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Abstract@#Introduction: Atherosclerosis is a chronic inflammatory disease initiated by the accumulation of macrophage derived foam cells in the intima layer of artery. In mice model of atherosclerosis, murine norovirus-4 has been shown to accelerate atherogenesis. In cells, lipid biometabolism is regulated by peroxisome proliferator activated receptor γ (PPARγ). Since PPARγ is predominantly expressed in macrophages and mice macrophages are MNV-1 proliferation-permissive host, we hypothesised that PPARγ ligands may regulate atherogenesis. Methods: MNV-1 was generated via RNA-based recovery system and used to infect the RAW 264.7 cells, then subjected to oxidized low-density lipoprotein (oxLDL)-loaded and treated with ciglitazone or 15-deoxy-Delta(12,14)-PGJ(2)(15d-PGJ2). Foam cell formation was evaluated and the MNV-1 infection in all treatments was confirmed using virus titration (50% tissue culture infective dose; TCID50) and polymerase chain reaction (PCR). Results: Increment of lipid droplets was observed in all oxLDL treatment involving MNV-1 infection, ciglitazone or 15d-PGJ2 in the cytosol of RAW 264.7 cells over time compared to non-oxLDL treated cells. From the cholesterol ester (CE) content analysis amongst the oxLDL-loaded cells however, we found MNV-1 did not elicit increment of CE content. Treatment with 15d-PGJ2 resulted in increase of the CE content in oxLDL-treated cells. Interestingly, MNV-1 and ciglitazone had synergistic effect in reducing the CE content in oxLDL-treated cells. Conclusion: oxLDL stimulates foam cells formation in RAW 264.7 cells. However, MNV-1 infection did not contribute to RAW 264.7 cells derived-foam cells formation. On the other hand, 15d-PGJ2 promotes foam cells formation whilst ciglitazone inhibits the formation of foam cells derived from MNV-1-infected macrophages.
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The effect and mechanism of the ciglitazone on lung cancer cells A549 growth in vitro and in vivo were studied. Various concentrations of ciglitazone were added to the cultured A549 line, and the proliferation and differentiation of A549 cells were examined by MTT and cytometry analysis. A549 cells (1 × 106/mouse) were inoculated subcutaneously into 20 nude mice, which were randomly divided into two groups: the control group, the ciglitazone treated group. The weights of subcutaneous tumors were measured. The expression of cyclin D1 and P21 in the lung was detected by immohistochemistry and Western blot respectively. The results showed that the proliferation of A549 was inhibited significantly by ciglitazone in a dose- and time-dependent manner. There were more cells arrested in G1/G0 phase and the expression of PPARγ was markedly upregulated in ciglitazone-treated group. Direct injection of ciglitazone into A549-induced tumors could suppress tumor growth in nude mice and the growth inhibitory rate was 36 %. The expression of cyclin D1 was decreased and P21 increased significantly in ciglitazone-treated group as compared with control group. It was concluded that ciglitazone could inhibit A549 proliferation dose-dependently and time-dependently and induce differentiation, which might be related to the modulation of cell cycle interfered by PPARγ.
RÉSUMÉ
AIM: We hypothesized that PPAR? ligands stimulate endothelial-derived nitric oxide(NO) release to protect the vascular wall.Thus,the purpose of this study is to investigate the effects of ciglitazone(Cig) and fenofibrate(Fen) on angiotensin Ⅱ(AngⅡ)-induced decrease in endothelial NO synthase(eNOS) expression and NO production in human umbilical vein endothelial cells(HUVECs).METHODS: HUVECs were preincubated for 24 h with Cig(10~(-7), 10~(-6),10~(-5),10~(-4) mol/L) or Fen(10~(-5) and 10~(-4) mol/L),then incubated for 12 h with 10~(-7) mol/L AngⅡ.Total RNA was extracted,and the expression of mRNA and protein of eNOS was assessed by RT-PCR and Western blotting.NO production was measured by Griees method.RESULTS: In the presence of 10~(-7) mol/L AngⅡ for 12 h,NO production in cultured HUVECs was decreased(P