丹参饮治疗糖尿病心肌病的网络药理学研究
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摘要
目的通过整合网络药理学和生物信息学方法,构建活性成分-作用靶点、蛋白-蛋白相互作用(PPI)、关键靶点相应的生物功能和通路网络,预测丹参饮治疗糖尿病心肌病的分子作用机制。方法采用中药系统药理学数据库和分析平台(TCMSP)数据库筛选及预测丹参饮的生物活性成分及其潜在作用靶点,同时检索PharmGKB等4个数据库挖掘糖尿病心肌病的相关靶点,对2种靶点进行PPI网络构建,交互处理得到丹参饮治疗糖尿病心肌病的关键靶点,并利用SystemsDock WebSite对其进行分子对接验证;运用DAVID(Version 6.8)平台对关键靶点进行Pathway分析,结合Omicshare数据库筛选核心通路并利用Reactome数据库进行注释。结果以口服生物利用度(OB)和类药性(DL)数值作为筛选标准,从丹参饮中共获得78个活性成分,涉及到506个丹参饮治疗糖尿病心肌病的可能靶点,这些靶点主要富集在磷脂酰肌醇3-激酶/蛋白激酶B(PI3K-Akt)、丝裂原活化蛋白激酶(MAPK)等多条信号通路上。结论本研究揭示了丹参饮治疗糖尿病心肌病可能的作用机制,体现了中药复方多成分、多靶点、多途径治疗疾病的特点,为进一步深入研究其作用机制提供了新思路。
Objective Based on the network pharmacology and bioinformatics methods, the networks of active components-targets,protein-protein interactions, and the corresponding biological functions and pathways of key targets were established to predict the molecular mechanism of Danshen Decoction in the treatment of diabetic cardiomyopathy. Methods TCMSP database was used to screen and predict the bioactive components of Danshen Decoction and potential targets. Four databases including PharmGKB were searched for related targets of diabetic cardiomyopathy. The PPI network was constructed for the two types of targets. The key targets were obtained by interactive processing and verified by molecular docking by SystemsDock Web Site. Pathway analysis was performed on the key targets using the DAVID platform(Version 6.8), and the core pathway was screened by Omicshare database and annotated by using Reactome database. Results Taking oral bioavailability(OB) and drug-like(DL) as screening criteria, 78 active ingredients were screened from Danshen Decoction, involving 506 potential targets for treating of diabetic cardiomyopathy. These targets were mainly rich in PI3 K-Akt, MAPK and other signaling pathways. Conclusion This study reveals the possible mechanism of Danshen Decoction in the treatment of diabetic cardiomyopathy, embodying the characteristics of multi-component, multi-target and multi-channel of Traditional Chinese Medicine compound, which provides a new idea for further research on its mechanism of action.
Objective Based on the network pharmacology and bioinformatics methods, the networks of active components-targets,protein-protein interactions, and the corresponding biological functions and pathways of key targets were established to predict the molecular mechanism of Danshen Decoction in the treatment of diabetic cardiomyopathy. Methods TCMSP database was used to screen and predict the bioactive components of Danshen Decoction and potential targets. Four databases including PharmGKB were searched for related targets of diabetic cardiomyopathy. The PPI network was constructed for the two types of targets. The key targets were obtained by interactive processing and verified by molecular docking by SystemsDock Web Site. Pathway analysis was performed on the key targets using the DAVID platform(Version 6.8), and the core pathway was screened by Omicshare database and annotated by using Reactome database. Results Taking oral bioavailability(OB) and drug-like(DL) as screening criteria, 78 active ingredients were screened from Danshen Decoction, involving 506 potential targets for treating of diabetic cardiomyopathy. These targets were mainly rich in PI3 K-Akt, MAPK and other signaling pathways. Conclusion This study reveals the possible mechanism of Danshen Decoction in the treatment of diabetic cardiomyopathy, embodying the characteristics of multi-component, multi-target and multi-channel of Traditional Chinese Medicine compound, which provides a new idea for further research on its mechanism of action.
引文
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[29]周静,李惠芬,王洪志,等.丹参水溶性成分与脂溶性成分抑菌作用的考察[J].时珍国医国药,2008,19(9):2130-2131.
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[32]李显辉.丹参素对高糖环境下心肌细胞的保护作用及其机制[J].山东医药,2016,56(45):48-50.
[33]颜仁梁,林励.檀香的研究进展[J].中药新药与临床药理,2003,5(3):218-220.
[34]倪青,汪升薏,黄静.益气活血中药对糖尿病心肌病大鼠心肌细胞凋亡的影响[J].北京中医药,2016,36(6):560-563.
[35]张明发,沈雅琴.砂仁临床药理作用的研究进展[J].抗感染药学,2013,10(1):8-13.
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[37]艾文,谢培益,陈延伟,等.EGFR在大鼠1型糖尿病心肌病纤维化作用的实验研究[J].心血管康复医学杂志,2013,22(3):219-222.
[38]Dittrich E,Schmaldienst S,Soleiman A,et al.Rapamycinassociated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy[J].Transpl Inter,2010,17(4):215-220.
[39]孙晓慧,王燕,牟艳玲.2型糖尿病大鼠心肌PI3K/Akt/mTOR信号通路的改变及Sirt1的调控机制研究[J].中国药理学通报,2017,33(6):793-798.
[40]王文聪,谢春毅.丝裂原活化蛋白激酶MAPK信号通路与糖尿病心肌病关系的研究进展[J].当代医学,2016,22(14):8-10.
[41]赵青,万毅刚,王朝俊,等.慢性肾脏病肾组织炎症信号通路p38MAPK的调节机制及中药的干预作用[J].中国中药杂志,2012,37(12):1700-1704.
[42]王学敏,张慧,安聪,等.Wnt信号通路对中枢神经系统再生修复的作用及中医药研究近况[J].中医药临床杂志,2018,30(8):1386-1390.
[43]蒋晓蕊,苗琳,吴晓燕,等.丹参酮IIA对心血管系统保护作用及机制的研究进展[J].中国当代医药,2014,21(14):183-185.
[44]张凯,储全根,毕华剑,等.抵当汤对糖尿病大鼠心肌组织JAK2/STAT3信号通路的影响[J].安徽中医药大学学报,2016,35(2):65-69.
[45]黄岸清.基于PI3K/Akt/FoxO3a通路白藜芦酵保护糖尿病心肌病大鼠心功能的机制研究[D].广州:南方医科大学,2017.
[2]Kannel W B,McGee D L.Diabetes and cardiovascular disease.The Framingham study[J].JAMA,1979,241(19):2035-2038.
[3]赵富花,刘永刚,何进来.丹参饮的临床新用途[J].时珍国医国药,2005,16(2):160-161.
[4]程肖蕊,周文霞,张永祥.网络药理学实验研究相关技术[J].中国药理学与毒理学杂志,2012,26(2):131-137.
[5]Zhang Y Q,Mao X,Guo Q Y,et al.Network pharmacology-based approaches capture essence of Chinese herbal medicines[J].Chin Herb Med,2016,8(2):107-116.
[6]Hur K Y,Kim S H,Choi M,et al.Protective effects of magnesium lithospermate B against diabetic atherosclerosis via Nrf2-ARE-NQO1 transcriptional pathway[J].Atherosclerosis,2010,211(1):69-76.
[7]Qu J,Ren X,Hou R Y,et al.The protective effect of magnesium lithospermate B against glucose-induced intracellular oxidative damage[J].Biochem Biophys Res Commun,2011,411(1):32-39.
[8]Abourashed E A,El-Alfy A T.Chemical diversity and pharmacological significance of the secondary metabolites of nutmeg(Myristica fragrans Houtt.)[J].Phytochem Rev Proceed Phytochem Soc Eur,2016,doi:10.1007/s11101-016-9469-x.
[9]Vinothkumar V,Manoharan S,Nirmal M R,et al.Geraniol modulates cell proliferation,apoptosis,inflammation,and angiogenesis during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis[J].Mol Cell Biochem,2012,369(1/2):17-25.
[10]El-Ghorab A H,Nauman M,Anjum F M.A comparative study on chemical composition and antioxidant activity of ginger(Zingiber officinale)and cumin(Cuminum cyminum)[J].J Agric Food Chem,2010,58(14):8231-8237.
[11]Kim J H,Lee H J,Jeong S J,et al.Essential oil of Pinus koraiensis leaves exerts antihyperlipidemic effects via up-regulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A:Cholesterol acyltransferase[J].Phytother Res,2012,26(9):1314-1319.
[12]Zhong Z,Chen X,Tan W,et al.Germacrone inhibits the proliferation of breast cancer cell lines by inducing cell cycle arrest and promoting apoptosis[J].Eur JPharmacol,2011,667(1):50-55.
[13]Barrero A F,Herrador M M,del Moral J F Q,et al.Efficient synthesis of the anticancerβ-elemene and other bioactive elemanes from sustainable germacrone[J].Org Biomol Chem,2011,9(4):1118-1125.
[14]Liu Z L,Zhao N N,Liu C M,et al.Identification of insecticidal constituents of the essential oil of Curcuma wenyujin rhizomes active against Liposcelis bostrychophila Badonnel[J].Molecules,2012,17(10):12049-12060.
[15]Emiliya C,Voja P,Andrija S,et al.The effect of camphor and borneol on rat thymocyte viability and oxidative stress[J].Molecules,2012,17(9):10258-10266.
[16]Octavio J G,Baccarelli A A,Hyang-Min B,et al.CYP2E1 epigenetic regulation in chronic,low-level toluene exposure:Relationship with oxidative stress and smoking habit[J].Toxicol Appl Pharmacol,2015,286(3):207-215.
[17]Anas S,Anton A,Resmi M.Identification of compounds in the essential oil of Nutmeg seeds(Myristica fragrans Houtt.)that inhibit locomotor activity in mice[J].Inter JMol Sci,2010,11(11):4771-4781.
[18]Rui F,Hong J C,Yi W X,et al.Insecticidal activity of essential oil of Carum Carvi fruits from China and its main components against two grain storage insects[J].Molecules,2010,15(12):9391-9402.
[19]Jiang X P,Tang J Y,Xu Z,et al.Sulforaphane attenuates di-N-butylphthalate-induced reproductive damage in pubertal mice:Involvement of the Nrf2-antioxidant system[J].Environ Toxicol,2017,32(7):1908-1917.
[20]Hatano V Y,Torricelli A S,Giassi A C C,et al.Anxiolytic effects of repeated treatment with an essential oil from Lippia alba and(R)-(-)-carvone in the elevated T-maze[J].Braz J Med Biol Res,2012,45(3):238-243.
[21]Neto J D N,Almeida A A C D,Oliveira J D S,et al.Antioxidant effects of nerolidol in mice hippocampus after open field test[J].Neurochem Res,2013,38(9):1861-1870.
[22]Battiprolu P K,Gillette T G,Wang Z V,et al.Diabetic cardiomyopathy:Mechanisms and therapeutic targets[J].Drug Discov Today,2010,7(2):e135-e143.
[23]梁隽婷,胡淑宏,邢国利.益气养阴活血法治疗糖尿病性心脏病疗效观察[J].中医药信息,2003,20(3):39.
[24]Peng J,Lu R,Deng H W,et al.Involvement ofα-calcitonin gene-related peptide in monophosphoryl lipid A-induced delayed preconditioning in rat hearts[J].Eur JPharmacol,2002,436(1):89-96.
[25]罗彩莲.丹参的药理作用与临床应用[J].中国当代医药,2012,19(12):11-12.
[26]何长国.血府逐瘀汤配合西药治疗冠心病心绞痛34例[J].中国临床保健杂志,2007,10(2):185-186.
[27]杨庆福,李彩玲,陈俭,等.复方丹参滴丸对冠心病心绞痛患者血管内皮功能的影响[J].新乡医学院学报,2003,20(2):127-128.
[28]孙学刚,贾钰华,陈育尧.定心方及丹参酮对血小板膜粘附分子表达的影响[J].山东中医药大学学报,2001,25(1):61-63.
[29]周静,李惠芬,王洪志,等.丹参水溶性成分与脂溶性成分抑菌作用的考察[J].时珍国医国药,2008,19(9):2130-2131.
[30]李彩蓉,甘受益,黄红霞.丹参酮IIA磺酸钠对2型糖尿病大鼠心肌的保护作用[J].湖北科技学院学报:医学版,2014,28(6):466-468.
[31]臧慧梅.丹酚酸B通过PPARα抑制2型糖尿病小鼠的心肌肥厚[D].济南:山东大学,2017.
[32]李显辉.丹参素对高糖环境下心肌细胞的保护作用及其机制[J].山东医药,2016,56(45):48-50.
[33]颜仁梁,林励.檀香的研究进展[J].中药新药与临床药理,2003,5(3):218-220.
[34]倪青,汪升薏,黄静.益气活血中药对糖尿病心肌病大鼠心肌细胞凋亡的影响[J].北京中医药,2016,36(6):560-563.
[35]张明发,沈雅琴.砂仁临床药理作用的研究进展[J].抗感染药学,2013,10(1):8-13.
[36]李翔.基于网络药理学的芪参益气方抗心肌缺血整合作用研究[D].杭州:浙江大学,2014.
[37]艾文,谢培益,陈延伟,等.EGFR在大鼠1型糖尿病心肌病纤维化作用的实验研究[J].心血管康复医学杂志,2013,22(3):219-222.
[38]Dittrich E,Schmaldienst S,Soleiman A,et al.Rapamycinassociated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy[J].Transpl Inter,2010,17(4):215-220.
[39]孙晓慧,王燕,牟艳玲.2型糖尿病大鼠心肌PI3K/Akt/mTOR信号通路的改变及Sirt1的调控机制研究[J].中国药理学通报,2017,33(6):793-798.
[40]王文聪,谢春毅.丝裂原活化蛋白激酶MAPK信号通路与糖尿病心肌病关系的研究进展[J].当代医学,2016,22(14):8-10.
[41]赵青,万毅刚,王朝俊,等.慢性肾脏病肾组织炎症信号通路p38MAPK的调节机制及中药的干预作用[J].中国中药杂志,2012,37(12):1700-1704.
[42]王学敏,张慧,安聪,等.Wnt信号通路对中枢神经系统再生修复的作用及中医药研究近况[J].中医药临床杂志,2018,30(8):1386-1390.
[43]蒋晓蕊,苗琳,吴晓燕,等.丹参酮IIA对心血管系统保护作用及机制的研究进展[J].中国当代医药,2014,21(14):183-185.
[44]张凯,储全根,毕华剑,等.抵当汤对糖尿病大鼠心肌组织JAK2/STAT3信号通路的影响[J].安徽中医药大学学报,2016,35(2):65-69.
[45]黄岸清.基于PI3K/Akt/FoxO3a通路白藜芦酵保护糖尿病心肌病大鼠心功能的机制研究[D].广州:南方医科大学,2017.