Elimination of Intracellular Calcium Overload by BAPTA-AM-Loaded Liposomes: A Promising Therapeutic Agent for Acute Liver Failure,ACS Applied Materials & Interfaces

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Elimination of Intracellular Calcium Overload by BAPTA-AM-Loaded Liposomes: A Promising Therapeutic Agent for Acute Liver Failure
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2019-10-17 , DOI: 10.1021/acsami.9b13690
Zailin Fu _{1,

2} , Qiaomei Fan _{2,

3} , Yang Zhou ₄ , Yi Zhao ₅ , Zhiyu He ₄

Affiliation

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 Ca²⁺ 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.

中文翻译：

BAPTA-AM脂质体消除细胞内钙超载：急性肝衰竭的有希望的治疗剂。

在过去的几十年中，已经证明细胞内钙超载通过多种信号途径诱导细胞死亡。在这项研究中，我们使用了BAPTA-AM，一种著名的膜渗透性Ca ²⁺螯合剂，可通过减轻细胞内钙超载来防止细胞损伤。我们探索了载有BAPTA-AM的脂质体（BAL）在治疗以严重肝坏死和凋亡为特征的急性肝衰竭（ALF）小鼠模型中的临床潜力。我们发现BAL可以显着抑制D-GalN诱导的LO2细胞损伤，因为它可以逆转形态变化并调节TNF-α和NF-κB表达，从而使细胞存活率提高60％，并降低RAW 264.7巨噬细胞中LPS刺激的炎症反应。。通过全身给药，BAL可以迅速在受损的肝组织中蓄积，并在D-GalN / LPS诱导的ALF小鼠模型中表现出出色的治疗效果，包括提高存活率（从10％到80％），恢复正常肝脏指标和肝脏健康指标改善肝脏血液微循环（将血流量增加80％，将流量增加60％）和凝血功能。BAL的潜在肝保护作用大概是基于其对氧化应激的抑制作用，对TNF-α受体的限制以及线粒体介导的凋亡途径的抑制作用和抗凋亡能力，这些作用是通过有效清除超载的细胞间钙而实现的。BAL作为ALF治疗的一种新的治疗策略具有巨大的潜力，其卓越的细胞抢救能力为治疗许多其他以快速且大量细胞损伤为特征的疾病提供了充足的机会。BAL的潜在肝保护作用大概是基于其对氧化应激的抑制作用，对TNF-α受体的限制以及线粒体介导的凋亡途径的抑制作用和抗凋亡能力，这些作用是通过有效清除超载的细胞间钙而实现的。BAL作为ALF治疗的一种新的治疗策略具有巨大的潜力，其卓越的细胞抢救能力为治疗许多其他以细胞快速大量破坏为特征的疾病提供了充足的机会。BAL的潜在肝保护作用大概是基于其对氧化应激的抑制作用，对TNF-α受体的限制以及线粒体介导的凋亡途径的抑制作用和抗凋亡能力，这些作用是通过有效清除超载的细胞间钙而实现的。BAL作为ALF治疗的一种新的治疗策略具有巨大的潜力，其卓越的细胞抢救能力为治疗许多其他以细胞快速大量破坏为特征的疾病提供了充足的机会。

更新日期：2019-10-17

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