研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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

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

J. Nutr. 139 巻頁： 1328-1332 2009年5月

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

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 24 巻頁： 228-235 2009年5月

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

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

HEART AND VESSELS 24 巻 ( 3 ) 頁： 228 - 235 2009年5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：Heart and Vessels

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 4°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 μM), moderate dose (10 μM), and high dose (100 μM) 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/dtmax (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 μ) of edaravone. © Springer Japan 2009.

DOI： 10.1007/s00380-008-1106-1

Pro-apoptotic effects of dietary (n-3) fatty acids are enhanced in colonocytes of SOD2 knockout mice. 査読有り国際誌

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

J. Nutr. 139 巻頁： 1328-1332 2009年5月

Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury. 査読有り

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. 296 巻頁： H823-H832 2009年3月

Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury 査読有り国際誌 Open Access

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

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 296 巻 ( 3 ) 頁： H823 - H832 2009年3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：American Journal of Physiology - Heart and Circulatory Physiology

Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardiopro- tective 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. © 2009 the American Physiological Society.

DOI： 10.1152/ajpheart.00774.2008

Mechanisms of asbestos-induced carcinogenesis.

Toyokuni S.

Nagoya J. Med. Sci. 71 巻頁： 1-10 2009年2月

MECHANISMS OF ASBESTOS-INDUCED CARCINOGENESIS 国際誌

Toyokuni Shinya

NAGOYA JOURNAL OF MEDICAL SCIENCE 71 巻 ( 1-2 ) 頁： 1 - 10 2009年2月

MECHANISMS OF ASBESTOS-INDUCED CARCINOGENESIS

TOYOKUNI S.

Nagoya Journal of Medical Science 71 巻 ( 1 ) 頁： 1 - 10 2009年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：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. 査読有り国際誌

Toyokuni S.

Nagoya journal of medical science 71 巻 ( 1-2 ) 頁： 1 - 10 2009年2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：Nagoya journal of medical science

Scopus

Mechanisms of asbestos-induced carcinogenesis.

Toyokuni S

Nagoya journal of medical science 71 巻 ( 1-2 ) 頁： 1 - 10 2009年2月

Mechanisms of asbestos-induced carcinogenesis.

Toyokuni S

Nagoya J. Med. Sci. 71 巻頁： 1-10 2009年2月

Role of iron in carcinogenesis : Cancer as a ferrotoxic disease

TOYOKUNI Shinya

Cancer science 100 巻 ( 1 ) 頁： 9 - 16 2009年1月

Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. 査読有り国際誌 Open Access

Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe K, Kamitsuji Y, Toyokuni SY, Hosoi H, Sugimoto T, Toguchida J, Nakahata T

International journal of cancer 124 巻 ( 1 ) 頁： 55 - 67 2009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：International Journal of Cancer

Malignant rhabdoid tumors (MRT) exhibit a very poor prognosis because of their resistance to chemotherapeutic agents and new therapies are needed for the treatment of this cancer. Here, we show that the histone deacetylase (HDAC) inhibitor FK228 (depsipeptide) has an antitumor effect on MRT cells both in vitro and in vivo. FK228 is a unique cyclic peptide and is among the most potent inhibitors of both Class I and Class II HDACs. FK228 inhibited proliferation and induced apoptosis in all MRT cell lines tested. Preincubation with the pancaspase inhibitor zVAD-fmk did not completely rescue FK228-induced cell death, although it did inhibit apoptosis. Transmission electron microscopy (TEM) showed that FK228 could stimulate MRT cells to undergo apoptosis, necrosis or autophagy. FK228 converted unconjugated microtubule-associated protein light chain 3 (LC3-I) to conjugated light chain 3 (LC3-II) and induced localization of LC3 to autophagosomes. Apoptosis inducing factor (AIF), which plays a role in caspase-independent cell death, translocated to the nucleus in response to FK228 treatment. Moreover, small interfering RNA (siRNA) targeting of AIF prevented the morphological changes associated with autophagy and redistribution of LC3 to autophagosomes. Disrupting autophagy with chloroquine treatment enhanced FK228-induced cell death. In vivo, FK228 caused a reduction in tumor size and induced autophagy in tumor tissues. Using immunoelectron microscopy, we confirmed AIF translocation into the nucleus of FK228-induced autophagic cells in vivo. Thus, FK228 is a novel candidate for an antitumor agent for MRT cells. © 2008 Wiley-Liss, Inc.

DOI： 10.1002/ijc.23897

*Role of iron in carcinogenesis: Cancer as a ferrotoxic disease. 招待有り査読有り

Toyokuni S.

Cancer Sci. 100 巻頁： 6-16 2009年1月

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 30 巻頁： 158-164 2009年1月

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

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

LABORATORY INVESTIGATION 89 巻頁： 292A - 292A 2009年1月

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

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

MODERN PATHOLOGY 22 巻頁： 292A - 292A 2009年1月

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

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

Carcinogenesis 30 巻 ( 1 ) 頁： 158 - 64 2009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：Carcinogenesis

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. 査読有り国際誌 Open Access

Toyokuni S

Cancer science 100 巻 ( 1 ) 頁： 9 - 16 2009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：Cancer Science

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. © 2009 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2008.01001.x

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論文 - 豊國 伸哉

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論文 - 豊國　伸哉