Abstract
Advanced liver fibrosis can lead to cirrhosis, resulting in an accelerated risk of hepatocellular carcinoma and liver failure. Fuzheng Huayu formula (FZHY) is a traditional Chinese medicine formula treated liver fibrosis in China approved by a Chinese State Food and Drug Administration (NO: Z20050546), composed of Salvia Miltiorrhiza bge., Prunus davidiana (Carr.) Franch., cultured Cordyceps sinensis (BerK.) Sacc. Mycelia, Schisandra chinensis (Turcz.) Baill., Pinus massoniana Lamb., and Gynostemma pentaphyllum (Thunb.) Makino. However, the main active substances and mechanism of FZHY are unclear. The aim of this study is to identify a novel anti-fibrotic compound, which consists of the main active ingredients of FZHY, and investigate its mechanism of pharmacological action. The main active ingredients of FZHY were investigated by quantitative analysis of FZHY extracts and FZHY-treated plasma and liver in rats. The anti-fibrotic composition of the main active ingredients was studied through uniform design in vivo, and its mechanism was evaluated in carbon tetrachloride (CCl4)- and bile duct ligation (BDL)-induced liver fibrosis models in rats and mice, and transforming growth factor beta 1-induced LX-2 cell activation model in vitro. A novel Chinese medicine, namely JY5 formula, consisting of salvianolic acid B, schisantherin A, and amygdalin, the main active ingredients of FZHY, significantly alleviated hepatic hydroxyproline content and collagen deposition in CCl4-and BDL-induced fibrotic liver in rats and mice. In addition, JY5 inhibited the activation of hepatic stellate cells (HSCs) by inactivating Notch signaling in vitro and in vivo. In this study, we found a novel JY5 formula, which exerted anti-hepatic fibrotic effects by inhibiting the Notch signaling pathway, consequently suppressing HSCs activation. These results provide an adequate scientific basis for clinical research and application of the JY5 formula, which may be a potential novel therapeutic candidate for liver fibrosis.
Highlights
Liver fibrosis is a common pathological feature of chronic liver diseases including chronic viral hepatitis, metabolic-associated fatty liver disease, and cholestatic liver diseases
The above indicators were significantly reduced after intervention with JY5, fuzheng huayu formula (FZHY), or SORA (Supplementary Figures S3B,C and Figures 2D,E). These results demonstrated that JY5 formula had significant antihepatic fibrosis effects
In the bile duct of ligation (BDL)-induced liver fibrosis experiment, the treatment effect of JY5 was consistent with the results in the carbon tetrachloride (CCl4)-induced liver fibrosis experiments (Figures 5K–O). These results demonstrate that JY5 significantly represses the activation of hepatic stellate cells (HSCs) in CCl4 -and BDL-induced liver fibrosis
Summary
Liver fibrosis is a common pathological feature of chronic liver diseases including chronic viral hepatitis, metabolic-associated fatty liver disease, and cholestatic liver diseases. It is a consequence of an abnormal wound healing response, characterized by excessive deposition of extracellular matrix (ECM). Some clinical studies (Lee et al, 2015) have shown that liver fibrosis, even early cirrhosis, is reversible, providing reliable evidence for conducting clinical studies on anti-hepatic fibrosis drugs. A number of anti-hepatic fibrosis drug studies have been conducted in recent years, some of which have been researched in clinical trials (Lemoinne and Friedman, 2019). To date, there are no clinically approved by FDA or effective medical therapies aimed towards hepatic fibrosis
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