Network pharmacology, molecular docking, and in vivo evaluation of Cassia tora Linn: Anthraquinones as multi-target agents against diabetes mellitus

Diabetes mellitus is a major global health challenge, and conventional single-target therapies often fail to prevent its long-term complications. This study investigated the antidiabetic mechanisms of Cassia tora Linn. (CTL) seed anthraquinones using an integrated network pharmacology, molecular docking, and in vivo validation approach. Thirty-five reported phytoconstituents were screened using ADME criteria (oral bioavailability ≥۳۰% and drug-likeness ≥۰.۱۸), resulting in the selection of ten bioactive anthraquinones. Target prediction identified ۱,۰۰۳ compound-associated targets, and ۴,۱۲۵ diabetes-related genes were retrieved from the GeneCards, OMIM, and DisGeNET databases, yielding ۲۸۹ common targets. Protein–protein interaction analysis identified AKT۱, PPARG, SRC, EGFR, BCL۲, PTGS۲, and CASP۳ as major hub genes. KEGG enrichment analysis revealed the significant involvement of the PI۳K-Akt, PPAR, AGE-RAGE, MAPK, insulin resistance, and lipid metabolism pathways (P<۰.۰۵). Molecular docking demonstrated the strong binding affinities of rhein, chrysophanol, and emodin toward AKT۱ and PPARγ, with docking scores comparable to or better than those of metformin and pioglitazone. The computational findings were validated in streptozotocin-induced diabetic Wistar rats, which were treated orally with CTL extract (۲۰۹ mg/kg) or chrysophanol (۱۰۳.۰۲ mg/kg) for ۲۸ days. Both treatments significantly reduced fasting blood glucose levels, increased serum insulin levels, improved lipid profiles, and restored SGOT and SGPT levels compared to the diabetic controls (p<۰.۰۰۱). Western blot analysis showed a ۲.۳-fold increase in AKT۱ phosphorylation and a ۱.۸-fold increase in PPARγ expression, while histopathological examination demonstrated marked pancreatic protection, with CTL extract showing the greatest tissue restoration. Overall, Cassia tora seed anthraquinones exhibit potent antidiabetic activity by coordinating the modulation of multiple molecular targets and signalling pathways, particularly the AKT۱/PPARγ signaling pathway. These findings suggest that Cassia tora seed anthraquinones may exert antidiabetic effects through the coordinated modulation of multiple targets and signaling pathways, particularly those involving AKT۱ and PPARγ. The computational findings should be considered predictive, and further mechanistic, pharmacokinetic, and clinical studies are required to establish their therapeutic relevance in humans.

کلیدواژه ها:

Cassia tora Linn ، Anthraquinones ، network pharmacology ، Molecular docking ، Diabetes Mellitus