基于网络药理学研究杨桃根防治糖尿病肾病的作用机制

Study on the mechanism of the root of Averrhoa carambola L.in the treatment of diabetic kidney disease based on network pharmacology

基于网络药理学研究杨桃根防治糖尿病肾病(DKD)的作用机制。利用PubChem Search、Chemspider、Swiss Target Prediction和GeneCards数据库获取杨桃根主要药效成分和治疗DKD的作用靶点,活性成分-靶点网络图采用Cytoscape进行构建。通过String在线数据库构建靶蛋白相互作用网络,并利用CytoHubba插件筛选关键靶点。利用WebGestalt在线数据库对关键靶点进行GO和KEGG富集分析。最后,通过动物实验对筛选的关键靶点和信号通路进行初步验证。结果共筛选到24个活性成分,成分-疾病的共同靶点59个。进一步网线分析显示,主要活性成分为桃根环己二酮、苦瓜苷C、樱桃素和胡萝卜甾醇等14个,关键靶点为MMP9、MMP2、EGFR、FGF2、STAT3、MAPK1、VEGFA和CASP3,主要涉及的信号通过包括AGE-RAGE信号通路、Relaxin信号通路、胰岛素抵抗信号通路和缺氧诱导因子信号通路。胱抑素C(CysC)和HE染色均提示杨桃根提取物能改善糖尿病小鼠肾功能。Western-blot显示,杨桃根提取物可以通过降低AGE-RAGE信号通路相关的TGFβ1和NF-κB蛋白发挥防治DKD的作用。综上,杨桃根发挥防治DKD的作用是通过多成分、多靶点、多途径而实现的。

To study the mechanism of the root of Averrhoa carambola L.(RAC)in the treatment of diabetic kidney disease(DKD)based on network pharmacology.The active components of the RAC and the targets for treatment of DKD were screened and predicted by utilizing PubChem Search,Chemspider,Swiss target prediction and Genecards database.Cytoscape was used to construct the active components-target network map.The protein interaction network map was constructed by String database and the core targets were screened out by CytoHubba.Next,GO and KEGG analyses were conducted by WebGestalt.Finally,key screening targets and signaling pathways were primary validated by animal experiments.A total of 24 active ingredients were obtained,and 59 common targets for ingredients and diseases were screened.Further network analysis showed that the main active ingredients included 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione,cuneataside C,prunasin and daucosterol.The key targets were MMP9,MMP2,EGFR,FGF2,STAT3,MAPK1,VEGFA,and CASP3.In addition,regulation key KEGG signal pathways involved AGE-RAGE signaling pathway,Relaxin signaling pathway,insulin resistance signaling pathway and hypoxia-inducible factor signaling pathway.Cystatin C(CysC)and HE staining suggested that the extract of RAC could improve renal function in diabetic mice.Western-blot showed that the extract of RAC played an important role in preventing and treating DKD by reducing TGFβ1 and NF-κB proteins associated with the AGE-RAGE signaling pathway.In summary,the RAC plays a role in preventing and treatment DKD through multi-component,multi-target,and multi-pathways.