白术内酯Ⅲ纳米粒改善免疫球蛋白A肾病大鼠肠道免疫屏障功能

The improvement of intestinal immune barrier function in immunoglobulin A nephropathy rats by Atractylolactone-Ⅲ nanoparticles

目的探究白术内酯Ⅲ(AT-Ⅲ)对免疫球蛋白A肾病(IgAN)大鼠肠道免疫屏障和肾脏的改善作用,并开发AT-Ⅲ纳米颗粒以期优化其保护作用。方法本研究采用沸石咪唑骨架(ZIF-8)负载AT-Ⅲ制备ZIF-8@AT-Ⅲ纳米粒,通过透射电子显微镜、X射线多晶衍射仪对制备的样品进行形态结构表征。将48只大鼠随机分为正常对照组、IgAN组、IgAN+AT-Ⅲ组、IgAN+ZIF-8@AT-Ⅲ组。使用AT-Ⅲ和ZIF-8@AT-Ⅲ分别处理IgAN大鼠,检测大鼠的肝肾功能、肾小球IgA沉淀以及肠道免疫屏障功能。结果成功制备了具有高载药量、稳定性、pH响应性的ZIF-8@AT-Ⅲ纳米粒。ZIF-8@AT-Ⅲ纳米粒平均粒径为(70.62±1.07)nm,Zeta电位为(-26.46±1.22)mV,载药量为(19.2±1.3)%,包封率为(64.0±0.6)%,且在pH 5.5的环境中快速释放,释放量显著高于pH 7.4环境。AT-Ⅲ和ZIF-8@AT-Ⅲ可缓解肠壁结构的破坏和炎症细胞的浸润,显著下调血清中的二胺氧化酶和D-乳酸含量,上调肠黏膜组织中紧密连接蛋白1和紧密连接蛋白5的表达,改善IgAN大鼠的免疫屏障功能以及肠道通透性,抑制肾小球IgA沉积并缓解肾脏损伤。且ZIF-8@AT-Ⅲ的治疗效果优于AT-Ⅲ。结论AT-Ⅲ通过改善大鼠肠道免疫屏障功能以及肠道通透性减轻IgAN。ZIF-8@AT-Ⅲ是提升AT-Ⅲ对IgAN治疗效果的良好载药系统。

Objective To explore the effects of Atractylenolide-Ⅲ(AT-Ⅲ)on the intestinal immune barrier and kidney of rats with immunoglobulin A nephropathy(IgAN),and develop AT-Ⅲ nanoparticles to optimize its protective efficacy.Methods In this study,the zeolitic imidazolate framework(ZIF-8)loaded with AT-Ⅲ was used to prepare ZIF-8@AT-Ⅲ nanoparticles.Morphological and structural characterization of the prepared samples was conducted using transmission electron microscopy and X-ray powder diffraction.48 rats were randomly divided into the normal control group,IgAN group,IgAN+AT-Ⅲ group,and IgAN+ZIF-8@AT-Ⅲ group.IgAN rats were treated with AT-Ⅲ and ZIF-8@AT-Ⅲ,and the detections of hepatic and renal function,glomerular IgA deposition,and intestinal immune barrier function were performed.Results The synthesis of ZIF-8@AT-Ⅲ nanoparticles with elevated drug loading,stability,and pH responsiveness had been successfully accomplished.The average particle size of ZIF-8@AT-Ⅲ nanoparticles was(70.62±1.07)nm,the Zeta potential was(-26.46±1.22)mV,the drug loading capacity was(19.2±1.3%),and the encapsulation efficiency was(64.0%±0.6%).Furthermore,rapid release was observed in a pH 5.5 environment,which was significantly higher than that in the pH 7.4 environment.Both AT-Ⅲ and ZIF-8@AT-Ⅲ could alleviate the destruction of intestinal wall structure and the infiltration of inflammatory cells,significantly downregulate the levels of(DAO)and(D-LA)in the serum.Moreover,there is a noteworthy upregulation in the expression of(ZO-1)and Claudin-5 in intestinal mucosal tissue,thereby substantially improving the immune barrier function and intestinal permeability in IgAN rats.This intervention also inhibited the deposition of IgA in renal glomeruli and alleviated kidney damage,and ZIF 8@AT-Ⅲ was more effective than AT-Ⅲ.Conclusion AT-Ⅲ alleviates IgAN in rats by improving intestinal immune barrier function and permeability.ZIF-8-loaded AT-Ⅲ serves as an excellent drug delivery system,enhancing the therapeutic efficacy of AT-Ⅲ in IgAN treatment.