目的 构建中药“体外化学成分-体内移行成分-功效靶点”多维网络，解析三叶糖脂清片（Sanye Tang Zhi Qing Tablets，SYTZQT）治疗2型糖尿病、动脉粥样硬化及高脂血症“异病同治”的药效物质基础，并预测其潜在的质量标志物（quality marker，Q-Markers）。方法 采用超高效液相色谱-四极杆-飞行时间质谱法（UPLC-Q-TOF-MS^E）鉴定SYTZQT体外化学成分组；采用UPLC-Q-TOF-MS^E结合UPLC-MS/MS法确认SYTZQT体内移行成分组；通过TCMSP、SwissTargetPrediction、OMIM、Unipro和GeneCards等数据库获取入血成分治疗2型糖尿病、动脉粥样硬化及高脂血症的共有功效靶点，并建立“成分-靶点-疾病”关联性；通过分子对接技术确认SYTZQT药效成分与关键靶点结合的稳定性，预测其潜在的Q-Markers。结果 从三叶糖脂清片中鉴定得到74种化学成分；从大鼠血浆中鉴定得到37种化学成分。经入血成分-靶点-疾病分析，找到入血成分与3种疾病的共同作用靶点69个，其中核心靶点为白介素6（interleukin 6，IL-6）、肿瘤坏死因子-α（tumor necrosis factor，TNF-α）、过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma，PPARG）、基质金属蛋白酶9（matrix metalloprotein 9，MMP-9）、表皮生长因子（epidermal growth factor receptor，EGFR）等。20个核心靶点映射关键效应成分为木犀草素、迷迭香酸、芦丁、芍药苷、芍药内酯苷、荷叶碱等，其相关信号通路主要包括高级糖基化终末产物-受体（AGE-RAGE）信号通路、脂质与动脉粥样硬化通路等。分子对接研究显示上述成分与TNF-α、IL-6等效应靶点的结合能均小于−20 kJ/mol，表明具有较好的结合能力。结论 木犀草素、迷迭香酸、芦丁、芍药苷、芍药内酯苷、荷叶碱是SYTZQT治疗2型糖尿病、动脉粥样硬化及高脂血症等糖脂代谢紊乱疾病的共同物质基础，在“体外化学成分-体内移行成分-功效靶点”研究中具有良好的传递性、可测性和有效性，可作为其潜在的Q-Markers。

Objective To construct a multidimensional network of “in vitro components - in vivo transferring components - efficacy targets” of traditional Chinese medicine, to analyze the effective substance basis of the Sanye Tang Zhi Qing Tablets (SYTZQT) for the treatment of type 2 diabetes, atherosclerosis and hyperlipidemia, and to predict the potential quality markers (Q-Markers). Methods An UPLC-Q-TOF/MS^E method was used to identify the in vitro chemical constituents of SYTZQT. A combined UPLC-Q-TOF/MS^E and UPLC-MS/MS method was used to confirm thein vivo components of SYTZQT. With the help of TCMSP, SwissTargetPrediction, OMIM, Unipro and GeneCards databases, this study revealed the common efficacy targets of SYTZQT in the treatment of different diseases including type 2 diabetes, atherosclerosis and hyperlipidemia. The component- target- disease correlation was established in this study. Additionally, this study confirmed the combining ability of SYTZQT active ingredients and key targets through molecular docking technology. In this way potential Q-Markers of SYTZQT were predicted based on the above-mentioned technologies.Results In this paper, 74 chemical components were identified from SYTZQT powder; 37 chemical components were identified from rat plasma. After the blood component-target-disease analysis, 69 common targets of the blood components and the three diseases were found, among which the core targets were interleukin 6 (IL-6), tumor necrosis factor (TNF-α), peroxisome proliferator-activated receptor gamma (PPARG), matrix metalloproteinase 9 (MMP-9), and epidermal growth factor receptor (EGFR). The key effector components of the 20 core target mapping are luteolin, rosmarinic acid, rutin, paeoniflorin, albiflorin, nuciferine, and the related signaling pathways mainly include AGE-RAGE signaling pathway, lipid and atherosclerosis pathway. Molecular docking studies showed that the binding energy of the above components to TNF-α, IL-6 and other effector targets was less than −20 kJ/mol, indicating a better binding ability. Conclusion Luteolin, rosmarinic acid, rutin, paeoniflorin, albiflorin, nuciferine serve as a common material basis for treating type 2 diabetes, atherosclerosis, and hyperlipidemia associated with disorders of glucose and lipid metabolism in SYTZQT tablets. They demonstrate good translatability, measurability, and effectiveness in the “in vitrochemical components - in vivo migrating components - efficacy targets” research, can be used as its potential Q-Markers.

R284.1

天津市教委科研计划项目（2021KJ159）