β-sitosterol potential against chronic hyperglycemia induced diabetic nephropathy: A dual approach using computational and in-vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Solanum surattense (SS) fruit extract is traditionally used to treat diabetes. β-sitosterol (BSIT) is an active constituent of SS and extensively explored for its antihyperglycemic potential through acute preclinical studies. However, the effect of BSIT on diabetic nephropathy (DN) against uncontrolled chronic hyperglycemia is limited.

AIM OF THE STUDY: To explore β-sitosterol's therapeutic benefits in DN, while also elucidating the underlying mechanism.

MATERIALS AND

METHODS

A streptozotocin-induced chronic hyperglycemia model in Wistar rats was employed. Thereafter, biomarkers for diabetes, kidney, and liver functions, etc., were studied using commercially available kits. Moreover, renal oxidative stress and inflammation biomarkers were estimated using ELISA kits. Pancreas, kidney, and liver tissues underwent H&E staining. Furthermore, network pharmacology and molecular docking were used to predict the mechanism.

RESULTS

β-sitosterol administration (15 and 20 mg/kg, p.o., n=6) for forty days significantly improved glycaemic control and lipid profile. This treatment also restored renal and hepatic functions (reduced creatinine, urea, albuminuria, bilirubin, liver enzymes, etc.). Moreover, BSIT ameliorated the electrolyte and iron homeostasis. β-sitosterol was also found to reduce renal Nox-4, ROS, MDA and TNF-α significantly, while enhancing SOD, CAT, and GSH. Histologically, BSIT showed mild-to-moderate effects on islet atrophy and renal tubule vacuolization. Moreover, network pharmacology depicted that β-sitosterol may work through AMPK and ppar signalling pathways. β-sitosterol's docking to ppar-γ, ppar-δ, AMPK, and LXRα activator sites showed binding energies of -9.6, -7.0, -7.3, and -10.6 kcal/mol, respectively.

CONCLUSIONS

Overall results analysis revealed that β-sitosterol at a dose of 20 mg/kg substantially ameliorates DN.