大黄糖络丸调控RXRA/TNF-α/GLUT4通路改善2型糖尿病骨骼肌胰岛素抵抗  

Molecular Mechanism of Dahuang Tangluo(大黄糖络)Pill in Improving Insulin Resistance of Skeletal Muscle in Type 2 Diabetes Mellitus Based on RXRA/TNF-α/GLUT4 Pathway

作　　者：赵思晨 梁永林 朱向东 白敏 张禄璐 安冬 裴晓丽 ZHAO Sichen;LIANG Yonglin;ZHU Xiangdong;BAI Min;ZHANG Lulu;AN Dong;PEI Xiaoli(School of Basic Medicine,Gansu University of Chinese Medicine,Lanzhou 730030;Ningxia Medical,University,Yinchuan 750004)

机构地区：[1]甘肃中医药大学基础医学院,兰州730030 [2]宁夏医科大学,银川750004

出　　处：《中药药理与临床》2024年第9期55-63,共9页Pharmacology and Clinics of Chinese Materia Medica

基　　金：甘肃省高等学校产业支撑计划项目(编号:2021CYZC-03);甘肃省优秀博士生项目(编号:23JRRA1218)。

摘　　要：目的:基于网络药理学和分子对接技术预测大黄糖络丸改善2型糖尿病骨骼肌胰岛素抵抗(T2DM-IRSM)的分子机制并进行动物实验验证。方法:采用网络药理学和分子对接技术预测大黄糖络丸干预2型糖尿病骨骼肌胰岛素抵抗的可能靶点,并采用分子生物学技术验证相关靶点。选取30只SPF级9周龄雄性ZDF(fa/fa)大鼠纳入试验,适应性喂养1 w后采用5008饲料诱导3 w复制模型,成模后随机分为模型对照组、罗格列酮0.36 mg/kg组和大黄糖络丸0.54、1.08、2.16 g/kg组,另选6只9周龄SPF级雄性ZDF(fa/+)大鼠作为正常对照组,连续干预12 w。双周测定大鼠体质量和空腹血糖(FBG),结束后全自动生化分析仪测定血清葡萄糖(GLU);ELISA法检测血清空腹胰岛素(FINS)并计算稳态模型胰岛素抵抗指数(HOMA-IR)和胰岛素敏感指数(ISI);采用HE染色法观察骨骼肌病理形态变化。结果:网络药理学预测结果中PPI网络互作分析发现肿瘤坏死因子(TNF)、葡萄糖转运蛋白4型(SLC2A4,又称GLUT4)、类视黄醇X受体α(RXRA)是“药物-疾病”交集靶点中的关键靶点,槲皮素、汉黄芩素、豆甾醇、(2R)-7-羟基-5-甲氧基-2-苯基苯并二氢吡喃-4-酮等为药物的关键活性成分。GO富集分析结果中生物过程(BP)涉及腺苷酸环化酶激活肾上腺素能受体信号通路、肾上腺素能受体信号通路、化学信号介导的全身动脉血压调节等;细胞组成(CC)涉及膜筏、膜微区、膜区等;分子功能(MF)涉及G蛋白偶联胺受体活性、核受体活性、配体激活的转录因子活性等。KEGG富集分析涉及的关键通路包括脂肪细胞因子信号通路、唾液分泌、心肌细胞中的肾上腺素能信号、cGMP-PKG信号通路、化学致癌-受体活化等。分子对接结果表明槲皮素、汉黄芩素、豆甾醇、(2R)-7-羟基-5-甲氧基-2-苯基苯并二氢吡喃-4-酮和TNF-α、GLUT4、RXRA靶点均能较好的结合,以上靶点均主要富集于RXRA/TNF-�Objective:To predict the molecular mechanism of Dahuang Tangluo(大黄糖络)Pill in improving insulin resistance in skeletal muscle of type 2 diabetes mellitus(T2DM-IRSM)based on network pharmacology and molecular docking technology and perform animal experiment verification.Methods:The network pharmacology and molecular docking technology were used to predict the possible targets of Dahuang Tangluo Pill in the intervention of T2DM-IRSM,and molecular biological technology was used to verify the relevant targets.A total of 30 SPF 9-week-old male ZDF(fa/fa)rats were selected for the experiment.After adaptive feeding for one week,a 5008 feed was used to induce a 3-week replication model.After modeling,rats were randomly divided into a model control group,a rosiglitazone group of 0.36 mg/kg,and Dahuang Tangluo Pill groups of 2.16,1.08,and 0.54 g/kg.Additionally,six 9-week-old SPF male ZDF(fa/+)rats were selected as the normal control group.The intervention was conducted for 12 weeks.Body mass and fasting blood glucose(FBG)were detected every two weeks.After completion,serum glucose(GLU)was measured using a fully automated biochemical analyzer.Serum fasting insulin(FINS)was measured by Elisa,and the steady-state model insulin resistance index(HOMA-IR)and insulin sensitivity index(ISI)were calculated.HE staining method was used to observe the pathological changes in skeletal muscle morphology.Result:The PPI network interaction analysis in network pharmacology prediction results revealed that tumor necrosis factor(TNF),glucose transporter type 4(SLC2A4,also known as GLUT4),and retinoid X receptorαRXRA were key targets in the intersection of drugs and disease.Quercetin,baicalin,stigmasterol,and(2R)-7-hydroxy-5-methoxy-2-phenylbenzodihydropyran-4-one were key active ingredients of drugs.The biological processes(BP)in GO enrichment analysis results included activation of adrenergic receptor signaling pathway by adenylate cyclase,adrenergic receptor signaling pathway,and chemical signal-mediated systemic arterial blood pr

关 键 词：大黄糖络丸 2型糖尿病 骨骼肌胰岛素抵抗 类视黄醇X受体α/肿瘤坏死因子α/葡萄糖转运蛋白4型信号通路 网络药理学 

分 类 号：R285.5[医药卫生—中药学]