基于整合药理学平台探究三棱抗血栓形成及抗血小板聚集的分子机制
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摘要
目的:探讨三棱抗血小板聚集及抗血栓形成的分子机制。方法:利用中药整合药理学平台(TCM-IP)的中药材数据库、中药成分数据库和疾病靶标数据库的数据信息和分析功能,检索三棱所含的化学成分信息,构建三棱作用的潜在靶标和疾病靶标之间的相互作用网络,然后富集计算核心靶标,进行基因功能分析和通路分析,再进一步构建"中药材-化学成分-核心靶标-关键通路"多维关系网络。结果:对三棱预测活性成分主要包括黄酮、酚酸等成分,如山柰酚、三棱酸等;抗血栓形成涉及202个核心靶标,包括蛋白激酶Cδ(PRKCD),葡萄糖激酶(GCK),腺嘌呤核糖核苷酸活化蛋白激酶α-2催化亚基等;涉及内分泌系统、循环系统、神经退行性疾病等相关生物过程和信号通路。抗血小板聚集涉及136个核心靶标,包括PRKCD,细胞色素C氧化酶蛋白7C(COX7C),GCK等;涉及帕金森病、循环系统、神经退行性疾病等相关生物过程和信号通路。结论:三棱主要通过调控中枢神经系统的神经递质活性达到调节血管内皮细胞黏附分子表达以及血小板线粒体功能介导血小板的凋亡,从而发挥抗血栓形成及抗血小板聚集的药效作用。
Objective: To study on the molecular mechanism of anti-platelet aggregation and antithrombosis of Sparganii Rhizoma. Method: Based on the data information and analysis functions of traditional Chinese medicine(TCM) database, TCM composition database and target database in TCM platform for integration of pharmacology,information of chemical compositions in Sparganii Rhizoma was retrieved,interaction network between potential targets of Sparganii Rhizoma and disease targets was built,and the key targets were enriched and calculated,the gene functions and pathways were analyzed,multidimensional relationship network of " herbal medicines-chemical components-key targets-key pathways " was built. Result: Active ingredients of Sparganii Rhizoma mainly included flavonoids and phenolic acids,such as mountain kaempferol,sanleng acid,linoleic acid,etc. Anti-thrombosis involved 202 key targets,including protein kinase Cδ(PRKCD),glucose kinase(GCK),(PRKAA2),adenosine ribonucleotide activated protein kinase α-2 catalytic subunit,etc; and it was related to the endocrine system,circulatory system,neurodegenerative diseases and other related biological processes and signal pathways. Anti-platelet aggregation involved 136 key targets,including PRKCD,cytochrome C oxidase protein 7 C(COX7 C),GCK,etc; and it was involved in Parkinson's disease,circulatory system,neurodegenerative diseases and other related biological processes and signal pathways. Conclusion: Sparganii Rhizoma regulates vascular endothelial cell adhesion molecule expression and platelet mitochondrial function mediated apoptosis of platelets mainly through regulating neurotransmitter activity in the central nervous system,in order to exert antithrombotic effect and anti-platelet aggregation effect.
Objective: To study on the molecular mechanism of anti-platelet aggregation and antithrombosis of Sparganii Rhizoma. Method: Based on the data information and analysis functions of traditional Chinese medicine(TCM) database, TCM composition database and target database in TCM platform for integration of pharmacology,information of chemical compositions in Sparganii Rhizoma was retrieved,interaction network between potential targets of Sparganii Rhizoma and disease targets was built,and the key targets were enriched and calculated,the gene functions and pathways were analyzed,multidimensional relationship network of " herbal medicines-chemical components-key targets-key pathways " was built. Result: Active ingredients of Sparganii Rhizoma mainly included flavonoids and phenolic acids,such as mountain kaempferol,sanleng acid,linoleic acid,etc. Anti-thrombosis involved 202 key targets,including protein kinase Cδ(PRKCD),glucose kinase(GCK),(PRKAA2),adenosine ribonucleotide activated protein kinase α-2 catalytic subunit,etc; and it was related to the endocrine system,circulatory system,neurodegenerative diseases and other related biological processes and signal pathways. Anti-platelet aggregation involved 136 key targets,including PRKCD,cytochrome C oxidase protein 7 C(COX7 C),GCK,etc; and it was involved in Parkinson's disease,circulatory system,neurodegenerative diseases and other related biological processes and signal pathways. Conclusion: Sparganii Rhizoma regulates vascular endothelial cell adhesion molecule expression and platelet mitochondrial function mediated apoptosis of platelets mainly through regulating neurotransmitter activity in the central nervous system,in order to exert antithrombotic effect and anti-platelet aggregation effect.
引文
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[2]吴纯伟,路丽,梁生旺,等.药物靶标预测技术在中药网络药理学中的应用[J].中国中药杂志,2016,41(3):377-382.
[3]徐男,黄欣,孙蓉,等.与三棱“功效-毒性-物质基础”相关的化学成分、制备工艺和质量控制研究进展[J].中国药房,2016,27(33):4749-4752.
[4]张军武,郭斌,尉亚辉.黑三棱的生物学、药理作用及化学成分研究进展[J].吉林农业大学学报,2012,34(6):639-644.
[5]徐男,曹铭晨,黄欣,等.三棱乙酸乙酯部位HPLC指纹图谱及4种酚类成分含量测定[J].中国医院药学杂志,2017,37(18):1783-1786.
[6]许海玉,刘振明,付岩,等.中药整合药理学计算平台的开发与应用[J].中国中药杂志,2017,42(18):3633-3638.
[7]贾斯达,袁晋青.血栓形成机制和临床抗栓策略的研究进展[J].中国分子心脏病学杂志,2016,16(3):1748-1752.
[8] Chari R,Getz T,Nagy B,et al. Protein kinase Cδdifferentially regulates platelet functional responses[J].Arterioscler Thromb Vasc Biol,2009,29(5):699-705.
[9] TAN M,XU X,Ohba M,et al. Thrombin rapidly induces protein kinase D phosphorylation,and protein kinase C delta mediates the activation[J]. J Biol Chem,2003,278(5):2824-2828.
[10] Bair A M,Thippegowda P B,Freichel M,et al. Ca2+entry via TRPC channels is necessary for thrombininduced NF-kappaB activation in endothelial cells through AMP-activated protein kinase and protein kinase Cδ[J]. J Biol Chem,2009,284(1):563-574.
[11] LI Z,NI J. Role of microRNA-26a in the diagnosis of lower extremity deep vein thrombosis in patients with bone trauma[J]. Exp Ther Med,2017,14(5):5069-5074.
[12] Chee M J,Pissios P,Maratos-Flier E. Neurochemical characterization of neurons expressing melaninconcentrating hormone receptor 1 in the mouse hypothalamus[J]. J Comp Neurol,2013,521(10):2208-2234.
[13] Sanabra C,Mengod G. Neuroanatomical distribution and neurochemical characterization of cells expressing adenylyl cyclase isoforms in mouse and rat brain[J]. J Chem Neuroanat,2011,41(1):43-54.
[14]袁媛.线粒体途径介导血小板凋亡的研究进展[J].医学综述,2014,20(22):4066-4068.
[15]赵丽丽,陈梦醒,张明逸,等.血小板内蛋白激酶C活化诱导血小板发生凋亡[J].中国实验血液学杂志,2013,21(5):1207-1210.
[16]夏乐敏,郑秦,张爱萍,等.线粒体途径在免疫性骨髓衰竭性血小板凋亡中的作用机制研究[J].中国实验血液学杂志,2017,25(1):176-180.
[17]甘卫冬,眭承志.从血管内皮功能探讨雌激素与血瘀关联性的研究[J].中国骨质疏松杂志,2014,20(6):711-713.
[18] Rodilla Fiz A M,GarvíLópez M,Gómez Garrido M.Changes in haemostasis and thrombosis associated with thyroid disease:presentation of 2 cases[J]. Rev Esp Anestesiol Reanim,2016,63(6):357-360.
[19] Basarici I,Belgi A,Yalcinkaya S. Tricuspid valve thrombus:a case report associated with gonadotropinreleasing hormone analogue therapy and review of the literature[J]. Can J Cardiol,2008,24(5):401-403.
[20] LIU S,PAN S,TAN J,et al. Oxytocin inhibits ox-LDLinduced adhesion of monocytic THP-1 cells to human brain microvascular endothelial cells[J]. Toxicol Appl Pharmacol,2017,337:104-110.
[21] WU F,LIU L,ZHOU H. Endothelial cell activation in central nervous system inflammation[J]. J Leukoc Biol,2017,101(5):1119-1132.
[22]孙竞,高静.靶向线粒体抗神经退行性疾病新型药物研究进展[J].国际药学研究杂志,2016,43(1):79-86.
[23]邱洁,邬加佳,郭开华.雌激素对体外大鼠血小板线粒体功能的影响[J].中国老年学杂志,2008(16):1594-1596.
[24] Bódis J,Papp S,Vermes I,et al."Platelet-associated regulatory system(PARS)"with particular reference to female reproduction[J]. J Ovarian Res,2014,doi:10. 1186/1757-2215-7-55.
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[27]田丽莉,朱国福.斑马鱼在中药研究中的应用[J].中国中药杂志,2015,40(5):822-827.
[28]李晓稳,佟玲,李东翔,等斑马鱼神经元损伤模型在养血清脑颗粒质量控制中的应用分析[J].中国实验方剂学杂志,2016,22(9):1-4.
[29]陈志亮.斑马鱼在药物筛选中的应用[J].中国中药杂志,2015,40(7):1235-1239.
[30] QI Y,ZHAO X,LIU H,et al. Identification of a quality marker(Q-marker)of Danhong injection by the Zebrafish thrombosis model[J]. Molecules,2017,22(9):E1443.
[31]宁青,韦英杰,王丹丹,等.斑马鱼药物代谢模型的适用性研究进展[J].中草药,2015,46(8):1231-1236.
[32]韩利文,李智平,何秋霞,等.采用双向验证法和斑马鱼模型探索血管生成相关的内源性代谢物及代谢网络的变化[J].中国药理学与毒理学杂志,2016,30(10):1041-1045.