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ABSTRACT: A potential adverse effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) on the pancreas remains controversial. We evaluated the DPP-4i effects on pancreatic amylase and lipase activity in patients with type 2 diabetes. These enzymes were slightly but significantly increased, suggesting DPP-4i cause a low-grade inflammatory change in the exocrine pancreas.
Diabetes research and clinical practice 04/2013; · 2.16 Impact Factor
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Masaya Koshizaka,
Minoru Takemoto,
Seiya Sato, Hirotake Tokuyama,
Masaki Fujimoto,
Emiko Okabe,
Ryoichi Ishibashi,
Takahiro Ishikawa,
Yuya Tsurutani,
Shunichiro Onishi,
Morito Mezawa,
Peng He,
Satoshi Honjo,
Shiro Ueda,
Yasushi Saito,
Koutaro Yokote
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ABSTRACT: Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.
Experimental Diabetes Research 01/2012; 2012:159874. · 1.20 Impact Factor
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Tatsushi Shimoyama,
Shûichi Hiraoka,
Minoru Takemoto,
Masaya Koshizaka, Hirotake Tokuyama,
Takahiko Tokuyama,
Aki Watanabe,
Masaki Fujimoto,
Harukiyo Kawamura,
Seiya Sato,
Yuya Tsurutani,
Yasushi Saito,
Bernard Perbal,
Haruhiko Koseki,
Koutaro Yokote
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ABSTRACT: CCN3 belongs to the CCN family, which constitutes multifunctional secreted proteins that act as matrix cellular regulators. We investigated the pathophysiological roles of CCN3 in the vessels.
We examined the effects of CCN3 on the proliferation and migration of rat vascular smooth muscle cells (VSMC). CCN3 knockout mice were created, and vascular phenotypes and neointimal hyperplasia induced by photochemically induced thrombosis were investigated. CCN3 suppressed the VSMC proliferation induced by fetal bovine serum. The neutralizing antibody for transforming growth factor-beta did not affect the growth inhibitory effect of CCN3. Moreover, CCN3 enhanced the mRNA expression of cyclin-dependent kinase inhibitors, p21 and p15. Gamma secretase inhibitor, an inhibitor of Notch signaling, partially inhibited the enhanced expression of p21 induced by CCN3. CCN3 also inhibited the VSMC migration. Finally, the histopathologic evaluation of the arteries 21 days after the endothelial injury revealed a 6-fold enhancement of neointimal thickening in the null mice compared with the wild-type mice.
CCN3 suppresses neointimal thickening through the inhibition of VSMC migration and proliferation. Our findings indicate the involvement of CCN3 in vascular homeostasis, especially on injury, and the potential usefulness of this molecule in the modulation of atherosclerotic vascular disease.
Arteriosclerosis Thrombosis and Vascular Biology 02/2010; 30(4):675-82. · 6.37 Impact Factor
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ABSTRACT: V gamma 9 V delta 2 T cells exert potent cytotoxicity toward various tumor cells and adoptive transfer of V gamma 9 V delta 2 T cells is an attractive proposition for cell based immunotherapy. V gamma 9 V delta 2 T cells expanded in the presence of Zoledronate and IL-2 express CD16 (Fc gamma RIII), which raises the possibility that V gamma 9 V delta 2 T cells could be used in conjunction with tumor targeting monoclonal antibody drugs to increase antitumor cytotoxicity by antibody dependent cellular cytotoxicity (ADCC). Cytotoxic activity against CD20-positive B lineage lymphoma or chronic lymphocytic leukemia (CLL) and HER2-positive breast cancer cells was assessed in the presence of rituximab and trastuzumab, respectively. Cytotoxicity of V gamma 9 V delta 2 T cells against CD20-positive targets was higher when used in combination with rituximab. Similarly, V gamma 9 V delta 2 T cells used in combination with trastuzumab resulted in greater cytotoxicity against HER2-positive cells in comparison with either agent alone and this effect was restricted to the CD16(+)V gamma 9 V delta 2 T cell population. Our results show that CD16(+)V gamma 9 V delta 2 T cells recognize monoclonal antibody coated tumor cells via CD16 and exert ADCC similar to that observed with NK cells, even when target cells are relatively resistant to monoclonal antibodies or V gamma 9 V delta 2 T cells alone. Combination therapy involving ex vivo expanded CD16(+)V gamma 9 V delta 2 T cells and monoclonal antibodies may enhance the clinical outcomes for patients treated with monoclonal antibody therapy.
International Journal of Cancer 07/2008; 122(11):2526-34. · 5.44 Impact Factor
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ABSTRACT: Chemokine receptors CCR2, CCR5 and CXCR3 are involved in the regulation of macrophage- and T cell-mediated immune responses and in the migration and activation of these cells. In order to determine whether blockade of these chemokine receptors modulates intestinal inflammation, we investigated here the effect of a non-peptide chemokine receptor antagonist, TAK-779 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-tetrahydro-2H-pyran-4-aminium chloride), in mice with dextran sodium sulfate (DSS)-induced experimental colitis. C57BL/6 mice were fed 5% DSS in their drinking water for up to 7 days with or without the administration of TAK-779. The severity of inflammation in the colon was assessed by clinical signs and histological examination. Infiltration of inflammatory cells into the mucosa was analyzed by immunohistochemistry, and the expression of cytokine and chemokine mRNAs in tissues was quantitated by reverse transcription-PCR. During DSS-induced colitis, the recruitment of monocytes/macrophages into the colonic mucosa and the induction of proinflammatory cytokines correlated with the severity of intestinal inflammation. The onset of clinical signs and histopathologic features were delayed in animals treated with TAK-779. The expression of CCR2, CCR5 and CXCR3 mRNAs was inhibited in the TAK-779-treated mice. Consistent with these results, infiltration of monocytes/macrophages into the lamina propria was almost completely inhibited and the expression of colonic IL-1beta and IL-6 was significantly decreased in the TAK-779-treated mice. The blockade of CCR2, CCR5 and CXCR3 prevents murine experimental colitis by inhibiting the recruitment of inflammatory cells into the mucosa. Therefore, chemokines and their receptors may be therapeutic targets for the treatment of inflammatory bowel disease.
International Immunology 09/2005; 17(8):1023-34. · 3.41 Impact Factor
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ABSTRACT: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8(+) T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25(+)CD4(+) regulatory T (Treg) cells might be involved in a inhibition of CD8(+) T cell priming or in the modulation of the magnitude of the 'peak' antiviral CD8(+) T cell response primed by DNA immunization.
B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 microg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25(+) cells. Induction of HBV-specific CD8(+) T cells in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-gamma staining.
DNA immunization induced HBV-specific CD8(+) T cells. At the peak T cell response (d 10), 7.1+/-2.0% of CD8(+) T cells were HBV-specific after DNA immunization, whereas 12.7+/-3.2% of CD8(+) T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8(+) T cells in the absence of CD25(+) Treg cells (n = 6, P<0.05). Similarly, fewer HBV-specific memory T cells were detected in the presence of these cells (1.3+/-0.4%) in comparison to Treg-depleted mice (2.6+/-0.9%) on d 30 after DNA immunization (n = 6, P<0.01). Both IFN-gamma production and the avidity of the HBV-specific CD8(+) T cell response to antigen were higher in HBV-specific CD8(+) T cells induced in the absence of Treg cells.
CD25(+) Treg cells suppress priming and/or expansion of antigen-specific CD8(+) T cells during DNA immunization and the peak CD8(+) T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8(+) T cell response and may affect the quality of memory T cell pools. The elimination of Treg cells or their inhibition may be important in immunotherapeutic strategies to control HBV infection by inducing virus-specific cytotoxic T lymphocyte responses in chronically infected subjects.
World Journal of Gastroenterology 07/2005; 11(24):3772-7. · 2.47 Impact Factor
