作者：李佳，何俊，刘福明

单位：

1.213000江苏省常州市德安医院康复中心 2.210029江苏省南京市，南京中医药大学附属医院 江苏省中医院心血管内科 通信作者：何俊，E-mail：hj197874@126.com

单位（英文）：

1.Department of Rehabilitation, Dean Hospital of Changzhou, Changzhou 213000, China 2.Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine/Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China Corresponding author: HE Jun, E-mail: hj197874@126.com

关键词：

动脉粥样硬化; 亚临床动脉粥样硬化; 绞股蓝; 虎杖; 网络药理学; 分子对接技术;

关键词（英文）：

Atherosclerosis; Subclinical atherosclerosis; Gynostemma pentaphyllum; Fallopia japonica; Networkpharmacology; Molecular docking

中图分类号：

DOI：

10.12114/j.issn.1008-5971.2022.00.327

基金项目：

江苏省重点研发计划项目（BE2020683）

摘要：

目的 基于网络药理学与分子对接技术探讨绞股蓝-虎杖治疗亚临床动脉粥样硬化（Sub-AS）的潜在分子机制。方法 通过中药系统药理学数据库和分析平台筛选绞股蓝、虎杖的活性成分及靶点，通过Genecards、OMIM数据库筛选Sub-AS相关靶点，通过Venny在线平台获取绞股蓝-虎杖治疗Sub-AS的潜在靶点，通过STRING 11.5构建蛋白质-蛋白质相互作用（PPI）网络并进行拓扑分析以筛选绞股蓝-虎杖治疗Sub-AS的关键靶点；之后针对绞股蓝-虎杖治疗Sub-AS的关键靶点进行GO功能富集分析和KEGG通路富集分析，构建药物活性成分-疾病靶点-通路网络；最后通过Auto Dock vina V1.2.0和Py Mol对筛选出的绞股蓝-虎杖核心活性成分与核心疾病靶点进行分子对接。结果 本研究共得到绞股蓝、虎杖活性成分24种，靶点208个；Sub-AS相关靶点1 321个。最终得到97个绞股蓝-虎杖治疗Sub-AS的潜在靶点。构建PPI网络并进行拓扑分析，结果显示，肿瘤坏死因子（TNF）、白介素（IL）6、IL4、IL10、IL1B、血管内皮生长因子（VEGF）A、基质金属蛋白酶（MMP）9、CXCL8、CCL2、细胞间黏附分子（ICAM）1、RELA是绞股蓝-虎杖治疗SubAS的关键靶点。GO功能富集分析结果显示，细胞组成条目91个，主要包括膜筏、受体复合体、外侧细胞膜、细胞外基质等；分子功能条目128个，主要包括信号受体调节活动、氧化还原反应等；生物过程条目253个，主要包括正调控细胞运动、调控细胞附着、负调控细胞分化等。KEGG通路富集分析结果显示，绞股蓝-虎杖治疗Sub-AS的关键靶点主要参与的通路是TNF信号通路、IL-17信号通路等。药物活性成分-疾病靶点-通路网络显示，度值最高的药物活性成分是槲皮素，其次为木犀草素、β-谷甾醇；度值最高的疾病靶点是HSP90AB1，其次是PTGS2、RELA、TNF、IL6、IL1B、ICAM1；富集的通路主要包括IL-17信号通路和癌症通路，其次是脂质和动脉硬化、流体剪切应力与动脉粥样硬化。分子对接结果显示，槲皮素-TNF、槲皮素-PTGS2、木犀草素-PTGS2、木犀草素-ICAM1、木犀草素-HSP90AB1的对接模式较好。结论绞股蓝-虎杖抗Sub-AS的主要活性成分有槲皮素、木犀草素、β-谷甾醇等，其可作用于TNF、IL6等多个靶点，通过调控IL-17信号通路、TNF信号通路等发挥作用。

英文摘要：

【Abstract】　Objective To explore the potential molecular mechanism of gynostemma pentaphyllum and fallopia japonica in the treatment of subclinical atherosclerosis (Sub-AS) based on network pharmacology and molecular docking. Methods The active components and targets of gynostemma pentaphyllum and fallopia japonica were screened through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the Sub-AS related targets were screened through the Genecards and OMIM databases, and the potential targets of gynostemma pentaphyllum and fallopia japonica in the treatment of Sub-AS were obtained through the Venny online platform. Protein-protein interaction (PPI) network was constructed by STRING 11.5 and topological analysis was constructed to screen key targets of gynostemma pentaphyllum and fallopia japonica in the treatment of Sub-AS. After that, GO functional enrichment analysis and KEGG pathway enrichment analysis were performed on the key targets of gynostemma pentaphyllum and fallopia japonica in the treatment of Sub-AS, and the drug active component-disease target-pathway network was constructed. Finally, molecular docking between the screened core active components of gynostemma pentaphyllum and fallopia japonica and core disease targets was performed by AutoDock vina V1.2.0 and PyMol. Results A total of 24 active components and 208 related targets of gynostemma pentaphyllum and fallopia japonica, and 1 321 Sub-AS-related targets were obtained. Finally, there were 97 potential targets of gynostemma pentaphyllum and fallopia japonica in the treatment of Sub-AS. PPI network was constructed and topological analysis was performed, and the results showed that tumor necrosis factor (TNF) , interleukin (IL) 6, IL4, IL10, IL1B, vascular endothelial growth factor (VEGF) A , matrix metalloproteinase (MMP) 9 , CXCL8, CCL2, intercellular adhesion molecule (ICAM) 1, and RELA were the key targets of gynostemma pentaphyllum and fallopia japonica in the treatment of Sub-AS. GO function enrichment analysis results showed that there were 91 cell composition items, mainly including membrane rafts, receptor complexes, lateral cell membranes, extracellular matrix, etc; there were 128 molecular function items, mainly involving signal receptor regulatory activities, redox reactions, etc; there were 253 biological process items, mainly including positive regulation of cell movement, regulation of cell attachment, negative regulation of cell differentiation, etc. KEGG pathway enrichment analysis results showed that the main pathways involved in key targets of gynostemma pentaphyllum and fallopia japonica in the treatment of Sub-AS were TNF signaling pathway and the IL-17 signaling pathway. The drug active component-disease target-pathway network showed that the drug active component with the highest degree value was quercetin, followed by luteolin and β-sitosterol; the disease target with the highest degree value was HSP90AB1, followed by PTGS2, RELA, TNF, IL6, IL1B, ICAM1; the enriched pathways mainly included the IL-17 signaling pathway and the cancer pathway, followed by lipid and arteriosclerosis, fluid shear stress and atherosclerosis. The molecular docking results showed that the docking modes of quercetin-TNF, quercetin-PTGS2, luteolin-PTGS2, luteolin-ICAM1 and luteolin-HSP90AB1 were better. Conclusion The main active components of gynostemma pentaphyllum and fallopia japonica against in the treatment of Sub-AS are quercetin, luteolin, β-sitosterol, etc, which can act on multiple targets such as TNF and IL6, and play a role by regulating IL-17 signal pathway and TNF signal pathway.

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