Abstract
The present work aims to evaluate the anti-diabetic potentials of 16 anthraquinones, two naphthopyrone glycosides, and one naphthalene glycoside from Cassia obtusifolia via inhibition against the protein tyrosine phosphatases 1B (PTP1B) and α-glucosidase. Among them, anthraquinones emodin and alaternin exhibited the highest inhibitory activities on PTP1B and α-glucosidase, respectively. Moreover, we examined the effects of alaternin and emodin on stimulation of glucose uptake by insulin-resistant human HepG2 cells. The results showed that alaternin and emodin significantly increased the insulin-provoked glucose uptake. In addition, our kinetic study revealed that alaternin competitively inhibited PTP1B, and showed mixed-type inhibition against α-glucosidase. In order to confirm enzyme inhibition, we predicted the 3D structure of PTP1B using Autodock 4.2 to simulate the binding of alaternin. The docking simulation results demonstrated that four residues of PTP1B (Gly183, Arg221, Ile219, Gly220) interact with three hydroxyl groups of alaternin and that the binding energy was negative (−6.30 kcal/mol), indicating that the four hydrogen bonds stabilize the open form of the enzyme and potentiate tight binding of the active site of PTP1B, resulting in more effective PTP1B inhibition. The results of the present study clearly demonstrate that C. obtusifolia and its constituents have potential anti-diabetic activity and can be used as a functional food for the treatment of diabetes and associated complications.
Highlights
Type 2 diabetes (DM2) is characterized by resistance of insulin-sensitive tissues, such as muscles, liver and fat, to insulin action
19 Cassia compounds were selected, and their inhibitory potential against α-glucosidase and Protein tyrosine phosphatases 1B (PTP1B) were evaluated in order to evaluate their anti-diabetic potential
It was hypothesized that the presence of these constituents of C. obtusifolia was directly attributed to the potent α-glucosidase and PTP1B inhibitory activity
Summary
Type 2 diabetes (DM2) is characterized by resistance of insulin-sensitive tissues, such as muscles, liver and fat, to insulin action. The mechanism of the insulin resistance is unknown, it is tightly associated with obesity [1]. Protein tyrosine phosphatases 1B (PTP1B), a member of the PTP family, is thought to function as a negative regulator of insulin signal transduction. PTP1B directly interacts with an activated insulin receptor or insulin receptor substrate-1 (IRS-1) to dephosphorylate phosphotyrosine residues, resulting in down-regulation of insulin action [2]. PTP1B overexpression in rat primary adipose tissues and 3T3/L1 adipocytes has been shown to decrease insulin-sensitive GLUT4 translocation [5], and insulin receptor and IRS-1 phosphorylation [6], respectively. PTP1B inhibitors are potential therapeutic candidates to restore insulin sensitivity and treat DM2 and obesity. One of the Molecules 2017, 22, 28; doi:10.3390/molecules22010028 www.mdpi.com/journal/molecules
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