Biochemistry and Pathophysiology of Glycation of DNA: Implications in Diabetes (original) (raw)
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Chemical research in toxicology, 2017
More precise identification and treatment monitoring of prediabetic/diabetic individuals will require additional biomarkers to complement existing diagnostic tests. Candidates include hyperglycemia-induced adducts such as advanced glycation end products (AGEs) of proteins, lipids, and DNA. The potential for DNA-AGEs as diabetic biomarkers was examined in a longitudinal study using the Lepr(db/db) animal model of metabolic syndrome. The DNA-AGE, N(2)-(1-carboxyethyl)-2'-deoxyguanosine (CEdG) was quantified by mass spectrometry using isotope dilution from the urine and tissue of hyperglycemic and normoglycemic mice. Hyperglycemic mice (fasting plasma glucose, FPG, ≥ 200 mg/dL) displayed a higher median urinary CEdG value (238.4 ± 112.8 pmol/24 h) than normoglycemic mice (16.1 ± 11.8 pmol/24 h). Logistic regression analysis revealed urinary CEdG to be an independent predictor of hyperglycemia. Urinary CEdG was positively correlated with FPG in hyperglycemic animals and with HbA1c f...
Journal of Clinical Laboratory Analysis, 2010
Diabetic hyperglycemia is associated with increased production of reactive oxygen species (ROS). ROS reacts with DNA resulting in various products, such as 8‐hydroxydeoxyguanosine (8‐OHdG), that excrete in urine owing to DNA repair processes. Urinary 8‐OHdG has been proposed as an indicator of oxidative damage to DNA. This study aimed to evaluate relationship between oxidative damage to DNA and protein glycation in patients with Type 1 diabetes. We measured urinary 8‐OHdG level in diabetic patients and healthy subjects and discussed its relationship to glycated hemoglobin (HbA1c) and glycated serum protein (GSP) levels. Furthermore plasma malondialdehyde (MDA) level monitored as an important indicator of lipid peroxidation in diabetes. We studied 32 patients with Type 1 diabetes mellitus and compared the measured factors with those of 48 age‐matched nondiabetic controls. GSP and MDA were measured bycolorimetric assay. Urinary 8‐OHdG measurement was carried out using ELISA. In this s...
Glycobiology, 2014
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 2carboxyethyl-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.
Increased oxidative damage to all DNA bases in patients with type II diabetes mellitus
FEBS Letters, 1999
Gas chromatography‐mass spectrometry was used to measure the oxidative DNA damage in diabetic subjects and controls. Levels of multiple DNA base oxidation products, but not DNA base de‐amination or chlorination products, were found to be elevated in white blood cell DNA from patients with type II diabetes as compared with age‐matched controls. The chemical pattern of base damage is characteristic of that caused by an attack on DNA by hydroxyl radical. An increased formation of the highly reactive hydroxyl radical could account for many of the reports of oxidative stress in diabetic subjects. There was no evidence of an increased DNA damage by reactive nitrogen or chlorine species.
Role of Natural Compounds in the Prevention of Dna and Proteins Damage by Glycation
Glycation is a non-enzymatic process which involves an interaction between the carbonyl groups of reducing sugars and amino groups of proteins, lipids, nucleic acids resulting in the formation of Amadori products (early glycation products). These products then rearrange themselves and get converted to more stable and irreversible advanced end glycation products (AGEs). Glycation products have been implicated in various diseases like cataract, diabetes mellitus, Alzheimers etc. In the present workthe effect of glycation on DNA and proteins was studied. When plasmid DNA (pBR 322) was incubated with lysine andmethylglyoxal in the presence of metal ion a conformational change was observed on the agarose gel electrophoresis which indicated the damage to DNA by glycation. Different sugars were also incubated with plasmid DNA to check their comparative deleterious effects. In the presence of Lysine and metal ion, pentose sugar and sugar phosphates caused maximum damage to DNA as compared t...
Reversal of glycoxidative damage of DNA and protein by antioxidants
Annals of Phytomedicine: An International Journal
Diabetes is a metabolic and endocrinological disorder. It is a manifestation of hyperglycemia and glucotoxicity for a long period of time. The high glucose concentra tion leads to secondary complications of diabetes like cataract, cardiovascular and, neurological disorders. The reactive carbonyl group of glucose reacts with amino groups of biomolecules like DNA and proteins leading to their structu ral altera tions. In the present study, effect of non-enzymatic glycation was checked on proteins and the structure of DNA. It was observed that there was an increase in the generation of early and advanced glycation products when BSA was incubated with methylglyoxal. There wa s a decrease in the amount of glycation products in the presence of most of the antioxidants except sodium acetate. The glycation system caused strand breakage and led to change in the conformation of pBR322 plasmid, from supercoiled to open circular. This structural damage of DNA increased in the presence of FeCl 3 , indicating the role of metal ions in the generation of free radicals. Antioxidants like sodium azide, eugenol and melatonin significantly reversed the DNA damage, induced by glycation system, as shown by agarose gel electrophoresis. Eugenol and mannitol were able to show significantly high percentage of DPPH inhibition and ABTS, as compared to sodium acetate and sodium azide. The amount of eugenol and mannitol used were able to show similar antioxidant capacity, as compared to 50 µg of vitamin C, a standard and potent antioxidant. It can be concluded from this study that generation of free radicals is the major rou te for glycation-induced DNA dama ge as shown by the reversal of damage in the presence of antioxidants. The study indicates the significance of natural antioxidants in the prevention of glycation related diseases.
Recent Advances in the Associations of Advanced Glycation End Products (Ages) and Cancer
American Journal of Biomedical Science & Research, 2019
Mini Review Advanced glycation end products (AGEs) are a group of heterogeneous molecules formed by non-enzymatic reactions. These reactions occur between the carbonyl group of reducing sugars, such as glucose, fructose, ADP-ribose, or dicarbonyl derivatives such as glyoxal, methyl glyoxal, 3-deoxyglucosone, and the nucleophilic amino group of proteins, lipids or nucleic acids [1,2]. Advanced glycation end products are generated exogenously in food, especially in thermal processed food, but are also produced endogenously under physiological or pathological conditions [1,3,4]. In vivo glycation takes place slowly but continuously throughout life. The accumulation of AGEs has been linked to agerelated diseases including diabetes mellitus, atherosclerosis and cancer [5,6,7]. Advanced glycation end products can be divided into fluorescent and nonfluorescent forms, as well as cross-and non-cross-linked types. The commonest AGEs are 3-deoxyglucosone-derived pyrraline and pentosidine, glyoxal-or methyl glyoxal-derived Nε-(carboxylmethyl)-L-lysine (CML), the cross-linked glyoxal-lysine dimer (GOLD), and methylglyoxal-lysine dimer (MOLD) and S-carboxymethylcysteine. It has been shown that the levels of these compounds are high in plasma and tissues during aging as well as in various cancers [8,9]. The underlying mechanisms of AGE formation include the Maillard reaction, the polyol and glycolysis pathways, lipid peroxidation, and high oxidative stress, almost all of which require a hyper glycemic cellular microenvironment. Cancer cells are characterized by an increased glucose uptake and a high rate of glycolysis (the Warburg effect), to meet their energy requirements. Consequently, under hyper glycemic conditions, glycation is increased in cancer cells and AGE accumulation is accelerated. The gradual build-up of AGEs is involved in the pathogenesis and development of cancers [10,11]. Cancer patients show increased AGE levels in their tumour tissues, plasma and in their serum samples [12,13]. For example, primary colorectal carcinoma tissue displays a higher intensity of AGE expression compared with normal colonic mucosa [14]. The serum concentrations of glucose-derived AGEs in gastric cancer patients without diabetes are found to be markedly increased compared with healthy people of comparable age [15,16]. Methylglyoxal and 3-deoxyglucosone modified DNA were found in sera of breast cancer patients and various AGE modified proteins occurred in their tumor tissues [17]. The levels of AGEs are increased in the saliva of myeloma patients with bone lesions [18]. Histone proteins are particularly susceptible to glycation because of their long half-lives and the nucleophilic tails of their molecules Copy Right@ Qiuyu Wang This work is licensed under Creative Commons Attribution 4.0 License AJBSR.MS.ID.000888.
FEBS Letters, 1997
Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative DNA damage and also of oxidative stress. We have investigated oxidative D N A damage in patients with non-insulin-dependent diabetes mellitus (NIDDM) by urinary 8-OHdG assessments. We determined the total urinary excretion of 8-OHdG from 24 h urine samples of 81 N I D D M patients 9 years after the initial diagnosis and of 100 non-diabetic control subjects matched for age and gender. The total 24 h urinary excretion of 8-OHdG was markedly higher in N I D D M patients than in control subjects (68.2 ± 39.4 /ig vs. 49.6 ± 37.7 fig, P = 0.001). High glycosylated hemoglobin was associated with a high level of urinary 8-OHdG. The increased excretion of urinary 8-OHdG is seen as indicating an increased systemic level of oxidative DNA damage in N I D D M patients. © 1997 Federation of European Biochemical Societies.
Analytical and Bioanalytical Chemistry, 2008
Methylglyoxal and glyoxal are generated from the oxidation of carbohydrates and lipids, and like D-glucose have been shown to nonenzymatically react with proteins to form advanced glycation end products (AGEs). AGEs can occur both in vitro and in vivo, and these compounds have been shown to exacerbate many of the long-term complications of diabetes. Earlier studies in our laboratory reported D-glucose, D-galactose, and D/L-glyceraldehyde formed AGEs with nucleosides. The objective of this study was to focus on purines and pyrimidines and to analyze these DNA nucleoside derived AGE adducts with glyoxal or methylglyoxal using a combination of analytical techniques. Studies using UV and fluorescence spectroscopy along with mass spectrometry provided for a thorough analysis of the nucleoside AGEs and demonstrated that methylglyoxal and glyoxal reacted with 2'-deoxyguanosine via the classic Amadori pathway, and did not react appreciably with 2'-deoxyadenosine, 2'-deoxythymidine, and 2'-deoxycytidine. Additional findings revealed that methylglyoxal was more reactive than glyoxal.