Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Genetic Reconstruction of Mouse Spermatogonial Stem Cell Self-Renewal In Vitro by Ras-Cyclin D2 Activation Reviewed International journal

Jiyoung Lee, Mito Kanatsu-Shinohara, Hiroko Morimoto, Yasuhiro Kazuki, Seiji Takashima, Mitsuo Oshimura, Shinya Toyokuni, Takashi Shinohara

CELL STEM CELL Vol. 5 ( 1 ) page： 76 - 86 2009.7

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

Spermatogonial stem cells (SSCs) undergo self-renewal division and support spermatogenesis. Although several cytokines coordinate to drive SSC self-renewal, little is known about the mechanisms underlying this process. We investigated the molecular mechanism by reconstructing SSC self-renewal in vitro without exogenous cytokines. Activation of Ras or overexpression of cyclins D2 and E1, both of which were induced by Ras; enabled long-term self-renewal of cultured spermatogonia. SSCs with activated Ras responded properly to differentiation signals and underwent spermatogenesis, whereas differentiation was abrogated in cyclin transfectants after spermatogonial transplantation. Both Ras- and cyclin-transfected cells produced seminomatous tumors, suggesting that excessive self-renewing stimulus induces oncogenic transformation. In contrast, cells that overexpressed cyclin D1 or D3 failed to make germ cell colonies after transplantation, which indicated that cyclin expression pattern is an important determinant to long-term SSC recolonization. Thus, the Ras-cyclin D2 pathway regulates the balance between tissue maintenance and tumorigenesis in the SSC population.

DOI： 10.1016/j.stem.2009.04.020

Abnormal DNA methyltransferase expression in mouse germline stem cells results in spermatogenic defects. Reviewed

Takashima S, Takehashi M, Lee J, Chuma S, Okano M, Hata K, Suetake I, Nakatsuji N, Miyoshi H, Tajima S, Tanaka Y, Toyokuni S, Sasaki H, Kanatsu-Shinohara M, Shinohara S.

Vol. 81 page： 155-164 2009.7

Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro by Ras-cyclin D2 activation. Reviewed

Lee J, Kanatsu-Shinohara M, Morimoto H, Kazuki Y, Takashima S, Oshimura M, Toyokuni S and Shinohara T.

Cell Stem Cell Vol. 5 page： 76-86 2009.7

Abnormal DNA Methyltransferase Expression in Mouse Germline Stem Cells Results in Spermatogenic Defects Reviewed

Seiji Takashima, Masanori Takehashi, Jiyoung Lee, Shinichiro Chuma, Masaki Okano, Kenichiro Hata, Isao Suetake, Norio Nakatsuji, Hiroyuki Miyoshi, Shoji Tajima, Yoriko Tanaka, Shinya Toyokuni, Hiroyuki Sasaki, Mito Kanatsu-Shinohara, Takashi Shinohara

BIOLOGY OF REPRODUCTION Vol. 81 ( 1 ) page： 155 - 164 2009.7

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

Although spermatogonial stem cells (SSCs) are committed to spermatogenesis, they may also convert to an embryonic stem cell-like pluripotent state at a low frequency. Because changes in DNA methylation patterns are associated with this conversion, we examined the effect of manipulating DNA methyltransferase (Dnmt) expression on the fate of cultured SSCs, germline stem (GS) cells. Dnmt1 knockdown induced apoptosis in GS cells, which was attenuated by the loss of Trp53. In contrast, GS cells proliferated normally in vitro after Dnmt3a/Dnmt3b ablation or during Dnmt3l overexpression. However, Dnmt3a/Dnmt3b double-mutant cells showed hypomethylation in the SineB1 repetitive sequence, and Dnmt3l-overexpressing cells showed hypermethylation in major and minor satellite sequences; neither cell type formed teratomas and completed spermatogenesis following transplantation into the seminiferous tubules. Although genetic manipulation did not increase the conversion of GS cells to a pluripotent state, these results underscore the important role of DNMTs in survival and spermatogenic differentiation in SSCs.

DOI： 10.1095/biolreprod.108.074708

Proapoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of manganese-dependent superoxide dismutase knockout mice. International journal

Yang-Yi Fan, Yang Zhan, Harold M Aukema, Laurie A Davidson, Lan Zhou, Evelyn Callaway, Yanan Tian, Brad R Weeks, Joanne R Lupton, Shinya Toyokuni, Robert S Chapkin

The Journal of nutrition Vol. 139 ( 7 ) page： 1328 - 1332 2009.7

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

We recently demonstrated that (n-3) PUFA trigger the induction of apoptosis in the colon by enhancing phospholipid oxidation and mitochondrial Ca2+ accumulation. To further elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, a 2 x 2 experiment was designed using both wild type (control) and manganese-dependent superoxide dismutase (SOD2) heterozygous knockout mice (SOD2(+/-)), which exhibit increased mitochondrial oxidative stress. Mice were fed diets differing only in the type of fat [corn oil or fish oil containing (n-3) PUFA] at 15% by weight for 4 wk. Dietary (n-3) PUFA treatment enhanced (22%) apoptosis in colonic crypts. In addition, SOD2 haploinsufficiency enhanced (20%) apoptosis, which was further increased (36%) by (n-3) PUFA feeding. Dietary lipid source and genotype interactively modulated nitrotyrosine levels (P = 0.027) and inflammation (P = 0.032). These findings demonstrate that the proapoptotic effects of (n-3) PUFA are enhanced in oxidatively stressed SOD2(+/-) mice. Thus, (n-3) PUFA appear to promote an oxidation-reduction imbalance in the intestine, which may directly or indirectly trigger apoptosis and thereby reduce colon cancer risk.

DOI： 10.3945/jn.109.106203

The potential role of reactive oxygen species in mammary neoplasm

Arafah M., Khabaz M., Toyokuni S.

Australian Journal of Basic and Applied Sciences Vol. 3 ( 3 ) page： 2949 - 2954 2009.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Australian Journal of Basic and Applied Sciences

The current study investigated the presence of oxidative stress markers (8-OHdG and HNE) in breast carcinoma in females from Saudi Arabia, and to examine the growth modulatory effects of HNE (induce cell growth inhibition) by measuring the expression of Ki-67 protein (cell proliferation antigen). Furthermore, to record if there is any significant prognostic indicator of these markers. In order to estimate the level of oxidative damage in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (HNE) expressions were investigated in breast carcinoma and benign lesions of breast, and were estimated by semi-quantitative immunohistochemical method. The observations of the present study showed that the level of expressions of 8-OHdG and HNE were significantly higher than those in controls. Reduction of oxidative stress is thought to be a very important measure for primary prevention of breast carcinoma. © 2009, INSInet Publication.

Scopus

The potential role of reactive oxygen species in mammary neoplasm

Arafah M

Australian Journal of Basic and Applied Sciences Vol. 3 ( 3 ) page： 2949 - 2954 2009.7

ITPase-deficient mice show growth retardation and die before weaning

M. Behmanesh, K. Sakumi, N. Abolhassani, S. Toyokuni, S. Oka, Y. N. Ohnishi, D. Tsuchimoto, Y. Nakabeppu

CELL DEATH AND DIFFERENTIATION Vol. 16 ( 10 ) page： 1315 - 1322 2009.6

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

Inosine triphosphate pyrophosphatase (ITPase), the enzyme that hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding purine nucleoside monophosphate and pyrophosphate, is encoded by the Itpa gene. In this study, we established Itpa knockout (KO) mice and used them to show that ITPase is required for the normal organization of sarcomeres in the heart. Itpa(-/-) mice died about 2 weeks after birth with features of growth retardation and cardiac myofiber disarray, similar to the phenotype of the cardiac alpha-actin KO mouse. Inosine nucleotides were found to accumulate in both the nucleotide pool and RNA of Itpa(-/-) mice. These data suggest that the role of ITPase in mice is to exclude ITP from the ATP pool, and the main target substrate of this enzyme is rITP. Our data also suggest that cardiomyopathy, which is mainly caused by mutations in sarcomeric protein-encoding genes, is also caused by a defect in maintaining the quality of the ATP pool, which is an essential requirement for sarcomere function.

DOI： 10.1038/cdd.2009.53

Pro-apoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of SOD2 knockout mice. Reviewed

Fan YY, Zhan Y, Aukema HM, Davidson LA, Zhou L, Callaway E, Tian Y, Weeks BR, Lupton JR, Toyokuni S, Chapkin RS.

J. Nutr. Vol. 139 page： 1328-1332 2009.5

Effect of edaravone, a novel free radical scavenger, supplemented to cardioplegia on myocardial function after cardioplegic arrest: in vitro study of isolated rat heart. Reviewed

Yamazaki K, Miwa S, Toyokuni S, Nemoto S, Oriyanhan W, Takaba K, Saji Y, Marui A, Nishina T, Ikeda T and Komeda M.

Heart Vessels Vol. 24 page： 228-235 2009.5

Effect of edaravone, a novel free radical scavenger, supplemented to cardioplegia on myocardial function after cardioplegic arrest: in vitro study of isolated rat heart. Reviewed

Kazuhiro Yamazaki, Senri Miwa, Shinya Toyokuni, Shintaro Nemoto, Wnimunk Oriyanhan, Kiyoaki Takaba, Yoshiaki Saji, Akira Marui, Takeshi Nishina, Tadashi Ikeda, Masashi Komeda

Heart and vessels Vol. 24 ( 3 ) page： 228 - 235 2009.5

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

Cardioplegic arrest has been the main mechanism of myocardial protection during open-heart surgery; however, it causes myocardial injury during ischemia-reperfusion. Free radical scavengers are widely known to attenuate ischemia-reperfusion injury in various settings. We investigated the effects of edaravone, a novel free radical scavenger that was originally used for cerebral protection, on myocardial function during ischemia-reperfusion after cardioplegic arrest. Rat hearts were excised and perfused using Langendorff apparatus. The hearts were cardioplegically arrested for 90 min using St. Thomas' Hospital cardioplegic solution (ST solution) at 4A degrees C every 45 min and then reperfused for 20 min. The hearts were divided into 4 groups (n = 13 in each group). In Group ST, the hearts were arrested using the ST solution alone. In Groups L, M, and H, the hearts were arrested using the ST solution supplemented with a low-dose (1 mu M), moderate dose (10 mu M), and high dose (100 mu M) of edaravone, respectively. Left ventricular function (+dp/dt (max)) and the levels of the cardiac enzymes released were measured before and after cardioplegic arrest. At the end of the study, the water content and the tissue oxidative stress (8-hydroxy-2'-deoxyguanosine) of the heart were measured. During reperfusion, the edaravone-treated groups showed a greater functional recovery with regard to the +dp/dt (max) (P < 0.05). The lactate level was the lowest (P < 0.01) in Group M. The water content of the hearts in the edaravone-treated groups was significantly lower (P < 0.05) than that in Group ST. Oxidative stress was significantly lower (P < 0.01) in the edaravone-treated hearts than in Group ST, and it was the lowest in Group M. The addition of edaravone to the cardioplegic solution ameliorates the impairment in myocardial function by reducing the oxidative stress after cardioplegic arrest. In this study, the maximum improvement in the myocardial function was achieved by addition of a moderate dose (10 mu M) of edaravone.

DOI： 10.1007/s00380-008-1106-1

Pro-apoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of SOD2 knockout mice. Reviewed

Fan YY, Zhan Y, Aukema HM, Davidson LA, Zhou L, Callaway E, Tian Y, Weeks BR, Lupton JR, Toyokuni S, Chapkin RS

J. Nutr. Vol. 139 page： 1328-1332 2009.5

Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury. Reviewed

Hiraumi Y, Iwai-Kanai E, Baba S, Yui Y, Kamitsuji Y, Mizushima Y, Matsubara H, Watanabe M, Watanabe KI, Toyokuni S, Matsubara H, Nakahata T, Adachi S.

Am. J. Physiol. Heart Circ. Physiol. Vol. 296 page： H823-H832 2009.3

Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury Reviewed

Yoshimi Hiraumi, Eri Iwai-Kanai, Shiro Baba, Yoshihiro Yui, Yuri Kamitsuji, Yasuhiro Mizushima, Hiroshi Matsubara, Motonobu Watanabe, Ken-ichirou Watanabe, Shinya Toyokuni, Hiroaki Matsubara, Tatsutoshi Nakahata, Souichi Adachi

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Vol. 296 ( 3 ) page： H823 - H832 2009.3

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

Hiraumi Y, Iwai-Kanai E, Baba S, Yui Y, Kamitsuji Y, Mizushima Y, Matsubara H, Watanabe M, Watanabe K, Toyokuni S, Matsubara H, Nakahata T, Adachi S. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury. Am J Physiol Heart Circ Physiol 296: H823-H832, 2009. First published January 9, 2009; doi:10.1152/ajpheart.00774.2008.-Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.

DOI： 10.1152/ajpheart.00774.2008

Mechanisms of asbestos-induced carcinogenesis.

Toyokuni S.

Nagoya J. Med. Sci. Vol. 71 page： 1-10 2009.2

MECHANISMS OF ASBESTOS-INDUCED CARCINOGENESIS International journal

Toyokuni Shinya

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 71 ( 1-2 ) page： 1 - 10 2009.2

MECHANISMS OF ASBESTOS-INDUCED CARCINOGENESIS

TOYOKUNI S.

Nagoya Journal of Medical Science Vol. 71 ( 1 ) page： 1 - 10 2009.2

Publishing type：Research paper (scientific journal) Publisher：名古屋大学

Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM and the development of animal models, the carcinogenic mechanisms of the disease remain unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be summarized as follows: (1) the "oxidative stress theory" is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of free radicals due to their inability to digest the fibers, and epidemiological studies indicating that iron-containing asbestos fibers appear more carcinogenic; (2) the "chromosome tangling theory" postulates that asbestos fibers damage chromosomes when cells divide; and (3) the "theory of adsorption of many specific proteins as well as carcinogenic molecules" states that asbestos fibers in vivo concentrate proteins or chemicals including the components of cigarette smoke. Elucidation of the major mechanisms underlying DMM would be helpful for the development of novel strategies to prevent DMM induction in people who have already been exposed to asbestos.

DOI： 10.18999/nagjms.71.1-2.1

Mechanisms of asbestos-induced carcinogenesis.

Toyokuni S.

Nagoya journal of medical science Vol. 71 ( 1-2 ) page： 1 - 10 2009.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Nagoya journal of medical science

Scopus

Mechanisms of asbestos-induced carcinogenesis.

Toyokuni S

Nagoya journal of medical science Vol. 71 ( 1-2 ) page： 1 - 10 2009.2

Mechanisms of asbestos-induced carcinogenesis.

Toyokuni S

Nagoya J. Med. Sci. Vol. 71 page： 1-10 2009.2

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