Insulin-Mimetic Dihydroxanthyletin-Type Coumarins from Angelica decursiva with Protein Tyrosine Phosphatase 1B and ?-Glucosidase Inhibitory Activities and Docking Studies of Their Molecular Mechanisms.

ABSTRACT: As a traditional medicine, Angelica decursiva has been used for the treatment of many diseases. The goal of this study was to evaluate the potential of four natural major dihydroxanthyletin-type coumarins-(+)-trans-decursidinol, Pd-C-I, Pd-C-II, and Pd-C-III-to inhibit the enzymes, protein tyrosine phosphatase 1B (PTP1B) and ?-glucosidase. In the kinetic study of the PTP1B enzyme's inhibition, we found that (+)-trans-decursidinol, Pd-C-I, and Pd-C-II led to competitive inhibition, while Pd-C-III displayed mixed-type inhibition. Moreover, (+)-trans-decursidinol exhibited competitive-type, and Pd-C-I and Pd-C-II mixed-type, while Pd-C-III showed non-competitive type inhibition of ?-glucosidase. Docking simulations of these coumarins showed negative binding energies and a similar proximity to residues in the PTP1B and ?-glucosidase binding pocket, which means they are closely connected and strongly binding with the active enzyme site. In addition, dihydroxanthyletin-type coumarins are up to 40 µM non-toxic in HepG2 cells and have substantially increased glucose uptake and decreased expression of PTP1B in insulin-resistant HepG2 cells. Further, coumarins inhibited ONOO^--mediated albumin nitration and scavenged peroxynitrite (ONOO^-), and reactive oxygen species (ROS). Our overall findings showed that dihydroxanthyletin-type coumarins derived from A. decursiva is used as a dual inhibitor for enzymes, such as PTP1B and ?-glucosidase, as well as for insulin susceptibility.

SUBMITTER: Ali MY 

PROVIDER: S-EPMC7919472 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature