三七对糖尿病肾病、糖尿病脑病和糖尿病心肌病“异病同治”的网络药理学作用机制分析

Study on network pharmacological mechanism of "treating different diseases with same method" of Notoginseng Radix et Rhizoma in treating diabetic nephropathy, diabetic encephalopathy and diabetic cardiomyopathy

基于网络药理学方法探究三七对糖尿病肾病、糖尿病脑病和糖尿病心肌病"异病同治"的关键靶标与通路等分子作用机制。通过TCMSP数据库及文献挖掘搜集得到三七化学成分,通过SwissTargetPrediction数据库预测三七潜在靶标,通过OMIM和GeneCards数据库获取糖尿病肾病、糖尿病脑病和糖尿病心肌病靶点,将三七成分靶标分别与疾病靶点取交集,使用Cytoscape构建三七"成分-靶点-疾病"网络,并通过Cytoscape中的ClueGo插件分别对交集靶点进行富集分析,同时通过STRING数据库构建蛋白-蛋白相互作用(PPI)网络,通过Cytoscape进行拓扑参数学分析得到三七治疗3个疾病的共同关键靶点。筛选出三七化学成分166个,成分靶标835个,糖尿病肾病、糖尿病脑病、糖尿病心肌病相关的疾病靶点分别为216,194,230个,得到成分靶标与疾病靶点的交集分别为54,45,57个。通过对交集靶点富集分析发现,三七对糖尿病肾病、糖尿病脑病、糖尿病心肌病"异病同治"的共同关键通路为AGE-RAGE信号通路和FoxO信号通路,共同核心靶标为TNF,STAT3,IL6,VEGFA,MAPK8,CASP3,SIRT1等7个靶点,通过文献查阅的方式对筛选出的核心靶点进行验证,发现分析出的共同核心靶点中TNF,IL6,VEGFA,CASP3,SIRT1已有相关文献报道。此外,共有核心靶点STAT3对应最多的化合物,表明三七中有较多的化合物能对STAT3发挥调节作用。该研究表明三七可能通过调控AGE-RAGE信号通路和FoxO信号通路,作用于TNF,STAT3,IL6,VEGFA,MAPK8,CASP3,SIRT1等靶点,发挥抗糖尿病肾病、糖尿病脑病和糖尿病心肌病的作用,该研究为三七"异病同治"的作用机制提供了参考。

Pharmacology network was used to investigate the common key target and signaling pathway of Notoginseng Radix et Rhizoma in the protection against diabetic nephropathy(DN), diabetic encephalopathy(DE) and diabetic cardiomyopathy(DCM). The chemical components of Notoginseng Radix et Rhizoma were obtained through TCMSP database and literature mining, and SwissTargetPrediction database was used to predict potential targets of Notoginseng Radix et Rhizoma. The disease targets of DN, DE and DCM were obtained through OMIM and GeneCards databases. The overlapped targets of component targets and disease targets of DN, DE and DCM were obtained, and the network of "chemical component-target-disease" was established. The enriched GO and KEGG of the overlapped genes were investigated by using ClueGo plug-in with Cytoscape. At the same time, the PPI network was constructed through STRING database, and the common key targets for the treatment of three diseases by Notoginseng Radix et Rhizoma were obtained through topological parametric mathematical analysis by Cytoscape. A total of 166 chemical components and 835 component targets were screened out from Notoginseng Radix et Rhizoma. Briefly, 216, 194 and 230 disease targets of DN, DE and DCM were collected, respectively. And 54, 45 and 57 overlapped targets were identified when overlapping these disease targets with component targets of Notoginseng Radix et Rhizoma, respectively. Enrichment analysis indicated that the AGE-RAGE signaling pathway and FoxO signaling pathway were the common pathways in the protection of Notoginseng Radix et Rhizoma against DN, DE and DCM. Network analysis of the overlapped targets showed that TNF, STAT3, IL6, VEGFA, MAPK8, CASP3 and SIRT1 were identified as key targets of Notoginseng Radix et Rhizoma against DN, DE and DCM, the selected key targets were verified by literature review, and it was found that TNF, IL6, VEGFA, CASP3 and SIRT1 had been reported in the literature. In addition, there were the most compounds corresponding to the commom core target STAT3, indicating that more compounds in Notoginseng Radix et Rhizoma could regulate STAT3. This study indicated that Notoginseng Radix et Rhizoma potentially protected against DN, DE and DCM through regulating AGE-RAGE signaling pathway and FoxO signaling pathway and 7 common targets including TNF, STAT3, IL6, VEGFA, MAPK8, CASP3 and SIRT1. This study provided a reference for the research of "different diseases with same treatment" and also elucidated the potential mechanism of Notoginseng Radix et Rhizoma against DN, DE and DCM.