背景:自身免疫性肝炎(AIH),主要由T细胞介导,以肝脏炎症为特征。尽管在理解其发病机制方面取得了进展,有效的治疗选择是有限的。柚林宁,柑橘类水果中丰富的类黄酮,以其抗炎特性和预防各种炎症性疾病的能力而闻名,包括药物性肝损伤。然而,柚皮苷对AIH的确切影响及其相关机制仍知之甚少。
目的:我们的目的是确定柚皮苷在AIH中的作用,探索其在这种疾病中的作用和作用。
方法:网络药理学,分子对接,并利用分子动力学模拟来预测连接柚皮苷的HUB目标,T细胞介导的自身免疫性疾病,AIH.细胞热转移测定用于确定柚皮苷与HUB靶标的结合能力。一项体内实验证实了柚皮苷治疗对AIH发育和潜在机制的影响。
结果:柚皮苷对ConA诱导的AIH有治疗作用。Naringin之间有455个共享目标,T细胞介导的自身免疫性疾病,AIH.10个HUB基因(AKT1、ALB、IL-6,IL-1β,CTNNB1,TNF,TP53,MAPK3,VEGFA,和JUN)是通过PPI网络确定的。基因本体论分析显示参与基因表达调控,脂多糖介导的信号,和I-κ激酶/NFκB信号传导。路径分析提示TNF,Th1/Th2细胞分化,和Toll样受体通路,具有有利的柚皮苷-HUB基因结合。分子对接确认白蛋白(ALB),IL-1β,IL-6和TNF是柚皮苷的主要靶标。分子动力学模拟显示ALB-柚皮苷的稳定结合,TNF-柚皮苷,和IL-1β-柚皮苷复合物。柚皮苷对AIH的肝保护作用由血清ALB升高和包括IL-1β在内的肝脏炎性细胞因子降低支持,IL-6和TNF-α。
结论:我们的数据强调了柚皮苷作为T细胞介导的自身免疫性疾病包括AIH的预防或治疗剂的潜力。
BACKGROUND: Autoimmune hepatitis (AIH), primarily mediated by T cells, is characterized by liver inflammation. Despite the advancements in understanding its pathogenesis, effective therapeutic options are limited. Naringin, a flavonoid abundant in citrus fruits, is recognized for its anti-inflammatory properties and ability to protect against various inflammatory diseases, including drug-induced liver injury. However, the exact effects of naringin on AIH and the mechanisms involved remain poorly understood.
OBJECTIVE: We aim to determine the role of naringin in AIH, exploring its targets and actions in this disease.
METHODS: Network pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict the HUB targets connecting naringin, T cell-mediated autoimmune disorders, and AIH. Cellular thermal shift assays were used to determine the binding abilities of naringin with the HUB targets. An in vivo experiment confirmed the impact of naringin treatment on AIH development and underlying mechanisms.
RESULTS: Naringin demonstrated therapeutic effects on ConA-induced AIH. There were 455 shared targets between naringin, T cell-mediated autoimmune diseases, and AIH. Ten HUB genes (AKT1, ALB, IL-6, IL-1β, CTNNB1, TNF, TP53, MAPK3, VEGFA, and JUN) were identified through the PPI network. Gene ontology analysis revealed involvement in gene expression regulation, lipopolysaccharide-mediated signaling, and I-kappa kinase/NFκB signaling. Pathway analysis suggested TNF, Th1/Th2 cell differentiation, and Toll-like receptor pathways, with favorable naringin-HUB gene binding. Molecular docking confirmed albumin (ALB), IL-1β, IL-6, and TNF as primary targets for naringin. Molecular dynamics simulations showed stable binding in ALB-naringin, TNF-naringin, and IL-1β-naringin complexes. Naringin\'s hepatoprotective effect on AIH was supported by increased serum ALB and decreased hepatic inflammatory cytokines including IL-1β, IL-6, and TNF-α.
CONCLUSIONS: Our data underscore the potential of naringin as a preventive or therapeutical agent in T cell-mediated autoimmune diseases including AIH.