Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis  

作　　者：Jian-ping LI Yan GAO Shi-feng CHU Zhao ZHANG Cong-yuan XIA Zheng MOU Xiu-yun SONG Wen-bin HE Xiao-feng GUO Nai-hong CHEN 

机构地区：[1]State Key of Laboratory Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China [2]Shanxi University of Traditional Chinese Medicine, Taiyuan 030024, China

出　　处：《Acta Pharmacologica Sinica》2014年第8期1031-1044,共14页中国药理学报（英文版）

基　　金：This work was supported by National Natural Science Foun- dation of China grants （No 81274122, 81373510, 81273629, 81373998） and by the Beijing Natural Science Foundation （No 7131013）, Research Fund for the Doctoral Program of Higher Education of China （No 2012110613001）, National 863 Program of China （No 2012AA020303）, PCSIRT （No IRT1007）, National Key Sci-Tech Major Special Item （No 2012ZX09301002-004, 2012ZX09103101-006）, and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study （No BZ0150）.

摘　　要：Aim： To investigate the anti-fibrosis effects of ginsenoside Rgl on alcohol- and CCl4-induced hepatic fibrosis in rats and to explore the mechanisms of the effects. Methods： Rats were given 6% alcohol in water and injected with CCI, （2 mL/kg, sc） twice a week for 8 weeks. Rgl （10, 20 and 40 mg/kg per day, po） was administered in the last 2 weeks. Hepatic fibrosis was determined by measuring serum biochemical parameters, HE staining, Masson＇s trichromic staining, and hydroxyproline and α-SMA immunohistochemical staining of liver tissues. The activities of antioxidant enzymes, lipid peroxidation, and Nrf2 signaling pathway-related proteins （Nrf2, Ho-1 and Nqol） in liver tissues were analyzed. Cultured hepatic stellate cells （HSCs） of rats were prepared for in vitro studies. Results： In the alcohol- and CCl4-treated rats, Rgl administration dose-dependently suppressed the marked increases of serum ALT, AST, LDH and ALP levels, inhibited liver inflammation and HSC activation and reduced liver fibrosis scores. Rgl significantly increased the activities of antioxidant enzymes （SOD, GSH-Px and CAT） and reduced MDA levels in liver tissues. Furthermore, Rgl significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rgl （1 μmol/L） induced Nrf2 translocation, and suppressed CCl4-induced cell proliferation, reversed CCl4. induced changes in MDA, GPX, PCIII and HA contents in the supernatant fluid and α-SMA expression in the cells. Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl4-treated HSCs in vitro. Conclusion： Rgl exerts protective effects in a rat model of alcohol- and CCl4-induced hepatic fibrosis via promoting the nuclear translocation of Nrf2 and expression of antioxidant enzymes.Aim： To investigate the anti-fibrosis effects of ginsenoside Rgl on alcohol- and CCl4-induced hepatic fibrosis in rats and to explore the mechanisms of the effects. Methods： Rats were given 6% alcohol in water and injected with CCI, （2 mL/kg, sc） twice a week for 8 weeks. Rgl （10, 20 and 40 mg/kg per day, po） was administered in the last 2 weeks. Hepatic fibrosis was determined by measuring serum biochemical parameters, HE staining, Masson＇s trichromic staining, and hydroxyproline and α-SMA immunohistochemical staining of liver tissues. The activities of antioxidant enzymes, lipid peroxidation, and Nrf2 signaling pathway-related proteins （Nrf2, Ho-1 and Nqol） in liver tissues were analyzed. Cultured hepatic stellate cells （HSCs） of rats were prepared for in vitro studies. Results： In the alcohol- and CCl4-treated rats, Rgl administration dose-dependently suppressed the marked increases of serum ALT, AST, LDH and ALP levels, inhibited liver inflammation and HSC activation and reduced liver fibrosis scores. Rgl significantly increased the activities of antioxidant enzymes （SOD, GSH-Px and CAT） and reduced MDA levels in liver tissues. Furthermore, Rgl significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rgl （1 μmol/L） induced Nrf2 translocation, and suppressed CCl4-induced cell proliferation, reversed CCl4. induced changes in MDA, GPX, PCIII and HA contents in the supernatant fluid and α-SMA expression in the cells. Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl4-treated HSCs in vitro. Conclusion： Rgl exerts protective effects in a rat model of alcohol- and CCl4-induced hepatic fibrosis via promoting the nuclear translocation of Nrf2 and expression of antioxidant enzymes.

关 键 词：ginseng GINSENOSIDE Rgl hepatic fibrosis hepatic stellate cells ALCOHOL CCL4 antioxidant enzymes Nrf2 pathway 

分 类 号：Q516[生物学—生物化学] TS262.91[轻工技术与工程—发酵工程]