黄芪总皂苷(TAS)是黄芪的主要活性成分,并具有有效的抗肝纤维化作用。然而,TAS治疗原发性硬化性胆管炎(PSC)的疗效及其潜在机制尚不清楚.在这项研究中,两种PSC小鼠模型,包括3,5-二乙氧基羰基-1,4-二氢-2,4,6-Collidine(DDC)诱导的PSC和Mdr2-/-自发PSC,Tgr5-/-小鼠用于研究TAS的治疗效果和机制。TAS治疗,特别是56毫克/千克的剂量,显着改善PSC相关的肝损伤,胆汁淤积,胶原蛋白沉积,导管反应(DR),DDC诱导和Mdr2-/-自发性PSC小鼠的纤维化。此外,TAS治疗通过抑制TNF-α的表达显著减轻体内PSC相关炎症反应和HIBEpiC细胞,IL-6和IL-1β。机械上,TAS治疗挽救了PSC降低的肝脏TGR5表达,从而减弱了NF-κBp65的磷酸化。值得注意的是,TAS对DDC诱导的小鼠PSC的治疗功效在Tgr5-/-小鼠中被取消,提示TAS的抗PSC作用可能依赖于增强TGR5的表达。总之,TAS改善DR,通过挽救TGR5表达在PSC小鼠的两种模型中的炎症和肝纤维化。我们的发现可能有助于设计治疗PSC的新治疗策略。
Total astragalus saponins (TAS) are the main active components of astragali radix, and have potent anti-hepatic fibrosis effect. However, the therapeutic efficacy of TAS and their potential mechanisms in the treatment of primary sclerosing cholangitis (PSC) remain unclear. In this study, two mouse models of PSC, including 3,5-Diethoxycarbonyl-1,4-Dihydro-2,4,6-Collidine (DDC)-induced PSC and Mdr2-/- spontaneous PSC, and the
Tgr5-/- mice were used to investigate the therapeutic effect and mechanisms of TAS. Treatment with TAS, particularly with a dose of 56 mg/kg, significantly ameliorated the PSC-related liver injury, cholestasis, collagen deposition, ductular reaction (DR), and fibrosis in the DDC-induced and Mdr2-/-spontaneous PSC mice. Furthermore, treatment with TAS significantly mitigated the PSC-related inflammatory responses in vivo and HIBEpiC cells by inhibiting the expression of TNF-α, IL-6, and IL-1β. Mechanistically, treatment with TAS rescued the PSC-decreased hepatic
TGR5 expression to attenuate the NF-κB p65 phosphorylation. Notably, the therapeutic efficacy of TAS on PSC in DDC-induced mice was abrogated in
Tgr5-/- mice, suggesting the anti-PSC effect of TAS may depend on enhancing
TGR5 expression. In conclusion, TAS ameliorated DR, inflammation and liver fibrosis in both models of PSC mice by rescuing
TGR5 expression. Our findings may aid in the design of new therapeutic strategies for the treatment of PSC.