基于能量代谢探讨吴茱萸炮制黄连对溃疡性结肠炎的增效作用

Synergistic effect of Coptidis Rhizoma processed with Euodiae Fructus on ulcerative colitis through energy metabolism

基于靶向能量代谢组学、肠屏障蛋白表达和葡萄糖转运的差异,探讨吴茱萸炮制黄连对溃疡性结肠炎(ulcerative colitis,UC)的增效机制。小鼠饮用4%葡聚糖硫酸钠构建UC模型,随机分为模型组、黄连组及萸黄连组,给药14 d后结肠组织病理学及炎症指标等检测评价炮制对UC药效的影响;运用靶向能量代谢组学评价炮制对结肠组织能量代谢的影响;采用分子对接预测能量代谢物与肠屏障紧密连接蛋白Claudin和葡萄糖转运体2(glucose transporter 2,GLUT2)的结合度;大鼠在体单向肠灌流实验评价炮制对肠道葡萄糖转运的影响。结果表明黄连和萸黄连均可修复UC小鼠结肠组织损伤,下调组织炎症因子白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)水平,且萸黄连药效优于黄连。炮制品显著上调结肠组织糖酵解、三羧酸循环和氧化磷酸化多种代谢物水平,其中上调的1,6-二磷酸果糖和乙酰辅酶A能与Claudin和GLUT2良好结合,且炮制品还能提高GLUT2表达和转运葡萄糖活性。该研究提示吴茱萸炮制黄连可能提高葡萄糖转运从而改善结肠能量代谢,促进屏障修复,发挥炮制增效作用。

Based on the differences in targeted energy metabolomics,intestinal barrier protein expression,and glucose transport,the synergistic mechanism of Coptidis Rhizoma(CR)processed with Euodiae Fructus(ECR)on ulcerative colitis(UC)was explored.Mice were administered 4%dextran sulfate sodium to induce UC model,and then randomly divided into a model group,a CR group,and an ECR group.After 14 days of treatment,the therapeutic effect of processing on UC was assessed through histopathology of colon tissue and inflammatory indexes.Targeted energy metabolomics analysis was performed to evaluate the effect of processing on colon tissue energy metabolism.Molecular docking was carried out to predict the binding affinity of energy metabolites with intestinal barrier tight junction protein Claudin and glucose transporter 2(GLUT2).In vivo unidirectional intestinal perfusion experiments in rats were conducted to evaluate the effect of processing on intestinal glucose transport.The results showed that both CR and ECR could repair colon tissue damage in UC mice,downregulate tissue inflammatory factors interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)levels,with the efficacy of ECR being superior to CR.Processed products significantly upregulated levels of multiple metabolites in colon tissue glycolysis,tricarboxylic acid cycle,and oxidative phosphorylation,among which the upregulated levels of 1,6-diphosphate fructose and acetyl coenzyme A could bind well with Claudin and GLUT2.Additionally,the processed product also increased the expression of GLUT2 and enhanced glucose transport activity.This study suggests that ECR may enhance glucose transport to improve colon energy metabolism,promote barrier repair,and exert synergistic effects through processing.