Anti‐Diabetic Effects and Molecular Mechanisms of Amide Alkaloids fromPiper longumBased on Network Pharmacology Integrated with Cellular Assays

Abstract

Piper longum is a well‐known spice and traditional medicine. It was revealed to possess anti‐diabetic activity, but few information about its active component and underlying mechanism could be available. In this study, retrofractamides A (1) and C (2) isolated from P. longum showed potent inhibitory activity against PTP1B. Therefore, the potential mechanism was predicted by network pharmacology and molecular docking. PI3K/AKT was obtained as the most remarkable pathway against type 2 diabetes mellitus (T2DM), and AKT1 and GSK3β were yielded as the top two core targets of retrofractamides A (1) and C (2). Molecular docking of compounds with AKT1 and GSK3β showed strong binding affinity between them. Additionally, cellular experiments with a L6 cell model was conducted to further verify the above predictions. Results indicated that retrofractamides A (1) and C (2) exerted anti‐diabetic effect via activating PI3K/AKT pathway, and they promoted glucose consumption, glucose uptake, glycogen synthesis and glycolysis.

Association between gut microbiota and onset of type 2 diabetes mellitus: a two-sample Mendelian randomization study

“…longum may also lower the levels of fasting blood glucose as well as alleviate insulin resistance in diabetic mice, enhancing the anti-oxidative capacity, increasing the hepatic glycogen content, decreasing the gene expression levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the livers, and thus regulating the disturbance of GM ( Hao et al., 2022 ). Moreover, longum has been made as a variety of pharmaceutical and probiotic supplements in recent years ( Zhao et al., 2020a ; Gou et al., 2023 ).…”