Suchergebnisse

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.

Carcinoma hepatocel·lular; Regeneració hepàtica; Nanocèria ; Carcinoma hepatocelular; Regeneración hepática; Nanoceria ; Hepatocellular carcinoma; Liver regeneration; Nanoceria ; Oxidative stress induced by the overproduction of free radicals or reactive oxygen species (ROS) has been considered as a key pathogenic mechanism contributing to the initiation and progression of injury in liver diseases. Consequently, during the last few years antioxidant substances, such as superoxide dismutase (SOD), resveratrol, colchicine, eugenol, and vitamins E and C have received increasing interest as potential therapeutic agents in chronic liver diseases. These substances have demonstrated their efficacy in equilibrating hepatic ROS metabolism and thereby improving liver functionality. However, many of these agents have not successfully passed the scrutiny of clinical trials for the prevention and treatment of various diseases, mainly due to their unspecificity and consequent uncontrolled side effects, since a minimal level of ROS is needed for normal functioning. Recently, cerium oxide nanoparticles (CeO2NPs) have emerged as a new powerful antioxidant agent with therapeutic properties in experimental liver disease. CeO2NPs have been reported to act as a ROS and reactive nitrogen species (RNS) scavenger and to have multi-enzyme mimetic activity, including SOD activity (deprotionation of superoxide anion into oxygen and hydrogen peroxide), catalase activity (conversion of hydrogen peroxide into oxygen and water), and peroxidase activity (reducing hydrogen peroxide into hydroxyl radicals). Consequently, the beneficial effects of CeO2NPs treatment have been reported in many different medical fields other than hepatology, including neurology, ophthalmology, cardiology, and oncology. Unlike other antioxidants, CeO2NPs are only active at pathogenic levels of ROS, being inert and innocuous in healthy cells. In the current article, we review the potential of CeO2NPs in several experimental models of liver disease and their safety as a therapeutic agent in humans as well. ; Researches referred by the authors were funded by Fundació La Marató de TV3 (grant Marató 120930), Dirección General de Investigación Científica y Técnica (SAF15-64126-R and RTI2018-094734-B-C21, PID2019-105502RB, and BES-2017-08023), Agència de Gestió d'Ajuts Universitaris i de Recerca (SGR 2017/2019), and Instituto de Salud Carlos III (FIS PI15-00077 and FIS PI19-00774) co-financed by FEDER, European Union, "A way of making Europe" and the National Natural Science Foundation of China (31950410536). The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III.

[Background and aims]: The 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. ; [Methods]: Cirrhosis 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. ; [Results]: CH-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. ; [Conclusions]: Endothelial 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. ; Supported by grants from the Ministerio de Economia y Competitividad (SAF 2015-64126-R to WJ, PI15-00077 to GC and SAF2016-75358-R to MM-R), co-financed by FEDER, European Union, a way of making Europe, Fundacio La Marato de TV3 (Marato 120930), Spanish MINECO (MAT2015-70725-R) and the Catalan Agència de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR-143 to VP and 2016-BP-00301 to EC). JR-V is the recipient of a BIOTRACK Postdoctoral Fellowship supported by the European Community's Seventh Framework Programme and the MINECO (Contract 229673). CIBERehd is financed by the Instituto de Salud Carlos III. ; Peer reviewed

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipids. Antisteatotic effects of cerium oxide nanoparticles (CeO2NPs) have recently been shown in animal models of liver disease. However, it is unclear whether the activity of CeO2NPs is related solely to the decrease in oxidative stress or, in addition, they directly decrease liver fatty acid accumulation. To address this question, in this work, we used an in vitro model of hepatocellular steatosis, exposing HepG2 cells to oleic and palmitic acid. Cell uptake of CeO2NPs and their effect on oxidative stress and viability of hepatic cells cultured with H2O2 were also evaluated. Results show that CeO2NPs were uptaken by HepG2 cells and reduced oxidative stress and improved cell viability. Treatment with oleic and palmitic acid increased lipogenesis and the content of different fatty acids. CeO2NPs reduced palmitic and stearic acid and most fatty acids consisting of more than 18 carbon atoms. These effects were associated with significant changes in elongase and desaturase activity. In conclusion, CeO2NPs directly protected HepG2 cells from cell injury in oxidative stress conditions and reduced fatty acid content in steatotic conditions by inducing specific changes in fatty acid metabolism, thus showing potential in the treatment of NAFLD. ; This research was funded by Ministerio de Economía y Competitividad, grant number PI15-00077 to G.C. and SAF2016-75358-R to M.M-R., co-financed by FEDER, European Union, "A way of making Europe".; "Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement de la Generalitat de Catalunya, convocatòria d'Indústria del Coneixement modalitat B", grant number 2018_PROD_00187 toW.J, cofinanced by the European Union through the European Regional Development Fund (ERDF), "A way of making Europe".; CIBERehd is financed by the Instituto de Salud Carlos III.; Wuyi University Funding for Hight Talents Introduction, grant number 2018TP010 to E.C. and 2018TP011 to M.Z.; Foundation from Department of Education of Guangdong Province, grant number 2016KCXTD005 and 2017KSYS010, to E.C. and M.Z. The APC was funded by Wuyi University Funding for Hight Talents Introduction, grant number 2018TP010 to E.C. ; Peer reviewed

This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH). ; 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. ; Peer reviewed

Some findings of these studies were previously presented at The International Liver Congress (ILC) 2017 Meeting of the European Association for the Study of the Liver (EASL) (19–23 April, 2017; Amsterdam, The Netherlands). ; Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, ranging from steatosis to non-alcoholic steatohepatitis (NASH). Recently, cerium oxide nanoparticles (CeO2NPs) have emerged as a new antioxidant agent with hepatoprotective properties in experimental liver disease. The aim of the current investigation was to elucidate whether CeO2NPs display beneficial effects in an experimental model of NAFLD.Therefore, fifteen Wistar rats were subjected to a methionine and choline deficient diet (MCDD) for 6 weeks and intravenously treated with CeO2NP or vehicle during the weeks three and four of the diet. The effect of CeO2NPs on serum biochemistry, hepatic steatosis, inflammation, fatty acid content and expression of reactive oxygen species (ROS) and lipid metabolism related genes was assessed. MCDD fed rats showed increased inflammation, enhanced hepatic lipid accumulation of both saturated and unsaturated fatty acids (FAs) and overexpression of genes related to fatty liver and ROS metabolism. Treatment with CeO2NPs was able to reduce the size and content of hepatocyte lipid droplets, the hepatic concentration of triglyceride- and cholesterol ester-derived FAs and the expression of several genes involved in cytokine, adipokine and chemokine signaling pathways. These findings suggest that CeO2NPs could be of beneficial value in NAFLD. ; This research was supported by grants to W. Jiménez from Ministerio de Economia y Competitividad [grants SAF2015-64126R, 12-35979, BES-2013-063685, SAFRTI2018-094734-B-C21], to M. Morales-Ruiz [grant SAF2016-75358-R] and to G. Casals [grant P74844I/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]. The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III. ; Peer reviewed