AIM： To ascertain whether constitutive androstane receptor （CAR） activation by 1,4-bis-[2-（3,5,- dichloropyridyloxy）] benzene （TCPOBOP） modulates steatohepatitis in the methionine choline-deficient （MCD） diet...AIM： To ascertain whether constitutive androstane receptor （CAR） activation by 1,4-bis-[2-（3,5,- dichloropyridyloxy）] benzene （TCPOBOP） modulates steatohepatitis in the methionine choline-deficient （MCD） diet-fed animal.METHODS： C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol.RESULTS： Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis （44.6 ＋ 5.4% vs 30.4 ＋ 4.5%, P 〈 0.05） and serum triglyceride levels （48 ＋ 8 vs 20 ＋ 1 mg/dL, P 〈 0.05） in MCD diet- fed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal co-oxidation and peroxisomal p-oxidation, namely CYP4A10, LPBE, and 3-ketoacyI-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters.CONCLUSION： CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.展开更多
In the present study,we aimed to evaluate the anti-inflammatory mechanism of galanthamine,a classic therapeutic drug for Alzheimer s disease(AD).The co-culture system of hippocampal nerve cell line HT-22 and microglia...In the present study,we aimed to evaluate the anti-inflammatory mechanism of galanthamine,a classic therapeutic drug for Alzheimer s disease(AD).The co-culture system of hippocampal nerve cell line HT-22 and microglial cell line BV-2 was established to observe the effect of galanthamine on the expressions of inflammatory factors induced by lipopolysaccharide(LP S).MTT method was used to observe the protective effect of galanthamine on neurons.ELISA and qPCR methods were used to detect the expressions of interleukin-β(IL-1β) and IL-1 receptor antagonist(IL-1 RA) at the protein and mRNA levels,respectively.IL-1β and IL-1 RA were evaluated by the ELISA method after pretreating with galanthamine and α7 nAChR blockerα-bungarotoxin(α-bun),mAChR blocker atropine(Atr),PI3 K inhibitor LY294002,IKKβ inhibitor SC514,or MEK inhibitor PD98059,respectively.The results showed that galanthamine significantly inhibited LPS-induced increased IL-1β and IL-1 RA expressions and maintained the ratio of IL-1β/IL-1 RA.α-Bun could block the regulatory effect of galanthamine on IL-1β and IL-1 RA.As PI3 K and NF-κB pathways were blocked,the regulatory effect of galanthamine on the IL-1β expression was significantly inhibited.Blocking PI3 K and MEK pathways could significantly inhibit the regulation of galanthamine on IL-1 RA expression.In summary,galanthamine regulated the inflammatory activity of the IL-1 subfamily to play an anti-inflammatory role mediated by α7 nAChR and PI3 K/NF-κB/MAPK pathways,which probably provided a new strategy for AD treatment.展开更多
基金NIH grants T32 DK07198-26 (to ESB) andDK41876 (to GJG),and the Palumbo and Mayo Foundation
文摘AIM： To ascertain whether constitutive androstane receptor （CAR） activation by 1,4-bis-[2-（3,5,- dichloropyridyloxy）] benzene （TCPOBOP） modulates steatohepatitis in the methionine choline-deficient （MCD） diet-fed animal.METHODS： C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol.RESULTS： Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis （44.6 ＋ 5.4% vs 30.4 ＋ 4.5%, P 〈 0.05） and serum triglyceride levels （48 ＋ 8 vs 20 ＋ 1 mg/dL, P 〈 0.05） in MCD diet- fed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal co-oxidation and peroxisomal p-oxidation, namely CYP4A10, LPBE, and 3-ketoacyI-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters.CONCLUSION： CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.
基金National Natural Science Foundation of China (Grant No. 81100801)Peking Union Medical College Small-Scale Characteristic School Education Project。
文摘In the present study,we aimed to evaluate the anti-inflammatory mechanism of galanthamine,a classic therapeutic drug for Alzheimer s disease(AD).The co-culture system of hippocampal nerve cell line HT-22 and microglial cell line BV-2 was established to observe the effect of galanthamine on the expressions of inflammatory factors induced by lipopolysaccharide(LP S).MTT method was used to observe the protective effect of galanthamine on neurons.ELISA and qPCR methods were used to detect the expressions of interleukin-β(IL-1β) and IL-1 receptor antagonist(IL-1 RA) at the protein and mRNA levels,respectively.IL-1β and IL-1 RA were evaluated by the ELISA method after pretreating with galanthamine and α7 nAChR blockerα-bungarotoxin(α-bun),mAChR blocker atropine(Atr),PI3 K inhibitor LY294002,IKKβ inhibitor SC514,or MEK inhibitor PD98059,respectively.The results showed that galanthamine significantly inhibited LPS-induced increased IL-1β and IL-1 RA expressions and maintained the ratio of IL-1β/IL-1 RA.α-Bun could block the regulatory effect of galanthamine on IL-1β and IL-1 RA.As PI3 K and NF-κB pathways were blocked,the regulatory effect of galanthamine on the IL-1β expression was significantly inhibited.Blocking PI3 K and MEK pathways could significantly inhibit the regulation of galanthamine on IL-1 RA expression.In summary,galanthamine regulated the inflammatory activity of the IL-1 subfamily to play an anti-inflammatory role mediated by α7 nAChR and PI3 K/NF-κB/MAPK pathways,which probably provided a new strategy for AD treatment.
