Histomorphological changes and molecular mechanisms underlying the ameliorative effect of resveratrol on the liver of silver nanoparticles-exposed rats.

ABSTRACT

Exposure to the deleterious effects of silver nanoparticles (AgNPs) is inevitable due to their wide use in medicine and daily life. The current study aimed to delineate the histomorphological changes and the molecular mechanisms underlying the ameliorative effect of Resveratrol (RSV) on rats' livers exposed to AgNPs. Fifty healthy adult male Wistar albino rats were divided into four groups control, AgNPs-exposed, RSV-treated after AgNPs exposure, and recovery groups. Liver sections were examined by light and electron microscopes, and immunohistochemistry was performed for detection of activated caspase3 and TNFα. Serum ALT and AST, plasma levels of TNFα, IL-6, GSH and SOD were measured. mRNA expression of SIRT1, ADORA3, PAI, CDK1, Nrf2 and NFκB genes in liver tissue homogenate was performed using qRT-PCR. AgNPs-exposure for 28 days caused marked liver tissue damage with trapping in hepatocytes and Kupffer cells, while RSV treatment ameliorated liver ultrastructure and function. Our results clarified the molecular basis of RSV ameliorative effect on liver tissue by significant upregulation of SIRT1-NrF2 signaling pathway with increased levels of the antioxidant GSH and SOD, which represent the antioxidant effect of RSV. Significant upregulation of the protective ADORA3 with downregulation of the proinflammatory PAI-1 and NFκB mRNA expression levels besides decreased plasma levels of TNFα, IL-6 and decreased immunoexpression of TNFα in liver tissue, represent the anti-inflammatory effect of RSV. In addition, decreased immunoexpression of caspase3 and downregulation of CDK1 expression, represent its antiapoptotic effect. In conclusion: RSV ameliorates AgNPs-induced liver damage by antioxidant, anti-inflammatory and antiapoptotic effects.Abbreviations AgNPs Silver nanoparticles, RSV Resveratrol, ROS Reactive oxygen species, ESR Electron spin resonance, DMPO 5,5-Dimethyl-1-pyrroline-N-oxide, H2O2 Hydrogen peroxide, SOD Superoxide dismutase, CAT Catalase, GPx Glutathione peroxidase, MPTP Methyl-4-phenyl-1.2.3.6-tetrahydropyridine, MDA Malondialdehyde, TNF Tumor necrosis factor, GSH Glutathione, Nrf2 Nuclear factor-erythroid 2-related factor 2, ARE Antioxidant response elements, KEAP1 Kelch-1ike ECH-associated protein l, AMPK AMP-activated protein kinase, HO-1 Heme oxygenase-1, NF-κB Nuclear factor-kappa B, SIRT1 Sirtuins, FOXO Forkhead box, UCP2 Uncoupling protein 2, STZ Streptozotocin nicotinamide, HSC hepatic stellate cells, ECM extracellular matrix.