Abstract
Hepatic fibrosis (HF) represents the excessive wound healing where an excess amount of connective tissues is formed within the liver, finally resulting in cirrhosis or even hepatocellular carcinoma (HCC). Therefore, it is significant to discover the efficient agents and components to treat HF, thus restraining the further progression of hepatopathy. Astragalus membranaceus (Fisch.) Bunge [also called Astragali Radix (AR)] is a famous herb in traditional Chinese medicine (TCM), which possesses a variety of biological activities and exerts good therapeutic effects in the treatment of HF. Flavonoids account for the major active ingredients related to the AR pharmacological effects. Total AR flavonoids have been proved to exert inhibitory effects on hepatic fibrosis. This study aimed to further undertake network pharmacology analysis coupled with experimental validation and molecular docking to investigate the effects and mechanism of multiple flavonoid components from AR against liver fibrosis. The results of the network pharmacology analysis showed that the flavonoids from AR exerted their pharmacological effects against liver fibrosis by modulating multiple targets and pathways. The experimental validation data showed that the flavonoids from AR were able to suppress transforming growth factor beta 1 (TGF-β1)-mediated activation of hepatic stellate cells (HSCs) and reduce extracellular matrix deposition in HSC-T6 cells via regulating the nuclear factor kappa B (NF-κB) signal transduction pathway. The results of the molecular docking study further showed that the flavonoids had a strong binding affinity for IκB kinase (IKKβ) after docking into the crystal structure. The above results indicated that, flavonoids possibly exerted the anti-inflammatory effect on treating HF by mediating inflammatory signaling pathways. The potential mechanism of these flavonoids against liver fibrosis may be related to suppression of the NF-κB pathway through effective inhibition of IKKβ. This study not only provides a scientific basis for clarifying the effects and mechanism of AR flavonoids against liver fibrosis but also suggests a novel promising therapeutic strategy for the treatment of liver fibrosis.
Highlights
Hepatic fibrosis (HF) is a pathological event where connective tissues abnormally proliferate in liver, which is associated with a variety of factors, causing excess extracellular matrix (ECM) deposition within liver (Trautwein et al, 2015)
The results of molecular docking showed that the flavonoids had high affinity for IKKβ (Figure 10), suggesting that the mechanism of the flavonoids against liver fibrosis may be related to suppression of the NF-κB pathway through effective inhibition of IKKβ
This study aimed to undertake network pharmacology analysis coupled with experimental validation and molecular docking to investigate the effects and mechanism of Astragali Radix (AR) flavonoids against liver fibrosis
Summary
Hepatic fibrosis (HF) is a pathological event where connective tissues abnormally proliferate in liver, which is associated with a variety of factors, causing excess extracellular matrix (ECM) deposition within liver (Trautwein et al, 2015). For HF, its pathogenic mechanisms are chronic virus infection, nonalcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), together with toxin-related stimuli (such as drugs and alcohol), autoimmune hepatitis, hereditary metabolic disease and cholestatic diseases (Fan et al, 2019). Such injury to liver parenchyma will activate the hepatic stellate cells (HSCs), the cells responsible for storing vitamin A and are involved in HF occurrence (Huang et al, 2017). As a result, applying TCM herbs may serve as the efficient way to prevent and treat HF
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