Mechanism of Gexia zhuyu decoction in the intervention of metabolic-associated fatty liver disease by inhibiting ferroptosis
OBJECTIVE To explore the potential mechanism of action of Gexia zhuyu decoction in the intervention of metabolic-associated fatty liver disease(MAFLD)based on ferroptosis.METHODS With the help of network pharmacology,the central targets of Gexia zhuyu decoction intervening in ferroptosis of MAFLD were screened,then gene ontology,Kyoto Encyclopedia Gene and Genomes enrichment analysis and molecular docking were performed.Juvenile zebrafish with normal development at 3 d post-fertilization were randomly divided into control group,model group(5 mmol/L thioacetamide),magnesium isoglycyrrhizinate group(positive control,5 mg/mL),and Gexia zhuyu decoction low-,medium-and high-concentration groups(20,40,80 μg/mL,calculated by crude drugs).After cultured for 72 h,the contents of alanine transaminase(ALT),aspartate transaminase(AST),total cholesterol(TC),triglyceride(TG),malondialdehyde(MDA),superoxide dismutase(SOD),glutathione(GSH),reactive oxygen species(ROS)and Fe2+were determined;the cellular structure of the liver tissues and hepatic steatosis were observed;the protein expression of silence information regulator 1(SIRT1),nuclear factor-erythroid 2-related factor 2(Nrf2)and glutathione peroxidase 4(GPX4)were detected.RESULTS The central targets of potential active ingredients of Gexia zhuyu decoction that act on ferroptosis in MAFLD included tumor proteins p53,SIRT1,Nrf2,etc.,which were enriched in biological processes such as positive/negative regulation of RNA polymerase n promoter transcription,cellular components such as nucleus and cytoplasm,molecular functions such as protein binding,as well as signaling pathways such as ferroptosis and the cancer pathway,and they might be tightly linked to the main active ingredients.Compared with model group,the contents of ALT,AST,TC,TG,MDA,ROS and Fe2+were all decreased significantly in each administration group,while the contents of SOD and GSH were increased significantly(P＜0.05);the pathological damage of liver tissue cells had improved,and the accumulation of liver lipids had decreased.The protein expressions of SIRT1,Nrf2 and GPX4 had been significantly upregulated(P＜0.05).CONCLUSIONS Gexia zhuyu decoction can regulate lipid metabolism,improve the level of oxidative stress,maintain Fe2+homeostasis,and inhibit the process of ferroptosis in juvenile zebrafish with MAFLD,and the above effects may be related to the activation of the SIRT1/Nrf2/GPX4 axis.
万方数据
维普
