沈阳医学院学报2025，Vol.27Issue(2)：141-148,8.DOI:10.16753/j.cnki.1008-2344.2025.02.006
环黄芪醇改善阿奇霉素诱导药物性肝损伤的作用机制研究
Mechanisms of cycloastragenol in ameliorating azithromycin-induced drug-induced liver injury
摘要
Abstract
Objective:To investigate the targets and mechanisms of cycloastragenol in ameliorating azithromycin-induced drug-induced liver injury(DILI)based on network pharmacology and in vitro experiment validation.Methods:Potential targets of cycloastragenol and DILI were predicted using databases.The common and key targets were screened and subjected to GO and KEGG enrichment analyses,as well as molecular docking validation.Primary hepatocytes from C57BL/6 mice were isolated.The optimal concentration and time for azithromycin-induced DILI in mouse primary hepatocytes were determined using CCK8 and ROS assays.The expression of genes and proteins such as NF-κB p65,p-NF-κB p65,AMPKα,and p-AMPKα was assessed using RT-qPCR and Western blot to evaluate the intervention effect of cycloastragenol(10-50 μmol/L).Results:Network pharmacology analysis identified 10 key genes related to cycloastragenol's improvement of DILI,including heat shock protein 90AA1(HSP90AA1),matrix metalloproteinase 2(MMP2),etc.GO enrichment analysis suggested that cycloastragenol primarily regulates biological processes such as membrane potential and chemical synaptic transmission,and affects cellular components such as neuronal cell bodies and distal axons,and related kinase activities.KEGG enrichment analysis showed that it mainly exerts intervention effects through neuro-signaling pathways and IL-17 signaling pathways.Molecular docking demonstrated strong binding of cycloastragenol to HSP90AA1,MMP2,NF-κB p65,AMPKα,nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase 1(HO-1),and NAD(P)H:quinone oxidoreductase 1(NQO1),with a binding energy≤-5.0 kcal/mol for Nrf2.In vitro experiments showed that azithromycin(50 μmol/L,12 h)significantly reduced hepatocyte viability and increased ROS levels(P＜0.01).Different concentrations of cycloastragenol significantly improved the activity of mouse primary hepatocytes,reduced the generation of intracellular ROS,downregulated the phosphorylation level of NF-κB p65,and upregulated the mRNA and protein levels of AMPKα,Nrf2,HO-1,NQO1(P＜0.05).Conclusions:Cycloastragenol may alleviate azithromycin-induced hepatocyte oxidative stress and inflammation by inhibiting NF-κB phosphorylation and activating the AMPK/Nrf2/HO-1/NQO1 pathway,with its mechanism likely closely linked to targeting Nrf2.However,the complex mechanisms of DILI may involve additional unverified pathways.Therefore,further studies are necessary to validate the efficacy and safety of cycloastragenol in animal models.关键词
环黄芪醇/网络药理学/分子对接/药物性肝损伤Key words
cycloastragenol/network pharmacology/molecular docking/drug-induced liver injury分类
中医学引用本文复制引用
张翠锋,钱海溢,何溢宸,王佳音,解心怡,徐启祥,郭文俊..环黄芪醇改善阿奇霉素诱导药物性肝损伤的作用机制研究[J].沈阳医学院学报,2025,27(2):141-148,8.基金项目
安徽省高校自然科学研究项目重点项目(No.2023AH051762 （）
No.2022AH051229) （）
皖南医学院校中青年科研基金项目(No.WK2023ZQNZ08) （No.WK2023ZQNZ08）
国家级大学生创新创业训练计划项目(No.202210368052 （）
No.202310368014 （）
No.202410368019) （）
安徽省大学生创新创业项目(No.S202310368095 （）
No.S202310368087) （）
