Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Molecular mechanisms of oxidative stress-induced carcinogenesis: From epidemiology to oxygenomics

Toyokuni, S

IUBMB LIFE Vol. 60 ( 7 ) page： 441 - 447 2008.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed International journal

Kousuke Ishino, Takahiro Shibata, Takeshi Ishii, Yu-Ting Liu, Shinya Toyokuni, Xiaochun Zhu, Lawrence M Sayre, Koji Uchida

Chemical research in toxicology Vol. 21 ( 6 ) page： 1261 - 1270 2008.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

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, N-alpha-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, N-epsilon-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.

DOI： 10.1021/tx800080x

Pluripotency of a single spermatogonial stem cell in mice Reviewed

Mito Kanatsu-Shinohara, Jiyoung Lee, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokun, Masahito Ikawa, Tomoyuki Nakamura, Atsuo Gura, Takashi Shinohara

BIOLOGY OF REPRODUCTION Vol. 78 ( 4 ) page： 681 - 687 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SOC STUDY 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 11 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 KIf4) 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.

DOI： 10.1095/biolreprod.107.066068

Visualization and characterization of UVB-induced reactive oxygen species in a human skin equivalent model

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

ARCHIVES OF DERMATOLOGICAL RESEARCH Vol. 300 ( SUPPL. 1 ) page： S51 - S56 2008.4

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

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Target Genes of Oxidative Stress-induced Carcinogenesis

TOYOKUNI Shinya

Vol. 63 ( 2 ) page： 282 2008.3

Target Genes of Oxidative Stress-induced Carcinogenesis

TOYOKUNI Shinya

Vol. 63 ( 2 ) page： 282 - 282 2008.3

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 Vol. 14 ( 1 ) page： 32 - 40 2008.1

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

Vol. 38 ( 1 ) page： 70 - 78 2008.1

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 Vol. 14 ( 1 ) page： 32 - 40 2008.1

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

Shigekazu Takemura, Yukiko Minamiyama, Shinya Toyokuni, Susumu Imaoka, Seikan Hai, Shoji Kubo, Kazuhiro Hirohashi, Yoshihiko Funae, Shigeru Okada

HEPATOLOGY RESEARCH Vol. 38 ( 1 ) page： 70 - 78 2008.1

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

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 three days before LPS injection. Liver injury was analyzed 8 h 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.
Conclusions: Overexpression of CYP3A aggravated LPS-induced liver injury in rats, apparently through the formation of reactive oxygen species.

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 Reviewed

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

CLINICAL CANCER RESEARCH Vol. 14 ( 1 ) page： 32 - 40 2008.1

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

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

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

Hepatol. Res. Vol. 38 page： 70-78 2008

Pluripotency of a single spermatogonial stem cell. Reviewed

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

Biol. Reprod. Vol. 78 page： 681-687 2008

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. Reviewed

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

Clin. Cancer Res. Vol. 14 page： 32-40 2008

Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. Invited Reviewed

Toyokuni S.

IUBMB Life Vol. 60 page： 441-447 2008

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

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

Mol. Carcinog. Vol. 47 page： 638-646 2008

Protein N-acylation: H2O2-mediated covalent modification of protein by lipid peroxidation-derived saturated aldehydes. Reviewed

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

Chem. Res. Toxicol. Vol. 21 page： 1261-1270 2008

A reporter gene assay to prove the ability of natural compounds to modulate gluthathione peroxidase, superoxide dismutase and catalase gene promoters in V79 cells. Reviewed

Ullmann K, Wiencierz A M, Müller C, Thierbach R, Steege A, Toyokuni S and Steinberg P.

Free Radic. Res. Vol. 42 page： 746-753 2008

The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Reviewed

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 Differ. Vol. 15 page： 1712-1722 2008

Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inihibitor FK228 through AIF translocation. Reviewed

Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe KI, Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Tokuchida J and Nakahata T.

Int. J. Cancer Vol. 124 page： 55-67 2008

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Papers - TOYOKUNI Shinya