Network Pharmacology Research and Preliminary Verification of Gegen Qinlian Decoction for the Treatment of Non-Alcoholic Fatty Liver Disease

Abstract

Gegen Qinlian decoction (GQD) is a traditional Chinese medicine that is used to treat non-alcoholic fatty liver disease (NAFLD) in the clinic. The pharmacodynamics and cellular pathways governing the effects of GQD on NAFLD remain undefined. In this study, we investigated GQD pharmacology through assessment of its chemical constituents and evaluated and screened its components using drug likeness, pharmacokinetic characteristics (absorption, distribution, metabolism, excretion, and toxicity), and appropriate compensation mechanisms. We performed predictions of the active GQD ingredients based on reverse pharmacophore matching and compared multiple NAFLD-related genes to determine potential GQD targets. Molecular docking experiments of the active components were performed to reveal cellular targets. Annotation analysis of both target genes and related pathways were assessed through the DAVID database. Cytoscape software was used to construct a “component-target-path” network for the treatment of NAFLD by GQD. Through data analysis, 9 active GQD substances and 10 targets related to NAFLD encompassing 4 cellular pathways were identified. Data were verified through enzyme-linked immunosorbent assay and Western blot analysis. These findings provide new references for the network pharmacology of Chinese medicinal compounds and NAFLD treatment.

Constituents, Pharmacokinetics, and Pharmacology of Gegen-Qinlian Decoction

“…Specifically, at the minimal active dose (1.24 g/kg/day), triglyceride (TG) was reduced from about 1.1 mm to about 0.8 mm (p < 0.05), serum total cholesterol (CHO) was reduced from about 2.7 mm to about 2.1 mm (p < 0.05), total bile acid (TBA) was reduced from about 35 μm to about 20 μm (p < 0.01) (Zhang et al, 2020). In general, GQD treatment reduced lipid droplets in the liver; attenuated elevated serum levels of alanine aminotransferase and aspartate aminotransferase; decreased serum levels of triglyceride, cholesterol, total bile acid, lowdensity lipoprotein, and free fatty acid; and decreased TNF-α level in both serum and the liver Guo et al, 2017;Guo et al, 2018;Hao et al, 2020;Zhang et al, 2020). The mechanisms of GQD were associated with an increase in the gene and protein expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) , which plays a complementary role in the fine-tuning of lipid transport, catabolism, and storage (Ahmadian et al, 2013).…”

“…For example, GQD is effective against inflammatory intestinal diseases, including diarrhea (Liu et al, 2019b;Hua et al, 2019), ulcerative colitis (Xu B.-L. et al, 2015;Li et al, 2016;Fan et al, 2019;Zhao Y. et al, 2020), and intestinal adverse reactions caused by chemotherapeutic agents . In addition, as the intestinal flora is closely related to metabolic diseases (Nicholson et al, 2012), GQD has significant effects against NAFLD Guo et al, 2017;Guo et al, 2018;Hao et al, 2020;Zhang et al, 2020), type 2 diabetes mellitus (T2DM) (Zhang et al, 2013;Cao et al, 2020;Tu et al, 2020) and other metabolic diseases. Furthermore, based on its significant anti-inflammatory effect, GQD can be used to treat inflammatory diseases, such as lipopolysaccharide (LPS)- (Ding et al, 2020) and influenza A virus- (Shi et al, 2020) induced lung injury.…”

“…According to a network pharmacology research, nine compounds, including xambioona, baicalin, phaseo, worenine, wogonoside, inermine, glabrene, puerarin, and glabridin were identified as the active constituents of GQD for treating NAFLD (Hao et al, 2020). These compounds may target 17 target genes that are closely related to four pathways (AMPK, NAFLD, adipocytokine signaling, and PPAR) (Hao et al, 2020).…”

“…According to a network pharmacology research, nine compounds, including xambioona, baicalin, phaseo, worenine, wogonoside, inermine, glabrene, puerarin, and glabridin were identified as the active constituents of GQD for treating NAFLD (Hao et al, 2020). These compounds may target 17 target genes that are closely related to four pathways (AMPK, NAFLD, adipocytokine signaling, and PPAR) (Hao et al, 2020). In a preclinical study where pioglitazone hydrochloride (5.25 mg/kg/day) was used as positive control, oral administration of GQD water extract at the dosage of 1.24, 3.73, or 11.2 g/kg/day for 49 days abated liver injuries in nine NAFLD model rats by regulating lipid metabolism and reducing liver inflammation (Zhang et al, 2020).…”

“…Therefore, gut microbiota analysis is a new Frontier for understanding the action mechanisms of TCMs (Feng et al, 2019). Studies have shown that GQD has antidiarrheal (Liu et al, 2019b;Hua et al, 2019), anti-colitis (Xu B.-L. et al, 2015;Li et al, 2016;Fan et al, 2019;Zhao Y. et al, 2020), anti-nonalcoholic fatty liver disease (NAFLD) Guo et al, 2017;Guo et al, 2018;Hao et al, 2020;Zhang et al, 2020), antidiabetic (Zhang et al, 2013;Cao et al, 2020;Tu et al, 2020), anti-lung injury (Ding et al, 2020;Shi et al, 2020), antitumor (Wang N. et al, 2015;Lv et al, 2019) and other pharmacological effects. Metabolomics (Tian et al, 2013;Hua et al, 2019), network pharmacology (Li et al, 2014b;Cao et al, 2020;Ding et al, 2020;Hao et al, 2020;Xu et al, 2020;Zhong et al, 2020), gut microbiota analysis Guo et al, 2018;Liu et al, 2019b;Lv et al, 2019), and other methods have been comprehensively used to explain the action mechanism of GQD.…”