Original Article

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

Authors: 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
DOI: 10.1038/aps.2014.41

Abstract

Jian-ping LI1, Yan GAO1, Shi-feng CHU1, Zhao ZHANG1, Cong-yuan XIA1, Zheng MOU1, Xiu-yun SONG1, Wen-bin HE1, 2, Xiao-feng GUO2, Nai-hong CHEN1, *
1State 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; 2Shanxi University of Traditional Chinese Medicine, Taiyuan 030024, China

Aim: To investigate the anti-fibrosis effects of ginsenoside Rg1 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 CCl4 (2 mL/kg, sc) twice a week for 8 weeks. Rg1 (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 Nqo1) 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, Rg1 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. Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues. Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rg1 (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: Rg1 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.

Keywords: ginseng; ginsenoside; Rg1; hepatic fibrosis; hepatic stellate cells; alcohol; CCl4; antioxidant enzymes; Nrf2 pathway

This work was supported by National Natural Science Foundation 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).
* To whom correspondence should be addressed.
E-mail chennh@imm.ac.cn
Received 2014-01-02 Accepted 2014-04-11
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