Abstract
Methylglyoxal (MGO) is a highly reactive metabolite of glucose present at elevated levels in diabetic patients. Its cytotoxicity is associated with endothelial dysfunction, which plays a role in cardiovascular and cerebrovascular complications. Although curcumin has many therapeutic benefits, these are limited due to its low bioavailability. We aimed to improve the bioavailability of curcumin and evaluate a potential synergistic effect of curcumin and reconstituted high-density lipoprotein (rHDL) nanoparticles (Cur-rHDLs) on MGO-induced cytotoxicity and oxidative stress in murine cerebrovascular endothelial cells (bEnd.3). Cur-rHDL nanoparticles (14.02 ± 0.95 nm) prepared by ultracentrifugation and containing curcumin were quantified by LC–MS/MS. The synergistic effect of cur-rHDL nanoparticles was tested on bEnd.3 cytotoxicity, reactive oxygen species (ROS) production, chromatin condensation, endoplasmic reticulum (ER) stress, and endothelial barrier integrity by impedancemetry. The uptake of curcumin, alone or associated with HDLs, was also assessed by mass spectrometry. Pretreatment with Cur-rHDLs followed by incubation with MGO showed a protective effect on MGO-induced cytotoxicity and chromatin condensation, as well as a strong protective effect on ROS production, endothelial cell barrier integrity, and ER stress. These results suggest that Cur-rHDLs could be used as a potential therapeutic agent to limit MGO-induced dysfunction in cerebrovascular endothelial cells by enhancing the bioavailability and protective effects of curcumin.
Highlights
Type 2 diabetes (T2D) is a global health issue that increases the risk of cardiovascular and cerebrovascular diseases, including ischemic stroke and its hemorrhagic complications.Prolonged hyperglycemia leads to various biochemical modifications, such as oxidative stress, apoptosis, and glycation, mediated by methylglyoxal (MGO), a physiological reactive carbonyl compound derived from glucose metabolism
We investigated the effect of curcumin-enriched reconstituted high-density lipoprotein (rHDL) on MGO-induced chromatin condensation in cerebral endothelial cells by DAPI staining
We evaluated the cellular free curcumin compared compared to that of Cur-rHDLs bEnd cells to understand the impact of encapsulation on curcumin uptake
Summary
Type 2 diabetes (T2D) is a global health issue that increases the risk of cardiovascular and cerebrovascular diseases, including ischemic stroke and its hemorrhagic complications.Prolonged hyperglycemia leads to various biochemical modifications, such as oxidative stress, apoptosis, and glycation, mediated by methylglyoxal (MGO), a physiological reactive carbonyl compound derived from glucose metabolism. MGO induces massive intracellular oxidative stress, in endothelial cells (ECs) at the interface between blood and different tissues. This reactive compound is a precursor of advanced glycation products (AGEs) but has a greater potential than AGEs or glucose itself to induce vascular damage [5]. A potent but hydrophobic antioxidant, anti-inflammatory, and anti-apoptotic compound, has been used to limit MGO-induced cytotoxicity in different cell types such as mouse embryonic stem cells [11] and human hepatoma cells [12] but not in ECs. In the present study, we sought to test the protective effect of curcumin on MGO-induced intracellular oxidative stress and cytotoxicity in cerebral ECs. We tested the capacity of curcumin to limit the increase in endothelial permeability induced by MGO by monitoring real-time cell impedance
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