Network and experimental pharmacology to decode the antihyperglycemic action of selected ethnobotanicals

Background: Medicinal plants Curcuma longa, Emblica officinalis, Momordica charantia, Pterocarpus marsupium, Salacia chinensis, and Tinospora cordifolia are ethnopharmacologically proven for their antidiabetic activity. However, their combined effect against diabetes has not been proven yet. Hence, this study is examined the combined effect of aforementioned medicinal plants through network and experimental pharmacology. Methods: For network pharmacology, compound SMILES from all plants were assessed for drug-likeness score, targets were identified and enriched. The network was constructed using Cytoscape ver. 3.5.1 and molecular docking was performed using Schrodinger suite 2019. Further experimental studies were carried in a high-fat diet low-dose streptozotocin-induced diabetic model. In addition, α-amylase and α-glucosidase enzyme inhibition assays were performed via in vitro approach. Results Among all bioactives, (S)-tembetarine from E. officinalis was predicted for highest drug-likeness score i.e., 1.2. Similarly, enrichment analysis of their targets enriched 202 KEGG pathways, 167 different cellular components, 2334 biological processes, and 301 molecular functions. In addition, a docking study revealed Lobatoside I from M. charantia to have highest binding affinity with α-amylase and (−)-(3S)-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-(6E)-6-hepten-3-ol from C. longa to have a highest binding affinity with α-glucosidase. Further experimental pharmacology reflected that the efficacy of a combined extract of aforementioned ethnobotanicals ameliorated hyperglycemia by reversing glucose homeostasis which was confirmed through oral glucose tolerance test and insulin tolerance test. Also, it ameliorated lipid metabolism and glycogenesis. Further log concentration of α-amylase and α-glucosidase inhibition assay of combined extract ranged from 1.5 to 3.5. Bodyweight was gradually increased and there was a depletion in food intake. In addition, there was a decrease in nitrogen metabolites, TG, LDL, VLDL, and TC levels, and an increase in HDL and hepatic glycogen content after 18 days of combination therapy. Conclusion: The study demonstrated significant antidiabetic activity by improving glucose homeostasis, inhibiting α-amylase and α-glucosidase enzymes, and ameliorating metabolic abnormalities through multi-target mechanisms.