Computational Chemistry, Network Pharmacology, and Computational Biology Integrated with Experimental Assays for Determining the Anti-Diabetic and Kidney-Protecting Effects of Rutoside (Rutin) Molecule

Diabetic Nephropathy (DN), a major complication of diabetes mellitus, is a leading cause of end-stage renal disease worldwide. This study explores the therapeutic potential of rutoside (rutin) in combating DN using a streptozotocin (STZ)-induced diabetic rat model. Additionally, we conducted mechanistic evaluations to elucidate the underlying pathways involved in rutin-mediated renoprotection, focusing on network pharmacological analysis and molecular interactions through in silico molecular docking studies, and experimental validation of its antioxidant and anti-inflammatory effects. A network pharmacological approach was used with the initial screening of the pharmacokinetic properties of rutin and toxicity evaluation, which indicated low GI absorption with a bioavailability value of ۰.۱۷ and no major toxicity associated with the rutin molecule. Target prediction revealed ۹۷ biological targets of rutin and ۸۵۸ targets of diabetic nephropathy; among these ۳۵ targets were found to be common between rutin and diabetic nephropathy, and these targets have a significant probability in the pathogenesis of the disease. A Protein-Protein Interaction (PPI) network of these common targets was constructed to identify linkages between the different protein targets. Identification of hub genes and Gene Ontology (GO) and KEGG enrichment pathways was also carried out to demonstrate the involvement of different genes, and their functions, besides the signalling pathways, and how these pathways are connected with diabetic nephropathy. Three target proteins, including MTOR, PIK۳R۱, and NFKB۱, were identified by network pharmacology to be the most closely related protein targets to DN and were subjected to in silico molecular docking analysis to identify key molecular interactions and the involved amino acid residues of the targets. Rutin treatment exhibited a considerable hypoglycaemic index in comparison to the diabetic group. Treatment with rutin also led to a substantial reduction in raised levels of the cytokines involved in inflammation. The antioxidant enzymes were effectively brought to appropriate levels and under control by rutin treatment. Oral administration of rutin to diabetic rats considerably improved renal CAT; catalase, SOD; superoxide dismutase, and GSH; glutathione. The TNF-α and IL-۱β levels in the renal cells were significantly (p< ۰.۰۰۱) reduced when rutin was administered orally to diabetic rats. In conclusion, our study provided evidence based on bioinformatics, network pharmacology, as well as experimental data about the protective effects of rutin in diabetic nephropathy, and as such, rutin can be a potential drug candidate for future research in this field.

کلیدواژه ها:

Rutin ، Antioxidant ، Diabetic Nephropathy ، Apoptosis ، Anti-inflammatory ، Molecular docking