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131.
Saturated fatty acids are implicated in the development of diabetes via the impairment of pancreatic islet β-cell viability and function. Liver X receptors (LXRs) and eicosapentaenoate (EPA) are known regulators of fatty acid metabolism. However, their roles in the pathogenesis of diabetes remain incompletely understood. The aim of this study was to determine the effects of EPA and the LXR agonist T0901317 on saturated fatty acid (palmitic acid)-induced apoptosis in the insulinoma β-cell line INS-1, a model for insulin-secreting β-cells. T0901317 significantly promoted palmitic acid-induced apoptotic cell death in the INS-1 cells. Consistent with these results, caspase-3 activity and BAX and sterol regulatory element binding protein-1c (SREBP-1c) mRNA levels were markedly increased in INS-1 cells co-administered palmitic acid and T0901317. The production of reactive oxygen species was considerably higher in the cells cultured concurrently with T0901317 and palmitic acid than in the cells incubated with either agent alone. EPA treatment attenuated the cellular death promoted by palmitic acid and T0901317 in the INS-1 cells, disclosing a possible mediating mechanism involving the inhibition of SREBP-1c. Finally, T0901317 up-regulated the palmitic acid-induced expression of p27(KIP1), transforming growth factor beta 1, and SMAD3 proteins in INS-1 cells. These results demonstrate that palmitic acid-induced apoptosis in β-cells is enhanced by T0901317 via the activation of LXRs and is blocked by EPA via the inhibition of SREBP-1c, suggesting that the regulation of lipogenesis and lipotoxicity affecting pancreatic β-cell viability and insulin production may be a unique strategy for diabetes therapy. 相似文献
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Env-specific IgG and IgM were detected in 25 and 60%, respectively, of volunteers immunized with NYVAC expressing clade C gp120. The serum sample with the highest IgM titre but undetectable IgG neutralized the homologous isolate with a reciprocal IC90 titre of 7.8 in the absence of complement, and 24.4 in the presence of complement (P = 0.0003). These results suggest that vaccine-induced, Env-specific IgM may have antiviral activity and should be subjected to further investigation. 相似文献
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Role of the AheABC efflux pump in Aeromonas hydrophila intrinsic multidrug resistance 总被引:1,自引:0,他引:1
Hernould M Gagné S Fournier M Quentin C Arpin C 《Antimicrobial agents and chemotherapy》2008,52(4):1559-1563
Gene inactivation and complementation experiments showed that the tripartite AheABC efflux pump of Aeromonas hydrophila extruded at least 13 substrates, including nine antibiotics. The use of phenylalanine-arginine-beta-naphthylamide (PAbetaN) revealed an additional system(s) contributing to intrinsic resistance. This is the first analysis of the role of multidrug efflux systems in Aeromonas spp. 相似文献
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Kamat CD Gadal S Mhatre M Williamson KS Pye QN Hensley K 《Journal of Alzheimer's disease : JAD》2008,15(3):473-493
Oxidative damage is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and stroke (brain ischemia/reperfusion injury). The availability of transgenic and toxin-inducible models of these conditions has facilitated the preclinical evaluation of putative antioxidant agents ranging from prototypic natural antioxidants such as vitamin E (alpha-tocopherol) to sophisticated synthetic free radical traps and catalytic oxidants. Literature review shows that antioxidant therapies have enjoyed general success in preclinical studies across disparate animal models, but little benefit in human intervention studies or clinical trials. Recent high-profile failures of vitamin E trials in Parkinson's disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The translational disappointment of antioxidants likely arises from a combination of factors including failure to understand the drug candidate's mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. This review discusses the rationale for using antioxidants in the prophylaxis or mitigation of human neurodiseases, with a critical discussion regarding ways in which future preclinical studies may be adjusted to offer more predictive value in selecting agents for translation into human trials. 相似文献
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Zhang M Liu H Tian Z Huang J Remo M Li QQ 《Clinical and experimental pharmacology & physiology》2007,34(3):230-237
1. Bax is a very important pro-apoptosis molecule. HCT116/Bax(-/-) cells do not express the pro-apoptosis Bcl-2 family member, Bax. In the present study, the anticancer effects of gossypol on HCT116 and HCT116/Bax(-/-) cells were compared in terms of inhibition of cell growth, inhibition of colony formation and induction of apoptosis. 2. Following treatment with concentrations more than 20 micromol/L gossypol, only slight differences (not significant) were seen between HCT116 and HCT116/Bax(-/-) cells in terms of the inhibition of cell growth and induction of apoptosis. No difference was seen in the inhibition of colony formation. Gossypol had no effect at concentrations < 2 micromol/L. The only effective concentration of gossypol to result in differences between HCT116 and HCT116/Bax(-/-) cells was 5 micromol/L. However, even at this concentration, Bax deficiency did not result in complete abolition of gossypol-induced growth inhibition or apoptosis. Exposure of cells to 5 micromol/L gossypol for 24 h did not cause any significant difference in the activation of caspase 2 between HCT116 and HCT116/Bax(-/-) cells; however, activation of caspase 3, 8 and 9 was significantly elevated in HCT116 cells, with the effect on caspase 3 activation being the greatest, compared with HCT116/Bax(-/-) cells. 3. These findings suggest that the contribution of Bax to gossypol-induced growth inhibition and apoptosis is dose dependent and that gossypol-induced apoptosis requires activation of caspase 3, 8, and 9. 相似文献