黄芪治疗肾透明细胞癌作用机制的网络药理学分析

Network pharmacological analysis on mechanism of Huangqi(Astragalus membranaceus)in the treatment of renal clear cell carcinoma

目的基于生物信息方法分析黄芪治疗肾透明细胞癌(ccRCC)的有效成分及潜在作用机制。方法通过TCMSP筛选黄芪的活性成分及作用靶点。利用OMIM、Genecards、PharmGkb、DrugBank及TTD数据库筛选ccRCC疾病靶点并与黄芪作用靶点进行交集,获得黄芪治疗ccRCC的靶点。构建药物—成分—靶点—疾病网络图,筛选黄芪治疗ccRCC的核心成分。用Cytoscape3.8.0软件、STRING数据库分别建立黄芪治疗ccRCC靶点的蛋白质相互作用网络及可视化图,筛选黄芪治疗ccRCC的核心靶点。借助R语言和Bioconductor软件包对黄芪治疗ccRCC的靶点进行KEGG、GO富集分析。采用分子对接技术验证黄芪核心活性成分与核心靶点的作用强度。结果筛选得到黄芪活性成分21个,共有395个潜在作用靶点,药物—疾病交集靶点180个,核心活性成分为槲皮素、山柰酚、黄芪皂苷、芒柄花素、异鼠李素等,核心靶点有转录活化因子(JUN)、肿瘤蛋白P53(TP53)、苏氨酸激酶1(AKT1)、丝裂原活化蛋白激酶14(MAPK14)等。KEGG、GO通路富集分析显示,黄芪治疗ccRCC的机制与调控PI3K-AKT、MAPK、AGE-RAGE、TNF等信号通路有关。分子对接实验显示,黄芪的5个核心活性成分与4个核心靶点均有较强的结合能力,其中黄芪皂苷与AKT1结合最紧密。结论黄芪治疗ccRCC的活性成分有槲皮素、山柰酚、黄芪皂苷、芒柄花素、异鼠李素等,可能通过作用于JUN、TP53、AKT1、MAPK14等靶点,参与PI3K-AKT等信号通路,发挥调节机体免疫功能及影响细胞增殖、分化、凋亡、迁移等,从而达到治疗ccRCC的效果。

Objective To investigate the active ingredients and potential mechanisms of action of Huangqi(Astragalus membranaceus)in the treatment of renal clear cell carcinoma(ccRCC)by bioinformatics methods.Methods The active ingredients and action targets of Huangqi were screened by TCMSP.Targets of ccRCC were screened by OMIM,Genecards,PharmGkb,DrugBank,TTD databases,and then we used them to intersect with targets of Huangqi in order to acquire the treatment targets of Huangqi.A drug-ingredient-target-disease network diagram was constructed to screen the core ingredients of Huangqi in the treatment of ccRCC,and the core targets were screened through the protein-protein interaction network and visualization maps which were constructed by STRING database and Cytoscape 3.8.0 software,respectively.KEGG and GO enrichment of obtained targets were analyzed with the help of R software and Bioconductor packages.Finally,the action intensity of the core active ingredients and key targets were verified via molecule docking.Results Twenty-one active ingredients,395 potential targets,and 180 drug-disease intersection targets of Huangqi were screened out;quercetin,kaempferol,astragaloside,quercetin,kaempferol,astragaloside,formononetin,and isorhamnetin,etc.were identified as core active ingredients;and AKT1,TP53,MAPK14,JUN,and ESR1,etc.were identified as core targets.The KEGG and GO pathway enrichment analysis showed that the treatment mechanism of Huangqi was associated with the regulation of signal pathway such as PI3K-AKT,MAPK,AGE-RAGE,and TNF.Molecular docking experiments showed that the 5 core active ingredients of Huangqi had strong binding ability to all 4 key targets,and Huangqi showed the strongest binding ability to AKT1.Conclusion The active ingredients,quercetin,kaempferol,astragaloside,etc.,in Huangqi may play a role in regulating the immune function of the body through the key targets JUN,TP53,AKT1,and MAPK14,etc.,participating in signaling pathways such as PI3K-AKT,and treating ccRCC by affecting cell proliferation,differentiation,apoptosis and migration.