title: Large graphene quantum dots alleviate immune-mediated liver damage.
abstract: We investigated the effect of large (40 nm) graphene quantum dots (GQDs) in concanavalin A (Con A; 12 mg/kg i.v.)-induced mouse hepatitis, a T cell-mediated liver injury resembling fulminant hepatitis in humans. Intravenously injected GQDs (50 mg/kg) accumulated in liver and reduced Con A-mediated liver damage, as demonstrated by histopathological analysis and a decrease in liver lipid peroxidation and serum levels of liver transaminases. The cleavage of apoptotic markers caspase-3/PARP and mRNA levels of proapoptotic mediators Puma, Noxa, Bax, Bak1, Bim, Apaf1, and p21, as well as LC3-I conversion to autophagosome-associated LC3-II and expression of autophagy-related (Atg) genes Atg4b, Atg7, Atg12, and beclin-1, were attenuated by GQDs, indicating a decrease in both apoptosis and autophagy in the liver tissue. This was associated with the reduced liver infiltration of immune cells, particularly the T cells producing proinflammatory cytokine IFN-γ, and a decrease in IFN-γ serum levels. In the spleen of GQD-exposed mice, mRNA expression of IFN-γ and its transcription factor T-bet was reduced, while that of the IL-33 ligand ST2 was increased. The hepatoprotective effect of GQDs was less pronounced in ST2-deficient mice, indicating that it might depend on ST2 upregulation. In vitro, GQDs inhibited splenocyte IFN-γ production, reduced the activation of extracellular signal-regulated kinase in macrophage and T cell lines, inhibited macrophage production of the free radical nitric oxide, and reduced its cytotoxicity toward hepatocyte cell line HepG2. Therefore, GQDs alleviate immune-mediated fulminant hepatitis by interfering with T cell and macrophage activation and possibly by exerting a direct hepatoprotective effect.
authors.affiliation: Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac , 69 Svetozara Markovica Street, 34000 Kragujevac, Serbia.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Volarevic
authors.forename: Verica
authors.initials: V
authors.lastname: Paunovic
authors.forename: Zoran
authors.initials: Z
authors.lastname: Markovic
authors.forename: Bojana
authors.initials: B
authors.lastname: Simovic Markovic
authors.forename: Maja
authors.initials: M
authors.lastname: Misirkic-Marjanovic
authors.forename: Biljana
authors.initials: B
authors.lastname: Todorovic-Markovic
authors.forename: Sanja
authors.initials: S
authors.lastname: Bojic
authors.forename: Ljubica
authors.initials: L
authors.lastname: Vucicevic
authors.forename: Svetlana
authors.initials: S
authors.lastname: Jovanovic
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Arsenijevic
authors.forename: Ivanka
authors.initials: I
authors.lastname: Holclajtner-Antunovic
authors.forename: Momir
authors.initials: M
authors.lastname: Milosavljevic
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dramicanin
authors.forename: Tamara
authors.initials: T
authors.lastname: Kravic-Stevovic
authors.forename: Darko
authors.initials: D
authors.lastname: Ciric
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D003208:Concanavalin A / Q000009:adverse effects; D019610:Cytoprotection / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006108:Graphite / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006505:Hepatitis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D045663:Quantum Dots / Q000737:chemistry*
chemical_list: D015415:Biomarkers; D003208:Concanavalin A; D006108:Graphite
keywords: apoptosis; autophagy; graphene; hepatitis; quantum dot