基于谱效相关及代谢组学解析陈皮在六君子汤中“要补气，先理气”的药效物质基础与组方原理

The qi activity theory is the general principle that throughout the basic theory of traditional Chinese medicine (TCM). It has the statement that "qi is the root of all" and deficiency of qi can cause many diseases. Regulating qi and Tonifying qi are the classical principle of TCM. Therefore, it is of great significance to clarify the principle of compatibility between regulating qi and tonifying qi. This project takes the theory of "nourish the body when used with tonics" of chenpi which recorded in the "Compendium of Materia Medica" as the starting point. Takes the research strategies of metabolomics as the focusing point. And takes the relevance of the various components of chenpi with the effect of regulating qi and tonifying qi as the entry point. To evaluate the regulation of gastric motility and lipid metabolism of different components of chenpi in the decoction of Liujunzi decoction by using the animal model of hyperlipidemia of spleen deficiency. First, the in vivo and in vitro fingerprints of chenpi of diverse origins and storage years were established. Secondly, the pharmacodynamic correlation between chenpi and invigorating compound was established through the analysis of spectral correlation analysis. Finally, LC-MS technology was used to identify the active ingredients, and the metabolism studies were performed on the component that performed the best pharmacodynamics to analyze changes in lipid metabolism and find closely related biomarkers. The purpose of this study is to clarify the pharmaceutical effect substantial basis and compatibility mechanism of regulating qi and tonifying qi through the research of the spectrum and metabolomics of chenpi in compound prescription. In order to rationally explain the scientific essence of the interdependence of regulating qi and tonifying qi through new technologies, it provides theoretical support for clinical drug use.

气机理论是贯穿中医基础理论的总纲，有“气为一身之本”的说法。气虚较为常见，易引发多种疾病，理气补气是中医经典组方原则，因此，明晰理气与补气的配伍原理具有重要意义。本课题以《本草纲目》所载陈皮“同补药则补”理论为出发点，基于代谢组学研究策略，以陈皮拆分组分与理气补气作用的相关性为切入点，采用脾虚高脂血症动物模型评价陈皮拆分组分在六君子汤全方及拆方中的胃动力和脂质代谢调节作用；选择不同产地，不同存储年限的陈皮药材饮片，建立其体内外指纹图谱，通过谱效关系关联度分析方法，建立陈皮与补气复方药效学相关性；采用LC-MS技术，对活性成分进行鉴定；对最佳药效组方进行代谢组学研究，分析脂质代谢的变化，找寻密切相关的生物标志物。本研究旨在通过陈皮在复方中谱效关系和代谢组学的研究，明确其理气补气的药效物质基础和组方原理，从而通过新技术手段合理来阐释理气补气作用相互依存的科学实质，为临床用药提供依据。

本课题根据“要补气，先理气”的组方理论，以含有理气药陈皮的六君子汤为例，探讨陈皮佐助治疗脾虚证组方原理，以期阐明陈皮在方剂作用中的“理气”作用。本课题建立了15批含有不同陈化年份、不同产地陈皮药材的六君子汤的指纹图谱，通过谱效关系研究发现，不同地区、不同采收年限的陈皮药材指纹图谱主要受其年份的影响，其改善脾虚的作用效果也有差异，其中陈化年份5年以上的陈皮作用较好，证实了陈皮在六君子汤中发挥作用是多种成分协同起效的，这为陈皮中有效物质的辨识奠定了基础。课题采用脾虚动物模型和高脂血症脾虚模型评价含有不同批次陈皮的六君子汤的胃动力调节及胃肠道免疫作用，研究发现含有不同陈化年份、不同产地陈皮药材的六君子汤可以促进脾虚模型及脾虚高血脂模型大鼠的胃排空率及小肠推进率，通过调节胃肠动力激素含量、升高免疫细胞的数量，增强胃肠道相关因子及其蛋白质的表达，进而促进受损肠黏膜细胞的修复，增强肠黏膜防御能力，同时改善脾虚高脂血症大鼠血脂激素水平；脾虚及脾虚高血脂模型动物实验结果表明，陈皮在方中配伍后的作用优于六君子汤陈皮阴性组；脂质代谢组学研究发现，六君子汤干预后，低剂量组有43种潜在生物标志物回调，中剂量组有50种，高剂量组有56种，与甘油磷脂代谢、鞘脂代谢、甘油酯代谢、密切相关，提示六君子汤对脾虚高血脂调节作用可能是通过多个代谢物靶点的干预来实现。本研究是逐层递进，多方面协同阐释了陈皮在六君子汤干预脾虚作用中理气的重要性，为药物的临床应用提供更加可靠的依据。