目的:探讨水飞蓟宾(S IL)在急性肝损伤中对肝细胞胀亡的影响及其机制。方法:用D氨基半乳糖(D G a lN)诱导大鼠急性肝损伤模型,用S IL进行干预,于不同时间点检测血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(A ST)活性及肝组织核转录因子κB(N...目的:探讨水飞蓟宾(S IL)在急性肝损伤中对肝细胞胀亡的影响及其机制。方法:用D氨基半乳糖(D G a lN)诱导大鼠急性肝损伤模型,用S IL进行干预,于不同时间点检测血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(A ST)活性及肝组织核转录因子κB(NFκB)活性,观察肝组织病理及肝细胞胀亡情况,并计算胀亡指数(O I)。结果:S IL能明显降低急性肝损伤模型大鼠血清ALT、A ST活性(P均<0.05),抑制NFκB活性(P<0.05),镜下显示肝组织损伤减轻程度,减少肝细胞胀亡,降低O I(P均<0.05)。结论:S IL可减少D G a lN所致大鼠肝细胞胀亡,其机制可能与抑制NFκB活性有关。展开更多
Non-alcoholic steatohepatitis(NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK ...Non-alcoholic steatohepatitis(NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57 BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h,then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibininsignificantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2 E1 and CYP4 A in vivo.These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity(CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity(CYP2 E1 and CYP4 A) to relieve oxidative stress.展开更多
AIM： To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma （HCC） cell growth, METHODS： Human HCC cell lines were treated with different doses of silibinin. The effects of silibini...AIM： To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma （HCC） cell growth, METHODS： Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined. RESULTS： We demonstrated that silibinin significantly reduced the growth of HUH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. Silibinin-reduced HuH7 cell growth was associated with significantly up- regulated p21/CDK4 and p27/CDK4 complexes, down- regulated Rb-phosphorylation and E2F1/DP1 complex. Silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and upregulated activated caspase-3 and -9. Silibinin＇s antiangiogenic effects were indicated by down-regulated metalloproteinase-2 （MMP2） and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten （PTEN） and decreased p-Akt production, indicating the role of PTEN/ PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 （AC-H3 and AC-H4）, indicating a possible role of altered histone acetylation in silibininreduced HCC cell proliferation. CONCLUSION： Our results defined silibinin＇s in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.展开更多
文摘目的:探讨水飞蓟宾(S IL)在急性肝损伤中对肝细胞胀亡的影响及其机制。方法:用D氨基半乳糖(D G a lN)诱导大鼠急性肝损伤模型,用S IL进行干预,于不同时间点检测血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(A ST)活性及肝组织核转录因子κB(NFκB)活性,观察肝组织病理及肝细胞胀亡情况,并计算胀亡指数(O I)。结果:S IL能明显降低急性肝损伤模型大鼠血清ALT、A ST活性(P均<0.05),抑制NFκB活性(P<0.05),镜下显示肝组织损伤减轻程度,减少肝细胞胀亡,降低O I(P均<0.05)。结论:S IL可减少D G a lN所致大鼠肝细胞胀亡,其机制可能与抑制NFκB活性有关。
基金supported by Major Technological Innovation Project of Hubei Province(Grant no.2016ACA140,China)Innovation and Entrepreneurship Training Project for College Students of the Ministry of Education(Grant no.201610512001,China)
文摘Non-alcoholic steatohepatitis(NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57 BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h,then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibininsignificantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2 E1 and CYP4 A in vivo.These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity(CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity(CYP2 E1 and CYP4 A) to relieve oxidative stress.
基金Supported by UCI institutional research grants from GI Division Chao Family Comprehensive Cancer Center(K.-Q.H.)
文摘AIM： To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma （HCC） cell growth, METHODS： Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined. RESULTS： We demonstrated that silibinin significantly reduced the growth of HUH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. Silibinin-reduced HuH7 cell growth was associated with significantly up- regulated p21/CDK4 and p27/CDK4 complexes, down- regulated Rb-phosphorylation and E2F1/DP1 complex. Silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and upregulated activated caspase-3 and -9. Silibinin＇s antiangiogenic effects were indicated by down-regulated metalloproteinase-2 （MMP2） and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten （PTEN） and decreased p-Akt production, indicating the role of PTEN/ PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 （AC-H3 and AC-H4）, indicating a possible role of altered histone acetylation in silibininreduced HCC cell proliferation. CONCLUSION： Our results defined silibinin＇s in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.
