Molecular mechanisms underlying the effects of beta-sitosterol on TGF-β1/Nrf2/SIRT1/p53-mediated signaling in the kidney of a high-fat diet and sucrose-induced type-2 diabetic rat

Diabetic nephropathy, a severe problem of diabetes mellitus, is exacerbated by high-fat diets, prompting a need for interventions. Previous study from our laboratory has shown that β-sitosterol, a potent plant sterol has anti-inflammatory and glucose-lowering efficacy by involving insulin metabolic signalling pathway but its role on anti-oxidant signaling pathways, play a crucial role in mitigating oxidative stress and inflammation associated diabetic nephropathy, highlighting its importance as a potential therapeutic target for managing this debilitating complication of diabetes is unknown. This study was aimed to intricate the molecular mechanisms involved in the potential of β-sitosterol (BSIT) on TGF-β1/Nrf2/SIRT1/p53 signaling in high fat diet (HFD) and sucrose induced diabetic nephropathy (DN) in the rat kidney by employing various comprehensive bioinformatic analysis. We have used various comprehensive methods such as pathway predictions, Drug-Protein Interaction, Functional annotation analysis, and molecular docking techniques. Further, in vivo analysis of BSIT on biochemical profiles, gene and protein expression analysis of anti-oxidant and inflammatory signaling molecules was performed in the kidney of high fat diet (HFD) and sucrose-induced diabetic nephropathy. Computational studies provided insights into β-sitosterol's binding affinities and interaction modes with key proteins, suggesting its potential to regulate TGF-β1/Nrf2/SIRT1/p53 signaling pathways. Results of in vivo findings validated computational predictions, showcasing BSIT's multifaceted effects in mitigating diabetic nephropathy and associated complications including regulation of lipid metabolism, combating oxidative stress, and inflammation. The findings underscore BSIT's therapeutic potential by preserving cellular viability, regulating cell death, enhancing antioxidant defence, and stabilizing metabolic processes. Our study concludes that BSIT's ability to potentially regulate TGF-β1/Nrf2/SIRT1/p53 pathways, emphasizing its promising role in managing diabetic nephropathy and associated complications.