School of Pharmaceutical Sciences, Jilin University, Changchun 130021, PR China.
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, PR China; Research Center of Natural Drugs, Jilin University, Changchun 130021, PR China.
Phytomedicine. 2024 Jun;128:155366. doi: 10.1016/j.phymed.2024.155366. Epub 2024 Jan 15.
Yinhua Miyanling tablets (YMT), comprising 10 Chinese medicinal compounds, is a proprietary Chinese medicine used in the clinical treatment of urinary tract infections. Medicinal compounds, extracts, or certain monomeric components in YMT all show good effect on ulcerative colitis (UC). However, no evidence supporting YMT as a whole prescription for UC treatment is available.
To evaluate the anti-UC activity of YMT and elucidate the underlying mechanisms. The objective of the study was to provide evidence for the add-on development of YMT to treat UC.
First, YMT's protective effect on the intestinal barrier was evaluated using a lipopolysaccharide (LPS)-induced Caco-2 intestinal injury model. Second, the UC mouse model was established using dextran sodium sulfate (DSS) to determine YMT's influence on symptoms, inflammatory factors, intestinal barrier, and histopathological changes in the colon. Third, an integrated method combining metabolomics and network pharmacology was employed to screen core targets and key metabolic pathways with crucial roles in YMT's therapeutic effect on UC. Molecular docking was employed to identify the key targets with high affinity. Finally, western blotting was performed to validate the mechanism of YMT action against UC.
YMT enhanced the transepithelial electrical resistance value and improved the expression of proteins of the tight junctions dose-dependently in LPS-induced Caco-2 cells. UC mice treated with YMT exhibited alleviated pathological lesions of the colon tissue in the in vivo pharmacodynamic experiments. The colonic lengths tended to be normal, and the levels of inflammatory factors (TNF-α, IL-6, and iNOS) along with those of the core enzymes (MPO, MDA, and SOD) improved. YMT effectively ameliorated DSS-induced colonic mucosal injury; pathological changes along with ultrastructure damage were significantly alleviated (evidenced by a relatively intact colon tissue, recovery of epithelial damage, repaired gland, reduced infiltration of inflammatory cells and epithelial cells arranged closely with dense microvilli). Seven key targets (IL-6, TNF-α, MPO, COX-2, HK2, TPH, and CYP1A2) and four key metabolic pathways (arachidonic acid metabolism, linoleate metabolism, glycolysis, and gluconeogenesis and tyrosine biosynthesis) were identified to play vital roles in the treatment on UC using YMT.
YMT exerts beneficial therapeutic effects on UC by regulating multiple endogenous metabolites, targets, and metabolic pathways, suggestive of its potential novel application in UC treatment.
银花泌炎灵片（YMT）由 10 种中药成分组成，是一种用于治疗尿路感染的中药方剂。YMT 的药物成分、提取物或某些单体成分对溃疡性结肠炎（UC）均有良好的疗效。然而，目前尚无证据表明 YMT 作为一个整体方剂可用于治疗 UC。
评估 YMT 对 UC 的治疗作用，并阐明其作用机制。本研究旨在为 YMT 联合治疗 UC 提供依据。
首先，采用脂多糖（LPS）诱导 Caco-2 肠损伤模型评估 YMT 对肠道屏障的保护作用。其次，使用葡聚糖硫酸钠（DSS）建立 UC 小鼠模型，以确定 YMT 对 UC 症状、炎症因子、肠道屏障和结肠组织病理学变化的影响。然后，采用代谢组学和网络药理学相结合的综合方法筛选出 YMT 治疗 UC 的关键靶点和关键代谢途径。分子对接用于识别与 UC 治疗作用相关的具有高亲和力的关键靶点。最后，通过 Western blot 验证 YMT 治疗 UC 的作用机制。
YMT 可提高 LPS 诱导的 Caco-2 细胞中紧密连接蛋白的表达，并呈剂量依赖性增加细胞间的跨上皮电阻值。在体内药效学实验中，YMT 治疗 UC 小鼠可减轻结肠组织的病理损伤。YMT 可使结肠长度趋于正常，炎症因子（TNF-α、IL-6 和 iNOS）水平以及核心酶（MPO、MDA 和 SOD）水平均得到改善。YMT 可有效改善 DSS 诱导的结肠黏膜损伤，明显减轻病理变化和超微结构损伤（表现为相对完整的结肠组织，上皮损伤得到修复，腺管恢复，炎症细胞浸润减少，上皮细胞排列紧密，微绒毛密集）。通过 YMT 治疗 UC，鉴定出 7 个关键靶点（IL-6、TNF-α、MPO、COX-2、HK2、TPH 和 CYP1A2）和 4 个关键代谢途径（花生四烯酸代谢、亚油酸代谢、糖酵解和糖异生及酪氨酸生物合成）。
YMT 通过调节多种内源性代谢物、靶点和代谢途径对 UC 发挥有益的治疗作用，提示其在 UC 治疗中具有潜在的新应用价值。
