研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Analysis of ghrelin transgenic mice driven by rat insulin II promoter and transgenic mice driven by rat glucagon promoter

Iwakura, H; Hosoda, K; Son, C; Fujikura, J; Tomita, T; Noguchi, M; Takaya, K; Masuzaki, H; Ogawa, Y; Hayashi, T; Inoue, G; Akamizu, T; Hosoda, H; Kojima, M; Itoh, H; Toyokuni, S; Kangawa, K; Nakao, K

DIABETES 53 巻頁： A357 - A357 2004年6月

PAX6 regulates islet β-cell function 国際誌

Hamasaki, A, Yamada, Y, Nagashima, K, Fujimoto, S, Ban, N, Toyokuni, S, Kurose, T, Seino, Y

DIABETES 53 巻頁： A394 - A394 2004年6月

Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. 国際誌

Tomoyuki Tanaka, Shinya Akatsuka, Munetaka Ozeki, Tomoyuki Shirase, Hiroshi Hiai, Shinya Toyokuni

Oncogene 23 巻 ( 22 ) 頁： 3980 - 9 2004年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal damage leading to a high incidence of renal cell carcinoma (RCC) in rats. Differential display analysis of such RCCs revealed elevated expression of annexin 2 (Anx2), a substrate for kinases and a receptor for tissue-type plasminogen activator and plasminogen. We conducted this study to clarify the significance of Anx2 in Fenton reaction-based carcinogenesis. Messenger RNA and protein levels of Anx2 were increased time-dependently in the rat kidney after Fe-NTA administration as well as in LLC-PK1 cells after exposure to H2O2. The latter was inhibited by pretreatment with N-acetylcysteine, pyrrolidine dithiocarbamate or catalase. Immunohistochemistry revealed negligible staining in the normal renal proximal tubules, but strong staining in regenerating proximal tubules, karyomegalic cells and RCCs. Metastasizing RCCs showed higher Anx2 protein levels. Anx2 was phosphorylated at serine and tyrosine residues in these cells and coimmunoprecipitated with phosphorylated actin. Overexpression of Anx2 induced a higher cell proliferation rate in LLC-PK1 cells. In contrast, a decrease in proliferation leading to apoptosis was observed after Anx2 antisense treatment to cell lines established from Fe-NTA-induced RCCs. These results suggest that Anx2 is regulated by redox status, and that persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer.

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Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis

Tanaka T, Akatsuka S, Ozeki M, Shirase T, Hiai H, Toyokuni S

ONCOGENE 23 巻 ( 22 ) 頁： 3980 - 3989 2004年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncogene

DOI： 10.1038/sj.onc.1207555

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Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI. 国際誌

Wolf-Ruediger Schäbitz, Holger Schade, Sabine Heiland, Rainer Kollmar, Jürgen Bardutzky, Nils Henninger, Harald Müller, Ulrich Carl, Shinya Toyokuni, Clemens Sommer, Stefan Schwab

Stroke 35 巻 ( 5 ) 頁： 1175 - 9 2004年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Hyperbaric oxygenation (HBO) after focal cerebral ischemia reduces infarct size and improves outcome when applied early after stroke. Here, we evaluated effects of HBO on permanent focal cerebral ischemia and applied magnetic resonance imaging (MRI) monitoring to study lesion evolution. METHODS: Rats underwent permanent middle cerebral artery occlusion (MCAO). Two hours later, animals were treated with HBO (100% O(2)/2 atm; n=17) for 1 hour or treated with room air (n=17). Animals underwent serial MRI studies (DWI, PI, T2) beginning 90 minutes after MCAO. Neuroscore was assessed (5-point rating scale). Animals were euthanized and brains were 2,3,5-triphenyltetrazolium chloride (TTC)-stained for infarct volume calculation 120 hours after MCAO. Immunohistochemistry was performed with antibodies against c-FOS and 4-hydroxy-2-nonenal-modified proteins (HNE) to check for effects of oxidative stress caused by HBO treatment. RESULTS: HBO reduced infarct volume by 38% (P<0.001). As shown by MRI, neuroprotection began 5 hours after ischemia and remained effective for 5 days. The relative regional cerebral blood flow was not different between groups at 3.5 and 5 hours after occlusion. There was less neurological deficit in HBO-treated animals compared with controls (P<0.05). Lipid peroxidation of cerebral vessels after HBO treatment as measured by HNE staining and pattern of c-FOS induction were not significantly different between groups at 3.5 and 8 hours after ischemia. CONCLUSIONS: As monitored by MRI HBO treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage.

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Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI

Schabitz WR, Schade H, Heiland S, Kollmar R, Bardutzky J, Henninger N, Muller H, Carl U, Toyokuni S, Sommer C, Schwab S

STROKE 35 巻 ( 5 ) 頁： 1175 - 1179 2004年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Stroke

Background - Hyperbaric oxygenation (HBO) after focal cerebral ischemia reduces infarct size and improves outcome when applied early after stroke. Here, we evaluated effects of HBO on permanent focal cerebral ischemia and applied magnetic resonance imaging (MRI) monitoring to study lesion evolution. Methods - Rats underwent permanent middle cerebral artery occlusion (MCAO). Two hours later, animals were treated with HBO (100% O2/2 atm; n=17) for 1 hour or treated with room air (n=17). Animals underwent serial MRI studies (DWI, PI, T2) beginning 90 minutes after MCAO. Neuroscore was assessed (5-point rating scale). Animals were euthanized and brains were 2,3,5-triphenyltetrazolium chloride (TTC)-stained for infarct volume calculation 120 hours after MCAO. Immunohistochemistry was performed with antibodies against c-FOS and 4-hydroxy-2-nonenal-modified proteins (HNE) to check for effects of oxidative stress caused by HBO treatment. Results - HBO reduced infarct volume by 38% (P<0.001). As shown by MRI, neuroprotection began 5 hours after ischemia and remained effective for 5 days. The relative regional cerebral blood flow was not different between groups at 3.5 and 5 hours after occlusion. There was less neurological deficit in HBO-treated animals compared with controls (P<0.05). Lipid peroxidation of cerebral vessels after HBO treatment as measured by HNE staining and pattern of c-FOS induction were not significantly different between groups at 3.5 and 8 hours after ischemia. Conclusion - As monitored by MRIHBO treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage.

DOI： 10.1161/01.STR.0000125868.86298.8e

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Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens

HIROYASU Makoto, AKATSUKA Shinya, SHIRASE Tomoyuki, TODA Yoshinobu, HIAI Hiroshi, TOYOKUNI Shinya

Pathology international 54 巻 ( 4 ) 頁： 251 - 255 2004年4月

Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens. 国際誌

Makoto Hiroyasu, Shinya Akatsuka, Tomoyuki Shirase, Yoshinobu Toda, Hiroshi Hiai, Shinya Toyokuni

Pathology international 54 巻 ( 4 ) 頁： 251 - 5 2004年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although the human genome project has been completed, the functions of many genes remain undetermined. In situ hybridization (ISH) is a key method for identifying cells in which a given messenger RNA is transcribed. Paraffin-embedded specimens remain precious materials for research, but preservation of high-quality RNA in these specimens is not expected unless ample caution was taken during fixation. Peptide nucleic acid (PNA) is a recently developed hybrid molecule with genetic information that has high stability and high affinity to the complementary DNA or RNA. We applied a PNA probe to mRNA ISH of liver specimens obtained by autopsy and embedded in paraffin 28-48 years ago. An 18-mer PNA probe for glyceraldehyde 3-phosphate dehydrogenase was used. Staining was then analyzed in association with morphology by hematoxylin and eosin staining, and with the time between death of the patient and tissue fixation. Notably, specimens fixed with formalin and embedded in paraffin 48 years ago yielded excellent results if the time before fixation was short enough (<8 h). There was a significant inverse correlation between the intensity of ISH staining and the time before fixation. Oligonucleotide PNA probe, albeit at high cost, would increase the value of paraffin-embedded specimens in storage for use in human medical research.

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Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic beta cells. 国際誌 Open Access

Inada A, Hamamoto Y, Tsuura Y, Miyazaki J, Toyokuni S, Ihara Y, Nagai K, Yamada Y, Bonner-Weir S, Seino Y

Molecular and cellular biology 24 巻 ( 7 ) 頁： 2831 - 41 2004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：Molecular and Cellular Biology

Transcriptional control mediated by the cyclic AMP-responsive element (CRE) represents an important mechanism of gene regulation. To test our hypothesis that increased inducible cyclic AMP early repressor (ICER) Iγ inhibits function of CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic β cells, we generated transgenic mice with β-cell-directed expression of ICER Iγ, a powerful repressor that is greatly increased in diabetes. Three transgenic lines clearly show that increased ICER Iγ expression in β cells results in early severe diabetes. From birth islets were severely disorganized with a significantly increased proportion of α cells throughout the islet. Diabetes results from the combined effects of impaired insulin expression and a decreased number of β cells. The decrease in β cells appears to result from impaired proliferation rather than from increased apoptosis after birth. Cyclin A gene expression is impaired by the strong inhibition of ICER; the suppression of cyclin A results in a substantially decreased proliferation of β cells in the postnatal period. These results suggest that CRE and CRE-binding factors have an important role in pancreatic β-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of β-cell mass.

DOI： 10.1128/MCB.24.7.2831-2841.2004

Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens.

Hiroyasu M, Akatsuka S, Shirase T, Toda Y, Hiai H, Toyokuni S

Pathology international 54 巻 ( 4 ) 頁： 251 - 5 2004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：Pathology International

DOI： 10.1111/j.1440-1827.2004.01620.x

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Detection of glyceraldehyde 3-phosphate dehydrogenase messenger RNA using a peptide nucleic acid probe in paraffin-embedded archival specimens

Hiroyasu M, Akatsuka S, Shirase T, Toda Y, Hiai H, Toyokuni S

PATHOLOGY INTERNATIONAL 54 巻 ( 4 ) 頁： 251 - 255 2004年4月

A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: Caspase-independent, necrosis-like programmed cell death mediated by serine protease activity 査読有り

Okada M., Adachi S., Imai T., Watanabe K.I., Toyokuni S.Y., Ueno M., Zervos A.S., Kroemer G., Nakahata T.

Blood 103 巻 ( 6 ) 頁： 2299 - 2307 2004年3月

記述言語：日本語掲載種別：学位論文（博士）出版者・発行元：Blood

Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL-positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate-induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate-treated BCR-ABL-positive human leukemic cells. Moreover, zVAD-fmk-preincubated, imatinib mesylate-treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2. © 2004 by The American Society of Hematology.

DOI： 10.1182/blood-2003-05-1605

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A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

Okada M, Adachi S, Imai T, Watanabe K, Toyokuni SY, Ueno M, Zervos AS, Kroemer G, Nakahata T

BLOOD 103 巻 ( 6 ) 頁： 2299 - 2307 2004年3月

PJ-628 Oxidant Stress-Mediated Myocardial Cell Injury in Selenium-Deficient Mice : Age-Dependent Roles of Glutathion Peroxidase Inhibition(Cardiomyopathy, Basic and Clinical 2 (M) : PJ105)(Poster Session (Japanese))

Hiraoka Yuuji, Okada Ikutaro, Tamura Takashi, Akagi Tadasu, Hama Norio, Tanabe Masato, Suzuki Joji, Fujimori Mariko, Takahashi Nobuki, Shimizu Takayuki, Sarazawa Katsuhiko, Shinnmura Tetuo, Toyokuni Shinya, Kihara Yasuki, Nakajima Hisayoshi, Inoue Hiroshi

Circulation journal : official journal of the Japanese Circulation Society 68 巻 ( 0 ) 頁： 634 2004年3月

フリーラジカルによる発がんの標的遺伝子

豊國伸哉

日本衞生學雜誌 59 巻 ( 2 ) 頁： 105 2004年3月

Circulation journal : official journal of the Japanese Circulation Society 68 巻 ( 0 ) 2004年3月

Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation 査読有り国際誌

Imaoka, S; Osada, M; Minamiyama, Y; Yukimura, T; Toyokuni, S; Takemura, S; Hiroi, T; Funae, Y

CANCER LETTERS 203 巻 ( 2 ) 頁： 117 - 125 2004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 Letters

We investigated the biological effects of the active oxygen produced by P450s. First, we identified which isoforms of P450 efficiently produced active oxygen using electron spin resonance. Eight forms of P450 purified from rat liver were used. Of these, CYP1A2, 2B1, 2C11 and 3A2 produced hydroxyl radicals efficiently. Phenobarbital (PB) which is a typical inducer of CYP2B1 and 3A2 induced production of hydroxyl radicals by rat liver and ketoconazole, an inhibitor of P450, inhibited production of hydroxyl radicals in vitro. PB is a tumor promoter as well as the P450-inducer. We investigated oxidation of the genomic DNA by the hydroxyl radicals produced by PB-inducible P450 in vitro and in vivo. 8-Hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation in vivo was assayed by HPLC. PB strongly induced the production of 8-OHdG in the rat liver. While ketoconazole inhibited the production of 8-OHdG in vivo. These results suggest that active oxygen produced by P450 oxidized genomic DNA and induction of P450 increased oxidative stress that may contribute to tumor initiation and promotion. © 2003 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2003.09.009

Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway. 国際誌

Hiroyuki Okumura, Noritoshi Nagaya, Takefumi Itoh, Ichiro Okano, Jun Hino, Kenji Mori, Yoshitane Tsukamoto, Hatsue Ishibashi-Ueda, Senri Miwa, Keiichi Tambara, Shinya Toyokuni, Chikao Yutani, Kenji Kangawa

Circulation 109 巻 ( 2 ) 頁： 242 - 8 2004年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown. METHODS AND RESULTS: Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28+/-4% to 16+/-1%, P<0.01), left ventricular end-diastolic pressure (19+/-2 to 8+/-2 mm Hg, P<0.05), and myocardial apoptotic death (19+/-2% to 9+/-4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphorylation in cardiac tissues and that pretreatment with wortmannin significantly attenuated AM-induced Akt phosphorylation. Moreover, pretreatment with wortmannin abolished the beneficial effects of AM: a reduction of infarct size, a decrease in left ventricular end-diastolic pressure, and inhibition of myocardial apoptosis after ischemia/reperfusion. CONCLUSIONS: Short-term infusion of AM significantly attenuated myocardial ischemia/reperfusion injury. These cardioprotective effects are attributed mainly to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway.

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Adrenomedullin infusion attenuates myocardial ischemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway

Okumura H, Nagaya N, Itoh T, Okano I, Hino J, Mori K, Tsukamoto Y, Ishibashi-Ueda H, Miwa S, Tambara K, Toyokuni S, Yutani C, Kangawa K

CIRCULATION 109 巻 ( 2 ) 頁： 242 - 248 2004年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Circulation

Background-Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown. Methods and Results-Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28±4% to 16±1%, P<0.01), left ventricular end-diastolic pressure (19±2 to 8±2 mm Hg, P<0.05), and myocardial apoptotic death (19±2% to 9±4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphorylation in cardiac tissues and that pretreatment with wortmannin significantly attenuated AM-induced Akt phosphorylation. Moreover, pretreatment with wortmannin abolished the beneficial effects of AM: a reduction of infarct size, a decrease in left ventricular end-diastolic pressure, and inhibition of myocardial apoptosis after ischemia/reperfusion. Conclusions-Short-term infusion of AM significantly attenuated myocardial ischemia/reperfusion injury. These cardioprotective effects are attributed mainly to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway.

DOI： 10.1161/01.CIR.0000109214.30211.7C

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CD9 is a surface marker on mouse and rat male germline stem cells. 査読有り国際誌 Open Access

Kanatsu-Shinohara M, Toyokuni S, Shinohara T

Biology of reproduction 70 巻 ( 1 ) 頁： 70 - 5 2004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：Biology of Reproduction

Spermatogenesis is dependent on a small population of stem cells. Despite the biological significance of spermatogonial stem cells, their analysis has been hampered by their scarcity. However, spermatogonial stem cells can be enriched by selection with an antibody against cell-surface molecules. In this investigation, we searched for new antigens expressed on spermatogonial stem cells. Using the spermatogonial transplantation technique, we examined expression of the CD9 molecule, which is commonly expressed on stem cells of other tissues. Selection of both mouse and rat testis cells with anti-CD9 antibody resulted in 5- to 7-fold enrichment of spermatogonial stem cells from intact testis cells, indicating that CD9 is commonly expressed on spermatogonial stem cells of both species. Therefore, CD9 may be involved in the common machinery in stem cells of many self-renewing tissues, and the identification of a common surface antigen on spermatogonial stem cells of different species has important implications for the development of a technique to enrich stem cells from other mammalian species.

DOI： 10.1095/biolreprod.103.020867

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論文 - 豊國　伸哉