Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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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 International journal

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 International journal Open Access

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. Reviewed International journal

Toyokuni S.

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

Language：English 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

Role of iron in carcinogenesis : Cancer as a ferrotoxic disease

TOYOKUNI Shinya

Cancer Sci. Vol. 100 ( 1 ) page： 9 - 16 2009.1

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

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, Nakahata T

Int. J. Cancer Vol. 124 ( 1 ) page： 55 - 67 2009.1

*Role of iron in carcinogenesis: Cancer as a ferrotoxic disease. Invited Reviewed

Toyokuni S.

Cancer Sci. Vol. 100 page： 6-16 2009.1

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

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

Carcinogenesis Vol. 30 page： 158-164 2009.1

Biased Immunoglobulin VH Recombination and Increased Expression of Chemokine Receptor XCR1 Are Distinct Features of Bone Marrow-Derived Diffuse Large B-Cell Lymphoma International journal

Yamashita, Y; Kajiura, D; Nakamura, S; Toyokuni, S; Mori, N

LABORATORY INVESTIGATION Vol. 89 page： 292A - 292A 2009.1

Biased Immunoglobulin VH Recombination and Increased Expression of Chemokine Receptor XCR1 Are Distinct Features of Bone Marrow-Derived Diffuse Large B-Cell Lymphoma International journal

Yamashita, Y; Kajiura, D; Nakamura, S; Toyokuni, S; Mori, N

MODERN PATHOLOGY Vol. 22 page： 292A - 292A 2009.1

Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Reviewed International journal

Yi Zhong, Janice Onuki, Toshinari Yamasaki, Osamu Ogawa, Shinya Akatsuka, Shinya Toyokuni

Carcinogenesis Vol. 30 ( 1 ) page： 158 - 64 2009.1

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

A growing number of studies indicate a link between oxidative stress and cancer. We previously developed a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Here, we performed a genome-wide analysis to study characteristics of genomic alteration and identify putative genes involved in the development of Fe-NTA-induced RCCs. Array-based comparative genomic hybridization analyses revealed a chromosomal loss spanning chromosome 8 in most of the RCCs studied, with a common deletion at 8q31-32, which was confirmed by loss of heterozygosity (LOH) analysis. Studies of gene expression in RCCs or following Fe-NTA treatment revealed globally decreased transcription levels of 34 genes derived from chromosome 8 that are expressed in the kidney. Among them, the aminoacylase 1 (Acy1) gene, which maps to 8q32 and is highly expressed in the kidney, displayed a significantly decreased level of expression in RCCs. Significant amounts of the Acy1 protein were detected in the cytoplasm as well as in the nuclei of renal proximal tubular cells of untreated rats. Transfection of Acy1 into RCC cell lines inhibited proliferation and colony formation on soft agar. An increased number of apoptotic cells were observed following Acy1 transfection. The rat 8q31-32 chromosomal region corresponds to human 3p21.31-24.1, a hot spot where LOH is frequently found in various human cancers. Thus, Fe-NTA-induced renal tumor model is ideal for studying the link between deletions within this region and tumor formation. Our data demonstrate that Acy1 functions as a tumor suppressor in this rat RCC model. © The Author 2008. Published by Oxford University Press. All rights reserved.

DOI： 10.1093/carcin/bgn255

Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Reviewed International journal Open Access

Shinya Toyokuni

Cancer science Vol. 100 ( 1 ) page： 9 - 16 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Iron is abundant universally. During the evolutionary processes, humans have selected iron as a carrier of oxygen inside the body. However, iron works as a double-edged sword, and its excess is a risk for cancer, presumably via generation of reactive oxygen species. Thus far, pathological conditions such as hemochromatosis, chronic viral hepatitis B and C, exposure to asbestos fibers, as well as endometriosis have been recognized as iron overload-associated risks for human cancer. Indeed, iron is carcinogenic in animal experiments. These reports unexpectedly revealed that there are target genes in iron-induced carcinogenesis and that iron-catalyzed oxidative DNA damage is not random in vivo. Several iron transporters and hepcidin, a peptide hormone regulating iron metabolism, were discovered in the past decade. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy decreased cancer risk in the apparently normal population. These results warrant reconsideration of the role of iron in carcinogenesis and suggest that fine control of body iron stores would be a wise strategy for cancer prevention. (Cancer Sci 2009; 100: 9-16).

DOI： 10.1111/j.1349-7006.2008.01001.x

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