PDF(Pubmed)
Abstract：
In this in vitro study, for the first time, we evaluate the effects of simvastatin-loaded liposome nanoparticles (SIM-LipoNPs) treatment on fibrosis-induced liver microtissues, as simvastatin (SIM) has shown potential benefits in the non-alcoholic fatty liver disease process. We developed multicellular liver microtissues composed of hepatic stellate cells, hepatoblastoma cells and human umbilical vein endothelial cells. The microtissues were supplemented with a combination of palmitic acid and oleic acid to develop fibrosis models. Subsequently, various groups of microtissues were exposed to SIM and SIM-LipoNPs at doses of 5 and 10 mg/mL. The effectiveness of the treatments was evaluated by analysing cell viability, production of reactive oxygen species (ROS) and nitric oxide (NO), the expression of Kruppel-like factor (KLF) 2, and pro-inflammatory cytokines (interleukin(IL)-1 α, IL-1 β, IL-6 and tumour necrosis factor-α), and the expression of collagen I. Our results indicated that SIM-LipoNPs application showed promising results. SIM-LipoNPs effectively amplified the SIM-klf2-NO pathway at a lower dosage compatible with a high dosage of free SIM, which also led to reduced oxidative stress by decreasing ROS levels. SIM-LipoNPs administration also resulted in a significant reduction in pro-inflammatory cytokines and Collagen I mRNA levels, as a marker of fibrosis. In conclusion, our study highlights the considerable therapeutic potential of using SIM-LipoNPs to prevent liver fibrosis progress, underscoring the remarkable properties of SIM-LipoNPs in activating the KLF2-NO pathway and anti-oxidative and anti-inflammatory response.
摘要：
在这项体外研究中，第一次,我们评估了辛伐他汀脂质体纳米粒（SIM-LipoNPs）治疗对纤维化诱导的肝微组织的影响，辛伐他汀（SIM）在非酒精性脂肪性肝病过程中显示出潜在的益处。我们开发了由肝星状细胞组成的多细胞肝微组织，肝母细胞瘤细胞和人脐静脉内皮细胞。用棕榈酸和油酸的组合补充微组织以开发纤维化模型。随后，各组微组织暴露于剂量为5和10mg/mL的SIM和SIM-LipoNP。通过分析细胞活力来评估治疗的有效性。活性氧（ROS）和一氧化氮（NO）的产生，Kruppel样因子（KLF）2和促炎细胞因子（白细胞介素（IL）-1α，IL-1β,IL-6和肿瘤坏死因子-α），和胶原蛋白I的表达。我们的结果表明，SIM-LipoNPs的应用显示出有希望的结果。SIM-LipoNP在与高剂量游离SIM相容的较低剂量下有效地放大了SIM-klf2-NO途径，这也通过降低ROS水平导致氧化应激降低。SIM-LipoNP给药还导致促炎细胞因子和胶原蛋白ImRNA水平显着降低，作为纤维化的标志。总之,我们的研究突出了使用SIM-LipoNPs预防肝纤维化进展的相当大的治疗潜力，强调了SIM-LipoNPs在激活KLF2-NO途径以及抗氧化和抗炎反应方面的显着特性。
