研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Characteristics and modifying factors of asbestos-induced oxidative DNA damage. 査読有り国際誌 Open Access

Jiang L, Nagai H, Ohara H, Hara S, Tachibana M, Hirano S, Shinohara Y, Kohyama N, Akatsuka S, Toyokuni S

Cancer science 99 巻 ( 11 ) 頁： 2142 - 51 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

Respiratory exposure to asbestos has been linked with mesothelioma in humans. However, its carcinogenic mechanism is still unclear. Here we studied the ability of chrysotile, crocidolite and amosite fibers to induce oxidative DNA damage and the modifying factors using four distinct approaches. Electron spin resonance analyses revealed that crocidolite and amosite containing high amounts of iron, but not chrysotile, catalyzed hydroxyl radical generation in the presence of H2O2, which was enhanced by an iron chelator, nitrilotriacetic acid, and suppressed by desferal. Natural iron chelators, such as citrate, adenosine 5′-triphosphate and guanosine 5′-triphosphate, did not inhibit this reaction. Second, we used time-lapse video microscopy to evaluate how cells cope with asbestos fibers. RAW264.7 cells, MeT-5 A and HeLa cells engulfed asbestos fibers, which reached not only cytoplasm but also the nucleus. Third, we utilized supercoiled plasmid DNA to evaluate the ability of each asbestos to induce DNA double strand breaks (DSB). Crocidolite and amosite, but not chrysotile, induced DNA DSB in the presence of iron chelators. We cloned the fragments to identify break sites. DSB occurred preferentially within repeat sequences and between two G:C sequences. Finally, i.p. administration of each asbestos to rats induced not only formation of nuclear 8-hydroxy-2′-deoxyguanosine in the mesothelia, spleen, liver and kidney but also significant iron deposits in the spleen. Together with the established carcinogenicity of i.p. chrysotile, our data suggest that asbestos-associated catalytic iron, whether constitutional or induced by other mechanisms, plays an important role in asbestos-induced carcinogenesis and that chemoprevention may be possible through targeting the catalytic iron. © 2008 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2008.00934.x

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. 査読有り国際誌 Open Access

Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S

Cell death and differentiation 15 巻 ( 11 ) 頁： 1712 - 22 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cell Death and Differentiation

Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl+) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl+ leukemias.

DOI： 10.1038/cdd.2008.107

Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme <i>Ogg1</i> deficient mice 査読有り国際誌 Open Access

Liao, J; Seril, DN; Lu, GG; Zhang, M; Toyokuni, S; Yang, AL; Yang, GY

MOLECULAR CARCINOGENESIS 47 巻 ( 8 ) 頁： 638 - 646 2008年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Molecular Carcinogenesis

Ogg1 DNA repair enzyme recognizes and excises oxidative stress-caused 8-hydroxyl-deoxyguanosine (8-OHdG) from GC base-pairs. Ogg1 knockout mice are phenotypically normal, but exhibit elevated levels of 8-OHdG in nuclear and mitochondrial DNA, as well as moderately elevated mutagenesis and spontaneous lung tumors and UV-induced skin tumors. To elucidate the mechanistic role of inflammation-caused oxidative stress in carcinogenesis, the development of chronic ulcerative colitis (UC)-induced carcinoma in Ogg1 knockout mice was studied using a dextran sulfate sodium (DSS)-induced UC model without the use of a carcinogen. Ogg1 (-/-), Ogg1 (+/-), and wild type C57BL/6 mice were subjected to long-term, cyclic DSS treatment to induce chronic UC and carcinogenesis. In wild type C57BL/6 control mice after 15 cycles of DSS treatment, colorectal adenocarcinoma incidence was 24.1% (7/29 mice), with a tumor volume of 27.9 ± 5.2 mm3. Ogg1 (-/-) mice showed significantly increased adenocarcinoma development in the colon with a tumor incidence of 57.1% (12 of 21 mice, P < 0.05) and a tumor volume of 35.1 ± 6.1 mm3. Ogg1 mice (+/-) also exhibited significantly increased tumor development in the colon with a tumor incidence of 50.0% (13/26 mice) and a tumor volume of 29.1 ± 7.2 mm3. Histopathologic analyses revealed that colorectal tumors were well-differentiated tubular adenocarcinomas or mucinous carcinoma and adjacent colonic mucosa showed mild to moderate chronic UC. Using immunohistochemical approaches, Ogg1 (-/-) and (+/-) mice exhibited similar numbers and staining intensities of macrophages in UC areas as seen in Ogg1 (+/+) mice, but markedly increased numbers and staining intensities of 8-OHdG positive inflammatory and epithelial cells. These results provide important evidence on the relationship between inflammation-caused oxidative stress, DNA repair enzyme Ogg1, and carcinogenesis. © 2008 Wiley-Liss, Inc.

DOI： 10.1002/mc.20427

Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. 査読有り国際誌 Open Access

Toyokuni S

IUBMB life 60 巻 ( 7 ) 頁： 441 - 7 2008年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：IUBMB Life

Oxidative stress is associated with inflammation, radiation, reperfusion, and iron overload. Epidemiological observations have shown that oxidative stress is one of the major sources of carcinogenesis, the top-ranked cause of human mortality worldwide. In situations of oxidative stress, reactive oxygen and nitrogen species contribute to the alteration of genome information, presumably followed by selection of the adapted proliferating cells in a given environment. Recent data suggest that common molecular mechanisms exist in oxidative stress-induced carcinogenesis, including p16INK4A inactivation. Thus far, oxidative DNA damage in the genome as a cause of mutation has been recognized to be randomly distributed based on in vitro experiments, while localization of oxidative DNA damage in vivo has not been pursued. However, using a novel technique based on DNA immunoprecipitation in combination with genome information, we now know that the localization of oxidative DNA damage is not random in vivo. We propose to call this rather novel research area "oxygenomics." Many signaling pathways start from the recognition of DNA damage. Thus, possible underlying principles should be elucidated in association with each cell type, the genomic location of the damage with its transcriptional activity as well as the chromatin status determining the epigenetic effect. © 2008 IUBMB.

DOI： 10.1002/iub.61

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PubMed

Protein N-acylation: H2O2-mediated covalent modification of protein by lipid peroxidation-derived saturated aldehydes. 査読有り国際誌

Ishino K, Shibata T, Ishii T, Liu YT, Toyokuni S, Zhu X, Sayre LM, Uchida K

Chemical research in toxicology 21 巻 ( 6 ) 頁： 1261 - 70 2008年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Chemical Research in Toxicology

Various lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the degenerated proteins have been found in cells and tissues during aging, oxidative stress, and in a variety of pathological states. The critical agents that give rise to this protein degeneration may be represented by aldehydes. Although the covalent modification of proteins by aldehydes alone has been well-studied, the effect of reactive oxygen species, such as H2O2, upon aldehyde modification of the protein has received little attention. We have now established a unique protein modification in which H2O2 and, to a lesser extent, alkyl hydroperoxides mediate the binding of alkanals to the lysine residues of protein to generate structurally unusual N-acylation products. Upon the reaction of a lysine-containing peptide, Nα-benzoylglycyl- lysine, with hexanal in the presence of H2O2, a product containing one molecule of hexanal per peptide was detected. On the basis of the chemical and spectroscopic evidence, the product was identified to be the acylation product, Nε-hexanoyllysine. H2O2 mediated the N-acylation of the lysine derivative by the saturated aldehydes of 1-6 carbons in length. The H2O2-mediated acylation of the protein was immunochemically confirmed by reaction of the proteins with hexanal in the presence of H2O2. Furthermore, the enhanced N-acylations (N-acetylation and N-hexanoylation) were also observed in the kidney of rats exposed to ferric nitrilotriacetate, a well-characterized inducer of oxidative stress. Mechanistic studies using a phosphonium lysine derivative suggest a Baeyer-Villiger-like reaction proceeding through peroxide addition to the aldehyde Schiff base. These data suggest that the hydroperoxides, including H2O2, might be involved not only in the oxidative modification of protein but also in the covalent binding of the saturated aldehydes to proteins under oxidative stress. © 2008 American Chemical Society.

DOI： 10.1021/tx800080x

Pluripotency of a single spermatogonial stem cell in mice. 査読有り国際誌 Open Access

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

Biology of reproduction 78 巻 ( 4 ) 頁： 681 - 7 2008年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biology of Reproduction

Although pluripotent stem cells were recently discovered in postnatal testis, attempts to analyze their developmental potential have led to conflicting claims that spermatogonial stem cells are pluripotent or that they lose spermatogenic potential after conversion into pluripotent stem cells. To examine this issue, we analyzed the developmental fate of a single spermatogonial stem cell that appeared during transfection experiments. After transfection of a neomycin-resistance gene into germline stem cells, we obtained an embryonic stem-like, multipotent germline stem cell line. Southern blot analysis revealed that the germline stem and multipotent germline stem clones have the same transgene integration pattern, demonstrating their identical origin. The two lines, however, have different DNA methylation patterns. The multipotent germline stem cells formed chimeras after blastocyst injection but did not produce sperm after germ cell transplantation, whereas the germline stem cells could produce only spermatozoa and did not differentiate into somatic cells. Interestingly, the germline stem cells expressed several transcription factors (Pou5f1, Sox2, Myc, and Klf4) required for reprogramming fibroblasts into a pluripotent state, suggesting that they are potentially pluripotent. Thus, our study provides evidence that a single spermatogonial stem cell can acquire pluripotentiality but that conversion into a pluripotent cell type is accompanied by loss of spermatogenic potential. © 2008 by the Society for the Study of Reproduction, Inc.

DOI： 10.1095/biolreprod.107.066068

Visualization and characterization of UVB-induced reactive oxygen species in a human skin equivalent model 査読有り国際誌

Hakozaki, T; Date, A; Yoshii, T; Toyokuni, S; Yasui, H; Sakurai, H

ARCHIVES OF DERMATOLOGICAL RESEARCH 300 巻 ( SUPPL. 1 ) 頁： S51 - S56 2008年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives of Dermatological Research

Reactive oxygen species (ROS) play important roles in the process of ultraviolet-induced skin damage or photoaging. Although many enzymatic and chemical methods have been developed for evaluating ROS, evaluation methods for ROS generation in living systems are quite limited. Here we propose a unique system to visualize UVB-induced ROS and investigate the biological impact of ROS. In brief, a human skin equivalent model (HSEM) was exposed to UVB. Emitted luminescence from the HSEM was visualized and semi-quantified by using a chemiluminescent probe (CLA) and an ultra low-light imaging apparatus. The effects of anti-oxidative compounds such as ascorbate, β-carotene, superoxide dismutase (SOD), and yeast ferment filtrate (YFF) on the HSEM were evaluated by semi-quantification of emitted chemiluminescence (CL) intensities, MTT assay and 8-hydroxy-2′-deoxyguanosine (8-OHdG) staining. Visualization of time- and space-dependent dynamics of ROS generation in the HSEM was successfully achieved by utilizing a sensitive two-dimensional ultra-low light luminograph. Treatments with β-carotene and SOD effectively suppressed CL intensity, indicating the generation of 1O2 and O 2.- in the HSEM under UVB exposure. Tested anti-oxidative compounds also attenuated UVB-induced CL and ameliorated the induced skin damages in terms of 8-OHdG formation and cell death. As a conclusion, this model is useful for not only visualizing the production of UVB-induced ROS in real-time but also evaluating the efficacy of topically applied anti-oxidative compounds to suppress ROS generation and attenuate sequential chemical and biological responses. © 2007 Springer-Verlag.

DOI： 10.1007/s00403-007-0804-3

豊國伸哉

日本衞生學雜誌 63 巻 ( 2 ) 頁： 282 2008年3月

酸化ストレス発がんの標的遺伝子について

豊國伸哉

日本衞生學雜誌 63 巻 ( 2 ) 頁： 282 - 282 2008年3月

Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress.

Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K, Fujii S

Clinical cancer research : an official journal of the American Association for Cancer Research 14 巻 ( 1 ) 頁： 32 - 40 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Cancer Research

Purpose: Endometriotic cysts are known to transforminto ovarian cancers, such as clear cell and endometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Experimental Design: Contents of human ovarian cysts, including 21 endometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts,were analyzed for the concentrations of free "catalytic" iron, lactose dehydrogenase, potential antioxidant, lipid peroxide, and 8-hydroxy-2′- deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in endometriotic cyst were determined in vitro. Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxidant, lipidperoxide, and 8-OHdG were also significantly higher in endometriotic cysts (P < 0.01). There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01). The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of endometriotic cyst couldproducemore reactiveoxygen species and could induce genemutations more frequently than the contents in the other cysts. Conclusions: Abundant free iron in the contents of endometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst. © 2008 American Association for Cancer Research.

DOI： 10.1158/1078-0432.CCR-07-1614

Scopus

PubMed

Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats

TAKEMURA Shigekazu, MINAMIYAMA Yukiko, TOYOKUNI Shinya, IMAOKA Susumu, HAI Seikan, KUBO Shoji, HIROHASHI Kazuhiro, FUNAE Yoshihiko, OKADA Shigeru

Hepatology research : the official journal of the Japan Society of Hepatology 38 巻 ( 1 ) 頁： 70 - 78 2008年1月

Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress

Yamaguchi Ken, Mandai Masaki, Toyokuni Shinya, Hamanishi Junzo, Higuchi Toshihiro, Takakura Kenji, Fujii Shingo

CLINICAL CANCER RESEARCH 14 巻 ( 1 ) 頁： 32 - 40 2008年1月

Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats 査読有り国際誌

Takemura, S; Minamiyama, Y; Toyokuni, S; Imaoka, S; Hai, S; Kubo, S; Hirohashi, K; Funae, Y; Okada, S

HEPATOLOGY RESEARCH 38 巻 ( 1 ) 頁： 70 - 78 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hepatology Research

Aim: CYP3A2 is a male-specific isoform of cytochrome P450 enzyme which is expressed abundantly in male rats but not in intact female rats. Having previously reported that hepatic CYP3A2 promotes lipopolysaccharide (LPS)-induced liver injury in male rats, we further examined the impact of CYP3A on LPS-induced liver injury by comparing intact and hypophysectomized female rats. In hypophysectomized female rats, phenobarbital (PB), a cytochrome P450 inducer, markedly increased the hepatic content and activity of CYP3A1/2, but did not do so in intact rats. CYP2B1 increased to similar levels in PB-treated hypophysectomized and intact rats. Methods: Rats were administered 10 mg/kg LPS intravenously and some were given PB for threedays before LPS injection. Liver injury was analyzed 8h after LPS injection. Results: PB-LPS increased plasma alanine aminotransferase significantly more in hypophysectomized female rats than in intact female rats. Ketoconazole, a CYP3A inhibitor, inhibited the increase of liver injury. Hepatic 8-hydroxydeoxyguanosine in nuclei and 4-hydroxy-2-nonenal-modified proteins, measured to evaluate oxidative stress by LPS treatment, increased markedly more in PB-treated, hypophysectomized female rats, than in intact female rats. Conclusion: Overexpression of CYP3A aggravated LPS-induced liver injury in rats, apparently through the formation of reactive oxygen species. © 2007 The Japan Society of Hepatology.

DOI： 10.1111/j.1872-034X.2007.00212.x

Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress 査読有り

Ken Yamaguchi, Masaki Mandai, Shinya Toyokuni, Junzo Hamanishi, Toshihiro Higuchi, Kenji Takakura, Shingo Fujii

CLINICAL CANCER RESEARCH 14 巻 ( 1 ) 頁： 32 - 40 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC CANCER RESEARCH

Purpose: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and enclometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress.
Experimental Design: Contents of human ovarian cysts, including 21 enclometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free "catalytic" iron, lactose clehydrogenase, potential antioxiclant, lipid peroxide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in enclometriotic cyst were determined in vitro.
Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxiclant, lipid peroxide, and 8-OHdG were also significantly higher in enclometriotic cysts (P < 0.01).There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01).The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of enclometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts.
Conclusions: Abundant free iron in the contents of enclometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.

DOI： 10.1002/path.4377

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Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. 査読有り

Zhong Y, Onuki J, Yamasaki T. Ogawa O, Akatsuka S and Toyokuni S.

Carcinogenesis 頁： in press 2008年

Overexpression of CYP3A aggravates endotoxin-induced liver injury in hypophysectomized female rats. 査読有り

Takemura S, Minamiyama Y, Toyokuni S, Imaoka S, Hai S, Kubo S, Hirohashi K, Funae Y and Okada S.

Hepatol. Res. 38 巻頁： 70-78 2008年

Pluripotency of a single spermatogonial stem cell. 査読有り

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

Biol. Reprod. 78 巻頁： 681-687 2008年

Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. 査読有り

Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K and Fujii S.

Clin. Cancer Res. 14 巻頁： 32-40 2008年

Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. 招待有り査読有り

Toyokuni S.

IUBMB Life 60 巻頁： 441-447 2008年

Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. 査読有り

Liao J, Seril DN, Lu GG, Zhang M, Toyokuni S, Yang AL and Yang GY.

Mol. Carcinog. 47 巻頁： 638-646 2008年

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