements of plasma properties, such as electron dynamics and chemical species generation in both gaseous and aqueous phases, were assessed. Currently, direct irradiation methods for plasma discharges contacting biological surfaces, such as the skin and teeth, are related to plasma biological interactions. Indirect methods using plasma-treated liquids are based on plasma–liquid interactions. The use of these two methods is rapidly increasing in preclinical studies and cancer therapy. The authors address the prospects for further developments in cancer therapeutic applications by understanding the interactions between the plasma and living organisms.

    DOI: 10.1080/10715762.2023.2230351

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

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

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  21. New iron export pathways acting via holo-ferritin secretion. 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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  22. Iron links endogenous and exogenous nanoparticles. 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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  23. Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression.

    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.]

    DOI: 10.1038/s41418-023-01195-0

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  24. 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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    DOI: 10.1101/2023.08.14.553187

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  25. Ferroptosis as ultimate target of cancer therapy. 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.

    DOI: 10.1089/ars.2022.0048

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  26. Carbon nanotube recognition by human Siglec-14 provokes inflammation. 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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  27. Sleep-wake patterns are altered with age, Prdm13 signaling in the DMH, and diet restriction in mice. 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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  28. Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1. 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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  29. Organic decomposition and synthesis reactions in lactated solution exposed to nonequilibrium atmospheric pressure plasma

    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.

    DOI: 10.1002/ppap.202200193

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  30. BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis-resistance. 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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  31. Field-effect transistor antigen/antibody-TMDs sensors for the detection of COVID-19 samples. 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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  32. DNA oxidative damage caused by the aromatic amine MOCA —Examination of 8-hydroxy-2’-deoxyguanosine levels in rat liver—

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

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

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

    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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  36. Environmental impact on carcinogenesis under BRCA1 haploinsufficiency.

    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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  37. Plasma activated Ringer's lactate solution.

    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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  38. Exposure of low-temperature plasma after vaccination in tongue promotes systemic IgM induction against spike protein of SARS-CoV-2. 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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  39. Low-temperature plasma as magic wand to differentiate between the good and the evil. 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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  40. Extracellular fine particles and carcinogenesis

    Toyokuni Shinya

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

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    DOI: 10.14952/SEIKAGAKU.2023.950177

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  41. 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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  42. 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.

    DOI: 10.1038/s41598-022-20334-0

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  43. 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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  44. 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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  45. 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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  46. 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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  47. 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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  48. 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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  49. 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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  50. 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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  51. 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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  52. 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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  53. 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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  54. 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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  55. 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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  56. 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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  57. 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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  58. 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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  59. 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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  60. 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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  61. 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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  62. 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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  63. 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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  64. 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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  65. 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.

  66. 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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  67. 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.

  68. 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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  69. 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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  70. 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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  71. 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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  72. 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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  73. 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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  74. 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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  75. 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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  76. 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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  77. 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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  78. 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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  79. 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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  80. 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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  81. 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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  82. 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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  83. 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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  84. 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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  85. 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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  86. 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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  87. 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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  88. 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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  89. 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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  90. 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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  91. 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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  92. 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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  93. 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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  94. 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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  95. 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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  96. 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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  97. 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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  98. 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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  99. 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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  100. 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 Ross Buchan, Erin M Buckingham, Hikmet Budak, Mauricio Budini, Geert Bultynck, Florin Burada, Joseph R Burgoyne, M Isabel Burón, Victor Bustos, Sabrina Büttner, Elena Butturini, Aaron Byrd, Isabel Cabas, Sandra Cabrera-Benitez, Ken Cadwell, Jingjing Cai, Lu Cai, Qian Cai, Montserrat Cairó, Jose A Calbet, Guy A Caldwell, Kim A Caldwell, Jarrod A Call, Riccardo Calvani, Ana C Calvo, Miguel Calvo-Rubio Barrera, Niels Os Camara, Jacques H Camonis, Nadine Camougrand, Michelangelo Campanella, Edward M Campbell, François-Xavier Campbell-Valois, Silvia Campello, Ilaria Campesi, Juliane C Campos, Olivier Camuzard, Jorge Cancino, Danilo Candido de Almeida, Laura Canesi, Isabella Caniggia, Barbara Canonico, Carles Cantí, Bin Cao, Michele Caraglia, Beatriz Caramés, Evie H Carchman, Elena Cardenal-Muñoz, Cesar Cardenas, Luis Cardenas, Sandra M Cardoso, Jennifer S Carew, Georges F Carle, Gillian Carleton, Silvia Carloni, Didac Carmona-Gutierrez, Leticia A Carneiro, Oliana Carnevali, Julian M Carosi, Serena Carra, Alice Carrier, Lucie Carrier, Bernadette Carroll, A Brent Carter, Andreia Neves Carvalho, Magali Casanova, Caty Casas, Josefina Casas, Chiara Cassioli, Eliseo F Castillo, Karen Castillo, Sonia Castillo-Lluva, Francesca Castoldi, Marco Castori, Ariel F Castro, Margarida Castro-Caldas, Javier Castro-Hernandez, Susana Castro-Obregon, Sergio D Catz, Claudia Cavadas, Federica Cavaliere, Gabriella Cavallini, Maria Cavinato, Maria L Cayuela, Paula Cebollada Rica, Valentina Cecarini, Francesco Cecconi, Marzanna Cechowska-Pasko, Simone Cenci, Victòria Ceperuelo-Mallafré, João J Cerqueira, Janete M Cerutti, Davide Cervia, Vildan Bozok Cetintas, Silvia Cetrullo, Han-Jung Chae, Andrei S Chagin, Chee-Yin Chai, Gopal Chakrabarti, Oishee Chakrabarti, Tapas Chakraborty, Trinad Chakraborty, Mounia Chami, Georgios Chamilos, David W Chan, Edmond Y W Chan, Edward D Chan, H Y Edwin Chan, Helen H Chan, Hung Chan, Matthew T V Chan, Yau Sang Chan, Partha K Chandra, Chih-Peng Chang, Chunmei Chang, Hao-Chun Chang, Kai Chang, Jie Chao, Tracey Chapman, Nicolas Charlet-Berguerand, Samrat Chatterjee, Shail K Chaube, Anu Chaudhary, Santosh Chauhan, Edward Chaum, Frédéric Checler, Michael E Cheetham, Chang-Shi Chen, Guang-Chao Chen, Jian-Fu Chen, Liam L Chen, Leilei Chen, Lin Chen, Mingliang Chen, Mu-Kuan Chen, Ning Chen, Quan Chen, Ruey-Hwa Chen, Shi Chen, Wei Chen, Weiqiang Chen, Xin-Ming Chen, Xiong-Wen Chen, Xu Chen, Yan Chen, Ye-Guang Chen, Yingyu Chen, Yongqiang Chen, Yu-Jen Chen, Yue-Qin Chen, Zhefan Stephen Chen, Zhi Chen, Zhi-Hua Chen, Zhijian J Chen, Zhixiang Chen, Hanhua Cheng, Jun Cheng, Shi-Yuan Cheng, Wei Cheng, Xiaodong Cheng, Xiu-Tang Cheng, Yiyun Cheng, Zhiyong Cheng, Zhong Chen, Heesun Cheong, Jit Kong Cheong, Boris V Chernyak, Sara Cherry, Chi Fai Randy Cheung, Chun Hei Antonio Cheung, King-Ho Cheung, Eric Chevet, Richard J Chi, Alan Kwok Shing Chiang, Ferdinando Chiaradonna, Roberto Chiarelli, Mario Chiariello, Nathalia Chica, Susanna Chiocca, Mario Chiong, Shih-Hwa Chiou, Abhilash I Chiramel, Valerio Chiurchiù, Dong-Hyung Cho, Seong-Kyu Choe, Augustine M K Choi, Mary E Choi, Kamalika Roy Choudhury, Norman S Chow, Charleen T Chu, Jason P Chua, John Jia En Chua, Hyewon Chung, Kin Pan Chung, Seockhoon Chung, So-Hyang Chung, Yuen-Li Chung, Valentina Cianfanelli, Iwona A Ciechomska, Mariana Cifuentes, Laura Cinque, Sebahattin Cirak, Mara Cirone, Michael J Clague, Robert Clarke, Emilio Clementi, Eliana M Coccia, Patrice Codogno, Ehud Cohen, Mickael M Cohen, Tania Colasanti, Fiorella Colasuonno, Robert A Colbert, Anna Colell, Miodrag Čolić, Nuria S Coll, Mark O Collins, María I Colombo, Daniel A Colón-Ramos, Lydie Combaret, Sergio Comincini, Márcia R Cominetti, Antonella Consiglio, Andrea Conte, Fabrizio Conti, Viorica Raluca Contu, Mark R Cookson, Kevin M Coombs, Isabelle Coppens, Maria Tiziana Corasaniti, Dale P Corkery, Nils Cordes, Katia Cortese, Maria do Carmo Costa, Sarah Costantino, Paola Costelli, Ana Coto-Montes, Peter J Crack, Jose L Crespo, Alfredo Criollo, Valeria Crippa, Riccardo Cristofani, Tamas Csizmadia, Antonio Cuadrado, Bing Cui, Jun Cui, Yixian Cui, Yong Cui, Emmanuel Culetto, Andrea C Cumino, Andrey V Cybulsky, Mark J Czaja, Stanislaw J Czuczwar, Stefania D'Adamo, Marcello D'Amelio, Daniela D'Arcangelo, Andrew C D'Lugos, Gabriella D'Orazi, James A da Silva, Hormos Salimi Dafsari, Ruben K Dagda, Yasin Dagdas, Maria Daglia, Xiaoxia Dai, Yun Dai, Yuyuan Dai, Jessica Dal Col, Paul Dalhaimer, Luisa Dalla Valle, Tobias Dallenga, Guillaume Dalmasso, Markus Damme, Ilaria Dando, Nico P Dantuma, April L Darling, Hiranmoy Das, Srinivasan Dasarathy, Santosh K Dasari, Srikanta Dash, Oliver Daumke, Adrian N Dauphinee, Jeffrey S Davies, Valeria A Dávila, Roger J Davis, Tanja Davis, Sharadha Dayalan Naidu, Francesca De Amicis, Karolien De Bosscher, Francesca De Felice, Lucia De Franceschi, Chiara De Leonibus, Mayara G de Mattos Barbosa, Guido R Y De Meyer, Angelo De Milito, Cosimo De Nunzio, Clara De Palma, Mauro De Santi, Claudio De Virgilio, Daniela De Zio, Jayanta Debnath, Brian J DeBosch, Jean-Paul Decuypere, Mark A Deehan, Gianluca Deflorian, James DeGregori, Benjamin Dehay, Gabriel Del Rio, Joe R Delaney, Lea M D Delbridge, Elizabeth Delorme-Axford, M Victoria Delpino, Francesca Demarchi, Vilma Dembitz, Nicholas D Demers, Hongbin Deng, Zhiqiang Deng, Joern Dengjel, Paul Dent, Donna Denton, Melvin L DePamphilis, Channing J Der, Vojo Deretic, Albert Descoteaux, Laura Devis, Sushil Devkota, Olivier Devuyst, Grant Dewson, Mahendiran Dharmasivam, Rohan Dhiman, Diego di Bernardo, Manlio Di Cristina, Fabio Di Domenico, Pietro Di Fazio, Alessio Di Fonzo, Giovanni Di Guardo, Gianni M Di Guglielmo, Luca Di Leo, Chiara Di Malta, Alessia Di Nardo, Martina Di Rienzo, Federica Di Sano, George Diallinas, Jiajie Diao, Guillermo Diaz-Araya, Inés Díaz-Laviada, Jared M Dickinson, Marc Diederich, Mélanie Dieudé, Ivan Dikic, Shiping Ding, Wen-Xing Ding, Luciana Dini, Jelena Dinić, Miroslav Dinic, Albena T 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Negoita, Thomas Neill, Amanda L Neisch, Luca M Neri, Mihai G Netea, Patrick Neubert, Thomas P Neufeld, Dietbert Neumann, Albert Neutzner, Phillip T Newton, Paul A Ney, Ioannis P Nezis, Charlene C W Ng, Tzi Bun Ng, Hang T T Nguyen, Long T Nguyen, Hong-Min Ni, Clíona Ní Cheallaigh, Zhenhong Ni, M Celeste Nicolao, Francesco Nicoli, Manuel Nieto-Diaz, Per Nilsson, Shunbin Ning, Rituraj Niranjan, Hiroshi Nishimune, Mireia Niso-Santano, Ralph A Nixon, Annalisa Nobili, Clevio Nobrega, Takeshi Noda, Uxía Nogueira-Recalde, Trevor M Nolan, Ivan Nombela, Ivana Novak, Beatriz Novoa, Takashi Nozawa, Nobuyuki Nukina, Carmen Nussbaum-Krammer, Jesper Nylandsted, Tracey R O'Donovan, Seónadh M O'Leary, Eyleen J O'Rourke, Mary P O'Sullivan, Timothy E O'Sullivan, Salvatore Oddo, Ina Oehme, Michinaga Ogawa, Eric Ogier-Denis, Margret H Ogmundsdottir, Besim Ogretmen, Goo Taeg Oh, Seon-Hee Oh, Young J Oh, Takashi Ohama, Yohei Ohashi, Masaki Ohmuraya, Vasileios Oikonomou, Rani Ojha, Koji Okamoto, Hitoshi Okazawa, Masahide Oku, Sara Oliván, Jorge M A Oliveira, Michael Ollmann, James A Olzmann, Shakib Omari, M Bishr Omary, Gizem Önal, Martin Ondrej, Sang-Bing Ong, Sang-Ging Ong, Anna Onnis, Juan A Orellana, Sara Orellana-Muñoz, Maria Del Mar Ortega-Villaizan, Xilma R Ortiz-Gonzalez, Elena Ortona, Heinz D Osiewacz, Abdel-Hamid K Osman, Rosario Osta, Marisa S Otegui, Kinya Otsu, Christiane Ott, Luisa Ottobrini, Jing-Hsiung James Ou, Tiago F Outeiro, Inger Oynebraten, Melek Ozturk, Gilles Pagès, Susanta Pahari, Marta Pajares, Utpal B Pajvani, Rituraj Pal, Simona Paladino, Nicolas Pallet, Michela Palmieri, Giuseppe Palmisano, Camilla Palumbo, Francesco Pampaloni, Lifeng Pan, Qingjun Pan, Wenliang Pan, Xin Pan, Ganna Panasyuk, Rahul Pandey, Udai B Pandey, Vrajesh Pandya, Francesco Paneni, Shirley Y Pang, Elisa Panzarini, Daniela L Papademetrio, Elena Papaleo, Daniel Papinski, Diana Papp, Eun Chan Park, Hwan Tae Park, Ji-Man Park, Jong-In Park, Joon Tae Park, Junsoo Park, Sang Chul Park, Sang-Youel Park, Abraham H Parola, Jan B Parys, Adrien Pasquier, Benoit Pasquier, João F Passos, Nunzia Pastore, Hemal H Patel, Daniel Patschan, Sophie Pattingre, Gustavo Pedraza-Alva, Jose Pedraza-Chaverri, Zully Pedrozo, Gang Pei, Jianming Pei, Hadas Peled-Zehavi, Joaquín M Pellegrini, Joffrey Pelletier, Miguel A Peñalva, Di Peng, Ying Peng, Fabio Penna, Maria Pennuto, Francesca Pentimalli, Cláudia Mf Pereira, Gustavo J S Pereira, Lilian C Pereira, Luis Pereira de Almeida, Nirma D Perera, Ángel Pérez-Lara, Ana B Perez-Oliva, María Esther Pérez-Pérez, Palsamy Periyasamy, Andras Perl, Cristiana Perrotta, Ida Perrotta, Richard G Pestell, Morten Petersen, Irina Petrache, Goran Petrovski, Thorsten Pfirrmann, Astrid S Pfister, Jennifer A Philips, Huifeng Pi, Anna Picca, Alicia M Pickrell, Sandy Picot, Giovanna M Pierantoni, Marina Pierdominici, Philippe Pierre, Valérie Pierrefite-Carle, Karolina Pierzynowska, Federico Pietrocola, Miroslawa Pietruczuk, Claudio Pignata, Felipe X Pimentel-Muiños, Mario Pinar, Roberta O Pinheiro, Ronit Pinkas-Kramarski, Paolo Pinton, Karolina Pircs, Sujan Piya, Paola Pizzo, Theo S Plantinga, Harald W Platta, Ainhoa Plaza-Zabala, Markus Plomann, Egor Y Plotnikov, Helene Plun-Favreau, Ryszard Pluta, Roger Pocock, Stefanie Pöggeler, Christian Pohl, Marc Poirot, Angelo Poletti, Marisa Ponpuak, Hana Popelka, Blagovesta Popova, Helena Porta, Soledad Porte Alcon, Eliana Portilla-Fernandez, Martin Post, Malia B Potts, Joanna Poulton, Ted Powers, Veena Prahlad, Tomasz K Prajsnar, Domenico Praticò, Rosaria Prencipe, Muriel Priault, Tassula Proikas-Cezanne, Vasilis J Promponas, Christopher G Proud, Rosa Puertollano, Luigi Puglielli, Thomas Pulinilkunnil, Deepika Puri, Rajat Puri, Julien Puyal, Xiaopeng Qi, Yongmei Qi, Wenbin Qian, Lei Qiang, Yu Qiu, Joe Quadrilatero, Jorge Quarleri, Nina Raben, Hannah Rabinowich, Debora Ragona, Michael J Ragusa, Nader Rahimi, Marveh Rahmati, Valeria Raia, Nuno Raimundo, Namakkal-Soorappan Rajasekaran, Sriganesh Ramachandra Rao, Abdelhaq Rami, Ignacio Ramírez-Pardo, David B Ramsden, Felix Randow, Pundi N Rangarajan, Danilo Ranieri, Hai Rao, Lang Rao, Rekha Rao, Sumit Rathore, J Arjuna Ratnayaka, Edward A Ratovitski, Palaniyandi Ravanan, Gloria Ravegnini, Swapan K Ray, Babak Razani, Vito Rebecca, Fulvio Reggiori, Anne Régnier-Vigouroux, Andreas S Reichert, David Reigada, Jan H Reiling, Theo Rein, Siegfried Reipert, Rokeya Sultana Rekha, Hongmei Ren, Jun Ren, Weichao Ren, Tristan Renault, Giorgia Renga, Karen Reue, Kim Rewitz, Bruna Ribeiro de Andrade Ramos, S Amer Riazuddin, Teresa M Ribeiro-Rodrigues, Jean-Ehrland Ricci, Romeo Ricci, Victoria Riccio, Des R Richardson, Yasuko Rikihisa, Makarand V Risbud, Ruth M Risueño, Konstantinos Ritis, Salvatore Rizza, Rosario Rizzuto, Helen C Roberts, Luke D Roberts, Katherine J Robinson, Maria Carmela Roccheri, Stephane Rocchi, George G Rodney, Tiago Rodrigues, Vagner Ramon Rodrigues Silva, Amaia Rodriguez, Ruth Rodriguez-Barrueco, Nieves Rodriguez-Henche, Humberto Rodriguez-Rocha, Jeroen Roelofs, Robert S Rogers, Vladimir V Rogov, Ana I Rojo, Krzysztof Rolka, Vanina Romanello, Luigina Romani, Alessandra Romano, Patricia S Romano, David Romeo-Guitart, Luis C Romero, Montserrat Romero, Joseph C Roney, Christopher Rongo, Sante Roperto, Mathias T Rosenfeldt, Philip Rosenstiel, Anne G Rosenwald, Kevin A Roth, Lynn Roth, Steven Roth, Kasper M A Rouschop, Benoit D Roussel, Sophie Roux, Patrizia Rovere-Querini, Ajit Roy, Aurore Rozieres, Diego Ruano, David C Rubinsztein, Maria P Rubtsova, Klaus Ruckdeschel, Christoph Ruckenstuhl, Emil Rudolf, Rüdiger Rudolf, Alessandra Ruggieri, Avnika Ashok Ruparelia, Paola Rusmini, Ryan R Russell, Gian Luigi Russo, Maria Russo, Rossella Russo, Oxana O Ryabaya, Kevin M Ryan, Kwon-Yul Ryu, Maria Sabater-Arcis, Ulka Sachdev, Michael Sacher, Carsten Sachse, Abhishek Sadhu, Junichi Sadoshima, Nathaniel Safren, Paul Saftig, Antonia P Sagona, Gaurav Sahay, Amirhossein Sahebkar, Mustafa Sahin, Ozgur Sahin, Sumit Sahni, Nayuta Saito, Shigeru Saito, Tsunenori Saito, Ryohei Sakai, Yasuyoshi Sakai, Jun-Ichi Sakamaki, Kalle Saksela, Gloria Salazar, Anna Salazar-Degracia, Ghasem H Salekdeh, Ashok K Saluja, Belém Sampaio-Marques, Maria Cecilia Sanchez, Jose A Sanchez-Alcazar, Victoria Sanchez-Vera, Vanessa Sancho-Shimizu, J Thomas Sanderson, Marco Sandri, Stefano Santaguida, Laura Santambrogio, Magda M Santana, Giorgio Santoni, Alberto Sanz, Pascual Sanz, Shweta Saran, Marco Sardiello, Timothy J Sargeant, Apurva Sarin, Chinmoy Sarkar, Sovan Sarkar, Maria-Rosa Sarrias, Surajit Sarkar, Dipanka Tanu Sarmah, Jaakko Sarparanta, Aishwarya Sathyanarayan, Ranganayaki Sathyanarayanan, K Matthew Scaglione, Francesca Scatozza, Liliana Schaefer, Zachary T Schafer, Ulrich E Schaible, Anthony H V Schapira, Michael Scharl, Hermann M Schatzl, Catherine H Schein, Wiep Scheper, David Scheuring, Maria Vittoria Schiaffino, Monica Schiappacassi, Rainer Schindl, Uwe Schlattner, Oliver Schmidt, Roland Schmitt, Stephen D Schmidt, Ingo Schmitz, Eran Schmukler, Anja Schneider, Bianca E Schneider, Romana Schober, Alejandra C Schoijet, Micah B Schott, Michael Schramm, Bernd Schröder, Kai Schuh, Christoph Schüller, Ryan J Schulze, Lea Schürmanns, Jens C Schwamborn, Melanie Schwarten, Filippo Scialo, Sebastiano Sciarretta, Melanie J Scott, Kathleen W Scotto, A Ivana Scovassi, Andrea Scrima, Aurora Scrivo, David Sebastian, Salwa Sebti, Simon Sedej, Laura Segatori, Nava Segev, Per O Seglen, Iban Seiliez, Ekihiro Seki, Scott B Selleck, Frank W Sellke, Joshua T Selsby, Michael Sendtner, Serif Senturk, Elena Seranova, Consolato Sergi, Ruth Serra-Moreno, Hiromi Sesaki, Carmine Settembre, Subba Rao Gangi Setty, Gianluca Sgarbi, Ou Sha, John J Shacka, Javeed A Shah, Dantong Shang, Changshun Shao, Feng Shao, Soroush Sharbati, Lisa M Sharkey, Dipali Sharma, Gaurav Sharma, Kulbhushan Sharma, Pawan Sharma, Surendra Sharma, Han-Ming Shen, Hongtao Shen, Jiangang Shen, Ming Shen, Weili Shen, Zheni Shen, Rui Sheng, Zhi Sheng, Zu-Hang Sheng, Jianjian Shi, Xiaobing Shi, Ying-Hong Shi, Kahori Shiba-Fukushima, Jeng-Jer Shieh, Yohta Shimada, Shigeomi Shimizu, Makoto Shimozawa, Takahiro Shintani, Christopher J Shoemaker, Shahla Shojaei, Ikuo Shoji, Bhupendra V Shravage, Viji Shridhar, Chih-Wen Shu, Hong-Bing Shu, Ke Shui, Arvind K Shukla, Timothy E Shutt, Valentina Sica, Aleem Siddiqui, Amanda Sierra, Virginia Sierra-Torre, Santiago Signorelli, Payel Sil, Bruno J de Andrade Silva, Johnatas D Silva, Eduardo Silva-Pavez, Sandrine Silvente-Poirot, Rachel E Simmonds, Anna Katharina Simon, Hans-Uwe Simon, Matias Simons, Anurag Singh, Lalit P Singh, Rajat Singh, Shivendra V Singh, Shrawan K Singh, Sudha B Singh, Sunaina Singh, Surinder Pal Singh, Debasish Sinha, Rohit Anthony Sinha, Sangita Sinha, Agnieszka Sirko, Kapil Sirohi, Efthimios L Sivridis, Panagiotis Skendros, Aleksandra Skirycz, Iva Slaninová, Soraya S Smaili, Andrei Smertenko, Matthew D Smith, Stefaan J Soenen, Eun Jung Sohn, Sophia P M Sok, Giancarlo Solaini, Thierry Soldati, Scott A Soleimanpour, Rosa M Soler, Alexei Solovchenko, Jason A Somarelli, Avinash Sonawane, Fuyong Song, Hyun Kyu Song, Ju-Xian Song, Kunhua Song, Zhiyin Song, Leandro R Soria, Maurizio Sorice, Alexander A Soukas, Sandra-Fausia Soukup, Diana Sousa, Nadia Sousa, Paul A Spagnuolo, Stephen A Spector, M M Srinivas Bharath, Daret St Clair, Venturina Stagni, Leopoldo Staiano, Clint A Stalnecker, Metodi V Stankov, Peter B Stathopulos, Katja Stefan, Sven Marcel Stefan, Leonidas Stefanis, Joan S Steffan, Alexander Steinkasserer, Harald Stenmark, Jared Sterneckert, Craig Stevens, Veronika Stoka, Stephan Storch, Björn Stork, Flavie Strappazzon, Anne Marie Strohecker, Dwayne G Stupack, Huanxing Su, Ling-Yan Su, Longxiang Su, Ana M Suarez-Fontes, Carlos S Subauste, Selvakumar Subbian, Paula V Subirada, Ganapasam Sudhandiran, Carolyn M Sue, Xinbing Sui, Corey Summers, Guangchao Sun, Jun Sun, Kang Sun, Meng-Xiang Sun, Qiming Sun, Yi Sun, Zhongjie Sun, Karen K S Sunahara, Eva Sundberg, Katalin Susztak, Peter Sutovsky, Hidekazu Suzuki, Gary Sweeney, J David Symons, Stephen Cho Wing Sze, Nathaniel J Szewczyk, Anna Tabęcka-Łonczynska, Claudio Tabolacci, Frank Tacke, Heinrich Taegtmeyer, Marco Tafani, Mitsuo Tagaya, Haoran Tai, Stephen W G Tait, Yoshinori Takahashi, Szabolcs Takats, Priti Talwar, Chit Tam, Shing Yau Tam, Davide Tampellini, Atsushi Tamura, Chong Teik Tan, Eng-King Tan, Ya-Qin Tan, Masaki Tanaka, Motomasa Tanaka, Daolin Tang, Jingfeng Tang, Tie-Shan Tang, Isei Tanida, Zhipeng Tao, Mohammed Taouis, Lars Tatenhorst, Nektarios Tavernarakis, Allen Taylor, Gregory A Taylor, Joan M Taylor, Elena Tchetina, Andrew R Tee, Irmgard Tegeder, David Teis, Natercia Teixeira, Fatima Teixeira-Clerc, Kumsal A Tekirdag, Tewin Tencomnao, Sandra Tenreiro, Alexei V Tepikin, Pilar S Testillano, Gianluca Tettamanti, Pierre-Louis Tharaux, Kathrin Thedieck, Arvind A Thekkinghat, Stefano Thellung, Josephine W Thinwa, V P Thirumalaikumar, Sufi Mary Thomas, Paul G Thomes, Andrew Thorburn, Lipi Thukral, Thomas Thum, Michael Thumm, Ling Tian, Ales Tichy, Andreas Till, Vincent Timmerman, Vladimir I Titorenko, Sokol V Todi, Krassimira Todorova, Janne M Toivonen, Luana Tomaipitinca, Dhanendra Tomar, Cristina Tomas-Zapico, Sergej Tomić, Benjamin Chun-Kit Tong, Chao Tong, Xin Tong, Sharon A Tooze, Maria L Torgersen, Satoru Torii, Liliana Torres-López, Alicia Torriglia, Christina G Towers, Roberto Towns, Shinya Toyokuni, Vladimir Trajkovic, Donatella Tramontano, Quynh-Giao Tran, Leonardo H Travassos, Charles B Trelford, Shirley Tremel, Ioannis P Trougakos, Betty P Tsao, Mario P Tschan, Hung-Fat Tse, Tak Fu Tse, Hitoshi Tsugawa, Andrey S Tsvetkov, David A Tumbarello, Yasin Tumtas, María J Tuñón, Sandra Turcotte, Boris Turk, Vito Turk, Bradley J Turner, Richard I Tuxworth, Jessica K Tyler, Elena V Tyutereva, Yasuo Uchiyama, Aslihan Ugun-Klusek, Holm H Uhlig, Marzena Ułamek-Kozioł, Ilya V Ulasov, Midori Umekawa, Christian Ungermann, Rei Unno, Sylvie Urbe, Elisabet Uribe-Carretero, Suayib Üstün, Vladimir N Uversky, Thomas Vaccari, Maria I Vaccaro, Björn F Vahsen, Helin Vakifahmetoglu-Norberg, Rut Valdor, Maria J Valente, Ayelén Valko, Richard B Vallee, Angela M Valverde, Greet Van den Berghe, Stijn van der Veen, Luc Van Kaer, Jorg van Loosdregt, Sjoerd J L van Wijk, Wim Vandenberghe, Ilse Vanhorebeek, Marcos A Vannier-Santos, Nicola Vannini, M Cristina Vanrell, Chiara Vantaggiato, Gabriele Varano, Isabel Varela-Nieto, Máté Varga, M Helena Vasconcelos, Somya Vats, Demetrios G Vavvas, Ignacio Vega-Naredo, Silvia Vega-Rubin-de-Celis, Guillermo Velasco, Ariadna P Velázquez, Tibor Vellai, Edo Vellenga, Francesca Velotti, Mireille Verdier, Panayotis Verginis, Isabelle Vergne, Paul Verkade, Manish Verma, Patrik Verstreken, Tim Vervliet, Jörg Vervoorts, Alexandre T Vessoni, Victor M Victor, Michel Vidal, Chiara Vidoni, Otilia V Vieira, Richard D Vierstra, Sonia Viganó, Helena Vihinen, Vinoy Vijayan, Miquel Vila, Marçal Vilar, José M 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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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Autophagy  

    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.

    DOI: 10.1080/15548627.2020.1797280

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  101. 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.

    DOI: 10.2174/0929867328666210629121731

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  102. 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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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:The Japanese Society of Toxicology  

    <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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  103. 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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  104. 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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  105. 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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  106. 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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  107. 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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  108. 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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  109. 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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  110. 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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  111. 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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  112. 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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  113. 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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  114. 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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  115. 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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  116. 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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  117. 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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  118. 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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  119. 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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    DOI: 10.1111/cas.14405

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  120. 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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  121. 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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    DOI: 10.1080/10715762.2020.1743285

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  122. 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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  123. 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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    DOI: 10.1038/s41598-020-58667-3

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  124. 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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    DOI: 10.1080/10715762.2020.1733548

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  125. 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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  126. 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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  127. 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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  128. 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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  129. 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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  130. 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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  131. 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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    DOI: 10.1016/j.tox.2019.01.011

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  132. 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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  133. 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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  134. 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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  135. 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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  136. 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>

    DOI: 10.14869/toxpt.46.1.0_P-233

  137. 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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  138. 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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  139. 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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  140. 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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  141. Ferroptosis in Cancer Research

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 195-195   2018.12

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  142. 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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  143. 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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  144. 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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  145. Ferroptosis in Cancer Research International journal

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 195-195   2018.12

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  146. 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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  147. 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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  148. 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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  149. 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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  150. 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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  151. 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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  152. 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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  153. 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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  154. 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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  155. 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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  156. 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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  157. 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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  158. 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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  159. 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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  160. 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   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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  161. 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.

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  162. 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.

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  163. 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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  164. 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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  165. 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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  166. 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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  167. 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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  168. 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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  169. 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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  170. 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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  171. 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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  172. 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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  173. Molecular mechanisms in oxidative stress-induced carcinogenesis

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 163 - 163   2018.1

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  174. 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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  175. 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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  176. Molecular mechanisms in oxidative stress-induced carcinogenesis International journal

    Toyokuni Shinya

    CANCER SCIENCE   Vol. 109   page: 163-163   2018.1

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  177. 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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  178. 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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  179. 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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  180. 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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  181. 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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    DOI: doi: 10.1111/pin.12598.

  182. 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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  183. 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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  184. 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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  185. 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.

  186. 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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  187. 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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  188. 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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  189. 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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  190. 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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  191. 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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  192. 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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  193. 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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  194. 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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  195. 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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  196. 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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  197. 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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  198. 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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  199. 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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  200. 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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  201. 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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  202. 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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  203. 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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  204. 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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  205. 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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  206. 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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  207. 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.

  208. 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.

  209. 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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  210. 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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  211. 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: doi: 10.1016/j.humpath.2017.02.007.

  212. 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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  213. Cancer and trace metal element

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

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  214. 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.

  215. 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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  216. 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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  217. 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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  218. 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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  219. 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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  220. 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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  221. 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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  222. 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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  223. 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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  224. 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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  225. 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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  226. 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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  227. 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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  228. Chemical reaction mechanism in non-thermal plasma from the viewpoint of oxidative stress toward clinical cancer applications

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

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

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  229. 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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  230. 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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  231. 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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  232. 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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  233. 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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  234. 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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  235. 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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  236. 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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  237. Biphasic effects of L-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells 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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  238. 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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  239. 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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  240. 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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  241. 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.

  242. 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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  243. Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. 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 - 80   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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  244. 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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  245. 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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  246. 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.

  247. 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.

  248. 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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    DOI: doi: 10.1016/j.bbcan.2016.07.004.

  249. 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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  250. 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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    DOI: 10.1016/j.cpme.2015.12.002

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  251. 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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  252. [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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  253. [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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  254. 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.

  255. 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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    DOI: doi: 10.1111/cas.12947.

  256. 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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  257. 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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  258. 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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  259. 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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  260. 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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    DOI: 10.1016/j.abb.2015.11.025

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  261. 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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  262. 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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  263. 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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  264. 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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    DOI: doi: 10.1016/j.bbamcr.2016.01.026.

  265. 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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  266. 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.

  267. 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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  268. Pain-reducing anesthesia prevents oxidative stress in human term placenta International journal

    Tsuzuki Yoko, Yamashita Yoriko, Hattori Yuka, Hua Li Guang, Akatsuka Shinya, Kotani Tomomi, Kikkawa Fumitaka, Naiki-Ito Aya, Takahashi Satoru, Nishiwaki Kimitoshi, Toyokuni Shinya

    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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  269. Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. 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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  270. 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.

  271. 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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  272. 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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  273. 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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  274. 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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  275. 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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  276. 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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  277. 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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  278. 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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  279. 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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  280. 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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  281. 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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  282. 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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  283. Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin 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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  284. 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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  285. 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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    DOI: 10.3164/jcbn.56-3-editorial

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  286. [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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  287. Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells International journal

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

    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-<i>d</i>]pyridazine-1,4-(<i>2H,3H</i>) 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 ~25% of the crocidolite/amosite response. MWCNTs with different diameters (~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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  288. 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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  289. 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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  290. 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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  291. 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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  292. 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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  293. 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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  294. Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders.

    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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  295. Napsin A is a specific marker for ovarian clear cell adenocarcinoma. 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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  296. 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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  297. 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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  298. 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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  299. 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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  300. 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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  301. 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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  302. 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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  303. 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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  304. 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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  305. 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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  306. 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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  307. 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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  308. 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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  309. 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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  310. Application of intermittent microwave irradiation to western blot analysis. Reviewed International journal

    Liu YT, Toyokuni S

    Methods Mol Biol   Vol. 1314   page: 185-190   2015

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  311. 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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  312. 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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  313. 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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  314. 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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  315. 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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  316. 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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  317. 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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  318. 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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  319. 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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  320. 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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  321. 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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  322. 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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  323. 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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  324. 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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  325. 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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  326. Connective tissue growth factor and beta-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma 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 - 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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  327. 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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  328. 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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  329. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion. 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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  330. 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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  331. 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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    Toyokuni S

    Nagoya Journal of Medical Science   Vol. 76 ( 1-2 ) page: 1 - 2   2014.3

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  333. 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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  334. 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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  335. 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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  336. 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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  337. 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 - 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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  338. 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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  339. 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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  340. 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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  341. 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.

  342. 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.

  343. 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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  344. 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.

  345. 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.

  346. 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.

  347. 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.

  348. 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.

  349. 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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  350. 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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  351. 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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  352. 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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  353. Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions. 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

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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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  354. 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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  355. 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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  356. 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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  357. 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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  358. 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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  359. 【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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  360. 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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  361. 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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  362. 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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  363. 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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  364. 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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  365. 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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  366. 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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  367. 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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  368. CD146 and insulin-like growth factor 2 mRNA-binding protein 3 predict prognosis of asbestos-induced rat mesothelioma

    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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