Abstract
Proteins undergo glycation resulting in the generation of advanced glycation end products (AGEs) that play a central role in the onset and advancement of diabetes-associated secondary complications. Aminoguanidine (AG) acts as an antiglycating agent by inhibiting AGE generation by blocking reactive carbonyl species (RCS) like, methylglyoxal (MGO). Previous studies on antiglycating behavior of AG gave promising results in the treatment of diabetes-associated microvascular complications, but it was discontinued as it was found to be toxic at high concentrations (>10 mmol/L). The current article aims at glycation inhibition by conjugating gold nanoparticles (Gnp) with less concentration of AG (0.5-1.0 mmol/L). The HPLC results showed that AG-Gnp fairly hampers the formation of glycation adducts. Moreover, the in vivo studies revealed AG-Gnp mediated inhibition in the production of total-AGEs and -Nε-(carboxymethyl)lysine (CML) in the diabetic rat model. This inhibition was found to be directly correlated with the antioxidant parameters, blood glucose, insulin, and glycosylated hemoglobin levels. Furthermore, the histopathology of AG-Gnp-treated rats showed good recovery in the damaged pancreatic tissue as compared to diabetic rats. We propose that this approach might increase the efficacy of AG at relatively low concentrations to avoid toxicity and might facilitate to overcome the hazardous actions of antiglycating drugs.
Highlights
In diabetes mellitus, hyperglycemia-mediated glycation starts with the nucleophilic addition between the carbonyl group of reducing sugars with free amino groups of proteins [1,2,3]
The absorption spectrum of aminoguanidine gold nanoparticles (Gnp-human serum albumin (HSA)-AG) showed a peak at 529 nm that corresponds to AG-gold nanoparticles (AGGnp) with a blue shift suggesting its binding to Gold nanoparticles (Gnp)
Cytotoxicity assay showed no significant increase in lactate dehydrogenase (LDH) leakage after incubation of platelets with 0.5 and 1.0 mmol/L aminoguanidine-bioconjugated gold nanoparticles (AG-Gnp)
Summary
Hyperglycemia-mediated glycation starts with the nucleophilic addition between the carbonyl group of reducing sugars with free amino groups of proteins [1,2,3]. Autoxidation of glucose and glycoxidation of proteins give rise to reactive oxygen species (ROS) that lead to the generation of reactive carbonyl species (RCS) or dicarbonyls such as glyoxal (GO), methylglyoxal (MGO), and 3-deoxyglucosone (3-DG) [6, 21]. Glycation is a slow process but increases several folds during persistent hyperglycemia [14], plasma amines react with the carbonyl group of sugars, Amadori products, and RCS, thereby preventing the nucleophilic addition reaction between >C=O and –NH2 [15]. Antioxidants quench glycation-derived ROS, whereas transport proteins such as ceruloplasmin bind with the transition metal ions and prevent them to participate in autoxidation and glycoxidation reactions [16, 17]
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