Prevalence of Autoantibodies against 3-DG-Glycated H2A Protein in Type 2 Diabetes.

Advanced glycation end-products (AGEs) have been found to be critically involved in initiation or progression of diabetes secondary complications (nephropathy, retinopathy, neuropathy, and angiopathy). Various hyper-glycating carbonyl compounds such as 3-deoxyglucosone (3-DG) are produced in pathophysiological conditions that form AGEs in high quantity both in vivo and in vitro. In the first stage of this study, we glycated histone H2A protein by 3-DG, and the results showed the formation of various intermediates and AGEs as well as structural changes in the protein. In the second stage, we studied the immunogenicity of native and 3-DG-glycated H2A protein in female rabbits. The modified H2A was highly immunogenic, eliciting high titer immunogen-specific antibodies, while the unmodified form was almost nonimmunogenic. Antibodies against standard carboxymethyllysine (CML) and pentosidine were detected in the immunized female rabbits, which demonstrates the immunogenic nature of AGEs (CML and pentosidine) as well. The results show both structural perturbation and AGEs have the capacity of triggering the immune system due to the generation of neoepitopes that render the molecule immunogenic. This study shows the presence of autoantibodies against 3-DG-modified H2A, CML, and pentosidine in the sera of type 2 diabetes patients having secondary complications. Autoantibodies against damaged H2A and AGEs may be significant in the assessment of initiation/progression of secondary complications in type 2 diabetes mellitus patients or may be used as a marker for early detection of secondary complications in diabetes.

Glycoxidation of biological macromolecules: a critical approach to halt the menace of glycation.

Glycation is the result of covalent bonding of a free amino group of biological macromolecules with a reducing sugar, which results in the formation of a Schiff base that undergoes rearrangement, dehydration and cyclization to form a more stable Amadori product. The final products of nonenzymatic glycation of biomacromolecules like DNA, proteins and lipids are known as advanced glycation end products (AGEs). AGEs may be generated rapidly or over long times stimulated by distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. Both Schiff base and Amadori glycation products generate free radicals resulting in decline of antioxidant defense mechanisms and can damage cellular organelles and enzymes. This critical review primarily focuses on the mechanistic insight of glycation and the most probable route for the formation of glycation products and their therapeutic interventions. Furthermore, the prevention of glycation reaction using therapeutic drugs such as metformin, pyridoxamine and aminoguanidine (AG) are discussed with special emphasis on the novel concept of the bioconjugation of these drugs like, AG with gold nanoparticles (GNPs). At or above 10 mM concentration, AG is found to be toxic and therefore has serious health concerns, and the study warrants doing this novel bioconjugation of AG with GNPs. This approach might increase the efficacy of the AG at a reduced concentration with low or no toxicity. Using the concept of synthesis of GNPs with abovementioned drugs, it is assumed that toxicity of various drugs which are used at high doses can be minimized more effectively.