Abstract：
Intestinal ischemia/reperfusion injury (IRI) poses a serious threat to human survival and quality of life with high mortality and morbidity rates. The current absence of effective treatments for intestinal IRI highlights the urgent need to identify new therapeutic targets. Ursolic acid (UA), a pentacyclic triterpene natural compound, has been shown to possess various pharmacological properties including intestinal protection. However, its potential protective efficacy on intestinal IRI remains elusive. This study aimed to investigate the effect of UA on intestinal IRI and explore the underlying mechanisms. To achieve this, we utilized network pharmacology to analyze the mechanism of UA in intestinal IRI and assessed UA\'s effects on intestinal IRI using a mouse model of superior mesenteric artery occlusion/reperfusion and an in vitro model of oxygen-glucose deprivation and reperfusion-induced IEC-6 cells. Our results demonstrated that UA improved necroptosis through the RIP1/RIP3/MLKL pathway, reduced necroinflammation via the HMGB1/TLR4/NF-κB pathway, attenuated morphological damage, and enhanced intestinal barrier function. Furthermore, UA pretreatment downregulated the phosphorylation level of signal transducer and activator of transcription 3 (STAT3). The effects of UA were attenuated by the STAT3 agonist Colivelin. In conclusion, our study suggests that UA can improve intestinal IRI by inhibiting necroptosis in enterocytes via the suppression of STAT3 activation. These results provide a theoretical basis for UA treatment of intestinal IRI and related clinical diseases.
摘要：
肠缺血/再灌注损伤(IRI)严重威胁着人类的生存和生活质量,具有较高的致死率和致残率。目前缺乏有效的肠道IRI治疗方法，这凸显了迫切需要确定新的治疗靶点。熊果酸（UA），五环三萜天然化合物，已被证明具有各种药理特性，包括肠道保护。然而,其对肠道IRI的潜在保护功效仍然难以捉摸。本研究旨在探讨UA对肠道IRI的影响及其机制。为了实现这一点，我们利用网络药理学分析UA在肠道IRI中的作用机制,并使用小鼠肠系膜上动脉闭塞/再灌注模型和体外氧糖剥夺和再灌注诱导的IEC-6细胞模型评估UA对肠道IRI的影响.我们的结果表明，UA通过RIP1/RIP3/MLKL途径改善坏死，通过HMGB1/TLR4/NF-κB途径减少坏死性炎症，衰减的形态损伤，增强肠屏障功能。此外，UA预处理下调信号转导和转录激活因子3(STAT3)的磷酸化水平。UA的作用被STAT3激动剂Colivelin减弱。总之,我们的研究表明,UA可通过抑制STAT3激活而抑制肠上皮细胞的坏死性凋亡,从而改善肠道IRI.本研究结果为UA治疗肠道IRI及相关临床疾病提供了理论依据。
