Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Involvement of aminoacylase 1 in ferric nitrilotriacetate (Fe-NTA)-induced rat renal cell carcinoma

Onuki, J; Liu, Y; Lee, W; Jiang, L; Dutta, KK; Akatsuka, S; Toyokuni, S

FREE RADICAL RESEARCH Vol. 40 page： S128 - S128 2006

Iron-Induced Carcinogenesis

Toyokuni, S

OXIDATIVE STRESS, DISEASE AND CANCER page： 789 - 805 2006

Novel aspects of oxidative stress-associated carcinogenesis

Toyokuni Shinya

ANTIOXIDANTS & REDOX SIGNALING Vol. 8 ( 7-8 ) page： 1373 - 1377 2006

Oxidative stress and cancer

Toyokuni Shinya

Annual Meeting of the Japanese Society of Toxicology Vol. 33 ( 0 ) page： 15 - 15 2006

Molecular characteristics of ferric nitrilotriacetate-induced deletions and base substitutions in the kidney of gpt delta transgenic mice

Jiang, L; Zhong, Y; Akatsuka, S; Onuki, J; Masumura, K; Nohmi, T; Toyokuni, S

FREE RADICAL RESEARCH Vol. 40 page： S128 - S128 2006

Iron-Induced Carcinogenesis

Toyokuni Shinya

OXIDATIVE STRESS, DISEASE AND CANCER page： 789 - 805 2006

Deletion and single nucleotide substitution at G:C are major mutations in the kidney of gpt delta transgenic mice after the Fenton reaction. Reviewed

Jiang L, Zhong Y, Akatsuka S, Liu Y-T, Dutta KK, Lee W-H, Onuki J, Masumura K, Nohmi T, Toyokuni S

Cancer Sci. Vol. 97 page： 1159-1167 2006

Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis

Akatsuka S., Aung T. T., Dutta K. K., Jiang L., Liu Y., Lee W., Onuki J., Shirase T., Naito Y., Yoshikawa T., Uchida K., Toyokuni S.

FREE RADICAL RESEARCH Vol. 40 page： S129 - S129 2006

Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis Reviewed

S. Akatsuka, T. T. Aung, K. K. Dutta, L. Jiang, Y. Liu, W. Lee, J. Onuki, T. Shirase, Y. Naito, T. Yoshikawa, K. Uchida, S. Toyokuni

FREE RADICAL RESEARCH Vol. 40 page： S129 - S129 2006

Imidapril, an Angiotensin-Converting Enzyme Inhibitor, Reduces Diabetes-Induced Renal Oxidative Damage in Mice

Naito Yuji, Uchiyama Kazuhiko, Akagiri Satomi, Aoi Wataru, Hasegawa Goji, Nakamura Naoto, Kokura Satoshi, Yoshida Norimasa, Ichikawa Hiroshi, Toyokuni Shinya, Yoshikawa Toshikazu

Journal of Clinical Biochemistry and Nutrition Vol. 37 ( 1 ) page： 29 - 37 2005.12

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

The aim of the present study was to determine whether imidapril, an angiotensin-converting enzyme inhibitor, prevents diabetic nephropathy and to determine the effect of imidapril on oxidative damage in the diabetic glomeruli in mice. We used female BKS.cg-m+Lepr<sup>db</sup>/+Lepr<sup>db</sup> (db/db) mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into the following four groups: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with imidapril at doses of 1 mg/kg and 5 mg/kg. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the imidapril-treated group and the non-treated db/db group. The systolic blood pressure was significantly increased in db/db mice compared with db/m mice. The increased blood pressure was significantly reduced by the treatment with imidapril at a dose of 5 mg/kg. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the imidapril-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with imidapril in a dose-dependent manner. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than in the imidapril-treated db/db mice. In conclusion, imidapril prevented the progression of diabetic nephropathy in mice, not only by decreasing the glomerular pressure but also by decreasing the oxidative stress in glomerular cells.

DOI： 10.3164/jcbn.37.29

Scopus

CiNii Research

Susceptibility of actin to modification by 4-hydroxy-2-nonenal. Reviewed International journal

Munetaka Ozeki, Aya Miyagawa-Hayashino, Shinya Akatsuka, Tomoyuki Shirase, Wen-Hua Lee, Koji Uchida, Shinya Toyokuni

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Vol. 827 ( 1 ) page： 119 - 126 2005.11

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

4-Hydroxy-2-nonenal (HNE), a major lipid peroxidation product, reacts with histidine, lysine or cysteine residues of proteins to form hemiacetal Michael adducts and thus interferes with the functions of the proteins. Here we undertook to identify HNE-modified proteins in the target organ of a ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis model with histidine-specific HNEJ-2 antibody. Immunoaffinity column separation and sequencing identified one of the major modified proteins as actin. To further explore the characteristics of actin as an HNE acceptor, we produced four novel monoclonal antibodies against HNE-modified keyhole limpet hemocyanin. All these antibodies (HNEJ-1, 3-5) recognized histidine adducts, but were different from HNEJ-2 in recognizing lysine and cysteine adducts to some extent. Actin, albumin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), metallothionein and superoxide dismutase were treated in vitro with HNE and evaluated with these antibodies. The results revealed that actin was most sensitive to HNE modification and metallothionein most resistant. Furthermore, the residue-specificity of GAPDH was in accord with that shown by our recent mass spectrometry data. Immunohistochemistry with the antibodies revealed cytoplasmic staining with or without nuclear staining in the renal proximal tubules after Fe-NTA administration. The results suggest that actin is a major target protein for HNE modification in vivo, and that our monoclonal antibodies are useful for evaluating the HNE adducts produced.

DOI： 10.1016/j.jchromb.2005.02.025

Susceptibility of actin to modification by 4-hydroxy-2-nonenal

OZEKI Munetaka, MIYAGAWA HAYASHINO Aya, AKATSUKA Shinya, SHIRASE Tomoyuki, LEE Wen-hua, UCHIDA Koji, TOYOKUNI Shinya

J Chromatogr B Anal Technol Biomed Life Sci Vol. 827 ( 1 ) page： 119 - 126 2005.11

Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p35

Yajima N, Yamada S, Morisaki T, Toyokuni S, Yonehara S, Sakamaki K

TRANSGENIC RESEARCH Vol. 14 ( 5 ) page： 593 - 604 2005.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Transgenic Research

Baculovirus p35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficent animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development. © Springer 2005.

DOI： 10.1007/s11248-005-4350-5

Web of Science

Scopus

PubMed

Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p 35. International journal

Nobuyuki Yajima, Shu-Ichi Yamada, Takayuki Morisaki, Shinya Toyokuni, Shin Yonehara, Kazuhiro Sakamaki

Transgenic research Vol. 14 ( 5 ) page： 593 - 604 2005.10

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

Baculovirus p 35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p 35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficient animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p 35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p 35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development.

PubMed

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Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1. International journal

Kimio Kawasaki, Akiyoshi Nishio, Hajime Nakamura, Kazushige Uchida, Toshiro Fukui, Masaya Ohana, Hazuki Yoshizawa, Shinya Ohashi, Hiroyuki Tamaki, Minoru Matsuura, Masanori Asada, Toshiki Nishi, Hiroshi Nakase, Shinya Toyokuni, Wenrui Liu, Junji Yodoi, Kazuichi Okazaki, Tsutomu Chiba

Laboratory investigation; a journal of technical methods and pathology Vol. 85 ( 9 ) page： 1104 - 1117 2005.9

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

Thioredoxin-1 (TRX-1) is a redox-active protein involved in scavenging reactive oxygen species and regulating redox-sensitive transcription factors. TRX-1 is induced in various inflammatory conditions and shows cytoprotective action. We investigated the roles of TRX-1 in the host defense mechanism against Helicobacter felis (H. felis) infection. Transgenic (TG) mice overexpressing human TRX-1 and wild-type (WT) mice were orally inoculated with H. felis. After 2 months, histology, oxidative damage, and gene expression of several cytokines, including macrophage inflammatory protein-2 (MIP-2), a murine equivalent to interleukin (IL)-8, in the gastric mucosa were investigated. Furthermore, the effects of TRX-1 on oxidative stress and neutrophil migration were studied both in vivo and in vitro. The gastric mucosa was thickened in H. felis-infected WT mice, but not in infected TRX-1-TG mice. Histologically, all H. felis-infected WT mice developed moderate-to-severe gastritis, whereas the development of gastritis was significantly suppressed in infected TRX-1-TG mice. Oxidative damage markers, 8-hydroxy-2′-deoxyguanosine and malondialdehyde, increased in the stomach of infected WT mice, but not TRX-1-TG mice. Upregulation of IL-1β and tumor necrosis factor-α gene expression in H. felis-infected TRX-1-TG mice was significantly lower than in WT mice. However, upregulation of MIP-2 and IL-7 was not different between the two groups. TRX-1 suppressed oxidative cytotoxicity and DNA damage, and inhibited neutrophil migration both in vivo and in vitro. The present study suggests that overexpression of TRX-1 suppresses H. felis-induced gastritis by inhibiting chemotaxis of neutrophils and reducing oxidative stress. © 2005 USCAP, Inc All Rights Reserved.

DOI： 10.1038/labinvest.3700305

Genetic and epigenetic properties of mouse male germline stem cells during long-term culture Reviewed

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

DEVELOPMENT Vol. 132 ( 18 ) page： 4155 - 4163 2005.9

Language：English Publishing type：Research paper (scientific journal) Publisher：COMPANY OF BIOLOGISTS LTD

Although stem cells are believed to divide infinitely by self-renewal division, there is little evidence that demonstrates their infinite replicative potential. Spermatogonial stem cells are the founder cell population for spermatogenesis. Recently, in vitro culture of spermatogonial stem cells was described. Spermatogonial stem cells can be expanded in vitro in the presence of glial cell line-derived neurotrophic factor (GDNF), maintaining the capacity to produce spermatogenesis after transplantation into testis. Here, we examined the stability and proliferative capacity of spermatogonial stem cells using cultured cells. Spermatogonial stem cells were cultured over 2 years and achieved similar to 10(85)-fold expansion. Unlike other germline cells that often acquire genetic and epigenetic changes in vitro, spermatogonial stem cells retained the euploid karyotype and androgenetic imprint during the 2-year experimental period, and produced normal spermatogenesis and fertile offspring. However, the telomeres in spermatogonial stem cells gradually shortened during culture, suggesting that they are not immortal. Nevertheless, the remarkable stability and proliferative potential of spermatogonial stem cells suggest that they have a unique machinery to prevent transmission of genetic and epigenetic damages to the offspring, and these characteristics make them an attractive target for germline modification.

DOI： 10.1242/dev.02004

Germline niche transplantation restores fertility in infertile mice Reviewed

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

HUMAN REPRODUCTION Vol. 20 ( 9 ) page： 2376 - 2382 2005.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

BACKGROUND: Stem cells interact closely with their microenvironment or niche, and abnormalities in niche compromise the self-renewing tissue. In testis, for example, Sertoli cells interact with germ cells, and defects in Sertoli cells compromises spermatogenesis, leading to male infertility. However, it has not been possible to restore spermatogenesis from endogenous stem cells in infertile testis with environmental defects METHODS AND RESULTS: When healthy Sertoli cells from infertile white spotting (W) mouse were transplanted into the seminiferous tubules of infertile Steel (SI) mouse testis that had defective Sertoli cells, spermatogenesis occurred from SI stem cells in the recipient testis. On average, 1.1% of the recipient tubules showed spermatogenesis. Furthermore, in a microinsemination experiment with germ cells that developed in the testis, we obtained four normal offspring from 114 successfully injected oocytes. CONCLUSIONS: This study demonstrates that defects in male germline microenvironment can be corrected by Sertoli cell transplantation. Although further improvements are required to enhance the low efficiency of spermatogenesis, the ability to correct environmental defect by niche transplantation has important implications in developing new strategies for treating incurable disorders in self-renewing tissues.

DOI： 10.1093/humrep/dei096

Nestin-positive cells in adult pancreas express amylase and endocrine precursor cells

Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

PANCREAS Vol. 31 ( 2 ) page： 126 - 131 2005.8

Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells.

Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

Pancreas Vol. 31 ( 2 ) page： 126 - 31 2005.8

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

The neural precursor cell-specific marker nestin is expressed in fetal and adult pancreas, but its role is not fully understood. Using nestin-enhanced green fluorescent protein (EGFP) transgenic mice and fluorescence activated cell sorter, we characterized nestin-positive cells in adult mice pancreas. EGFP mRNA- and protein-positive cells expressed amylase, a pancreatic exocrine marker. Interestingly, EGFP mRNA-negative and protein-positive cells expressed insulin, glucagon, somatostatin and pancreatic polypeptide, pancreatic endocrine markers. These findings demonstrate that nestin-positive cells comprise a portion of pancreatic exocrine cells and suggest that they can be differentiated into pancreatic endocrine cells. Copyright © 2005 by Lippincott Williams & Wilkins.

DOI： 10.1097/01.mpa.0000172564.80921.f7

Scopus

PubMed

Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells. International journal

Hiroyuki Ueno, Yuichiro Yamada, Rie Watanabe, Eri Mukai, Masaya Hosokawa, Akira Takahashi, Akihiro Hamasaki, Hideya Fujiwara, Shinya Toyokuni, Masahiro Yamaguchi, Jun Takeda, Yutaka Seino

Pancreas Vol. 31 ( 2 ) page： 126 - 31 2005.8

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

PubMed

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Papers - TOYOKUNI Shinya