Polydatin Reverses Diabetes‐Induced Apoptosis of Pancreatic β‐Cells by Inhibiting the TNF/TNF‐R1/Caspase‐3 Signaling Axis
TL;DR
Investigating whether PD prevents pancreatic β‐cells against diabetes‐related apoptosis and exploring the associated molecular mechanisms revealed that PD attenuated diabetic β‐apoptosis, likely through inhibition of the TNF/TNF‐R1/caspase‐3 pathway, suggesting that PD may be a novel anti‐DM therapeutic target.
Abstract
Background Pancreatic β‐apoptosis is a critical pathological event in diabetes mellitus (DM), yet effective therapeutic agents that directly protect β‐cells are lacking. Polydatin (PD), a natural stilbenoid, has shown potential in regulating glucolipid metabolism; however, its role and mechanism in protecting pancreatic β‐cells from apoptosis remain largely unexplored. Objective The present work focused on investigating whether PD prevents pancreatic β‐cells against diabetes‐related apoptosis and exploring the associated molecular mechanisms, with a particular focus on the TNF/TNF‐R1/caspase‐3 signaling axis. Methods Network pharmacology and bioinformatics were applied in combination with experimental validation. Potential targets of PD and DM were retrieved from public databases. Key candidate targets were screened via protein–protein interaction (PPI) analysis, least absolute shrinkage and selection operator (LASSO) regression, functional enrichment (GO/KEGG), differential expression, receiver operating characteristic (ROC), and clinical correlation analyses. Binding interactions were assessed by molecular docking alongside dynamic simulations. In vitro and in vivo DM models were established with high glucose (HG)–stimulated MIN6 β‐cells and high‐fat/HG diet‐fed mice with low‐dose streptozotocin (STZ) administration, respectively. Results TNF was identified as a central target of PD against DM, with elevated expression under diabetic conditions and a significant correlation with fasting blood glucose levels. PD exhibited strong binding affinity to both TNF (Vina score: –8.9 kcal·mol−1) and TNF‐R1 (Vina score: –8.8 kcal·mol−1). Cellular experiments demonstrated that PD enhanced β‐cell cycle progression (upregulated Ki67 expression), downregulated TNF‐R1 expression, and facilitated insulin secretion under HG stimulation. In diabetic mice, PD significantly increased the islet β‐cell mass and area; downregulated the expression of TNF, TNF‐R1, and cleaved‐caspase‐3; and restored PARP1 expression. Conclusion This study revealed that PD attenuated diabetic β‐apoptosis, likely through inhibition of the TNF/TNF‐R1/caspase‐3 pathway, suggesting that PD may be a novel anti‐DM therapeutic target.