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Oxidative Stress Boosts the Uptake of Cerium Oxide Nanoparticles by Changing Brain Endothelium Microvilli Pattern.

ABSTRACT: Vascular oxidative stress is considered a worsening factor in the progression of Alzheimer's disease (AD). Increased reactive oxygen species (ROS) levels promote the accumulation of amyloid-? peptide (A?), one of the main hallmarks of AD. In turn, A? is a potent inducer of oxidative stress. In early stages of AD, the concomitant action of oxidative stress and A? on brain capillary endothelial cells was observed to compromise the blood-brain barrier functionality. In this context, antioxidant compounds might provide therapeutic benefits. To this aim, we investigated the antioxidant activity of cerium oxide nanoparticles (CNP) in human cerebral microvascular endothelial cells (hCMEC/D3) exposed to A? oligomers. Treatment with CNP (13.9 ± 0.7 nm in diameter) restored basal ROS levels in hCMEC/D3 cells, both after acute or prolonged exposure to A?. Moreover, we found that the extent of CNP uptake by hCMEC/D3 was +43% higher in the presence of A?. Scanning electron microscopy and western blot analysis suggested that changes in microvilli structures on the cell surface, under pro-oxidant stimuli (A? or H₂O₂), might be involved in the enhancement of CNP uptake. This finding opens the possibility to exploit the modulation of endothelial microvilli pattern to improve the uptake of anti-oxidant particles designed to counteract ROS-mediated cerebrovascular dysfunctions.

SUBMITTER: Dal Magro R

PROVIDER: S-EPMC7916071 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Oxidative Stress Boosts the Uptake of Cerium Oxide Nanoparticles by Changing Brain Endothelium Microvilli Pattern.

Dal Magro Roberta R Vitali Agostina A Fagioli Stefano S Casu Alberto A Falqui Andrea A Formicola Beatrice B Taiarol Lorenzo L Cassina Valeria V Marrano Claudia Adriana CA Mantegazza Francesco F Anselmi-Tamburini Umberto U Sommi Patrizia P Re Francesca F

Antioxidants (Basel, Switzerland) 20210209 2

Vascular oxidative stress is considered a worsening factor in the progression of Alzheimer's disease (AD). Increased reactive oxygen species (ROS) levels promote the accumulation of amyloid-β peptide (Aβ), one of the main hallmarks of AD. In turn, Aβ is a potent inducer of oxidative stress. In early stages of AD, the concomitant action of oxidative stress and Aβ on brain capillary endothelial cells was observed to compromise the blood-brain barrier functionality. In this context, antioxidant com ...[more]

PMID: 33572224

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Project description:Background and aimsThe occurrence of endothelial alterations in the liver and in the splanchnic vasculature of cirrhotic patients and experimental models of liver diseases has been demonstrated. However, the pathological role of the portal vein endothelium in this clinical context is scarcely studied and, therefore, deserves attention. In this context, we aimed to investigate whether pathological endothelial activation occurs in the portal vein of cirrhotic rats.MethodsCirrhosis was induced in wistar rats by CCl4 inhalation. We generated immortalized endothelial cells from the portal vein of control (CT-iPVEC) and cirrhotic rats (CH-iPVEC) by retroviral transduction of the SV40 T antigen. We assessed differential gene expression and intracellular reactive oxygen species (ROS) levels in iPVECs and in portal veins of control and cirrhotic rats. Finally, we assessed the therapeutic effectiveness of cerium oxide nanoparticles (CeO2NP) on reversing PVEC activation and macrophage polarization.ResultsCH-iPVECs overexpressed collagen-I, endothelin-1, TIMP-1, TIMP-2, IL-6 and PlGF genes. These results were consistent with the differential expression showed by whole portal veins from cirrhotic rats. In addition, CH-iPVECs showed a significant increase in intracellular ROS and the capacity of potentiating M1 polarization in macrophages. The treatment of CH-iPVECs with CeO2NPs blocked intracellular ROS formation and IL-6 and TIMP-2 gene overexpression. In agreement with the in vitro results, the chronic treatment of cirrhotic rats with CeO2NPs also resulted in the blockade of both ROS formation and IL-6 gene overexpression in whole portal veins.ConclusionsEndothelial cells from portal vein of cirrhotic rats depicted an abnormal phenotype characterized by a differential gene expression and the induction of M1 polarization in macrophages. We identified the excess of intracellular reactive oxygen species (ROS) as a major contributor to this altered phenotype. In addition, we demonstrated the utility of the nanomaterial cerium oxide as an effective antioxidant capable of reverse some of these pathological features associated with the portal vein in the cirrhosis condition.

Project description:Cerium oxide nanoparticles (nanoceria) are effective at quenching reactive oxygen species (ROS) in cell culture and animal models. Although nanoceria reportedly deposit in lungs, their efficacy in conferring lung protection during oxidative stress remains unexplored. Thus, the study evaluated the protective efficacy of nanoceria in rat lung tissue during hypobaric hypoxia.A total of 48 animals were randomly divided into four equal groups (control [C], nanoceria treated [T], hypoxia [H], and nanoceria treated plus hypoxia [T+H]). Animals were injected intraperitoneally with either a dose of 0.5 ?g/kg body weight/week of nanoceria (T and T+H groups) or vehicle (C and H groups) for 5 weeks. After the final dose, H and T+H animals were challenged with hypobaric hypoxia, while C and T animals were maintained at normoxia. Lungs were isolated and homogenate was obtained for analysis of ROS, lipid peroxidation, glutathione, protein carbonylation, and 4-hydroxynonenal-adduct formation. Plasma was used for estimating major inflammatory cytokines using enzyme-linked immunosorbent assay. Intact lung tissues were fixed and both transmission electron microscopy and histopathological examinations were carried out separately for detecting internalization of nanoparticles as well as altered lung morphology.Spherical nanoceria of 7-10 nm diameter were synthesized using a microemulsion method, and the lung protective efficacy of the nanoceria evaluated during hypobaric hypoxia. With repeated intraperitoneal injections of low micromole concentration, we successfully localized the nanoceria in rodent lung without any inflammatory response. The lung-deposited nanoceria limited ROS formation, lipid peroxidation, and glutathione oxidation, and prevented oxidative protein modifications like nitration and carbonyl formation during hypobaric hypoxia. We also observed reduced lung inflammation in the nanoceria-injected lungs, supporting the anti-inflammatory properties of nanoceria.Cumulatively, these results suggest nanoceria deposit in lungs, confer protection by quenching noxious free radicals during hypobaric hypoxia, and do not evoke any inflammatory response.

Dataset Information

Oxidative Stress Boosts the Uptake of Cerium Oxide Nanoparticles by Changing Brain Endothelium Microvilli Pattern.

Publications

Oxidative Stress Boosts the Uptake of Cerium Oxide Nanoparticles by Changing Brain Endothelium Microvilli Pattern.

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