Regulation of TGF-β1, PI3K/PIP3/Akt, Nrf-2/Keap-1 and NF-κB signaling pathways to avert bifenthrin induced hepatic injury: A palliative role of daidzein.

Abstract

Bifenthrin (BFN) is a noxious insecticide which is reported to damage various body organs. Daidzein (DZN) is a natural flavone with excellent pharmacological properties. This research was conducted to evaluate the alleviative strength of DZN to counteract BFN prompted liver toxicity in male albino rats. Thirty-two rats were divided into 4 groups i.e., the control, BFN (7 mg /kg), BFN (7 mg/kg) + DZN (20 mg/kg) and DZN (20 mg/kg) alone group. The biochemical assessment was performed by using qRT PCR as well as standard ELISA protocols. The findings are validated by applying pharmacodynamic techniques including molecular simulation. It was observed that BFN reduced the gene expressions of phosphoinositide 3-kinase (PI3K), phosphatidylinositol-3, 4, 5-triphosphate (PIP3), Protein kinase B (Akt), nuclear factor erythroid 2-related factor 2 (Nrf-2) while promoting the gene expressions of Kelch-like ECH-associated protein 1 (Keap-1). Moreover, BFN notably reduced the activities of glutathione reductase (GSR), heme-oxygenase-1 (HO-1), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) while elevating the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). BFN promoted the levels of matrix metallopeptidase 2 (MMP-2), Procollagen III N-terminal Pro-peptide (PIIINP), alkaline phosphatase (ALP), transforming growth factor-beta-1 (TGF-β1), aspartate aminotransferase (AST), tissue inhibitor of matrix metalloproteinases 1 (TIMP1), and alanine aminotransferase (ALT). The levels of nuclear factor- kappa B (NF-κB), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) were increased following the BFN intoxication. BFN enhanced the expressions of cysteine-aspartic acid protease-3 (Caspase-3) and Bcl-2-associated X protein (Bax) while suppressing the gene expression of B-cell lymphoma-2 (Bcl-2). Moreover, BFN disrupted the normal histology of liver tissues. Nonetheless, DZN treatment remarkably alleviated hepatic damages owing to its antioxidative, anti-apoptotic as well as anti-inflammatory abilities. However, DZN supplementation remarkably safeguarded which is further confirmed by in-silico assessment.