Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Mysterious link between iron overload and CDKN2A/2B. Reviewed

Toyokuni S

J Vol. 48 page： 46-49 2011

LATS2 is a tumor suppressor gene of malignant mesothelioma.

Murakami Hideki, Mizuno Tetsuya, Taniguchi Tetsuo, Fujii Makiko, Ishiguro Futoshi, Fukui Takayuki, Akatsuka Shinya, Horio Yoshitsugu, Hida Toyoaki, Kondo Yutaka, Toyokuni Shinya, Osada Hirotaka, Sekido Yoshitaka

Cancer research Vol. 71 ( 3 ) 2011

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

:Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive

DOI： 10.1158/0008-5472.CAN-10-2164

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脳梗塞発症前の運動の効果及び酸化ストレスに着目した作用機序の検討

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

理学療法学Supplement Vol. 2010 ( 0 ) page： AcOF1030 - AcOF1030 2011

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：公益社団法人日本理学療法士協会

【目的】脳梗塞時には活性酸素やフリーラジカルが大量に産生され、酸化ストレスとして組織損傷を拡大させるため、酸化ストレスは脳梗塞を増悪させる主要な因子である。一方、健常なラットを長期間運動させると、脳内で抗酸化酵素が増加し酸化ストレスの減少をもたらすことが報告されており、運動は脳内の抗酸化作用を高めることが示されている。また、先行研究では、脳梗塞モデルラット作成前に一定期間の運動をさせると、運動していないラットに比べて、脳梗塞後の梗塞体積が減少し運動機能障害も軽減するといった脳梗塞障害軽減効果が報告されている。しかし、運動により高まる脳内の抗酸化作用が、脳梗塞時の酸化ストレスに影響を及ぼしているかどうかは不明である。そこで本研究では、脳梗塞発症前の運動の効果および作用機序を酸化ストレスに着目して検討することを目的とした。 【方法】実験動物には Wistar系雄性ラット（5週齢）を用いた。無作為に運動群と非運動群に分け、運動群は3週間トレッドミル運動（15 m / min、30分/日）を毎日行った。非運動群は走行させずにトレッドミル装置内に暴露させた（1日30分間）。3週間後、各群に小泉法による脳梗塞モデル作成手術を施行した。手術24時間後に、運動機能評価として、麻痺の重症度を評価する Neurological Deficits（ND）、歩行時のバランス能力の評価として Beam Walking（BW）、はしご上の歩行における前肢の協調運動機能を評価するLadder test、前肢の感覚運動機能の評価として Limb Placing（LP）を行った。その直後に脳を採取し、TTC染色により非梗塞半球体積に対する梗塞体積の割合を算出した。また、酸化ストレスの指標として、酸化ストレスによる細胞膜障害の指標となる 4-hydroxy-2-nonenal [4-HNE]及びDNA障害の指標となる 8-Hydroxydeoxyguanosine[8-OHdG]の免疫染色を行った。統計学的検定には、対応のない t検定と Mann-WhitneyのU検定を用い、有意水準は5％未満とした。 【説明と同意】本研究は、名古屋大学医学部保健学科動物実験委員会の承諾を得て実施した（承認番号：022-028号）。 【結果】脳梗塞手術24時間後の運動機能のうち、 ND（麻痺の重症度）と Ladder test（前肢の協調運動機能障害）は運動群の方が非運動群に比べて軽度で、有意差が認められた（p < 0.05）。一方、 LP（前肢の感覚機能）や BW（歩行時の後肢機能）は群間に有意差は認められなかった。また、梗塞体積割合は、運動群の方が非運動群よりも有意に小さく（p < 0.05）、脳梗塞発症前の運動はその後の脳梗塞による組織損傷を軽減することが示された。酸化ストレス指標のうち、過酸化脂質の指標である4-HNEの免疫染色では、非運動群に比べて運動群は陽性細胞が少ない傾向にあった。また、DNAの酸化的損傷を示す8-OHdGは、梗塞側では運動群の方が陽性細胞が少ない傾向にあったが、非梗塞側は両群とも陽性細胞は見られなかった。 【考察】本研究は、脳梗塞発症前に3週間運動を継続することが、その後の脳梗塞の障害に及ぼす効果を酸化ストレスに着目して検討した。その結果、脳梗塞前に運動を行った運動群は非運動群と比較して、脳梗塞後の梗塞体積が減少し運動機能障害が軽減され、先行研究の結果と一致した。また、脳梗塞による細胞膜及びDNAに対する酸化ストレスが運動群で減少したことから、運動によって高められる脳内の抗酸化作用は、正常時だけでなく、脳梗塞時の酸化ストレスに対しても抑制効果をもたらす可能性が示唆された。これらのことから、3週間の運動が脳梗塞後の障害軽減効果をもたらした作用機序として、脳内の抗酸化作用を高めて脳梗塞の酸化ストレスを抑制したことにより、組織損傷が軽減し、運動機能障害が改善されたと考えられる。しかし、今回の運動条件がどの程度の抗酸化作用を有しているかは確認していないため、今後検討していく必要がある。 【理学療法学研究としての意義】本研究は、健常時の運動習慣の有無が脳梗塞を発症した場合の障害程度に及ぼす影響について検討した基礎研究であり、発症前の運動習慣が脳梗塞の予後を改善する可能性を示唆している。また、今後理学療法士が活躍の場を広げ予防医療の分野に携わる際、運動を推奨することの科学的根拠となる有用な知見である。

DOI： 10.14900/cjpt.2010.0.AcOF1030.0

CiNii Research

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Oxidative DNA Damage and Carcinogenesis

Jiang Li, Toyokuni Shinya

FREE RADICAL BIOLOGY IN DIGESTIVE DISEASES Vol. 29 page： 55 - 63 2011

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

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

MOLECULAR BIOLOGY OF THE CELL Vol. 22 2011

Oxidative DNA damage and carcinogenesis

Jiang L., Toyokuni S.

Free Radical Biology in Digestive Diseases Vol. 29 page： 55 - 63 2010.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Free Radical Biology in Digestive Diseases

Carcinogenesis follows multi-step processes involving both genetic alteration and increased cell proliferation. Oxidative stress can occur via overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Oxidative stress is always associated with inflammation, radiation, reperfusion, and iron overload. Epidemiological observations have shown that oxidative stress is one of the major pathologic mechanisms for cancer, the top-ranked cause of human mortality worldwide. During carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation through generation of oxidative DNA damage. Furthermore, signal transduction pathways are activated by reactive species, and they lead to the transcription of genes involved in cellular growth regulatory and stress protection pathways. This review examines the involvement of oxidative stress in the carcinogenic process starting from its history, and presents future perspectives.

DOI： 10.1159/000319941

Scopus

Oxidative DNA damage and carcinogenesis

Jiang L., Toyokuni S.

Frontiers of Gastrointestinal Research Vol. 29 page： 55 - 63 2010.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Frontiers of Gastrointestinal Research

DOI： 10.1159/0003199419

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A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats Reviewed

Yasumasa Okazaki, Mohammad Iqbal, Norito Kawakami, Yorihiro Yamamoto, Shinya Toyokuni, Shigeru Okada

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 47 ( 3 ) page： 198 - 207 2010.11

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

It is beneficial to seek scientific basis for the effects of functional foods. Natural pigments derived from plants are widely known as possible antioxidants. Black soybean contains a larger amount of anthocyanins than regular soybean. Here we studied the anti-oxidative effect of a beverage obtained via citric acid fermentation of black soybean (BBS), using a rat model of renal oxidative injury induced by a renal carcinogen, ferric nitrilotriacetate. BBS (10 ml/kg) was orally administered 30 min before ferric nitrilotriacetate treatment. Renal lipid peroxidation was significantly suppressed in the BBS-pretreated animals concomitant with decrease in 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2`-deoxyguanosine. Maintenance of renal activities of antioxidative enzymes including catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, glucose-6-phosphate dehydrogenase and quinone reductase was significantly better in the BBS-pretreated rats. Elevation of serum creatinine and urea nitrogen was significantly suppressed in the BBS-pretreated rats. These data suggest that dietary intake of BBS is useful for the prevention of renal tubular oxidative damage mediate by iron, and warrant further investigation.

Web of Science

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A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats

Okazaki Yasumasa, Iqbal Mohammad, Kawakami Norito, Yamamoto Yorihiro, Toyokuni Shinya, Okada Shigeru

Journal of Clinical Biochemistry and Nutrition Vol. 47 ( 3 ) page： 198 - 207 2010.11

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

It is beneficial to seek scientific basis for the effects of functional foods. Natural pigments derived from plants are widely known as possible antioxidants. Black soybean contains a larger amount of anthocyanins than regular soybean. Here we studied the antioxidative effect of a beverage obtained via citric acid fermentation of black soybean (BBS), using a rat model of renal oxidative injury induced by a renal carcinogen, ferric nitrilotriacetate. BBS (10 ml/kg) was orally administered 30 min before ferric nitrilotriacetate treatment. Renal lipid peroxidation was significantly suppressed in the BBS-pretreated animals concomitant with decrease in 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine. Maintenance of renal activities of antioxidative enzymes including catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, glucose-6-phosphate dehydrogenase and quinone reductase was significantly better in the BBS-pretreated rats. Elevation of serum creatinine and urea nitrogen was significantly suppressed in the BBS-pretreated rats. These data suggest that dietary intake of BBS is useful for the prevention of renal tubular oxidative damage mediate by iron, and warrant further investigation.

DOI： 10.3164/jcbn.10-52

Scopus

PubMed

CiNii Research

A Beverage Containing Fermented Black Soybean Ameliorates Ferric Nitrilotriacetate-Induced Renal Oxidative Damage in Rats

Okazaki Yasumasa, Iqbal Mohammad, Kawakami Norito, Yamamoto Yorihiro, Toyokuni Shinya, Okada Shigeru

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 47 ( 3 ) page： 198 - 207 2010.11

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

Hirotaka Nagai, Shinya Toyokuni

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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

DOI： 10.1016/j.abb.2010.06.015

Genome-Scale Approaches to Investigate Oxidative DNA Damage Reviewed International journal

Akatsuka Shinya, Toyokuni Shinya

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

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.

Web of Science

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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.

DOI： 10.3164/jcbn.10-38R

Scopus

PubMed

CiNii Research

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

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

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

Toyokuni S.

Nagoya journal of medical science Vol. 72 ( 3-4 ) page： 107 - 109 2010.8

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

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

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Papers - TOYOKUNI Shinya