Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylglyoxal (MG) is a reactive dicarbonyl compound endogenously produced mainly from glycolytic intermediates. Elevated MG levels in diabetes patients are believed to contribute to diabetic complications. MG is cytotoxic through induction of apoptosis. Curcumin, the yellow pigment of Curcuma longa, is known to have antioxidant and anti-inflammatory properties. In the present study, we investigated the effect of curcumin on MG-induced apoptotic events in human hepatoma G2 cells. We report that curcumin prevented MG-induced cell death and apoptotic biochemical changes such as mitochondrial release of cytochrome c, caspase-3 activation, and cleavage of PARP (poly [ADP-ribose] polymerase). Using the cell permeable dye 2',7'-dichlorofluorescein diacetate (DCF-DA) as an indicator of reactive oxygen species (ROS) generation, we found that curcumin abolished MG-stimulated intracellular oxidative stress. The results demonstrate that curcumin significantly attenuates MG-induced ROS formation, and suggest that ROS triggers cytochrome c release, caspase activation, and subsequent apoptotic biochemical changes.
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PMID:Curcumin inhibits ROS formation and apoptosis in methylglyoxal-treated human hepatoma G2 cells. 1596 83

Methylglyoxal (MGO) is an alpha-dicarbonyl compound produced from triose phosphate intermediates of glycolysis. It reacts rapidly with proteins to produce advanced glycation products. We have studied the effect of MGO modification of fibronectin on retinal capillary cell viability. Our studies show that pericytes grown on MGO-modified fibronectin (FN) undergo enhanced apoptosis through the p38MAPK-mediated oxidative pathway and that alphaB-crystallin, a stress protein present in pericytes, can protect them from MGO-mediated apoptosis. Our studies with vascular endothelial cells show that hyperglycemia-induced apoptosis is inhibited by overexpression of alphaB-crystallin. These observations suggest a novel role of alphaB-crystallin in hyperglycemia-mediated damage to vascular cells in diabetes.
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PMID:Dicarbonyl stress and apoptosis of vascular cells: prevention by alphaB-crystallin. 1603 35

Methylglyoxal is the most important intracellular glycation agent, formed nonenzymatically from triose phosphates during glycolysis in eukaryotic cells. Methylglyoxal-derived advanced glycation end-products are involved in neurodegenerative disorders (Alzheimer's, Parkinson's and familial amyloidotic polyneurophathy) and in the clinical complications of diabetes. Research models for investigating protein glycation and its relationship to methylglyoxal metabolism are required to understand this process, its implications in cell biochemistry and their role in human diseases. We investigated methylglyoxal metabolism and protein glycation in Saccharomyces cerevisiae. Using a specific antibody against argpyrimidine, a marker of protein glycation by methylglyoxal, we found that yeast cells growing on d-glucose (100 mM) present several glycated proteins at the stationary phase of growth. Intracellular methylglyoxal concentration, determined by a specific HPLC based assay, is directly related to argpyrimidine formation. Moreover, exposing nongrowing yeast cells to a higher d-glucose concentration (250 mM) increases methylglyoxal formation rate and argpyrimidine modified proteins appear within 1 h. A kinetic model of methylglyoxal metabolism in yeast, comprising its nonenzymatic formation and enzymatic catabolism by the glutathione dependent glyoxalase pathway and aldose reductase, was used to probe the role of each system parameter on methylglyoxal steady-state concentration. Sensitivity analysis of methylglyoxal metabolism and studies with gene deletion mutant yeast strains showed that the glyoxalase pathway and aldose reductase are equally important for preventing protein glycation in Saccharomyces cerevisiae.
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PMID:Protein glycation in Saccharomyces cerevisiae. Argpyrimidine formation and methylglyoxal catabolism. 1612 20

Dicarbonyl and oxidative stress may play important roles in the development of diabetes complications, and their response to hyperglycemia could determine individual susceptibility to diabetic nephropathy. This study examines the relationship of methylglyoxal, 3-deoxyglucosone (3DG), and oxidative stress levels to diabetic nephropathy risk in three populations with diabetes. All subjects in the Overt Nephropathy Progressor/Nonprogressor (ONPN) cohort (n = 14), the Natural History of Diabetic Nephropathy study (NHS) cohort (n = 110), and the Pima Indian cohort (n = 45) were evaluated for clinical nephropathy, while renal structural measures of fractional mesangial volume [Vv(Mes/glom)] and glomerular basement membrane (GBM) width were determined by electron microscopy morphometry in the NHS and Pima Indian cohorts. Methylglyoxal and 3DG levels reflected dicarbonyl stress, while reduced glutathione (GSH) and urine 8-isoprostane (8-IP) measured oxidative stress. Cross-sectional measures of methylglyoxal production by red blood cells incubated in 30 mmol/l glucose were increased in nephropathy progressors relative to nonprogressors in the ONPN (P = 0.027) and also reflected 5-year GBM thickening in the NHS cohort (P = 0.04). As nephropathy progressed in the NHS cohort, in vivo levels of methylglyoxal (P = 0.036), 3DG (P = 0.004), and oxidative stress (8-IP, P = 0.007 and GSH, P = 0.005) were seen, while increased methylglyoxal levels occurred as nephropathy progressed (P = 0.0016) in the type 2 Pima Indian cohort. Decreased glyceraldehyde-3-phosphate dehydrogenase activity also correlated with increased methylglyoxal levels (P = 0.003) in the NHS cohort. In conclusion, progression of diabetic nephropathy is significantly related to elevated dicarbonyl stress and possibly related to oxidative stress in three separate populations, suggesting that these factors play a role in determining individual susceptibility.
Diabetes 2005 Nov
PMID:Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress. 1624 55

Hypertension is a life-threatening disease that is associated with increased cardiovascular risks. Causes and mechanisms for hypertension development remain poorly understood. Methylglyoxal (MG), a highly reactive molecule, is a metabolite of sugar. Increased circulation and tissue levels of MG have been documented not only in diabetes but also in hypertension. Many recent studies also link MG-induced vascular damage to the pathogenic process of hypertension. As such, an etiological role of MG in hypertension development is proposed.
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PMID:Is methylglyoxal a causative factor for hypertension development? 1684 97

Protein glycation by methylglyoxal is a nonenzymatic post-translational modification whereby arginine and lysine side chains form a chemically heterogeneous group of advanced glycation end-products. Methylglyoxal-derived advanced glycation end-products are involved in pathologies such as diabetes and neurodegenerative diseases of the amyloid type. As methylglyoxal is produced nonenzymatically from dihydroxyacetone phosphate and d-glyceraldehyde 3-phosphate during glycolysis, its formation occurs in all living cells. Understanding methylglyoxal glycation in model systems will provide important clues regarding glycation prevention in higher organisms in the context of widespread human diseases. Using Saccharomyces cerevisiae cells with different glycation phenotypes and MALDI-TOF peptide mass fingerprints, we identified enolase 2 as the primary methylglyoxal glycation target in yeast. Two other glycolytic enzymes are also glycated, aldolase and phosphoglycerate mutase. Despite enolase's activity loss, in a glycation-dependent way, glycolytic flux and glycerol production remained unchanged. None of these enzymes has any effect on glycolytic flux, as evaluated by sensitivity analysis, showing that yeast glycolysis is a very robust metabolic pathway. Three heat shock proteins are also glycated, Hsp71/72 and Hsp26. For all glycated proteins, the nature and molecular location of some advanced glycation end-products were determined by MALDI-TOF. Yeast cells experienced selective pressure towards efficient use of d-glucose, with high methylglyoxal formation as a side effect. Glycation is a fact of life for these cells, and some glycolytic enzymes could be deployed to contain methylglyoxal that evades its enzymatic catabolism. Heat shock proteins may be involved in proteolytic processing (Hsp71/72) or protein salvaging (Hsp26).
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PMID:Yeast protein glycation in vivo by methylglyoxal. Molecular modification of glycolytic enzymes and heat shock proteins. 1706 14

Methylglyoxal (MG) is a highly reactive alpha-oxoaldehyde formed endogenously in numerous enzymatic and nonenzymatic reactions. It modifies arginine and lysine residues in proteins forming advanced glycation end-products such as N(delta)-(5-methyl-4-imidazolon-2-yl)-L-ornithine (MG-H1), 2-amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl)pentanoic acid (MG-H2), 2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)pentanoic acid (MG-H3), argpyrimidine, N(delta)-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine (THP), N(epsilon)-(1-carboxyethyl)lysine (CEL), MG-derived lysine dimer (MOLD), and 2-ammonio-6-({2-[4-ammonio-5-oxido-5-oxopently)amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene}amino)hexanoate (MODIC), which have been identified in vivo and are associated with complications of diabetes and some neurodegenerative diseases. In foodstuffs and beverages, MG is formed during processing, cooking, and prolonged storage. Fasting and metabolic disorders and/or defects in MG detoxification processes cause accumulation of this reactive dicarbonyl in vivo. In addition, the intake of low doses of MG over a prolonged period of time can cause degenerative changes in different tissues, and can also exert anticancer activity. MG in biological samples can be quantified by HPLC or GC methods with preliminary derivatization into more stable chromophores and/or fluorophores, or derivatives suitable for determination by MS by use of diamino derivatives of benzene and naphthalene, 6-hydroxy-2,4,5-triaminopyrimidine, cysteamine, and o-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine. The methods include three basic steps: deproteinization, incubation with derivatization agent, and chromatographic analysis with or without preliminary extraction of the formed products.
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PMID:Methylglyoxal in food and living organisms. 1710 72

Methylglyoxal (MG) is a reactive dicarbonyl compound endogenously produced mainly from glycolytic intermediates. MG is cytotoxic through induction of cell death, and elevated MG levels in diabetes patients are believed to contribute to diabetic complications. In this report, we show for the first time that MG treatment triggers apoptosis in human osteoblasts. We further show that MG-induced apoptosis of osteoblasts involves specific apoptotic biochemical changes, including oxidative stress, c-Jun N-terminal kinase (JNK) activation, mitochondrial membrane potential changes, cytochrome C release, increased Bax/Bcl-2 protein ratios, and activation of caspases (caspase-9, caspase-3) and p21-activated protein kinase 2 (PAK2). Treatment of osteoblasts with SP600125, a JNK-specific inhibitor, led to a reduction in MG-induced apoptosis and decreased activation of caspase-3 and PAK2, indicating that JNK activity is upstream of these events. Experiments using anti-sense oligonucleotides against PAK2 further showed that PAK2 activation is required for MG-induced apoptosis in osteoblasts. Interestingly, we also found that MG treatment triggered nuclear translocation of NF-kappaB, although the precise regulatory role of NF-kappaB activation in MG-induced apoptosis remains unclear. Lastly, we examined the effect of MG on osteoblasts in vivo, and found that exposure of rats to dietary water containing 100-200 microM MG caused bone mineral density (BMD) loss. Collectively, these results reveal for the first time that MG treatment triggers apoptosis in osteoblasts via specific apoptotic signaling, and causes BMD loss in vivo.
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PMID:Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. 1713 86

Methylglyoxal is a cytotoxic metabolite that is produced in vivo mainly from glycolysis. Increased production of methylglyoxal can be induced by tumor necrosis factor and occurs in a number of pathological conditions, including diabetes and neurodegenerative disorders. Methylglyoxal is highly reactive and can modify proteins, which results in the formation of advanced glycation end products. Yet, we, and others, have recently proposed a role for methylglyoxal as a signaling molecule. In this study, we show that methylglyoxal inhibits TNF-induced NF-kappaB activation and NF-kappaB-dependent reporter gene expression by inhibiting the DNA binding capacity of NF-kappaB p65. Methylglyoxal slightly delayed, but did not inhibit, TNF-induced degradation of IkappaBalpha and strongly inhibited TNF-induced NF-kappaB-dependent re-synthesis of IkappaBalpha. The TNF-induced nuclear translocation of NF-kappaB p65 was also delayed, but not inhibited, in the presence of methylglyoxal. TNF-induced phosphorylation of p65 was not affected by methylglyoxal. We show that the conserved Cys 38 residue, which is located in the DNA binding loop of NF-kappaB p65 and responsible for the redox regulation of the transcription factor, is involved in the methylglyoxal-mediated inhibition of p65 DNA-binding. Furthermore, overexpression of p65 inhibited TNF-induced cell death; however, in the presence of exogenously added methylglyoxal, overexpression of p65 caused far greater TNF-induced cell death. These findings suggest that methylglyoxal provides another control mechanism for modulating the expression of NF-kappaB-responsive genes and that methylglyoxal may be responsible for tipping the balance towards TNF-induced cell death in cells with constitutive NF-kappaB activation.
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PMID:Methylglyoxal suppresses TNF-alpha-induced NF-kappaB activation by inhibiting NF-kappaB DNA-binding. 1761 81

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.
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PMID:The structural modification of DNA nucleosides by nonenzymatic glycation: an in vitro study based on the reactions of glyoxal and methylglyoxal with 2'-deoxyguanosine. 1796 53


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