黄酒、姜、吴茱萸炮制黄连“缓寒”共性与“异用”特性机制研究

Coptidis Rhizoma processed with yellow wine, Zingiberis Rhizoma and Euodiae Fructus are typical representatives of counter processing. The cold property is relieved and the efficiency is altered after processing. However, it is not clear what kind of components though which way to show the commonness and characteristics. On the basis of previous studies, this project proposes the following hypothesis: during the processing of Coptidis Rhizoma, the yellow wine, Zingiberis Rhizoma and Euodiae Fructus show "relieving cold property" commonness by influencing the levels of shared biomarkers, and show "changing efficiency" characteristics by influencing the metabolic behaviors of different target organ(s), and both the commonness and characteristics are closely related to the volatile components of processing excipients. The changes of drug property and efficacy before and after processing will be confirmed by adopting the TCM syndrome models; The mechanism of "relieving cold property" commonness will be clarified by analyzing the change rules of shared biomarkers (between the wine/Zingiberis Rhizoma/Euodiae Fructus processed Coptidis Rhizoma and the crude Coptidis Rhizoma treating groups) contents and the related metabolic networks, based on the humoral metabolomics study; The mechanism of "changing efficiency" characteristics will be clarified by investigating the target organ(s) of the crude/wine processed/Zingiberis Rhizoma processed/Euodiae Fructus processed Coptidis Rhizoma, and their interventions on the metabolic behaviors of their own target organ(s), based on the tissue metabolomics study; The material basis of "relieving cold property" and "changing efficiency" will be revealed by splitting the excipient components. This project could elucidate the counter processing mechanism of Coptidis Rhizoma from perspectives of the "relieving cold property" commonness and "changing efficiency" characteristics.

热性辅料黄酒、姜、吴茱萸炮制黄连是中药炮制反制典型代表，炮制后呈现“缓寒”共性和“异用”特性变化，但通过哪类组分、以何种途径表现出共性及特性尚不明晰。在前期基础上，提出假说：黄酒、姜、吴茱萸炮制黄连，通过影响机体共有生物标志物的含量变化呈现“缓寒”共性，通过影响不同目标脏器（群）的代谢网络呈现“异用”特性，且共性与特性均与辅料挥发性组分紧密相关。拟采用中医证候模型，确证黄连炮制前后寒热药性和功效的改变；采用体液代谢组学，分析酒/姜/萸黄连组与生黄连组共有生物标志物含量的组间变化规律和相关代谢网络，阐明“缓寒”共性机制；采用组织代谢组学，探讨生/酒/姜/萸黄连的目标脏器（群）及其对各自目标脏器（群）代谢网络的干预作用，阐明“异用”特性机制；采用辅料组分拆分，探讨黄酒、姜、吴茱萸中致使黄连寒性缓和及功效异用的物质基础。本项目可从“缓寒”共性和“异用”特性角度揭示黄连反制的炮制规律及相关机制。

热性辅料黄酒、姜、吴茱萸炮制黄连是中药炮制“反制”的典型代表。炮制后，黄连寒性均得以缓和，临床应用各有侧重。本项目获得以下研究结果，①通过代谢组学方法和中医证候模型的药效学研究，证实黄连经不同热性辅料炮制后药性均有所缓和，且酒黄连擅清上焦火热、姜黄连可清胃和胃、萸黄连能疏肝和胃。②通过血清和脏器代谢组学研究，总结炮制后的共性与特性机制如下：酒/姜/萸黄连药性相对缓和，其“缓寒”机制与机体物质能量代谢和蛋白质合成相关通路密切相关。酒黄连通过干预心脏组织中的丙氨酸、天冬氨酸和谷氨酸代谢、ABC转运蛋白、亚油酸代谢和嘌呤代谢，以及肺组织中的丙氨酸、天冬氨酸和谷氨酸代谢、嘌呤代谢、泛酸和CoA生物合成、组氨酸代谢和神经活性配体受体信号通路，而在心肺组织发挥了缓和黄连寒性、抗氧化、抗炎、解毒和保护作用；姜/萸黄连通过干预胃组织中的嘌呤代谢，结肠组织中的精氨酸、脯氨酸代谢和初级胆汁酸生物合成，而在缓和黄连寒性、维持胃肠粘膜完整性、促进蠕动和胃肠激素分泌等方面表现尤为突出，且姜黄连在胃组织表现出的抗氧化作用最强；萸黄连可协同干预结肠和肝脏组织的内部代谢，通过促进胆汁合成与分泌，加快肝-肠循环的运行和胆汁酸的利用，而发挥其疏肝利胆作用，同时萸黄连在肝脏组织中表现出的热性最强。③基于酒/姜/萸黄连及其辅料拆分组分模拟炮制品组样本点在血清和主要脏器主成分分析得分图中的相对位置，确定黄酒挥发性组分、姜和吴茱萸挥发与去挥发组分可能是各辅料促使黄连寒性缓和及功效异用的物质基础，且吴茱萸挥发性组分的贡献度略高于其去挥发组分。项目以代谢组学技术为核心，从“缓寒”共性和“异用”特性角度阐明了黄酒、姜、吴茱萸反制黄连的炮制规律和相关机制，对其他反制中药炮制机理研究具有借鉴意义。