基于整合药理学的中药质量标志物发现与应用
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摘要
中药质量标志物是中药质量控制的新概念、新模式,将引领中药质量发展新方向。其中,如何表征中药整体质量属性及其生物学效应,是质量标志物研究的关键科学问题。针对此关键科学问题,本文提出基于整合药理学的中药质量标志物发现与确证的研究思路,即通过"化学指纹-代谢指纹-网络靶标-生物效应-中医功效"多维关联系统筛选候选中药质量标志物,在此基础上,基于"肠吸收-活性评价-数据挖掘"体系建立中药质量标志物与生物活性之间精确定量模型并明确其贡献度。以元胡止痛片和心速宁胶囊为案例,介绍基于整合药理学的中药质量标志物的研究进展。
Quality marker( Q-marker) is a new concept and pattern for quality control of traditional Chinese medicine( TCM),which will lead the development direction for quality control of TCM. Among them,how to characterize the overall quality attribute of TCM and its biological effect,is a critical scientific problem in the study of Q-marker. In this paper,integrated pharmacology is utilized to screen out and confirm the Q-marker from the complex system of TCM,so as to solve the critical scientific problem. System biology in vivo is firstly applied to establish the correlation of chemical fingerprints of TCM,their metabolic fingerprints,network targets,biological effects and efficacy of TCM,which is used to preliminary screen out Q-marker of TCM. Following that,a pharmacological method in vitro,including intestinal absorption in vitro coupled with bioactivity assessment,is employed to simultaneously determine the absorbed doses of TCM and evaluate their biological activity.Furthermore,data mining is utilized to establish the exact quantitative mathematic model between Q-marker of TCM and bioactivity. Meanwhile, two representative examples, including Yuanhu Zhitong tablets, Xinsuning capsules,are introduced to identify Q-marker of TCM and establish their quality standards related with bioactivity,which will be beneficial to improve the level of quality control of TCM and ensure the effectiveness and safety of clinical applications.
Quality marker( Q-marker) is a new concept and pattern for quality control of traditional Chinese medicine( TCM),which will lead the development direction for quality control of TCM. Among them,how to characterize the overall quality attribute of TCM and its biological effect,is a critical scientific problem in the study of Q-marker. In this paper,integrated pharmacology is utilized to screen out and confirm the Q-marker from the complex system of TCM,so as to solve the critical scientific problem. System biology in vivo is firstly applied to establish the correlation of chemical fingerprints of TCM,their metabolic fingerprints,network targets,biological effects and efficacy of TCM,which is used to preliminary screen out Q-marker of TCM. Following that,a pharmacological method in vitro,including intestinal absorption in vitro coupled with bioactivity assessment,is employed to simultaneously determine the absorbed doses of TCM and evaluate their biological activity.Furthermore,data mining is utilized to establish the exact quantitative mathematic model between Q-marker of TCM and bioactivity. Meanwhile, two representative examples, including Yuanhu Zhitong tablets, Xinsuning capsules,are introduced to identify Q-marker of TCM and establish their quality standards related with bioactivity,which will be beneficial to improve the level of quality control of TCM and ensure the effectiveness and safety of clinical applications.
引文
[1]刘昌孝,陈士林,肖小河,等.中药质量标志物(Q-Marker):中药产品质量控制的新概念[J].中草药,2016,47(9):1443-1457.
[2]LIU C X,CHEGN Y Y,GUO D A,et al.A new concept on quality marker for quality assessment and process control of Chinese medicines[J].Chin Herb Med,2017,9(1):3-13.
[3]闫广利,孙晖,张爱华,等.基于中医方证代谢组学的中药质量标志物发现研究[J].中草药,2018,49(16):3729-3734.
[4]刘妍如,唐志书,宋忠兴,等.多元统计及“成分-靶点-疾病”在线关联分析脑心通胶囊中质量标志物[J].中草药,2018,49(12):2775-2785.
[5]张铁军,白钢,陈常青,等.基于“五原则”的复方中药质量标志物(Q-marker)研究路径[J].中草药,2018,49(1):1-13.
[6]张铁军,许浚,申秀萍,等.基于中药质量标志物(Q-Marker)的元胡止痛滴丸的“性-效-物”三元关系和作用机制研究[J].中草药,2016,47(13):2199-2211.
[7]刘昌孝.中药药物代谢动力学研究思路与实践[M].北京:科学出版社,2013.
[8]孙蓉,李晓宇,王亮,等.基于“效-毒”相关的Q-marker合理辨识与科学控制[J].世界科学技术-中医药现代化,2016,18(8):1224-1231.
[9]LIAO M L,SHANG H H,LI Y Z,et al.An integrated approach to uncover quality marker underlying the effects of Alisma orientale on lipid metabolism,using chemical analysis and network pharmacology[J].Phytomedicine,2018,45:93-104.
[10]XIANG W,SUO T C,YU H,et al.A new strategy for choosing"Q-markers"via network pharmacology,application to the quality control of a Chinese medical preparation[J].J Food Drug Anal,2018,26(2):858-868.
[11]黄璐琦,郭兰萍,胡娟,等.道地药材形成的分子机制及其遗传基础[J].中国中药杂志,2008,33(20):2303-2308.
[12]郭兰萍,刘俊英,吉力,等.茅苍术道地药材挥发油组成特征分析[J].中国中药杂志,2002,27(11):814-819.
[13]黄璐琦,张瑞贤.“道地药材”的生物学探讨[J].中国药学杂志,1997,32(9):563-566.
[14]黄璐琦,钱丹,邓超.双分子标记法的构建及在中药研究中的应用[J].中国中药杂志,2015,40(2):165-168.
[15]吴婉莹,果德安.中药整体质量控制标准体系构建的思路与方法[J].中国中药杂志,2014,39(3):351-356.
[16]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):357-362.
[17]杨洪军,许海玉.整合药理学---元胡止痛方的探索[M].北京:科学出版社,2015.
[18]王萍,唐仕欢,苏瑾,等.基于整合药理学的中药现代研究进展[J].中国中药杂志,2018,43(7):1297-1302.
[19]Bostr9m J,Hogner A,Schmitt S.Do structurally similar ligands bind in a similar fashion?[J].J Med Chem,2006,49(23):6716-6725.
[20]CHENG T,WANG Y,Bryant S H.Investigating the correlations among the chemical structures,bioactivity profiles and molecular targets of small molecules[J].Bioinformatics,2010,26(22):2881-2888.
[21]Schufenhauer A,Floersheim P,Acklin P,et al.Similarity metrics for ligands relecting the similarity of the target proteins[J].J Chem Inf Comput Sci,2003,43(2):391-405.
[22]吴雪松,许浚,张喜民,等.元胡止痛方的化学成分及药理作用研究进展[J].中草药,2015,46(7):1081-1095.
[23]刘昌孝.我国药物代谢动力学研究的发展及其对创新药物研发的重要作用[J].中国药理学与毒理学杂志,2015,29(5):686-687.
[24]LI Y,WANG Y,TAI W,et al.Challenges and solutions of pharmacokinetics for efficacy and safety of traditional Chinese medicine[J].Curr Drug Metab,2015,16(9):765-776.
[25]WANG X Y,LI W,MA X H,et al.Simultaneous determination of caffeic acid and its major pharmacologically active metabolites in rat plasma by LC-MS/MS and its application in pharmacokinetic study[J].Biomed Chromatogr,2015,29(4):552-559.
[26]ZHANG Y C,XU H Y,CHEN X M,et al.Study on the application of intestinal absorption in vitro coupled with bioactivity assessment in Yuanhu Zhitong preparation[J].J Med Plants Res,2012,6(10):1941-1947.
[27]黄斌,陈晓萌,张迎春,等.元胡止痛方肠吸收液对大鼠离体胸主动脉环张力的影响[J].中国实验方剂学杂志,2012,18(5):117-120.
[28]ZHANG F B,HUANG B,ZHAO Y,et al.BNC protects H9c2 cardiomyoblasts from H2O2-induced oxidative injury through ERK1/2 signaling pathway[J].Evid Based Complement Alternat Med,2013,doi:10.1155/2013/802784.
[29]ZHANG J J,GENG Y,GUO F F,et al.Screening and identification of critical transcription factors involved in the protection of cardiomyocytes against hydrogen peroxide-induced damage by Yixin-shu[J].Sci Rep,2017,7(1):13867.
[30]赵筱萍,范骁辉,余杰,等.一类基于组效关系神经网络模型的中药药效预测方法[J].中国中药杂志,2004,29(11):1082-1085.
[31]李振坤,陈建新,杨洪军,等.基于LARS算法的川芎成分组合与血管活性关系分析[J].中国实验方剂学杂志,2009,15(3):24-26.
[32]XU H Y,LI K,CHEN Y J,et al.Study on the absorbed fingerprint-efficacy of Yuanhu Zhitong tablet based on chemical analysis,vasorelaxation evaluation and data mining[J].PLo S One,2013,8(12):e81135.
[33]许海玉,唐仕欢,陈建新,等.基于代谢组学的中药“组效关系”研究思路与策略[J].世界科学技术-中医药现代化,2011,13(1):30-35.
[34]任建勋,范晓迪,刘建勋.双参芎连颗粒对Apo E基因敲除小鼠动脉粥样硬化炎症反应的干预作用[J].中国实验方剂学杂志,2017,23(24):106-111.
[35]肖小河,鄢丹,袁海龙,等.基于成分敲除/敲入的中药药效组分辨识与质量控制模式的商建[J].中草药,2009,40(9):1345-1348.
[36]XU H Y,ZHANG Y C,TAO Y,et al.Study of chemical fingerprint for Yuanhu Zhitong tablet by UPLC/Q-TOF-MS[J].J Liq Chromatogr R T,2013,36(6):807-820.
[37]ZHANG Y C,XU H Y,CHEN X M,et al.Simultaneous quantification of 17 constituents from Yuanhu Zhitong tablet using rapid resolution liquid chromatography coupled with a triple quadrupole electro spray tandem mass spectrometry[J].J Pharm Biomed Anal,2011,56(3):497-504.
[38]TAO Y,XU H,WANG S,et al.Identification of the absorbed constituents after oral administration of Yuanhu Zhitong prescription extract and its pharmacokinetic study by rapid resolution liquid chromatography/quadrupole time-of-flight[J].J Chromatogr B Analyt Technol Biomed Life Sci,2013,935(2):1-9.
[39]WANG P,ZHANG T L,YU G H,et al.Polypharmacokinetic strategy-delineated metabolic fate of bioactive compounds in a traditional Chinese medicine formula,Yuanhu Zhitong tablets,using parallel reaction monitoring mode[J].Phytomedicine,2018,53:53-61.
[40]XU H,TAO Y,LU P,et al.A computational drug-target network for yuanhu zhitong prescription[J].Evid Based Complement Alternat Med,2013,doi:10.1155/2013/658531.
[41]LI K,LI J,SU J,et al.Identification of quality markers of Yuanhu Zhitong tablets based on integrative pharmacology and data mining[J].Phytomedicine,2018,44:212-219.
[42]GUO R,ZHANG X,SU J,et al.Identifying potential quality markers of Xin-Su-Ning capsules acting on arrhythmia by integrating UHPLC-LTQ-Orbitrap,ADMEprediction and network target analysis[J].Phytomedicine,2018,44:117-128.
[2]LIU C X,CHEGN Y Y,GUO D A,et al.A new concept on quality marker for quality assessment and process control of Chinese medicines[J].Chin Herb Med,2017,9(1):3-13.
[3]闫广利,孙晖,张爱华,等.基于中医方证代谢组学的中药质量标志物发现研究[J].中草药,2018,49(16):3729-3734.
[4]刘妍如,唐志书,宋忠兴,等.多元统计及“成分-靶点-疾病”在线关联分析脑心通胶囊中质量标志物[J].中草药,2018,49(12):2775-2785.
[5]张铁军,白钢,陈常青,等.基于“五原则”的复方中药质量标志物(Q-marker)研究路径[J].中草药,2018,49(1):1-13.
[6]张铁军,许浚,申秀萍,等.基于中药质量标志物(Q-Marker)的元胡止痛滴丸的“性-效-物”三元关系和作用机制研究[J].中草药,2016,47(13):2199-2211.
[7]刘昌孝.中药药物代谢动力学研究思路与实践[M].北京:科学出版社,2013.
[8]孙蓉,李晓宇,王亮,等.基于“效-毒”相关的Q-marker合理辨识与科学控制[J].世界科学技术-中医药现代化,2016,18(8):1224-1231.
[9]LIAO M L,SHANG H H,LI Y Z,et al.An integrated approach to uncover quality marker underlying the effects of Alisma orientale on lipid metabolism,using chemical analysis and network pharmacology[J].Phytomedicine,2018,45:93-104.
[10]XIANG W,SUO T C,YU H,et al.A new strategy for choosing"Q-markers"via network pharmacology,application to the quality control of a Chinese medical preparation[J].J Food Drug Anal,2018,26(2):858-868.
[11]黄璐琦,郭兰萍,胡娟,等.道地药材形成的分子机制及其遗传基础[J].中国中药杂志,2008,33(20):2303-2308.
[12]郭兰萍,刘俊英,吉力,等.茅苍术道地药材挥发油组成特征分析[J].中国中药杂志,2002,27(11):814-819.
[13]黄璐琦,张瑞贤.“道地药材”的生物学探讨[J].中国药学杂志,1997,32(9):563-566.
[14]黄璐琦,钱丹,邓超.双分子标记法的构建及在中药研究中的应用[J].中国中药杂志,2015,40(2):165-168.
[15]吴婉莹,果德安.中药整体质量控制标准体系构建的思路与方法[J].中国中药杂志,2014,39(3):351-356.
[16]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):357-362.
[17]杨洪军,许海玉.整合药理学---元胡止痛方的探索[M].北京:科学出版社,2015.
[18]王萍,唐仕欢,苏瑾,等.基于整合药理学的中药现代研究进展[J].中国中药杂志,2018,43(7):1297-1302.
[19]Bostr9m J,Hogner A,Schmitt S.Do structurally similar ligands bind in a similar fashion?[J].J Med Chem,2006,49(23):6716-6725.
[20]CHENG T,WANG Y,Bryant S H.Investigating the correlations among the chemical structures,bioactivity profiles and molecular targets of small molecules[J].Bioinformatics,2010,26(22):2881-2888.
[21]Schufenhauer A,Floersheim P,Acklin P,et al.Similarity metrics for ligands relecting the similarity of the target proteins[J].J Chem Inf Comput Sci,2003,43(2):391-405.
[22]吴雪松,许浚,张喜民,等.元胡止痛方的化学成分及药理作用研究进展[J].中草药,2015,46(7):1081-1095.
[23]刘昌孝.我国药物代谢动力学研究的发展及其对创新药物研发的重要作用[J].中国药理学与毒理学杂志,2015,29(5):686-687.
[24]LI Y,WANG Y,TAI W,et al.Challenges and solutions of pharmacokinetics for efficacy and safety of traditional Chinese medicine[J].Curr Drug Metab,2015,16(9):765-776.
[25]WANG X Y,LI W,MA X H,et al.Simultaneous determination of caffeic acid and its major pharmacologically active metabolites in rat plasma by LC-MS/MS and its application in pharmacokinetic study[J].Biomed Chromatogr,2015,29(4):552-559.
[26]ZHANG Y C,XU H Y,CHEN X M,et al.Study on the application of intestinal absorption in vitro coupled with bioactivity assessment in Yuanhu Zhitong preparation[J].J Med Plants Res,2012,6(10):1941-1947.
[27]黄斌,陈晓萌,张迎春,等.元胡止痛方肠吸收液对大鼠离体胸主动脉环张力的影响[J].中国实验方剂学杂志,2012,18(5):117-120.
[28]ZHANG F B,HUANG B,ZHAO Y,et al.BNC protects H9c2 cardiomyoblasts from H2O2-induced oxidative injury through ERK1/2 signaling pathway[J].Evid Based Complement Alternat Med,2013,doi:10.1155/2013/802784.
[29]ZHANG J J,GENG Y,GUO F F,et al.Screening and identification of critical transcription factors involved in the protection of cardiomyocytes against hydrogen peroxide-induced damage by Yixin-shu[J].Sci Rep,2017,7(1):13867.
[30]赵筱萍,范骁辉,余杰,等.一类基于组效关系神经网络模型的中药药效预测方法[J].中国中药杂志,2004,29(11):1082-1085.
[31]李振坤,陈建新,杨洪军,等.基于LARS算法的川芎成分组合与血管活性关系分析[J].中国实验方剂学杂志,2009,15(3):24-26.
[32]XU H Y,LI K,CHEN Y J,et al.Study on the absorbed fingerprint-efficacy of Yuanhu Zhitong tablet based on chemical analysis,vasorelaxation evaluation and data mining[J].PLo S One,2013,8(12):e81135.
[33]许海玉,唐仕欢,陈建新,等.基于代谢组学的中药“组效关系”研究思路与策略[J].世界科学技术-中医药现代化,2011,13(1):30-35.
[34]任建勋,范晓迪,刘建勋.双参芎连颗粒对Apo E基因敲除小鼠动脉粥样硬化炎症反应的干预作用[J].中国实验方剂学杂志,2017,23(24):106-111.
[35]肖小河,鄢丹,袁海龙,等.基于成分敲除/敲入的中药药效组分辨识与质量控制模式的商建[J].中草药,2009,40(9):1345-1348.
[36]XU H Y,ZHANG Y C,TAO Y,et al.Study of chemical fingerprint for Yuanhu Zhitong tablet by UPLC/Q-TOF-MS[J].J Liq Chromatogr R T,2013,36(6):807-820.
[37]ZHANG Y C,XU H Y,CHEN X M,et al.Simultaneous quantification of 17 constituents from Yuanhu Zhitong tablet using rapid resolution liquid chromatography coupled with a triple quadrupole electro spray tandem mass spectrometry[J].J Pharm Biomed Anal,2011,56(3):497-504.
[38]TAO Y,XU H,WANG S,et al.Identification of the absorbed constituents after oral administration of Yuanhu Zhitong prescription extract and its pharmacokinetic study by rapid resolution liquid chromatography/quadrupole time-of-flight[J].J Chromatogr B Analyt Technol Biomed Life Sci,2013,935(2):1-9.
[39]WANG P,ZHANG T L,YU G H,et al.Polypharmacokinetic strategy-delineated metabolic fate of bioactive compounds in a traditional Chinese medicine formula,Yuanhu Zhitong tablets,using parallel reaction monitoring mode[J].Phytomedicine,2018,53:53-61.
[40]XU H,TAO Y,LU P,et al.A computational drug-target network for yuanhu zhitong prescription[J].Evid Based Complement Alternat Med,2013,doi:10.1155/2013/658531.
[41]LI K,LI J,SU J,et al.Identification of quality markers of Yuanhu Zhitong tablets based on integrative pharmacology and data mining[J].Phytomedicine,2018,44:212-219.
[42]GUO R,ZHANG X,SU J,et al.Identifying potential quality markers of Xin-Su-Ning capsules acting on arrhythmia by integrating UHPLC-LTQ-Orbitrap,ADMEprediction and network target analysis[J].Phytomedicine,2018,44:117-128.
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