Department of Pharmacy , The First People's Hospital of Yuhang District , Hangzhou 310000 , P. R. China.
Department of Pharmacy , Zhejiang University of Technology , Hangzhou 310000 , P. R. China.
ACS Appl Mater Interfaces. 2019 Oct 30;11(43):39574-39585. doi: 10.1021/acsami.9b13690. Epub 2019 Oct 17.
In the past few decades, intracellular calcium overload has been shown to induce cell death through multiple signaling pathways. In this study, we used BAPTA-AM, a well-known membrane-permeable Ca chelator, to prevent cell injury by allaying the intracellular calcium overload. We explored the clinical potentials of BAPTA-AM-loaded liposome (BAL) in the treatment of the acute liver failure (ALF) mouse model, which is characterized by severe hepatic necrosis and apoptosis. We discovered that BAL can significantly inhibit D-GalN-induced LO2 cell damage as it increased cell viability by 60% and downregulated the LPS-stimulated inflammatory response in RAW 264.7 macrophages by reversing the morphological change and modulating TNF-α and NF-κB expressions. Through systemic administration, BAL can rapidly accumulate in damaged liver tissue and exhibit excellent treatment effects on the D-GalN/LPS-induced ALF mouse model, including elevation of the survival rate (from 10 to 80%), recovery of normal liver indexes and liver health indicators, improvement of liver blood microcirculation (increased the blood flow volume by 80% and flow rate by 60%), and blood coagulation. The underlying hepatoprotective effect of BAL is presumably based on the antinecrosis and antiapoptosis abilities attributed to its inhibition on oxidative stress, restriction on TNF-α receptor, and mitochondria-mediated apoptotic pathway by effectively clearing the overloaded intercellular calcium. BAL holds great potential as a new therapeutic strategy for ALF treatment, and its prominent cell rescue ability provides ample opportunities for the treatment of many other diseases that are characterized by rapid and massive cell damage.
在过去的几十年中，已经证实细胞内钙超载通过多种信号通路诱导细胞死亡。在这项研究中，我们使用 BAPTA-AM，一种众所周知的膜通透钙螯合剂，通过缓解细胞内钙超载来防止细胞损伤。我们探索了负载 BAPTA-AM 的脂质体（BAL）在急性肝衰竭（ALF）小鼠模型治疗中的临床潜力，该模型的特征是严重的肝坏死和细胞凋亡。我们发现 BAL 可以显著抑制 D-GalN 诱导的 LO2 细胞损伤，因为它使细胞活力提高了 60%，并通过逆转形态变化和调节 TNF-α 和 NF-κB 的表达来下调 LPS 刺激的 RAW 264.7 巨噬细胞的炎症反应。通过全身给药，BAL 可以迅速积聚在受损的肝组织中，并对 D-GalN/LPS 诱导的 ALF 小鼠模型表现出极好的治疗效果，包括提高存活率（从 10%提高到 80%）、恢复正常的肝指数和肝脏健康指标、改善肝血液微循环（血流量增加 80%，流速增加 60%）和凝血。BAL 的潜在保肝作用可能基于其抑制氧化应激、限制 TNF-α 受体以及通过有效清除细胞内超载钙来抑制线粒体介导的凋亡途径的抗坏死和抗凋亡能力。BAL 作为治疗 ALF 的一种新的治疗策略具有很大的潜力，其突出的细胞保护能力为治疗许多其他以快速和大量细胞损伤为特征的疾病提供了充足的机会。
