Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension. Reviewed International journal

Takenaka H, Kihara Y, Iwanaga Y, Onozawa Y, Toyokuni S, Kita T

Journal of molecular and cellular cardiology Vol. 41 ( 6 ) page： 989 - 97 2006.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Molecular and Cellular Cardiology

Angiotensin II (Ang-II) plays pivotal roles in the progression of left ventricular (LV) remodeling in diseased hearts; it remains to be elucidated how Ang-II links to degradation of the extracellular matrix (ECM). Using hypertensive Dahl salt-sensitive rats that show the distinctive transition from concentric LV hypertrophy to LV remodeling, we chronically treated them with an angiotensin type-1 receptor blocker (telmisartan 5 mg/kg/day, ARB group) or vehicle (0.5% CMC, CHF group). During the process of LV remodeling, we assessed, (1) in-vivo LV shape and function; (2) animal survival; (3) amounts of ECM in LV using a scanning electron microscope (SEM); (4) mRNA (by real time RT-PCR) and protein (by immunoblotting) levels in LV of NADPH oxidase, glutathione peroxidase-1 (GPX-1), and matrix metalloproteinase (MMP)-2, -9, and -13; (5) immunohistochemical staining of myocardial 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine; (6) nuclear factor kappa-B (NFκB) protein levels in the nuclear extract; and (7) endogenous activities of MMP-2 and -9 by an antibody capture method. Compared with CHF, ARB group showed an improvement of survival and preserved LV shape and function, and ECM density in SEM that was accompanied by decreases in oxidative stress-mediated protein degenerations, activities of GPX-1, NADPH oxidase, NFκB, and MMP-2, -9, and -13. Local activation of Ang-II in hypertrophic LV triggers MMP-mediated ECM degradation, namely LV remodeling, at least in part, through NADPH oxidase-induced oxidative stress and the subsequent NFκB activation. © 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yjmcc.2006.07.019

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Novel screening method for ultraviolet protection: Combination of a human skin-equivalent model and 8-hydroxy-2 '-deoxyguanosine Reviewed International journal

Shinya Toyokuni, Hiroyuki Yasui, Akira Date, Tomohiro Hakozaki, Shinya Akatsuka, Haruyasu Kohda, Takashi Yoshii, Hiromu Sakurai

PATHOLOGY INTERNATIONAL Vol. 56 ( 12 ) page： 760 - 762 2006.12

Deletion and single nucleotide substitution at G:C in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment

JIANG Li, ZHONG Yi, AKATSUKA Shinya, LIU Yu-Ting, DUTTA Khokon Kumar, LEE Wen-Hua, ONUKI Janice, MASUMURA Ken-ichi, NOHMI Takehiko, TOYOKUNI Shinya

Cancer Sci Vol. 97 ( 11 ) page： 1159 - 1167 2006.11

Deletion and single nucleotide substitution at G:C in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment. Reviewed International journal Open Access

Li Jiang, Yi Zhong, Shinya Akatsuka, Yu-Ting Liu, Khokon Kumar Dutta, Wen-Hua Lee, Janice Onuki, Ken-ichi Masumura, Takehiko Nohmi, Shinya Toyokuni

Cancer science Vol. 97 ( 11 ) page： 1159 - 67 2006.11

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

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces oxidative renal proximal tubular damage that subsequently leads to a high incidence of renal cell carcinoma in rodents, presenting an intriguing model of free radical-induced carcinogenesis. In the present study, we used gpt delta transgenic mice, which allow efficient detection of point mutations and deletions in vivo, to evaluate the mutation spectra, in association with the formation of 8-oxoguanine and acrolein-modified adenine during the first 3 weeks of carcinogenesis. Immunohistochemical analysis revealed the highest levels of 8-oxoguanine and acrolein-modifed adenine in the renal proximal tubules after 1 week of repeated administration. DNA immunoprecipitation and quantitative polymerase chain reaction analysis showed that the relative abundance of 8-oxoguanine and acrolein-modified adenine at the gpt reporter gene were increased at the first week in the kidney. Similarly, in both 6-thioguanine and Spi(-) selections performed on the renal specimens after Fe-NTA administration, the mutant frequencies were increased in the Fe-NTA-treated mice at the first week. Further analyzes of 79 mutant clones and 93 positive plaques showed a high frequency of G:C pairs as preferred targets for point mutation, notably G:C to C:G transversion-type mutation followed by deletion, and of large-size (>1 kilobase) deletions with short homologous sequences in proximity to repeated sequences at the junctions. The results demonstrate that the iron-based Fenton reaction is mutagenic in vivo in the renal tubular cells and induces characteristic mutations.

DOI： 10.1111/j.1349-7006.2006.00301.x

Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis. Reviewed International journal Open Access

Akatsuka S, Aung TT, Dutta KK, Jiang L, Lee WH, Liu YT, Onuki J, Shirase T, Yamasaki K, Ochi H, Naito Y, Yoshikawa T, Kasai H, Tominaga Y, Sakumi K, Nakabeppu Y, Kawai Y, Uchida K, Yamasaki A, Tsuruyama T, Yamada Y, Toyokuni S

The American journal of pathology Vol. 169 ( 4 ) page： 1328 - 42 2006.10

Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Pathology

Oxidative stress is a persistent threat to the genome and is associated with major causes of human mortality, including cancer, atherosclerosis, and aging. Here we established a method to generate libraries of genomic DNA fragments containing oxidatively modified bases by using specific monoclonal antibodies to immunoprecipitate enzyme-digested genome DNA. We applied this technique to two different base modifications, 8-hydroxyguanine and 1,N 6-propanoadenine (acrotein-Ade), in a ferric nitrilotriacetate- induced murine renal carcinogenesis model. Renal cortical genomic DNA derived from 10- to 12-week-old male C57BL/6 mice, of untreated control or 6 hours after intraperitoneal injection of 3 mg iron/kg ferric nitrilotriacetate, was enzyme digested, immunoprecipitated, cloned, and mapped to each chromosome. The results revealed that distribution of the two modified bases was not random but differed in terms of chromosomes, gene size, and expression, which could be partially explained by chromosomal territory. In the wild-type mice, low GC content areas were more likely to harbor the two modified bases. Knockout of OGG1, a repair enzyme for genomic 8-hydroxyguanine, increased the amounts of acrolein-Ade as determined by quantitative polymerase chain reaction analyses. This versatile technique would introduce a novel research area as a high-throughput screening method for critical genomic loci under oxidative stress. Copyright © American Society for Investigative Pathology.

DOI： 10.2353/ajpath.2006.051280

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alpha-Tocopherol induces calnexin in renal tubular cells: Another protective mechanism against free radical-induced cellular damage Reviewed International journal Open Access

Wen-Hua Lee, Shinya Akatsuka, Tomoyuki Shirase, Khokon Kumar Dutta, Li Jiang, Yu-Ting Liu, Janice Onuki, Yoshihiro Yamada, Katsuya Okawa, Youichiro Wada, Akira Watanabe, Takahide Kohro, Noriko Noguchi, Shinya Toyokuni

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 453 ( 2 ) page： 168 - 78 2006.9

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

Pre-administration of alpha-tocopherol is protective against oxidative renal tubular damage and subsequent carcinogenesis by ferric nitrilotriacetate (Fe-NTA) in rats. We searched for mechanisms other than the scavenging effect of alpha-tocopherol with microarray analyses, which implicated calnexin, a chaperone for glycoproteins. Renal mRNA levels of calnexin significantly increased 3 h after an injection of Fe-NTA in rats fed a standard diet whereas those fed an alpha-tocopherol-supplemented diet showed an increase prior to injection, but after injection showed a decrease in renal calnexin mRNA levels, with unaltered protein levels. In experiments using LLG-PK1 cells, addition of alpha-tocopherol was protective against oxidative stress by H,0, concomitant with calnexin induction. Knockdown of calnexin by siRNA significantly reduced this protection. Furthermore, COS-7 cells transfected with the calnexin gene were more resistant to H2O2. Together with the fact that alpha-tocopherol induced N-acetylglucosaminyltransferase 3, our data suggest that alpha-tocopherol modifies glycoprotein metabolism partially by conferring mild ER stress. This adds another molecular mechanism of alpha-tocopherol toward cancer prevention. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.abb.2006.07.002

Overexpression of LYL1 gene induces T- and B-cell leukemia in mice

Zhong, Y; Jiang, L; Toyokuni, S; Hiai, H; Yamada, Y

EXPERIMENTAL HEMATOLOGY Vol. 34 ( 9 ) page： 47 - 47 2006.9

Overexpression of LYL1 gene induces T- and B-cell leukemia in mice International journal

Zhong, Y, Jiang, L, Toyokuni, S, Hiai, H, Yamada, Y

EXPERIMENTAL HEMATOLOGY Vol. 34 ( 9 ) page： 47 - 47 2006.9

Historical aspects of free radical chemistry and biology: What's new in oxidative stress-induced carcinogenesis and its prevention? Reviewed International journal

Toyokuni Shinya

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 39 ( 1 ) page： 1 - 2 2006.7

Historical Aspects of Free Radical Chemistry and Biology: What’s New in Oxidative Stress-induced Carcinogenesis and Its Prevention?

Toyokuni Shinya

Journal of Clinical Biochemistry and Nutrition Vol. 39 ( 1 ) page： 1 - 2 2006.7

Novel aspects of oxidative stress-associated carcinogenesis Reviewed

Shinya Toyokuni

Antioxidants and Redox Signaling Vol. 8 ( 7-8 ) page： 1373 - 7 2006.7

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

Oxidative stress is associated with carcinogenesis. Reactive oxygen and nitrogen species contribute to the accumulation of mutations in the genome, presumably followed by selective processes. Recent data suggest that preferred signaling pathways exist for oxidative stress-associated carcinogenesis. Whether this completely depends on random mutations induced by reactive species or whether instead some fragile genomic loci are sensitive to oxidative damage in association with changes of transcriptional activity or other topologic or non-topologic effects remains to be explored. Reliable markers for oxidative stress as well as for oxidative stress-induced preneoplastic lesions must be established. © Mary Ann Liebert, Inc.

DOI： 10.1089/ars.2006.8.1373

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What has been Learned from the Studies of Oxidative Stress-induced Carcinogenesis: Proposal of the Concept of Oxygenomics

Toyokuni Shinya, Akatsuka Shinya

Journal of Clinical Biochemistry and Nutrition Vol. 39 ( 1 ) page： 3 - 10 2006.7

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

Epidemiological studies have demonstrated that oxidative stress associated with a variety of pathological conditions is one of the major causes of carcinogenesis. Reactive oxygen and nitrogen species contribute to genomic alterations, presumably followed by selection of the best-adapted proliferating cells in a given environment. Recent data suggest that there exist common signaling pathways for oxidative stress-associated carcinogenesis. So far, oxidative DNA damage has been assumed to be randomly distributed based on in vitro experiments, and localization of oxidative DNA damage in the genome in vivo has rarely been studied. However, by the use of novel techniques in combination with constructed genome databases, it was found that the localization of oxidative DNA appears to be not random in vivo. We propose to call this rather novel research area "oxygenomics". Not a few signaling pathways start from the recognition of DNA damage. Possible underlying principles should be elucidated in association with cell type, the function of each genomic location, and its transcriptional activity as well as chromatin status determining epigenetic information. Furthermore, this concept may contribute to the development of novel oxidative stress biomarkers. Thus, oxygenomics is a promising research area.

DOI： 10.3164/jcbn.39.3

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What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics Reviewed

Shinya Toyokuni, Shinya Akatsuka

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 39 ( 1 ) page： 3 - 10 2006.7

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

Epidemiological studies have demonstrated that oxidative stress associated with a variety of pathological conditions is one of the major causes of carcinogenesis. Reactive oxygen and nitrogen species contribute to genomic alterations, presumably followed by selection of the best-adapted proliferating cells in a given environment. Recent data suggest that there exist common signaling pathways for oxidative stress-associated carcinogenesis. So far, oxidative DNA damage has been assumed to be randomly distributed based on in vitro experiments, and localization of oxidative DNA damage in the genome in vivo has rarely been studied. However, by the use of novel techniques in combination with constructed genome databases, it was found that the localization of oxidative DNA appears to be not random in vivo. We propose to call this rather novel research area "oxygenomics". Not a few signaling pathways start from the recognition of DNA damage. Possible underlying principles should be elucidated in association with cell type, the function of each genomic location, and its transcriptional activity as well as chromatin status determining epigenetic information. Furthermore, this concept may contribute to the development of novel oxidative stress biomarkers. Thus, oxygenomics is a promising research area.

Web of Science

researchmap

What has been learned from the studies of oxidative stress-induced carcinogenesis: proposal of the concept of oxygenomics

Toyokuni Shinya, Akatsuka Shinya

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 39 ( 1 ) page： 3 - 10 2006.7

Historical aspects of free radical chemistry and biology: What's new in oxidative stress-induced carcinogenesis and its prevention? Reviewed International journal

Toyokuni Shinya

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 39 ( 1 ) page： 1 - 2 2006.7

Production of knockout mice by random or targeted mutagenesis in spermatogonial stem cells Reviewed International journal Open Access

M Kanatsu-Shinohara, M Ikawa, M Takehashi, N Ogonuki, H Miki, K Inoue, Y Kazuki, J Lee, S Toyokuni, M Oshimura, A Ogura, T Shinohara

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 103 ( 21 ) page： 8018 - 23 2006.5

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Stem cells represent a unique population of cells with self-renewal capacity. Although they are important therapeutic targets, the genetic manipulation of tissue-specific stem cells has been limited, which complicates the study and practical application of these cells. Here, we demonstrate successful gene trapping and homologous recombination in spermatogonial stem cells. Cultured spermatogonial stem cells were transfected with gene trap or gene targeting vectors. Mutagenized stem cells were expanded clonally by drug selection. These cells underwent spermatogenesis and produced heterozygous offspring after transplantation into the seminiferous tubules of infertile mouse testes. Heterozygous mutant mice were intercrossed to produce homozygous gene knockouts. Using this strategy, the efficiency of homologous recombination for the occludin gene focus was 1.7% using a nonisogenic DNA construct. These results demonstrate the feasibility of altering genes in tissue-specific stem cells in a manner similar to embryonic stem cells and have important implications for gene therapy and animal transgenesis.

DOI： 10.1073/pnas.0601139103

ヒト大腸癌予後因子としてのNKT細胞腫瘍内浸潤

鶴山竜昭, 橘強, 小野寺久, 幸田晴康, 豊國伸哉, 日合弘, 山邉博彦, 玉木敬二, 真鍋俊明

日本病理学会会誌 Vol. 95 ( 1 ) page： 213 - 213 2006.4

Anchorage-independent growth of mouse male germline stem cells in vitro Reviewed International journal

M Kanatsu-Shinohara, K Inoue, J Lee, H Miki, N Ogonuki, S Toyokuni, A Ogura, T Shinohara

BIOLOGY OF REPRODUCTION Vol. 74 ( 3 ) page： 522 - 9 2006.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SOC STUDY REPRODUCTION

Spermatogenesis originates from a small number of spermatogonial stem cells that reside on the basement membrane and undergo self-renewal division to support spermatogenesis throughout the life of adult animals. Although the recent development of a technique to culture spermatogonial stem cells allowed reproduction of self-renewal division in vitro, much remains unknown about how spermatogonial stem cells are regulated. In this study, we found that spermatogonial stem cells could be cultured in an anchorage-independent manner, which is characteristic of stem cells from other types of self-renewing tissues. Although the cultured cells grew slowly (doubling time, similar to 4.7 days), they expressed markers of spermatogonia, and grew exponentially for at least 5 months to achieve 1.5 x 10(10)-fold expansion. The cultured cells underwent spermatogenesis following transplantation into the seminiferous tubules of infertile animals and fertile offspring were obtained by microinsemination of germ cells that had developed within the testes of recipients of the cultured cells. These results indicate that spermatogonial stem cells can undergo anchorage-independent, self-renewal division, and suggest that stem cells have the common property to survive and proliferate in the absence of exogenous substrata.

DOI： 10.1095/biolreprod.105.046441

Differences in oxidative stress dependence between gastric adenocarcinoma subtypes

Bancel Brigitte, Esteve Jacques, Souquet Jean-Christophe, Toyokuni Shinya, Ohshima Hiroshi, Pignatelli Brigitte

WORLD JOURNAL OF GASTROENTEROLOGY Vol. 12 ( 7 ) page： 1005 - 1012 2006.2

Differences in oxidative stress dependence between gastric adenocarcinoma subtypes.

Bancel B, Esteve J, Souquet JC, Toyokuni S, Ohshima H, Pignatelli B

World journal of gastroenterology Vol. 12 ( 7 ) page： 1005 - 12 2006.2

Language：English Publishing type：Research paper (scientific journal) Publisher：World Journal of Gastroenterology

Aim: To investigate the extent of oxidative stress in preneoplastic and neoplastic gastric mucosa in relation to their pathological criteria and histological subtypes. Methods: A total of 104 gastric adenocarcinomas from 98 patients (88 infiltrative and 16 intraepithelial tumors) were assessed immunohistochemically for expression of iNOS and occurrence of nitrotyrosine (NTYR)-containing proteins and 8-hydroxy-2′-deoxyguanosine (8-OH-dG)-containing DNA, as markers of NO production and damages to protein and DNA. Results: Tumor cells staining for iNOS, NTYR and 8-OH-dG were detected in 41%, 62% and 50% of infiltrative carcinoma, respectively. The three markers were shown for the first time in intraepithelial carcinoma. The expression of iNOS was significantly more frequent in tubular carcinoma (TC) compared to diffuse carcinoma (DC) (54% vs 18%; P=0.008) or in polymorphous carcinoma (PolyC) (54% vs 21%; P=0.04). NTYR staining was obviously more often found in TC than that in PolyC (72% vs 30%; P=0.03). There was a tendency towards a higher rate of iNOS staining when distant metastasis (pM) was present. In infiltrative TC, the presence of oxidative stress markers was not significantly correlated with histological grade, density of inflammation, the depth of infiltration (pT), lymph nodes dissemination (pN) and pathological stages (pTNM). Conclusion: The iNOS-oxidative pathway may play an important role in TC, but moderately in PolyC and DC. DNA oxidation and protein nitration occur in the three subtypes. Based on the significant differences of NTYR levels, TC and PolyC appear as two distinct subtypes. © 2006 The WJG Press. All rights reserved.

DOI： 10.3748/wjg.v12.i7.1005

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Papers - TOYOKUNI Shinya