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その他
Takuwa, Yoh ; 多久和 陽
出版情報: 金沢がん生物学国際シンポジウム2004 = International Symposium on Tumor Biology in Kanazawa 2004.  pp.11-12,  2004-02-13.  Cancer Research Institute, Kanazawa University / The Institute of Medical Science, the University of Tokyo / Kanazawa Association of Tumor Biologists
URL: http://hdl.handle.net/2297/34344
概要: [Curriculum Vitae & Summary] International Symposium on Tumor Biology in Kanazawa 2004 / Kanazawa, Japan February 12 and 13, 2004
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Cui, Hong ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Du, Wa ; Takuwa, Noriko ; Zhang, Wei ; Asano, Masahide ; Shibamoto, Toshishige ; Takuwa, Yoh
出版情報: Journal of Allergy and Clinical Immunology.  132  pp.1205-1214,  2013-11-01.  Elsevier
URL: http://hdl.handle.net/2297/36259
概要: Background Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in vascular endothelial cells (ECs). However, the role of S1P 2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P 2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2-null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr-null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2-null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2-null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2-deficient ECs showed more severe disassembly of adherens junctions with augmented S-nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis. © 2013 American Academy of Allergy, Asthma & Immunology. 続きを見る
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Qia, Xun ; Okamoto, Yasuo ; Murakawa, Tomomi ; Wang, Fei ; Oyama, Osamu ; Ohkawa, Ryunosuke ; Yoshioka, Kazuaki ; Du, Wa ; Sugimoto, Naotoshi ; Yatomi, Yutaka ; Takuwa, Noriko ; Takuwa, Yoh
出版情報: European Journal of Pharmacology.  634  pp.121-131,  2010-05-01.  Elsevier BV
URL: http://hdl.handle.net/2297/23922
概要: 金沢大学医薬保健研究域医学系<br />Therapeutic angiogenesis is a promising strategy for treating ischemia. The lysophospholipid m ediator sphingosine-1-phosphate (S1P) acts on vascular endothelial cells to stimulate migration and tube formation, and plays the critical role in developmental angiogenesis. We developed poly(lactic-co-glycolic-acid) (PLGA)-based S1P-containing microparticles (PLGA-S1P), which are biodegradable and continuously release S1P, and studied the effects of PLGA-S1P on neovascularization in murine ischemic hindlimbs. Intramuscular injections of PLGA-S1P stimulated blood flow in C57BL/6 mice dose-dependently, with repeated administrations at a 3-day interval, rather than a single bolus or 6-day interval, over 28. days conferring the optimal stimulating effect. In Balb/c mice that exhibit limb necrosis and dysfunction due to retarded blood flow recovery, injections of PLGA-S1P stimulated blood flow with alleviation of limb necrosis and dysfunction. PLGA-S1P alone did not induce edema in ischemic limbs, and rather blocked vascular endothelial growth factor-induced edema. PLGA-S1P not only increased the microvessel densities in ischemic muscle, but promoted coverage of vessels with smooth muscle cells and pericytes, thus stabilizing vessels. PLGA-S1P stimulated Akt and ERK with increased phosphorylation of endothelial nitric oxide synthase in ischemic muscle. The effects of the nitric oxide synthase inhibitor, Nω-nitro-l-arginine methylester, showed that PLGA-S1P-induced blood flow stimulation was partially dependent on nitric oxide. Injections of PLGA-S1P also increased the expression of angiogenic factors and the recruitment of CD45-, CD11b- and Gr-1-positive myeloid cells, which are implicated in post-ischemic angiogenesis, into ischemic muscle. These results indicate that PLGA-based, sustained local delivery of S1P is a potentially useful therapeutic modality for stimulating post-ischemic angiogenesis. © 2010 Elsevier B.V. 続きを見る
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Takabatake, Masayoshi ; Takuwa, Yoh ; Takuwa, Noriko ; Yasuno, Hironobu ; Matsumoto, Sayaka ; Shibutani, Makoto ; Mitsumori, Kunitoshi
出版情報: Journal of Veterinary Medical Science.  70  pp.483-485,  2008-05-01.  日本獣医学会
URL: http://hdl.handle.net/2297/10947
概要: 金沢大学医薬保健研究域医学系<br />We report a case of mixed epithelial and stromal tumor of the kidney (MESTK) in a 32-week-old heterozygous sphingosine 1-phosphate-2 (S1P2) receptor deficient female mouse. A white solid mass replacing the left kidney was observed at the left retroperitoneal wall. Histologically, the tumor mass consisted of dimorphic cellular components of epithelial and stromal cells. Epithelial cells formed various sized irregular-shaped tubular structures resembling renal tubules surrounded by stromal cells. Immunohistochemically, epithelial cells were positive for cytokeratin, while stromal cells showed positive immunoreactivity with α-smooth muscle actin as well as vimentin. Based on the morphological and immunohistochemical findings, this tumor was diagnosed as a MESTK. 続きを見る
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Takuwa, Yoh ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Takuwa, Noriko
出版情報: BBA - Molecular and Cell Biology of Lipids.  781  pp.483-488,  2008-09-01.  Elsevier
URL: http://hdl.handle.net/2297/11734
概要: 金沢大学医薬保健研究域医学系<br />The plasma lysophospholipid mediator sphingosine-1-phosphate (S1P) is produced exclusively by sphingosine kinase (SPHK) 1 and SPHK2 in vivo, and plays diverse biological and pathophysiological roles by acting largely through three members of the G protein-coupled S1P receptors, S1P1, S1P2 and S1P3. S1P1 expressed on endothelial cells mediates embryonic vascular maturation and maintains vascular integrity by contributing to eNOS activation, inhibiting vascular permeability and inducing endothelial cell chemotaxis via Gi-coupled mechanisms. By contrast, S1P2, is expressed in high levels on vascular smooth muscle cells (VSMCs) and certain types of tumor cells, inhibiting Rac and cell migration via a G12/13-and Rho-dependent mechanism. In rat neointimal VSMCs, S1P1 is upregulated to mediate local production of platelet-derived growth factor, which is a key player in vascular remodeling. S1P3 expressed on endothelial cells also mediates chemotaxis toward S1P and vasorelaxation via NO production in certain vascular bed, playing protective roles for vascular integrity. S1P3 expressed on VSMCs and cardiac sinoatrial node cells mediates vasopressor and negative chronotropic effect, respectively. In addition, S1P3, together with S1P2 and SPHK1, is suggested to play a protective role against acute myocardial ischemia. However, our recent work indicates that overexpressed SPHK1 is involved in cardiomyocyte degeneration and fibrosis in vivo, in part through S1P activation of the S1P3 signaling. We also demonstrated that exogenously administered S1P accelerates neovascularization and blood flow recovery in ischemic limbs, suggesting its usefulness for angiogenic therapy. These results provide evidence for S1P receptor subtype-specific pharmacological intervention as a novel therapeutic approach to cardiovascular diseases and cancer. © 2008 Elsevier B.V. All rights reserved. 続きを見る
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Du, Wa ; Takuwa, Noriko ; Yoshioka, Kazuaki ; Okamoto, Yasuo ; Gonda, Koichi ; Sugihara, Kazushi ; Fukamizu, Akiyoshi ; Asano, Masahide ; Takuwa, Yoh
出版情報: Cancer Research.  70  pp.772-781,  2010-01-15.  American Association for Cancer Research
URL: http://hdl.handle.net/2297/21765
概要: 金沢大学医薬保健研究域医学系<br />Sphingosine-1-phosphate (S1P) has been implicated in tumor angiogenesis by acting through the Gi-coupled chemotactic receptor S1P1. Here, we report that the distinct receptor S1P2 is responsible for mediating the G12/13/Rho-dependent inhibitory effects of S1P on Akt, Rac, and cell migration, thereby negatively regulating tumor angiogenesis and tumor growth. By using S1P2LacZ/+ mice, we found that S1P2 was expressed in both tumor and normal blood vessels in many organs, in both endothelial cells (EC) and vascular smooth muscle cells, as well as in tumor-associated, CD11b-positive bone marrow-derived cells (BMDC). Lewis lung carcinoma or B16 melanoma cells implanted in S1P2-deficient (S1P2-/-) mice displayed accelerated tumor growth and angiogenesis with enhanced association of vascular smooth muscle cells and pericytes. S1P2-/- ECs exhibited enhanced Rac activity, Akt phosphorylation, cell migration, proliferation, and tube formation in vitro. Coinjection of S1P2-/- ECs and tumor cells into wild-type mice also produced a relative enhancement of tumor growth and angiogenesis in vivo. S1P2-/- mice were also more efficient at recruiting CD11b-positive BMDCs into tumors compared with wild-type siblings. Bone marrow chimera experiments revealed that S1P2 acted in BMDCs to promote tumor growth and angiogenesis. Our results indicate that, in contrast to endothelial S1P1, which stimulates tumor angiogenesis, S1P 2 on ECs and BMDCs mediates a potent inhibition of tumor angiogenesis, suggesting a novel therapeutic tactic for anticancer treatment. ©2010 AACR. 続きを見る
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多久和, 陽 ; Takuwa, Yoh
出版情報: 日本平滑筋学会雑誌 = Nihon heikatsukin gakkaizassi.  11  pp.J-22-,  2007-06-26.  Japan Society of Smooth Muscle Research = 日本平滑筋学会
URL: http://hdl.handle.net/2297/23619
概要: 金沢大学医薬保健研究域医学系
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論文
Wang, Fei ; Okamoto, Yasuo ; Inoki, Isao ; Yoshioka, Kazuaki ; Du, Wa ; Qi, Xun ; Takuwa, Noriko ; Gonda, Koichi ; Yamamoto, Yasuhiko ; Ohkawa, Ryunosuke ; Nishiuchi, Takumi ; Sugimoto, Naotoshi ; Yatomi, Yutaka ; Mitsumori, Kunitoshi ; Asano, Masahide ; Kinoshita, Makoto ; Takuwa, Yoh
出版情報: The journal of clinical investigation.  120  pp.3979-3995,  2010-11-01.  American Society for Clinical Investigation
URL: http://hdl.handle.net/2297/25352
概要: 金沢大学医薬保健研究域医学系<br />Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that has pleiotropic effec ts in a variety of cell types including ECs, SMCs, and macrophages, all of which are central to the development of atherosclerosis. It may therefore exert stimulatory and inhibitory effects on atherosclerosis. Here, we investigated the role of the S1P receptor S1PR2 in atherosclerosis by analyzing S1pr2–/– mice with an Apoe–/– background. S1PR2 was expressed in macrophages, ECs, and SMCs in atherosclerotic aortas. In S1pr2–/–Apoe–/– mice fed a high-cholesterol diet for 4 months, the area of the atherosclerotic plaque was markedly decreased, with reduced macrophage density, increased SMC density, increased eNOS phosphorylation, and downregulation of proinflammatory cytokines compared with S1pr2+/+Apoe–/– mice. Bone marrow chimera experiments indicated a major role for macrophage S1PR2 in atherogenesis. S1pr2–/–Apoe–/– macrophages showed diminished Rho/Rho kinase/NF-κB (ROCK/NF-κB) activity. Consequently, they also displayed reduced cytokine expression, reduced oxidized LDL uptake, and stimulated cholesterol efflux associated with decreased scavenger receptor expression and increased cholesterol efflux transporter expression. S1pr2–/–Apoe–/– ECs also showed reduced ROCK and NF-κB activities, with decreased MCP-1 expression and elevated eNOS phosphorylation. Pharmacologic S1PR2 blockade in S1pr2+/+Apoe–/– mice diminished the atherosclerotic plaque area in aortas and modified LDL accumulation in macrophages. We conclude therefore that S1PR2 plays a critical role in atherogenesis and may serve as a novel therapeutic target for atherosclerosis. 続きを見る
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金沢大学フロンティアサイエンス機構 ; 長谷川, 浩 ; 桑原, 貴之 ; 児玉, 昭雄 ; 徳田, 規夫 ; 田中, 康規 ; 中村, 裕之 ; 井上, 啓 ; 堀, 修 ; 平尾, 敦 ; 横井, 毅 ; 土屋, 弘行 ; 宮地, 利明 ; 多久和, 陽 ; 白土, 明子 ; Hasegawa, Hiroshi ; Kuwabara, Takayuki ; Kodama, Akio ; Tokuda, Norio ; Tanaka, Yasunori ; Nakamura, Hiroyuki ; Inoue, Hiroshi ; Hori, Osamu ; Hirao, Atsushi ; Yokoi, Tsuyoshi ; Tsuchiya, Hiroyuki ; Miyachi, Toshiaki ; Takuwa, Yoh ; Shiratsuchi, Akiko
出版情報: FSO Newsletter = Frontier Science Organization Newsletter.  7  pp.1-12,  2011-03-25.  金沢大学フロンティアサイエンス機構 = Frontier Science Organization Kanazawa University
URL: http://hdl.handle.net/2297/30097
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論文
多久和, 陽 ; Takuwa, Yoh
出版情報: 平成26(2014)年度 科学研究費補助金 挑戦的萌芽研究 研究成果報告書 = 2014 Fiscal Year Final Research Report.  2013-04-01 - 2015-03-31  pp.4p.-,  2015-06-15. 
URL: http://hdl.handle.net/2297/00050715
概要: 金沢大学医薬保健研究域医学系<br />小胞膜上では、産生されたPI-3-Pはホスファターゼによる脱リン酸化を受け、PI-3-Pレベルは適正に調節される。内皮において小胞輸送を制御するPI3K-C2αのカウンターパー ト分子であるMTMメンバーを同定してその機能を明らかにした。内皮に発現するMTMファミリーメンバーを同定し、GFPタグを付加した分子を発現させて、エンドソームに発現していることを確認した。このホスファターゼ分子はPI-3-Pレベルを負に調節し、PI3K-C2αとともに小胞運動の調節に関与していた。この機能を介して内皮細胞の遊走、細胞間接着および形態形成に重要な役割をはたすと示唆された。<br />We studied phosphatidylinositol 3-phosphate (PI-3-P) phosphatase in vascular endothelial cells. Among 14 isoforms of MTM family members, we identified one isoform which was relatively abundantly expressed in endothelial cells. Fluorescent imaging showed the expression of GFP-tagged phosphatase in endosomes. The phosphatase negatively regulated cellular PI-3-P level and was involved in the regulation of endosomal movement. The PI-3-P phosphatase controlled migration, cell-cell adhesion and morphogenesis of endothelial cells through regulating PI-3-P level.<br />研究課題/領域番号:25670162, 研究期間(年度):2013-04-01 - 2015-03-31 続きを見る