目的 采用网络药理学的方法探讨白藜芦醇在糖尿病视网膜病变治疗中的潜在机制，为白藜芦醇防治糖尿病视网膜病变提供理论依据。方法 使用CTD、DGIdb、Drugbank、Swiss Target Prediction、TCMSP数据库获得白藜芦醇的作用靶点。从GeneCard、DisGeNET、OMIM、DrugBank数据库获得糖尿病视网膜病变疾病相关靶点。使用Venn图取交集即为白藜芦醇抗糖尿病视网膜病变作用靶点。将白藜芦醇抗糖尿病视网膜病变靶点蛋白上传至String数据库，将所得数据导入Cytoscape 3.7.1，构建白藜芦醇抗糖尿病视网膜病变靶点蛋白的蛋白互作（PPI）网络，并筛选出核心作用靶点。使用DAVID数据库对白藜芦醇抗糖尿病视网膜病变靶点基因进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析。对核心作用靶点与白藜芦醇结合力进行分子对接验证。利用细胞活力实验观察白藜芦醇对高糖作用下的人视网膜血管内皮细胞（HRCECs）细胞增殖的影响；检测不同浓度（40、80、160 μmol/L）白藜芦醇对高糖作用下HRCECs细胞STAT3、VEGFA、TNF mRNA表达的影响。结果 共获得白藜芦醇抗糖尿病视网膜病变作用靶点130个，并筛选出核心靶基因10个。KEGG途径分析富集的信号通路包括TNF信号通路、HIF-1信号通路、FoxO信号通路等。分子对接显示，核心靶基因AKT1、IL-6、TNF、VEGFA、IL-1B、MAPK3、EGFR、JUN、STAT3及CASP3与白藜芦醇亲和力较好，尤其与STAT3、VEGFA和TNF具有强烈的结合活性。细胞实验显示，与模型组相比，白藜芦醇能明显抑制高糖作用下HRCECs的细胞增殖能力（P＜0.05、0.01）。同时能明显降低高糖作用下HRCECs细胞STAT3、VEGFA、TNF mRNA表达（P＜0.05、0.01）。结论 白藜芦醇治疗糖尿病视网膜病变具有多靶点、多途径的特点。白藜芦醇可能通过作用于VEGFA、AKT1、CASP3、IL-6、STAT3、EGFR、TNF、和MAPK3等核心靶点基因，影响TNF信号通路和HIF信号通路等发挥对糖尿病视网膜病变的治疗作用。

Objective To explore the potential mechanism of resveratrol in treatment of diabetic retinopathy by network pharmacology, and to provide a theoretical basis for resveratrol to prevent and treat diabetic retinopathy. Methods The target of resveratrol was obtained by using CTD, DGIdb, Drugbank, Swiss Target Prediction, and TCMSP database. Diabetic retinopathy related targets were obtained from GeneCard, DisGeNET, OMIM, DrugBank database. The intersection of the two are the targets of resveratrol against diabetic retinopathy. The resveratrol anti-diabetic retinopathy target protein was uploaded to String database, and the obtained data were imported into Cytoscape 3.7.1 to construct the protein interaction (PPI) network of resveratrol anti-diabetic retinopathy target protein, and the core targets were screened. GO and KEGG pathway enrichment analysis of resveratrol anti-diabetic retinopathy target genes were performed using DAVID database. The binding ability of resveratrol to the core action target was verified by molecular docking. The effects of resveratrol on the proliferation of human retinal vascular endothelial cells (HRCECs) were investigated by cell viability assay. The effects of resveratrol (40, 80, 160 μmol/L) on mRNA expression of STAT3, VEGFA and TNF in HRCECs cells treated with high glucose were investigated. Results 130 Targets of resveratrol against diabetic retinopathy were obtained, and 10 core target genes were screened out. The signal pathways enriched by KEGG pathway analysis include TNF signal pathway, HIF-1 signal pathway, FOXO signal pathway and so on. Molecular docking showed that resveratrol had good affinity with the core target genes AKT1, IL-6, TNF, VEGFA, IL-1B, MAPK3, EGFR, JUN, STAT3, and CASP3, especially with STAT3, VEGFA, and TNF. In addition, compared with model group, cell experiment showed that resveratrol could significantly inhibit the proliferation of HRCECs cells under the effect of high glucose (P < 0.05, 0.01). At the same time, the mRNA expressions of STAT3, VEGFA and TNF in HRCECs cells under high glucose were significantly reduced (P < 0.05, 0.01). Conclusion Resveratrol in treatment of diabetic retinopathy has the characteristics of multi-target and multi-pathway. Resveratrol may play a therapeutic role in diabetic retinopathy by acting on core target genes such as VEGFA, AKT1, CASP3, IL-6, STAT3, EGFR, TNF, and MAPK3, and affecting TNF signaling pathway and HIF signaling pathway.

R285

河南省医学科技攻关计划(联合共建)项目(LHGJ20190492)