Abstract
Huaganjian decoction (HGJD) was first recorded in the classic “Jing Yue Quan Shu” during the Ming dynasty, and it has been extensively applied in clinical practice to treat liver diseases for over 300 years in China. However, its bioactive constituents and relevant pharmacological mechanism are still unclear. In this study, a strategy integrating network analysis and metabolomics was applied to reveal mechanism of HGJD in treating cholestatic hepatic injury (CHI). Firstly, we observed the therapeutic effect of HGJD against CHI with an alpha-naphthylisothiocyanate (ANIT) induced CHI rat model. Then, we utilized UPLC-Q-Exactive MS/MS method to analyze the serum migrant compounds of HGJD in CHI rats. Based on these compounds, network analysis was conducted to screen for potential active components, and key signaling pathways interrelated to therapeutic effect of HGJD. Meanwhile, serum metabolomics was utilized to investigate the underlying metabolic mechanism of HGJD against CHI. Finally, the predicted key pathway was verified by western blot and biochemical analysis using rat liver tissue from in vivo efficacy experiment. Our results showed that HGJD significantly alleviated ANIT induced CHI. Totally, 31 compounds originated from HGJD have been identified in the serum sample. PI3K/Akt/Nrf2 signaling pathway related to GSH synthesis was demonstrated as one of the major pathways interrelated to therapeutic effect of HGJD against CHI. This research supplied a helpful strategy to determine the potential bioactive compounds and mechanism of traditional Chinese medicine.
Highlights
Cholestatic hepatic injury (CHI) occurs mainly due to intrahepatic cholestasis
Huaganjian decoction (HGJD) significantly decreased the biochemical indicators which were related to cholestatic hepatic injury (CHI), and improved the inflammatory infiltration induced by ANIT
The results suggested that HGJD had a protective effect against ANITinduced CHI
Summary
Its main characteristics are aberrant metabolism of bile acid and accumulating of toxic bile acids in the liver. Signals such as oxidative stress and inflammatory responses are activated, leading to parenchymal cell death of liver and bile duct (Cai and Boyer, 2021). CHI may further develop into fibrosis, cirrhosis, hepatocellular carcinoma and eventually liver failure. Ursodeoxycholic acid (UDCA), and obeticholic acid (OCA) are main therapeutic options for CHI (Hohenester and Beuers, 2017). Some patients have an inadequate response to UDCA therapy and the side effects of OCA in this treatment remain to be improved (Hirschfield et al, 2015; Kowdley et al, 2018)
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