Anti-Inflammatory CeO2 Nanoparticles Prevented Cytotoxicity Due to Exogenous Nitric Oxide Donors via Induction Rather Than Inhibition of Superoxide/Nitric Oxide in HUVE Cells.

Mohd Javed Akhtar,Hisham Alhadlaq,Maqusood Ahamed

doi:10.3390/molecules26175416

Abstract

The mechanism behind the cytoprotective potential of cerium oxide nanoparticles (CeO2 NPs) against cytotoxic nitric oxide (NO) donors and H2O2 is still not clear. Synthesized and characterized CeO2 NPs significantly ameliorated the lipopolysaccharide (LPS)-induced cytokines IL-1β and TNF-α. The main goal of this study was to determine the capacities of NPs regarding signaling effects that could have occurred due to reactive oxygen species (ROS) and/or NO, since NP-induced ROS/NO did not lead to toxicity in HUVE cells. Concentrations that induced 50% cell death (i.e., IC50s) of two NO donors (DETA-NO; 1250 ± 110 µM and sodium nitroprusside (SNP); 950 ± 89 µM) along with the IC50 of H2O2 (120 ± 7 µM) were utilized to evaluate cytoprotective potential and its underlying mechanism. We determined total ROS (as a collective marker of hydrogen peroxide, superoxide radical (O2•−), hydroxyl radical, etc.) by DCFH-DA and used a O2•− specific probe DHE to decipher prominent ROS. The findings revealed that signaling effects mediated mainly by O2•− and/or NO are responsible for the amelioration of toxicity by CeO2 NPs at 100 µg/mL. The unaltered effect on mitochondrial membrane potential (MMP) due to NP exposure and, again, CeO2 NPs-mediated recovery in the loss of MMP due to exogenous NO donors and H2O2 suggested that NP-mediated O2•− production might be extra-mitochondrial. Data on activated glutathione reductase (GR) and unaffected glutathione peroxidase (GPx) activities partially explain the mechanism behind the NP-induced gain in GSH and persistent cytoplasmic ROS. The promoted antioxidant capacity due to non-cytotoxic ROS and/or NO production, rather than inhibition, by CeO2 NP treatment may allow cells to develop the capacity to tolerate exogenously induced toxicity.

Highlights

Cerium oxide (CeO2) nanoparticles (NPs, particles with at least one dimension less than 100 nm) belong to the rare-earth elements of the lanthanide family
A matte texture was evidenced in high-resolution transmission electron microscopy (TEM) (HR-TEM) images captured at 2 nm (Figure 1B), clearly confirming the typical planes found in crystals
CeO2 NPs appear to be heterogenous in size, but the shape is rhomboid or cubical overall in TEM images, which is in close agreement with scanning electron microscopy (SEM) images (Figure 1C)

Summary

Introduction

Cerium oxide (CeO2) nanoparticles (NPs, particles with at least one dimension less than 100 nm) belong to the rare-earth elements of the lanthanide family. CeO2 NPs have recently been shown to be internalized in primary isolated human placental cells [7] Due to their free-radical scavenging property, CeO2 NPs have been implicated in the protection of cells against several kinds of exogenous pro-oxidant agents [2]. These rare-earth NPs have been reported to have mixed effects on angiogenesis [8] and inflammation [9]. It has been established that ROS could act as signaling mediators due to reversible oxidative modifications of proteins, which can initiate a cascade of phosphorylation reactions leading to altered gene expression [11]. ROS are dual signaling molecules that result in a diverse array of cell phenotypes ranging from cell survival to death

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