Anti-α-Glucosidase and Antiglycation Activities of α-Mangostin and New Xanthenone Derivatives: Enzymatic Kinetics and Mechanistic Insights through In Vitro Studies.

Francine Medjiofack Djeujo,Valeria Francesconi,Michele Tonelli,Eugenio Ragazzi,Maddalena Gonella,Guglielmina Froldi

doi:10.3390/molecules27020547

Francine Medjiofack Djeujo, Valeria Francesconi + Show 4 more

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https://doi.org/10.3390/molecules27020547

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Abstract

Diabetes mellitus is characterized by chronic hyperglycemia that promotes ROS formation, causing severe oxidative stress. Furthermore, prolonged hyperglycemia leads to glycation reactions with formation of AGEs that contribute to a chronic inflammatory state. This research aims to evaluate the inhibitory activity of α-mangostin and four synthetic xanthenone derivatives against glycation and oxidative processes and on α-glucosidase, an intestinal hydrolase that catalyzes the cleavage of oligosaccharides into glucose molecules, promoting the postprandial glycemic peak. Antiglycation activity was evaluated using the BSA assay, while antioxidant capacity was detected with the ORAC assay. The inhibition of α-glucosidase activity was studied with multispectroscopic methods along with inhibitory kinetic analysis. α-Mangostin and synthetic compounds at 25 µM reduced the production of AGEs, whereas the α-glucosidase activity was inhibited only by the natural compound. α-Mangostin decreased enzymatic activity in a concentration-dependent manner in the micromolar range by a reversible mixed-type antagonism. Circular dichroism revealed a rearrangement of the secondary structure of α-glucosidase with an increase in the contents of α-helix and random coils and a decrease in β-sheet and β-turn components. The data highlighted the anti-α-glucosidase activity of α-mangostin together with its protective effects on protein glycation and oxidation damage.

Highlights

The main causes of morbidity in diabetes mellitus (DM) are chronic complications resulting from prolonged hyperglycemia [1]
Micro- and macrovascular damage occurs at the arterial level, causing cardiovascular and cerebrovascular diseases that can result in cardiac infarction and stroke [2,3]
In the condition of chronic hyperglycemia, glucose tends to form covalent adducts with plasma proteins through a nonenzymatic process known as glycation [1,4]

Summary

Introduction

The main causes of morbidity in diabetes mellitus (DM) are chronic complications resulting from prolonged hyperglycemia [1]. These can be alleviated through careful and continuous blood glucose control. In the condition of chronic hyperglycemia, glucose tends to form covalent adducts with plasma proteins (albumin, fibrinogen, globulins, collagen) through a nonenzymatic process known as glycation [1,4]. Recent studies suggest that AGEs interact with the plasma membrane by specific receptors (RAGE), changing intracellular signal transmission, modifying gene expression, and promoting the release of pro-inflammatory molecules and free radicals [5]. The enzyme α-glucosidase is an intestinal hydrolase located in the brush-rim membrane of intestinal cells that catalyzes the cleavage of food oligosaccharides into glucose molecules, promoting the postprandial

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