Elimination of Intracellular Calcium Overload by BAPTA-AM-Loaded Liposomes: A Promising Therapeutic Agent for Acute Liver Failure

Abstract

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.

Agonist-induced Piezo1 activation promote mitochondrial-dependent apoptosis in vascular smooth muscle cells

“…Therefore, we hypothesized that Ca 2+ might enter the cell through Piezo1 activated and consequently damage the mitochondria, which induces the production of a significant quantity of ROS and apoptosis. BAPTA-AM, a well-established intracellular calcium ion chelator, is often used in research related to Ca 2+ [ 31 , 32 ]. The mitochondria and NADPH oxidase produce ROS[ 33 ].…”

Glutathione ameliorates Hypoxia/Reoxygenation (H/R) induced hepatocyte oxidative damage via regulating HO-1 signaling

“…Future study is merited to activation of Kupffer cells results in generation of reactive oxygen species (ROS) (Cannistrà et al, 2016;Peralta et al, 2013). These processes lead to the activation of inflammation and immune responses, related with multiple cells and signaling molecules, and eventually result in increased level of apoptosis and necrosis (Fu et al, 2019). Current pharmocological research on reducing liver ischemia-reperfusion injury is mainly focused on some Chinese herbal medicines, including whether the concerned drugs could clear ROS or reduce apoptosis.…”

1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic Acid Acetoxymethyl Ester Loaded Reactive Oxygen Species Responsive Hyaluronic Acid–Bilirubin Nanoparticles for Acute Kidney Injury Therapy via Alleviating Calcium Overload Mediated Endoplasmic Reticulum Stress

“…24,25 Despite its potential as a cell rescuer, BA's poor water solubility, short half-life, lack of specificity for kidney targeting, and poor cellular uptake limit its wide in vivo application. 24,26 Recent studies developed nanoscale liposomes (composed of Lipoid S100 and cholesterol) for the delivery of BAPTA-AM, in which the liposome only acted as drug carriers for enhancing the aqueous solubility of BAPTA-AM but did not achieve targeting properties and microenvironment-responsive drug release and also did not achieve synergistic treatment effects of the carriers, resulting in undesired biodistribution and unsatisfactory treatment efficacy in vivo. 24,25 Inspired by the strong binding ability of natural polysaccharide hyaluronic acid (HA) to the CD44 receptors that are overexpressed in injured kidney proximal tubules, we chose hydrophilic HA as a backbone component of drug delivery vehicles to achieve precise kidney-targeted delivery and enhance payload accumulation.…”