目的 采用網絡藥理學的方法探討白藜蘆醇在糖尿病視網膜病變治療中的潛在機制，為白藜蘆醇防治糖尿病視網膜病變提供理論依據。方法 使用CTD、DGIdb、Drugbank、Swiss Target Prediction、TCMSP數據庫獲得白藜蘆醇的作用靶點。從GeneCard、DisGeNET、OMIM、DrugBank數據庫獲得糖尿病視網膜病變疾病相關靶點。使用Venn圖取交集即為白藜蘆醇抗糖尿病視網膜病變作用靶點。將白藜蘆醇抗糖尿病視網膜病變靶點蛋白上傳至String數據庫，將所得數據導入Cytoscape 3.7.1，構建白藜蘆醇抗糖尿病視網膜病變靶點蛋白的蛋白互作（PPI）網絡，并篩選出核心作用靶點。使用DAVID數據庫對白藜蘆醇抗糖尿病視網膜病變靶點基因進行基因本體（GO）和京都基因與基因組百科全書（KEGG）通路富集分析。對核心作用靶點與白藜蘆醇結合力進行分子對接驗證。利用細胞活力實驗觀察白藜蘆醇對高糖作用下的人視網膜血管內皮細胞（HRCECs）細胞增殖的影響；檢測不同濃度（40、80、160 μmol/L）白藜蘆醇對高糖作用下HRCECs細胞STAT3、VEGFA、TNF mRNA表達的影響。結果 共獲得白藜蘆醇抗糖尿病視網膜病變作用靶點130個，并篩選出核心靶基因10個。KEGG途徑分析富集的信號通路包括TNF信號通路、HIF-1信號通路、FoxO信號通路等。分子對接顯示，核心靶基因AKT1、IL-6、TNF、VEGFA、IL-1B、MAPK3、EGFR、JUN、STAT3及CASP3與白藜蘆醇親和力較好，尤其與STAT3、VEGFA和TNF具有強烈的結合活性。細胞實驗顯示，與模型組相比，白藜蘆醇能明顯抑制高糖作用下HRCECs的細胞增殖能力（P＜0.05、0.01）。同時能明顯降低高糖作用下HRCECs細胞STAT3、VEGFA、TNF mRNA表達（P＜0.05、0.01）。結論 白藜蘆醇治療糖尿病視網膜病變具有多靶點、多途徑的特點。白藜蘆醇可能通過作用于VEGFA、AKT1、CASP3、IL-6、STAT3、EGFR、TNF、和MAPK3等核心靶點基因，影響TNF信號通路和HIF信號通路等發(fā)揮對糖尿病視網膜病變的治療作用。

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.

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河南省醫(yī)學科技攻關計劃(聯(lián)合共建)項目(LHGJ20190492)