研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Nestin-positive cells in adult pancreas express amylase and endocrine precursor cells

Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

PANCREAS 31 巻 ( 2 ) 頁： 126 - 131 2005年8月

Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells.

Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

Pancreas 31 巻 ( 2 ) 頁： 126 - 31 2005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：Pancreas

The neural precursor cell-specific marker nestin is expressed in fetal and adult pancreas, but its role is not fully understood. Using nestin-enhanced green fluorescent protein (EGFP) transgenic mice and fluorescence activated cell sorter, we characterized nestin-positive cells in adult mice pancreas. EGFP mRNA- and protein-positive cells expressed amylase, a pancreatic exocrine marker. Interestingly, EGFP mRNA-negative and protein-positive cells expressed insulin, glucagon, somatostatin and pancreatic polypeptide, pancreatic endocrine markers. These findings demonstrate that nestin-positive cells comprise a portion of pancreatic exocrine cells and suggest that they can be differentiated into pancreatic endocrine cells. Copyright © 2005 by Lippincott Williams & Wilkins.

DOI： 10.1097/01.mpa.0000172564.80921.f7

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PubMed

Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells. 国際誌

Hiroyuki Ueno, Yuichiro Yamada, Rie Watanabe, Eri Mukai, Masaya Hosokawa, Akira Takahashi, Akihiro Hamasaki, Hideya Fujiwara, Shinya Toyokuni, Masahiro Yamaguchi, Jun Takeda, Yutaka Seino

Pancreas 31 巻 ( 2 ) 頁： 126 - 31 2005年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1097/01.mpa.0000172564.80921.f7

PubMed

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Establishment of a diabetic mouse model with progressive diabetic nephropathy.

Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y

The American journal of pathology 167 巻 ( 2 ) 頁： 327 - 36 2005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：American Journal of Pathology

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER Iγ) in pancreatic β cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Iγ transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER Iγ transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors. Copyright © American Society for Investigative Pathology.

DOI： 10.1016/s0002-9440(10)62978-1

Scopus

PubMed

Establishment of a diabetic mouse model with progressive diabetic nephropathy

Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y

AMERICAN JOURNAL OF PATHOLOGY 167 巻 ( 2 ) 頁： 327 - 336 2005年8月

Establishment of a diabetic mouse model with progressive diabetic nephropathy 査読有り

A Inada, K Nagai, H Arai, J Miyazaki, K Nomura, H Kanamori, S Toyokuni, Y Yamada, S Bonner-Weir, GC Weir, A Fukatsu, Y Seino

AMERICAN JOURNAL OF PATHOLOGY 167 巻 ( 2 ) 頁： 327 - 336 2005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：AMER SOC INVESTIGATIVE PATHOLOGY, INC

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER I gamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER I gamma transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER I gamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.

DOI： 10.1016/S0002-9440(10)62978-1

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Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells. 査読有り国際誌 Open Access

Hamahata K, Adachi S, Matsubara H, Okada M, Imai T, Watanabe K, Toyokuni SY, Ueno M, Wakabayashi S, Katanosaka Y, Akiba S, Kubota M, Nakahata T

European journal of pharmacology 516 巻 ( 3 ) 頁： 187 - 96 2005年6月

記述言語：英語掲載種別：学位論文（博士）出版者・発行元：European Journal of Pharmacology

We have previously reported that calcium ionophore A23187 differentially induces necrosis in CEM cells, a T-lymphoblastic leukemia cell line, and apoptosis in HL60 cells, a promyelocytic leukemia cell line. Stimulation with VP16, however, induces typical apoptosis in both cell lines. Necrosis in CEM cells, characterized by cell shrinkage and clustering, began within 5 min of treatment. Swelling of the mitochondria, lumpy chromatin condensation and intact plasma membranes were evident by electron microscopy. These A23187-mediated changes in CEM cells were suppressed by clonazepam or CGP37157, inhibitors of the mitochondrial Na+/Ca2+ exchanger. The changes, however, were not affected by cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. In both CEM and HL60 cells, intra-cellular calcium increased with similar amplitude within 1 min of treatment with 2 μM A23187. Intra-mitochondrial calcium increased with clonazepam pre-treatment alone in both CEM and HL60 cells. However, intra-mitochondrial calcium did not change drastically in response to A23187 in CEM or HL60 cells, either untreated or pre-treated with clonazepam. A23187 induces necrosis in CEM cells concurrent with mitochondrial dysfunction, which is independent of the mitochondrial permeability transition, but affected by intra-mitochondrial calcium, while HL60 cells lack these early changes. Differences in the responses to A23187 between these two cell lines might derive from differences in the susceptibility of the mitochondrial membrane to rapid increases in intra-cellular calcium. © 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2005.04.018

Annexin II overexpression correlates with a poor prognosis in surgically resected non-small-cell lung cancer.

Ichikawa, M; Mio, T; Toyokuni, S; Tanaka, F; Wada, H; Mishima, M; Yanagihara, K

JOURNAL OF CLINICAL ONCOLOGY 23 巻 ( 16 ) 頁： 682S - 682S 2005年6月

Annexin II overexpression correlates with a poor prognosis in surgically resected non-small-cell lung cancer. 査読有り国際誌

Ichikawa, M, Mio, T, Toyokuni, S, Tanaka, F, Wada, H, Mishima, M, Yanagihara, K

JOURNAL OF CLINICAL ONCOLOGY 23 巻 ( 16 ) 頁： 682S - 682S 2005年6月

Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis. 査読有り国際誌 Open Access

Dutta KK, Nishinaka Y, Masutani H, Akatsuka S, Aung TT, Shirase T, Lee WH, Yamada Y, Hiai H, Yodoi J, Toyokuni S

Laboratory investigation; a journal of technical methods and pathology 85 巻 ( 6 ) 頁： 798 - 807 2005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：Laboratory Investigation

Thioredoxin is a major component of thiol-reducing system. Recently, we identified thioredoxin-binding protein-2 (TBP-2) as a negative regulator of thioredoxin. Here, we report the role of TBP-2 in oxidative renal tubular injury and the subsequent carcinogenesis by ferric nitrilotriacetate. TBP-2 was abundantly expressed in the rat kidney. Immunohistochemical analysis revealed that TBP-2 was present in association with nuclei and mitochondrial intermembrane space in the proximal tubular cells and coimmunoprecipitated with cytochrome c. After acute oxidative tubular damage, TBP-2 protein, but not messenger RNA, markedly decreased, demonstrating shortened half-life of this protein. Most cases of the induced renal cell carcinoma showed undetectable levels of TBP-2 protein, which was associated with the methylation of CpG island in the promoter region. Genome sequence analyses identified the poly-A tract in the 3′ untranslated region as a mutation hot spot in this rather nonselective environment. Collectively, the amounts of TBP-2 protein were inversely associated with proliferation of tubular cells, as evaluated by proliferating cell nuclear antigen. These results suggest that loss of TBP-2 is essential for proliferation of not only neoplastic but also non-neoplastic renal tubular cells, and that TBP-2 is a target gene in oxidative stress-induced renal carcinogenesis by ferric nitrilotriacetate. © 2005 USCAP, Inc All rights reserved.

DOI： 10.1038/labinvest.3700280

Transcriptional control of fetal liver hematopoiesis: dominant negative effect of the overexpression of the LIM domain mutants of LMO2. 査読有り国際誌 Open Access

Terano T, Zhong Y, Toyokuni S, Hiai H, Yamada Y

Experimental hematology 33 巻 ( 6 ) 頁： 641 - 51 2005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：Experimental Hematology

Objective. The LIM-finger protein LMO2 forms a transcription factor complex with other hematopoietic regulator proteins, such as TAL1 (SCL), LDB1, GATA1, 2, and 3, in the promoters of several erythroid genes. To elucidate the functional role of two LIM domains in LMO2, we introduced deletion or mutation in each of the LIM domains and analyzed their phenotypic effects on the hematopoietic system when overexpressed in vivo or in vitro. Materials and Methods. Protein interactions of LIM-modified LMO2 constructs with TAL1, LDB1, and GATAs were examined in an immunoprecipitation assay. In vivo hematopoiesis in transgenic mice with wild-type and LIM-modified Lmo2 was studied morphologically and by measuring the progenitor cells in fetal liver. Their effects on the erythroid differentiation of the dimethylsulfoxide (DMSO)-induced murine erythroleukemia (MEL) cells were evaluated. Results. Deletion of the LIM2 domain, but not of the LIM1 domain, abolished its binding of GATA proteins. Overexpression of wild-type LMO2 is known to have dominant negative inhibitory effects on erythropoietic development. Enforced expression of LMO2 constructs with mutant or absent LIM2 but with an intact LIM1 domain resulted in fetal death, small livers and hearts, and decreased hematopoiesis, as well as a hypoplastic thymus. DMSO-induced erythroid differentiation of the MEL cells was inhibited by the overexpressed LMO2 with mutant LIM2 but not by the LMO2 with modified LIM1. Conclusion. Overexpression of the LMO2 with modified LIM2 inhibited hematopoiesis probably by interfering with the formation of the physiological complex or by replacing the functional LMO2 with mutants with reduced affinity to GATA proteins. In this experiment, no evident effect of the LMO2 with modified LIM1 could be observed. © 2005 International. Society for Experimental Hematology. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2005.01.018

Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice. 査読有り国際誌 Open Access

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

The Journal of biological chemistry 280 巻 ( 15 ) 頁： 15247 - 56 2005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：Journal of Biological Chemistry

We developed and analyzed two types of transgenic mice: rat insulin II promoter-ghrelin transgenic (RIP-G Tg) and rat glucagon promoter-ghrelin transgenic mice (RGP-G Tg). The pancreatic tissue ghrelin concentration measured by C-terminal radioimmunoassay (RIA) and plasma desacyl ghrelin concentration of RIP-G Tg were about 1000 and 3.4 times higher than those of nontransgenic littermates, respectively. The pancreatic tissue n-octanoylated ghrelin concentration measured by N-terminal RIA and plasma n-octanoylated ghrelin concentration of RIP-G Tg were not distinguishable from those of nontransgenic littermates. RIP-G Tg showed suppression of glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion, pancreatic insulin mRNA and peptide levels, β cell mass, islet architecture, and GLUT2 and PDX-1 immunoreactivity in RIP-G Tg pancreas were not significantly different from those of nontransgenic littermates. Islet batch incubation study did not show suppression of insulin secretion of RIP-G Tg in vitro. The insulin tolerance test showed lower tendency of blood glucose levels in RIP-G Tg. Taking lower tendency of triglyceride level of RIP-G Tg into consideration, these results may indicate that the suppression of insulin secretion is likely due to the effect of desacyl ghrelin on insulin sensitivity. RGP-G Tg, in which the pancreatic tissue ghrelin concentration measured by C-RIA was about 50 times higher than that of nontransgenic littermates, showed no significant changes in insulin secretion, glucose metabolism, islet mass, and islet architecture. The present study raises the possibility that desacyl ghrelin may have influence on glucose metabolism. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M411358200

その他リンク： http://orcid.org/0000-0001-8033-0736

CYP3A induction more impairs endotoxemic liver injury via reactive oxygen species in rats

Minamiyama, Y; Takemura, S; Kodai, S; Toyokuni, S; Yoshikawa, T; Okada, S

GASTROENTEROLOGY 128 巻 ( 4 ) 頁： A709 - A709 2005年4月

Long-term culture of mouse male germline stem cells under serum-or feeder-free conditions. 査読有り国際誌

Kanatsu-Shinohara M, Miki H, Inoue K, Ogonuki N, Toyokuni S, Ogura A, Shinohara T

Biology of reproduction 72 巻 ( 4 ) 頁： 985 - 91 2005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：Biology of Reproduction

Spermatogonial stem cells are the only stem cells in the body that transmit genetic information to the next generation. These cells can be cultured for extended periods in the presence of serum and feeder cells. However, little is known about factors that regulate self-renewal division of spermatogonial stem cells. In this investigation we examined the possibility of establishing culture systems for spermatogonial stem cells that lack serum or a feeder cell layer. Spermatogonial stem cells could expand in serum-free conditions on mouse embryonic fibroblasts (MEFs), or were successfully cultivated without feeder cells on a laminin-coated plate. However, they could not expand when both serum and feeder cells were absent. Although the cells cultured on laminin differed phenotypically from those on feeder cells, they grew exponentially for at least 6 mo, and produced normal, fertile progeny following transplantation into infertile mouse testis. This culture system will provide a new opportunity for understanding the regulatory mechanism that governs spermatogonial stem cells. © 2005 by the Society for the Study of Reproduction, Inc.

DOI： 10.1095/biolreprod.104.036400

CYP3A induction more impairs endotoxemic liver injury via reactive oxygen species in rats 国際誌

Minamiyama, Y, Takemura, S, Kodai, S, Toyokuni, S, Yoshikawa, T, Okada, S

GASTROENTEROLOGY 128 巻 ( 4 ) 頁： A709 - A709 2005年4月

多発隆起型早期胆嚢癌の1切除例

浦井俊二, 早雲孝信, 羽生泰樹, 河村卓二, 塩せいじ, 池浦司, 吉野琢哉, 平井潔, 豊國伸哉

日本消化器病學會雜誌 = The Japanese journal of gastro-enterology 102 巻 ( 3 ) 頁： 340 - 345 2005年3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：一般財団法人日本消化器病学会

症例は75歳，女性．スクリーニングの腹部超音波検査で胆嚢内に複数の隆起性病変を認め，入院となった．CT，ERCPなどの所見より隆起型胆嚢癌と診断し，開腹胆摘術を行った．病理組織学的に3個の乳頭腺癌を認め，深達度は最大の腫瘍がmp，他はmであった．全割切片による検索で上皮内癌を認め，癌周囲には異形成をともなっていた．Ki-67標識率は固有上皮部2.6％，異形成部9.7％，上皮内癌部26.6％，癌部36.9％であった．p53蛋白過剰発現を認めなかった．<br>

DOI： 10.11405/nisshoshi.102.340

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Selenium Supplementation Rescues Cardiac Output in Patients with Severe Heart Failure who are Intractable to ACE Inhibitors and β-Blockers(Heart Failure, Clinical 14 (M), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

Hiraoka Yuuji, Kihara Yasuki, Sarazawa Katsuhiko, Inai Yoshihito, Kitagawa Motoaki, Takahashi Nobuki, Hamanaka Ichirou, Yamazaki Taketoshi, Akagi Tadasu, Hama Norio, Tanabe Masato, Sakurai Hiromu, Toyokuni Shinya, Ueda Kinzou

Circulation journal : official journal of the Japanese Circulation Society 69 巻 ( 0 ) 頁： 310 2005年3月

Circulation journal : official journal of the Japanese Circulation Society 69 巻 ( 0 ) 2005年3月

Genetic selection of mouse male germline stem cells in vitro: offspring from single stem cells. 査読有り国際誌 Open Access

Kanatsu-Shinohara M, Toyokuni S, Shinohara T

Biology of reproduction 72 巻 ( 1 ) 頁： 236 - 40 2005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 originates from a small population of spermatogonial stem cells. These cells are believed to divide infinitely and support spermatogenesis throughout life in the male. In this investigation, we examined the possibility of deriving transgenic offspring from single spermatogonial stem cells. Spermatogonial stem cells were transfected in vitro with a plasmid vector containing a drug resistant gene. Stably transfected stem cell clones were isolated by in vitro drug selection; these clones were expanded and used to produce transgenic progeny following spermatogonial transplantation into infertile recipients. An average of 49% of the offspring carried the transgene, and the recipient mice continued to produce monoclonal transgenic progeny a year after transplantation. Thus, a somatic cell-based genetic approach can be used to modify and select clones of spermatogonial stem cells in a manner similar to embryonic stem cells. The feasibility of genetic selection using postnatal spermatogonial stem cells demonstrates their extensive proliferative potential and provides the opportunity to develop new methods for generating stable animal transgenics or for germline gene therapy.

DOI： 10.1095/biolreprod.104.035659

Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis. 査読有り国際誌 Open Access

Chuma S, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Hosokawa M, Nakatsuji N, Ogura A, Shinohara T

Development (Cambridge, England) 132 巻 ( 1 ) 頁： 117 - 22 2005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：Development

Primordial germ cells (PGCs) are derived from a population of pluripotent epiblast cells in mice. However, little is known about when and how PGCs acquire the capacity to differentiate into functional germ cells, while keeping the potential to derive pluripotent embryonic germ cells and teratocarcinomas. In this investigation, we show that epiblast cells and PGCs can establish colonies of spermatogenesis after transfer into postnatal seminiferous tubules of surrogate infertile mice. Furthermore, we obtained normal fertile offspring by microinsemination using spermatozoa or spermatids derived from PGCs harvested from fetuses as early as 8.5 days post coitum. Thus, fetal male germ cell development is remarkably flexible, and the maturation process, from epiblast cells through PGCs to postnatal spermatogonia, can occur in the postnatal testicular environment. Primordial germ cell transplantation techniques will also provide a novel tool to assess the developmental potential of PGCs, such as those manipulated in vitro or recovered from embryos harboring lethal mutations.

DOI： 10.1242/dev.01555

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論文 - 豊國 伸哉

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論文 - 豊國　伸哉