Abstract
Diabetic hyperglycemia provokes glycation of haemoglobin (Hb), an abundant protein in red blood cells (RBCs), by increasing its exposure to carbohydrates. Acetylsalicylic acid (ASA; Aspirin) is one of the first agents, which its antiglycation effect was witnessed. Although the precise molecular mechanism of action of ASA on protein glycation is not indisputably perceived, acetylation as its main molecular mechanism has been proposed. This report aims to unravel the meticulous mechanism of action of ASA by using two ASA analogues; benzoic acid (BA) and para-nitrobenzoic acid (NBA), despite their lack of acetyl group. In this regard, the inhibitory effect of these two chemicals in comparison with ASA on Hb fructation is reported. UV-visible spectroscopy, intrinsic advanced glycation end products (AGE) fluorescence spectroscopy, extrinsic thioflavin T (ThT) binding fluorescence spectroscopy, 2,4,6-trinitrobenzenesulfonic acid (TNBSA) assay, and single cell gel electrophoresis (SCGE) were used to explore the effects of BA and NBA in comparison with aforementioned chemicals in the context of protein glycation. In spite of the lack of acetyl substitution, NBA is reported as a novel agent with prominent inhibitory efficacy than ASA on the protein glycation. This fact brings up a possible new mechanism of action of ASA and reconsiders acetylation as the sole mechanism of inhibition of protein glycation.
Highlights
Diabetes is a condition in which the concentration of blood carbohydrates, and the range of glycation increase simultaneously, which result in hyperglycemia, oxidative stress and diabetic complications
The blood glucose is 10- to 1,000-fold greater than fructose concentration, fructose tends to accumulate in erythrocytes through the metabolic polyol pathway [6] and transporter-mediated influx involved by a membrane-associated glucose transporter isoform GLUT5 [7]
Diabetes is a major public health problem featured by hyperglycemia
Summary
Diabetes is a condition in which the concentration of blood carbohydrates, and the range of glycation increase simultaneously, which result in hyperglycemia, oxidative stress and diabetic complications. Carbonyl groups of reducing sugars including aldoses and ketoses reversibly react with free ε-amino groups of lysines and the α-amino groups at the N-terminal of proteins in order to form respectively labile aldimines and ketimines, which are collectively named as Schiff bases These early-stage glycation products readily undertake irreversible processes such as glycoxidation, dehydration, condensation, cross-linking, cyclization etc to generate yellow-brown colored, fluorescent, highly cross-linked and weakly soluble species known as advanced glycation end products (AGEs) [4] In this process, the structure and function of proteins are adversely being altered, most importantly, blood proteins with a long half-life, such as haemoglobin (Hb), are more likely to undergo glycation under hyperglycemic condition [5]. To shed light on the ASA’s molecular mechanism with respect to inhibition of protein glycation and explore new compounds with an inhibitory effect on glycation along with approving efficacy and fewer side effects rather than ASA, we are exploring the anti-glycation effect of two structurally ASA-related candidates including benzoic acid (BA) and para-nitrobenzoic acid (NBA)
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