比较蛋白质组学研究芪参益气方有效组分的配伍机制
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摘要
芪参益气方由黄芪、丹参、三七和降香四味中药组成,主要用于治疗气虚血瘀型冠心病。该方临床疗效确切,四味药暗合方剂“君臣佐使”配伍规律,但其作用机理尚不甚明晰。本文以蛋白质组学技术为主要研究手段,分别从整体动物水平和细胞水平探讨芪参益气方有效组分的配伍机制。
本文首先应用双向电泳结合激光解析飞行时间质谱的分析方法,分析了芪参益气方给药对大鼠心肌组织蛋白质组的影响,阐述了该方改善能量代谢、保护受损细胞等作用的分子机制。通过比较蛋白质组学方法对全方及各有效组分(黄芪皂苷、丹参酚酸类成分、三七总皂苷和降香挥发油)单独给药情况下的蛋白质组改变进行分析,提出了贡献指数(contribution Index)用于评判各组分在不同作用途径上对全方药效的贡献,发现黄芪和三七表现出主要的恢复能量代谢和线粒体呼吸链功能作用,而丹参则通过改善氧化应激产生心肌保护作用,四个组分均在保护细胞完整结构方面有良好表现,基本揭示了芪参益气方有效组分配伍抗心肌缺血的作用机制,为从分子水平诠释方剂“君”、“臣”、“佐”、“使”配伍理论的现代生物学意义提供了新方法。
其次本文通过双向电泳分析条件优化,建立人脐静脉内皮细胞蛋白质组分析方法,并将其应用于芪参益气方促进人脐静脉内皮细胞增殖的比较蛋白质组学研究。该部分实验从蛋白质水平上初步解释了芪参益气方与增殖相关的作用机理,并且通过对有效组分单独作用的蛋白质组分析,初步发现了芪参益气方的作用主要与黄芪降低能量消耗,黄芪、三七、降香促进血管生成,以及丹参的抗氧化、抗粘附作用相关,探讨了芪参益气方有效组分促进人脐静脉内皮细胞增殖的配伍机制。
本文首次采用蛋白质组学技术对芪参益气方以及各有效组分的作用进行研究,并且采用贡献指数的归纳方式,提出了该方可能的配伍机制,证明了蛋白质组学技术在中药方剂分子机制和配伍理论研究中的可行性和适用性。
QI-SHEN-YI-QI formula(QSYQ),made from Panax notoginseng,Radix Salvia miltiorrhiza Bge,Radix Astragalus membranaceus Bge and Dalbergia odorifera T.Chen, is an traditional Chinese prescription for treating 'Qi-deficiency,blood stasis' coronary heart disease in China.This herbal remedy exerts remarkable therapeutical efficacy in clinical,however reliable scientific evidences are still too rare to elucidate the veracity and safety of it.To improve the understanding of the molecular processes and mechanisms afford by QSYQ and its components,the proteomics technology was used as a main research tool on both animal and cell levels.
Firstly,two-dimensional electrophoresis(2DE) with matrix-assisted laser desorption/ionization mass spectrometry(MALDI-MS) was used to study differential protein profiles of myocardium during the acute ischemia period after the treatment of QSYQ,and it was suggested the molecular mechanism of energy metabolism improvements and injured cell protections.Compared the protein profiles with treatment of QSYQ and effective components(saponins from Radix Astragalus membranaceus,phenolic acids from Salvia miltiorrhiza,ginsenosides from Radix Panax notoginseng,and essential oils from Dalbergia sissoo) in comparative proteomic approach,a contribution index was proposed to reflect how much contribution of individual agent on protein expression response to the overall prescription.It basically revealed the anti-ischemic mechanism of QSYQ effective components,and provided a new method to explain the modern biology meaning of action mechanism of Chinese prescription from the molecular level.
Secondly,suitable proteomic analysis methods was established by optimizing 2DE conditions,and applied to proteomics research of promoting proliferation of human umbilical vein endothelial cell(HUVEC) with QSYQ treatment.It preliminarily illustrated the QSYQ-related proliferation mechanism from the protein level,and initially approached the synergistic effects of effective components in this formula,with the different protein expressions in single treatments.
In this paper,comparative proteomic approach was firstly used for the mechanism study of QSYQ and effective components.Then,a contribution index was proposed for inducting the synergistic effects of the formula.The finding suggested comparative proteomic approach can be a useful tool to identify potential targets of Chinese prescription and illustrate the mechanisms of action of drug synergistic effects.
本文首先应用双向电泳结合激光解析飞行时间质谱的分析方法,分析了芪参益气方给药对大鼠心肌组织蛋白质组的影响,阐述了该方改善能量代谢、保护受损细胞等作用的分子机制。通过比较蛋白质组学方法对全方及各有效组分(黄芪皂苷、丹参酚酸类成分、三七总皂苷和降香挥发油)单独给药情况下的蛋白质组改变进行分析,提出了贡献指数(contribution Index)用于评判各组分在不同作用途径上对全方药效的贡献,发现黄芪和三七表现出主要的恢复能量代谢和线粒体呼吸链功能作用,而丹参则通过改善氧化应激产生心肌保护作用,四个组分均在保护细胞完整结构方面有良好表现,基本揭示了芪参益气方有效组分配伍抗心肌缺血的作用机制,为从分子水平诠释方剂“君”、“臣”、“佐”、“使”配伍理论的现代生物学意义提供了新方法。
其次本文通过双向电泳分析条件优化,建立人脐静脉内皮细胞蛋白质组分析方法,并将其应用于芪参益气方促进人脐静脉内皮细胞增殖的比较蛋白质组学研究。该部分实验从蛋白质水平上初步解释了芪参益气方与增殖相关的作用机理,并且通过对有效组分单独作用的蛋白质组分析,初步发现了芪参益气方的作用主要与黄芪降低能量消耗,黄芪、三七、降香促进血管生成,以及丹参的抗氧化、抗粘附作用相关,探讨了芪参益气方有效组分促进人脐静脉内皮细胞增殖的配伍机制。
本文首次采用蛋白质组学技术对芪参益气方以及各有效组分的作用进行研究,并且采用贡献指数的归纳方式,提出了该方可能的配伍机制,证明了蛋白质组学技术在中药方剂分子机制和配伍理论研究中的可行性和适用性。
QI-SHEN-YI-QI formula(QSYQ),made from Panax notoginseng,Radix Salvia miltiorrhiza Bge,Radix Astragalus membranaceus Bge and Dalbergia odorifera T.Chen, is an traditional Chinese prescription for treating 'Qi-deficiency,blood stasis' coronary heart disease in China.This herbal remedy exerts remarkable therapeutical efficacy in clinical,however reliable scientific evidences are still too rare to elucidate the veracity and safety of it.To improve the understanding of the molecular processes and mechanisms afford by QSYQ and its components,the proteomics technology was used as a main research tool on both animal and cell levels.
Firstly,two-dimensional electrophoresis(2DE) with matrix-assisted laser desorption/ionization mass spectrometry(MALDI-MS) was used to study differential protein profiles of myocardium during the acute ischemia period after the treatment of QSYQ,and it was suggested the molecular mechanism of energy metabolism improvements and injured cell protections.Compared the protein profiles with treatment of QSYQ and effective components(saponins from Radix Astragalus membranaceus,phenolic acids from Salvia miltiorrhiza,ginsenosides from Radix Panax notoginseng,and essential oils from Dalbergia sissoo) in comparative proteomic approach,a contribution index was proposed to reflect how much contribution of individual agent on protein expression response to the overall prescription.It basically revealed the anti-ischemic mechanism of QSYQ effective components,and provided a new method to explain the modern biology meaning of action mechanism of Chinese prescription from the molecular level.
Secondly,suitable proteomic analysis methods was established by optimizing 2DE conditions,and applied to proteomics research of promoting proliferation of human umbilical vein endothelial cell(HUVEC) with QSYQ treatment.It preliminarily illustrated the QSYQ-related proliferation mechanism from the protein level,and initially approached the synergistic effects of effective components in this formula,with the different protein expressions in single treatments.
In this paper,comparative proteomic approach was firstly used for the mechanism study of QSYQ and effective components.Then,a contribution index was proposed for inducting the synergistic effects of the formula.The finding suggested comparative proteomic approach can be a useful tool to identify potential targets of Chinese prescription and illustrate the mechanisms of action of drug synergistic effects.
引文
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