1.

論文

論文
Takuwa, Yoh ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Takuwa, Noriko
出版情報: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids.  1781  pp.483-488,  2008-09-01.  Elsevier
URL: http://hdl.handle.net/2297/11867
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
2.

論文

論文
Ishikura, Kazuhide ; Misu, Hirofumi ; Kumazaki, Masafumi ; Takayama, Hiroaki ; Matsuzawa-Nagata, Naoto ; Tajima, Natsumi ; Chikamoto, Keita ; Lan, Fei ; Ando, Hitoshi ; Ota, Tsuguhito ; Sakurai, Masaru ; Takeshita, Yumie ; Kato, Kenichiro ; Fujimura, Akio ; Miyamoto, Ken-ichi ; Saito, Yoshiro ; Kameo, Satomi ; Okamoto, Yasuo ; Takuwa, Yoh ; Takahashi, Kazuhiko ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; Kaneko, Shuichi ; Takamaura, Toshinari
出版情報: Diabetologia.  57  pp.1968-1976,  2014-09-01.  Springer Verlag
URL: http://hdl.handle.net/2297/39052
概要: Aims/hypothesis Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis. Methods We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice. Results Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP-/-mice. SeP+/-mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia. Conclusions/interpretation The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg. 続きを見る
3.

論文

論文
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
4.

論文

論文
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
5.

論文

論文
Nozaki, Shinichi ; Maeda, Mitsuaki ; Tsuda, Hiroyuki ; Sledge Jr., George
出版情報: Breast Cancer Research and Treatment.  83  pp.195-199,  2004-02-01.  Springer Verlag
URL: http://hdl.handle.net/2297/1833
概要: 金沢大学医学部附属病院<br />Irsogladine is a commonly used anti-gastric ulcer agent in Japan, and recent in vivo studies have shown it to have anti-angiogenic properties. The exact role of irsogladine as an inhibitor of angiogenesis remains uncertain. In this study, we show that irsogladine inhibited breast cancer regrowth and pulmonary metastasis but had no anti-angiogenic function against HUVEC cells. Irsogladine failed to inhibit proliferation, tubular formation, and the uPA/MMP-1 mRNA expression of HUVEC cells. We also examined the effect of irsogladine in an orthotopic transplant model of human breast cancer metastasis in athymic mice. Human MDA-MB-435 cells were injected into the mammary fat pads. After 9 weeks, the tumors were resected under general anesthesia. Irsogladine or vehicle was given p.o. daily thereafter. Daily administration of irsogladine at 120 mg/kg per day over a 5-week period had no effect on the body weight of the mice. Tumor regrowth, average volume of pulmonary metastases, and the number of metastases were inhibited by 40, 48 and 64%, respectively. These results suggest that irsogladine may be useful in the breast cancer adjuvant setting. 続きを見る
6.

論文

論文
Nakamura, Mitsuhiro ; Bodily, Jason M. ; Beglina, Melanie ; Kyo, Satoru ; Inoue, Masaki ; Laimins, Laimonis A.
出版情報: Virology.  387  pp.442-448,  2009-05-10.  Elsevier
URL: http://hdl.handle.net/2297/17396
概要: 金沢大学附属病院産科婦人科<br />Human papillomaviruses (HPV) are the causative agents of cervical cancer and have been shown to increase expression of pro-angiogenic factors from infected cells. Many angiogenic factors are regulated by hypoxia inducible factor 1α (HIF-1α). We investigated whether HPV31 affects the levels of HIF-1α under normal and hypoxic conditions. Our studies indicate that cells containing complete HPV31 genomes showed enhanced levels of HIF-1α upon treatment with the hypoxia mimic DFO, which resulted from protein stabilization and led to increased expression of some but not all HIF-1α target genes. Both HPV E6 and E7 were able independently to enhance induction of HIF-1α upon DFO treatment. Enhancement of HIF-1α stability was not restricted to high-risk HPV types, as HPV11, a low risk HPV type, mediated a similar effect. These findings shed light on mechanisms by which HPV contributes to angiogenesis both in benign cervical lesions and in cervical cancers. © 2009 Elsevier Inc. All rights reserved. 続きを見る
7.

論文

論文
Yang, Xiaoqin ; Lu, Peirong ; Fujii, Chifumi ; Nakamoto, Yasunari ; Gao, Ji Liang ; Kaneko, Shuichi ; Murphy, Philip M. ; Mukaida, Naofumi
出版情報: International Journal of Cancer.  118  pp.1869-1876,  2006-04-15.  Wiley-Liss
URL: http://hdl.handle.net/2297/6666
概要: 金沢大学がん研究所がん病態制御<br />We previously observed that a chemokine, macrophage inflammatory protein-1 α/CCL3, and its receptor, CCR1, were aberrantly expressed in human hepatocellular carcinoma (HCC) tissues. Here, we show that CCL3 and CCR1 are also expressed in 2 different models of this cancer; N-nitrosodiethylamine (DEN)-induced HCC and HCC induced by hepatitis B virus surface (HBs) antigen-primed splenocyte transfer to myelo-ablated syngeneic HBs antigen transgenic mice. At 10 months after DEN treatment, foci number and sizes were remarkably reduced in CCR1- and CCL3-deficient mice, compared with those of wild-type (WT) mice, although tumor incidence were marginally, but significantly, higher in CCR1- and CCL3-deficient mice than in WT mice. Of note is that tumor angiogenesis was also markedly diminished in CCL3- and CCR1-deficient mice, with a concomitant reduction in the number of intratumoral Kupffer cells, a rich source of growth factors and matrix metalloproteinases (MMPs). Among growth factors and MMPs that we examined, only MMP9 and MMP13 gene expression was augmented progressively in liver of WT mice after DEN treatment. Moreover, MMP9, but not MMP13, gene expression was attenuated in CCR1- and CCL3-deficient mice, compared with that of WT mice. Furthermore, MMP9 was expressed mainly by mononuclear cells but not hepatoma cells, and MMP9-expressing cell numbers were decreased in CCR1- or CCL3-deficient mice, compared with WT mice. These observations suggest the contribution of the CCR1-CCL3 axis to HCC progression. © 2005 Wiley-Liss, Inc. 続きを見る
8.

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論文
Yang, Xiaoqin ; Lu, Peirong ; Ishida, Yuko ; Kuziel, William A. ; Fujii, Chifumi ; Mukaida, Naofumi
出版情報: International Journal of Cancer.  118  pp.335-345,  2006-11-15.  Wiley-Liss
URL: http://hdl.handle.net/2297/6665
概要: 金沢大学がん研究所がん病態制御<br />The liver parenchyma is populated by hepatocytes and several nonparenchymal cell types, inclu ding Kupffer cells and hepatic stellate cells. Both Kupffer cells and hepatic stellate cells are responsive to the chemokine CCL2, but the precise roles of CCL2 and these cells in liver tumor formation remain undefined. Hence, we investigated the effects of the lack of the major CCL2 receptor, CCR2, on liver tumor formation induced by intraportal injection of the murine colon adenocarcinoma cell line, colon 26. Wild-type mice showed macroscopic tumor foci in the liver 10 days after injection of colon 26 cells. After 10 days, CCL2 proteins were detected predominantly in tumor cells, coincident with increased intratumoral macrophage and hepatic stellate cell numbers. Although tumor formation occurred at similar rates in wild-type and CCR2-deficient mice up to 10 days after tumor cell injection, the number and size of tumor foci were significantly attenuated in CCR2-deficient mice relative to wild-type mice thereafter. Moreover, neovascularization and matrix metalloproteinase 2 expression were diminished in CCR2-deficient mice with a concomitant reduction in the accumulation of macrophages and hepatic stellate cells. Furthermore, matrix metalloproteinase 2 was detected predominantly in hepatic stellate cells but not in macrophages. We provided the first definitive evidence that the absence of CCR2-mediated signals can reduce the trafficking of hepatic stellate cells, a main source of matrix metalloproteinase 2, and consequently can diminish neovascularization during liver tumor formation. © 2005 Wiley-Liss, Inc. 続きを見る
9.

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論文
Mukaida, Naofumi
出版情報: Reference Module in Biomedical Research.  2014  pp.1056-,  2014-12-15.  Elsevier
URL: http://hdl.handle.net/2297/43880
概要: Chemokines are a family of structurally related cytokines with four cysteines at their well-conserved positions. Most chemokines are secreted proteins with a molecular weight about 10. kDa and their α helix structure at carboxyl-terminal portion is responsible for preferential binding to proteoglycans on the vascular endothelial cells and to extracellular matrix proteins. Chemokine receptors comprise a large branch of the rhodopsin family of cell-surface G-protein-coupled receptors with seven-transmembrane domains. Chemokines bind their corresponding receptors, thereby modulating the movement and functions of their target cells, particularly leukocyte trafficking, under physiological and pathological conditions. © 2014 Elsevier Inc. All rights reserved.<br />[Book Chapter] 続きを見る
10.

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論文
Mukaida, Naofumi ; Sasaki, So-ichiro
出版情報: World Journal of Gastroenterology.  22  pp.5301-5316,  2016-06-21.  WJG Press / Baishideng Publishing Group Co., Limited
URL: http://hdl.handle.net/2297/46183
概要: Tumor microenvironments have a crucial role in cancer initiation and progression, and share many molecular and pathological features with wound healing process. Unless treated, tumors, however, do not heal in contrast to wounds that heal within a limited time framework. Wounds heal in coordination of a myriad of types of cells, particularly endothelial cells, leukocytes, and fibroblasts. Similar sets of cells also contribute to cancer initiation and progression, and as a consequence, anti-cancer treatment strategies have been proposed and tested by targeting endothelial cells and/or leukocytes. Compared with endothelial cells and leukocytes, less attention has been paid to the roles of cancer-associated fibroblasts (CAFs), fibroblasts present in tumor tissues, because their heterogeneity hinders the elucidation on them at cellular and molecular levels. Here, we will discuss the origin of CAFs and their crucial roles in cancer initiation and progression, and the possibility to develop a novel type of anti-cancer treatment by manipulating the migration and functions of CAFs. © 2016 Baishideng Publishing Group Inc. All rights reserved. 続きを見る