title: Cerium oxide nanoparticles reduce steatosis, portal hypertension and display anti-inflammatory properties in rats with liver fibrosis.
abstract: OBJECTIVE
  Cerium oxide nanoparticles (CeO2NPs) have proven to behave as free radical scavengers and/or anti-inflammatory agents. The aim of the study was to determine whether CeO2NPs display hepatoprotective properties in experimental chronic liver disease.
  
  
  METHODS
  Systemic and hepatic effects of nanoparticles were assessed in CCl4-treated rats receiving CeO2NPs or vehicle twice weekly for two weeks and CCl4 treatment was continued for 8 additional weeks. Thereafter, mean arterial pressure and portal pressure (PP) were assessed and serum samples obtained to measure standard hepatic and renal function tests. Organ and subcellular distribution of NPs were assessed using mass spectrometry (ICP-MS) and transmission electron microscopy. Liver samples were obtained to evaluate steatosis, α-SMA expression, macrophage infiltration, apoptosis and mRNA expression of oxidative stress, inflammatory or vasoactive related genes.
  
  
  RESULTS
  Most CeO2NPs were located in the liver and it reduced hepatic steatosis, ameliorated systemic inflammatory biomarkers and improved PP without affecting mean arterial pressure. In addition, a marked reduction in mRNA expression of inflammatory cytokines (TNFα, IL1β, COX-2, iNOS), ET-1 and messengers related to oxidative (Epx, Ncf1, Ncf2) or endoplasmic reticulum (Atf3, Hspa5) stress signaling pathways was observed in the liver of rats receiving CeO2NPs. This was associated with reduced macrophage infiltration and reduced abundance of caspase-3, α-SMA and inflammatory cytokines.
  
  
  CONCLUSIONS
  CeO2NPs administration to CCl4-treated rats protects against chronic liver injury by reducing liver steatosis and portal hypertension and markedly attenuating the intensity of the inflammatory response, thereby suggesting that CeO2NPs may be of therapeutic value in chronic liver disease.
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Denise
authors.initials: D
authors.lastname: Oró
authors.affiliation: Institut Català de Nanociència i Nanotecnologia (ICN2), Bellaterra, Spain.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Yudina
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain; Department Ciencies Fisiologiques I, University of Barcelona, Barcelona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Fernández-Varo
authors.affiliation: Institut Català de Nanociència i Nanotecnologia (ICN2), Bellaterra, Spain.
authors.forename: Eudald
authors.initials: E
authors.lastname: Casals
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Reichenbach
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Gregori
authors.initials: G
authors.lastname: Casals
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Bernardino
authors.initials: B
authors.lastname: González de la Presa
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sandalinas
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carvajal
authors.affiliation: Institut Català de Nanociència i Nanotecnologia (ICN2), Bellaterra, Spain; Institut Català de Recerca i Estudis Avançats, (ICREA), Barcelona, Spain; Vall d'Hebron Insitute of Research (VHIR), Barcelona, Spain. Electronic address: victor.puntes@icn.cat.
authors.forename: Victor
authors.initials: V
authors.lastname: Puntes
authors.affiliation: Biochemistry and Molecular Genetics Service, Hospital Clínic Universitari, IDIBAPS, CIBERehd, Barcelona, Spain; Department Ciencies Fisiologiques I, University of Barcelona, Barcelona, Spain. Electronic address: wjimenez@clinic.ub.es.
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jiménez
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002563:Cerium / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000188:drug therapy*; D006975:Hypertension, Portal / Q000188:drug therapy*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy*; D053758:Nanoparticles / Q000008:administration & dosage*; D051381:Rats; D017382:Reactive Oxygen Species
chemical_list: D000199:Actins; D000893:Anti-Inflammatory Agents; D053148:Caspase 3; D002563:Cerium; D017382:Reactive Oxygen Species; C498862:Acta2 protein, rat; C030583:ceric oxide
keywords: Cerium oxide nanoparticles; Experimental fibrosis; Hepatic inflammation; Oxidative stress; Portal pressure