药学学报, 2019, 54(11): 1990-1999
引用本文:
李珊, 吕明, 杨剑, 鲍兴茹, 肖光旭, 朱彦. 活性筛选和网络分析初步阐释常用活血化瘀中药抗血小板黏附的分子机制[J]. 药学学报, 2019, 54(11): 1990-1999.
LI Shan, L� Ming, YANG Jian, BAO Xing-ru, XIAO Guang-xu, ZHU Yan. Exploring molecular mechanisms of anti-platelet adhesion of Chinese medicine for promoting blood circulation and removing blood stasis by activity screen and network analysis[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 1990-1999.

活性筛选和网络分析初步阐释常用活血化瘀中药抗血小板黏附的分子机制
李珊1,3, 吕明1,2,3, 杨剑1,3, 鲍兴茹1, 肖光旭1,3, 朱彦1,3
1. 天津中医药大学, 天津市现代中药重点实验室, 天津 300193;
2. 中国中医科学院中药研究所, 北京 100700;
3. 天津国际生物医药联合研究院, 中药新药研发中心, 天津 300457
摘要:
血小板黏附是血栓形成的关键环节,活血化瘀中药具有良好的抗血小板黏附作用,但其药效差异和机制尚不明晰。本文结合活性筛选、用药分析、通路聚类、靶点预测和分子对接方法,初步阐释常用活血化瘀中药抗血小板黏附的分子机制。发现58种市售活血化瘀中成药中约50.0%显著抑制二磷酸腺苷(adenosine diphosphate,ADP)诱导的体外血小板黏附,约96.6%显著抑制凝血酶诱导的体外血小板黏附。所涉及的动物实验获得天津国际生物医药联合研究院动物伦理委员会批准。结合中医传承辅助平台(V2.0)对活性排前20的中成药用药规律分析发现丹参-川芎配伍使用最为频繁。生物反应信号网络分析(ingenuity pathway analysis,IPA)揭示白细胞介素-1(interleukin-1,IL-1)、淀粉样前体蛋白(amyloid precursorprotein,APP)和CC类趋化因子配体2(C-C motif ligand 2,CCL2)为丹参-川芎抗血小板黏附的关键靶点,而动脉粥样硬化、神经炎症和趋化因子信号通路为主要机制,并运用分子对接技术进一步验证了靶点CCL2与丹参-川芎中共有的活性化合物绿原酸间相互作用。该研究为活血化瘀类中药抗血小板和抗血栓治疗提供一定的理论依据和临床参考。
关键词:    血小板黏附      活血化瘀中药      活性筛选      网络分析      丹参-川芎     
Exploring molecular mechanisms of anti-platelet adhesion of Chinese medicine for promoting blood circulation and removing blood stasis by activity screen and network analysis
LI Shan1,3, L� Ming1,2,3, YANG Jian1,3, BAO Xing-ru1, XIAO Guang-xu1,3, ZHU Yan1,3
1. Tianjin Modern Medicine Key Laboratory of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China;
2. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China;
3. Tianjin International Biomedical Research Institute, Chinese Medicine New Drug Research and Development Center, Tianjin 300457, China
Abstract:
Platelet adhesion is a key process in thrombosis. Anti-platelet adhesion effect of some Chinese medicines for promoting blood circulation and removing blood stasis (PBCRBS) has been reported, but their relative efficacies as a whole and specific targets remained unclear. This paper combined activity screening, drug compatibility analysis, pathway clustering, target prediction, and molecular docking to explore the mechanism of anti-platelet adhesion by PBCRBS Chinese medicine. Screening the activity of anti-platelet adhesion of 58 commercially available PBCRBS Chinese patent medicines showed that about 50.0% significantly inhibit ADP-induced platelet adhesion in vitro, and about 96.6% significantly inhibit thrombin-induced platelet adhesion in vitro. The animal experiment involved was approved by the Animal Ethics Committee of Tianjin International Biomedical Research Institute. Combined with the auxiliary platform for TCM (V2.0) inheritance showed that the compatibility of Danshen-Chuanxiong was used most frequently among the top 20 active proprietary Chinese patent medicines. IPA network analysis revealed that IL-1, APP and CCL2 might be the key targets for anti-platelet adhesion function of Danshen-Chuanxiong against atherosclerosis, neuroinflammation and chemokine signaling pathways as the main mechanisms. Molecular docking analysis confirmed the interaction between one of the active compounds shared by Danshen and Chuanxiong, i.e. chlorogenic acid, with its target CCL2. This study provides TCM theory guidance and experimental support for targeting platelet adhesion in anti-thrombosis therapy by Chinese medicine for promoting blood circulation and removing blood stasis.
Key words:    platelet adhesion    Chinese medicine for promoting blood circulation and removing blood stasis    activity screening    network analysis    Danshen-Chuanxiong   
收稿日期: 2019-04-18
DOI: 10.16438/j.0513-4870.2019-0297
基金项目: 国家自然科学基金资助项目(81274128,81873037);国家重点研发计划(2018YFC1704500).
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