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

Md Yousof Ali,Jae Sue Choi,Hyun Ah Jung,Susoma Jannat

doi:10.3390/antiox10020292

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 α-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 α-glucosidase. Docking simulations of these coumarins showed negative binding energies and a similar proximity to residues in the PTP1B and α-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 α-glucosidase, as well as for insulin susceptibility.

Highlights

Introduction iationsDiabetes mellitus (DM) has risen quickly in recent decades and currently, over 415 million DM sufferers worldwide, predicted to hit 642 million by 2040 [1]
Protein tyrosine phosphatase 1B (PTP1B) catalyzes the dephosphorylation of tyrosine residues in the activated insulin receptor β subunit (IR-β) and insulin receptor substrate-1 (IRS-1), resulting in decreased insulin regulation [8,9]
The inhibitory ability of PTP1B and α-glucosidase was evaluated using pNPP and p-nitrophenyl α-D-glucopyranoside (pNPG) as a substrate to evaluate the anti-diabetic activity of the four dihydroxanthyletintype coumarins (Figure 1) extracted from A. decursiva, and the results are expressed as IC50 values and presented in Table 1. (+)-Trans-decursidinol had the highest inhibitory activity of PTP1B among the isolated compounds, with an IC50 of 2.33 ± 0.07 μM, which was three-fold higher than the positive control, ursolic acid (IC50 = 6.87 ± 0.19 μM)

Summary

Introduction

Introduction iationsDiabetes mellitus (DM) has risen quickly in recent decades and currently, over 415 million DM sufferers worldwide, predicted to hit 642 million by 2040 [1]. The incidence of DM in younger people, even before puberty, is rising, including some obese children [2,3]. Type 2 diabetes mellitus (T2DM) is due to insulin resistance or deficiency, the predominant type of diabetes that accounts for over 90 percent of the DM incidences [3,4,5,6]. Protein tyrosine phosphatase 1B (PTP1B) is part of the intracellular PTP that is active in the negative regulation of insulin and leptin signaling systems [7]. PTP1B catalyzes the dephosphorylation of tyrosine residues in the activated insulin receptor β subunit (IR-β) and insulin receptor substrate-1 (IRS-1), resulting in decreased insulin regulation [8,9].

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