2022/08/17 更新

写真a

トヨクニ シンヤ
豊國 伸哉
TOYOKUNI Shinya
所属
大学院医学系研究科 総合医学専攻 病理病態学 教授
大学院担当
大学院医学系研究科
学部担当
医学部
職名
教授
連絡先
メールアドレス
外部リンク

学位 1

  1. 医学博士 ( 1991年3月   京都大学 ) 

研究キーワード 11

  1. フェロトーシス

  2. 変異

  3. DNA傷害

  4. 中皮腫

  5. カーボンナノチューブ

  6. アスベスト

  7. 酸化ストレス

  8. 発がん

  9. 変異

  10. フェロトーシス

研究分野 4

  1. その他 / その他  / 人体病理学

  2. その他 / その他  / 実験病理学

  3. ライフサイエンス / 実験病理学

  4. その他 / その他  / 人体病理学

現在の研究課題と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. アスベスト誘発中皮腫発がん機構の解明

  4. 繊維状無機物質の発がん評価法の開発

  5. 発がん過程における酸素ラジカルの意義に関する研究

  6. 先端モデル動物支援プラットフォーム:病理形態解析支援

  7. フェロトーシスにおける細胞内鉄制御機構の破綻

  8. 転写と染色体領域の視点から見たゲノムDNA損傷位置情報の解析

  9. 酸化ストレス発がん克服のための標的分子の同定

  10. 新規ナノマテリアルのリスク評価

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経歴 10

  1. 名古屋大学   教授

    2008年7月

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    国名:日本国

  2. 名古屋大学   低温プラズマ科学研究センター   副センター長

    2020年4月 - 現在

  3. 名古屋大学   大学院医学系研究科   Nagoya Journal of Medical Science 編集長

    2010年4月 - 現在

  4. 名古屋大学   大学院医学系研究科   治験審査委員会 委員

    2010年4月 - 2016年3月

  5. 京都大学大学院医学研究科基礎病態学講座病態生物医学専攻・准教授

    2004年4月 - 2008年6月

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    国名:日本国

  6. 京都大学医学部病理学教室第一講座・助教授

    1998年6月 - 2004年3月

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    国名:日本国

  7. 京都大学医学部病理学教室第一講座・講師

    1993年4月 - 1998年5月

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    国名:日本国

  8. 京都大学医学部病理学教室第一講座・助手

    1992年10月 - 1993年4月

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    国名:日本国

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

    1990年9月 - 1992年9月

  10. 天理よろづ相談所病院ジュニアレジデント

    1985年5月 - 1987年4月

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    国名:日本国

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学歴 3

  1. 京都大学   医学研究科   病理学

    1987年4月 - 1991年3月

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    国名: 日本国

  2. 京都大学   医学研究科   病理学

    1987年4月 - 1991年3月

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    国名: 日本国

  3. 京都大学   医学部

    1979年4月 - 1985年3月

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    国名: 日本国

所属学協会 18

  1. 日本酸化ストレス学会   理事

    2015年1月 - 現在

  2. 日本癌学会   学術評議員

    2002年4月 - 現在

  3. 日本病理学会   全国区理事

    1995年4月 - 現在

  4. 日本鉄バイオサイエンス学会   理事長

    2012年4月 - 現在

  5. 日本がん予防学会   理事

    2009年4月 - 現在

  6. 日本微量元素学会   理事

    2017年4月 - 現在

  7. Society for Free Radical Research Asia/International   President

    2014年1月 - 現在

  8. 日本微量元素学会

    2017年4月 - 現在

  9. 日本セルデス学会

  10. The New York Academy of Sciences

  11. 日本分子生物学会

  12. International Academy of Pathology

  13. American Association for the Advancement of Science

  14. American Association for Investigative Pathology

  15. American Association for Cancer Research

  16. 日本医学教育学会

  17. 日本分子生物学会

  18. 日本生化学会

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委員歴 4

  1. 名古屋大学附属図書館医学部分館   分館長  

    2021年4月 - 現在   

  2. 編入学制度運用委員会   委員  

    2012年4月 - 現在   

  3. 学部教育委員会   委員  

    2012年4月 - 現在   

  4. 学部教育委員会   委員  

    2012年4月 - 現在   

受賞 10

  1. 日本微量元素学会学会賞

    2022年3月   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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    受賞区分:国内学会・会議・シンポジウム等の賞  受賞国:日本国

  2. 日本酸化ストレス学会学会賞

    2021年5月   日本酸化ストレス学会  

    豊國 伸哉

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    受賞区分:国内学会・会議・シンポジウム等の賞 

    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年1月   Society for Free Radical Research India (SFRR India)  

    Shinya Toyokuni

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    受賞区分:国内外の国際的学術賞  受賞国:インド

  4. 日本病理学賞

    2015年5月   日本病理学会  

    豊國 伸哉

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    受賞国:日本国

  5. 日本酸化ストレス学会学術賞

    2009年6月   日本酸化ストレス学会  

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    受賞国:日本国

  6. 日本病理学会学術奨励賞

    2000年4月   日本病理学会  

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    受賞国:日本国

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

    1998年5月   SFRR Japan  

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    受賞国:日本国

  8. 米国国家研究委員会研究員賞

    1990年9月  

  9. 日本酸化ストレス学会 学会賞

    2021年5月   日本酸化ストレス学会   発がん過程における酸化ストレスの意義の解明

    豊國伸哉

  10. 日本病理学賞

    2015年5月   日本病理学会  

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    受賞国:日本国

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論文 1113

  1. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. 招待有り 査読有り

    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   171 巻 ( 2 ) 頁: 273-285   2017年10月

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    記述言語:英語  

    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. 招待有り 査読有り

    Toyokuni S.

    Pathol Int.   66 巻 ( 5 ) 頁: 245-259   2016年5月

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    担当区分:筆頭著者   記述言語:英語  

    DOI: doi: 10.1111/pin.12396.

  3. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. 査読有り

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

    Cancer Science     2017年11月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1111/cas.13460.

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

    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   108 巻   頁: E1330-1338   2011年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  5. Iron overload signature in chrysotile-induced malignant mesothelioma. 査読有り

    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   228 巻   頁: 366-377   2012年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  6. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer. 査読有り

    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   7 巻 ( 8 ) 頁: e43403   2012年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

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

    J Pathol   233 巻   頁: 502-414   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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   133 巻   頁: 1-2   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2019.01.042

    Web of Science

  9. On 'Photoperoxidation in isolated chloroplasts: I. Kinetics and stoichiometry of fatty acid peroxidation' by Robert L. Heath and Lester Packer. 国際誌

    Toyokuni S, Kong Y, Mi D

    Archives of biochemistry and biophysics   726 巻   頁: 109133 - 109133   2022年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    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.

    DOI: 10.1016/j.abb.2022.109133

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  10. Ferroptosis as ultimate target of cancer therapy.

    Motooka Y, Toyokuni S

    Antioxidants & redox signaling     2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1089/ars.2022.0048

    PubMed

  11. BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance. 国際誌

    Kong Y, Akatsuka S, Motooka Y, Zheng H, Cheng Z, Shiraki Y, Mashimo T, Imaoka T, Toyokuni S

    Redox biology   54 巻   頁: 102356 - 102356   2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    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.

    DOI: 10.1016/j.redox.2022.102356

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

    Soyama H, Nishio M, Otani J, Sakuma T, Takao S, Hara S, Masuda T, Mimori K, Toyokuni S, Lydon JP, Nakao K, Nishina H, Fukumoto T, Maehama T, Suzuki A

    Proceedings of the National Academy of Sciences of the United States of America   119 巻 ( 29 ) 頁: e2123134119   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Proceedings of the National Academy of Sciences of the United States of America  

    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.

    DOI: 10.1073/pnas.2123134119

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  13. Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells. 国際誌

    Igarashi N, Miyata K, Loo TM, Chiba M, Hanyu A, Nishio M, Kawasaki H, Zheng H, Toyokuni S, Kon S, Moriyama K, Fujita Y, Takahashi A

    Nature communications   13 巻 ( 1 ) 頁: 4157 - 4157   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Communications  

    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.

    DOI: 10.1038/s41467-022-31642-4

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

    Lyu Q, Jiang L, Zheng H, Hayashi S, Sato K, Toyokuni S

    Journal of clinical biochemistry and nutrition   71 巻 ( 1 ) 頁: 55 - 63   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    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 per se can be toxic despite less toxicity in comparison to C-cigarettes, which warrants further investigation.

    DOI: 10.3164/jcbn.21-134

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    CiNii Research

  15. 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   4 巻 ( 6 ) 頁: 651 - 662   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Metabolism  

    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.

    DOI: 10.1038/s42255-022-00591-z

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

    Ito D., Iwata N., Ishikawa K., Nakamura K., Hashizume H., Miron C., Tanaka H., Kajiyama H., Toyokuni S., Mizuno M., Hori M.

    Applied Physics Express   15 巻 ( 5 )   2022年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Applied Physics Express  

    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+O2+N2 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.

    DOI: 10.35848/1882-0786/ac6360

    Scopus

  17. PCBP2 knockdown promotes ferroptosis in malignant mesothelioma. 国際誌

    Yue L, Luo Y, Jiang L, Sekido Y, Toyokuni S

    Pathology international   72 巻 ( 4 ) 頁: 242 - 251   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    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.

    DOI: 10.1111/pin.13209

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  18. Editorial: Centennial anniversary of vitamin E discovery.

    Toyokuni S, Noguchi N, Niki E

    Free radical biology & medicine   183 巻   頁: 125 - 126   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    DOI: 10.1016/j.freeradbiomed.2022.03.018

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  19. 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   132 巻 ( 2 )   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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.

    CiNii Research

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

    Sato Y, Oguchi A, Fukushima Y, Masuda K, Toriu N, Taniguchi K, Yoshikawa T, Cui X, Kondo M, Hosoi T, Komidori S, Shimizu Y, Fujita H, Jiang L, Kong Y, Yamanashi T, Seita J, Yamamoto T, Toyokuni S, Hamazaki Y, Hattori M, Yoshikai Y, Boor P, Floege J, Kawamoto H, Murakawa Y, Minato N, Yanagita M

    The Journal of clinical investigation   132 巻 ( 2 )   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Investigation  

    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.

    DOI: 10.1172/JCI146071

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  21. 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   132 巻 ( 2 )   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    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.

  22. Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis. 国際誌

    Cheng Z, Akatsuka S, Li GH, Mori K, Takahashi T, Toyokuni S

    Cancer science   113 巻 ( 1 ) 頁: 65 - 78   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    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.

    DOI: 10.1111/cas.15175

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  23. Tetrachloroaurate (III)-induced oxidation increases non-thermal plasma-induced oxidative stress. 国際誌

    Okazaki Y, Sasaki K, Ito N, Tanaka H, Matsumoto KI, Hori M, Toyokuni S

    Free radical research   56 巻 ( 1 ) 頁: 17 - 27   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    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.

    DOI: 10.1080/10715762.2022.2026348

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

    Tanaka H., Matsumura S., Ishikawa K., Hashizume H., Ito M., Nakamura K., Kajiyama H., Kikkawa F., Ito M., Ohno K., Okazaki Y., Toyokuni S., Mizuno M., Hori M.

    Japanese Journal of Applied Physics   61 巻 ( SA )   2022年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Applied Physics  

    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.

    DOI: 10.35848/1347-4065/ac2037

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  25. 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   advpub 巻 ( 0 )   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:The Society for Free Radical Research Japan  

    <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>

    DOI: 10.3164/jcbn.21-172

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  26. Iron as spirit of life to share under monopoly

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

    Journal of Clinical Biochemistry and Nutrition   advpub 巻 ( 0 )   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SOCIETY FOR FREE RADICAL RESEARCH JAPAN  

    <p>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(<i>rC</i>)-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.</p>

    DOI: 10.3164/jcbn.22-43

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  27. Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles. 国際誌

    Toyokuni S, Kong Y, Zheng H, Mi D, Katabuchi M, Motooka Y, Ito F

    Journal of cancer prevention   26 巻 ( 4 ) 頁: 244 - 249   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.15430/JCP.2021.26.4.244

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  28. Embryonal erythropoiesis and aging exploit ferroptosis 国際誌

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

    REDOX BIOLOGY   48 巻   頁: 102175 - 102175   2021年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    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.

    DOI: 10.1016/j.redox.2021.102175

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  29. Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin 国際誌

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

    REDOX BIOLOGY   47 巻   頁: 102174 - 102174   2021年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    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.

    DOI: 10.1016/j.redox.2021.102174

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  30. Mitochondrial involvement in the development and progression of diseases. 国際誌

    Valacchi G, Pecorelli A, Toyokuni S

    Archives of biochemistry and biophysics   711 巻   頁: 109006 - 109006   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2021.109006

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  31. CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. 国際誌

    Yanatori I, Richardson DR, Dhekne HS, Toyokuni S, Kishi F

    Blood   138 巻 ( 16 ) 頁: 1490 - 1503   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    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 also be secreted by the exosome pathway, and serum ferritin levels classically reflect body iron stores. Iron metabolism–associated proteins such as ferritin are intricately regulated by cellular iron levels via the iron responsive element-iron regulatory protein (IRE-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 of CD63 messenger RNA that is responsible for regulating its expression in response to increased iron. Cellular iron loading caused a marked increase in CD63 expression and the secretion of CD63+ EVs from cells, which were shown to contain ferritin-H and ferritin-L. 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, is significant for understanding the local cell-to-cell exchange of ferritin and iron.

    DOI: 10.1182/blood.2021010995

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  32. Mice lacking DYRK2 exhibit congenital malformations with lung hypoplasia and altered Foxf1 expression gradient 国際誌

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

    COMMUNICATIONS BIOLOGY   4 巻 ( 1 ) 頁: 1204 - 1204   2021年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Communications Biology  

    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.

    DOI: 10.1038/s42003-021-02734-6

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  33. Role of ferroptosis in nanofiber-induced carcinogenesis

    Toyokuni Shinya, Ito Fumiya, Motooka Yashiro

    Metallomics Research   1 巻 ( 1 ) 頁: rev-14 - rev-21   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japan Society for Biomedical Research on Trace Elements  

    <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>

    DOI: 10.11299/metallomicsresearch.mr202102

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

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

    PLASMA PROCESSES AND POLYMERS   18 巻 ( 10 )   2021年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Plasma Processes and Polymers  

    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.

    DOI: 10.1002/ppap.202100056

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  35. Low temperature plasma irradiation products of sodium lactate solution that induce cell death on U251SP glioblastoma cells were identified 国際誌

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

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 18488 - 18488   2021年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    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.

    DOI: 10.1038/s41598-021-98020-w

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  36. Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia 国際誌

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

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   22 巻 ( 17 )   2021年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    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 re-action 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 alveo-larization 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 pro-tein-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.

    DOI: 10.3390/ijms22179500

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  37. Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer 国際誌

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

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   118 巻 ( 35 )   2021年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Proceedings of the National Academy of Sciences of the United States of America  

    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.

    DOI: 10.1073/pnas.2025647118

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  38. Role and management of oxidative stress in human disease 国際誌

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

    FREE RADICAL RESEARCH   55 巻 ( 8 ) 頁: 755 - 757   2021年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    DOI: 10.1080/10715762.2021.1991083

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  39. Non-thermal plasma-induced DMPO-OH yields hydrogen peroxide 国際誌

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

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   705 巻   頁: 108901 - 108901   2021年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    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.

    DOI: 10.1016/j.abb.2021.108901

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  40. Lysosomal nitric oxide determines transition from autophagy to ferroptosis after exposure to plasma-activated Ringer's lactate 国際誌

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

    REDOX BIOLOGY   43 巻   頁: 101989 - 101989   2021年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    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.

    DOI: 10.1016/j.redox.2021.101989

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  41. L-Dehydroascorbate efficiently degrades non-thermal plasma-induced hydrogen peroxide 国際誌

    Okazaki Y.

    Archives of Biochemistry and Biophysics   700 巻   2021年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2021.108762

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  42. Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy 国際誌

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

    CANCERS   13 巻 ( 5 ) 頁: 1 - 15   2021年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancers  

    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.

    DOI: 10.3390/cancers13051141

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  43. Role of ferroptosis in carcinogenesis and tumor biology

    Toyokuni Shinya

    FREE RADICAL BIOLOGY AND MEDICINE   165 巻   2021年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2020.12.249

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  44. Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation 国際誌

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

    CELL REPORTS   34 巻 ( 6 ) 頁: 108734 - 108734   2021年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell Reports  

    Needle-like multi-walled carbon nanotubes (MWCNTs) are engulfed by macrophages, which cause inflammation and asbestosis-like pathogenesis in rodents; however, how macrophages recognize MWCNTs remains unclear. Omori et al. demonstrate that Tim4 recognizes MWCNTs through aromatic-aromatic interactions and mediates macrophage phagocytosis leading to granulomas.

    DOI: 10.1016/j.celrep.2021.108734

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  45. Mechanism of asbestos-induced carcinogenesis via dysregulation of redox-active iron 国際誌

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   112 巻   頁: 998 - 998   2021年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  46. Mechanism of asbestos-induced carcinogenesis via dysregulation of redox-active iron 国際誌

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   112 巻   頁: 998 - 998   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  47. 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   112 巻   頁: 610 - 610   2021年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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

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

    CANCER SCIENCE   112 巻   頁: 245 - 245   2021年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  49. 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   112 巻   頁: 996 - 996   2021年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  50. Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue 国際誌

    Homma T.

    Free Radical Biology and Medicine   162 巻   頁: 255 - 265   2021年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    DOI: 10.1016/j.freeradbiomed.2020.10.023

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  51. Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma 国際誌

    Yamashita K.

    Genes Chromosomes and Cancer   60 巻 ( 1 ) 頁: 26 - 37   2021年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Genes Chromosomes and Cancer  

    DOI: 10.1002/gcc.22899

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  52. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 国際誌

    Klionsky Daniel J., Abdel-Aziz Amal Kamal, Abdelfatah Sara, Abdellatif Mahmoud, Abdoli Asghar, Abel Steffen, Abeliovich Hagai, Abildgaard Marie H., Abudu Yakubu Princely, Acevedo-Arozena Abraham, Adamopoulos Iannis E., Adeli Khosrow, Adolph Timon E., Adornetto Annagrazia, Aflaki Elma, Agam Galila, Agarwal Anupam, Aggarwal Bharat B., Agnello Maria, Agostinis Patrizia, Agrewala Javed N., Agrotis Alexander, Aguilar Patricia V, Ahmad S. Tariq, Ahmed Zubair M., Ahumada-Castro Ulises, Aits Sonja, Aizawa Shu, Akkoc Yunus, Akoumianaki Tonia, Akpinar Hafize Aysin, Al-Abd Ahmed M., Al-Akra Lina, Al-Gharaibeh Abeer, Alaoui-Jamali Moulay A., Alberti Simon, Alcocer-Gomez Elisabet, Alessandri Cristiano, Ali Muhammad, Al-Bari M. Abdul Alim, Aliwaini Saeb, Alizadeh Javad, Almacellas Eugenia, Almasan Alexandru, Alonso Alicia, Alonso Guillermo D., Altan-Bonnet Nihal, Altieri Dario C., Alves Sara, da Costa Cristine Alves, Alzaharna Mazen M., Amadio Marialaura, Amantini Consuelo, Amaral Cristina, Ambrosio Susanna, Amer Amal O., Ammanathan Veena, An Zhenyi, Andersen Stig U., Andrabi Shaida A., Andrade-Silva Magaiver, Andres Allen M., Angelini Sabrina, Ann David, Anozie Uche C., Ansari Mohammad Y., Antas Pedro, Antebi Adam, Anton Zurine, Anwar Tahira, Apetoh Lionel, Apostolova Nadezda, Araki Toshiyuki, Araki Yasuhiro, Arasaki Kohei, Araujo Wagner L., Araya Jun, Arden Catherine, Arevalo Maria-Angeles, Arguelles Sandro, Arias Esperanza, Arikkath Jyothi, Arimoto Hirokazu, Ariosa Aileen R., Armstrong-James Darius, Arnaune-Pelloquin Laetitia, Aroca Angeles, Arroyo Daniela S., Arsov Ivica, Artero Ruben, Asaro Dalia Maria Lucia, Aschner Michael, Ashrafizadeh Milad, Ashur-Fabian Osnat, Atanasov Atanas G., Au Alicia K., Auberger Patrick, Auner Holger W., Aurelian Laure, Autelli Riccardo, Avagliano Laura, Avalos Yenniffer, Aveic Sanja, Aveleira Celia Alexandra, AvinWittenberg Tamar, Aydin Yucel, Ayton Scott, Ayyadevara Srinivas, Azzopardi Maria, Baba Misuzu, Backer Jonathan M., Backues Steven K., Bae Dong-Hun, Bae Ok-Nam, Bae Soo Han, Baehrecke Eric H., Baek Ahruem, Baek Seung-Hoon, Baek Sung Hee, Bagetta Giacinto, Bagniewska-Zadworna Agnieszka, Bai Hua, Bai Jie, Bai Xiyuan, Bai Yidong, Bairagi Nandadulal, Baksi Shounak, Balbi Teresa, Baldari Cosima T., Balduini Walter, Ballabio Andrea, Ballester Maria, Balazadeh Salma, Balzan Rena, Bandopadhyay Rina, Banerjee Sreeparna, Banerjee Sulagna, Bao Yan, Baptista Mauricio S., Baracca Alessandra, Barbati Cristiana, Bargiela Ariadna, Barila Daniela, Barlow Peter G., Barmada Sami J., Barreiro Esther, Barreto George E., Bartek Jiri, Bartel Bonnie, Bartolome Alberto, Barve Gaurav R., Basagoudanavar Suresh H., Bassham Diane C., Jr Robert C. Bast, Basu Alakananda, Batoko Henri, Batten Isabella, Baulieu Etienne E., Baumgarner Bradley L., Bayry Jagadeesh, Beale Rupert, Beau Isabelle, Beaumatin Florian, Bechara Luiz R. G., Beck George R. Jr., Beers Michael F., Begun Jakob, Behrends Christian, Behrens Georg M. N., Bei Roberto, Bejarano Eloy, Bel Shai, Behl Christian, Belaid Amine, Belgareh-Touze Naima, Bellarosa Cristina, Belleudi Francesca, Bello Perez Melissa, Bello-Morales Raquel, de Oliveira Beltran Jackeline Soares, Beltran Sebastian, Benbrook Doris Mangiaracina, Bendorius Mykolas, Benitez Bruno A., Benito-Cuesta Irene, Bensalem Julien, Berchtold Martin W., Berezowska Sabina, Bergamaschi Daniele, Bergami Matteo, Bergmann Andreas, Berliocchi Laura, Berlioz-Torrent Clarisse, Bernard Amelie, Berthoux Lionel, Besirli Cagri G., Besteiro Sebastien, Betin Virginie M., Beyaert Rudi, Bezbradica Jelena S., Bhaskar Kiran, Bhatia-Kissova Ingrid, Bhattacharya Resham, Bhattacharya Sujoy, Bhattacharyya Shalmoli, Bhuiyan Md Shenuarin, Bhutia Sujit Kumar, Bi Lanrong, Bi Xiaolin, Biden Trevor J., Bijian Krikor, Billes Viktor A., Binart Nadine, Bincoletto Claudia, Birgisdottir Asa B., Bjorkoy Geir, Blanco Gonzalo, Blas-Garcia Ana, Blasiak Janusz, Blomgran Robert, Blomgren Klas, Blum Janice S., Boada-Romero Emilio, Boban Mirta, BoeszeBattaglia Kathleen, Boeuf Philippe, Boland Barry, Bomont Pascale, Bonaldo Paolo, Bonam Srinivasa Reddy, Bonfili Laura, Bonifacino Juan S., Boone Brian A., Bootman Martin D., Bordi Matteo, Borner Christoph, Bornhauser Beat C., Borthakur Gautam, Bosch Jurgen, Bose Santanu, Botana Luis M., Botas Juan, Boulanger Chantal M., Boulton Michael E., Bourdenx Mathieu, Bourgeois Benjamin, Bourke Nollaig M., Bousquet Guilhem, Boya Patricia, Bozhkov Peter V, Bozi Luiz H. M., Bozkurt Tolga O., Brackney Doug E., Brandts Christian H., Braun Ralf J., Braus Gerhard H., Bravo-Sagua Roberto, Bravo-San Pedro Jose M., Brest Patrick, Bringer Marie-Agnes, Briones-Herrera Alfredo, Broaddus V. Courtney, Brodersen Peter, Alvarez Elida M. C., Brodsky Jeffrey L., Brody Steven L., Bronson Paola G., Bronstein Jeff M., Brown Carolyn N., Brown Rhoderick E., Brum Patricia C., Brumell John H., Brunetti-Pierri Nicola, Bruno Daniele, Bryson-Richardson Robert J., Bucci Cecilia, Buchrieser Carmen, Bueno Marta, Buitrago-Molina Laura Elisa, Buraschi Simone, Buch Shilpa, Buchan J. Ross, Buckingham Erin M., Budak Hikmet, Budini Mauricio, Bultynck Geert, Burada Florin, Burgoyne Joseph R., Buron M. Isabel, Bustos Victor, Buttner Sabrina, Butturini Elena, Byrd Aaron, Cabas Isabel, Cabrera-Benitez Sandra, Cadwell Ken, Cai Jingjing, Cai Lu, Cai Qian, Cairo Montserrat, Calbet Jose A., Caldwell Guy A., Caldwell Kim A., Call Jarrod A., Calvani Riccardo, Calvo Ana C., Barrera Miguel Calvo-Rubio, Camara Niels Os, Camonis Jacques H., Camougrand Nadine, Campanella Michelangelo, Campbell Edward M., Campbell-Valois Francois-Xavier, Campello Silvia, Campesi Ilaria, Campos Juliane C., Camuzard Olivier, Cancino Jorge, de Almeida Danilo Candido, Canesi Laura, Caniggia Isabella, Canonico Barbara, Canti Carles, Cao Bin, Caraglia Michele, Carames Beatriz, Carchman Evie H., Cardenal-Munoz Elena, Cardenas Cesar, Cardenas Luis, Cardoso Sandra M., Carew Jennifer S., Carle Georges F., Carleton Gillian, Carloni Silvia, Carmona-Gutierrez Didac, Carneiro Leticia A., Carnevali Oliana, Carosi Julian M., Carra Serena, Carrier Alice, Carrier Lucie, Carroll Bernadette, Carter A. Brent, Carvalho Andreia Neves, Casanova Magali, Casas Caty, Casas Josefina, Cassioli Chiara, Castillo Eliseo F., Castillo Karen, Castillo-Lluva Sonia, Castoldi Francesca, Castori Marco, Castro Ariel F., Castro-Caldas Margarida, Castro-Hernandez Javier, Castro-Obregon Susana, Catz Sergio D., Cavadas Claudia, Cavaliere Federica, Cavallini Gabriella, Cavinato Maria, Cayuela Maria L., Rica Paula Cebollada, Cecarini Valentina, Cecconi Francesco, Cechowska-Pasko Marzanna, Cenci Simone, Ceperuelo-Mallafre Victoria, Cerqueira Joao J., Cerutti Janete M., Cervia Davide, Cetintas Vildan Bozok, Cetrullo Silvia, Chae Han-Jung, Chagin Andrei S., Chai Chee-Yin, Chakrabarti Gopal, Chakrabarti Oishee, Chakraborty Tapas, Chakraborty Trinad, Chami Mounia, Chamilos Georgios, Chan 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, Chandra Partha K., Chang Chih-Peng, Chang Chunmei, Chang Hao-Chun, Chang Kai, Chao Jie, Chapman Tracey, Charlet-Berguerand Nicolas, Chatterjee Samrat, Chaube Shail K., Chaudhary Anu, Chauhan Santosh, Chaum Edward, Checler Frederic, Cheetham Michael E., Chen ChangShi, Chen Guang-Chao, Chen Jian-Fu, Chen Liam L., Chen Leilei, Chen Lin, Chen Mingliang, Chen MuKuan, Chen Ning, Chen Quan, Chen Ruey-Hwa, Chen Shi, Chen Wei, Chen Weiqiang, Chen XinMing, Chen Xiong-Wen, Chen Xu, Chen Yan, Chen Ye-Guang, Chen Yingyu, Chen Yongqiang, Chen YuJen, Chen Yue-Qin, Chen Zhefan Stephen, Chen Zhi, Chen Zhi-Hua, Chen Zhijian J., Chen Zhixiang, Cheng Hanhua, Cheng Jun, Cheng Shi-Yuan, Cheng Wei, Cheng Xiaodong, Cheng Xiu-Tang, Cheng Yiyun, Cheng Zhiyong, Chen Zhong, Cheong Heesun, Cheong Jit Kong, Chernyak Boris V, Cherry Sara, Cheung Chi Fai Randy, Cheung Chun Hei Antonio, Cheung King-Ho, Chevet Eric, Chi Richard J., Chiang Alan Kwok Shing, Chiaradonna Ferdinando, Chiarelli Roberto, Chiariello Mario, Chica Nathalia, Chiocca Susanna, Chiong Mario, Chiou Shih-Hwa, Chiramel Abhilash I, Chiurchiu Valerio, Cho Dong-Hyung, Choe Seong-Kyu, Choi Augustine M. K., Choi Mary E., Choudhury Kamalika Roy, Chow Norman S., Chu Charleen T., Chua Jason P., Chua John Jia En, Chung Hyewon, Chung Kin Pan, Chung Seockhoon, Chung So-Hyang, Chung Yuen-Li, Cianfanelli Valentina, Ciechomska Iwona A., Cifuentes Mariana, Cinque Laura, Cirak Sebahattin, Cirone Mara, Clague Michael J., Clarke Robert, Clementi Emilio, Coccia Eliana M., Codogno Patrice, Cohen Ehud, Cohen Mickael M., Colasanti Tania, Colasuonno Fiorella, Colbert Robert A., Colell Anna, Coll Nuria S., Collins Mark O., Colombo Maria I, Colon-Ramos Daniel A., Combaret Lydie, Comincini Sergio, Cominetti Marcia R., Consiglio Antonella, Conte Andrea, Conti Fabrizio, Contu Viorica Raluca, Cookson Mark R., Coombs Kevin M., Coppens Isabelle, Corasaniti Maria Tiziana, Corkery Dale P., Cordes Nils, Cortese Katia, Costa Maria do Carmo, Costantino Sarah, Costelli Paola, Coto-Montes Ana, Crack Peter J., Crespo Jose L., Criollo Alfredo, Crippa Valeria, Cristofani Riccardo, Csizmadia Tamas, Cuadrado Antonio, Cui Bing, Cui Jun, Cui Yixian, Cui Yong, Culetto Emmanuel, Cumino Andrea C., Cybulsky Andrey V, Czaja Mark J., Czuczwar Stanislaw J., D'Adamo Stefania, D'Amelio Marcello, D'Arcangelo Daniela, D'Lugos Andrew C., D'Orazi Gabriella, da Silva James A., Dafsari Hormos Salimi, Dagda Ruben K., Dagdas Yasin, Daglia Maria, Dai Xiaoxia, Dai Yun, Dai Yuyuan, Dal Col Jessica, Dalhaimer Paul, Dalla Valle Luisa, Dallenga Tobias, Dalmasso Guillaume, Damme Markus, Dando Ilaria, Dantuma Nico P., Darling April L., Das Hiranmoy, Dasarathy Srinivasan, Dasari Santosh K., Dash Srikanta, Daumke Oliver, Dauphinee Adrian N., Davies Jeffrey S., Davila Valeria A., Davis Roger J., Davis Tanja, Naidu Sharadha Dayalan, De Amicis Francesca, De Bosscher Karolien, De Felice Francesca, De Franceschi Lucia, De Leonibus Chiara, de Mattos Barbosa Mayara G., De Meyer Guido R. Y., De Milito Angelo, De Nunzio Cosimo, De Palma Clara, De Santi Mauro, De Virgilio Claudio, De Zio Daniela, Debnath Jayanta, DeBosch Brian J., Decuypere JeanPaul, Deehan Mark A., Deflorian Gianluca, DeGregori James, Dehay Benjamin, Del Rio Gabriel, Delaney Joe R., Delbridge Lea M. D., Delorme-Axford Elizabeth, Delpino M. Victoria, Demarchi Francesca, Dembitz Vilma, Demers Nicholas D., Deng Hongbin, Deng Zhiqiang, Dengjel Joern, Dent Paul, Denton Donna, DePamphilis Melvin L., Der Channing J., Deretic Vojo, Descoteaux Albert, Devis Laura, Devkota Sushil, Devuyst Olivier, Dewson Grant, Dharmasivam Mahendiran, Dhiman Rohan, di Bernardo Diego, Di Cristina Manlio, Di Domenico Fabio, Di Fazio Pietro, Di Fonzo Alessio, Di Guardo Giovanni, Di Guglielmo Gianni M., Di Leo Luca, Di Malta Chiara, Di Nardo Alessia, Di Rienzo Martina, Di Sano Federica, Diallinas George, Diao Jiajie, Diaz-Araya Guillermo, Diaz-Laviada Ines, Dickinson Jared M., Diederich Marc, Dieude Melanie, Dikic Ivan, Ding Shiping, Ding Wen-Xing, Dini Luciana, Dinic Miroslav, Dinkova-Kostova Albena T., Dionne Marc S., Distler Jorg H. W., Diwan Abhinav, Dixon Ian M. C., Djavaheri-Mergny Mojgan, Dobrinski Ina, Dobrovinskaya Oxana, Dobrowolski Radek, Dobson Renwick C. J., Emre Serap Dokmeci, Donadelli Massimo, Dong Bo, Dong Xiaonan, Dong Zhiwu, Ii Gerald W. Dorn, Dotsch Volker, Dou Huan, Dou Juan, Dowaidar Moataz, Dridi Sami, Drucker Liat, Du Ailian, Du Caigan, Du Guangwei, Du Hai-Ning, Du Li-Lin, du Toit Andre, Duan Shao-Bin, Duan Xiaoqiong, Duarte Sonia P., Dubrovska Anna, Dunlop Elaine A., Dupont Nicolas, Duran Raul V, Dwarakanath Bilikere S., Dyshlovoy Sergey A., Ebrahimi-Fakhari Darius, Eckhart Leopold, Edelstein Charles L., Efferth Thomas, Eftekharpour Eftekhar, Eichinger Ludwig, Eid Nabil, Eisenberg Tobias, Eissa N. Tony, Eissa Sanaa, Ejarque Miriam, El Andaloussi Abdeljabar, El-Hage Nazira, El-Naggar Shahenda, Eleuteri Anna Maria, El-Shafey Eman S., Elgendy Mohamed, Eliopoulos Aristides G., Elizalde Maria M., Elks Philip M., Elsasser Hans-Peter, Elsherbiny Eslam S., Emerling Brooke M., Emre N. C. Tolga, Eng Christina H., Engedal Nikolai, Engelbrecht Anna-Mart, Engelsen Agnete S. T., Enserink Jorrit M., Escalante Ricardo, Esclatine Audrey, Escobar-Henriques Mafalda, Eskelinen Eeva-Liisa, Espert Lucile, Eusebio Makandjou-Ola, Fabrias Gemma, Fabrizi Cinzia, Facchiano Antonio, Facchiano Francesco, Fadeel Bengt, Fader Claudio, Faesen Alex C., Fairlie W. Douglas, Falco Alberto, Falkenburger Bjorn H., Fan Daping, Fan Jie, Fan Yanbo, Fang Evandro F., Fang Yanshan, Fang Yognqi, Fanto Manolis, Farfel-Becker Tamar, Faure Mathias, Fazeli Gholamreza, Fedele Anthony O., Feldman Arthur M., Feng Du, Feng Jiachun, Feng Lifeng, Feng Yibin, Feng Yuchen, Feng Wei, Araujo Thais Fenz, Ferguson Thomas A., Fernandez-Checa Jose C., FernandezVeledo Sonia, Fernie Alisdair R., Ferrante Anthony W. Jr., Ferraresi Alessandra, Ferrari Merari F., Ferreira Julio C. B., Ferro-Novick Susan, Figueras Antonio, Filadi Riccardo, Filigheddu Nicoletta, FilippiChiela Eduardo, Filomeni Giuseppe, Fimia Gian Maria, Fineschi Vittorio, Finetti Francesca, Finkbeiner Steven, Fisher Edward A., Fisher Paul B., Flamigni Flavio, Fliesler Steven J., Flo Trude H., Florance Ida, Florey Oliver, Florio Tullio, Fodor Erika, Follo Carlo, Fon Edward A., Forlino Antonella, Fornai Francesco, Fortini Paola, Fracassi Anna, Fraldi Alessandro, Franco Brunella, Franco Rodrigo, Franconi Flavia, Frankel Lisa B., Friedman Scott L., Frohlich Leopold F., Fruhbeck Gema, Fuentes Jose M., Fujiki Yukio, Fujita Naonobu, Fujiwara Yuuki, Fukuda Mitsunori, Fulda Simone, Furic Luc, Furuya Norihiko, Fusco Carmela, Gack Michaela U., Gaffke Lidia, Galadari Sehamuddin, Galasso Alessia, Galindo Maria F., Kankanamalage Sachith Gallolu, Galluzzi Lorenzo, Galy Vincent, Gammoh Noor, Gan Boyi, Ganley Ian G., Gao Feng, Gao Hui, Gao Minghui, Gao Ping, Gao Shou-Jiang, Gao Wentao, Gao Xiaobo, Garcera Ana, Garcia Maria Noe, Garcia Veronica E., Garcia-Del Portillo Francisco, Garcia-Escudero Vega, GarciaGarcia Aracely, Garcia-Macia Marina, Garcia-Moreno Diana, Garcia-Ruiz Carmen, Garcia-Sanz Patricia, Garg Abhishek D., Gargini Ricardo, Garofalo Tina, Garry Robert F., Gassen Nils C., Gatica Damian, Ge Liang, Ge Wanzhong, Geiss-Friedlander Ruth, Gelfi Cecilia, Genschik Pascal, Gentle Ian E., Gerbino Valeria, Gerhardt Christoph, Germain Kyla, Germain Marc, Gewirtz David A., Afshar Elham Ghasemipour, Ghavami Saeid, Ghigo Alessandra, Ghosh Manosij, Giamas Georgios, Giampietri Claudia, Giatromanolaki Alexandra, Gibson Gary E., Gibson Spencer B., Ginet Vanessa, Giniger Edward, Giorgi Carlotta, Girao Henrique, Girardin Stephen E., Giridharan Mridhula, Giuliano Sandy, Giulivi Cecilia, Giuriato Sylvie, Giustiniani Julien, Gluschko Alexander, Goder Veit, Goginashvili Alexander, Golab Jakub, Goldstone David C., Golebiewska Anna, Gomes Luciana R., Gomez Rodrigo, Gomez-Sanchez Ruben, Gomez-Puerto Maria Catalina, Gomez-Sintes Raquel, Gong Qingqiu, Goni Felix M., Gonzalez-Gallego Javier, Gonzalez-Hernandez Tomas, Gonzalez-Polo Rosa A., Gonzalez-Reyes Jose A., Gonzalez-Rodriguez Patricia, Goping Ing Swie, Gorbatyuk Marina S., Gorbunov Nikolai V, Gorojod Roxana M., Gorski Sharon M., Goruppi Sandro, Gotor Cecilia, Gottlieb Roberta A., Gozes Illana, Gozuacik Devrim, Graef Martin, Graler Markus H., Granatiero Veronica, Grasso Daniel, Gray Joshua P., Green Douglas R., Greenhough Alexander, Gregory Stephen L., Griffin Edward F., Grinstaff Mark W., Gros Frederic, Grose Charles, Gross Angelina S., Gruber Florian, Grumati Paolo, Grune Tilman, Gu Xueyan, Guan Jun-Lin, Guardia Carlos M., Guda Kishore, Guerra Flora, Guerri Consuelo, Guha Prasun, Guillen Carlos, Gujar Shashi, Gukovskaya Anna, Gukovsky Ilya, Gunst Jan, Gunther Andreas, Guntur Anyonya R., Guo Chuanyong, Guo Chun, Guo Hongqing, Guo Lian-Wang, Guo Ming, Gupta Pawan, Fernandez Alvaro F., Gupta Shashi Kumar, Gupta Swapnil, Gupta Veer Bala, Gupta Vivek, Gustafsson Asa B., Gutterman David D., Ranjitha H. B., Haapasalo Annakaisa, Haber James E., Hadano Shinji, Hafren Anders J., Haidar Mansour, Hall Belinda S., Hallden Gunnel, Hamacher-Brady Anne, Hamann Andrea, Hamasaki Maho, Han Weidong, Hansen Malene, Hanson Phyllis I, Hao Zijian, Harada Masaru, Harhaji-Trajkovic Ljubica, Hariharan Nirmala, Haroon Nigil, Harris James, Hasegawa Takafumi, Nagoor Noor Hasima, Haspel Jeffrey A., Haucke Volker, Hawkins Wayne D., Hay Bruce A., Haynes Cole M., Hayrabedyan Soren B., Hays Thomas S., He Congcong, He Qin, He RongRong, He You-Wen, He Yu-Ying, Heakal Yasser, Heberle Alexander M., Hejtmancik J. Fielding, Helgason Gudmundur Vignir, Henkel Vanessa, Herb Marc, Hergovich Alexander, Herman-Antosiewicz Anna, Hernandez Agustin, Hernandez Carlos, Hernandez-Diaz Sergio, Hernandez-Gea Virginia, Herpin Amaury, Herreros Judit, Hervas Javier H., Hesselson Daniel, Hetz Claudio, Heussler Volker T., Higuchi Yujiro, Hilfiker Sabine, Hill Joseph A., Hlavacek William S., Ho Emmanuel A., Ho Idy H. T., Ho Philip Wing-Lok, Ho ShuLeong, Ho Wan Yun, Hobbs G. Aaron, Hochstrasser Mark, Hoet Peter H. M., Hofius Daniel, Hofman Paul, Hohn Annika, Holmberg Carina I, Hombrebueno Jose R., Hong Chang-Won, Hong Yi-Ren, Hooper Lora V, Hoppe Thorsten, Horos Rastislav, Hoshida Yujin, Hsin I-Lun, Hsu Hsin-Yun, Hu Bing, Hu Dong, Hu Li-Fang, Hu Ming Chang, Hu Ronggui, Hu Wei, Hu Yu-Chen, Hu Zhuo-Wei, Hua Fang, Hua Jinlian, Hua Yingqi, Huan Chongmin, Huang Canhua, Huang Chuanshu, Huang Chuanxin, Huang Chunling, Huang Haishan, Huang Kun, Huang Michael L. H., Huang Rui, Huang Shan, Huang Tianzhi, Huang Xing, Huang Yuxiang Jack, Huber Tobias B., Hubert Virginie, Hubner Christian A., Hughes Stephanie M., Hughes William E., Humbert Magali, Hummer Gerhard, Hurley James H., Hussain Sabah, Hussain Salik, Hussey Patrick J., Hutabarat Martina, Hwang Hui-Yun, Hwang Seungmin, Ieni Antonio, Ikeda Fumiyo, Imagawa Yusuke, Imai Yuzuru, Imbriano Carol, Imoto Masaya, Inman Denise M., Inoki Ken, Iovanna Juan, Iozzo Renato V, Ippolito Giuseppe, Irazoqui Javier E., Iribarren Pablo, Ishaq Mohd, Ishikawa Makoto, Ishimwe Nestor, Isidoro Ciro, Ismail Nahed, Issazadeh-Navikas Shohreh, Itakura Eisuke, Ito Daisuke, Ivankovic Davor, Ivanova Saska, Iyer Anand Krishnan V, Izquierdo Jose M., Izumi Masanori, Jaattela Marja, Jabir Majid Sakhi, Jackson William T., Jacobo-Herrera Nadia, Jacomin Anne-Claire, Jacquin Elise, Jadiya Pooja, Jaeschke Hartmut, Jagannath Chinnaswamy, Jakobi Arjen J., Jakobsson Johan, Janji Bassam, JansenDurr Pidder, Jansson Patric J., Jantsch Jonathan, Januszewski Slawomir, Jassey Alagie, Jean Steve, JeltschDavid Helene, Jendelova Pavla, Jenny Andreas, Jensen Thomas E., Jessen Niels, Jewell Jenna L., Ji Jing, Jia Lijun, Jia Rui, Jiang Liwen, Jiang Qing, Jiang Richeng, Jiang Teng, Jiang Xuejun, Jiang Yu, Jimenez-Sanchez Maria, Jin Eun-Jung, Jin Fengyan, Jin Hongchuan, Jin Li, Jin Luqi, Jin Meiyan, Jin Si, Jo Eun-Kyeong, Joffre Carine, Johansen Terje, Johnson Gail V. W., Johnston Simon A., Jokitalo Eija, Jolly Mohit Kumar, Joosten Leo A. B., Jordan Joaquin, Joseph Bertrand, Ju Dianwen, Ju Jeong-Sun, Ju Jingfang, Juarez Esmeralda, Judith Delphine, Juhasz Gabor, Jun Youngsoo, Jung Chang Hwa, Jung SungChul, Jung Yong Keun, Jungbluth Heinz, Jungverdorben Johannes, Just Steffen, Kaarniranta Kai, Kaasik Allen, Kabuta Tomohiro, Kaganovich Daniel, Kahana Alon, Kain Renate, Kajimura Shinjo, Kalamvoki Maria, Kalia Manjula, Kalinowski Danuta S., Kaludercic Nina, Kalvari Ioanna, Kaminska Joanna, Kaminskyy Vitaliy O., Kanamori Hiromitsu, Kanasaki Keizo, Kang Chanhee, Kang Rui, Kang Sang Sun, Kaniyappan Senthilvelrajan, Kanki Tomotake, Kanneganti Thirumala-Devi, Kanthasamy Anumantha G., Kanthasamy Arthi, Kantorow Marc, Kapuy Orsolya, Karamouzis Michalis V, Karim Md Razaul, Karmakar Parimal, Katare Rajesh G., Kato Masaru, Kaufmann Stefan H. E., Kauppinen Anu, Kaushal Gur P., Kaushik Susmita, Kawasaki Kiyoshi, Kazan Kemal, Ke Po-Yuan, Keating Damien J., Keber Ursula, Kehrl John H., Keller Kate E., Keller Christian W., Kemper Jongsook Kim, Kenific Candia M., Kepp Oliver, Kermorgant Stephanie, Kern Andreas, Ketteler Robin, Keulers Tom G., Khalfin Boris, Khalil Hany, Khambu Bilon, Khan Shahid Y., Khandelwal Vinoth Kumar Megraj, Khandia Rekha, Kho Widuri, Khobrekar Noopur V, Khuansuwan Sataree, Khundadze Mukhran, Killackey Samuel A., Kim Dasol, Kim Deok Ryong, Kim Do-Hyung, Kim Dong-Eun, Kim Eun Young, Kim Eun-Kyoung, Kim HakRim, Kim Hee-Sik, Kim Hyung-Ryong, Kim Jeong Hun, Kim Jin Kyung, Kim Jin-Hoi, Kim Joungmok, Kim Ju Hwan, Kim Keun Il, Kim Peter K., Kim Seong-Jun, Kimball Scot R., Kimchi Adi, Kimmelman Alec C., Kimura Tomonori, King Matthew A., Kinghorn Kerri J., Kinsey Conan G., Kirkin Vladimir, Kirshenbaum Lorrie A., Kiselev Sergey L., Kishi Shuji, Kitamoto Katsuhiko, Kitaoka Yasushi, Kitazato Kaio, Kitsis Richard N., Kittler Josef T., Kjaerulff Ole, Klein Peter S., Klopstock Thomas, Klucken Jochen, Knovelsrud Helene, Knorr Roland L., Ko Ben C. B., Ko Fred, Ko JiunnLiang, Kobayashi Hotaka, Kobayashi Satoru, Koch Ina, Koch Jan C., Koenig Ulrich, Kogel Donat, Koh Young Ho, Koike Masato, Kohlwein Sepp D., Kocaturk Nur M., Komatsu Masaaki, Konig Jeannette, Kono Toru, Kopp Benjamin T., Korcsmaros Tamas, Korkmaz Gozde, Korolchuk Viktor I, Korsnes Monica Suarez, Koskela Ali, Kota Janaiah, Kotake Yaichiro, Kotler Monica L., Kou Yanjun, Koukourakis Michael I, Koustas Evangelos, Kovacs Attila L., Kovacs Tibor, Koya Daisuke, Kozako Tomohiro, Kraft Claudine, Krainc Dimitri, Kramer Helmut, Krasnodembskaya Anna D., Kretz-Remy Carole, Kroemer Guido, Ktistakis Nicholas T., Kuchitsu Kazuyuki, Kuenen Sabine, Kuerschner Lars, Kukar Thomas, Kumar Ajay, Kumar Ashok, Kumar Deepak, Kumar Dhiraj, Kumar Sharad, Kume Shinji, Kumsta Caroline, Kundu Chanakya N., Kundu Mondira, Kunnumakkara Ajaikumar B., Kurgan Lukasz, Kutateladze Tatiana G., Kutlu Ozlem, Kwak SeongAe, Kwon Ho Jeong, Kwon Taeg Kyu, Kwon Yong Tae, Kyrmizi Irene, La Spada Albert, Labonte Patrick, Ladoire Sylvain, Laface Ilaria, Lafont Frank, Lagace Diane C., Lahiri Vikramjit, Lai Zhibing, Laird Angela S., Lakkaraju Aparna, Lamark Trond, Lan Sheng-Hui, Landajuela Ane, Lane Darius J. R., Lane Jon D., Lang Charles H., Lange Carsten, Langer Rupert, Lapaquette Pierre, Laporte Jocelyn, LaRusso Nicholas F., Lastres-Becker Isabel, Lau Wilson Chun Yu, Laurie Gordon W., Lavandero Sergio, Law Betty Yuen Kwan, Law Helen Ka-wai, Layfield Rob, Le Weidong, Le Stunff Herve, Leary Alexandre Y., Lebrun Jean-Jacques, Leck Lionel Y. W., Leduc-Gaudet Jean-Philippe, Lee Changwook, Lee Chung-Pei, Lee Da-Hye, Lee Edward B., Lee Erinna F., Lee Gyun Min, Lee He-Jin, Lee Heung Kyu, Lee Jae Man, Lee Jason S., Lee Jin-A, Lee Joo-Yong, Lee Jun Hee, Lee Michael, Lee Min Goo, Lee Min Jae, Lee Myung-Shik, Lee Sang Yoon, Lee Seung-Jae, Lee Stella Y., Lee Sung Bae, Lee Won Hee, Lee Ying-Ray, Lee Yong-ho, Lee Youngil, Lefebvre Christophe, Legouis Renaud, Lei Yu L., Lei Yuchen, Leikin Sergey, Leitinger Gerd, Lemus Leticia, Leng Shuilong, Lenoir Olivia, Lenz Guido, Lenz Heinz Josef, Lenzi Paola, Leon Yolanda, Leopoldino Andreia M., Leschczyk Christoph, Leskela Stina, Letellier Elisabeth, Leung Chi-Ting, Leung Po Sing, Leventhal Jeremy S., Levine Beth, Lewis Patrick A., Ley Klaus, Li Bin, Li Da-Qiang, Li Jianming, Li Jing, Li Jiong, Li Ke, Li Liwu, Li Mei, Li Min, Li Min, Li Ming, Li Mingchuan, Li Pin-Lan, Li MingQing, Li Qing, Li Sheng, Li Tiangang, Li Wei, Li Wenming, Li Xue, Li Yi-Ping, Li Yuan, Li Zhiqiang, Li Zhiyong, Li Zhiyuan, Lian Jiqin, Liang Chengyu, Liang Qiangrong, Liang Weicheng, Liang Yongheng, Liang YongTian, Liao Guanghong, Liao Lujian, Liao Mingzhi, Liao Yung-Feng, Librizzi Mariangela, Lie Pearl P. Y., Lilly Mary A., Lim Hyunjung J., Lima Thania R. R., Limana Federica, Lin Chao, Lin Chih-Wen, Lin Dar-Shong, Lin Fu-Cheng, Lin Jiandie D., Lin Kurt M., Lin Kwang-Huei, Lin Liang-Tzung, Lin Pei-Hui, Lin Qiong, Lin Shaofeng, Lin Su-Ju, Lin Wenyu, Lin Xueying, Lin Yao-Xin, Lin Yee-Shin, Linden Rafael, Lindner Paula, Ling Shuo-Chien, Lingor Paul, Linnemann Amelia K., Liou YihCherng, Lipinski Marta M., Lipovsek Saska, Lira Vitor A., Lisiak Natalia, Liton Paloma B., Liu Chao, Liu Ching-Hsuan, Liu Chun-Feng, Liu Cui Hua, Liu Fang, Liu Hao, Liu Hsiao-Sheng, Liu Hua-feng, Liu Huifang, Liu Jia, Liu Jing, Liu Julia, Liu Leyuan, Liu Longhua, Liu Meilian, Liu Qin, Liu Wei, Liu Wende, Liu Xiao-Hong, Liu Xiaodong, Liu Xingguo, Liu Xu, Liu Xuedong, Liu Yanfen, Liu Yang, Liu Yang, Liu Yueyang, Liu Yule, Livingston J. 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S., Yamaguchi Masamitsu, Yamaguchi Osamu, Yamamoto Ai, Yamashina Shunhei, Yan Shengmin, Yan Shian-Jang, Yan Zhen, Yanagi Yasuo, Yang 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, Yao Honghong, Yao Shenggen, Yao Xiaoqiang, Yao Yong-Gang, Yao Yong-Ming, Yasui Takahiro, Yazdankhah Meysam, Yen Paul M., Yi Cong, Yin Xiao-Ming, Yin Yanhai, Yin Zhangyuan, Yin Ziyi, Ying Meidan, Ying Zheng, Yip Calvin K., Yiu Stephanie Pei Tung, Yoo Young H., Yoshida Kiyotsugu, Yoshii Saori R., Yoshimori Tamotsu, Yousefi Bahman, Yu 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, Yuan Junying, Yuan Ling-Qing, Yuan Shilin, Yuan Shyng-Shiou F., Yuan Yanggang, Yuan Zengqiang, Yue Jianbo, Yue Zhenyu, Yun Jeanho, Yung Raymond L., Zacks David N., Zaffagnini Gabriele, Zambelli Vanessa O., Zanella Isabella, Zang Qun S., Zanivan Sara, Zappavigna Silvia, Zaragoza Pilar, Zarbalis Konstantinos S., Zarebkohan Amir, Zarrouk Amira, Zeitlin Scott O., Zeng Jialiu, Zeng Ju-deng, Zerovnik Eva, Zhan Lixuan, Zhang 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, Zhao Haobin, Zhao Lei, Zhao Shuang, Zhao Tongbiao, Zhao Xiao-Fan, Zhao Ying, Zhao Yongchao, Zhao Yongliang, Zhao Yuting, Zheng Guoping, Zheng Kai, Zheng Ling, Zheng Shizhong, Zheng Xi-Long, Zheng Yi, Zheng Zu-Guo, Zhivotovsky Boris, Zhong Qing, Zhou 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, Zhu Binglin, Zhu Changlian, Zhu Guo-Qing, Zhu Haining, Zhu Hongxin, Zhu Hua, Zhu WeiGuo, Zhu Yanping, Zhu Yushan, Zhuang Haixia, Zhuang Xiaohong, Zientara-Rytter Katarzyna, Zimmermann Christine M., Ziviani Elena, Zoladek Teresa, Zong Wei-Xing, Zorov Dmitry B., Zorzano Antonio, Zou Weiping, Zou Zhen, Zou Zhengzhi, Zuryn Steven, Zwerschke Werner, Brand-Saberi Beate, Dong X. Charlie, Kenchappa Chandra Shekar, Li Zuguo, Lin Yong, Oshima Shigeru, Rong Yueguang, Sluimer Judith C., Stallings Christina L., Tong Chun-Kit

    AUTOPHAGY   17 巻 ( 1 ) 頁: 1 - 382   2021年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元: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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  53. Cancer Treatments Using Low-Temperature Plasma. 国際誌

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

    Current medicinal chemistry   28 巻 ( 41 ) 頁: 8549 - 8558   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Current Medicinal Chemistry  

    Low-temperature plasma (LTP) is a partially ionized gas that contains elec-trons, 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 ex-periments 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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  54. カーボンナノチューブによる毒性発現機構

    山口 慎一朗, 守田 匡伸, 伊藤 文哉, 謝 祺琳, 豊國 伸哉, 中山 勝文

    日本毒性学会学術年会   48.1 巻 ( 0 ) 頁: O-4 - 4   2021年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本毒性学会  

    <p>カーボンナノチューブ(CNTs)は次世代ナノ材料として期待されているものの、その毒性の懸念から国際化学物質事務局ChemSecがCNTsをSIN (Substitute It Now)リストに加えたため、今後のCNTsの使用継続について国際的に大きく議論されている。多層CNTs(MWCNTs)は生体内に入ると主にマクロファージに取り込まれ、そのマクロファージ細胞死およびNLRP3インフラマソーム活性化によるIL-1β分泌が毒性発現に関与すると考えられているが、マクロファージがどのように細胞表面上でMWCNTsを認識するのかはよく分かっていない。本研究で我々は貪食受容体スクリーニングによりT cell immunoglobulin mucin 4(Tim4)およびTim1がMWCNTsを認識することを見出した。CRISPR/Cas9システムによって作製した<i>Tim4<sup>-/- </sup>Tim1<sup>-/-</sup> </i>マウスや<i>Tim4<sup>-/-</sup></i> マウス由来腹腔マクロファージを用いた解析から、Tim4はマクロファージによるMWCNTsの貪食、およびその結果起きるIL-1β分泌に関与することが判明した。さらに<i>Tim4<sup>-/- </sup></i>マウス、あるいは抗Tim4モノクローナル抗体を全投与した野生型マウスにおいて、MWCNTs腹腔投与による横隔膜中皮細胞層の肉芽種形成が有意に抑制されていたことから、Tim4はMWCNTs曝露によるin vivo炎症応答に関与することが示唆された。一方、Tim1はヒト肺細胞株によるMWCNTsの認識に関与することが判明した。以上の結果は、Tim4およびTim1はMWCNTs受容体として機能することを示す。</p>

    DOI: 10.14869/toxpt.48.1.0_o-4

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  55. The new era for research on polyphenols and food factors 国際誌

    Oteiza P.I.

    Archives of Biochemistry and Biophysics   696 巻   2020年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2020.108678

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  56. The new era for redox research 国際誌

    Naito Yuji, Uchida Koji, Toyokuni Shinya

    FREE RADICAL RESEARCH   54 巻 ( 11-12 ) 頁: 787 - 789   2020年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    DOI: 10.1080/10715762.2020.1774177

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  57. Neural stem cell-specific ITPA deficiency causes neural depolarization and epilepsy 国際誌

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

    JCI INSIGHT   5 巻 ( 22 )   2020年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JCI Insight  

    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 (ItpacKO 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.

    DOI: 10.1172/jci.insight.140229

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

    Okazaki Yasumasa, Toyokuni Shinya

    JAPANESE JOURNAL OF APPLIED PHYSICS   59 巻 ( 11 )   2020年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  59. Carcinogenesis as Side Effects of Iron and Oxygen Utilization: From the Unveiled Truth toward Ultimate Bioengineering 国際誌

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

    CANCERS   12 巻 ( 11 ) 頁: 1 - 20   2020年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancers  

    Evolution from the first life on earth to humans took ~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.

    DOI: 10.3390/cancers12113320

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  60. Induction of cancer cell-specific ferroptosis by non-thermal plasma exposure 国際誌

    Okazaki Y.

    Japanese Journal of Applied Physics   59 巻 ( 11 )   2020年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Applied Physics  

    DOI: 10.35848/1347-4065/abbc56

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

    Yanatori I.

    Biochimica et Biophysica Acta - General Subjects   1864 巻 ( 11 )   2020年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochimica et Biophysica Acta - General Subjects  

    DOI: 10.1016/j.bbagen.2020.129685

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  62. Adjusted multiple gases in the plasma flow induce differential antitumor potentials of plasma-activated solutions 国際誌

    Nakamura K.

    Plasma Processes and Polymers   17 巻 ( 10 )   2020年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Plasma Processes and Polymers  

    DOI: 10.1002/ppap.201900259

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  63. Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice 国際誌

    Nishio M.

    Cancer Science   111 巻 ( 10 ) 頁: 3576 - 3587   2020年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    DOI: 10.1111/cas.14581

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  64. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice 国際誌

    Hayashi S.

    Redox Biology   37 巻   2020年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    DOI: 10.1016/j.redox.2020.101726

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  65. 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   79回 巻   頁: OJ1 - 1   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本癌学会  

  66. Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and β-catenin induction in mesothelium 国際誌

    Ito F.

    Redox Biology   36 巻   2020年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    DOI: 10.1016/j.redox.2020.101616

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  67. Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma 国際誌

    Ohara Y.

    Oncology Reports   44 巻 ( 3 ) 頁: 838 - 848   2020年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncology Reports  

    DOI: 10.3892/or.2020.7669

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  68. Role of carbonic anhydrases in ferroptosis-resistance 国際誌

    Li Z.

    Archives of Biochemistry and Biophysics   689 巻   2020年8月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2020.108440

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  69. Ferroptosis at the crossroads of infection, aging and cancer 国際誌

    Toyokuni S.

    Cancer Science   111 巻 ( 8 ) 頁: 2665 - 2671   2020年8月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    DOI: 10.1111/cas.14496

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  70. Non-thermal plasma-activated lactate solution kills U251SP glioblastoma cells in an innate reductive manner with altered metabolism 国際誌

    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   688 巻   2020年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2020.108414

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  71. Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats 国際誌

    Okazaki Y.

    Cancer Science   111 巻 ( 6 ) 頁: 2016 - 2027   2020年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    DOI: 10.1111/cas.14405

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  72. Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats 査読有り 国際誌

    Okazaki Y.

    Cancer Science   111 巻 ( 4 ) 頁: 1180 - 1192   2020年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    DOI: 10.1111/cas.14358

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  73. Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice 査読有り 国際誌

    Funahashi S.

    Free Radical Research   54 巻 ( 2-3 ) 頁: 195 - 205   2020年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    DOI: 10.1080/10715762.2020.1743285

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  74. 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   109 巻 ( 1 ) 頁: 314 - 314   2020年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本病理学会  

  75. Plasma-activated medium promotes autophagic cell death along with alteration of the mTOR pathway 国際誌

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

    SCIENTIFIC REPORTS   10 巻 ( 1 )   2020年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    DOI: 10.1038/s41598-020-58667-3

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  76. Augmented oxidative stress increases 8-oxoguanine preferentially in the transcriptionally active genomic regions 査読有り 国際誌

    Akatsuka S.

    Free Radical Research     2020年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    DOI: 10.1080/10715762.2020.1733548

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  77. Oxidative stress-dependent and -independent death of glioblastoma cells induced by non-thermal plasma-exposed solutions 査読有り 国際誌

    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   9 巻 ( 1 ) 頁: 13657   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    DOI: 10.1038/s41598-019-50136-w

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  78. 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 国際誌

    Yanatori I.

    Archives of Biochemistry and Biophysics   672 巻   頁: 108071   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2019.108071

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  79. Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia 査読有り 国際誌

    Li Z.

    Redox Biology   26 巻   頁: 101297 - 101297   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    DOI: 10.1016/j.redox.2019.101297

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  80. 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   78回 巻   頁: E - 1077   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本癌学会  

  81. L-Dehydroascorbic acid recycled by thiols efficiently scavenges non-thermal plasma-induced hydroxyl radicals 査読有り 国際誌

    Okazaki Yasumasa, Tanaka Hiromasa, Hori Masaru, Toyokuni Shinya

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   669 巻   頁: 87 - 95   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2019.05.019

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  82. 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   108 巻 ( 1 ) 頁: 460 - 461   2019年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本病理学会  

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

    Toxicology   415 巻   頁: 26-36   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.tox.2019.01.011

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  84. Non-thermal plasma-activated medium modified metabolomic profiles in the glycolysis of U251SP glioblastoma 国際誌

    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   662 巻   頁: 83 - 92   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2018.12.001

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  85. 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   32 巻 ( 1 ) 頁: 19-26   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1293/tox.2018-0029

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  86. Nonthermal plasma specifically kills oral squamous cell carcinoma cells in a catalytic Fe(II)dependent manner 査読有り 国際誌

    Sato K.

    Journal of Clinical Biochemistry and Nutrition   65 巻 ( 4 ) 頁: 8 - 15   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    DOI: 10.3164/jcbn.18-91

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  87. Iron Metabolism and Ferroptosis 査読有り 国際誌

    Toyokuni Shinya, Yanatori Izumi

    FERROPTOSIS IN HEALTH AND DISEASE     頁: 27 - 41   2019年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Ferroptosis in Health and Disease  

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

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  88. 尿細管障害と糸球体障害に対する新規バイオマーカーとしての血中microRNAの検討

    香川 匠, Tomáš ZÁRYBNICKÝ, 大見 貴尚, 白井 勇司, 豊國 伸哉, 織田 進吾, 横井 毅

    日本毒性学会学術年会   46 巻 ( 0 ) 頁: P - 233   2019年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:日本毒性学会  

    <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

  89. 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   52 巻 ( 11-12 ) 頁: 1424 - 1431   2018年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10715762.2018.1500019

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

    Jiang Li, Akatsuka Shinya, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 830-830   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 830-830   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  92. Ferroptosis in Cancer Research

    Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 195-195   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  93. 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   109 巻   頁: 781-781   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  94. Asbestos exposure as a possible cause of ovarian carcinogenesis

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

    CANCER SCIENCE   109 巻   頁: 255-255   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

    Ohara Yuuki, Enomoto Atsushi, Takahashi Masahide, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 454-454   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  96. Analysis of the involvement of cancer-associated fibroblasts in the progression of malignant mesothelioma 国際誌

    Ohara Yuuki, Enomoto Atsushi, Takahashi Masahide, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 454-454   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  97. Asbestos exposure as a possible cause of ovarian carcinogenesis 国際誌

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

    CANCER SCIENCE   109 巻   頁: 255-255   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  98. Ferroptosis in Cancer Research 国際誌

    Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 195-195   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  99. Critical role of Hippo signaling pathway at the onset of squamous cell carcinomas 国際誌

    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   109 巻   頁: 781-781   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  100. Inflammatory microenvironment derived from asbestos increases mutagenesis to repairing mesothelial cell 国際誌

    Ito Fumiya, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 830-830 - 830   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Web of Science

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

    Jiang Li, Akatsuka Shinya, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 830-830   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

    Ito Fumiya, Hisashi Hideyuki, Toyokuni Shinya

    NAGOYA JOURNAL OF MEDICAL SCIENCE   80 巻 ( 4 ) 頁: 597 - 604   2018年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nagoya Journal of Medical Science  

    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 ~ 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 2B carcinogen to humans, which requires considerable regulations for use. In contrast, tangled MWCNTs of ~ 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.

    DOI: 10.18999/nagjms.80.4.597

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  103. 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     頁: 1-10   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10715762.2018.1514604

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

    Toyokuni S

    Free radical biology & medicine     2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2018.10.401

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  105. 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年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1515/hsz-2018-0199

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  106. 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     頁: 1-51   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10715762.2018.1528501

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  107. 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   77回 巻   頁: 1110 - 1110   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本癌学会  

  108. 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   77回 巻   頁: 118 - 118   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本癌学会  

  109. 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. 国際誌

    Uchida K, Shibata T, Toyokuni S, Daniel B, Zarkovic K, Zarkovic N, Sasson S

    Free radical biology & medicine   124 巻   頁: 12 - 20   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

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

    DOI: 10.1016/j.freeradbiomed.2018.05.079

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  110. Non-thermal plasma as a simple ferroptosis inducer in cancer cells: A possible role of ferritin 国際誌

    Furuta Takahiro, Shi Lei, Toyokuni Shinya

    PATHOLOGY INTERNATIONAL   68 巻 ( 7 ) 頁: 442 - 443   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    DOI: 10.1111/pin.12665

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  111. Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model. 国際誌

    Imai K, Kotani T, Tsuda H, Nakano T, Ushida T, Iwase A, Nagai T, Toyokuni S, Suzumura A, Kikkawa F

    Scientific reports   8 巻 ( 1 ) 頁: 9221   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

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

    DOI: 10.1038/s41598-018-27626-4

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  112. Acute fulminant invasive pulmonary aspergillosis in an immunocompetent host: An autopsy case report. 国際誌

    Ohara Y, Ito T, Ito M, Yamashita K, Toyokuni S

    Medical mycology case reports   20 巻   頁: 39 - 42   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Medical Mycology Case Reports  

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

    DOI: 10.1016/j.mmcr.2018.02.002

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  113. An autopsy case report: Differences in radiological images correlate with histology in Erdheim–Chester disease 国際誌

    Ohara Y., Kato S., Yamashita D., Satou A., Shimoyama Y., Hamaie C., Sato M., Ban N., Yamamoto K., Yamada T., Kawai H., Ohshima K., Nakamura S., Toyokuni S.

    Pathology International   68 巻 ( 6 ) 頁: 374 - 381   2018年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    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 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS-induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio-histological correlation can help further both the understanding and diagnosis of ECD.

    DOI: 10.1111/pin.12663

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  114. 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   29 巻 ( 1 ) 頁: 71 - 71   2018年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本微量元素学会  

  115. Ferroptosis in carcinogenesis and tumor biology 国際誌

    Toyokuni Shinya

    FREE RADICAL BIOLOGY AND MEDICINE   120 巻   頁: S19 - S19   2018年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2018.04.081

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  116. Expression of P-REX2a is associated with poor prognosis in endometrial malignancies. 国際誌

    Takeshita S, Yamashita Y, Shiomi K, Suzuki N, Yoshida J, Naiki-Ito A, Suzuki S, Akatsuka S, Toyokuni S, Takahashi T, Mase S, Arakawa A, Sugiura-Ogasawara M, Takahashi S

    Oncotarget   9 巻 ( 37 ) 頁: 24778 - 24786   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncotarget  

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

    DOI: 10.18632/oncotarget.25349

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

    Akatsuka S, Li GH, Toyokuni S

    Free radical research     頁: 1-5   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/10715762.2018.1467562

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  118. Effect of molecular hydrogen on uterine inflammation during preterm labour. 国際誌

    Nakano T, Kotani T, Imai K, Iitani Y, Ushida T, Tsuda H, Li H, Iwase A, Toyokuni S, Kikkawa F

    Biomedical reports   8 巻 ( 5 ) 頁: 454 - 460   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biomedical Reports  

    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<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<0.05). The protein levels of Cox2 in the LPS group were also significantly increased compared with those in the control (P<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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  119. Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model. 国際誌

    Ohara Y, Chew SH, Misawa N, Wang S, Somiya D, Nakamura K, Kajiyama H, Kikkawa F, Tsuyuki Y, Jiang L, Yamashita K, Sekido Y, Lipson KE, Toyokuni S

    Oncotarget   9 巻 ( 26 ) 頁: 18494 - 18509   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncotarget  

    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.

    DOI: 10.18632/oncotarget.24892

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  120. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. 国際誌

    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   72 巻 ( 5 ) 頁: 729 - 738   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Histopathology  

    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.

    DOI: 10.1111/his.13421

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  121. 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   107 巻 ( 1 ) 頁: 291 - 291   2018年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本病理学会  

  122. Glioblastoma Cell Lines Display Different Sensitivities to Plasma-Activated Medium 国際誌

    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   2 巻 ( 2 ) 頁: 99 - 102   2018年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1109/TRPMS.2017.2721973

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  123. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. 国際誌

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

    Cancer science   109 巻 ( 2 ) 頁: 330 - 339   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

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

    Ohara Yuuki, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 781-781   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  125. 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   109 巻   頁: 167-167   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  126. Molecular mechanisms in oxidative stress-induced carcinogenesis

    Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 163-163   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  127. Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice 国際誌

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

    CANCER SCIENCE   109 巻   頁: 167-167   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  128. Molecular mechanisms in oxidative stress-induced carcinogenesis 国際誌

    Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 163-163   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  129. Phlebotomy attenuates the growth of malignant mesothelioma on rat model 国際誌

    Ohara Yuuki, Toyokuni Shinya

    CANCER SCIENCE   109 巻   頁: 781-781   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  130. Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. 査読有り 国際誌

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

    Cancer Science     2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.13460.

  131. Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. 査読有り

    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   67 巻 ( 11 ) 頁: 564-574   2017年11月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1111/pin.12598.

  132. Role of catalytic iron and oxidative stress in nitrofen-induced congenital diaphragmatic hernia and its amelioration by Saireito (TJ-114). 国際誌

    Hirako S, Tsuda H, Ito F, Okazaki Y, Hirayama T, Nagasawa H, Nakano T, Imai K, Kotani T, Kikkawa F, Toyokuni S

    Journal of clinical biochemistry and nutrition   61 巻 ( 3 ) 頁: 176 - 182   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本酸化ストレス学会  

    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 asso-ciation with nitrofen and Saireito. We observed increased immuno- staining of 8-hydroxy-2'-deoxyguanosine in the lungs of neonates with CDH, which was ameliorated by maternal Saireito intake. Pulmonary transferrin receptor expression was significantly decreased in both CDH and CDH after Saireito in comparison to normal controls, indicating functional lung immaturity, whereas catalytic Fe(ll) and pulmonaiy DMT1/ferroportin expression remained constant among the three groups. Saireito revealed a dose-dependent scavenging capacity with electron spin resonance spin trapping in vitro against hydroxyl radicals but not against superoxide. Finally, nitrofen revealed dose-dependent cytotoxicity to IMR90-SV cells, accompanied by an increase in oxidative stress, as seen by 5(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and catalytic Fe(ll). Saireito ameliorated all of these in IMR90-SV cells. In conclusion, catalytic Fe(ll)-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 nitrof en-induced CDH.

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  133. Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. 国際誌

    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   67 巻 ( 11 ) 頁: 564 - 574   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    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 p16INKA 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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  134. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. 国際誌

    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   171 巻 ( 2 ) 頁: 273 - 285   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell  

    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 Q10. 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. 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 Q10. 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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  135. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. 査読有り

    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年10月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1111/his.13421.

  136. Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. 査読有り 国際誌

    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年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/his.13421.

  137. 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. 査読有り

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

    Journal of Biological Chemistry   292 巻 ( 32 ) 頁: 13205-13229   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

  138. 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. 国際誌

    Yanatori I, Richardson DR, Toyokuni S, Kishi F

    The Journal of biological chemistry   292 巻 ( 32 ) 頁: 13205 - 13229   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Biological Chemistry  

    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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  139. 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. 査読有り 国際誌

    Yanatori I, Richardson DR, Toyokuni S, Kishi F

    Journal of Biological Chemistry   292 巻 ( 32 ) 頁: 13205-13229   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1074/jbc.M117.776021.

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

    Ito Fumiya, Shi Lei, Toyokuni Shinya

    AMERICAN JOURNAL OF HEMATOLOGY   92 巻 ( 8 ) 頁: E365-E365   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  141. IRON OVERLOAD ENHANCED CELL DEATH INDUCED BY CARCINOGENIC FIBROUS MATERIALS 国際誌

    Fumiya Ito, Lei Shi, Shinya Toyokuni

    AMERICAN JOURNAL OF HEMATOLOGY   92 巻 ( 8 ) 頁: E365 - E365   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

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  142. Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells. 査読有り

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

    Scientific Reports   7 巻 ( 1 ) 頁: 6085   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1038/s41598-017-05620-6.

  143. Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells. 国際誌

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

    Scientific reports   7 巻 ( 1 ) 頁: 6085 - 6085   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    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.

    DOI: 10.1038/s41598-017-05620-6

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  144. Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy. 査読有り

    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   108 巻   頁: 904-917   2017年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.freeradbiomed.2017.04.368.

  145. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats. 査読有り

    Okazaki Y, Okada S, Toyokuni S.

    Journal of Clinical Biochemistry and Nutrition   61 巻 ( 1 ) 頁: 18-24   2017年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.3164/jcbn.16-114.

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

    Okazaki Y, Okada S, Toyokuni S

    Journal of clinical biochemistry and nutrition   61 巻 ( 1 ) 頁: 18 - 24   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本酸化ストレス学会  

    Daily intake of vegetables can reduce the risk of cancer and lifestyle-related diseases. However, supplementary intake of p-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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  147. Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy. 国際誌

    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   108 巻   頁: 904 - 917   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    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.

    DOI: 10.1016/j.freeradbiomed.2017.04.368

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  148. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. 国際誌

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

    Free radical biology & medicine   108 巻   頁: 610 - 626   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    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.

    DOI: 10.1016/j.freeradbiomed.2017.04.024

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  149. Astaxanthin ameliorates ferric nitrilotriacetate-induced renal oxidative injury in rats. 査読有り 国際誌

    Okazaki Y, Okada S, Toyokuni S

    Journal of Clinical Biochemistry and Nutrition   61 巻 ( 1 ) 頁: 18-24   2017年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3164/jcbn.16-114.

  150. Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics. 査読有り

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

    Scientific Reports   7 巻 ( 1 ) 頁: 1821   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1038/s41598-017-01951-6.

  151. Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics. 国際誌

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

    Scientific reports   7 巻 ( 1 ) 頁: 1821   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    Estradiol (E2) and the oestrogen receptor-alpha (ERα) 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/ERα signalling modulation in breast cancer cells. Moreover, specific inhibition of the BIG3-PHB2 interaction using the ERα activity-regulator synthetic peptide (ERAP: 165-177 amino acids), derived from α-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 α-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.

    DOI: 10.1038/s41598-017-01951-6

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  152. Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells. 査読有り

    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   19 巻 ( 5 ) 頁: 636-647   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1093/neuonc/now237.

  153. Significance of low mTORC1 activity in defining the characteristics of brain tumor stem cells. 国際誌

    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

    Neuro-oncology   19 巻 ( 5 ) 頁: 636 - 647   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuro-Oncology  

    Background. The signifcance of mammalian target of rapamycin complex 1 (mTORC1) activity in the maintenance of cancer stem cells (CSCs) remains controversial. Previous fndings 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 signifcance of mTORC1 activity in brain tumor stem cells (BTSCs). Methods. 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. Results. 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. Conclusions. Our fndings 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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  154. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. 国際誌

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

    Human pathology   63 巻   頁: 63 - 69   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Pathology  

    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.

    DOI: 10.1016/j.humpath.2017.02.007

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  155. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. 国際誌

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

    Free radical biology & medicine   106 巻   頁: 91 - 99   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    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 exon 9, with CD44v8-10 among the variant isoforms expressed. The expression of CD44 variable exon 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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  156. In response to Sharing different perspectives to understand asbestos-induced carcinogenesis: Acomment to Jiang et al. (2016) by Alessandro Francesco Gualtieri (2017) 国際誌

    Toyokuni Shinya, Jiang Li

    CANCER SCIENCE   108 巻 ( 5 ) 頁: 1089 - 1090   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    DOI: 10.1111/cas.13224

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  157. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor. 査読有り

    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   108 巻 ( 4 ) 頁: 785-794   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1111/cas.13175.

  158. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. 査読有り

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

    Free Radical Biology & Medicine   108 巻   頁: 610-626   2017年4月

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    担当区分:筆頭著者   記述言語:英語  

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

  159. Iron and thiol redox signaling in cancer: An exquisite balance to escape ferroptosis. 査読有り 国際誌

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

    Free Radical Biology & Medicine   108 巻   頁: 610-626   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2017.04.024.

  160. Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor. 国際誌

    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   108 巻 ( 4 ) 頁: 785 - 794   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    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.

    DOI: 10.1111/cas.13175

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  161. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. 査読有り

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

    Human Pathology   63 巻   頁: 63-69   2017年2月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.humpath.2017.02.007.

  162. Primary extraskeletal osteosarcoma: a clinicopathological study of 18 cases focusing on MDM2 amplification status. 査読有り 国際誌

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

    Human Pathology   63 巻   頁: 63-69   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.humpath.2017.02.007.

  163. 今月の特集2 微量金属元素と生体機能-メタロミクス研究から臨床検査へ がんと微量金属元素

    伊藤 文哉, 豊國 伸哉

    臨床検査   61 巻 ( 2 ) 頁: 168 - 173   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:株式会社医学書院  

    DOI: 10.11477/mf.1542201106

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  164. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. 査読有り

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

    Free Radical Biology & Medicine   106 巻   頁: 91-99   2017年2月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

  165. Rheostatic CD44 isoform expression and its association with oxidative stress in human malignant mesothelioma. 査読有り 国際誌

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

    Free Radical Biology & Medicine   106 巻   頁: 91-99   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2017.02.011.

  166. 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   30 巻   頁: 27A-27A   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  167. 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   97 巻   頁: 27A-27A   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

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

    LABORATORY INVESTIGATION   97 巻   頁: 27A - 27A   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

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

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

    MODERN PATHOLOGY   30 巻   頁: 27A - 27A   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

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

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

    Journal of clinical biochemistry and nutrition   60 巻 ( 1 ) 頁: 33 - 38   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    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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  171. 発がんの根源的原因:毒性学にできること

    豊國 伸哉

    日本毒性学会学術年会   44 巻 ( 0 ) 頁: S11 - S11   2017年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本毒性学会  

    地球の生命体において鉄は必須であり、高等生物の生命は鉄・酸素・食物によって紡がれる。細胞内で電子の流れを作り制御された化学反応を行うのが酸素の主な役割であるが、体内に取り込まれた酸素の数%は活性酸素・フリーラジカルとなり生体分子に切断・修飾・重合などの傷害を与える。この反応は2価鉄触媒によるFenton反応として1894年より認識されていた。当初放射線の生物作用として理解されたが、1968年SOD発見により活性酸素・フリーラジカルの化学反応が細胞内で常時発生していることが認識されるようになった。発がんは1980年代に始まるがん遺伝子・がん抑制遺伝子の概念の確立により、論理的に理解されるようになった。発がん要因分類として、環境因子・習慣・職業曝露・食習慣・感染症・慢性炎症・遺伝的要因などが列挙され、それを防ぐような手立てが取られてきた。しかし日本では1981年以降、がんが死因の第1位であり右上りである。2014年には英国男性で初めてがんが死因の第1位になった。死因としてのがんの独走は今のがん予防法に大きな疑問を投げかける。私はこれまでの研究より、がんの独走を私たちが酸素と鉄を使用する宿命と理解したい。Wild typeのラットにFenton反応を起こすことでヒトのがんのゲノム変化と酷似したがんが発生することはこの仮説を強く支持する。アスベストや多層カーボンナノチューブによる発がんも異物発がんで基本的には過剰鉄を介するものであり、ラットとヒトで極めて類似したゲノム変化が見られることも注目に値する。これまでの観察により、これらの動物発がんは1ヶ月程度までの初期変化と正比例関係にあることは、毒性学にとって極めて重要であると考えたい。鉄の制御こそが今、がん制御に重要であると考えられる。鉄は一旦、血液内に入ると、体外への積極的な排泄経路はない。50才を過ぎると基礎代謝も低下し、女性は閉経を迎え、鉄が余分になる。私が年2回の全血献血を推奨する所以である。

    DOI: 10.14869/toxpt.44.1.0_SL5

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  172. 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   61 巻   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  173. Future perspective of strategic non-thermal plasma therapy for cancer treatment. 査読有り

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

    Journal of Clinical Biochemistry and Nutrition   60 巻 ( 1 ) 頁: 33-38   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.3164/jcbn.16-65.

  174. Future perspective of strategic non-thermal plasma therapy for cancer treatment. 査読有り 国際誌

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

    Journal of Clinical Biochemistry and Nutrition   60 巻 ( 1 ) 頁: 33-38   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3164/jcbn.16-65.

  175. Editorial: The cutting edge of zinc biology 国際誌

    Kambe Taiho, Fukada Toshiyuki, Toyokuni Shinya

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   611 巻   頁: 1 - 2   2016年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2016.09.006

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  176. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. 国際誌

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

    Biochimica et biophysica acta   1866 巻 ( 2 ) 頁: 339 - 349   2016年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochimica et Biophysica Acta - Reviews on Cancer  

    DOI: 10.1016/j.bbcan.2016.07.004

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  177. Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model 国際誌

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

    FREE RADICAL BIOLOGY AND MEDICINE   101 巻 ( 16 ) 頁: 524 - 533   2016年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2016.10.491

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  178. Chemical reaction mechanism in non-thermal plasma from the viewpoint of oxidative stress toward clinical cancer applications

    Toyokuni Shinya, Shi Lei, Okazaki Yasumasa, Richardson Des R.

    FREE RADICAL BIOLOGY AND MEDICINE   100 巻   頁: S131 - S131   2016年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2016.10.344

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

    Ohara Yuuki, Wang Shenqi, Jiang Li, Toyokuni Shinya

    FREE RADICAL BIOLOGY AND MEDICINE   100 巻   頁: S127 - S127   2016年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2016.10.332

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  180. Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma. 査読有り 国際誌

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

    Oncotarget   7 巻 ( 43 ) 頁: 69565 - 69578   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncotarget  

    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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  181. Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. 査読有り

    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.   pii: S0891-5849 巻 ( 16 ) 頁: 30978-9.   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.freeradbiomed.2016.10.491.

  182. Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model. 査読有り 国際誌

    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.   pii: S0891-5849 巻 ( 16 ) 頁: 30978-9.   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2016.10.491.

  183. Non-thermal plasma prevents progression of endometriosis in mice. 査読有り

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

    Free Radical Research   50 巻 ( 10 ) 頁: 1131-1139   2016年10月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  184. Non-thermal plasma prevents progression of endometriosis in mice. 国際誌

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

    Free radical research   50 巻 ( 10 ) 頁: 1131 - 1139   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    Endometriosis is observed in ∼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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  185. Special issue for the 7th Biennial Meeting of Society for Free Radical Research-Asia (SFRR-Asia 2015 Thailand) 国際誌

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

    FREE RADICAL RESEARCH   50 巻 ( 10 ) 頁: 1045 - 1046   2016年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    DOI: 10.1080/10715762.2016.1245859

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  186. Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. 査読有り 国際誌

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

    Toxicology letters   258 巻   頁: 249 - 258   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Toxicology Letters  

    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 50 mg/kg body weight BID (100 mg/kg BW/day) for 3 days, 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 1200 ppm 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(+)/1200 ppm 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.

    DOI: 10.1016/j.toxlet.2016.07.006

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  187. Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells. 国際誌

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

    Archives of biochemistry and biophysics   605 巻   頁: 109 - 16   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    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 μM) 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 μM). 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.

    DOI: 10.1016/j.abb.2016.05.016

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  188. Low-temperature plasma in biology and medicine 査読有り 国際誌

    Hori M.

    Archives of Biochemistry and Biophysics   605 巻   頁: 1 - 2   2016年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2016.06.014

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  189. Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. 査読有り

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

    Phytother Res.   30 巻 ( 9 ) 頁: 1474-80   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1002/ptr.5645.

  190. Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma. 査読有り

    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.     頁: 11829   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.18632/oncotarget.11829.

  191. Preliminary characterization of a murine model for 1-bromopropane neurotoxicity: Role of cytochrome P450. 査読有り

    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.   258 巻   頁: 249-58   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

  192. Biphasic effects of l-ascorbate on the tumoricidal activity of non-thermal plasma against malignant mesothelioma cells. 査読有り

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

    Arch Biochem Biophys.   605 巻   頁: 106-16   2016年9月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

  193. Antenatal Saireito (TJ-114) Can Improve Pulmonary Hypoplasia and Pulmonary Vascular Remodeling in Nitrofen-Induced Congenital Diaphragmatic Hernia. 査読有り 国際誌

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

    Phytotherapy research : PTR   30 巻 ( 9 ) 頁: 1474 - 80   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Phytotherapy Research  

    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 < 0.01), increased lung volume (p < 0.01), improved alveolarization and pulmonary artery remodeling using histological analysis, and improved respiratory function using gasometric analysis (pH; p < 0.05, and PCO2; p < 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 © 2016 John Wiley & Sons, Ltd.

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  194. Molecular hydrogen suppresses activated Wnt/beta-catenin signaling 査読有り 国際誌

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

    SCIENTIFIC REPORTS   6 巻 ( 6 ) 頁: 31986   2016年8月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    DOI: 10.1038/srep31986

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  195. Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. 査読有り 国際誌

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

    Biochemical and biophysical research communications   476 巻 ( 4 ) 頁: 600 - 606   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochemical and Biophysical Research Communications  

    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.

    DOI: 10.1016/j.bbrc.2016.06.003

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  196. Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis. 査読有り

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

    Biochem Biophys Res Commun.   476 巻 ( 4 ) 頁: 600-6   2016年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

  197. Molecular hydrogen suppresses activated Wnt/β-catenin signaling. 査読有り

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

    Sci Rep.   25 巻 ( 6 ) 頁: 31986   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1038/srep31986.

  198. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. 査読有り

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

    Biochim Biophys Acta. 2016 Jul 22.   pii: S0304-419X 巻 ( 16 ) 頁: 30049-X.   2016年7月

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    記述言語:英語  

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

  199. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis 査読有り 国際誌

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

    CANCER SCIENCE   107 巻 ( 7 ) 頁: 908 - 915   2016年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    DOI: 10.1111/cas.12947

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  200. Possible therapeutic option of aqueous plasma for refractory ovarian cancer 査読有り 国際誌

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

    CLINICAL PLASMA MEDICINE   4 巻 ( 1 ) 頁: 14 - 18   2016年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Clinical Plasma Medicine  

    DOI: 10.1016/j.cpme.2015.12.002

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  201. The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. 査読有り 国際誌

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

    Biochim Biophys Acta. 2016 Jul 22.   pii: S0304-419X 巻 ( 16 ) 頁: 30049-X.   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbcan.2016.07.004.

  202. [Iron function and carcinogenesis].

    Akatsuka S, Toyokuni S

    Nihon rinsho. Japanese journal of clinical medicine   74 巻 ( 7 ) 頁: 1168 - 75   2016年7月

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    掲載種別:研究論文(学術雑誌)  

    PubMed

  203. [Iron function and carcinogenesis].

    Akatsuka S, Toyokuni S

    Nihon rinsho. Japanese journal of clinical medicine   74 巻 ( 7 ) 頁: 1168 - 75   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  204. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium. 査読有り

      35 巻 ( 6 ) 頁: 3169-77   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.3892/or.2016.4726.

  205. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis. 査読有り

    Jiang L, Chew SH, Nakamura K, Ohara Y, Akatsuka S, Toyokuni S.

    Cancer Sci. 2016 Jul;107(7):908-15.   107 巻 ( 7 ) 頁: 908-15   2016年6月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1111/cas.12947.

  206. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis. 査読有り 国際誌

    Jiang L, Chew SH, Nakamura K, Ohara Y, Akatsuka S, Toyokuni S

    Cancer Sci. 2016 Jul;107(7):908-15.   107 巻 ( 7 ) 頁: 908-15   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.12947.

  207. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium 国際誌

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

    ONCOLOGY REPORTS   35 巻 ( 6 ) 頁: 3169 - 3177   2016年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncology Reports  

    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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  208. 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 査読有り 国際誌

    Toyokuni S.

    Pathology International   66 巻 ( 5 ) 頁: 245 - 259   2016年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    DOI: 10.1111/pin.12396

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  209. 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. 招待有り 査読有り 国際誌

    Toyokuni S

    Pathol Int.   66 巻 ( 5 ) 頁: 245-259   2016年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/pin.12396.

  210. Oxidative stress as an iceberg in carcinogenesis and cancer biology 査読有り 国際誌

    Toyokuni Shinya

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   595 巻   頁: 46 - 49   2016年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2015.11.025

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  211. Oxidative stress as an iceberg in carcinogenesis and cancer biology. 査読有り

    Toyokuni S.

    Arch Biochem Biophys. 2016 Apr 1;595:46-9.   595 巻   頁: 46-9   2016年4月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.abb.2015.11.025.

  212. Oxidative stress as an iceberg in carcinogenesis and cancer biology. 査読有り 国際誌

    Toyokuni S

    Arch Biochem Biophys. 2016 Apr 1;595:46-9.   595 巻   頁: 46-9   2016年4月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.abb.2015.11.025.

  213. Tribute issue: Helmut Sies and oxidative stress: Venit, vidit, vicit 査読有り 国際誌

    Forman H.

    Archives of Biochemistry and Biophysics   595 巻   2016年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Archives of Biochemistry and Biophysics  

    DOI: 10.1016/j.abb.2015.11.020

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  214. 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.   1863 巻 ( 4 ) 頁: 727-748   2016年4月

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    記述言語:英語  

    DOI: doi: 10.1016/j.bbamcr.2016.01.026.

  215. Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics. 国際誌

    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

    Biochimica et biophysica acta   1863 巻 ( 4 ) 頁: 727 - 48   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochimica et Biophysica Acta - Molecular Cell Research  

    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.

    DOI: 10.1016/j.bbamcr.2016.01.026

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  216. Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. 査読有り

    Wang Y, Okazaki Y, Shi L, Kohda H, Tanaka M, Taki K, Nishioka T, Hirayama T, Nagasawa H, Yamashita Y, Toyokuni S.

    Cancer Sci.   107 巻 ( 3 ) 頁: 250-257   2016年3月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1111/cas.12865.

  217. Pain-reducing anesthesia prevents oxidative stress in human term placenta. 査読有り

    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.   58 巻 ( 2 ) 頁: 156-60   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.3164/jcbn.15-138.

  218. Pain-reducing anesthesia prevents oxidative stress in human term placenta. 国際誌

    Tsuzuki Y, Yamashita Y, Hattori Y, Hua Li G, Akatsuka S, Kotani T, Kikkawa F, Naiki-Ito A, Takahashi S, Nishiwaki K, Toyokuni S

    Journal of clinical biochemistry and nutrition   58 巻 ( 2 ) 頁: 156 - 60   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本酸化ストレス学会  

    Anesthesia is sometimes used for the reduction of maternal pain in normal human term labor, but whether the drugs affect oxidative stress remains unclear. The placenta serves as an interface between the maternal and fetal vasculature. In this study, we immunohistochemically analyzed two markers for oxidative stress, namely 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-modified proteins (HNE), using placentas from 21 cases of normal tansvaginal delivery (V group), 20 Caesarean sections (C group), and 17 normal transvaginal deliveries with epidural anesthesia (E group). 8-OHdG staining in the nuclei of trophoblasts lining the chorionic villi was significantly stronger in the V group either compared with the C or E group (p<0.001), without significant differences in the C and E groups (p = 0.792). Moderate to intense staining by HNE of the intravascular serum of chorionic villi vasculature was frequently observed in the placentas from the V group, but less frequently of those in either C or E groups (p<0.001), nor the p value comparing the C and E groups was significant (p = 0.128) for HNE staining. Our results suggest that although the role of oxidative stress and its influences on fetal state in the placenta in labor remains unclear, it seems to be lessened by epidural anesthesia.

    DOI: 10.3164/jcbn.15-138

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  219. Role of hemoglobin and transferrin in multi-wall carbon nanotube-induced mesothelial injury and carcinogenesis. 査読有り 国際誌

    Wang Y, Okazaki Y, Shi L, Kohda H, Tanaka M, Taki K, Nishioka T, Hirayama T, Nagasawa H, Yamashita Y, Toyokuni S

    Cancer science   107 巻 ( 3 ) 頁: 250 - 7   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    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 >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.

    DOI: 10.1111/cas.12865

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  220. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. 査読有り

    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.   91 巻   頁: 154-163   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.freeradbiomed.2015.12.015.

  221. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. 国際誌

    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 radical biology & medicine   91 巻   頁: 154 - 63   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    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 (H2), 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. H2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H2 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 H2, involved in the process of activating microglia. These results suggested that H2 holds promise for the prevention of inflammation related to perinatal brain injury.

    DOI: 10.1016/j.freeradbiomed.2015.12.015

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  222. Plasma with high electron density and plasma-activated medium for cancer treatment 査読有り 国際誌

    Tanaka H., Mizuno M., Ishikawa K., Kondo H., Takeda K., Hashizume H., Nakamura K., Utsumi F., Kajiyama H., Kano H., Okazaki Y., Toyokuni S., Akiyama S., Maruyama S., Yamada S., Kodera Y., Kaneko H., Terasaki H., Hara H., Adachi T., Iida M., Yajima I., Kato M., Kikkawa F., Hori M.

    Clinical Plasma Medicine   3 巻 ( 2 ) 頁: 72 - 76   2015年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Clinical Plasma Medicine  

    Cancer treatment using non-thermal atmospheric pressure plasma is a brand new and challenging approach for cancer therapy. Conventional cancer therapies are surgery, radio-therapy, and chemo-therapy. We propose plasma-therapy as the fourth cancer therapy. Plasma cancer therapy involves direct plasma treatment of cancers including melanomas, head and neck cancer, pancreatic cancer and liver metastasis, and indirect plasma treatment of cancers by using plasma irradiated solutions such as plasma-activated medium (PAM).We have been recently studying plasma cancer therapy using target cancers such as ovarian cancers, brain tumors, gastric cancers and skin cancers. We have developed a plasma source with ultrahigh electron density, which we have applied to these cancer cells. In addition, we found that plasma-irradiated medium itself can kill these cancer cells. This medium was termed plasma-activated medium (PAM). In vitro and in vivo studies have suggested that PAM is an important tool for cancer therapy especially for disseminated cancers that are currently untreatable.Although many dramatic therapeutic effects of plasma therapy on cancer cells have been reported, the molecular mechanisms of the anti-tumor effects of plasma remain to be elucidated. The greatest challenge for plasma medical science is to understand the complex system that mediates plasma inputs resulting in physiological outputs such as cell death of cancer cells and proliferation of normal cells. Intracellular molecular mechanisms of PAM are also being intensively studied in order to understand the mode of action of PAM. In this review, we summarize the latest understanding of plasma cancer treatments.

    DOI: 10.1016/j.cpme.2015.09.001

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  223. Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. 査読有り

    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.   6 巻   頁: 578-586   2015年12月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.redox.2015.10.001.

  224. Cancer therapy using non-thermal atmospheric pressure plasma with ultra-high electron density 国際誌

    Tanaka Hiromasa, Mizuno Masaaki, Toyokuni Shinya, Maruyama Shoichi, Kodera Yasuhiro, Terasaki Hiroko, Adachi Tetsuo, Kato Masashi, Kikkawa Fumitaka, Hori Masaru

    PHYSICS OF PLASMAS   22 巻 ( 12 ) 頁: 122004   2015年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Physics of Plasmas  

    Cancer therapy using non-thermal atmospheric pressure plasma is a big challenge in plasma medicine. Reactive species generated from plasma are key factors for treating cancer cells, and thus, non-thermal atmospheric pressure plasma with high electron density has been developed and applied for cancer treatment. Various cancer cell lines have been treated with plasma, and non-thermal atmospheric plasma clearly has anti-tumor effects. Recent innovative studies suggest that plasma can both directly and indirectly affect cells and tissues, and this observation has widened the range of applications. Thus, cancer therapy using non-thermal atmospheric pressure plasma is promising. Animal experiments and understanding the mode of action are essential for clinical application in the future. A new academic field that combines plasma science, the biology of free radicals, and systems biology will be established.

    DOI: 10.1063/1.4933402

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  225. Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. 国際誌

    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 biology   6 巻   頁: 578 - 586   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Biology  

    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.

    DOI: 10.1016/j.redox.2015.10.001

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  226. プラズマ活性溶液の細胞影響 (小特集 プラズマが誘導する生体応答とそのバイオ・医療応用)

    田中 宏昌, 水野 正明, 豊國 伸哉, 丸山 彰一, 小寺 泰弘, 足立 哲夫, 寺崎 浩子, 加藤 昌志, 吉川 史隆, 堀 勝

    プラズマ・核融合学会誌   91 巻 ( 12 ) 頁: 776 - 779   2015年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:プラズマ・核融合学会  

    近年,非平衡大気圧プラズマの医療・バイオ応用が盛んに研究されている.プラズマに含まれる電子,イオン,ラジカル,光など様々な要因が複雑に細胞及び細胞を取り巻く環境に影響を及ぼし,細胞応答を引き起こしていると考えられている.最近,プラズマ照射された溶液(これはプラズマ活性溶液と名付けられた)ががん細胞にプログラム細胞死として知られるアポトーシスを誘導することがわかり,プラズマ活性溶液が細胞に及ぼす影響が活発に研究されている.脳腫瘍培養細胞においてはプラズマ活性溶液が生存・増殖シグナル伝達経路を抑制することによりアポトーシスへと導くことが明らかになった.これまでに,プラズマ活性溶液は脳腫瘍,卵巣がん,胃がん,非小肺がん細胞など様々ながん細胞に有効であり,抗癌剤耐性卵巣がん細胞に関しても有効であることがわかり,従来のがん治療法では困難な腹膜播種等の播種性のがん治療への応用が期待される.ここではこれまで研究で明らかになりつつあるプラズマ活性溶液の細胞影響とその分子機構について紹介する.

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  227. プラズマ活性溶液の細胞影響 (小特集 プラズマが誘導する生体応答とそのバイオ・医療応用)

    田中 宏昌, 水野 正明, 豊國 伸哉, 丸山 彰一, 小寺 泰弘, 足立 哲夫, 寺崎 浩子, 加藤 昌志, 吉川 史隆, 堀 勝

    プラズマ・核融合学会誌   91 巻 ( 12 ) 頁: 776 - 779   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:プラズマ・核融合学会  

    近年,非平衡大気圧プラズマの医療・バイオ応用が盛んに研究されている.プラズマに含まれる電子,イオン,ラジカル,光など様々な要因が複雑に細胞及び細胞を取り巻く環境に影響を及ぼし,細胞応答を引き起こしていると考えられている.最近,プラズマ照射された溶液(これはプラズマ活性溶液と名付けられた)ががん細胞にプログラム細胞死として知られるアポトーシスを誘導することがわかり,プラズマ活性溶液が細胞に及ぼす影響が活発に研究されている.脳腫瘍培養細胞においてはプラズマ活性溶液が生存・増殖シグナル伝達経路を抑制することによりアポトーシスへと導くことが明らかになった.これまでに,プラズマ活性溶液は脳腫瘍,卵巣がん,胃がん,非小肺がん細胞など様々ながん細胞に有効であり,抗癌剤耐性卵巣がん細胞に関しても有効であることがわかり,従来のがん治療法では困難な腹膜播種等の播種性のがん治療への応用が期待される.ここではこれまで研究で明らかになりつつあるプラズマ活性溶液の細胞影響とその分子機構について紹介する.

  228. Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury 査読有り 国際誌

    Nakano Tomoko, Kotani Tomomi, Mano Yukio, Tsuda Hiroyuki, Imai Kenji, Ushida Takafumi, Li Hua, Miki Rika, Sumigama Seiji, Sato Yoshiaki, Iwase Akira, Hirakawa Akihiro, Asai Masato, Toyokuni Shinya, Kikkawa Fumitaka

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   57 巻 ( 3 ) 頁: 178 - 182   2015年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    DOI: 10.3164/jcbn.15-90

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  229. Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury. 査読有り

    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.   57 巻 ( 3 ) 頁: 178-182   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.3164/jcbn.15-90.

  230. 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   57 巻 ( 6 ) 頁: 548 - 554   2015年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  231. Hepatic distribution of GST cannot explain the gap between humans and rodents for induction of cholangiocarcioma following exposure to dichloropropane

    Zhang L., Zong C., Ichihara S., Naito H., Toyokuni S., Kumagai S., Ichihara G.

    TOXICOLOGY LETTERS   238 巻 ( 2 ) 頁: S245 - S245   2015年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.toxlet.2015.08.721

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  232. Malignant mesothelioma as an oxidative stress-induced cancer: An update. 査読有り 国際誌

    Chew SH, Toyokuni S

    Free radical biology & medicine   86 巻   頁: 166 - 78   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    Abstract 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-β pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP1 as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still ~8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by β-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.

    DOI: 10.1016/j.freeradbiomed.2015.05.002

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  233. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury 国際誌

    Hattori Y., Kotani T., Tsuda H., Mano Y., Tu L., Li H., Hirako S., Ushida T., Imai K., Nakano T., Sato Y., Miki R., Sumigama S., Iwase A., Toyokuni S., Kikkawa F.

    Free Radical Research   49 巻 ( 8 ) 頁: 1026 - 1037   2015年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    Maternal inflammation is associated with spontaneous preterm birth and respiratory impairment among premature infants. Recently, molecular hydrogen (H2) has been reported to have a suppressive effect on oxidative stress and inflammation. The aim of this study was to evaluate the effects of H2 on fetal lung injury caused by maternal inflammation. 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 H2-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 H2 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 H2 intake. Antenatal H2 administration may decrease the pulmonary mobility associated with inflammation in premature infants.

    DOI: 10.3109/10715762.2015.1038257

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  234. Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin. 国際誌

    Toyokuni S, Jiang L, Wang S, Hirao A, Wada T, Soh C, Toyama K, Kawada A

    Pathology international   65 巻 ( 8 ) 頁: 415 - 9   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    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.

    DOI: 10.1111/pin.12320

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  235. Receptor role of the annexin A2 in the mesothelial endocytosis of crocidolite fibers 査読有り 国際誌

    Yamashita Kyoko, Nagai Hirotaka, Toyokuni Shinya

    LABORATORY INVESTIGATION   95 巻 ( 7 ) 頁: 749 - 764   2015年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Laboratory Investigation  

    DOI: 10.1038/labinvest.2015.28

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  236. Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials

    Toyokuni Shinya

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   56 巻 ( 3 ) 頁: 165 - 165   2015年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    DOI: 10.3164/jcbn.56-3-editorial

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  237. [Plasma-Activated Solution: Mechanism of Action, Clinical Application, and Industrialization].

    Tanaka H, Mizuno M, Toyokuni S, Maruyama S, Kodera Y, Kikkawa F, Hori M

    Fukuoka igaku zasshi = Hukuoka acta medica   106 巻 ( 4 ) 頁: 71 - 6   2015年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  238. Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells. 国際誌

    Funahashi S, Okazaki Y, Ito D, Asakawa A, Nagai H, Tajima M, Toyokuni S

    Journal of clinical biochemistry and nutrition   56 巻 ( 2 ) 頁: 111 - 7   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    Asbestos exposure is considered a social burden bycausing meso-thelioma. 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-dlpyridazine-1,4-(2H,3H) dione) to detect reactive oxygen species (ROS). Rat peripheral blood or RAW264.7 cells were used to assess the effects on neutro-phils 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 oxida-tive responses in inflammatory cells, indicating the importance of mesothelial cell evaluation for carcinogenesis.

    DOI: 10.3164/jcbn.14-92

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  239. 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   104 巻 ( 1 ) 頁: 336 - 336   2015年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本病理学会  

  240. Possible involvement of iron-induced oxidative insults in neurodegeneration. 国際誌

    Asano T, Koike M, Sakata S, Takeda Y, Nakagawa T, Hatano T, Ohashi S, Funayama M, Yoshimi K, Asanuma M, Toyokuni S, Mochizuki H, Uchiyama Y, Hattori N, Iwai K

    Neuroscience letters   588 巻 ( 1 ) 頁: 29 - 35   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Neuroscience Letters  

    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.

    DOI: 10.1016/j.neulet.2014.12.052

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  241. MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES 査読有り 国際誌

    Shinya Toyokuni, Li Jiang, Ryo Kitaura, Hisanori Shinohara

    NAGOYA JOURNAL OF MEDICAL SCIENCE   77 巻 ( 1-2 ) 頁: 195 - 202   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NAGOYA UNIV, SCH MED  

    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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  242. Minimal inflammogenicity of pristine single-wall carbon nanotubes.

    Toyokuni S, Jiang LI, Kitaura R, Shinohara H

    Nagoya journal of medical science   77 巻 ( 1-2 ) 頁: 195 - 202   2015年2月

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    掲載種別:研究論文(学術雑誌)  

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  243. Minimal inflammogenicity of pristine single-wall carbon nanotubes.

    Toyokuni S, Jiang LI, Kitaura R, Shinohara H

    Nagoya journal of medical science   77 巻 ( 1-2 ) 頁: 195 - 202   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  244. MINIMAL INFLAMMOGENICITY OF PRISTINE SINGLE-WALL CARBON NANOTUBES

    Toyokuni Shinya, Jiang Li, Kitaura Ryo, Shinohara Hisanori

    NAGOYA JOURNAL OF MEDICAL SCIENCE   77 巻 ( 1-2 ) 頁: 195 - 202   2015年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  245. Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders. 査読有り

    Hattori Y, Mukaide T, Jiang L, Kotani T, Tsuda H, Mano Y, Sumigama S, Hirayama T, Nagasawa H, Kikkawa F, Toyokuni S

    Journal of clinical biochemistry and nutrition   56 巻 ( 1 ) 頁: 57 - 63   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    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 oxi-dative 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.

    DOI: 10.3164/jcbn.14-82

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  246. Napsin A is a specific marker for ovarian clear cell adenocarcinoma. 国際誌

    Yamashita Y, Nagasaka T, Naiki-Ito A, Sato S, Suzuki S, Toyokuni S, Ito M, Takahashi S

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   28 巻 ( 1 ) 頁: 111 - 7   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Modern Pathology  

    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.

    DOI: 10.1038/modpathol.2014.61

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  247. Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials. 招待有り

    Toyokuni S.

    J Clin Biochem Nutr   56 巻   頁: 165   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  248. Application of intermittent microwave irradiation to western blot analysis. 査読有り

    Liu YT, Toyokuni S.

    Methods Mol Biol   1314 巻   頁: 185-190   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  249. Aging rather than sun exposure is a major determining factor for the density of miR-125b-positive epidermal stem cells in human skin. 査読有り

    Toyokuni S, Jiang L, Wang S, Hirao A, Wada T, Soh C, Tohyama K and Kawada A.

    Pathol Int   65 巻   頁: 415-419   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  250. Malignant mesothelioma as an oxidative stress-induced cancer: An update. 査読有り

    Chew SH and Toyokuni S.

    Free Radic Biol Med   86 巻   頁: 166-178   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  251. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury. 査読有り

    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   49 巻   頁: 1026-1037   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  252. Possible involvement of iron-induced oxidative insults in neurodegeneration. 査読有り

    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   588 巻   頁: 29-35   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  253. Receptor role of annexin A2 in the mesothelial endocytosis of crocidolite fibers. 査読有り

    Yamashita K, Nagai H and Toyokuni S.

    Lab Invest   95 巻   頁: 749-764   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  254. Minimal inflammogenicity of pristine single-wall carbon nanotubes. 査読有り

    Toyokuni S, Jiang L, Kitaura R and Shinohara S.

    Nagoya J Med Sci   77 巻   頁: 195-202   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  255. Asbestos and multi-walled carbon nanotubes generate distinct oxidative responses in inflammatory cells. 査読有り

    Funahashi F, Okazaki Y, Ito D, Asakawa A, Nagai H, Tajima M and Toyokuni S.

    J Clin Biochem Nutr 56: 111-117, 2015.   56 巻   頁: 111-117   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  256. Catalytic ferrous iron in amniotic fluid as a predictive marker of human maternal-fetal disorders. 査読有り

    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.   56 巻   頁: 57-63   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  257. Napsin A is a specific marker for ovarian clear cell adenocarcinoma. 査読有り

    Yamashita Y, Nagasaka T, Naiki-Ito A, Sato S, Suzuki S, Toyokuni S, Ito M and Takahashi S.

    Mod Pathol   28 巻   頁: 111-117   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  258. A trial to find appropriate animal models of dichloropropane-induced cholangiocarcinoma based on the hepatic distribution of glutathione S-transferases. 査読有り

    Zhang L, Zong C, Ichihara S, Naito H, Toyokuni S, Kumagai S, Ichihara G.

    J Occup Health.   57 巻 ( 6 ) 頁: 548-554   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1539/joh.15-0085-OA.

  259. A trial to find appropriate animal models of dichloropropane‐induced cholangiocarcinoma based on the hepatic distribution of glutathione S‐transferases 国際誌

    Zhang L, Zong C, Ichihara S, Naito H, Toyokuni S, Kumagai S, Ichihara G

    journal of Occupational Health   57 巻 ( 6 ) 頁: 548 - 554   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:公益社団法人 日本産業衛生学会  

    Determinants of workplace violence against clinical physicians in hospitals: Jeng-Cheng WU, et al. Department of Urology, Taipei Medical University Hospital, Taiwan-Objectives: Workplace violence in the health sector is a worldwide concern. Physicians play an essential role in health-care teamwork; thus, understanding how organizational factors influence workplace violence against physicians is critical. Methods: A total of 189 physicians from three public hospitals and one private hospital in Northern Taiwan completed a survey, and the response rate was 47.1%. This study was approved by the institutional review board of each participating hospital. The 189 physicians were selected from the Taipei area, Taiwan. Results: The results showed that 41.5% of the respondents had received at least one workplace-related physical or verbal violent threat, and that 9.8% of the respondents had experienced at least one episode of sexual harassment in the 3 months before the survey. Logistic regression analysis revealed that physicians in psychiatry or emergency medicine departments received more violent threats and sexual harassment than physicians in other departments. Furthermore, physicians with a lower workplace safety climate (OR=0.89; 95% CI=0.81-0.98) and more job demands (OR=1.15; 95% CI=1.02-1.30) were more likely to receive violent threats. Conclusions: This study found that workplace violence was associated with job demands and the workplace safety climate. Therefore, determining how to develop a workplace safety climate and ensure a safe job environment for physicians is a crucial management policy issue for health-care systems.

    DOI: 10.1539/joh.15-0085-oa

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  260. Application of intermittent microwave irradiation to western blot analysis. 査読有り 国際誌

    Liu YT, Toyokuni S

    Methods Mol Biol   1314 巻   頁: 185-190   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  261. Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials. 招待有り 国際誌

    Toyokuni S

    J Clin Biochem Nutr   56 巻   頁: 165   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  262. Minimal inflammogenicity of pristine single-wall carbon nanotubes 国際誌

    Toyokuni S., Jiang L., Kitaura R., Shinohara H.

    Nagoya Journal of Medical Science   77 巻 ( 1-2 ) 頁: 195 - 202   2015年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nagoya Journal of Medical Science  

    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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  263. Application of Intermittent Microwave Irradiation to Western Blot Analysis 国際誌

    Liu Yu-Ting, Toyokuni Shinya

    DETECTION OF BLOTTED PROTEINS: METHODS AND PROTOCOLS   1314 巻   頁: 185 - 190   2015年

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    担当区分:筆頭著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/978-1-4939-2718-0_20

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  264. Receptor role of annexin A2 in the mesothelial endocytosis of crocidolite fibers. 査読有り

    Yamashita K, Nagai H, Toyokuni S

    Lab Invest   95 巻   頁: 749-764   2015年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  265. グルタチオンS-トランスフェラーゼの肝臓内における分布は、 1,2-ジクロロプロパン曝露による胆管癌誘導作用におけるヒトとげっ歯類の違いを説明できない

    Lingyi ZHANG, Cai ZONG, 市原 佐保子, 内藤 久雄, 豊國 伸哉, 熊谷 信二, 市原 学

    日本毒性学会学術年会   42 巻 ( 0 ) 頁: P - 165   2015年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本毒性学会  

    <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.

    DOI: 10.14869/toxpt.42.1.0_P-165

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  266. アスベストによる中皮腫発がん機構の解明とナノマテリアルのリスク評価

    豊國 伸哉

    日本毒性学会学術年会   42 巻 ( 0 ) 頁: S4 - 2   2015年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本毒性学会  

    現在、日本人死因の第1位はがんである。産業・経済の発展を重視するあまり、リスク評価が十分になされないまま、ナノマテリアルが社会に多量に持ち込まれ、がんの原因となったことを忘れてはならない。それがアスベストであり、白石綿・青石綿・茶石綿が世界中で多量に使用された。日本では2006年に全面禁止となったが、アジア諸国を中心に現在も産生・使用されている。日本の中皮腫発生ピークは2025年と予想されており、今後10万人以上が中皮腫で死亡すると試算され、現在発生数が増加している。ラットで上記3種のアスベストの腹腔内10mg投与により中皮腫発がん実験を行った。2年の経過でほぼ全動物に中皮腫が発生した。アスベスト投与部の中皮細胞や貪食細胞に著明な鉄沈着を認め、Fenton反応促進性のニトリロ三酢酸の追加投与により、中皮腫発生が有意に早くなった。93%の腫瘍で<i>Cdkn2a/2b</i>のホモ欠損を認めた。アスベスト発がんでは局所の過剰鉄病態が重要なことが示唆された。このような背景のもと、すでに中皮腫の危険性の報告のあった多層カーボンナノチューブ(MWCNT)の評価を行った。MWCNTは軽量・高強度で熱伝導性が高く、導体・半導体になることからすでに使用されているが、物理的形状は石綿に酷似している。直径が15/50/115/150 nmのMWCNTを使用し中皮細胞毒性実験ならびに、上記と同様のラットを使用した発がん実験を行った。中皮細胞への毒性と発がん性はほぼ一致し、直径50 nmのMWCNTの発がん性が最も高かった。<i>Cdkn2a/2b</i>のホモ欠損をほぼ全例で認めた。このことは、剛性が高い50 nm直径のMWCNTは特に注意して扱うべきことを示唆している(IARC Group 2B)。ヒトにおいて体腔に繊維が到達することはそう容易ではないと考えられるが、感染症が克服され、ますます長寿化が進む現在、新素材の十分なリスク評価とリスク管理は重要と考える。参考文献:1. Nagai H <i>et al.</i> Proc Natl Acad Sci USA 108: E1330, 2011; 2. Jiang L, <i>et al.</i> J Pathol 228: 366, 2012; 3. Toyokuni S. Adv Drug Deliv Rev 65: 298, 2013

    DOI: 10.14869/toxpt.42.1.0_S4-2

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  267. 1-ブロモプロパン神経毒性のマウスモデルの確立

    宗 才, Edwin GARNER, 黄 晋彦, 張 霊逸, 張 堯, 櫻井 敏博, 豊國 伸哉, 市原 佐保子, 市原 学

    日本毒性学会学術年会   42 巻 ( 0 ) 頁: P - 13   2015年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本毒性学会  

    【目的】オゾン層破壊物質代替物質1-ブロモプロパン(1BP)はヒトとラットで神経毒性と生殖毒性を引き起こすことがわかっている。雄ラットは1000 ppmの1BPに1日8時間、5から7週間の曝露でも生存するのに対し、最近の 我々の研究で雄C57BL6/JJclマウスは300 ppmの1BPに7日間曝露後、肝臓の壊死を引き起こし、結果として生存できず、神経毒性影響が検出できなかった。本研究はサイトクロームP450の阻害剤、1ーアミノベンゾトライアゾール(ABT)を用い、1BPが引き起こす肝障害作用を抑制することによって、マウスを用いた1BP神経毒性モデルの確立を試みるとともに、P450による1BPの酸化が生殖毒性のパラメータにあたる影響を明らかにする。<br>【方法】42匹のC57BL/6JJclマウスを6匹ずつ7群に分け、4群にABT 50mg/kgを皮下注射で1日2回投与し、0、50、250、1200 ppmで1BP8時間の曝露を28日間行った。残る3群には生理食塩水を注射し、0、50、250 ppmの1BPに1日8時間、28日間曝露した。曝露終、麻酔下で臓器を剖出した。<br>【結果】ABT-・1BP 250 ppm群で、肝臓で壊死、炎症、肝臓細胞の変性像が見られた。一方、ABT+マウスでは、1200 ppmを含むすべての群で病理的な変化が見られなかった。脳重量は、ABT+・1200ppm群でABT+・0ppm群に比して有意に減少した。ABT-・1BP250 ppmのグループで、精子数がABT-・1BP 0ppm群に比して減少したが、ABT+・1BP250ppm群およびABT+・1BP50ppm群においてABT+・1BP0ppm群に比して精子数の変化は無かった。精嚢と前立腺はABTの投与の有無に関わらず、250 ppmの濃度で、それぞれの0ppm群に対して重量が減少した。<br>【考察】ABT投与は1-BPによる肝毒性を抑制した。本研究はP450が1-BPの代謝と毒性発現において重要な役割を担っていることを明らかにした。この方法によりマウスの1-BP神経毒性モデルの作成が期待される。

    DOI: 10.14869/toxpt.42.1.0_P-13

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  268. 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   70 巻   頁: 337 - 242   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  269. Minimal inflammogenicity of pristine single-wall carbon nanotubes 査読有り 国際誌

    Toyokuni S

    Nagoya Journal of Medical Science   77 巻 ( 1-2 ) 頁: 195 - 202   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nagoya Journal of Medical Science  

  270. Plasma medical science for cancer therapy: Toward cancer therapy using nonthermal atmospheric pressure plasma

    Tanaka H., Mizuno M., Ishikawa K., Takeda K., Nakamura K., Utsumi F., Kajiyama H., Kano H., Okazaki Y., Toyokuni S., Maruyama S., Kikkawa F., Hori M.

    IEEE Transactions on Plasma Science   42 巻 ( 12 ) 頁: 3760 - 3764   2014年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IEEE Transactions on Plasma Science  

    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.

    DOI: 10.1109/TPS.2014.2353659

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  271. Genome-wide profiling of 8-oxoguanine reveals its association with spatial positioning in nucleus. 国際誌

    Yoshihara M, Jiang L, Akatsuka S, Suyama M, Toyokuni S

    DNA research : an international journal for rapid publication of reports on genes and genomes   21 巻 ( 6 ) 頁: 603 - 12   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:DNA Research  

    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.

    DOI: 10.1093/dnares/dsu023

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  272. Direct exposure of non-equilibrium atmospheric pressure plasma confers simultaneous oxidative and ultraviolet modifications in biomolecules.

    Okazaki Y, Wang Y, Tanaka H, Mizuno M, Nakamura K, Kajiyama H, Kano H, Uchida K, Kikkawa F, Hori M, Toyokuni S

    Journal of clinical biochemistry and nutrition   55 巻 ( 3 ) 頁: 207 - 15   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本酸化ストレス学会  

    Thermal plasmas and lasers are used in medicine to cut and ablate tissues and for coagulation. Non-equilibrium atmospheric pressure plasma (NEAPP) is a recently developed, non-thermal technique with possible biomedical applications. Although NEAPP reportedly generates reactive oxygen/nitrogen species, electrons, positive ions, and ultraviolet radiation, little research has been done into the use of this technique for conventional free radical biology. Recently, we developed a NEAPP device with high electron density. Electron spin resonance spin-trapping revealed .OH as a major product. To obtain evidence of NEAPP-induced oxidative modifications in biomolecules and standardize them, we evaluated lipid peroxidation and DNA modifications in various in vitro and ex vivo experiments. Conjugated dienes increased after exposure to linoleic and 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.

    DOI: 10.3164/jcbn.14-40

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  273. Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model 査読有り 国際誌

    Mukaide T., Hattori Y., Misawa N., Funahashi S., Jiang L., Hirayama T., Nagasawa H., Toyokuni S.

    Free Radical Research   48 巻 ( 9 ) 頁: 990 - 5   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    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. © 2014 Informa UK, Ltd.

    DOI: 10.3109/10715762.2014.898844

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  274. FREE FERROUS IRON IN AMNIOTIC FLUID AS A PREDICTIVE MARKER OF FETAL DISORDERS IN PREGNANCY

    Hattori Yuka, Kotani Tomomi, Nakano Tomoko, Mano Yukio, Sumigama Seiji, Tsuda Hiroyuki, Usida Takafumi, Nagasawa Hideko, Toyokuni Shinya, Kikkawa Fumitaka

    PLACENTA   35 巻 ( 9 ) 頁: A71 - A71   2014年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  275. Iron and thiols as two major players in carcinogenesis: friends or foes? 国際誌

    Toyokuni Shinya

    FRONTIERS IN PHARMACOLOGY   5 巻   頁: 200 - 200   2014年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers in Pharmacology  

    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 Keap1 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. © 2014 Toyokuni.

    DOI: 10.3389/fphar.2014.00200

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  276. Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. 査読有り 国際誌

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

    J Pathol   233 巻 ( 4 ) 頁: 402 - 414   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pathology  

    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 β-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-GSK3β-β-catenin-TCF-Ctgf autocrine axis and suggest Ctgf as a therapeutic target. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    DOI: 10.1002/path.4377

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  277. Expression of chromobox homolog 7 ( CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation 査読有り 国際誌

    Shinjo Kanako, Yamashita Yoriko, Yamamoto Eiko, Akatsuka Shinya, Uno Nozomi, Kamiya Akihiro, Niimi Kaoru, Sakaguchi Yuka, Nagasaka Tetsuro, Takahashi Takashi, Shibata Kiyosumi, Kajiyama Hiroaki, Kikkawa Fumitaka, Toyokuni Shinya

    INTERNATIONAL JOURNAL OF CANCER   135 巻 ( 2 ) 頁: 308 - 318   2014年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Cancer  

    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 < 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 < 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 < 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. © 2013 UICC.

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  278. Lack of presence of the human cytomegalovirus in human glioblastoma.

    Yamashita Y, Ito Y, Isomura H, Takemura N, Okamoto A, Motomura K, Tsujiuchi T, Natsume A, Wakabayashi T, Toyokuni S, Tsurumi T

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   27 巻 ( 7 ) 頁: 922 - 9   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Modern Pathology  

    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. © 2014 USCAP, Inc All rights reserved.

    DOI: 10.1038/modpathol.2013.219

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  279. Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions. 査読有り 国際誌

    Nishiwaki S, Nakayama T, Murata M, Nishida T, Terakura S, Saito S, Kato T, Mizuno H, Imahashi N, Seto A, Ozawa Y, Miyamura K, Ito M, Takeshita K, Kato H, Toyokuni S, Nagao K, Ueda R, Naoe T

    PloS one   9 巻 ( 5 ) 頁: e96252   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    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-α and IFN-γ, 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. © 2014 Nishiwaki et al.

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  280. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion. 査読有り 国際誌

    Mano Y, Kotani T, Ito M, Nagai T, Ichinohashi Y, Yamada K, Ohno K, Kikkawa F, Toyokuni S

    Free radical biology & medicine   69 巻   頁: 324 - 30   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Biology and Medicine  

    Molecular hydrogen (H2) scavenges hydroxyl radicals. Recently, H2 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 H2 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 H2. Neonatal growth retardation was observed in the IR group, which was alleviated by the H2 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.©2014 ElsevierInc.Allrightsreserved.

    DOI: 10.1016/j.freeradbiomed.2014.01.037

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  281. Ovarian mucinous tumors arising from mature cystic teratomas-a molecular genetic approach for understanding the cellular origin 査読有り

    Fujii Kaho, Yamashita Yoriko, Yamamoto Toshimichi, Takahashi Koji, Hashimoto Katsunori, Miyata Tomoko, Kawai Kumi, Kikkawa Fumitaka, Toyokuni Shinya, Nagasaka Tetsuro

    HUMAN PATHOLOGY   45 巻 ( 4 ) 頁: 717 - 724   2014年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Pathology  

    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. © 2014 Elsevier Inc.

    DOI: 10.1016/j.humpath.2013.10.031

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  282. From Nagoya to the world

    Toyokuni S.

    Nagoya Journal of Medical Science   76 巻 ( 1-2 ) 頁: 1 - 2   2014年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Nagoya Journal of Medical Science  

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  283. From Nagoya to the world

    Toyokuni S

    Nagoya Journal of Medical Science   76 巻 ( 1-2 ) 頁: 1 - 2   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nagoya Journal of Medical Science  

  284. RAT MODEL DEMONSTRATES A HIGH RISK OF TREMOLITE BUT A LOW RISK OF ANTHOPHYLLITE FOR MESOTHELIAL CARCINOGENESIS 査読有り

    Dilinuer Aierken, Yasumasa Okazaki, Shan Hwu Chew, Akihiro Sakai, Yue Wang, Hirotaka Nagai, Nobuaki Misawa, Norihiko Kohyama, Shinya Toyokuni

    NAGOYA JOURNAL OF MEDICAL SCIENCE   76 巻 ( 1-2 ) 頁: 149 - 160   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NAGOYA UNIV, SCH MED  

    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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  285. 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   76 巻 ( 1-2 ) 頁: 149 - 60   2014年2月

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    掲載種別:研究論文(学術雑誌)  

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  286. 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   76 巻 ( 1-2 ) 頁: 149 - 60   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  287. 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   76 巻 ( 1-2 ) 頁: 149 - 160   2014年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  288. Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production. 国際誌

    Chew SH, Okazaki Y, Nagai H, Misawa N, Akatsuka S, Yamashita K, Jiang L, Yamashita Y, Noguchi M, Hosoda K, Sekido Y, Takahashi T, Toyokuni S

    Carcinogenesis   35 巻 ( 1 ) 頁: 164 - 72   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Carcinogenesis  

    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 transcription-PCR 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. © The Author 2013. Published by Oxford University Press. All rights reserved.

    DOI: 10.1093/carcin/bgt267

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  289. Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis 査読有り 国際誌

    Toyokuni Shinya

    REDOX REPORT   19 巻 ( 1 ) 頁: 1 - 7   2014年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Redox Report  

    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 because of the long incubation period for MM. © W. S. Maney & Son Ltd 2014.

    DOI: 10.1179/1351000213Y.0000000075

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  290. As a host society to SFRRI 2014 in Kyoto

    Handa Osamu, Naito Yuji, Toyokuni Shinya

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   54 巻 ( 1 ) 頁: 1 - 1   2014年1月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    DOI: 10.3164/jcbn.54-1E1

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  291. Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. 査読有り

    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   15 巻   頁: 169-178   2014年

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  292. Dexamethasone palmitate ameliorates macrophages-1 rich graft-versus-host disease by inhibiting macrophage functions. 査読有り

    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   9 巻   頁: e96252   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1371/journal.pone.0096252.

  293. Histological detection of catalytic ferrous iron with the selective turn-on fluorescent probe RhoNox-1 in a Fenton reaction-based rat renal carcinogenesis model. 査読有り

    Mukaide T, Hatori Y, Misawa N, Funahashi S, Jiang L, Hirayama T, Nagasawa H and Toyokuni S.

    Free Radic Res   48 巻   頁: 990-995   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.3109/10715762.2014.898844.

  294. Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis. 査読有り

    Aierken D, Okazaki Y, Chew SH, Sakai A, Wang Y, Nagai H, Misawa N, Kohyama N and Toyokuni S.

    Nagoya J Med Sci   76 巻   頁: 149-160   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  295. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage by in ut ero ischemia-reperfusion. 査読有り

    Mano Y, Kotani T, Ito M, Nagai T, Ichinohashi Y, Yamada K, Ohno K, Kikkawa F and Toyokuni S.

    Free Radic Biol Med   69 巻   頁: 324-330   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.freeradbiomed.2014.01.037.

  296. Lack of presence of the human cytomegalovirus in human glioblastoma. Modern Pathol 27: 922-929, 2014. 査読有り

    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   27 巻   頁: 922-929   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1038/modpathol.2013.219.

  297. Ovarian mucinous tumors arising from mature cystic teratomas-a molecular genetic approach for understanding the cellular origin. 査読有り

    Fujii K, Yamashita Y, Yamamoto T, Takahashi K, Hashimoto K, Miyata T, Kawai K, Kikkawa F, Toyokuni S, Nagasaka T.

    Human Pathol   45 巻   頁: 717-724   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1016/j.humpath.2013.10.031.

  298. Iron as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis. 査読有り

    Toyokuni, S.

    Redox Rep.   19 巻   頁: 1-7   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1179/1351000213Y.0000000075.

  299. Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production. 査読有り

    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   35 巻   頁: 164-172   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1093/carcin/bgt267.

  300. Direct exposure of non-equilibrium atmospheric pressure plasma confers simultaneous oxidative and ultraviolet modifications in biomolecules. 査読有り

    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   55 巻   頁: 207-215   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  301. Plasma medical science for cancer therapy using non-thermal atomospheric pressure plasma. 査読有り

    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   42 巻   頁: 3760-3764   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  302. Iron and thiols as two major players in carcinogenesis: friends or foes? 招待有り 査読有り

    Toyokuni S.

    Front Pharmacol   5 巻   頁: 200   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  303. Genome-wide profiling of 8-oxoguanine reveals its association with spatial positioning in nucleus. 査読有り

    Yoshihara M, Jiang L, Akatsuka S, Suyama M and Toyokuni S.

    DNA Res   21 巻   頁: 603-612   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  304. Iron and thiols as two major players in carcinogenesis: friends or foes? 招待有り 査読有り

    Toyokuni S

    Front Pharmacol   5 巻   頁: 200   2014年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  305. 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   6 巻 ( 2 ) 頁: 169 - 78   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PubMed

  306. Preclinical evaluation of an O-6-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains 査読有り

    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   6 巻 ( 2 ) 頁: 169 - 178   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:E-CENTURY PUBLISHING CORP  

    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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  307. 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   6 巻 ( 2 ) 頁: 169 - 178   2014年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Journal of Translational Research  

    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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  308. 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   2013 巻 ( 0 ) 頁: 0007 - 0007   2014年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:公益社団法人 日本理学療法士協会  

    【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。

    DOI: 10.14900/cjpt.2013.0007

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  309. 【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   32 巻   頁: 632 - 637   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  310. 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   6 巻 ( 2 ) 頁: 169 - 178   2014年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  311. Genotoxicity and carcinogenicity risk of carbon nanotubes 国際誌

    Toyokuni Shinya

    ADVANCED DRUG DELIVERY REVIEWS   65 巻 ( 15 ) 頁: 2098 - 2110   2013年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Advanced Drug Delivery Reviews  

    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. © 2013 Elsevier B.V.

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  312. Deferasirox Induces Mesenchymal-Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

    Toyokuni Shinya, Nagai Hirotaka, Okazaki Yasumasa, Chew Shan Hwu, Yasui Hiroyuki

    FREE RADICAL BIOLOGY AND MEDICINE   65 巻   頁: S25 - S25   2013年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2013.10.444

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  313. Deferasirox induces mesenchymal-epithelial transition in crocidolite-induced mesothelial carcinogenesis in rats.

    Nagai H, Okazaki Y, Chew SH, Misawa N, Yasui H, Toyokuni S

    Cancer prevention research (Philadelphia, Pa.)   6 巻 ( 11 ) 頁: 1222 - 30   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Prevention Research  

    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. ©2013 AACR.

    DOI: 10.1158/1940-6207.CAPR-13-0244

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  314. From nagoya to the world

    Toyokuni S.

    Nagoya Journal of Medical Science   75 巻 ( 1-2 ) 頁: 1 - 2   2013年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Nagoya Journal of Medical Science  

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  315. From nagoya to the world

    Toyokuni S

    Nagoya Journal of Medical Science   75 巻 ( 1-2 ) 頁: 1 - 2   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nagoya Journal of Medical Science  

  316. Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15 nm in diameter does not induce mesothelial carcinogenesis in rats. 国際誌

    Nagai H, Okazaki Y, Chew SH, Misawa N, Miyata Y, Shinohara H, Toyokuni S

    Pathology international   63 巻 ( 9 ) 頁: 457 - 62   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    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.

    DOI: 10.1111/pin.12093

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  317. Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice (vol 23, pg 85, 2005) 査読有り

    Naitoa Yuji, Akagiri Satomi, Uchiyama Kazuhiko, Kokura Satoshi, Yoshida Norimasa, Hasegawa Goji, Nakamura Naoto, Ichikawa Hiroshi, Toyokuni Shinya, Ijichi Tetsuo, Yoshikawa Toshikazu

    BIOFACTORS   39 巻 ( 5 ) 頁: 589 - 589   2013年9月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/biof.1135

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  318. CD146 and insulin-like growth factor 2 mRNA-binding protein 3 predict prognosis of asbestos-induced rat mesothelioma.

    Okazaki Y, Nagai H, Chew SH, Li J, Funahashi S, Tsujimura T, Toyokuni S

    Cancer science   104 巻 ( 8 ) 頁: 989 - 95   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    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. © 2013 Japanese Cancer Association.

    DOI: 10.1111/cas.12185

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  319. Lewis y antigen is expressed in oral squamous cell carcinoma cell lines and tissues, but disappears in the invasive regions leading to the enhanced malignant properties irrespective of sialyl-Lewis x.

    Hotta H, Hamamura K, Yamashita K, Shibuya H, Tokuda N, Hashimoto N, Furukawa K, Yamamoto N, Hattori H, Toyokuni S, Ueda M, Furukawa K

    Glycoconjugate journal   30 巻 ( 6 ) 頁: 585 - 97   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Glycoconjugate Journal  

    Expression and implication of carbohydrate antigens in squamous cell carcinomas (SCCs) in oral cavity was examined. In the cell lines, type 2H and Lewis y antigens were markedly expressed. In the tissues from SCC patients and benign disorders, type 2H was highly expressed in hyperplasia (96.4 %), displasia (92.9 %) and SCC (100 %). Lewis y was, in turn, expressed mainly in cancer tissues (91.3 %), suggesting that Lewis y is a cancer-associated antigen. Normal oral mucosa showed no expression of these blood group antigens. Surprisingly, Lewis y antigen disappeared in the invasion sites where Ki-67 was definitely stained. Over-expression of Lewis y with manipulation of a fucosyltransferase cDNA resulted in suppression of cell growth and invasion, and knockdown of Lewis y also brought about increased cell growth and invasion. In either situations, no changes in the expression of sialyl-Lewis x could be found. Lowered tumor growth and invasion into surrounding tissues were also shown in Lewis y-positive SCC grafts in nu/nu mice. All these results together with alternative staining between Lewis y and Ki-67 in cancer tissues and FUT1 transfectants suggested that loss of Lewis y is a crucial event for the late stage of SCCs. © 2012 Springer Science+Business Media New York.

    DOI: 10.1007/s10719-012-9458-2

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  320. Evaluation of two distinct methods to quantify the uptake of crocidolite fibers by mesothelial cells. 国際誌

    Yamashita K, Nagai H, Kondo Y, Misawa N, Toyokuni S

    Journal of clinical biochemistry and nutrition   53 巻 ( 1 ) 頁: 27 - 35   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    Exposure to asbestos fibers increases the risk of mesothelioma in humans. One hypothetical carcinogenic mechanism is that asbestos fibers may directly induce mutations in mesothelial cells. Although the uptake of asbestos fibers by mesothelial cells is recognized, methods for the quantification of the uptake have not been well established. In the present study, we evaluated two distinct methods, using crocidolite fibers and MeT5A mesothelial cells. One method is histological evaluation using the cell-block technique, which allows for the direct cross-sectional observation of cells and fibers. We found the bright field observation with ×1000 magnification (oil-immersion) of the sample with Kemechtrot staining was most suitable for this purpose. The other method is flow cytometric analysis, which permits the evaluation of a much larger number of cells. We observed that the side scatter (SSC) increased with the intracellular fibers, and that the "mean SSC ratio (treated/control)" was useful for quantification. We could collect the cells with abundant internalized crocidolite fibers by sorting. Results of the two methodologies were correlated well in the experiments. The quantities of internalized fibers increased with incubation time and loaded dosage, but they were inversely associated with cellular density in culture. © 2013 JCBN.

    DOI: 10.3164/jcbn.12-104

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  321. Repeated short-term daily exercise ameliorates oxidative cerebral damage and the resultant motor dysfunction after transient ischemia in rats.

    Hamakawa M, Ishida A, Tamakoshi K, Shimada H, Nakashima H, Noguchi T, Toyokuni S, Ishida K

    Journal of clinical biochemistry and nutrition   53 巻 ( 1 ) 頁: 8 - 14   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本酸化ストレス学会  

    Long-term exercise prior to brain ischemia enhances the activities of antioxidant enzymes and leads to a significant reduction in brain damage and neurological deficits in rats subjected to transient middle cerebral artery occlusion. However, it has not been established whether relatively short-term exercise generates similar results following middle cerebral artery occlusion. We aimed to determine whether short-term exercise could reduce oxidative damage and prevent sensori-motor dysfunction. Male Wistar rats were subjected to perform daily exercise on a treadmill for 30 min at a speed of 15 m/min for 3 weeks, followed by a 90-min middle cerebral artery occlusion. Animals were assessed after middle cerebral artery occlusion for neurological deficits and sensori-motor function. Brain tissues were processed to evaluate infarct volume and oxidative damage. Oxidative stress was assessed using immunohistochemistry for 4-hydroxy-2-nonenalmodified proteins and 8-hydroxy-2'-deoxyguanosine. Antioxidant enzymes were evaluated using immunohistochemistry for thioredoxin and activity assay for superoxide dismutase. Exercise for 3 weeks decreased the severity of paralysis and impairment in forelimb motor coordination. Furthermore, exercise had effect on superoxide dismutase and reduced the infarct volume and the number of cells immunopositive for 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Our results suggest that pre-conditioning treadmill exercise for 3 weeks is useful for ameliorating ischemia-induced brain injury. © 2013 JCBN.

    DOI: 10.3164/jcbn.12-72

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  322. Multispecificity of immunoglobulin M antibodies raised against advanced glycation end products: involvement of electronegative potential of antigens.

    Chikazawa M, Otaki N, Shibata T, Miyashita H, Kawai Y, Maruyama S, Toyokuni S, Kitaura Y, Matsuda T, Uchida K

    The Journal of biological chemistry   288 巻 ( 19 ) 頁: 13204 - 14   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Biological Chemistry  

    Background: Advanced glycation end products (AGEs) can act as neoantigens to trigger immune responses. Results: Natural IgM antibodies against AGEs recognize multiple molecules, including DNA and chemically modified proteins. Conclusion: There is a close relationship between the formation of AGEs and innate immune responses. Significance: Our findings highlight AGEs and related modified proteins as a source of multispecific natural antibodies. Copyright © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

    DOI: 10.1074/jbc.M113.452177

    DOI: 10.1074/jbc.m113.452177

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  323. CANCER AS A FERROTOXIC DISEASE: WHAT WE HAVE LEARNED FROM ANIMAL STUDIES TOWARD ITS PREVENTION 査読有り 国際誌

    Toyokuni Shinya, Jiang Li, Okazaki Yasumasa, Akatsuka Shinya

    AMERICAN JOURNAL OF HEMATOLOGY   88 巻 ( 5 ) 頁: E168 - E169   2013年5月

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    掲載種別:研究論文(学術雑誌)  

    Web of Science

  324. CANCER AS A FERROTOXIC DISEASE: WHAT WE HAVE LEARNED FROM ANIMAL STUDIES TOWARD ITS PREVENTION 査読有り 国際誌

    Toyokuni Shinya, Jiang Li, Okazaki Yasumasa, Akatsuka Shinya

    AMERICAN JOURNAL OF HEMATOLOGY   88 巻 ( 5 ) 頁: E168 - E169   2013年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  325. FROM NAGOYA TO THE WORLD 査読有り 国際誌

    Toyokuni Shinya

    NAGOYA JOURNAL OF MEDICAL SCIENCE   75 巻 ( 1-2 ) 頁: 1 - 2   2013年2月

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    掲載種別:研究論文(学術雑誌)  

    Web of Science

  326. Protective effect of cardioplegia with poly (ADP-ribose) polymerase-1 inhibitor against myocardial ischemia-reperfusion injury: in vitro study of isolated rat heart model.

    Yamazaki K, Tanaka S, Sakata R, Miwa S, Oriyanhan W, Takaba K, Minakata K, Marui A, Ikeda T, Toyokuni S, Komeda M, Ueda K

    Journal of enzyme inhibition and medicinal chemistry   28 巻 ( 1 ) 頁: 143 - 7   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Enzyme Inhibition and Medicinal Chemistry  

    Poly(ADP-ribose) polymerase (PARP)-1 inhibitor has been suggested to attenuate the ischemia-reperfusion injury. We investigated the protective effect of the cardioplegia with a PARP-1 inhibitor, 4-hydoxyquinazoline (4-HQ), against myocardial ischemia-reperfusion injury. Isolated rat hearts were perfused on a Langendorff apparatus and cardioplegically arrested for 90 min by perfusion with St. Thomas' Hospital solution (ST-solution). In the Group ST (n = 8), the hearts were arrested with the ST-solution alone. The Group HQ (n = 8) were treated with the ST-solution containing 4-HQ (10 μM) for cardioplegia. During reperfusion, the Group HQ showed significantly greater functional recovery of +dp/dtmax (p = 0.005) and lower enzymatic leakage (p < 0.01). NAD+ levels were also preserved higher in the Group HQ (p < 0.01). Immunohistochemical study revealed lesser extents of oxidative stress and apoptosis, in the Group HQ. Thus, addition of 4-HQ in the cardioplegia may provide a new intervention for myocardial protection against ischemia-reperfusion injury by decreasing NAD+ consumption and suppressing oxidative stress. © 2013 Informa UK, Ltd.

    DOI: 10.3109/14756366.2011.642373

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  327. FROM NAGOYA TO THE WORLD 査読有り 国際誌

    Toyokuni Shinya

    NAGOYA JOURNAL OF MEDICAL SCIENCE   75 巻 ( 1-2 ) 頁: 1 - 2   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  328. Deferasirox induces mesenchymal-epithelial transition in crocidolite-induced mesothelila carcinogenesis in rats. 査読有り

    Nagai H, Okazaki Y, Chew SH, Misawa N, Yasui H and Toyokuni S.

    Cancer Prev Res   6 巻 ( 11 ) 頁: 1222-1230   2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  329. Genotoxicity and carcinogenicity risk of carbon nanotubes. 査読有り

    Toyokuni S.

    Adv Drug Deliver Rev     2013年

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    担当区分:筆頭著者   記述言語:英語  

    DOI: doi:pii: S0169-409X(13)00149-X. 10.1016/j.addr.2013.05.011.

  330. Repeated short-term daily exercise ameliorates oxidative cerebral damage and the resultant motor dysfunction after transient ischemia in rats. 査読有り

    Hamakawa M, Ishida A, Tamakoshi K, Shimada H, Nakashima H, Noguchi T, Toyokuni S and Ishida K.

    J Clin Biochem Nutr   53 巻   頁: 8-14   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  331. CD146 and IMP3 predict prognosis of asbestos-induced rat mesothelioma. 査読有り

    Okazaki Y, Nagai H, Chew SH, Jiang L, Funahashi S, Tsujimura T and Toyokuni S.

    Cnacer Sci   104 巻   頁: 989-995   2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  332. Multi-specificity of IgM antibodies raised against advanced glycation end products: Involvement of electronegative potential of antigens. 査読有り

    Chikazawa M, Otaki N, Shibata T, Miyashita H, Kawai Y, Maruyama S, Toyokuni S, Kitaura Y, Matsuda T, Uchida K.

    J Biol Chem   288 巻   頁: 13204-13214   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  333. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. 査読有り

    Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, Kajiyama H, Kikkawa F, Takahashi T and Toyokuni S.

    PLoS One   8 巻 ( 3 ) 頁: e57724   2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  334. Evaluation of two distinct methods to quantify the uptake of crocidolite fibers by mesothelial cells. 査読有り

    Yamashita K, Nagai H, Kondo Y, Misawa N and Toyokuni S.

    J Clin Biochem Nutr   53 巻   頁: 27-35   2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  335. Metamorphosis of mesothelial cells with active horizontal motility in tissue culture. 査読有り

    Nagai H, Chew SH, Okazaki Y, Funahashi S, Namba T, Kato T, Enomoto A, Jiang L, Akatsuka S and Toyokuni S.

    Sci Rep   3 巻   頁: 1144   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  336. Protective effect of cardioplegia with poly(ADP-ribose)polymerase-1 inhibitor aganst myocardial ischemia-reperfusion injury: in vitro study if isolated rat heart model. 査読有り

    Yamazaki K, Tanaka S, Sakata R, Miwa S, Oriyanhan W, Takaba K, Minakata K, Marui A, Ikeda T, Toyokuni S, Komeda M and Ueda K.

    J Enzyme Inhibition Medicinal Chem   28 巻   頁: 143-147   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  337. Lewis y antigen is expressed in oral squamous cell carcinoma cell lines and tissues, but disappears in the invasive regions leading to the enhanced malignant properties irrespective of sialyl-Lewis x. 査読有り

    Hotta H, Hamamura K, Yamashita K, Shibuya H, Tokuda N, Hashimoto N, Furukawa K, Yamamoto N, Hattori H, Toyokuni S, Ueda M, Furukawa K.

    Glycoconj J   30 巻   頁: 585-597   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  338. Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15 nm in diameter does not induce mesothelial carcinogenesis in rats. 査読有り

    Nagai H, Okazaki Y, Chew SH, Misawa N, Miyata Y, Shinohara N and Toyokuni S.

    Pathol. Int.   63 巻   頁: 457-462   2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: doi: 10.1111/pin.12093.

  339. Metamorphosis of mesothelial cells with active horizontal motility in tissue culture. 国際誌

    Nagai H, Chew SH, Okazaki Y, Funahashi S, Namba T, Kato T, Enomoto A, Jiang L, Akatsuka S, Toyokuni S

    Scientific reports   3 巻   頁: 1144   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    Mesothelial cells, which have diverse roles in physiology and pathology, constitute the mesothelium along with connective tissue and the basement membrane; the mesothelium serves to shield the somatic cavities. After mesothelial injury, mesothelial cells undergo tissue recovery. However, the mechanism of mesothelial regeneration remains poorly understood. In this study, we used confocal time-lapse microscopy to demonstrate that transformed mesothelial cells (MeT5A) and mouse peritoneal mesothelial cells can randomly migrate between cells in cell culture and in ex vivo tissue culture, respectively. Moreover, peritoneal mesothelial cells changed their morphology from a flattened shape to a cuboidal one prior to the migration. Conversely, MDCKII epithelial cells forming tight cell-cell contacts with one another do not alter the arrangement of adjacent cells during movement. Our evidence complements the current hypotheses of mesothelial regeneration and suggests that certain types of differentiated mesothelial cells undergo morphological changes before initiating migration to repair injured sites.

    DOI: 10.1038/srep01144

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  340. Genotoxicity and carcinogenicity risk of carbon nanotubes. 査読有り

    Toyokuni S

    Adv Drug Deliver Rev     2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.addr.2013.05.011.

  341. Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. 国際誌

    Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, Kajiyama H, Kikkawa F, Takahashi T, Toyokuni S

    PloS one   8 巻 ( 3 ) 頁: e57724   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC. © 2013 Yamashita et al.

    DOI: 10.1371/journal.pone.0057724

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  342. Multi-specificity of IgM antibodies raised against advanced glycation end products: Involvement of electronegative potential of antigens. 査読有り

    Chikazawa M, Otaki N, Shibata T, Miyashita H, Kawai Y, Maruyama S, Toyokuni S, Kitaura Y, Matsuda T, Uchida K

    J Biol Chem   288 巻   頁: 13204-13214   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  343. ナノ材料(CNT)の物性と発がん性

    豊國 伸哉

    日本毒性学会学術年会   40 巻 ( 0 ) 頁: 1044   2013年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本毒性学会  

    1981年以降,日本人死因の第1位はがんである。喫煙や特定の感染症が発がんリスクとして同定された。しかし,産業・経済を重視するあまり,リスク評価が十分になされず,ナノマテリアルが社会に多量に持ち込まれ,がんの原因となったことも忘れてはならない。それが繊維状鉱物のアスベストであり白石綿・青石綿・茶石綿が使用された。日本では2006年に禁止となったが,アジアの諸国やロシアなどでは今も使用されている。日本の中皮腫発生ピークは2025年で今後40年間に10万人以上の方が中皮腫で死亡すると試算されている。ラットを使用して上記3種の石綿で,腹腔内10mg投与により中皮腫発がん実験を行った。2年の経過でほぼ全動物に中皮腫が発生した。石綿投与に伴い,同部の中皮細胞や貪食細胞に著明な鉄沈着を認め,Fenton反応促進性のニトリロ三酢酸の追加投与でどの石綿でも中皮腫発生が早くなった。93%の腫瘍でCdkn2A/2Bのホモ欠損を認めた。アスベスト発がんでは局所の過剰鉄病態が重要なことが示唆された。このような背景のもと,すでに中皮腫の危険性の報告のあった多層カーボンナノチューブ(CNT)の評価を行った。CNTは軽量・高強度で熱伝導性が高く導体・半導体になることからすでに電池・液晶パネルのマテリアルとして使用されているが,形状は石綿に酷似している。直径が15/50/115/150nmのCNTを使用し中皮細胞毒性実験と上記と同様のラットを使用した発がん実験を行った。中皮細胞への毒性と発がん性はほぼ一致し,50nmの発がん性が最も高かった。Cdkn2A/2Bのホモ欠損をほぼ全例で認めた。このことは,剛性が高い50nm直径のCNTは特に注意して扱うべきことを示唆している。一方,石綿はendocytosisで中皮細胞に取り込まれるが,CNTは突き刺さり入ることも明らかになった。ヒトで体腔に繊維が到達することはそう簡単ではないと考えられるが,ますます長寿化が進む現在,十分なリスク評価が必要と考えられる。&nbsp; <br>

    DOI: 10.14869/toxpt.40.1.0.1044.0

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  344. 脳梗塞発症前の運動による脳梗塞障害軽減効果及びその作用機序の検討〜酸化ストレスに着目して〜

    野口 泰司, 濱川 みちる, 玉越 敬悟, 戸田 拓弥, 豊國 伸哉, 石田 和人

    理学療法学Supplement   2012 巻 ( 0 ) 頁: 48101465 - 48101465   2013年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:公益社団法人 日本理学療法士協会  

    【はじめに、目的】脳梗塞発症時には活性酸素やフリーラジカルが大量に産生され、その酸化ストレスは組織障害を拡大させ脳梗塞を増悪させる因子である。一方で、健常なラットに長期間運動させると、脳内で抗酸化物質が増加し酸化ストレスの減少がもたらされることが報告されており、運動は脳内の抗酸化作用を高めることが示されている。また、先行研究では脳梗塞モデルラット作成前に一定期間の運動を行うと、運動していないラットに比べて、脳梗塞後の梗塞体積が減少し運動機能障害も軽減するといった脳梗塞障害軽減効果が報告されている。しかし、この運動により高まる脳内の抗酸化作用が、脳梗塞時の酸化ストレスに影響を及ぼしているかどうかは不明である。そこで本研究では、脳梗塞発症前の運動による脳梗塞障害軽減効果およびその作用機序を、脳内の抗酸化作用に着目して検討することを目的とする。【方法】実験動物にはWistar系雄性ラット(5 週齢)を用いた。無作為に(1)Sham群、(2)運動+sham群、(3)脳梗塞群、(4)運動+脳梗塞群に分け、脳梗塞+運動群と運動+sham群は3 週間のトレッドミル運動(15 m/min,30 分/日)を毎日行った。脳梗塞群とSham群は走行させずにトレッドミル装置内に暴露させた(1 日30 分間)。3 週間後、運動+脳梗塞群と脳梗塞群に対し、小泉法による脳梗塞モデル作成手術を施行した。手術24 時間後に、運動-感覚機能評価として、麻痺の重症度を評価するneurological deficits(ND)、歩行時のバランス能力の評価としてbeam walking(BW)、はしごの上の歩行における前肢の協調運動機能の評価としてladder test、前肢の感覚運動機能の評価としてlimb placing(LP)を行った。その直後に脳を採取し、TTC染色により非梗塞半球体積に対する梗塞体積の割合を算出した。また、酸化ストレス関連指標として、脂質過酸化の指標である4-hydroxy-2-nonenal(4-HNE)とDNAの酸化的損傷の指標となる8-Hydroxydeoxyguanosine(8-OHdG)、抗酸化酵素であるthioredoxin(TRX)の免疫組織化学染色を行い、陽性細胞数及び光学濃度を計測した。またSOD Assay kit-WST(同仁化学研究所)を用いて抗酸化酵素であるsuperoxide dismutase(SOD)活性を計測した。【倫理的配慮、説明と同意】本研究における全処置は名古屋大学動物実験指針に従って実施した。【結果】運動+脳梗塞群は脳梗塞群に比べて、NDとladder testのスコアが低値となり有意に障害が軽度であった。LPとBWは群間に有意差は認められなかった。また、梗塞体積割合は運動+脳梗塞群の方が脳梗塞群よりも有意に小さかった。4-HNE 及び8-OHdG陽性細胞数は、運動+脳梗塞群の方が脳梗塞群に比べ有意に少なかった。一方、TRXの光学濃度は群間に有意な差は認められなかったが、SOD活性は運動+脳梗塞群が脳梗塞群に比べ高値を示す傾向にあった。【考察】脳梗塞モデル作成前に3 週間のトレッドミル運動を継続することで、脳梗塞後の麻痺の重症度および前肢の協調運動機能障害が軽減すること、梗塞体積が縮小すること、また脳梗塞時の脂質やDNAに対する酸化ストレスを抑制することが示された。さらに抗酸化酵素であるSOD活性が高められることが示された。これらの結果より、脳梗塞前の運動による脳梗塞の障害軽減効果には酸化ストレスの抑制とSODの活性化が関与していることが示唆された。【理学療法学研究としての意義】脳梗塞発症前の運動による脳梗塞障害軽減効果を行動学的、組織化学的に示した。加えて、運動による酸化ストレスの抑制と抗酸化作用の増加の関連も示され、その作用機序の一端を明らかにした。これらの結果は、脳梗塞の予防として推奨されている運動の効果を科学的に検討し、予防医療分野における理学療法のさらなる発展に寄与するものと考える。

    DOI: 10.14900/cjpt.2012.0.48101465.0

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  345. がんモデルマウス・ラットライブラリ 第7回 中皮腫モデル

    豊國 伸哉

    細胞工学   32 巻   頁: 220 - 224   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CiNii Research

  346. CD146 and IMP3 predict prognosis of asbestos-induced rat mesothelioma. 査読有り

    Okazaki Y, Nagai H, Chew SH, Jiang L, Funahashi S, Tsujimura T, Toyokuni S

    Cnacer Sci   104 巻   頁: 989-995   2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  347. The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. 査読有り 国際誌

    Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S, Ishiguro F, Osada H, Sekido Y, Yokoi K, Usami N, Shames DS, Kondo M, Gazdar AF, Minna JD, Hasegawa Y

    International journal of cancer   131 巻 ( 12 ) 頁: 2820 - 31   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Cancer  

    Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21WAF1/CIP1 and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM. Copyright © 2012 UICC.

    DOI: 10.1002/ijc.27598

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  348. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes

    Mizuno T., Murakami H., Fujii M., Ishiguro F., Tanaka I., Kondo Y., Akatsuka S., Toyokuni S., Yokoi K., Osada H., Sekido Y.

    ONCOGENE   31 巻 ( 49 ) 頁: 5117 - 5122   2012年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncogene  

    Malignant mesothelioma (MM) shows frequent inactivation of the neurofibromatosis type 2 (NF2)-tumor-suppressor gene. Recent studies have documented that the Hippo signaling pathway, a downstream cascade of Merlin (a product of NF2), has a key role in organ size control and carcinogenesis by regulating cell proliferation and apoptosis. We previously reported that MMs show overexpression of Yes-associated protein (YAP) transcriptional coactivator, the main downstream effector of the Hippo signaling pathway, which results from the inactivation of NF2, LATS2 and/or SAV1 genes (the latter two encoding core components of the mammalian Hippo pathway) or amplification of YAP itself. However, the detailed roles of YAP remain unclear, especially the target genes of YAP that enhance MM cell growth and survival. Here, we demonstrated that YAP-knockdown inhibited cell motility, invasion and anchorage-independent growth as well as cell proliferation of MM cells in vitro. We analyzed genes commonly regulated by YAP in three MM cell lines with constitutive YAP-activation, and found that the major subsets of YAP-upregulating genes encode cell cycle regulators. Among them, YAP directly induced the transcription of CCND1 and FOXM1, in cooperation with TEAD transcription factor. We also found that knockdown of CCND1 and FOXM1 suppressed MM cell proliferation, although the inhibitory effects were less evident than those of YAP knockdown. These results indicate that constitutive YAP activation in MM cells promotes cell cycle progression giving more aggressive phenotypes to MM cells. © 2012 Macmillan Publishers Limited All rights reserved.

    DOI: 10.1038/onc.2012.5

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  349. Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. 国際誌

    Kubo Y, Takenaka H, Nagai H, Toyokuni S

    Journal of clinical biochemistry and nutrition   51 巻 ( 3 ) 頁: 221 - 6   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    The inhalation of asbestos is a risk factor for the development of malignant mesothelioma and lung cancer. Based on the broad surface area of asbestos fibers and their ability to enter the cytoplasm and nuclei of cells, it was hypothesized that proteins that adsorb onto the fiber surface play a role in the cytotoxicity and carcinogenesis of asbestos fibers. However, little is known about which proteins adsorb onto asbestos. Previously, we systematically identified asbestos-interacting proteins and classified them into eight sub-categories: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. Here, we report an adsorption profile of proteins for the three commercially used asbestos compounds: chrysotile, crocidolite and amosite. We quantified the amounts of adsorbed proteins by analyzing the silver-stained gels of sodium dodecyl sulfate-polyacrylamide gel electrophoresis with ImageJ software, using the bands for amosite as a standard. We found that histones were most adsorptive to crocidolite and that chromatin-binding proteins were most adsorptive to chrysotile. The results suggest that chrysotile and crocidolite directly interact with chromatin structure through different mechanisms. Furthermore, RNA-binding proteins preferably interacted with chrysotile, suggesting that chrysotile may interfere with transcription and translation. Our results provide novel evidence demonstrating that the specific molecular interactions leading to carcinogenesis are different between chrysotile and crocidolite. ©2012 JCBN.

    DOI: 10.3164/jcbn.12-39

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  350. Iron overload signature in chrysotile-induced malignant mesothelioma

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

    Journal of Pathology   228 巻 ( 3 ) 頁: 366 - 377   2012年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pathology  

    Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    DOI: 10.1002/path.4075

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  351. Asbestos surface provides a niche for oxidative modification: A novel role of free radicals in carcinogenesis

    Nagai H., Okazaki Y., Jiang L., Akatsuka S., Yamashita Y., Toyokuni S.

    FREE RADICAL BIOLOGY AND MEDICINE   53 巻   頁: S51 - S52   2012年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.freeradbiomed.2012.08.529

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  352. Bovine lactoferrin ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats. 査読有り

    Okazaki Y, Kono I, Kuriki T, Funahashi S, Fushimi S, Iqbal M, Okada S, Toyokuni S

    Journal of clinical biochemistry and nutrition   51 巻 ( 2 ) 頁: 84 - 90   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本酸化ストレス学会  

    Milk provides a well-balanced source of amino acids and other ingredients. One of the functional ingredients in milk is lactoferrin (LF). LF presents a wide variety of bioactivities and functions as a radical scavenger in models using iron-ascorbate complexes and asbestos. Human clinical trials of oral LF administration for the prevention of colon polyps have been successful and demonstrated that dietary compounds exhibit direct interactions. However, antioxidative properties of LF in distant organs require further investigation. To study the antioxidant property of LF, we employed bovine lactoferrin (bLF) using the rat model of ferric nitrilotriacetate (Fe-NTA)-induced renal tubular oxidative injury. We fed rats with bLF (0.05%, w/w) in basal chow for 4 weeks and sacrificed them after Fe-NTA treatment. After intraperitoneal administration of 9.0 mg iron/kg Fe-NTA for 4 and 24 h, bLF pretreatment suppressed elevation of serum creatinine and blood urea nitrogen levels. In addition, we observed protective effects against renal oxidative tubular damage and maintenance of antioxidant enzyme activities in the bLF-pretreated group. We thus demonstrated the antioxidative effect of bLF against Fe-NTA-induced renal oxidative injury. These results suggest that LF intake is useful for the prevention of renal tubular oxidative damage mediated by iron. ©2012 JCBN.

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  353. Iron overload signature in chrysotile-induced malignant mesothelioma. 査読有り

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

    J Pathol   228 巻   頁: 366-377   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  354. Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis: Shedding light on fiber entry mechanism 国際誌

    Nagai Hirotaka, Toyokuni Shinya

    CANCER SCIENCE   103 巻 ( 8 ) 頁: 1378 - 1390   2012年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    The emergence of nanotechnology represents an important milestone, as it opens the way to a broad spectrum of applications for nanomaterials in the fields of engineering, industry and medicine. One example of nanomaterials that have the potential for widespread use is carbon nanotubes, which have a tubular structure made of graphene sheets. However, there have been concerns that they may pose a potential health risk due to their similarities to asbestos, namely their high biopersistence and needle-like structure. We recently found that despite these similarities, carbon nanotubes and asbestos differ in certain aspects, such as their mechanism of entry into mesothelial cells. In the study, we showed that non-functionalized, multi-walled carbon nanotubes enter mesothelial cells by directly piercing through the cell membrane in a diameter- and rigidity-dependent manner, whereas asbestos mainly enters these cells through the process of endocytosis, which is independent of fiber diameter. In this review, we discuss the key differences, as well as similarities, between asbestos fibers and carbon nanotubes. We also summarize previous reports regarding the mechanism of carbon nanotube entry into non-phagocytic cells. As the entry of fibers into mesothelial cells is a crucial step in mesothelial carcinogenesis, we believe that a comprehensive study on the differences by which carbon nanotubes and asbestos fibers enter into non-phagocytic cells will provide important clues for the safer manufacture of carbon nanotubes through strict regulation on fiber characteristics, such as diameter, surface properties, length and rigidity. © 2012 Japanese Cancer Association.

    DOI: 10.1111/j.1349-7006.2012.02326.x

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  355. Mitochondria and free radical studies on health, disease and pollution. 招待有り 国際誌

    Majima HJ, Toyokuni S

    Free radical research   46 巻 ( 8 ) 頁: 925 - 6   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    DOI: 10.3109/10715762.2012.700784

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  356. The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. 国際誌

    Kobayashi H, Yamashita Y, Iwase A, Yoshikawa Y, Yasui H, Kawai Y, Uchida K, Uno N, Akatsuka S, Takahashi T, Kikkawa F, Toyokuni S

    Fertility and sterility   98 巻 ( 2 ) 頁: 415 - 22.e1   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Fertility and Sterility  

    Objective: To understand the role of ectopic endometriotic stromal cells in ovarian endometriosis (OEM) and the associated risks for infertility and carcinogenesis. Design: Analyses of secreted proteins and gene expression using immortalized eutopic/ectopic endometrial(-otic) stromal cells from OEM. Setting: University. Patient(s): Women with and without OEM. Intervention(s): Samples of endometrial(-otic) tissue from women with or without OEM. Main Outcome Measure(s): Immunohistochemical analysis of oxidative stress in OEM, gene expression profiles, and the identification of secreted proteins by mass spectrometry in immortalized endometrial(-otic) stromal cells. Result(s): 4-Hydroxy-2-nonenal-modified proteins and carboxymethyllysine were abundant in the stroma, rather than epithelia, of OEM patients, indicating the presence of oxidative stress. Immortalized ectopic endometriotic stromal cells exhibited high IRP1/IRP2/HIF-1β expression and contained lower amounts of iron and copper than their eutopic counterparts. Expression profiles, in combination with protein identification, revealed that complement component 3 (C3) and pentraxin-3 (PTX3) are the major proteins secreted from immortalized ectopic endometriotic stromal cells. Complement-3/PTX3 promoted the secretion of various cytokines by THP1 macrophage cells and thus supported M1 differentiation. Conclusion(s): Immortalized ectopic endometriotic stromal cells in OEM predominantly secrete C3 and PTX3 and exhibit a differential regulation of iron metabolism. Copyright © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.

    DOI: 10.1016/j.fertnstert.2012.04.047

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  357. Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells. 国際誌

    Horio M, Sato M, Takeyama Y, Elshazley M, Yamashita R, Hase T, Yoshida K, Usami N, Yokoi K, Sekido Y, Kondo M, Toyokuni S, Gazdar AF, Minna JD, Hasegawa Y

    Annals of surgical oncology   19 Suppl 3 巻 ( Suppl 3 ) 頁: S634 - 45   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Annals of Surgical Oncology  

    Background: The role of ZEB1, a master epithelial-to-mesenchymal transition gene, in malignant pleural mesothelioma (MPM) is unclear. Methods: The expression of ZEB1, E-cadherin, vimentin, and epithelial cell adhesion molecule (EpCAM) in 18 MPM cell lines and a normal pleural mesothelial cell line MeT-5A was determined by quantitative real-time polymerase chain reaction and Western blot testing. RNA interference-mediated transient and/or stable knockdown of ZEB1 and EpCAM was performed. Microarray expression analysis was performed with a TORAY-3D gene chip. Growth was evaluated by colorimetric proliferation and colony formation assays. Luciferase reporter assay was performed to access the effects of ZEB1 knockdown on EpCAM promoter activity. Results: Most MPM cell lines exhibited mesenchymal phenotype and expressed ZEB1. Transient ZEB1 knockdown suppressed growth in all four cell lines studied (ACC-MESO-1, H2052, Y-MESO-8A, Y-MESO-29) while stable ZEB1 knockdown suppressed growth only in Y-MESO-29. Genome-wide gene expression analysis revealed that EpCAM was the most prominently up-regulated gene by both transient and stable ZEB1 knockdown in ACC-MESO-1, with more marked up-regulation in stable knockdown. We hypothesized that EpCAM up-regulation counteracts the stable ZEB1 knockdown-induced growth inhibition in ACC-MESO-1. Transient EpCAM knockdown suppressed growth dramatically in ACC-MESO-1 cells expressing shZEB1 but only modestly in those expressing shGFP, supporting our hypothesis. Luciferase reporter assay showed that ZEB1 knockdown resulted in increased EpCAM promoter activity. EpCAM was also up-regulated in Y-MESO-29 expressing shZEB1, but this EpCAM up-regulation did not counteract ZEB1knockdown-induced growth suppression, suggesting that the counteracting effects of EpCAM may be cellular context dependent. Conclusions: RNA interference-mediated ZEB1 knockdown may be a promising therapeutic strategy for MPM, but one has to consider the possibility of diminished growth inhibitory effects of long-term ZEB1 knockdown, possibly as a result of EpCAM up-regulation and/or other gene expression changes resulting from ZEB1 knockdown. © 2011 Society of Surgical Oncology.

    DOI: 10.1245/s10434-011-2142-0

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  358. FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation 国際誌

    Ishii Kei, Kanatsu-Shinohara Mito, Toyokuni Shinya, Shinohara Takashi

    DEVELOPMENT   139 巻 ( 10 ) 頁: 1734 - 1743   2012年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Development  

    Fibroblast growth factor 2 (FGF2) and glial cell line-derived neurotrophic factor (GDNF) are required to recapitulate spermatogonial stem cell (SSC) self-renewal in vitro. Although studies have revealed the role of the GDNF signaling pathway in SSCs, little is known about how FGF2 is involved. In the present study, we assessed the role of the FGF2 signaling pathway using a mouse germline stem (GS) cell culture system that allows in vitro expansion of SSCs. Adding GDNF or FGF2 induced phosphorylation of MAPK1/3, and adding the MAP2K1 inhibitor PD0325091 reduced GS cell proliferation and MAPK1/3 phosphorylation. Moreover, GS cells transfected with an activated form of Map2k1 not only upregulated Etv5 and Bcl6b gene expression, but also proliferated in an FGF2-independent manner, suggesting that they act downstream of MAP2K1 signaling to drive SSC self-renewal. Although GS cells transfected with Map2k1, Etv5 or Bcl6b showed normal spermatogonial markers, transplanting GS cells expressing Bcl6b into infertile mouse testes resulted in the formation of a germ cell tumor, suggesting that excessive self-renewal signals causes tumorigenic conversion. These results show that FGF2 depends on MAP2K1 signaling to drive SSC self-renewal via upregulation of the Etv5 and Bcl6b genes. © 2012. Published by The Company of Biologists Ltd.

    DOI: 10.1242/dev.076539

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  359. In vitro transformation of mouse testis cells by oncogene transfection. 査読有り

    Morimoto H, Lee J, Tanaka T, Ishii K, Toyokuin S, Kanatsu-Shinohara M and Shinohara T.

    Biol Reprod   86 巻 ( 5 ) 頁: 1-11   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  360. In vitro transformation of mouse testis cells by oncogene transfection. 査読有り 国際誌

    Morimoto H, Lee J, Tanaka T, Ishii K, Toyokuni S, Kanatsu-Shinohara M, Shinohara T

    Biology of reproduction   86 巻 ( 5 ) 頁: 148, 1-11 - 11   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biology of Reproduction  

    Germ cell tumors (GCTs) are unique in that they exhibit diverse biological characteristics and pathological features. Although several in vivo GCT models are available, studies on GCTs are hampered because in vivo development of GCTs is time consuming and prevents a detailed molecular analysis of the transformation process. Here we developed a novel strategy to transform mouse testis cells in vitro. Lentivirus-mediated transfection of dominant negative Trp53, Myc, and activated Hras1 into a CD9-expressing testis cells caused tumorigenic conversion in vitro. Although these cells resembled embryonic stem (ES) cells, they were aneuploid and lacked Nanog expression, which is involved in the maintenance of the undifferentiated state in ES cells. Euploid ES-like cells were produced by transfecting the Yamanaka factors (Pou5f1, Myc, Klf4, and Sox2) into the same cell population. Although these cells expressed Nanog, they were distinct from ES cells in that they expressed CD44, a cancer stem cell antigen. Both treatments induced similar changes in the DNA methylation patterns in differentially methylated regions of imprinted genes. Moreover, despite the differences in their phenotype and karyotype, both cell types similarly produced mixed GCTs on transplantation, which were composed of teratomas, seminomas, and embryonal carcinomas. Thus, in vitro testis cell transformation facilitates an analysis of the GCT formation process, and our results also suggest the close similarity between GCT formation and reprogramming. © 2012 by the Society for the Study of Reproduction, Inc.

    DOI: 10.1095/biolreprod.111.095307

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  361. 過剰鉄と活性酸素を介した発がん機構と予防・治療への展開

    豊國 伸哉

    臨床血液   53 巻 ( 4 ) 頁: 401 - 408   2012年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:「臨床血液」編集部  

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  362. 過剰鉄と活性酸素を介した発がん機構と予防・治療への展開

    豊國 伸哉

    臨床血液   53 巻 ( 4 ) 頁: 401 - 408   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:「臨床血液」編集部  

  363. Genome-wide assessment of oxidatively generated DNA damage. 国際誌

    Akatsuka S, Toyokuni S

    Free radical research   46 巻 ( 4 ) 頁: 523 - 30   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    In the tide of science nouveau after the completion of genome projects of various species, there appeared a movement to understand an organism as a system rather than the sum of cells directed for certain functions. With the advent and spread of microarray techniques, systematic and comprehensive genome-wide approaches have become reasonably possible and more required on the investigation of DNA damage and the subsequent repair. The immunoprecipitation- based technique combined with high-density microarrays or next-generation sequencing is one of the promising methods to provide access to such novel research strategies. Oxygen is necessary for most of the life on earth for electron transport. However, reactive oxygen species are inevitably generated, giving rise to steady-state levels of DNA damage in the genome, that may cause mutations leading to cancer, ageing and degenerative diseases. Previously, we showed that there are many factors involved in the genomic distribution of oxidatively generated DNA damage including chromosome territory, and proposed this sort of research area as oxygenomics. Recently, RNA is also recognized as a target of this kind of modification. © 2012 Informa UK, Ltd.

    DOI: 10.3109/10715762.2011.633212

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  364. [Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy].

    Toyokuni S

    [Rinsho ketsueki] The Japanese journal of clinical hematology   53 巻 ( 4 ) 頁: 401 - 8   2012年4月

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    掲載種別:研究論文(学術雑誌)  

    PubMed

  365. [Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy].

    Toyokuni S

    [Rinsho ketsueki] The Japanese journal of clinical hematology   53 巻 ( 4 ) 頁: 401 - 8   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  366. Age- and sun exposure-dependent differences in 8-hydroxy-2 '-deoxyguanosine and N epsilon-(carboxymethyl)lysine in human epidermis

    Kawada Akira, Date Akira, Toyokuni Shinya

    JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY   66 巻 ( 4 ) 頁: AB174 - AB174   2012年4月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  367. 多層カーボンナノチューブの直径と剛性は、中皮細胞傷害と中皮腫形成に重要な因子である

    永井 裕崇, 岡崎 泰昌, 周 珊瑚, 三澤 伸明, 山下 依子, 赤塚 慎也, 石原 敏和, 山下 享子, 吉川 豊, 安井 裕之, 蒋 麗, 高橋 隆, 市原 学, 宮田 耕充, 篠原 久典, 豊國 伸哉

    日本病理学会会誌   101 巻 ( 1 ) 頁: 280 - 280   2012年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本病理学会  

  368. Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary

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

    LABORATORY INVESTIGATION   92 巻   頁: 302A - 302A   2012年2月

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  369. FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b genes through MAP2K1 activation. 査読有り

    Ishii K, Kanatsu-Shinohara M, Toyokuni S and Shinohara T.

    Development   139 巻   頁: 1734-1743   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  370. Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis. 査読有り

    Nagai H and Toyokuni S.

    Cancer Sci   103 巻   頁: 1378-1390   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  371. The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. 査読有り

    Kobayashi H, Yamashita Y, Iwase A, Yoshikawa Y, Yasui H, Kawai Y, Uchida K, Uno N, Akatsuka S, Takahashi T, Kikkawa F, Toyokuni S.

    Fertil Steril   98 巻   頁: 415-422   2012年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  372. Mitochondria and free radical studies on health, disease and pollusion (editorial). 招待有り

    Majima HJ and Toyokuni S.

    Free Radic Res   46 巻   頁: 925-926   2012年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  373. Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. 招待有り 査読有り

    Kubo Y, Takenaka H, Nagai H and Toyokuni S.

    J Clin Biochem Nutr   51 巻   頁: 221-226   2012年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  374. The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. 査読有り

    Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S, Ishiguro F, Osada H, Sekido Y, Yokoi K, Usami N, Shames DS, Kondo M, Gazdar AF, Minna JD and Hasegawa Y.

    INt J Cancer   131 巻   頁: 2820-2831   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  375. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle promoting genes. 査読有り

    Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, Akatsuka S, Toyokuni S and Sekido Y.

    Oncogene   31 巻   頁: 5117-5122   2012年

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  376. Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothalioma cells. 査読有り

    Horio M, Sato M, Takayama Y, Elshazley M, Yamashita R, Hase T, Yoshida K, Usami N, Yokoi K, Sekido Y, Kondo M, Toyokuni S, Gazdar AF, Minna JD and Hasegawa Y.

    Ann Surg Oncol   19 巻 ( Suppl 3 ) 頁: 634-645   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  377. Genome-wide assessment of oxidatively generated DNA damage. 査読有り

    Akatsuka S and Toyokuni S.

    Free Radic Res   46 巻   頁: 523-530   2012年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  378. Bovine lactoferrin ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats. 査読有り

    Okazaki Y, Kono H, Kuriki R, Funahashi S, Fushimi S, Iqbal M, Okada S and Toyokuni S.

    J Clin Biochem Nutr   51 巻   頁: 84-90   2012年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

  379. Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis. 査読有り

    Nagai H, Toyokuni S

    Cancer Sci   103 巻   頁: 1378-1390   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  380. FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b genes through MAP2K1 activation. 査読有り

    Ishii K, Kanatsu-Shinohara M, Toyokuni S, Shinohara T

    Development   139 巻   頁: 1734-1743   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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

    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, Toyokuni S

    PloS one   7 巻 ( 8 ) 頁: e43403   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis. © 2012 Akatsuka et al.

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  382. 過剰鉄と活性酸素を介した発がん機構と予防・治療への展開

    豊國 伸哉

    臨床血液   53 巻 ( 4 ) 頁: 401 - 408   2012年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本血液学会  

    DOI: 10.11406/rinketsu.53.401

  383. 酸化ストレスによるゲノム変化と発がん

    赤塚 慎也, 豊國 伸哉

    実験医学   vol.30 巻   頁: 2779 - 2785   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CiNii Research

  384. Asbestos surface provides a niche for oxidative modification

    NAGAI Hirotaka, ISHIHARA Toshikazu, LEE Wen-Hua, OHARA Hiroki, OKAZAKI Yasumasa, OKAWA Katsuya, TOYOKUNI Shinya

    Cancer science   102 巻 ( 12 ) 頁: 2118 - 2125   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  385. Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. 査読有り 国際誌

    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, Toyokuni S

    Proceedings of the National Academy of Sciences of the United States of America   108 巻 ( 49 ) 頁: E1330-8 - 8   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Proceedings of the National Academy of Sciences of the United States of America  

    Multiwalled carbon nanotubes (MWCNTs) have the potential for widespread applications in engineering and materials science. However, because of their needle-like shape and high durability, concerns have been raised that MWCNTs may induce asbestos-like pathogenicity. Although recent studies have demonstrated that MWCNTs induce various types of reactivities, the physicochemical features of MWCNTs that determine their cytotoxicity and carcinogenicity in mesothelial cells remain unclear. Here, we showed that the deleterious effects of nonfunctionalized MWCNTs on human mesothelial cells were associated with their diameter-dependent piercing of the cell membrane. Thin MWCNTs (diameter ∼ 50 nm) with high crystallinity showed mesothelial cell membrane piercing and cytotoxicity in vitro and subsequent inflammogenicity and mesotheliomagenicity in vivo. In contrast, thick (diameter ∼ 150 nm) or tangled (diameter ∼ 2-20 nm) MWCNTs were less toxic, inflammogenic, and carcinogenic. Thin and thick MWCNTs similarly affected macrophages. Mesotheliomas induced by MWCNTs shared homozygous deletion of Cdkn2a/2b tumor suppressor genes, similar to mesotheliomas induced by asbestos. Thus, we propose that different degrees of direct mesothelial injury by thin and thick MWCNTs are responsible for the extent of inflammogenicity and carcinogenicity. This work suggests that control of the diameter of MWCNTs could reduce the potential hazard to human health.

    DOI: 10.1073/pnas.1110013108

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  386. Asbestos surface provides a niche for oxidative modification. 国際誌

    Nagai H, Ishihara T, Lee WH, Ohara H, Okazaki Y, Okawa K, Toyokuni S

    Cancer science   102 巻 ( 12 ) 頁: 2118 - 25   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

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

    DOI: 10.1111/j.1349-7006.2011.02087.x

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  387. miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. 国際誌

    Nishikawa E, Osada H, Okazaki Y, Arima C, Tomida S, Tatematsu Y, Taguchi A, Shimada Y, Yanagisawa K, Yatabe Y, Toyokuni S, Sekido Y, Takahashi T

    Cancer research   71 巻 ( 19 ) 頁: 6165 - 73   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Research  

    Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. ©2011 AACR.

    DOI: 10.1158/0008-5472.CAN-11-1020

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  388. Age-and sun exposure-dependent differences in 8-hydroxy-2 '-deoxyguanosine and N-epsilon-(carboxymethyl)lysine in human epidermis

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

    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION   49 巻 ( 2 ) 頁: 121 - 124   2011年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Biochemistry and Nutrition  

    Aging and exposure to sunlight are two major factors in the deterioration of skin function. In this study, thirty-six fixed human skin samples from sun-exposed and unexposed areas from young and old individuals were used to evaluate the localization of oxidative stress according to levels and distribution of 8-hydroxy-2′-deoxyguanosine and N ε- (carboxymethyl)lysine in samples using immunohistochemistry. In the epidermis of the young, negligible amounts of 8-hydroxy-2′-deoxyguanosine and N ε-(carboxymethyl)lysine were detected in unexposed areas, whereas nuclear 8-hydroxy-2′-deoxyguanosine and cytoplasmic N ε-(carboxymethyl)lysine were increased in the lower epidermis in sun-exposed areas. In contrast, the aged presented prominent nuclear 8-hydroxy-2′-deoxyguanosine and nuclear N ε-(carboxymethyl) lysine in the epidermis of unexposed areas, concomitant with dermal increase in N ε-(carboxymethyl)lysine. However, the immunostaining of 8-hydroxy-2′-deoxyguanosine and N ε-(carboxymethyl)lysine revealed a decrease in the epidermis of sun-exposed areas in the aged. These results suggest an age-dependent difference in the adaptation and protective mechanisms of the epidermis against sunlight-associated oxidative stress, thus necessitating distinct standards for evaluation in each age group. Further investigation is warranted to elucidate underlying molecular mechanisms. ©2011 JCBN.

    DOI: 10.3164/jcbn.11-05

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  389. BMAL1 depletion represses growth of mesothelioma through induction of mitotic catastrophe

    Elshazley Momen H. K. A., Hasegawa Yoshinor, Sato Mitsuo, Hase Tetsunari, Yoshida Kenya, Toyokuni Shinya, Seikido Yoshitaka, Yokoi Kohei, Usami Noriyasu, Kondo Masashi

    CANCER RESEARCH   71 巻   2011年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1158/1538-7445.FBCR11-C37

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  390. MET Amplification is a Molecular Hallmark in Endometriosis-associated Ovarian Clear Cell Carcinoma and Correlates With Worse Prognosis

    Yamashita Y., Yatabe Y., Akatsuka S., Kajiyama H., Kikkawa F., Takahashi T., Toyokuni S.

    EUROPEAN JOURNAL OF CANCER   47 巻   頁: S529 - S529   2011年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  391. Elucidation of asbestos-induced mesothelial carcinogenesis toward its prevention

    Jiang L., Toyokuni S.

    Genes and Environment   33 巻 ( 1 ) 頁: 4 - 9   2011年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Genes and Environment  

    Human exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in the pleural and abdominal cavity. Despite advancements in the molecular analyses of human cases of DMM and animal models, the understanding of the carcinogenic mechanisms remains still limited. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be integrated as follows; (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of reactive oxygen species (ROS) due to their inability to digest the fibers, and that iron contained in crocidolite and amosite fibers works as a catalyst for the generation of ROS, (2) the "chromosome tangling theory" postulates that asbestos fibers impair the equivalent distribution of chromosomes during mitosis, and (3) the "theory of adsorbing many specific proteins as well as carcinogenic molecules" states that asbestos fibers in vivo concentrate specific proteins or chemicals including the components of cigarette smoke and radioactive chemical element. Recent studies suggest that local iron overload is a key event. Elucidation of the major mechanisms underlying DMM would be helpful for the development of strategies to prevent DMM generation in people who have been exposed to asbestos. © The Japanese Environmental Mutagen Society.

    DOI: 10.3123/jemsge.33.4

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  392. Iron as a target of chemoprevention for longevity in humans 国際誌

    Toyokuni Shinya

    FREE RADICAL RESEARCH   45 巻 ( 8 ) 頁: 906 - 917   2011年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Free Radical Research  

    Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases. © 2011 Informa UK, Ltd.

    DOI: 10.3109/10715762.2011.564170

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  393. Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice. 国際誌

    Fan YY, Ran Q, Toyokuni S, Okazaki Y, Callaway ES, Lupton JR, Chapkin RS

    Cancer prevention research (Philadelphia, Pa.)   4 巻 ( 8 ) 頁: 1267 - 74   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Prevention Research  

    An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2Het, Gpx4Het, and transgenic Gpx4Tg mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4Het > SOD2Het > Wt > Gpx4Tg), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4Het and SOD2Het mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4Tg mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P < 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk. ©2011 AACR.

    DOI: 10.1158/1940-6207.CAPR-10-0368

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  394. The human cytomegalovirus gene products essential for late viral gene expression assemble into prereplication complexes before viral DNA replication.

    Isomura H, Stinski MF, Murata T, Yamashita Y, Kanda T, Toyokuni S, Tsurumi T

    Journal of virology   85 巻 ( 13 ) 頁: 6629 - 44   2011年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Virology  

    The regulation of human cytomegalovirus (HCMV) late gene expression by viral proteins is poorly understood, and these viral proteins could be targets for novel antivirals. HCMV open reading frames (ORFs) UL79, -87, and -95 encode proteins with homology to late gene transcription factors of murine gammaherpesvirus 68 ORFs 18, 24, and 34, respectively. To determine whether these HCMV proteins are also essential for late gene transcription of a betaherpesvirus, we mutated HCMV ORFs UL79, -87, and -95. Cells were infected with the recombinant viruses at high and low multiplicities of infection (MOIs). While viral DNA was detected with the recombinant viruses, infectious virus was not detected unless the wild-type viral proteins were expressed in trans. At a high MOI, mutation of ORF UL79, -87, or -95 had no effect on the level of major immediate-early (MIE) gene expression or viral DNA replication, but late viral gene expression from the UL44, -75, and -99 ORFs was not detected. At a low MOI, preexpression of UL79 or -87, but not UL95, in human fibroblast cells negatively affected the level of MIE viral gene expression and viral DNA replication. The products of ORFs UL79, -87, and -95 were expressed as early viral proteins and recruited to prereplication complexes (pre-RCs), along with UL44, before the initiation of viral DNA replication. All