DNA damage by the glycation products of glyceraldehyde 3-phosphate and lysine

Mullokandov, Eduard; Franklin, William; Brownlee, Michael

doi:10.1007/s001250050085

Cited by 32 publications

(15 citation statements)

References 17 publications

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“…Although it is not yet clear how excessive entry of glucose or lipid elicits beta-cell injury, increased non-enzymatic glycation of cellular proteins has been identified in animal studies [58,59]. The presence of HNE-modified proteins suggests that oxidative stress with lipid peroxidation also contributes to islet-cell injury [60].…”

Section: Discussionmentioning

confidence: 99%

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

et al. 2002

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Impaired insulin secretion and insulin resistance are a characteristic feature of Type II (non-insulin-dependent) diabetes mellitus [1,2]. In spite of extensive studies on the pathophysiology of diabetes, islet pathology and its pathogenesis remain controversial.Classical studies using histochemical methods to identify endocrine cells have reported varying results, including the severe loss of beta cells [3], modest changes with amyloid deposition [4,5] and even no change of islet beta-cell population [6]. Immunohistochemical techniques for the identification of specific populations of islet endocrine cells, showed a nearly 50 % reduction in beta-cell volume density in European Type II non-obese diabetic patients compared with non-diabetic control subjects [7]. Other studies have reported a 24 % reduction of islet beta-cell area density, a 58 % increase in A cell area density and a deposition of amyloid that correlated with the severity of islet pathology [8]. In another study of European Type II diabetic patients, a separate research group has reported Diabetologia (2002) Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients Abstract Aims/hypothesis. We examined the pancreatic islet lesions in Japanese patients with Type II diabetes mellitus to determine if the damage was related to oxidative stress. Methods. Morphometric analyses were performed on immunostained sections of the tail portion of the pancreas from 14 diabetic and 15 non-diabetic patients. Amyloid deposition and oxidative stress-induced tissue damage were evaluated by Congo-red staining and immunostaining. Resistance to oxidative stress was assessed from immunostaining results for Cu, Zn-superoxide dismutase (SOD). Expression of (pro)insulin mRNA was assessed by in situ hybridisation. Results. The pancreas from diabetic patients had amyloid deposition in about 15 % of the islets, intensified reactions of 8-OHdG and HNE, as well as reduced expression of SOD. Islet volume density of beta cells and total beta-cell mass in the pancreas from diabetic patients were reduced by 22 % (p < 0.001) and 30 % (p < 0.05). Islet volume density and total mass of (pro)insulin mRNA-positive cells were similarly reduced in diabetic patients by 22 % (p < 0.001) and 39 % (p < 0.05), respectively. Islet volume density of A cells was increased by 20 % (p < 0.001) but total mass did not change. There were no changes in volume densities of islet, D and PP cells. Reduced beta-cell volume density correlated with increased positive staining of 8-OHdG. Conclusion/interpretation. Japanese Type II diabetic patients show a reduction of beta-cell mass and evidence of increased oxidative stress-related tissue damage that is correlated with the extent of the beta-cell lesions. [Diabetologia (2002) 45: 85±96]

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Section: Discussionmentioning

confidence: 99%

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

et al. 2002

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“…Glucose, fructose and their phosphorylated derivatives (>100 mM) were found to induce mutations and apoptosis in L5178Y murine lymphoma cells in vitro [32], and glucose, glucose 6-phosphate and glyceraldehyde 3-phosphate in reactions with lysine have been shown to induce mutations and the development of apurinic and apyrimidinic sites in plasmid DNA [33,34]. These studies probably reflect the formation of reactive α-oxoaldehydes in the degradation of monosaccharides, and early-stage glycation reactions and subsequent modification of DNA to form nucleotide AGEs derived from glyoxal, methylglyoxal and other carbonyl intermediates [21].…”

Section: Dna Glycation Mutagenesis and Ner (Nucleotide Excision Repair)mentioning

confidence: 99%

Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

Thornalley

2003

Biochemical Society Transactions

117

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Glycation of nucleotides in DNA forms AGEs (advanced glycation end-products). Nucleotide AGEs are: the imidazopurinone derivative dG-G [3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one], CMdG ( N (2)-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from glyoxal, dG-MG [6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one], dG-MG(2) [ N (2),7-bis-(1-hydroxy-2-oxopropyl)deoxyguanosine] and CEdG [ N (2)-(1-carboxyethyl)deoxyguanosine] derived from methylglyoxal, and dG-3DG [ N (2)-(1-oxo-2,4,5,6-tetrahydroxyhexyl)deoxyguanosine] derived from 3-deoxyglucosone and others. Glyoxal and methylglyoxal induce multi-base deletions, and base-pair substitutions - mostly occurring at G:C sites with G:C-->C:G and G:C-->T:A transversions. Suppression of nucleotide glycation by glyoxalase I and aldehyde reductases and dehydrogenases, and base excision repair, protects and recovers DNA from damaging glycation. The effects of DNA glycation may be most marked in diabetes and uraemia. Mutations arising from DNA glycation may explain the link of non-dietary carbohydrate intake to incidence of colorectal cancer. Overexpression of glyoxalase I was found in drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against DNA glycation. Experimental overexpression of glyoxalase I conferred resistance to drug-induced apoptosis. Glyoxalase I-mediated drug resistance was found in human leukaemia and lung carcinoma cells. Methylglyoxal-mediated glycation of DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of NAD(+) by poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of methylglyoxal. S - p -Bromobenzylglutathione cyclopentyl diester is a cell-permeable glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate carcinoma. Glyoxalase I overexpression was also found in invasive ovarian cancer and breast cancer.

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“…Plasmid DNA incubated with reactive AGE products produced double strand DNA breaks and base modifications [174]. A small study of 31 type II diabetic patients in Turkey found higher AGE DNA adduct concentration in patients with diabetes compared to controls, despite the use of oral hypoglycemic drugs [198].…”

Section: Mechanisms Of Peripheral Neuropathymentioning

confidence: 99%

Mechanisms of distal axonal degeneration in peripheral neuropathies

Cashman

Höke²

2015

Neuroscience Letters

168

181

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Peripheral neuropathy is a common complication of a variety of diseases and treatments, including diabetes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). Despite the fundamental difference between these insults, peripheral neuropathy develops as a combination of just six primary mechanisms: altered metabolism, covalent modification, altered organelle function and reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonal transport, and altered ion channel dynamics and expression. All of these pathways converge to lead to axon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itself have begun to be elucidated with studies of animal models with altered degeneration kinetics, including the slowed Wallerian degeneration (Wlds) and Sarmknockout animal models. These studies have shown axonal degeneration to occur througha programmed pathway of injury signaling and cytoskeletal degradation. Insights into the common disease insults that converge on the axonal degeneration pathway promise to facilitate the development of therapeutics that may be effective against other mechanisms of neurodegeneration.

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DNA damage by the glycation products of glyceraldehyde 3-phosphate and lysine

Cited by 32 publications

References 17 publications

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients

Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

Mechanisms of distal axonal degeneration in peripheral neuropathies

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