基于整合药理学平台的桂枝-白芍药对抗脓毒症的分子机制研究
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摘要
桂枝汤属于解表剂,为中医经典复方,临床上治疗脓毒症的疗效确切。但由于经方的复杂性,其抗脓毒症的机制难以明确,"桂枝-白芍"药对为调和营卫经典配伍,是桂枝汤的核心,该研究以桂枝-白芍为研究对象,借助整合药理学平台(TCMIP,http://www.tcmip.cn/),进行桂枝-白芍化学成分分析、疾病靶标预测、基因功能和通路富集分析,并建立"中药-化学成分-核心靶标-关键通路"的多维网络关系,对桂枝-白芍治疗脓毒症的作用机制进行探讨。"桂枝-白芍"药对预测结果表明桂枝-白芍药对抗脓毒症主要与45个化学成分相关,其活性成分可针对多个靶点、多条通路发挥抗脓毒症的作用,其作用涉及PF4,MyD88,TLR4,BDKRB2,CD14,NOS3等炎症靶标,主要通过Toll样受体信号通路、叉头转录因子Fox O信号通路、趋化因子信号通路等炎症通路、甲状腺素、胰岛素信号通路等代谢通路、催产素信号通路、雌激素信号通路等与内分泌系统相关通路来调节脓毒症。该研究为进一步开发桂枝-白芍药对及桂枝汤抗脓毒症的作用机制提供了科学依据。
Guizhi Decoction is a resolving agent,which is a classic prescription for traditional Chinese medicine. It is effective in the treatment of sepsis in clinical practice. However,due to the complexity of the prescription,its anti-sepsis mechanism is difficult to be clarified. The " Cinnamomi Ramulus-Paeoniae Radix Alba" drug pair,as the classic compatibility for medicinal and medicinal herbs,is the core of Guizhi Decoction. In this study,Cinnamomi Ramulus-Paeoniae Radix Alba drug pair was used as the research object and the molecular mechanism of its treatment of sepsis was investigated by analyzing the chemical compositions with integrative pharmacology platform( TCMIP,http://www.tcmip.cn/),predicting disease target,analyzing gene function and pathway of " Cinnamomi Ramulus-Paeoniae Radix Alba" in treatment of sepsis,and establishing a multi-dimensional network relationship of " Chinese medicine-chemical components-core targets-key pathways". The prediction results of " Cinnamomi Ramulus-Paeoniae Radix Alba" drug pair showed that its anti-sepsis effect was associated with 45 active components,and the active components played an anti-sepsis role through multiple targets and pathways,involving inflammatory targets such as PF4,MyD88,TLR4,BDKRB2,CD14,and NOS3. The sepsis was relieved mainly by regulating Toll like signaling pathway,Fox O signaling pathway,chemokines signaling pathway,thyroid and insulin endocrine signaling pathways and biological processes. This study provides a scientific basis for further development of Cinnamomi Ramulus-Paeoniae Radix Alba drug pair and Guizhi Decoction against sepsis.
Guizhi Decoction is a resolving agent,which is a classic prescription for traditional Chinese medicine. It is effective in the treatment of sepsis in clinical practice. However,due to the complexity of the prescription,its anti-sepsis mechanism is difficult to be clarified. The " Cinnamomi Ramulus-Paeoniae Radix Alba" drug pair,as the classic compatibility for medicinal and medicinal herbs,is the core of Guizhi Decoction. In this study,Cinnamomi Ramulus-Paeoniae Radix Alba drug pair was used as the research object and the molecular mechanism of its treatment of sepsis was investigated by analyzing the chemical compositions with integrative pharmacology platform( TCMIP,http://www.tcmip.cn/),predicting disease target,analyzing gene function and pathway of " Cinnamomi Ramulus-Paeoniae Radix Alba" in treatment of sepsis,and establishing a multi-dimensional network relationship of " Chinese medicine-chemical components-core targets-key pathways". The prediction results of " Cinnamomi Ramulus-Paeoniae Radix Alba" drug pair showed that its anti-sepsis effect was associated with 45 active components,and the active components played an anti-sepsis role through multiple targets and pathways,involving inflammatory targets such as PF4,MyD88,TLR4,BDKRB2,CD14,and NOS3. The sepsis was relieved mainly by regulating Toll like signaling pathway,Fox O signaling pathway,chemokines signaling pathway,thyroid and insulin endocrine signaling pathways and biological processes. This study provides a scientific basis for further development of Cinnamomi Ramulus-Paeoniae Radix Alba drug pair and Guizhi Decoction against sepsis.
引文
[1]师灵灵,韩艳秋,任慧娟,等.脓毒症的病理生理机制研究进展[J].中华医院感染学杂志,2016,26(8):1914.
[2]姚咏明,张艳敏.脓毒症发病机制最新认识[J].医学研究生学报,2017,30(7):678.
[3]赵建刚.脓毒症及感染性休克患者的治疗现状[J].中国处方药,2018,16(10):13.
[4]胡路明,吴俊林,吴建鹏.传统医学“整体观”在脓毒症诊治中的运用及拓展[J].安徽医药,2018,22(8):1591.
[5]韩娟,周大勇,武慧,等.中医药干预对脓毒症患者预后相关指标的影响[J].中国中医急症,2014,23(11):2006.
[6]杨广,李健,常卫东.活血法治疗脓毒症肠功能障碍的理论探讨[J].中国中西医结合消化杂志,2017(12):986.
[7]刘清泉.中医对脓毒症的认识及辩证体系的研究[C].成都:全国危重病急救医学学术会议,2004.
[8]陈畅,程锦堂,刘安.经典名方研发策略[J].中国中药杂志,2017,42(9):1814.
[9]许海玉,杨洪军.整合药理学:中药现代研究新模式[J].中国中药杂志,2014,39(3):357.
[10]袁海建,李卫,金建明,等.桂枝汤化学成分、药理作用机制与临床应用研究进展[J].中国中药杂志,2017,42(23):4556.
[11]徐锋,王德健,王凤,等.桂枝挥发油的药理作用研究进展[J].中华中医药杂志,2016,31(11):4653.
[12]徐锋.基于NLRP3炎症小体通路桂枝抗炎有效部位抗炎作用机制研究[D].成都:成都中医药大学,2017.
[13]谢长江,谢富华,张珊珊,等.白芍总苷对大鼠脓毒症的抗炎作用及机制研究[J].现代医药卫生,2012,28(16):2417.
[14]周丽芳.芍药苷对SD大鼠脓毒症性急性肝损伤模型Nrf2/γ-GCS表达的影响[D].衡阳:南华大学,2015.
[15]林乐清,金光勇.脓毒症心肌抑制发病机制的分子研究进展[J].医学研究杂志,2017,46(9):195.
[16]潘子木,胡占升.脓毒症模型大鼠心肌损伤不同时期线粒体功能的变化[J].解放军医学杂志,2018,43(10):849.
[17]王凤新,张博,白秀萍.脓毒症心肌损伤机制研究进展[J].内科急危重症杂志,2018(5):437.
[18]师灵灵,韩艳秋,任慧娟,等.脓毒症的病理生理机制研究进展[J].中华医院感染学杂志,2016,26(8):1914.
[19]张莹,马晓娟,史大卓.冠心病瘀毒理论与血小板-血栓-炎症网络[J].中国中西医结合杂志,2018,38(3):375.
[20]张晓军,刘健,万磊,等.基于细胞因子调控血小板活化观察新风胶囊改善佐剂关节炎大鼠肺功能机制[J].中医药临床杂志,2018,30(9):1637.
[21]陈珵,徐侃.血小板在炎症反应中作用的研究进展[J].海南医学,2017,28(4):623.
[22]江磊.脓毒症患者血小板TLR4表达变化与血小板活化的关系及对预后的影响研究[J].中国医学前沿杂志:电子版,2015,7(9):76.
[23]马丽萍,魏菁,常建星,等.血小板TLR4表达介导LPS诱导的血小板活化[J].中国实验血液学杂志,2009,17(6):1564.
[24] Ghosh M,Subramani J,Rahman M M,et al. CD13 restricts TLR4 endocytic signal transduction in inflammation[J]. J Immunol,2015,194(9):4466.
[25]阚诗云,邓兆岿,邱占军.中药调节TLR4信号通路治疗脓毒症肺损伤的研究进展[J].中国中医急症,2018,27(10):1866.
[26]谢展利.血浆高分子量激肽原在内毒素血症中致病作用的初步研究[D].苏州:苏州大学,2013.
[27] Saleh A,Stathopoulou M G,DadéS,et al. Angiogenesis related genes NOS3,CD14,MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults[J]. BMC Med Genet,2015,16:90.
[28]田慈,谢苗荣.脓毒症心肌损伤机制的研究进展[J].临床和实验医学杂志,2013,12(2):148.
[29]李岩.白芍及其化学成分的药理研究进展[J].职业与健康,2015,31(15):2153.
[30]蒋静,赵宇亮,付平.脓毒症性急性肾损伤与线粒体功能障碍[J].肾脏病与透析肾移植杂志,2018,27(2):187.
[31]李宏山,张玉想.脓毒症与神经内分泌[J].中华临床医师杂志:电子版,2013,7(7):3126.
[32]屈万明,杨朝晖.脓毒症时骨骼肌代谢机制的研究进展[J].医学综述,2013,19(2):249.
[33]刘敏.脓毒症患儿胰岛素抵抗程度与全身炎症反应、靶器官损伤的相关性[J].海南医学院学报,2017,23(11):1559.
[34]徐建波,张丽莉,王艺磊,等.海洋无脊椎动物甲状腺激素信号通路的研究进展[J].生物技术通报,2014(10):23.
[35]冯博,房玉涛,徐瑞山.桂枝汤的现代临床应用及作用机制研究进展[J].中国中药杂志,2018,43(12):2442.
[36] Musilova I,Andrys C,Drahosova M,et al. Late preterm prelabor rupture of fetal membranes:fetal inflammatory response and neonatal outcome[J]. Pediatr Res,2018,83(3):630.
[37] Serafim R,Gomes J A,Salluh J,et al. A comparison of the Quick-SOFA and systemic inflammatory response syndromecriteria for the diagnosis of sepsis and prediction of mortality:a systematic review and Meta-analysis[J]. Chest,2018,153(3):646.
[38]赵保胜,刘洪斌,马悦颖,等.桂枝汤含药血清对小鼠巨噬细胞Toll样受体3、4型及其下游信号转导通路元件的影响[J].中药药理与临床,2007,23(3):1.
[39]刘杰,陈琳,范彩荣,等.基于HPLC-DAD-Q-TOF-MS/MS的白芍和赤芍主要成分定性定量研究[J].中国中药杂志,2015,40(9):1762.
[40]谢长江,谢富华,张珊珊,等.白芍总苷对大鼠脓毒症的抗炎作用及机制研究[J].现代医药卫生,2012,28(16):2417.
[41]赵国桢,郭玉红,李博.中医药防治脓毒症的研究进展[J].中国中药杂志,2017,42(8):1423.
[2]姚咏明,张艳敏.脓毒症发病机制最新认识[J].医学研究生学报,2017,30(7):678.
[3]赵建刚.脓毒症及感染性休克患者的治疗现状[J].中国处方药,2018,16(10):13.
[4]胡路明,吴俊林,吴建鹏.传统医学“整体观”在脓毒症诊治中的运用及拓展[J].安徽医药,2018,22(8):1591.
[5]韩娟,周大勇,武慧,等.中医药干预对脓毒症患者预后相关指标的影响[J].中国中医急症,2014,23(11):2006.
[6]杨广,李健,常卫东.活血法治疗脓毒症肠功能障碍的理论探讨[J].中国中西医结合消化杂志,2017(12):986.
[7]刘清泉.中医对脓毒症的认识及辩证体系的研究[C].成都:全国危重病急救医学学术会议,2004.
[8]陈畅,程锦堂,刘安.经典名方研发策略[J].中国中药杂志,2017,42(9):1814.
[9]许海玉,杨洪军.整合药理学:中药现代研究新模式[J].中国中药杂志,2014,39(3):357.
[10]袁海建,李卫,金建明,等.桂枝汤化学成分、药理作用机制与临床应用研究进展[J].中国中药杂志,2017,42(23):4556.
[11]徐锋,王德健,王凤,等.桂枝挥发油的药理作用研究进展[J].中华中医药杂志,2016,31(11):4653.
[12]徐锋.基于NLRP3炎症小体通路桂枝抗炎有效部位抗炎作用机制研究[D].成都:成都中医药大学,2017.
[13]谢长江,谢富华,张珊珊,等.白芍总苷对大鼠脓毒症的抗炎作用及机制研究[J].现代医药卫生,2012,28(16):2417.
[14]周丽芳.芍药苷对SD大鼠脓毒症性急性肝损伤模型Nrf2/γ-GCS表达的影响[D].衡阳:南华大学,2015.
[15]林乐清,金光勇.脓毒症心肌抑制发病机制的分子研究进展[J].医学研究杂志,2017,46(9):195.
[16]潘子木,胡占升.脓毒症模型大鼠心肌损伤不同时期线粒体功能的变化[J].解放军医学杂志,2018,43(10):849.
[17]王凤新,张博,白秀萍.脓毒症心肌损伤机制研究进展[J].内科急危重症杂志,2018(5):437.
[18]师灵灵,韩艳秋,任慧娟,等.脓毒症的病理生理机制研究进展[J].中华医院感染学杂志,2016,26(8):1914.
[19]张莹,马晓娟,史大卓.冠心病瘀毒理论与血小板-血栓-炎症网络[J].中国中西医结合杂志,2018,38(3):375.
[20]张晓军,刘健,万磊,等.基于细胞因子调控血小板活化观察新风胶囊改善佐剂关节炎大鼠肺功能机制[J].中医药临床杂志,2018,30(9):1637.
[21]陈珵,徐侃.血小板在炎症反应中作用的研究进展[J].海南医学,2017,28(4):623.
[22]江磊.脓毒症患者血小板TLR4表达变化与血小板活化的关系及对预后的影响研究[J].中国医学前沿杂志:电子版,2015,7(9):76.
[23]马丽萍,魏菁,常建星,等.血小板TLR4表达介导LPS诱导的血小板活化[J].中国实验血液学杂志,2009,17(6):1564.
[24] Ghosh M,Subramani J,Rahman M M,et al. CD13 restricts TLR4 endocytic signal transduction in inflammation[J]. J Immunol,2015,194(9):4466.
[25]阚诗云,邓兆岿,邱占军.中药调节TLR4信号通路治疗脓毒症肺损伤的研究进展[J].中国中医急症,2018,27(10):1866.
[26]谢展利.血浆高分子量激肽原在内毒素血症中致病作用的初步研究[D].苏州:苏州大学,2013.
[27] Saleh A,Stathopoulou M G,DadéS,et al. Angiogenesis related genes NOS3,CD14,MMP3 and IL4R are associated to VEGF gene expression and circulating levels in healthy adults[J]. BMC Med Genet,2015,16:90.
[28]田慈,谢苗荣.脓毒症心肌损伤机制的研究进展[J].临床和实验医学杂志,2013,12(2):148.
[29]李岩.白芍及其化学成分的药理研究进展[J].职业与健康,2015,31(15):2153.
[30]蒋静,赵宇亮,付平.脓毒症性急性肾损伤与线粒体功能障碍[J].肾脏病与透析肾移植杂志,2018,27(2):187.
[31]李宏山,张玉想.脓毒症与神经内分泌[J].中华临床医师杂志:电子版,2013,7(7):3126.
[32]屈万明,杨朝晖.脓毒症时骨骼肌代谢机制的研究进展[J].医学综述,2013,19(2):249.
[33]刘敏.脓毒症患儿胰岛素抵抗程度与全身炎症反应、靶器官损伤的相关性[J].海南医学院学报,2017,23(11):1559.
[34]徐建波,张丽莉,王艺磊,等.海洋无脊椎动物甲状腺激素信号通路的研究进展[J].生物技术通报,2014(10):23.
[35]冯博,房玉涛,徐瑞山.桂枝汤的现代临床应用及作用机制研究进展[J].中国中药杂志,2018,43(12):2442.
[36] Musilova I,Andrys C,Drahosova M,et al. Late preterm prelabor rupture of fetal membranes:fetal inflammatory response and neonatal outcome[J]. Pediatr Res,2018,83(3):630.
[37] Serafim R,Gomes J A,Salluh J,et al. A comparison of the Quick-SOFA and systemic inflammatory response syndromecriteria for the diagnosis of sepsis and prediction of mortality:a systematic review and Meta-analysis[J]. Chest,2018,153(3):646.
[38]赵保胜,刘洪斌,马悦颖,等.桂枝汤含药血清对小鼠巨噬细胞Toll样受体3、4型及其下游信号转导通路元件的影响[J].中药药理与临床,2007,23(3):1.
[39]刘杰,陈琳,范彩荣,等.基于HPLC-DAD-Q-TOF-MS/MS的白芍和赤芍主要成分定性定量研究[J].中国中药杂志,2015,40(9):1762.
[40]谢长江,谢富华,张珊珊,等.白芍总苷对大鼠脓毒症的抗炎作用及机制研究[J].现代医药卫生,2012,28(16):2417.
[41]赵国桢,郭玉红,李博.中医药防治脓毒症的研究进展[J].中国中药杂志,2017,42(8):1423.