Treatment of Diabetes and Diabetes-Induced Cataracts as PPAR-γ Agonist and ALR2 Inhibitor by Synthesized Chalcones via In Silico, In Vitro and In Vivo Approaches
摘要
Objective: Diabetes and diabetes-induced diseases, such as cataracts, are growing global health problems, with ongoing research into better treatment options. In India, the prevalence of blindness is 15 per 1000 people, with cataracts alone accounting for 80% of cases. In this context, chalcones are frequently investigated by scientists as potential agents with diverse biological activities. Results and Discussion: Compounds IIa and IIc, which demonstrated ALR2 inhibition in in silico studies, were evaluated for the inhibition of rat lens aldose reductase, with Epalrestat used as the standard drug. Both compounds showed promising results, with IC50 values lower than that of the standard drug. Compounds IIb and IId, which exhibited promising results as PPAR-γ agonists in in silico analysis, were further evaluated in vivo using streptozotocin (STZ) and high-fat diet (HFD)-induced diabetic mice. The disease control group showed mature cataracts, while the treated groups exhibited the opposite at the end of the study. The mice were assessed for various parameters, including blood glucose, serum total cholesterol, triglycerides, HDL, LDL, aldose reductase levels, antioxidant enzyme activity, and lipid peroxidation at the conclusion of the treatment, in comparison with standard drug-treated groups (Epalrestat and Pioglitazone). Levels of aldose reductase, blood glucose, triglycerides, cholesterol, and LDL in the lens were significantly decreased, whereas antioxidant enzymes, total proteins, soluble proteins, and HDL were significantly increased in the treatment groups. The higher dose (200 mg/kg) of compound IIb showed pronounced protection. Six chalcones were synthesized via the Claisen–Schmidt condensation reaction and evaluated for anti-diabetic activity in silico against ALR2 and PPAR-γ receptors. The promising compounds were then assessed for their relative antidiabetic activity in vitro and in vivo. Conclusions: The results suggest that compound IIb may be effective against hyperglycemia-induced activation of the polyol pathway, oxidative and osmotic stress, as well as the subsequent development of diabetic cataracts.