异甘草素治疗糖尿病脑病的网络药理学分析和实验验证

Network Pharmacology Analysis and Experimental Verification of Isoliquiritigenin for the Treatment of Diabetic Encephalopathy

  • 摘要:
      目的  基于网络药理学分析和体外实验探讨异甘草素(Isoliquiritigenin, ILG)治疗糖尿病脑病(Diabetic encephalopathy, DE)的作用机制。
      方法  利用HERB数据库和SwissTargetPrediction数据库预测ILG的作用靶点, 再通过GeneCards、OMIM和PharmGkb获取DE相关疾病靶点, 并通过Venny软件获得ILG作用靶点与DE相关疾病靶点的交集靶点; 借助STRING数据库绘制PPI网络, 使用Cytoscape 3.9.1软件筛选出核心靶点; 利用R 4.0.3软件进行GO功能和KEGG信号通路富集分析; 最后使用分子对接技术和体外实验进行验证。
      结果  共筛选出65个ILG-DE交集靶点; 通过拓扑分析, 得到8个核心靶点为EGFR、ESR1、PTGS2、PPARG、GSK3β、CDK2、PIK3R1和F3。GO功能和KEGG通路富集分析显示LIG抗DE涉及多个生物学过程, 影响多种细胞组分和分子功能, 如对脂多糖的反应、蛋白磷酸化、蛋白激酶活性、蛋白丝氨酸/苏氨酸/酪氨酸激酶活性等。涉及的信号通路包括PI3K-Akt信号通路、癌症中的蛋白多糖信号通路、内分泌抵抗通路等。分子对接结果显示8个核心靶点与ILG均有较好的结合, 其中GSK3β与ILG的结合能为-7.22 kcal·mol-1。体外实验表明ILG可以改善SH-SY5Y细胞高糖损伤, 并激活P13K/AKT/GSK3β信号通路。
      结论  ILG可能通过作用于GSK3β调控P13K/AKT/GSK3β信号通路, 进而改善DE。

     

    Abstract:
      OBJECTIVE  This study aims to elucidate the mechanism of action of Isoliquiritigenin (ILG) in the treatment of Diabetic Encephalopathy (DE) based on network pharmacological analysis and in-vitro experiments.
      METHODS  The potential targets of ILG were predicted using the HERB database and SwissTargetPrediction database. DE-associated disease targets were obtained from GeneCards, OMIM, and PharmGkb, and the intersecting targets between ILG and DE were identified using the Venny software. A PPI network was constructed using the STRING database, and core targets were screened out using Cytoscape software. GO function and KEGG pathway enrichment analyses were undertaken using R 4.0.3, followed by validation via molecular docking techniques and in vitro experiments.
      RESULTS  65 intersecting targets between ILG and DE were identified in this study. Topological analysis yielded eight core targets namely, EGFR, ESR1, PTGS2, PPARG, GSK3β, CDK2, PIK3R1, and F3. GO function and KEGG pathway enrichment analyses revealed that ILG antagonizes DE through several biological processes which impact numerous cellular components and molecular functions such as response to lipopolysaccharides, protein phosphorylation, protein kinase activity, and serine/threonine/tyrosine kinase activity. Pathways implicated included the PI3K-Akt signaling pathway, protein polysaccharide signaling pathway in cancer, and endocrine resistance pathway. The molecular docking results showed that all eight core targets had a good binding with ILG, especially with GSK3β, with a binding energy of -7.22 kcal·mol-1. In vitro experiments indicated that ILG could improve high glucose-induced cell damage and activate the PI3K/AKT/GSK3β signaling pathway.
      CONCLUSION  ILG is likely to exert its effects on GSK3β to regulate the PI3K/AKT/GSK3β signaling pathway, thereby alleviating DE.

     

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