Abstract
Reactive carbonyl species (RCS) such as methylglyoxal (MGO) or glyoxal (GO) are the main precursors of the formation of advanced glycation end products (AGEs). AGEs are a major factor in the development of vascular complications in diabetes. Vasoprotectives (VPs) exhibit a wide range of activities beneficial to cardiovascular health. The present study aimed to investigate selected VPs and their structural analogs for their ability to trap MGO/GO, inhibit AGE formation, and evaluate their antioxidant potential. Ultra-high-performance liquid chromatography coupled with an electrospray ionization mass spectrometer (UHPLC-ESI-MS) and diode-array detector (UHPLC-DAD) was used to investigate direct trapping capacity and kinetics of quenching MGO/GO, respectively. Fluorimetric and colorimetric measurements were used to evaluate antiglycation and antioxidant action. All tested substances showed antiglycative effects, but hesperetin was the most effective in RCS scavenging. We demonstrated that rutin, diosmetin, hesperidin, and hesperetin could trap both MGO and GO by forming adducts, whose structures we proposed. MGO-derived AGE formation was inhibited the most by hesperetin, and GO-derived AGEs by diosmetin. High reducing and antiradical activity was confirmed for quercetin, rutin, hesperetin, and calcium dobesilate. Therefore, in addition to other therapeutic applications, some VPs could be potential candidates as antiglycative agents to prevent AGE-related complications of diabetes.
Highlights
In patients with long-term uncontrolled hyperglycemia in diabetes, pathological structural-functional changes in the vascular endothelium are observed [1]
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Methylglyoxal (40% in water), glyoxal (40% in water), 2,2-diphenyl-1-picrylhy-drazyl, 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid), methanol (HPLC grade), acetonitrile (HPLC gradient grade and LC-MS grade), water (LC-MS grade), diosmin, diosmetin, hesperidin, hesperetin, Trolox, metformin hydrochloride, bovine serum albumin, DMSO, 98–100% formic acid, 2-methylquinoxaline, quinoxaline, o-phenylenediamine, 2, 4, 6tripyridyl-s-triazine, iron(III) chloride hexahydrate, and iron(II) sulfate heptahydrate were purchased from Merck-Sigma-Aldrich (Sigma-Aldrich Sp. z o.o., Poznan, Poland); NaCl, KCl, Na2HPO4, and KH2PO4 were obtained from Chempur (Piekary Slaskie, Poland); quercetin and rutin were from Extrasynthese (Genay Cedex, France); calcium dobesilate was purchased from PPF Hasco-Lek S
Summary
In patients with long-term uncontrolled hyperglycemia in diabetes, pathological structural-functional changes in the vascular endothelium are observed [1] These are mainly associated with increased non-enzymatic glycation of proteins and with excessive formation and deposition of advanced glycation end products (AGEs) in the extracellular space and within cells of the blood vessel wall [2]. RCS-mediated AGEs affect the stability of blood vessel walls by reducing their integrity and increasing permeability [8] They induce local inflammation through the activation of protein kinase C and nuclear factor NF-kB, which leads to increased synthesis and secretion of proinflammatory cytokines and stimulation of macrophages and neutrophils [9]. The in vitro studies revealed that the trapping mechanism occurs under physiological conditions—the formation of adducts of methylglyoxal and myricetin in mice as well as methylglyoxal and metformin in humans has been demonstrated [21,22]
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