Ayanin combats against barium sulphate nanoparticles induced hepatotoxicity via modulating SIRT1/FOXO3a and HO-1/ferritin pathways: A biochemical, histopathological and computational approaches.

BACKGROUND: Barium sulphate nanoparticles (BaSO4NPs) are widely employed in different industrial applications and are reported to induce organ toxicities including hepatic impairments. Ayanin (AYN) is a naturally derived flavonoid that exhibits excellent pharmacological attributes.

OBJECTIVE: The current investigation was executed to determine the hepatoprotective potential of AYN against BaSO4NPs induced hepatotoxicity via assessing computational, biochemical, and histological parameters.

METHODOLOGY: Thirty-six Sprague Dawley rats were apportioned into four groups, i.e., control, BaSO4NPs (5.8 mgkg-1) group, BaSO4NPs (5.8 mgkg-1) + AYN (20 mgkg-1) group, and AYN (20 mgkg-1) alone treated group. Biochemical analyses were executed through standard assays and ELISA while mRNA expressions were determined through quantitative real-time polymerase chain reaction (qRT-PCR). High output computational analyses were performed to evaluate the efficacy of AYN.

FINDINGS: Our findings revealed that BaSO4NPs intoxication suppressed the gene expression of Sirtuin1 (SIRT1), heme-oxygenase-1 (HO-1), Forkhead box protein O3a (FOXO3a), and Ferritin Heavy Polypeptide1 (FTH1) while provoking the expression of Transferrin Receptor 1 (TfR1), tumor protein p53 (TP53) and tumor protein p21 (TP21). The enzymatic activities of superoxide dismutase (SOD), glutathione reductase (GSR), glutathione peroxidase (GPx), catalase (CAT), and contents of glutathione (GSH) were lowered while the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA) were exacerbated following the BaSO4NPs provision. Moreover, BaSO4NPs exposure augmented the concentrations of alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT), while reducing the concentrations of hepcidin, albumin, hemojuvelin, and total proteins in serum samples. The levels of cysteine-aspartic acid protease-9 (Caspase-9), Bcl-2-associated X protein (Bax), and cysteine-aspartic acid protease-3 (Caspase-3) were promoted while the levels of B-cell lymphoma-2 (Bcl-2) were diminished after BaSO4NPs administration. Hepatic tissues showed severe inflammation on BaSO4NPs exposure which was evident by escalated concentrations of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and cyclooxygenase-2 (COX-2). Besides, BaSO4NPs intoxication disrupted hepatic histology. Nonetheless, supplementation of AYN alleviated aforementioned hepatic impairments due to its anti-inflammatory, anti-oxidative and anti-apoptotic attributes. Our findings are further strengthened by in-silico results that demonstrated the strong binding affinities of AYN with key regulatory pathways.

CONCLUSION: BaSO4NPs provoked severe hepatic impairments by altering biochemical, computational and histological parameters. The concurrent therapy of AYN mitigated the adverse impacts of BaSO4NPs on hepatic tissues through the regulation of key signaling pathways, redox state, inflammatory and apoptotic indices, and histological alterations.