Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Genome-Scale Approaches to Investigate Oxidative DNA Damage Reviewed

Shinya Akatsuka, Shinya Toyokuni

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 47 ( 2 ) page： 91 - 97 2010.9

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

In the trend of biological science after the completion of the human genome project, appreciation of an organism as a system rather than the sum of many molecular functions is necessary. On the investigation of DNA damage and repair, therefore, the orientation toward systematic and comprehensive genome-scale approaches is rapidly growing. The immuno-precipitation-based technique combined with high-density microarrays is one of the promising methods to provide access to such novel research strategies. We propose this sort of research area as oxygenomics.

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Genome-Scale Approaches to Investigate Oxidative DNA Damage

Akatsuka Shinya, Toyokuni Shinya

Journal of Clinical Biochemistry and Nutrition Vol. 47 ( 2 ) page： 91 - 97 2010.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SOCIETY FOR FREE RADICAL RESEARCH JAPAN

In the trend of biological science after the completion of the human genome project, appreciation of an organism as a system rather than the sum of many molecular functions is necessary. On the investigation of DNA damage and repair, therefore, the orientation toward systematic and comprehensive genome-scale approaches is rapidly growing. The immunoprecipitation-based technique combined with high-density microarrays is one of the promising methods to provide access to such novel research strategies. We propose this sort of research area as oxygenomics.<br>

DOI： 10.3164/jcbn.10-38R

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Suppression of SLC11A2 expression is essential to maintain duodenal integrity during dietary iron overload. International journal

Tomoyuki Shirase, Kiyoshi Mori, Yasumasa Okazaki, Ken Itoh, Masayuki Yamamoto, Mitsuaki Tabuchi, Fumio Kishi, Li Jiang, Shinya Akatsuka, Kazuwa Nakao, Shinya Toyokuni

The American journal of pathology Vol. 177 ( 2 ) page： 677 - 85 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

Iron is essential for the survival of mammals, but iron overload causes fibrosis and carcinogenesis. Reduced iron absorption and regulated release into circulation in duodenal mucosa constitute two major mechanisms of protection against dietary iron overload; however, their relative contribution remains elusive. To study the significance of the former process, we generated SLC11A2 transgenic mice (TGs) under the control of the chicken beta-actin promoter. TGs were viable and fertile, and displayed no overt abnormalities up to 20 months. No significant difference in iron concentration was observed in major solid organs between TGs and their wild-type littermates, suggesting that increased number of iron transporters does not lead to increased iron absorption. To test the sensitivity to iron overload, TGs and wild-type mice were fed with an iron-rich diet containing 2% ferric citrate. Iron supplementation caused suppression of endogenous duodenal SLC11A2 expression, down-regulation of duodenal ferroportin, and overexpression of hepatic hepcidin, precluding excessive iron uptake both in the TGs and wild-type mice. However, iron-treated TGs revealed increased mortality, resulting from oxidative mucosal damage leading to hemorrhagic erosion throughout the whole intestinal area. These findings suggest that reduced iron release from duodenal cells into circulation plays a role in mitigating excessive iron uptake from the diet and that finely regulated duodenal absorption is essential to protect intestinal mucosa from iron-induced oxidative damage. (Am J Pathol 2010, 177:677-685; DOI: 10.2353/ajpath.2010.090823)

DOI： 10.2353/ajpath.2010.090823

TOWARD A NEW ERA OF THE NAGOYA JOURNAL OF MEDICAL SCIENCE: MESSAGE FROM THE NEW EDITOR-IN-CHIEF International journal

Toyokuni Shinya

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 72 ( 3-4 ) page： 107 - 109 2010.8

Toward a new era of the Nagoya journal of medical science: message from the new editor-in-chief.

Toyokuni S

Nagoya journal of medical science Vol. 72 ( 3-4 ) page： 107 - 9 2010.8

Lipid Peroxidation Generates Body Odor Component trans-2-Nonenal Covalently Bound to Protein in Vivo International journal

Kousuke Ishino, Chika Wakita, Takahiro Shibata, Shinya Toyokuni, Sachiko Machida, Shun Matsuda, Tomonari Matsuda, Koji Uchida

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 285 ( 20 ) page： 15302 - 15313 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

trans-2-Nonenal is an unsaturated aldehyde with an unpleasant greasy and grassy odor endogenously generated during the peroxidation of polyunsaturated fatty acids. 2-Nonenal covalently modified human serum albumin through a reaction in which the aldehyde preferentially reacted with the lysine residues. Modified proteins were immunogenic, and a specific monoclonal antibody (mAb) 27Q4 that cross-reacted with the protein covalently modified with 2-nonenal was raised from mouse. To verify the presence of the protein-bound 2-nonenal in vivo, the mAb 27Q4 against the 2-nonenal-modified keyhole limpet hemocyanin was raised. It was found that a novel 2-nonenal-lysine adduct, cis- and trans-N(epsilon)-3-[(hept-1-enyl)-4-hexyl-pyridinium]lysine (HHP-lysine), constitutes an epitope of the antibody. The immunoreactive materials with mAb 27Q4 were detected in the kidney of rats exposed to ferric nitrilotriacetate, an iron chelate that induces free radical-mediated oxidative tissue damage. Using high performance liquid chromatography with on-line electrospray ionization tandem mass spectrometry, we also established a highly sensitive method for detection of the cis- and trans-HHP-lysine and confirmed that the 2-nonenal-lysine adducts were indeed formed during the lipid peroxidation-mediated modification of protein in vitro and in vivo. Furthermore, we examined the involvement of the scavenger receptor lectin-like oxidized low density lipoprotein receptor-1 in the recognition of 2-nonenal-modified proteins and established that the receptor recognized the HHP-lysine adducts as a ligand.

DOI： 10.1074/jbc.M109.068023

A Novel Method for Efficient Collection of Normal Mesothelial Cells In Vivo Reviewed International journal

Jiang Li, Yamashita Yoriko, Toyokuni Shinya

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 46 ( 3 ) page： 265 - 268 2010.5

A Novel Method for Efficient Collection of Normal Mesothelial Cells In Vivo Reviewed

Li Jiang, Yoriko Yamashita, Shinya Toyokuni

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 46 ( 3 ) page： 265 - 268 2010.5

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Asbestos-induced mesothelioma is a challenging social problem in many countries, and oxidative stress via iron is closely associated with its carcinogenesis. Mesothelioma is thought to originate from the mesothelial cells that cover the somatic cavity such as pleural, pericardial and peritoneal cavities. They are single layered and so flat that it is extremely difficult to obtain pure mesothelial cells as control samples from experimental animals. Here we describe a novel method to collect mesothelial cells from animals by the use of simple equipments. Surface of the most organs including lung, spleen and liver are covered with a single layer of mesothelial cells. Scraping the surface of those organs with razor blades after snap-freeze in liquid nitrogen satisfactorily confers almost pure population of mesothelial cells. This simple method would be helpful for obtaining mesothelial control samples from animals to elucidate the molecular mechanisms of a variety of mesothelial pathology.

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A Novel Method for Efficient Collection of Normal Mesothelial Cells In Vivo

Jiang Li, Yamashita Yoriko, Toyokuni Shinya

Journal of Clinical Biochemistry and Nutrition Vol. 46 ( 3 ) page： 265 - 268 2010.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SOCIETY FOR FREE RADICAL RESEARCH JAPAN

DOI： 10.3164/jcbn.10-01

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リンパ腫ゲノムにおけるマイクロサテライト多型不安定性集積の空間統計学解析

鶴山竜昭, リチャード・カシンスキー, 赤塚慎也, 今井裕紀子, 竹内晴哉, 尾関宗孝, 奥野知子, 豊國伸哉, 玉木敬二

日本法医学雑誌 Vol. 64 ( 1 ) page： 54 - 54 2010.5

n-3 polyunsaturated fatty acids promote apoptosis in oxidatively stressed transgenic mouse models

Fan, YY; Toyokuni, S; Callaway, ES; Ran, Q; Lupton, JR; Chapkin, RS

CANCER RESEARCH Vol. 70 2010.4

A Quantitative trait locus responsible for inducing B-cell lymphoblastic lymphoma is a hotspot for microsatellite instability

KASZYNSKI Richard H., AKATSUKA Shinya, HIRATSUKA Takuya, JIN Guang, OZEKI Munetaka, OKUNO Tomoko, NAKAMURA Takuro, MANABE Toshiaki, TAKAKUWA Tetsuya, HIAI Hiroshi, TOYOKUNI Shinya, TAMAKI Keiji, TSURUYAMA Tatsuaki

Vol. 101 ( 3 ) page： 800 - 805 2010.3

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. International journal

Qian Hu, Shinya Akatsuka, Yoriko Yamashita, Hiroki Ohara, Hirotaka Nagai, Yasumasa Okazaki, Takashi Takahashi, Shinya Toyokuni

Laboratory investigation; a journal of technical methods and pathology Vol. 90 ( 3 ) page： 360 - 373 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by micro-array. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2'-deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

DOI： 10.1038/labinvest.2009.140

A Quantitative trait locus responsible for inducing B-cell lymphoblastic lymphoma is a hotspot for microsatellite instability

Richard H. Kaszynski, Shinya Akatsuka, Takuya Hiratsuka, Guang Jin, Munetaka Ozeki, Tomoko Okuno, Takuro Nakamura, Toshiaki Manabe, Tetsuya Takakuwa, Hiroshi Hiai, Shinya Toyokuni, Keiji Tamaki, Tatsuaki Tsuruyama

CANCER SCIENCE Vol. 101 ( 3 ) page： 800 - 5 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

While the molecular mechanisms underlying microsatellite instability (MSI) have been exhaustively investigated, identifying the patterns of MSI distribution within diverse cancer genomes has remained an elusive issue. In the present study, we conducted genome-wide MSI screening in B-cell lymphoblastic lymphomas (B-LBL) which spontaneously develop in the SL/Kh strain of mice. Tumor samples harvested from 16 mice were investigated using a framework map consisting of 150 microsatellite markers spaced at increments of roughly 0.5-3.0 centimorgans, spanning the entirety of mouse chromosomes (mus musculus chromosomes [MMU]) 3-6. MMU3 contains a quantitative trait locus (QTL), Bomb1 (bone marrow pre-B1), known to induce an aberrant expansion of pre-B cells in bone marrow prior to the onset of B-LBL in SL/Kh mice. The remaining chromosomes were selected on the basis of those most closely resembling MMU3 in terms of total estimated length (maximum variance 10 Mb). MSI was confirmed at 2 <= markers in DNA derived from tumor tissues in 15 SL/Kh mice (93.7%), while healthy splenic DNA samples screened in parallel were consistently negative for MSI. The overall MSI incidence was significantly higher on MMU3 compared with MMU4-6 (P = 0.031). Additionally, by applying spatial point pattern analysis combined with a 1-D version of Ripley's K-function, we successfully demonstrated the predilection of MSI-susceptible loci to structure a massive cluster within the Bomb1 locus. Our study is the first to suggest that a QTL concomitantly serves as a hotspot for MSI-susceptible loci and sheds new light on somatic cancer genetics. (Cancer Sci 2010; 101: 800-805)

DOI： 10.1111/j.1349-7006.2009.01437.x

前駆B芽球性リンパ腫におけるマイクロサテライト不安定性解析とポイントパターン解析の応用

鶴山竜昭, リチャード・カシンスキー, 赤塚慎也, 中村卓郎, 真鍋敏明, 日合弘, 玉木敬二, 豊國伸哉

日本病理学会会誌 Vol. 99 ( 1 ) page： 217 - 217 2010.3

From the Special Session of the "Special Coordination Funds for Promoting Science and Technology (H18-13-3-1)" Entitled "Malignant Mesothelioma" in the 55^<th> Annual Meeting of the Japanese Society of Occupational Medicine and Traumatology : Brief Overview and Approaches from the Basic Science

OTSUKI Takemi, NAKANO Takashi, HASEGAWA Seiki, OKADA Morihito, TSUJIMURA Tohru, SEKIDO Yoshitaka, TOYOKUNI Shinya, NISHIMOTO Hiroshi, FUKUOKA Kazuya, TANAKA Fumihiro

Japanese journal of occupational medicine and traumatology Vol. 58 ( 1 ) page： 1 - 8 2010.1

*Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. Reviewed

Hu Q, Akatsuka S, Yamashita Y, Ohara H, Nagai H, Okazaki Y, Takahashi T, Toyokuni S.

Lab. Invest. Vol. 90 page： 360-372 2010.1

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

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

Free Radic Res page： (in press) 2010

A quantitative trait locus for inducing B-cell lymphoblastic lymphoma is a hot spot for microsatellite instability. Reviewed

Kaszynski RH, Akatsuka S, Hiratsuka T, Jin G, Ozeki M, Okuno T, Nakamura T, Manabe T, Takakuwa T, Hiai H, Toyokuni S, Tamaki K and Tsuruyama T.

Cancer Sci Vol. 101 page： 800-805 2010

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

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

Vol. 186 page： 41-52 2010

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Papers - TOYOKUNI Shinya