基于网络药理学探讨人参虎杖复方抗小鼠动脉粥样硬化的作用

作者	单位
李丹丹,王娅,任智雄,贾子君,梅俊,张颖,周庆兵,徐凤芹	1.中国中医科学院西苑医院老年病研究所（北京 100091） 2.中国中医科学院眼科医院急诊科（北京 100040）

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中文摘要:

目的探讨人参虎杖复方对动脉粥样硬化小鼠的干预作用。方法基于网络药理学方法，利用TCMSP、GeneCards、David等数据库和CytoScape 3.6.1软件依次检索、分析人参虎杖复方作用于动脉粥样硬化潜在有效成分、作用靶点及其GO生物功能、KEGG疾病信号通路，并进行可视化展示。实验验证：采用高脂饲料连续喂养ApoE-/-小鼠2个月制备小鼠动脉粥样硬化模型，造模成功后按随机数字表法分为模型组、人参虎杖复方水煎剂组，每组6只；同时6只同期C57/BL6J小鼠作为对照组。以人参10 g和虎杖12 g折算临床等效剂量制备复方水煎剂连续灌胃12周。采用病理染色、ELISA检测血清白介素1β（IL-1β）含量，观察其对小鼠动脉粥样硬化的干预作用。结果人参虎杖复方作用于141个动脉粥样硬化靶点，共有120个潜在有效成分作用于28个核心靶点，其中IL-1β、IL-6、AP-1 转录因子亚基（JUN）、丝裂原活化蛋白激酶1、3、8、14（MAPK1、MAPK3、MAPK8、MAPK14）、单核细胞趋化因子（MCP-1/CCL2）、表皮生长因子（EGF）及受体（EGFR）可能为人参虎杖复方治疗动脉粥样硬化的重要靶点；涉及的生物过程主要包括调控转录因子活性、对血管内皮生长因子刺激的反应、一氧化氮（NO）生物合成过程的正调控、平滑肌细胞增殖的正调控等；涉及的信号通路主要包括NOD样受体信号通路、肿瘤坏死因子（TNF）信号通路、Toll样受体信号通路、磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（Akt）信号通路、HIF-1信号通路、血管内皮生长因子（VEGF）信号通路、MAPK信号通路等。动物实验初步表明：与模型组比较，人参虎杖复方水煎剂可以降低动脉粥样硬化小鼠血清IL-1β含量（P<0.01），减少AS小鼠主动脉斑块部位炎症细胞黏附、增加斑块内胶原纤维稳定性和血管中膜连续性。结论人参虎杖复方可能主要通过作用于炎症靶点，进而调节炎症反应相关信号通路发挥干预动脉粥样硬化的作用。

英文摘要:

Objective To investigate the intervention effect of Ginseng and Polygonum cuspidatum compound in atherosclerosis mice. Methods Based on the network pharmacology method，TCMSP， Gene cards， David and other databases and the software of CytoScape 3.6.1 were used to successively retrieve and analyze the potential effective components， targets， GO biological function and KEGG disease signal pathway of Ginseng and Polygonum cuspidatum compound on atherosclerosis， and then visualized them. Experimental verification： ApoE-/- mice were continuously fed with high-fat diet for 2 months to establish atherosclerosis model in mice. After successful modeling， the rats were divided into model group and Ginseng and Polygonum cuspidatum compound decoction group according to random number table， with 6 rats in each group. Meanwhile， C57/BL6J mice fed at the same time were selected as the control group. The compound water decoction was prepared with 10 g Ginseng and 12 g Polygonum cuspidatum as clinical equivalent dose by gavage for 12 weeks. The content of serum interleukin-1 β（IL-1β） was detected by ELISA，pathological staining was used to observe its intervention effect on atherosclerosis in mice. Results Ginseng and Polygonum cuspidatum compound could act on 141 targets in atherosclerosis， and there were 120 potential effective components can act on 28 core targets， mainly including IL-1β， IL-6， AP-1 transcription factor subunit（JUN）， mitogen-activated protein kinase 1， 3， 8， 14（MAPK1， MAPK3， MAPK8， MAPK14）， monocyte chemokine 1（MCP-1/CCL2）， epidermal growth factor（EGF） and epidermal growth factor receptors（EGFR），which maybe the important targets for the treatment of atherosclerosis with Ginseng and Polygonum cuspidatum compound. The biological processes involved in the 28 core targets mainly include regulatory sequence specific DNA binding transcription factor activity， cell response to vascular endothelial growth factor stimulation， positive regulation of nitric oxide biosynthesis process， positive regulation of smooth muscle cell proliferation. The signal pathways involved include nod like receptor signaling pathway， tumor necrosis factor（TNF）signaling pathway， hypoxia inducible factor 1（HIF-1）signaling pathway， Toll like receptor signaling pathway， phosphatidylinositol 3-kinase（PI3K）-protein kinase B（Akt）signaling pathway， vascular endothelial growth factor（VEGF） signaling pathway， MAPK signaling pathway， etc. Animal experiments preliminarily showed that the decoction of Ginseng and Polygonum cuspidatum compound can significantly reduce the serum IL-β content of atherosclerotic mice（P<0.01）. It could reduce the adhesion of inflammatory cells in the aortic plaque of atherosclerosis mice， increase the stability of collagen fibers in the plaque and the continuity of vascular media. Conclusion Ginseng and Polygonum cuspidatum compound can intervene atherosclerosis mainly by acting on inflammation target and regulating inflammation related signal pathway.

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