Cerium Oxide Nanoparticles Protect against Oxidant Injury and Interfere with Oxidative Mediated Kinase Signaling in Human-Derived Hepatocytes

Abstract

Nanopartícules d’òxid de ceri; Cèl·lules hepàtiques humanes; Fosfoproteòmica

Nanopartículas de óxido de cerio; Células hepáticas humanas; Fosfoproteómica

Cerium oxide nanoparticles; Human hepatic cells; Phosphoproteomics

Cerium oxide nanoparticles (CeO2NPs) possess powerful antioxidant properties, thus emerging as a potential therapeutic tool in non-alcoholic fatty liver disease (NAFLD) progression, which is characterized by a high presence of reactive oxygen species (ROS). The aim of this study was to elucidate whether CeO2NPs can prevent or attenuate oxidant injury in the hepatic human cell line HepG2 and to investigate the mechanisms involved in this phenomenon. The effect of CeO2NPs on cell viability and ROS scavenging was determined, the differential expression of pro-inflammatory and oxidative stress-related genes was analyzed, and a proteomic analysis was performed to assess the impact of CeO2NPs on cell phosphorylation in human hepatic cells under oxidative stress conditions. CeO2NPs did not modify HepG2 cell viability in basal conditions but reduced H2O2- and lipopolysaccharide (LPS)-induced cell death and prevented H2O2-induced overexpression of MPO, PTGS1 and iNOS. Phosphoproteomic analysis showed that CeO2NPs reverted the H2O2-mediated increase in the phosphorylation of peptides related to cellular proliferation, stress response, and gene transcription regulation, and interfered with H2O2 effects on mTOR, MAPK/ERK, CK2A1 and PKACA signaling pathways. In conclusion, CeO2NPs protect HepG2 cells from cell-induced oxidative damage, reducing ROS generation and inflammatory gene expression as well as regulation of kinase-driven cell survival pathways.

This research was funded by grants to W. Jiménez from Ministerio de Economia y Competitividad [grants, SAF2015-64126-R, RTI2018-094734-B-C21], to M. Morales-Ruiz [grant SAF2016-75358-R] and to G. Casals [grant PI-15/00777]; cofinanced by FEDER, European Union, a way of making Europe, Agència de Gestió d’Ajuts Universitaris i de Recerca [grant SGR 2014/219]; and Fundació La Marató de TV3 [grant Marató 120930]; Wuyi University Funding for Hight Talents Introduction, grant number 2018TP010 and Foundation from Department of Education of Guangdong Province, grant number 2016KCXTD005 and 2017KSYS010, to Eudald Casals The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III.