中药组分协同增效的靶点模块间协调关系定量分析模型构建

Elucidating the synergistic mechanism of Chinese herbal medicines (CHMs) and their components is the key to reveal the scientific connotation of CHMs compatibility, as well as to optimize prescriptions. How to quantitatively characterize the coordination between target community of distinct CHMs for new action “emergence”, is the essential procedure, as well as the bottleneck, for systematically elucidating the synergistic mechanism of CHMs. However, researches on this topic mainly focus on the target entity, such as target communities, modules and pathways, the targeted inter-module coordination related to synergism is far from clear. In our previous study, IMCC score was constructed to qualitatively detect the diversity of inter-module coordination. Base on the IMCC, here, we integrate the topological parameters, statistical analysis, and functional fitting screening to construct a quantitative model for inter-module coordination, using the ursodeoxycholic acid (UA) and jasminoidin (JA) treating cerebral ischemia as demonstration subjects. Subsequently, the quantitative analysis, comparative integration and correlation analysis are conducted on the drug-specific inter-module coordination, to identify the coordination between target modules related to synergism, and to investigate the internal mechanism of subsequent integration emergence and conservation. Finally, the potential synergistic mechanism of UA and JA from the perspective of inter-module coordination will be validated by biological experiments using the model of middle cerebral artery occlusion in rats. This study will provide a novel method for clarifying the “systematic integration” mechanism of synergistic compatibility of CHMs, and provide a new perspective for prescription analysis.

阐释中药及其组分配伍的协同增效机制是揭示中药配伍科学内涵、优化中药组方的关键。如何定量表征不同中药引发的靶点群之间相互协调，促进新作用机制的“涌现”，是系统阐明协同配伍机制必须要解答的问题，也是其瓶颈所在。目前对该机制的研究多集中在靶点实体（靶点群、模块、通路等），尚未开展对靶点群 (模块)间关系的研究。课题组前期提出了模块间协调差异的定性判别模型（IMCC）。在此基础上，本研究以熊胆酸、栀子苷干预脑缺血为示例，通过融合拓扑参数、统计筛选、功能优化建立模块间关系定量分析模型，对单一组分和配伍组的药物应答模块间关系进行定量、对比整合、相关性分析，进而识别协同增效的靶点模块间协调关系及其涌现和保守的内在机理，并采用大鼠大脑中动脉阻断模型进行生物学验证，从模块间协调关系角度揭示熊胆酸和栀子苷协同增效机制，为阐明中药配伍协同增效的“系统整合式”的作用机制提供新方法，为中药组方的深度解析提供新思路。

中药配伍是中医遣方用药和辨证施治的载体，阐明中药及其组分配伍的协同增效机制是揭示中药配伍科学内涵、优化中药组方、进一步提高临床疗效的关键。中药及其组分具有“霰弹效应”式的作用模式，而其作用点不仅包括靶点（基因、蛋白、代谢物等）、靶点群（如通路、模块、社团等），还包括靶点群之间的关系。因而，如何定量表征不同中药引发的靶点群之间相互协调，促进新作用机制的“涌现”，是系统阐明协同配伍机制的必须要解答的问题，也是其瓶颈所在。本研究以熊胆酸、栀子苷干预脑缺血为示例，通过融合拓扑参数、统计筛选、功能优化建立模块间关系定量分析模型，对单一组分和配伍组的药物应答模块间关系进行定量、对比整合、相关性分析，进而识别协同增效的靶点模块间协调关系及其涌现和保守的内在机理，并采用大脑中动脉阻断模型进行生物学验证。研究结果显示，（1）整合多维参数的模块间关系协调模型与生物学功能拟合程度高。（2）基于该模型，发现JA和UA干预后分别出现应答模块的聚合和离散，破坏了疾病应激状态下的高中心性的特征性拓扑结构。UA促进模块间连接密集化，提高模块网络鲁棒性，缩短模块间信息传递路径；JA阻断部分病理模块间信息传递路径。（3）其中，模块间协调关系最为密切的病理模块对介导了的MAPK通路与mTOR信号通路、长时程增强通路、血管平滑肌收缩通路等神经系统损伤通路之间的联系，是缺血性脑卒中的重要病理机制。（4）JA与UA的协同效应可以通过影响炎症因子、溶酶体、吞噬体多信号通路的串扰以及联合作用后的新信号通路“涌现”，形成协同增效的整合作用。阻断自噬激活和抑制炎症是JA和UA协同作用的两个重要途径，其中Dectin-1诱导的NF-κB激活途径是协同作用的途径之一。该研究丰富了中药的系统作用模式的内涵，为从“实体关系”角度阐释中药及其组分协同配伍“系统整合式”的作用机制提供新方法，为诠释中药配伍的科学内涵、设计靶点组合、优化组方提供新思路，为联合治疗的新药研发提供方法。