整合网络药理学和代谢组学研究降浊合剂治疗2型糖尿病的物质基础和作用机制

Integrated Network Pharmacology and Metabolomics to Decipher the Material Basis and Mechanism of Jiangzhuo Decoction against Type 2 Diabetes Mellitus

关键词:  降浊合剂  2型糖尿病  网络药理学  代谢组学  AGE-RAGE信号通路

Key words:  Jiangzhuo decoction  type 2 diabetes mellitus  network pharmacology  metabolomics  AGE-RAGE pathway

摘要:

目的 基于体内实验、代谢组学及网络药理学探讨降浊合剂治疗2型糖尿病（type 2 diabetes mellitus，T2DM）的药效物质基础及作用机制。方法 构建高脂饮食联合链脲佐菌素诱导的T2DM小鼠模型，给予二甲双胍和不同剂量降浊合剂干预8周。通过血清生化分析、肾组织病理染色（HE/PAS）及ELISA检测评估药效，代谢组学检测肝脏代谢变化。采用Q-TOF-LC-MS技术结合TCMSP数据库筛选降浊合剂化学成分，在TCMSP和SwissTargetPrediction数据库预测药物作用靶点，在GeneCards、OMIM等数据库预测T2DM相关靶点，获得共同靶点后运用网络药理学构建“药物—成分—靶点”网络，通过STRING、Metascape进行PPI网络和通路富集分析，结合AutoDock vina进行分子对接验证。结果 降浊合剂显著改善T2DM小鼠糖脂代谢及肾脏损伤，代谢组学显示其可逆转肝脏代谢紊乱。网络药理学筛选出260个共同靶点，涉及AGE-RAGE等关键信号通路。分子对接证实关键成分（大豆苷元、葛根素等）与核心靶点（IL-6、TNF-α等）结合良好，动物实验验证其通过抑制AGE-RAGE信号轴调控炎症因子释放。结论 本研究表明降浊合剂可降低T2DM小鼠的血糖水平，改善胰岛素抵抗情况，机制涉及改善肝脏代谢紊乱、抑制炎症反应，该研究结果为降浊合剂的临床应用奠定了理论基础。

Abstract:

OBJECTIVE Based on in vivo experiments, metabolomics and network pharmacology, we investigated the material basis and underlying mechanism of Jiangzhuo decoction (JZD) in the treatment of type 2 diabetes mellitus (T2DM). METHODS A T2DM mouse model was constructed using a high-fat diet combined with streptozotocin. Mice were treated with metformin or low/medium/high doses of JZD for 8 weeks. Serum biochemical parameters, renal histopathology (HE and PAS staining), and renal protein expression (ELISA) were analyzed. Liver metabolomic profiles were assessed. Components of JZD were screened via Q-TOF-LC-MS and the TCMSP database. Potential targets of JZD and T2DM-related genes were predicted via SwissTargetPrediction, GeneCards, and OMIM databases. Common targets were used to construct a "herb-compound-target" network. STRING and Metascape were employed for protein-protein interaction (PPI) network and pathway enrichment analysis. Molecular docking validation was performed using AutoDock Vina. RESULTS JZD significantly improved glucose-lipid metabolism and alleviated renal injury in T2DM mice by reversing hepatic metabolic disturbances, as demonstrated through metabolomics analysis. Network pharmacology identified 260 common targets, with AGE-RAGE signaling as a key enriched pathway. Molecular docking confirmed strong binding between core components (daidzein, puerarin, etc.) and critical targets (IL-6, TNF-α, etc.). Animal experiments validated JZD’s inhibition of the AGE-RAGE axis and downstream inflammatory cytokine release. CONCLUSION JZD ameliorates hyperglycemia and insulin resistance in T2DM mice via regulating hepatic metabolic homeostasis and inhibiting inflammation, providing a mechanistic basis for its clinical translation.