Hepatoprotective effect of Xiayuxue decoction ethyl acetate fraction against carbon tetrachloride-induced liver fibrosis in mice via inducing apoptosis and suppressing activation of hepatic stellate cells

Dingqi Zhang; Lijun Zhang; Gaofeng Chen; Ying Xu; Hailin Yang; Zhun Xiao; Jiamei Chen; Yongping Mu; Hua Zhang; Wei Liu; Ping Liu

doi:10.1080/13880209.2020.1855212

Hepatoprotective effect of Xiayuxue decoction ethyl acetate fraction against carbon tetrachloride-induced liver fibrosis in mice via inducing apoptosis and suppressing activation of hepatic stellate cells

Pharm Biol. 2020 Dec;58(1):1229-1243. doi: 10.1080/13880209.2020.1855212.

Authors

Dingqi Zhang^{1

2}, Lijun Zhang^{1

2}, Gaofeng Chen^{1

2}, Ying Xu^{1

2}, Hailin Yang^{1

2}, Zhun Xiao^{2

3}, Jiamei Chen^{1

2}, Yongping Mu^{1

2}, Hua Zhang^{1

2}, Wei Liu^{1

2}, Ping Liu^{1

2

3}

Affiliations

¹ Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China.
³ Institute of Interdisciplinary Complex Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Abstract

Context: Xiayuxue decoction (XYXD), a traditional Chinese medicine, is used for treating liver disease. However, the potential active constituents and mechanisms are still unclear.

Objective: To explore the main active fraction extracts, active ingredients and possible mechanisms of XYXD for anti-hepatic fibrosis.

Materials and methods: Different fractions including ethyl acetate fraction (EF) were prepared from XYXD. These fractions, especially EF, were used to evaluate cell viability, proliferation, cell cycle, cytotoxicity and activation in hepatic stellate cells (HSCs). Liver fibrosis model was established by CCl₄ in C57BL/6 mice, and allocated to CCl₄ group, XYXD group and EF group with normal mice as control. Further, mitochondrial apoptosis-related proteins of HSCs, destruction and angiogenesis of liver sinusoidal endothelial cells (LSECs) and active ingredients of EF were evaluated.

Results: The inhibition of proliferation, increase of S or/and G2/M phase population and suppression of α-SMA and COL-1 expression were obeserved in EF treated-JS1 and -LX2. Liver fibrosis-related indicators were improved by EF similar to XYXD in vivo. EF induced the apoptosis of HSCs in CCl₄-induced fibrosis, and inhibited the expression of HSCs apoptosis pathway-related proteins (JNK and p38-MAPKs), and LSECs destruction and angiogenesis. Multiple ingredients (emodin, rhein, aloe-emodin, prunasin) in EF have shown inhibited the activation of JS1.

Discussion and conclusion: EF was the main active fraction extracts of XYXD, and the underlying mechanisms might relate to induction of HSCs apoptosis. Emodin, rhein, aloe-emodin and prunasin were main active ingredients of EF, which provides a potential drug for the treatment of liver fibrosis.

Keywords: Xiayuxue decoction; activation; apoptosis; hepatic stellate cells; liver fibrosis.

MeSH terms

Animals
Apoptosis / drug effects*
Carbon Tetrachloride
Cell Cycle Checkpoints / drug effects
Drugs, Chinese Herbal / chemistry
Drugs, Chinese Herbal / pharmacology*
Drugs, Chinese Herbal / therapeutic use
Hepatic Stellate Cells / drug effects*
Liver / drug effects*
Liver Cirrhosis / drug therapy*
Liver Cirrhosis / pathology
MAP Kinase Signaling System / drug effects
Male
Medicine, Chinese Traditional
Mice
Mice, Inbred C57BL
Plant Extracts / pharmacology
Rats
Rats, Sprague-Dawley

Substances

Drugs, Chinese Herbal
Plant Extracts
Carbon Tetrachloride

Grants and funding

This work was partially funded by the National Natural Science Foundation of China [Grant number: 81703681], Key projects of National Natural Science Foundation of China [Grant number: 81530101], Shanghai Sailing Program [Grant number: 17YF1419800], Postgraduate innovation program of Shanghai university of Traditional Chinese Medicine [Grant number: Y201862]. The funding supported the design and conduct of the study, data collection and analysis, and preparation and submission of the manuscript.