Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Target genes in free radical-induced carcinogenesis

Toyokuni S

SFRR: PROCEEDINGS OF THE XII BIENNIAL MEETING OF THE SOCIETY FOR FREE RADICAL RESEARCH INTERNATIONAL page： 181 - 185 2004

Target genes and genomic areas in free radical-induced carcinogenesis

Toyokuni, S; Akatsuka, S; Shirase, T; Than, TA

FREE RADICAL BIOLOGY AND MEDICINE Vol. 36 page： S29 - S29 2004

Target genes in free radical-induced carcinogenesis Reviewed

S Toyokuni

SFRR: PROCEEDINGS OF THE XII BIENNIAL MEETING OF THE SOCIETY FOR FREE RADICAL RESEARCH INTERNATIONAL page： 181 - 185 2004

Language：English Publishing type：Research paper (international conference proceedings) Publisher：MEDIMOND PUBLISHING CO

Ferric nitrilotriacetate-induced renal carcinogenesis presents an intriguing model demonstrating what happens if repeated Fenton reaction occurs in vivo. We have asked a question whether there is any target gene in this carcinogenesis model. With a genetic approach, we found that p15 and p16 tumor suppressor genes are one of the major targets. Furthermore, allelic loss of p16 was present as early as three weeks after the start of the experiments. In this model, alterations in expressional levels of several genes were also observed by differential display analysis. Among them, annexin 2 was overexpressed in renal cell carcinoma, and was regulated by oxidative stress. Persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer.

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Formation of acrolein-derived 2'-deoxyadenosine adduct in an iron-induced carcinogenesis model. Reviewed International journal Open Access

Yoshichika Kawai, Atsunori Furuhata, Shinya Toyokuni, Yasuaki Aratani, Koji Uchida

The Journal of biological chemistry Vol. 278 ( 50 ) page： 50346 - 54 2003.12

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

Acrolein is a representative carcinogenic aldehyde found ubiquitously in the environment and formed endogenously through oxidation reactions, such as lipid peroxidation and myeloperoxidase-catalyzed amino acid oxidation. It shows facile reactivity toward DNA to form an exocyclic DNA adduct. To verify the formation of acrolein-derived DNA adduct under oxidative stress in vivo, we raised a novel monoclonal antibody (mAb21) against the acrolein-modified DNA and found that the antibody most significantly recognized an acrolein-modified 2' -deoxyadenosine. On the basis of chemical and spectroscopic evidence, the major antigenic product of mAb21 was the 1,N6-propano-2' -deoxyadenosine adduct. The exposure of rat liver epithelial RL34 cells to acrolein resulted in a significant accumulation of the acrolein-2' -deoxyadenosine adduct in the nuclei. Formation of this adduct under oxidative stress in vivo was immunohistochemically examined in rats exposed to ferric nitrilotriacetate, a carcinogenic iron chelate that specifically induces oxidative stress in the kidneys of rodents. It was observed that the acrolein-2' -deoxyadenosine adduct was formed in the nuclei of the proximal tubular cells, the target cells of this carcinogenesis model. The same cells were stained with a monoclonal antibody 5F6 that recognizes an acrolein-lysine adduct, by which cytosolic accumulation of acrolein-modified proteins appeared. Similar results were also obtained from myeloperoxidase knockout mice exposed to the iron complex, suggesting that the myeloperoxidase-catalyzed oxidation system might not be essential for the generation of acrolein in this experimental animal carcinogenesis model. The data obtained in this study suggest that the formation of a carcinogenic aldehyde through lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.

DOI： 10.1074/jbc.M309057200

Restoration of fertility in infertile mice by transplantation of cryopreserved male germline stem cells Reviewed International journal Open Access

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

HUMAN REPRODUCTION Vol. 18 ( 12 ) page： 2660 - 7 2003.12

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

BACKGROUND: The development of a spermatogonial transplantation technique has provided new possibilities for the treatment of male infertility. Previous studies have shown that spermatogonial stem cells could reinitiate spermatogenesis after cryopreservation and reintroduction into the seminiferous tubules of infertile recipient males, and this raised the possibility of banking frozen stem cells for male infertility treatment. It remains unknown, however, whether germ cells from freeze-thawed stem cells are fertile, leaving the possibility that the procedure compromises the integrity of the stem cells. METHODS AND RESULTS: Dissociated mouse testis cells were cryopreserved and transplanted into infertile recipient testes. The freeze-thawed testis cell populations contained higher concentrations of stem cells than fresh testis cell populations. Offspring were obtained from freeze-thawed stem cells transplanted into infertile males, and fertility restoration was more efficient in immature (5-10 days old) than in mature (6-12 weeks old) recipients. However, offspring were also obtained from infertile adult recipients using in-vitro microinsemination. CONCLUSIONS: This first successful application of frozen stem cell technology in the production of offspring by spermatogonial transplantation suggests the superiority of immature recipients for clinical applications. Thus, the combination of cryopreservation and transplantation of stem cells is a promising approach to overcome male infertility.

DOI： 10.1093/humrep/deg483

Effects of the phenolic contents of Mauritian endemic plant extracts on promoter activities of antioxidant enzymes. Reviewed International journal

Shinya Toyokuni, Tomoyuki Tanaka, Waka Kawaguchi, Neil Ryan Lai Fang, Munetaka Ozeki, Shinya Akatsuka, Hiroshi Hiai, Okezie I Aruoma, Theeshan Bahorun

Free radical research Vol. 37 ( 11 ) page： 1215 - 24 2003.11

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

Oxidative stress has been associated with a variety of pathologic conditions in humans. Increasing the transcriptional activities of antioxidant enzymes might be a strategy to prevent oxidative stress-associated diseases such as atherosclerosis and cancer. In the present paper, we studied the effects of extracts from 12 Mauritian endemic plants on the promoter activities of antioxidant enzymes; Cu, Zn-superoxide dismutase (Cu,Zn-SOD), Mn-superoxide dismutase (Mn-SOD), catalase, and glutathione dismutase (GPx). The levels of total phenolic compounds, total flavonoids, and proanthocyanidins were measured. Four luciferase expression vectors (pGL3-Basic) with promoter region of each enzyme were constructed, transfected to COS7 cells followed by an exposure to each extract (25 mug/ml, 24 h, non-toxic dose). Thereafter, luciferase activities were evaluated in comparison with a control luciferase vector with a herpes simplex virus thymidine kinase promoter. Mauritian endemic plants contained high amounts of total phenols, flavonoids and proanthocyanidins. Total phenols and flavonoids were proportionally associated with Cu,Zn-SOD promoter activity, whereas they were inversely correlated with catalase promoter activity. These results suggest that the chemopreventive potentials of the extracts might reside in their abilities to modulate the expression of the antioxidant enzyme genes.

DOI： 10.1080/10715760310001598150

Edaravone, a novel free radical scavenger, protects myocardium against oxidative stress after cardioplegic arrest

Yamazaki, K; Miwa, S; Toyokuni, S; Horii, T; Unimonh, O; Sasahashi, N; Takaba, K; Komeda, M

CIRCULATION Vol. 108 ( 17 ) page： 175 - 175 2003.10

Edaravone, a novel free radical scavenger, protects myocardium against oxidative stress after cardioplegic arrest International journal

Yamazaki, K, Miwa, S, Toyokuni, S, Horii, T, Unimonh, O, Sasahashi, N, Takaba, K, Komeda, M

CIRCULATION Vol. 108 ( 17 ) page： 175 - 175 2003.10

Novel aspects in free radical chemistry and biology Reviewed International journal

Toyokuni, S

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 417 ( 1 ) page： 2 - 2 2003.9

Long-term proliferation in culture and germline transmission of mouse male germline stem cells. Reviewed International journal

Mito Kanatsu-Shinohara, Narumi Ogonuki, Kimiko Inoue, Hiromi Miki, Atsuo Ogura, Shinya Toyokuni, Takashi Shinohara

Biology of reproduction Vol. 69 ( 2 ) page： 612 - 6 2003.8

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

Spermatogenesis is a complex process that originates in a small population of spermatogonial stem cells. Here we report the in vitro culture of spermatogonial stem cells that proliferate for long periods of time. In the presence of glial cell line-derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, and leukemia inhibitory factor, gonocytes isolated from neonatal mouse testis proliferated over a 5-month period (>10(14)-fold)and restored fertility to congenitally infertile recipient mice following transplantation into seminiferous tubules. Long-term spermatogonial stem cell culture will be useful for studying spermatogenesis mechanism and has important implications for developing new technology in transgenesis or medicine.

DOI： 10.1095/biloreprod.103.017012

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Long-term proliferation in culture and germline transmission of mouse male germline stem cells

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

BIOLOGY OF REPRODUCTION Vol. 69 ( 2 ) page： 612 - 616 2003.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biology of Reproduction

Spermatogenesis is a complex process that originates in a small population of spermatogonial stem cells. Here we report the in vitro culture of spermatogonial stem cells that proliferate for long periods of time. In the presence of glial cell line-derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, and leukemia inhibitory factor, gonocytes isolated from neonatal mouse testis proliferated over a 5-month period (>1014-fold) and restored fertility to congenitally infertile recipient mice following transplantation into seminiferous tubules. Long-term spermatogonial stem cell culture will be useful for studying spermatogenesis mechanism and has important implications for developing new technology in transgenesis or medicine.

DOI： 10.1095/biolreprod.103.017012

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Involvement of death receptor Fas in germ cell degeneration in gonads of Kit-deficient Wv/Wv mutant mice. Reviewed International journal Open Access

Sakata S, Sakamaki K, Watanabe K, Nakamura N, Toyokuni S, Nishimune Y, Mori C, Yonehara S

Cell death and differentiation Vol. 10 ( 6 ) page： 676 - 86 2003.6

Evidence for oxidative stress in NSAID-induced colitis in IL10-/- mice. International journal

Seiko Narushima, Douglas R Spitz, Larry W Oberley, Shinya Toyokuni, Toshio Miyata, Carol A Gunnett, Garry R Buettner, Juan Zhang, Hanan Ismail, Richard G Lynch, Daniel J Berg

Free radical biology & medicine Vol. 34 ( 9 ) page： 1153 - 66 2003.5

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

The goal of this study was to evaluate for evidence of oxidative stress in colonic inflammation in a novel model of inflammatory bowel disease, nonsteroidal anti-inflammatory drug- (NSAID-) treated interleukin-10-deficient (IL10(-/-)) mice. IL10(-/-) and wild-type (wt) mice were treated with a nonselective NSAID (piroxicam, 200 ppm in the diet) for 2 weeks to induce colitis, and parameters for oxidative stress in the colonic tissues were evaluated. Mean chemiluminescence enhanced with lucigenin in the colons from IL10(-/-) mice treated with piroxicam was more than 5-fold higher than that of the control wt group. Chemiluminescence was inhibited with diphenylethylene iodinium, but not allopurinol, indomethacin, or N-omega-nitro-L-arginine, indicating that flavin-containing enzymes were the source of the reactive oxygen species. Colonic aconitase activity in NSAID-treated IL10(-/-) mice decreased to 50% of the activity of control mice. There was no difference in the total glutathione levels in the colonic mucosa among the groups; however, glutathione disulfide levels were approximately 2-fold greater in the colon of NSAID-treated IL10(-/-) mice as compared with control groups. Immunohistochemistry studies of colons from NSAID-treated IL10(-/-) mice demonstrated intense staining with two antibodies that recognize advanced glycation endproducts formed through glycation and oxidation: anticarboxymethylysine and antipentosidine. The epithelial cells and lamina propria cells in the colons of NSAID-treated IL10(-/-) mice showed immunostaining with antinitrotyrosine, indicating the presence of reactive nitrogen species. Colonic epithelium of IL10(-/-) mice with colitis showed moderate immunostaining for 8-hydroxy-2'-deoxyguanosine in the nuclei. NSAID-treated IL10(-/-) mice treated with diphenylene idodonium chloride (DPI), an irreversible inhibitor of flavoprotein enzymes, experienced significantly reduced inflammation. Taken together, these results strongly indicate the presence of oxidative stress in the inflammatory bowel disease in NSAID-treated IL10(-/-) mice and suggests a role for oxidative stress in the pathophysiology of this model of inflammatory bowel disease.

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Evidence for oxidative stress in NSAID-induced colitis in IL10(-/-) mice

Narushima S, Spitz DR, Oberley LW, Toyckuni S, Miyata T, Gunnett CA, Buettner GR, Zhang J, Ismail H, Lynch RG, Berg DJ

FREE RADICAL BIOLOGY AND MEDICINE Vol. 34 ( 9 ) page： 1153 - 1166 2003.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Free Radical Biology and Medicine

The goal of this study was to evaluate for evidence of oxidative stress in colonic inflammation in a novel model of inflammatory bowel disease, nonsteroidal anti-inflammatory drug- (NSAID-) treated interleukin-10-deficient (IL10-/-) mice. IL10-/- and wild-type (wt) mice were treated with a nonselective NSAID (piroxicam, 200 ppm in the diet) for 2 weeks to induce colitis, and parameters for oxidative stress in the colonic tissues were evaluated. Mean chemiluminescence enhanced with lucigenin in the colons from IL10-/- mice treated with piroxicam was more than 5-fold higher than that of the control wt group. Chemiluminescence was inhibited with diphenylethylene iodinium, but not allopurinol, indomethacin, or N-ω-nitro-L-arginine, indicating that flavin-containing enzymes were the source of the reactive oxygen species. Colonic aconitase activity in NSAID-treated IL10-/- mice decreased to 50% of the activity of control mice. There was no difference in the total glutathione levels in the colonic mucosa among the groups; however, glutathione disulfide levels were approximately 2-fold greater in the colon of NSAID-treated IL10-/- mice as compared with control groups. Immunohistochemistry studies of colons from NSAID-treated IL10-/- mice demonstrated intense staining with two antibodies that recognize advanced glycation endproducts formed through glycation and oxidation: anticarboxymethylysine and antipentosidine. The epithelial cells and lamina propria cells in the colons of NSAID-treated IL10-/- mice showed immunostaining with antinitrotyrosine, indicating the presence of reactive nitrogen species. Colonic epithelium of IL10-/- mice with colitis showed moderate immunostaining for 8-hydroxy-2′-deoxyguanosine in the nuclei. NSAID-treated IL10-/- mice treated with diphenylene idodonium chloride (DPI), an irreversible inhibitor of flavoprotein enzymes, experienced significantly reduced inflammation. Taken together, these results strongly indicate the presence of oxidative stress in the inflammatory bowel disease in NSAID-treated IL10-/- mice and suggests a role for oxidative stress in the pathophysiology of this model of inflammatory bowel disease. © 2003 Elsevier Inc.

DOI： 10.1016/S0891-5849(03)00065-0

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Functional assessment of self-renewal activity of male germline stem cells following cytotoxic damage and serial transplantation. Reviewed International journal Open Access

Mito Kanatsu-Shinohara, Shinya Toyokuni, Takeshi Morimoto, Shigeyuki Matsui, Tasuku Honjo, Takashi Shinohara

Biology of reproduction Vol. 68 ( 5 ) page： 1801 - 7 2003.5

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

Spermatogenesis is dependent on a small population of stem cells. Although stem cells are believed to expand infinitely, there is little functional evidence regarding whether spermatogonial stem cells can increase in their number. Using the spermatogonial transplantation technique, we evaluated the proliferative potential of spermatogonial stem cells in two models of regeneration. After busulfan injection to deplete stem cells, the surviving stem cells were able to expand by at least 15.8-fold within 2 mo. On the other hand, a serial transplantation study indicated that one transplanted stem cell was able to expand by 3.8- and 12-fold within 2 and 4 mo, respectively. These results provide direct functional evidence for the expansion of stem cells and establish the basis for further characterization of the stem cell self-renewal process.

DOI： 10.1095/biolreprod.102.012575

Intermittent microwave irradiation facilitates antigen-antibody reaction in Western blot analysis

TOYOKUNI Shinya, KAWAGUCHI Waka, AKATSUKA Shinya, HIROYASU Makoto, HIAI Hiroshi

Pathol Int Vol. 53 ( 4 ) page： 259 - 261 2003.4