摘要
目的通过网络药理学分析及相关的动物实验探讨黄芪六一汤药效组分(HQD)调控肾小管上皮细胞自噬水平抗糖尿病肾病(DN)的机制。方法采用DN大鼠模型考察HQD抗DN的作用。利用SwissTargetPrediction数据库获得HQD主要入血成分的相关靶点,并与GeneCard、DisGeNET和OMIM数据库中筛选的疾病靶点取交集;利用STRING数据库和Cytoscape构建蛋白质-蛋白质相互作用(PPI)网络获得核心靶点;采用Metascape数据库对交集靶点进行基因本体(GO)注释及京都基因与基因组百科全书(KEGG)通路富集分析。利用DN大鼠模型对预测结果进行验证。结果与对照组比较,HQD能显著降低DN模型大鼠血糖(FBG)、血肌酐(Scr)、尿素氮(BUN)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL)、24 h尿白蛋白(24 h-U-Alb)值(P<0.05),抑制肾组织细胞凋亡(P<0.05)。网络药理学研究显示HQD主要通过STAT3、EGFR、VEGFA、JUN、TNF、AKT1、CASP3、mTOR、IL2等关键靶点,作用于癌症通路、癌症中的蛋白多糖、PI3K-Akt信号通路、MAPK等信号通路;动物验证实验显示HQD能下调PI3K/Akt/mTOR信号通路相关蛋白的表达,上调肾脏组织自噬相关蛋白Beclin-1、LC3Ⅱ/Ⅰ的表达(P<0.05),增加肾小管上皮细胞自噬体及自噬溶酶体数量。结论HQD抗DN的分子机制可能与抑制PI3K/Akt/mTOR信号通路激活,促进肾小管上皮细胞自噬水平,抑制细胞凋亡,减轻肾小管上皮细胞损伤有关。
Objective To investigate the mechanism by which the pharmacological component of Huangqi Liuyi Decocotion(HQD)modulates the level of autophagy in renal tubular epithelial cells against diabetic nephropathy(DN)through network pharmacological analysis and related animal experiments.Methods A rat model of DN was used to investigate the anti-diabetic nephropathy effect of HQD.The SwissTargetPrediction database was used to obtain the relevant targets of HQD's major blood-entry components and intersected with the disease targets screened in GeneCard,DisGeNET and OMIM databases;the STRING database and Cytoscape were used to construct a protein-protein interaction(PPI)network to obtain the core targets;Metascape database was used to analyze the GO and KEGG enrichment of the intersected targets.The predicted results were then validated using a diabetic nephropathy rat model.Results HQD significantly reduced blood glucose(FBG),blood creatinine(Scr),urea nitrogen(BUN),total cholesterol(TC),triacylglycerol(TG),low-density lipoprotein(LDL),and 24 h urinary albumin(24 h-U-Alb)values in rats with DN(P<0.05),and inhibited apoptosis of renal tissue cells(P<0.05).Network pharmacological studies showed that HQD mainly acted on the cancer pathway,proteoglycans in cancer,PI3K-Akt signaling pathway,MAPK and other signaling pathways through key targets such as STAT3,EGFR,VEGFA,JUN,TNF,AKT1,CASP3,mTOR,IL2,etc.Animal validation experiments showed that HQD could down-regulate PI3K/Akt/mTOR signaling pathway-related proteins,up-regulate the expression of autophagy-related proteins Beclin-1 and LC3Ⅱ/Ⅰ in renal tissues(P<0.05),and increase the number of autophagosomes and autophagic lysosomes in renal tubular epithelial cells.Conclusion The molecular mechanism of HQD against DN may be related to the inhibition of PI3K/Akt/mTOR signaling pathway activation,promotion of autophagy level in renal tubular epithelial cells,inhibition of apoptosis,and attenuation of renal tubular epithelial cell injury.
作者
王群
唐甜甜
韩伟
刘文
李亚辉
王庆学
WANG Qun;TANG Tiantian;HAN Wei;LIU Wen;LI Yahui;WANG Qingxue(College of Pharmacy,Guizhou University of Traditional Chinese Medicine,Guiyang 550025,China;College of Pharmacy,Guizhou Medical University,Guiyang 550000,China)
出处
《药物评价研究》
CAS
北大核心
2024年第6期1187-1198,共12页
Drug Evaluation Research
基金
贵州省科技计划项目(黔科合基础-ZK[2023]一般416)
2023年度贵州中医药大学学术新苗项目(贵科合学术新苗[2023]-13号)
贵州省卫生健康委科学技术基金项目(黔卫健函[2024]24号)
贵州中医药大学药用高分子材料研究中心(贵中医ZX合字[2024]071号)。
