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

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

CeO2-Zn Nanocomposite Induced Superoxide, Autophagy and a Non-Apoptotic Mode of Cell Death in Human Umbilical-Vein-Derived Endothelial (HUVE) Cells

In this study, a nanocomposite of cerium oxide-zinc (CeO2-Zn; 26 ± 11 nm) based on the antioxidant rare-earth cerium oxide (CeO2) nanoparticles (NPs) with the modifier zinc (Zn) was synthesized by sintering method and characterized. Its bio-response was examined in human umbilical-vein-derived endothelial (HUVE) cells to get insight into the components of vascular system. While NPs of CeO2 did not significantly alter cell viability up to a concentration of 200 µg/mL for a 24 h exposure, 154 ± 6 µg/mL of nanocomposite CeO2-Zn induced 50% cytotoxicity. Mechanism of cytotoxicity occurring due to nanocomposite by its Zn content was compared by choosing NPs of ZnO, possibly the closest nanoparticulate form of Zn. ZnO NPs lead to the induction of higher reactive oxygen species (ROS) (DCF-fluorescence), steeper depletion in antioxidant glutathione (GSH) and a greater loss of mitochondrial membrane potential (MMP) as compared to that induced by CeO2-Zn nanocomposite. Nanocomposite of CeO2-Zn, on the other hand, lead to significant higher induction of superoxide radical (O2•−, DHE fluorescence), nitric oxide (NO, determined by DAR-2 imaging and Griess reagent) and autophagic vesicles (determined by Lysotracker and monodansylcadeverine probes) as compared to that caused by ZnO NP treatment. Moreover, analysis after triple staining (by annexin V-FITC, PI, and Hoechst) conducted at their respective IC50s revealed an apoptosis mode of cell death due to ZnO NPs, whereas CeO2-Zn nanocomposite induced a mechanism of cell death that was significantly different from apoptosis. Our findings on advanced biomarkers such as autophagy and mode of cell death suggested the CeO2-Zn nanocomposite might behave as independent nanostructure from its constituent ones. Since nanocomposites can behave independently of their constituent NPs/elements, by creating nanocomposites, NP versatility can be increased manifold by just manipulating existing NPs. Moreover, data in this study can furnish early mechanistic insight about the potential damage that could occur in the integrity of vascular systems

Gadolinium Oxide Nanoparticles Induce Toxicity in Human Endothelial HUVECs via Lipid Peroxidation, Mitochondrial Dysfunction and Autophagy Modulation

In spite of the potential preclinical advantage of Gd2O3 nanoparticles (designated here as GO NPs) over gadolinium-based compounds in MRI, recent concerns of gadolinium deposits in various tissues undergoing MRI demands a mechanistic investigation. Hence, we chose human to measure umbilical vein endothelial cells (HUVECs) that line the vasculature and relevant biomarkers due to GO NPs exposure in parallel with the NPs of ZnO as a positive control of toxicity. GO NPs, as measured by TEM, had an average length of 54.8 ± 29 nm and a diameter of 13.7 ± 6 nm suggesting a fiber-like appearance. With not as pronounced toxicity associated with a 24-h exposure, GO NPs induced a concentration-dependent cytotoxicity (IC50 = 304 ± 17 µg/mL) in HUVECs when exposed for 48 h. GO NPs emerged as significant inducer of lipid peroxidation (LPO), reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and autophagic vesicles in comparison to that caused by ZnO NPs at its IC50 for the same exposure time (48 h). While ZnO NPs clearly appeared to induce apoptosis, GO NPs revealed both apoptotic as well as necrotic potentials in HUVECs. Intriguingly, the exogenous antioxidant NAC (N-acetylcysteine) co-treatment significantly attenuated the oxidative imbalance due to NPs preventing cytotoxicity significantly

Natural antioxidant curcumin attenuates NiO nanoparticle-induced cytotoxicity in mouse spermatogonia cells: A mechanistic study

Current research focuses on the effects of nanomaterials on the human reproductive system. Nanostructures can cross the epithelial and blood-testicular barriers and pose risks to the reproductive organs. Oxidative stress has been proposed as a possible mechanism of reproductive toxicity caused by nanomaterials. Dietary curcumin could be a therapeutic drug for nanomaterial-induced reproductive toxicity. Studies on effect of commonly used nickel (II) oxide nanoparticle (NiO NPs) on male reproductive organs and their attenuation by natural antioxidant curcumin is scarce. This work intended to study the attenuating potential of curcumin against NiO NPs-induced toxicity in mouse spermatogonia GC-1 spg cells. Plausible mechanisms of alleviating effect curcumin against NiO induced reproductive toxicity was explored through oxidative stress pathway. NiO NPs was synthesized via chemical co-precipitation route and characterized by SEM, TEM, and XRD. NiO NPs was found to induce dose-dependent cytotoxicity in GC-1 spg cells (10–320 µg/ml for 24 h) whereas curcumin did not exert any effect in concentration range of 1–80 µg/ml. Interestingly, cytotoxic response of NiO NPs in GC-1 spg cells was significantly attenuated by curcumin. The higher expression of caspase-3 gene and loss of mitochondrial membrane potential after treatment with NiO NPs were effectively alleviated by curcumin. The increase in intracellular pro-oxidant levels (hydrogen peroxide, malondialdehyde, and reactive oxygen species) after exposure to NiO NPs was also mitigated by curcumin. Moreover, glutathione depletion and lower activity of several antioxidant enzymes (GPx, SOD, and CAT) after NiO NPs were further almost reverted by curcumin. We believe, this is the first preliminary study showing that NiO NPs induced cytotoxicity in mouse spermatogonia cells was mitigated by curcumin via oxidative stress. The therapeutic effect of dietary antioxidant curcumin against nanomaterial-induced reproductive toxicity is warranted further research

Effect of Flecainide on Multifocal Ectopic Purkinje-Related Premature Contractions in an R814W SCN5A Carrier

Multifocal ectopic Purkinje-related premature contraction (MEPPC) is an autosomal dominant SCN5A channelopathy characterized by frequent multiform premature ventricular contractions originating from the His-Purkinje system. We present a patient with an MEPPC phenotype whose genetic testing identified a pathogenic SCN5A (HGNC:10593) variant amenable to precision antiarrhythmic therapy with flecainide

Synergistic toxicity of NiO nanoparticles and benzo[a]pyrene co-exposure in liver cells: Role of free oxygen radicals induced oxidative stress

Current attention has been given on health effects of combined exposure of nanoscale materials and organic pollutants. Nickel (II) oxide nanoparticles (NiO NPs) displays exceptional properties and is being used in various areas such as batteries, diesel–fuel additives, and biomedicals. Benzo[a]pyrene (BaP) is a ubiquitous pollutant. Cigarette smoke, diesel exhaust, and grilled foods are main sources of BaP exposure. Therefore, combined exposure of NiO NPs and BaP to humans is unavoidable. There is a dearth of knowledge on combined effects of NiO NPs and BaP in humans. This study was aimed to investigate co-exposure effects of NiO NPs and BaP in human liver cells (HepG2) and primary rat hepatocytes. We observed that individual and co-exposure of NiO NPs and BaP induced cytotoxicity, lactate dehydrogenase leakage, lipid peroxidation, depletion of mitochondrial membrane potential, and activation of caspases (-3 and -9) in both types of cells. Individual and co-exposure of NiO NPs and BaP further accelerated the generation of free oxygen radicals (reactive oxygen species and hydrogen peroxide) and depletion of antioxidants (glutathione and various antioxidant enzymes). Remarkably, NiO NPs and BaP exerted synergistic toxicity to both HepG2 cells and primary rat hepatocytes. Moreover, combined toxicity of NiO NPs and BaP in both cells was mediated through free oxygen radicals induced oxidative stress. This work warrants further research on risk assessment of co-exposure effects NiO NPs and BaP in an appropriate in vivo model

Co-Exposure to SiO2 Nanoparticles and Arsenic Induced Augmentation of Oxidative Stress and Mitochondria-Dependent Apoptosis in Human Cells

Widespread application of silica nanoparticles (nSiO2) and ubiquitous metalloid arsenic (As) may increase their chances of co-exposure to human beings in daily life. Nonetheless, studies on combined effects of nSiO2 and As in human cells are lacking. We investigated the co-exposure effects of nSiO2 and As in human liver (HepG2) and human fibroblast (HT1080) cells. Results showed that nSiO2 did not cause cytotoxicity. However, exposure of As caused oxidative stress and apoptosis in both types of cells. Interesting results were that co-exposure of a non-cytotoxic concentration of nSiO2 significantly augmented the As induced toxicity in both cells. Intracellular level of As was higher in the co-exposure group (nSiO2 + As) than the As group alone, suggesting that nSiO2 facilitates the cellular uptake of As. Co-exposure of nSiO2 and As potentiated oxidative stress indicated by pro-oxidants generation (reactive oxygen species, hydrogen peroxide and lipid peroxidation) and antioxidants depletion (glutathione level, and glutathione reductase, superoxide dismutase and catalase activities). In addition, co-exposure of nSiO2 and As also potentiated mitochondria-mediated apoptosis suggested by increased expression of p53, bax, caspase-3 and caspase-9 genes (pro-apoptotic) and decreased expression of bcl-2 gene (anti-apoptotic) along with depleted mitochondrial membrane potential. To the best of our knowledge, this is the first study showing that co-exposure of nSiO2 and As induced augmentation of oxidative stress and mitochondria-mediated apoptosis in HepG2 and HT1080 cells. Hence, careful attention is required for human health assessment following combined exposure to nSiO2 and As