研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Homozygous Deletion of CDKN2A/2B is a Hallmark of Iron-induced High-grade Rat Mesothelioma 査読有り国際誌

Okazaki, Y; Hu, QA; Akatsuka, S; Ohara, H; Nagai, H; Takahashi, T; Toyokuni, S

FREE RADICAL BIOLOGY AND MEDICINE 49 巻頁： S67 - S67 2010年

Biopersistent fiber-induced inflammation and carcinogenesis: lessons learned from asbestos toward safety of fibrous nanomaterials. 査読有り

Nagai H, Toyokuni S

Arch Biochem Biophys 502 巻頁： 1-7 2010年

CD8+CD122+ Regulatory T Cells and CD4+ Treg Cooperatively Prevent and Cure CD4+ cell-induced Colitis. 査読有り

Endharti AT, Okuno Y, Shi Z, Misawa N, Toyokuni S, Ito M, Isobe KI, Suzuki H

J Immunol 186 巻頁： 41-52 2010年

Stage-specific roles of fibulin-5 during oxidative stress-induced renal carcinogenesis in rats. 査読有り

Ohara H, Akatsuka S, Nagai H, Liu YT, Jiang L, Okazaki Y, Yamashita Y, Nakamura T, Toyokuni S

Free Radic Res 頁： (in press) 2010年

Toward a new era of the Nagoya Journal of Medical Science: message from the new editor-in-chief. 招待有り

Toyokuni S

Nagoy J Med Sci 72 巻頁： 107-109 2010年

脳梗塞モデルラット作成前に実施する運動の効果および作用機序の検討:～抗酸化作用に着目して～国際誌

濱川みちる, 石田章真, 玉越敬悟, 嶋田悠, 中島宏樹, 豊國伸哉, 石田和人

東海北陸理学療法学術大会誌 26 巻 ( 0 ) 頁： 35 - 35 2010年

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：東海北陸理学療法学術大会

【目的】脳梗塞モデル作成前の運動には、梗塞体積減少、運動機能改善などの脳梗塞の障害軽減効果があると報告されている。また、運動は抗酸化作用を高めることが報告されているが、抗酸化作用が脳梗塞の障害軽減効果にいかに関与するかについては不明である。そこで本研究では、脳梗塞発症前に運動を行うことの効果および作用機序を抗酸化作用に着目して検討する。【方法】実験動物にはWistar系雄性ラット(5週齢)を用いた。無作為に運動群と非運動群に分け、運動群はトレッドミル運動(15 m / min、30分/日)を3週間毎日行った。非運動群は1日30分間走行させずにトレッドミル装置内に暴露させた。介入終了の翌日、各群に脳梗塞モデル作成手術を施行した。手術24時間後に、麻痺の重症度を評価するNeurological Deficits(ND)、歩行時のバランス能力の評価としてBeam Walking(BW)、はしご上の歩行における前肢の協調運動機能を評価するLadder test、前肢の感覚運動機能の評価としてLimb Placing(LP)を行った。その直後に脳を採取し、TTC染色により非梗塞半球体積に対する梗塞体積の割合を算出した。また、酸化ストレス産物の指標として4-hydroxy-2-nonenal (4-HNE)及び8-Hydroxydeoxyguanosine(8-OHdG)の免疫染色を行った。統計学的検定には、対応のないt検定とMann-WhitneyのU検定を用い、有意水準は5％未満とした。【結果】NDとladder testにおいて、運動群が非運動群と比較して有意に障害が軽減した（<I>p</I> < 0.05）。また、他の機能評価や梗塞体積については群間に有意差は認められなかった。免疫染色では、非梗塞側半球で運動群に比べ非運動群は4-HNE陽性細胞が多くみられた。しかし、8-OHdG染色では差を認めなかった。【まとめ】脳梗塞前の運動は、梗塞後の運動機能改善効果をもたらしたものの、梗塞体積は非運動群と同程度であった。しかし、脂質過酸化の指標である4-HNE陽性細胞は非運動群の非梗塞側でより多く見られ、運動による酸化ストレス抑制効果が示された。<BR>本研究は科研費（22500456）の助成を受けたものである。

DOI： 10.11529/thpt.26.0.35.0

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S1-3 アスベスト誘発中皮腫の発がん機構の解明とその予防への応用(シンポジウム1:「生活習慣・環境因子とバイオマーカー」)

豊國伸哉

日本環境変異原学会大会プログラム・要旨集 ( 38 ) 頁： 75 2009年11月

ITPase-deficient mice show growth retardation and die before weaning. 査読有り

Behrmanech M, Sakumi K, Abolhassani N, Toyokuni S, Oka S, Ohnishi YN, Tsuchimoto D, Nakabeppu Y.

Cell Death Differ. 16 巻頁： 1315-1322 2009年10月

ITPase-deficient mice show growth retardation and die before weaning 査読有り国際誌 Open Access

Behmanesh, M; Sakumi, K; Abolhassani, N; Toyokuni, S; Oka, S; Ohnishi, YN; Tsuchimoto, D; Nakabeppu, Y

CELL DEATH AND DIFFERENTIATION 16 巻 ( 10 ) 頁： 1315 - 1322 2009年10月

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 Death and Differentiation

Inosine triphosphate pyrophosphatase (ITPase), the enzyme that hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding purine nucleoside monophosphate and pyrophosphate, is encoded by the Itpa gene. In this study, we established Itpa knockout (KO) mice and used them to show that ITPase is required for the normal organization of sarcomeres in the heart. Itpa-/- mice died about 2 weeks after birth with features of growth retardation and cardiac myofiber disarray, similar to the phenotype of the cardiac α-actin KO mouse. Inosine nucleotides were found to accumulate in both the nucleotide pool and RNA of Itpa-/- mice. These data suggest that the role of ITPase in mice is to exclude ITP from the ATP pool, and the main target substrate of this enzyme is rITP. Our data also suggest that cardiomyopathy, which is mainly caused by mutations in sarcomeric protein-encoding genes, is also caused by a defect in maintaining the quality of the ATP pool, which is an essential requirement for sarcomere function.

DOI： 10.1038/cdd.2009.53

Potent antioxidative acticity of Vineatrol® 30 grapevine-shoot extract. 査読有り

Müller C, Ullmann K, Wilkins A, Winterhalter P, Toyokuni S and Steinberg P.

Biosci Biotechnol Biochem 73 巻頁： 1831-1836 2009年8月

Elucidation of asbestos-induced carcinogenesis and its application to prevention, diagnosis and treatment in relation to iron 国際誌 Open Access

Toyokuni S.

Japanese Journal of Lung Cancer 49 巻 ( 4 ) 頁： 362 - 367 2009年8月

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 Lung Cancer

Objective. Respiratory exposure to asbestos has been associated with mesothelioma in humans. However, its carcinogenic mechanism is still unclear. Methods. Here we studied the ability of chrysotile, crocidolite and amosite fibers to induce oxidative DNA damage and the modifying factors using 4 distinct approaches. Results. Electron spin resonance analyses showed that crocidolite and amosite containing high amounts of iron, but not chrysotile, catalyzed hydroxyl radical formation in the presence of hydrogen peroxide, which was enhanced by an iron chelator, nitrilotriacetic acid, and suppressed by Desferal®. Iron chelators, such as citrate, ATP and GTP, did not inhibit this reaction. Second, we used time-lapse videomicroscopy to evaluate how cells deal with asbestos fibers. RAW264.7 cells, MeT-5A and HeLa cells engulfed asbestos fibers, which reached not only cytoplasm but also the nucleus. Third, we utilized supercoiled plasmid DNA to evaluate the ability of each type of asbestos to induce DNA double strand breaks (DSBs). Crocidolite and amosite, but not chrysotile, induced DNA DSBs in the presence of iron chelators. We cloned the fragments to identify break ends. DSBs tended to occur within repeat sequences and between two G:C sequences. Finally, intraperitoneal administration of each type of asbestos to rats induced not only formation of nuclear 8-hydroxy-2′-deoxyguanosine in the mesothelium but also significant iron deposits in the spleen. Conclusion. Together with the established carcinogenicity of intraperitoneal chrysotile, our data suggest that asbestos-associated catalytic iron, whether constitutional or induced by other mechanisms, plays a role in asbestos-induced carcinogenesis and that chemoprevention may be possible through targeting the catalytic iron. © 2009 The Japan Lung Cancer Society.

DOI： 10.2482/haigan.49.362

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Potent Antioxidative Activity of Vineatrol®30 Grapevine-shoot Extract 査読有り国際誌 Open Access

Müller, C; Ullmann, K; Wilkens, A; Winterhalter, P; Toyokuni, S; Steinberg, P

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 73 巻 ( 8 ) 頁： 1831 - 1836 2009年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Bioscience, Biotechnology and Biochemistry

The health promoting effects of a grapevine-shoot extract named Vineatrol®30, which contains resveratrol (Resv) as well as considerable amounts of Resv oligomers, have recently been investigated. In the present study, we analyzed the free radical scavenging capacity, the ability to inhibit lipid peroxidation, and the capacity to enhance the human glutathione peroxidase 1 (GPx) and the human superoxide dismutase 1 (SOD) gene promoter activities of Vineatrol®30. Vineatrol®30 was able to scavenge the 2,2'-azinobis-3- ethylbenzothiazoline-6-sulfonic acid radical cation and led to concentration-dependent inhibition of lipid peroxidation, Vineatrol®30 not being superior to Resv alone in both cases. Vineatrol®30 also enhanced the gene promoter activities of human GPx and SOD expressed in V79 cells, whereas this effect could not be demonstrated for Resv. In summary, the results presented in this study show that the Vineatrol®30 grapevine-shoot extract is a free radical scavenger and potent antioxidant at non-cytotoxic concentrations.

DOI： 10.1271/bbb.90213

B細胞性芽球型リンパ腫ゲノムにおけるマイクロサテライト不安定性(Microsatellite instability in the genome of B-lymphoblastic lymphoma)

リチャード・カシンスキー, 鶴山竜昭, 河野文彦, 平塚拓也, 尾関宗孝, 豊國伸哉, 日合弘, 玉木敬二

日本癌学会総会記事 68回巻頁： 163 - 163 2009年8月

Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro by Ras-cyclin D2 activation. 査読有り国際誌 Open Access

Lee J, Kanatsu-Shinohara M, Morimoto H, Kazuki Y, Takashima S, Oshimura M, Toyokuni S, Shinohara T

Cell stem cell 5 巻 ( 1 ) 頁： 76 - 86 2009年7月

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 Stem Cell

Spermatogonial stem cells (SSCs) undergo self-renewal division and support spermatogenesis. Although several cytokines coordinate to drive SSC self-renewal, little is known about the mechanisms underlying this process. We investigated the molecular mechanism by reconstructing SSC self-renewal in vitro without exogenous cytokines. Activation of Ras or overexpression of cyclins D2 and E1, both of which were induced by Ras, enabled long-term self-renewal of cultured spermatogonia. SSCs with activated Ras responded properly to differentiation signals and underwent spermatogenesis, whereas differentiation was abrogated in cyclin transfectants after spermatogonial transplantation. Both Ras- and cyclin-transfected cells produced seminomatous tumors, suggesting that excessive self-renewing stimulus induces oncogenic transformation. In contrast, cells that overexpressed cyclin D1 or D3 failed to make germ cell colonies after transplantation, which indicated that cyclin expression pattern is an important determinant to long-term SSC recolonization. Thus, the Ras-cyclin D2 pathway regulates the balance between tissue maintenance and tumorigenesis in the SSC population. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.stem.2009.04.020

Abnormal DNA methyltransferase expression in mouse germline stem cells results in spermatogenic defects. 査読有り

Takashima S, Takehashi M, Lee J, Chuma S, Okano M, Hata K, Suetake I, Nakatsuji N, Miyoshi H, Tajima S, Tanaka Y, Toyokuni S, Sasaki H, Kanatsu-Shinohara M, Shinohara S.

81 巻頁： 155-164 2009年7月

Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro by Ras-cyclin D2 activation. 査読有り

Lee J, Kanatsu-Shinohara M, Morimoto H, Kazuki Y, Takashima S, Oshimura M, Toyokuni S and Shinohara T.

Cell Stem Cell 5 巻頁： 76-86 2009年7月

Abnormal DNA methyltransferase expression in mouse germline stem cells results in spermatogenic defects. 査読有り国際誌

Takashima S, Takehashi M, Lee J, Chuma S, Okano M, Hata K, Suetake I, Nakatsuji N, Miyoshi H, Tajima S, Tanaka Y, Toyokuni S, Sasaki H, Kanatsu-Shinohara M, Shinohara T

Biology of reproduction 81 巻 ( 1 ) 頁： 155 - 64 2009年7月

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

Although spermatogonial stem cells (SSCs) are committed to spermatogenesis, they may also convert to an embryonic stem cell-like pluripotent state at a low frequency. Because changes in DNA methylation patterns are associated with this conversion, we examined the effect of manipulating DNA methyltransferase (Dnmt) expression on the fate of cultured SSCs, germline stem (GS) cells. Dnmt1 knockdown induced apoptosis in GS cells, which was attenuated by the loss of Trp53. In contrast, GS cells proliferated normally in vitro after Dnmt3a/Dnmt3b ablation or during Dnmt3l overexpression. However, Dnmt3a/Dnmt3b double-mutant cells showed hypomethylation in the SineB1 repetitive sequence, and Dnmt3l-overexpressing cells showed hypermethylation in major and minor satellite sequences; neither cell type formed teratomas and completed spermatogenesis following transplantation into the seminiferous tubules. Although genetic manipulation did not increase the conversion of GS cells to a pluripotent state, these results underscore the important role of DNMTs in survival and spermatogenic differentiation in SSCs. © 2009 by the Society for the Study of Reproduction, Inc.

DOI： 10.1095/biolreprod.108.074708

Proapoptotic Effects of Dietary (n-3) Fatty Acids Are Enhanced in Colonocytes of Manganese-Dependent Superoxide Dismutase Knockout Mice 国際誌 Open Access

Fan, YY; Zhan, Y; Aukema, HM; Davidson, LA; Zhou, L; Callaway, E; Tian, Y; Weeks, BR; Lupton, JR; Toyokuni, S; Chapkin, RS

JOURNAL OF NUTRITION 139 巻 ( 7 ) 頁： 1328 - 1332 2009年7月

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 Nutrition

We recently demonstrated that (n-3) PUFA trigger the induction of apoptosis in the colon by enhancing phospholipid oxidation and mitochondrial Ca 2+ accumulation. To further elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, a 2 x 2 experiment was designed using both wild type (control) and manganese-dependent superoxide dismutase (SOD2) heterozygous knockout mice (SOD2+/-), which exhibit increased mitochondrial oxidative stress. Mice were fed diets differing only in the type of fat [corn oil or fish oil containing (n-3) PUFA] at 15% by weight for 4 wk. Dietary (n-3) PUFA treatment enhanced (22%) apoptosis in colonic crypts. In addition, SOD2 haploinsufficiency enhanced (20%) apoptosis, which was further increased (36%) by (n-3) PUFA feeding. Dietary lipid source and genotype interactively modulated nitrotyrosine levels (P = 0.027) and inflammation (P = 0.032). These findings demonstrate that the proapoptotic effects of (n-3) PUFA are enhanced in oxidatively stressed SOD2+/- mice. Thus, (n-3) PUFA appear to promote an oxidation-reduction imbalance in the intestine, which may directly or indirectly trigger apoptosis and thereby reduce colon cancer risk. © 2009 American Society for Nutrition.

DOI： 10.3945/jn.109.106203

The potential role of reactive oxygen species in mammary neoplasm 査読有り国際誌

Arafah M., Khabaz M., Toyokuni S.

Australian Journal of Basic and Applied Sciences 3 巻 ( 3 ) 頁： 2949 - 2954 2009年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Australian Journal of Basic and Applied Sciences

The current study investigated the presence of oxidative stress markers (8-OHdG and HNE) in breast carcinoma in females from Saudi Arabia, and to examine the growth modulatory effects of HNE (induce cell growth inhibition) by measuring the expression of Ki-67 protein (cell proliferation antigen). Furthermore, to record if there is any significant prognostic indicator of these markers. In order to estimate the level of oxidative damage in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE) expressions were investigated in breast carcinoma and benign lesions of breast, and were estimated by semi-quantitative immunohistochemical method. The observations of the present study showed that the level of expressions of 8-OHdG and HNE were significantly higher than those in controls. Reduction of oxidative stress is thought to be a very important measure for primary prevention of breast carcinoma. © 2009, INSInet Publication.

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The potential role of reactive oxygen species in mammary neoplasm 国際誌

Arafah M, Khabaz M, Toyokuni S

Australian Journal of Basic and Applied Sciences 3 巻 ( 3 ) 頁： 2949 - 2954 2009年7月

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：Australian Journal of Basic and Applied Sciences

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