研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Gastric inhibitory polypeptide is the major insulinotropic factor in K(ATP) null mice. 査読有り国際誌

Katsushi Tsukiyama, Yuichiro Yamada, Kazumasa Miyawaki, Akihiro Hamasaki, Kazuaki Nagashima, Masaya Hosokawa, Shimpei Fujimoto, Akira Takahashi, Kentaro Toyoda, Shinya Toyokuni, Yutaka Oiso, Yutaka Seino

European journal of endocrinology 151 巻 ( 3 ) 頁： 407 - 12 2004年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, K(ATP) channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of K(ATP) channels, but the mice still showed a significant insulin response after oral glucose loading in vivo. Gastric inhibitory polypeptide (GIP) is a physiological incretin that stimulates insulin release upon ingestion of nutrients. To determine if GIP is the insulinotropic factor in insulin secretion in K(ATP) channel-deficient mice, we generated double-knockout Kir6.2 and GIP receptor null mice and compared them with Kir6.2 knockout mice. METHODS: Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice. An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice. RESULTS: Fasting glucose and insulin levels were similar in both groups. After oral glucose loading, blood glucose levels of double-knockout mice became elevated compared with Kir6.2-knockout mice, especially at 15 min (345+/-10 mg/dl vs 294+/-20 mg/dl, P<0.05) and 30 min (453+/-20 mg/dl vs 381+/-26 mg/dl, P<0.05). The insulin response was almost completely lost in double-knockout mice, although insulin secretion from isolated islets was stimulated by another incretin, glucagon-like peptide-1 in the double-knockout mice. Double-knockout mice and Kir6.2-knockout mice were similarly insulin sensitive as assessed by the insulin tolerance test. CONCLUSION: GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in K(ATP) channel-deficient mice.

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Prevention of myocardial reperfusion injury by poly(ADP-ribose) synthetase inhibitor, 3-aminobenzamide, in cardioplegic solution: in vitro study of isolated rat heart model. 国際誌 Open Access

Yamazaki K, Miwa S, Ueda K, Tanaka S, Toyokuni S, Unimonh O, Nishimura K, Komeda M

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 26 巻 ( 2 ) 頁： 270 - 5 2004年8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：European Journal of Cardio-thoracic Surgery

Objective: Cardioplegic arrest remains the method of choice for myocardial protection in cardiac surgery. Poly(adenosine 5′-diphosphate-ribose) synthetase (PARS) inhibitor has been suggested to attenuate the ischemia-reperfusion injury in myocardial infarction by preventing energy depletion associated with oxidative stress. We investigated the efficacy of a cardioplegic solution containing a PARS inhibitor, 3-aminobenzamide (3-AB), for myocardial protection against ischemia-reperfusion injury caused by cardioplegic arrest. Methods: Isolated hearts were set on a Langendorff apparatus and perfused. The hearts were arrested for 90 min with a cardioplegic solution given at 30-min intervals and then reperfused for 20 min. The hearts of rat in the 3-AB(-) group (n=8) were perfused with a standard cardioplegic solution and terminal warm cardoplegia, whereas the 3-AB(+) group (n=8) received these solutions supplemented with 3-AB (100 μM). Left ventricular function and release of cardiac enzymes were monitored before and after cardioplegic arrest. After reperfusion, NAD+ (nicotinamide-adenine dinucleotide) levels were assessed, and the tissues were examined immunohistochemically for oxidative stress and apoptosis. Results: During reperfusion, the 3-AB(+) group showed significantly higher (P=0.005) dp/dt and lower creatine phosphokinase (CPK) level and glucotamic-oxaloacetic transaminase (GOT) in the effluent (CPK; P=0.003, GOT; P<0.001). The cardiomyocytes of the 3-AB(+) group also preserved a higher NAD+ level (P<0.001). Immunohistochemical study of oxidative stress revealed a lesser extent (P=0.007) of nuclear staining and a lower fraction of apoptosis in the 3-AB(+) group. Conclusion: Cardioplegic solution supplemented with 3-AB provides efficient myocardial protection in cardioplegic ischemic reperfusion by suppressing oxidative stress and overactivation of PARS. © 2004 Published by Elsevier B.V.

DOI： 10.1016/j.ejcts.2004.04.044

Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. 査読有り国際誌 Open Access

Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M

Leukemia 18 巻 ( 8 ) 頁： 1357 - 63 2004年8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：Leukemia

Adult T-cell leukemia (ATL) is a fatal neoplasm derived from CD4-positive T-lymphocytes, and regardless of intensive chemotherapy, its mean survival time is less than 1 year. Nuclear factor-κB (NF-κB) activation was reported in HTLV-I associated cells, and has been implicated in oncogenesis and resistance to anticancer agents and apoptosis. We studied the effect of a proteasome inhibitor, bortezomib (formerly known as PS-341), on ATL cells in vitro and in vivo. Bortezomib could inhibit the degradation Of IκBα in ATL cells, resulting in suppression of NF-κB and induction of cell death in ATL cells in vitro. Susceptibilities to bortezomib were well correlated with NF-κB activation, suggesting that suppression of the NF-κB pathway was implicated in the cell death induced by bortezomib. Although the majority of the cell death was apoptosis, necrotic cell death was observed in the presence of a caspase inhibitor, z-VAD-fmk. When bortezomib was administered into SCID mice bearing tumors, it suppressed tumor growth in vivo, showing that bortezomib was effective against ATL cells in vivo. These studies revealed that bortezomib is highly effective against ATL cells in vitro and in vivo by induction of apoptosis, and its clinical application might improve the prognosis of patients with this fatal disease. © 2004 Nature Publishing Group All rights reserved.

DOI： 10.1038/sj.leu.2403400

その他リンク： http://orcid.org/0000-0002-7939-2080

Regulation of mouse spermatogonial stem cell self-renewing division by the pituitary gland. 査読有り国際誌 Open Access

Kanatsu-Shinohara M, Morimoto T, Toyokuni S, Shinohara T

Biology of reproduction 70 巻 ( 6 ) 頁： 1731 - 7 2004年6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 originates in spermatogonial stem cells, which have the unique mode of replication. It is considered that a single stem cell can produce two stem cells (self-renewing division), one stem and one differentiating (asymmetric division), or two differentiating cells (differentiating division). However, little is known regarding how each type of division is regulated. In this investigation, we focused on the analysis of self-renewing division and examined the effect of the pituitary gland using two models of stem cell self-renewing division. In the first experiment using newborn mice, the administration of GnRH-analogue, which represses the release of gonadotropin, reduced the number of stem cells during postnatal testicular development, suggesting that the pituitary gland enhances stem cell self-renewing division. In the second experiment, however, the number of stem cells increased dramatically in hypophysectomized adult recipients after spermatogonial transplantation. Thus, the pituitary gland affects the self-renewing division of stem cells, but these contradictory results suggest that its role may be different depending on the stage of the testicular development.

DOI： 10.1095/biolreprod.103.025668

PAX6 regulates islet β-cell function

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 control of carcinogenesis and tumor biology

Toyokuni S

ANTIOXIDANTS & REDOX SIGNALING 6 巻 ( 3 ) 頁： 481 - 482 2004年6月

Role of reactive oxygen species in skin carcinogenesis

Nishigori C, Hattori Y, Toyokuni S

ANTIOXIDANTS & REDOX SIGNALING 6 巻 ( 3 ) 頁： 561 - 570 2004年6月

Role of reactive oxygen species in skin carcinogenesis.

Nishigori C, Hattori Y, Toyokuni S

Antioxidants & redox signaling 6 巻 ( 3 ) 頁： 561 - 70 2004年6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：Antioxidants and Redox Signaling

Reactive oxygen species (ROS) are associated not only with initiation, but also with promotion and progression in the multistage carcinogenesis model. In the present review, we will focus on the involvement of ROS in skin carcinogenesis, especially that induced by ultraviolet (UV) radiation. UV-specific DNA damage has been well studied thus far. However, recent reports have revealed the previously unknown participation of oxidative stress in UV-induced skin carcinogenesis. Indeed, in addition to transition-type mutations at dipyrimidine sites, G:C to T:A transversions, which may be induced by the presence of 8-oxoguanine during DNA replication, are frequently observed in the ras oncogene and p53 tumor suppressor gene in human skin cancers of sun-exposed areas and in UV-induced mouse skin cancers. Recent studies have shown that not only UV-B, but also UV-A is involved in UV-induced carcinogenesis. A wide variety of biological phenomena other than direct influence by UV, such as inflammatory and immunological responses and oxidative modifications of DNA and proteins, appear to play roles in UV-induced skin carcinogenesis. Furthermore, it has become clear that genetic diseases such as xeroderma pigmentosum show deficient repair of oxidatively modified DNA lesions. The involvement of ROS in skin carcinogeneisis caused by arsenic and chemical carcinogens will also be discussed.

DOI： 10.1089/152308604773934314

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Redox control of carcinogenesis and tumor biology.

Toyokuni S

Antioxidants & redox signaling 6 巻 ( 3 ) 頁： 481 - 2 2004年6月

Role of reactive oxygen species in skin carcinogenesis. 国際誌

Chikako Nishigori, Yukari Hattori, Shinya Toyokuni

Antioxidants & redox signaling 6 巻 ( 3 ) 頁： 561 - 70 2004年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1089/152308604773934314

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PAX6 regulates islet beta-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

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.

DOI： 10.1038/sj.onc.1207555

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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.

DOI： 10.1161/01.STR.0000125868.86298.8e

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

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.

DOI： 10.1111/j.1440-1827.2004.01620.x

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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

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論文 - 豊國 伸哉

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論文 - 豊國　伸哉