Apilarnil Mitigates Copper Nanoparticle-Induced Hepatorenal Injury in Rats: Associations with Oxidative Stress, Inflammatory Markers and ER-Stress-Related Gene Expression

Background/Objectives: This study investigated the preventive effects of apilarnil (APL) against copper nanoparticle (CuNPs)-induced liver and kidney injury in rats. Methods: Thirty-five rats were randomly allocated into five groups (n = 7): Control (physiological saline), APL (400 mg/kg), CuNPs (100 mg/kg), CuNPs + APL200 (100 mg/kg CuNPs + 200 mg/kg APL) and CuNPs + APL400 (100 mg/kg CuNPs + 400 mg/kg APL). All treatments were administered orally by gavage for 28 consecutive days. Results: CuNPs administration increased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN) and creatinine levels, whereas APL attenuated these biochemical alterations. CuNPs also decreased superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities together with reduced glutathione (GSH) levels while increasing malondialdehyde (MDA), whereas APL attenuated these oxidative alterations. Furthermore, CuNPs markedly upregulated the mRNA expression of endoplasmic reticulum (ER) stress-related genes, including activating transcription factor 6 (ATF6), glucose-regulated protein 78 (GRP78), protein kinase RNA-like ER kinase (PERK) and C/EBP homologous protein (CHOP). In parallel, CuNPs increased the protein levels of Toll-like receptor 4 (TLR4), high-mobility group box 1 (HMGB1), nuclear factor-κB (NF-κB), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α), whereas APL attenuated these inflammatory responses. Histopathological examination showed that APL markedly attenuated CuNPs-induced hepatic and renal lesions and reduced the immunoreactivity of caspase-3 and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Conclusions: Overall, APL alleviated CuNPs-induced hepatorenal toxicity and was associated with improvements in oxidative stress parameters, ER stress-related gene expression, inflammatory protein concentrations, caspase-3 immunoreactivity, and oxidative DNA damage.