Glycoxidative damage to human DNA: Neo-antigenic epitopes on DNA molecule could be a possible reason for autoimmune response in type 1 diabetes

Abstract

Advanced glycation end-products (AGEs) are known to be mutagenic, diabetogenic and vascular disease risk factors. Methylglyoxal (MG) is a dicarbonyl species that reacts with biological macromolecule (proteins, DNA and lipids) to give AGEs. Nonenzymatic glycation of MG with lysine (Lys) in the presence of copper (Cu(2+)) is reported to generate reactive oxygen species (ROS) capable of causing DNA damage. We show that DNA modification in MG-Lys-Cu(2+) system results in the generation of strand breaks, base modification, hyperchromicity and increased fluorescence intensity. Superoxide generation in the MG-Lys system was found to be significantly higher when compared with that in the MG and Lys alone. Moreover, d-penicillamine and pyridoxal phosphate significantly inhibited the formation of glycation products. The presence of a major DNA glycation adduct, N(2)-carboxyethyl-2'-deoxyguanosine (CEdG), was detected by high performance liquid chromatography (HPLC) and confirmed by nuclear magnetic resonance (NMR). As reported earlier, modified DNA (MG-Lys-Cu(2+)-DNA) was highly immunogenic in experimental animals. Furthermore, induced anti-MG-Lys-Cu(2+)-DNA antibodies were effective probe for detecting glycoxidative lesions in human genomic DNA of type I diabetes patients. Our results clearly imply that interaction of MG-Lys and Cu(2+) leads to the formation of AGEs and also the production of potent ROS, capable of causing DNA damage, thereby playing an important role in diabetes mellitus.

An Immunohistochemical Analysis to Validate the Rationale behind the Enhanced Immunogenicity of D-Ribosylated Low Density Lipo-Protein

“…Recently, the presence of auto-antibodies in experimental and diabetes mellitus patients against the glycated DNA was investigated by our group [33]–[36]. There are also couple of recent reports for the presence of the auto-antibodies in the sera of the cancer patients which needs to be validated further [37].…”

Physicochemical analysis of structural alteration and advanced glycation end products generation during glycation of H2A histone by 3‐deoxyglucosone

“…A fluorescence study was carried out to confirm the generation of fluorogenic AGEs. Previous studies have revealed that a number of flurogenic AGEs including pentosidine are formed during the glycation process . When native and glycated‐H2A samples were excited at 335 nm, a 96.20% increase in emission intensity at λ max 398 nm was observed relative to the native H2A (Fig.…”

Glycation of H1 Histone by 3-Deoxyglucosone: Effects on Protein Structure and Generation of Different Advanced Glycation End Products

“…A 93.74% increase in absorbance (hyperchromicity) at 276 nm as well as increased absorbance between 300 to 400 nm was observed for 3-DG-glycated H1. Assessment of flourogenic pentosidine and formation of different AGEs in 3-DG-glycated H1 histone was investigated by exciting the samples at 335 and 365 nm [ 46 ]. 3-DG-glycated H1 had a 93.37% increase in emission intensity at λ em 395 nm relative to native H1 upon excitation at λ ex 335 nm ( Fig 3A ).…”