The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Paul J. Thornalley - One of the best experts on this subject based on the ideXlab platform.
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dicarbonyl stress and the glyoxalase system
2020Co-Authors: Naila Rabbani, Paul J. ThornalleyAbstract:Abstract Dicarbonyl stress is defined as the abnormal accumulation of reactive α-oxoaldehyde, dicarbonyl metabolites leading to cell and tissue dysfunction implicated in aging and disease. There is increased formation of arginine-derived hydroimidazolone adducts of proteins and guanosine-derived imidazopurinone adducts of DNA, linked to protein misfolding and mutagenesis, respectively. Methylglyoxal is a dominant mediator of dicarbonyl stress in vivo. It is metabolized by glutathione-dependent glyoxalase 1 (Glo1). The main drivers of dicarbonyl stress are increased formation of Methylglyoxal by glycolytic overload and decreased metabolism of Methylglyoxal by downregulation of Glo1. Proteins susceptible to dicarbonyl modification are enriched in protein folding, protein synthesis, and glucose metabolism. Dicarbonyl stress activates the unfolded protein response and downstream proinflammatory and prothrombotic responses. The pathobiology of dicarbonyl stress is most evident in obesity, vascular complications of diabetes, cardiovascular disease, renal failure, and aging. It may be corrected by dicarbonyl scavengers and inducers of Glo1 expression.
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Dicarbonyl proteome and genome damage in metabolic and vascular disease
2020Co-Authors: Naila Rabbani, Paul J. ThornalleyAbstract:Abstract Methylglyoxal is a potent protein-glycating agent. It is an arginine-directed glycating agent and often modifies functionally important sites in proteins. Glycation forms mainly MG-H1 [N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine] residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis-MS/MS and also by immunoblotting with specific monoclonal antibodies. Methylglyoxal-modified proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation end-product in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and aging. Proteins susceptible to Methylglyoxal modification with related functional impairment are called the DCP (dicarbonyl proteome). The DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and others. DCP component proteins are linked to mitochondrial dysfunction in diabetes and aging, oxidative stress, dyslipidaemia, cell detachment and anoikis and apoptosis. Methylglyoxal also modifies DNA where deoxyguanosine residues are modified to imidazopurinone MGdG {3-(2 -deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one} isomers. MGdG was the major quantitative adduct detected in vivo. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell-permeant glyoxalase I inhibitor. Glyoxalase I metabolizes >99% Methylglyoxal and thereby protects the proteome and genome. Gene deletion of GLO1 is embryonically lethal and GLO1 silencing increases Methylglyoxal concentration, MG-H1 and MGdG, premature aging and disease. Studies of Methylglyoxal glycation have importance for human health, longevity and treatment of disease
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glyoxalase ii does not support Methylglyoxal detoxification but serves as a general trypanothione thioesterase in african trypanosomes
Molecular and Biochemical Parasitology, 2009Co-Authors: Alexandra Wendler, Paul J. Thornalley, Naila Rabbani, Thorsten Irsch, Luise R KrauthsiegelAbstract:Glyoxalase I and II form a ubiquitous glutathione-dependent pathway for the detoxification of reactive and mutagenic ketoaldehydes. Methylglyoxal produced as spontaneous by-product of glycolysis is probably the main physiological substrate. Consequently, African trypanosomes with their exorbitant glucose turnover were expected to have a most efficient detoxification system. Trypanosoma brucei possesses a trypanothione [bis(glutathionyl)spermidine]-dependent glyoxalase II but lacks a glyoxalase I gene. Methylglyoxal reductase as well as dehydrogenase activities are negligible. However, the concentrations of Methylglyoxal and advanced glycation end products in the parasites are similar to those in different mammalian cells and the mechanism of Methylglyoxal elimination remains elusive. Glyoxalase II is an abundant protein. Overexpression of the gene as well as RNA interference in bloodstream and procyclic cells did not result in a growth phenotype. Deletion of both alleles in procyclic parasites revealed that the enzyme is not essential at least under culture conditions. Recombinant glyoxalase II hydrolyzed the trypanothione-thioesters of Methylglyoxal, glyoxal and 4,5-dioxovalerate, substrates of the classical glyoxalase system, with high efficiency. The absence of a glyoxalase I, however, renders these thioesters unlikely as physiological substrates. Here we show that trypanothione-thioesters can be generated from the respective coenzyme A derivative by transesterification. S-Acetyl- and S-propionyltrypanothione obtained by this spontaneous reaction proved to be excellent substrates of T. brucei glyoxalase II. This offers a function for the parasite glyoxalase II as general trypanothione thioesterase independent of ketoaldehyde detoxification.
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high glucose increases angiopoietin 2 transcription in microvascular endothelial cells through Methylglyoxal modification of msin3a
Journal of Biological Chemistry, 2007Co-Authors: Tetsuya Taguchi, Paul J. Thornalley, Naila Rabbani, Takeshi Matsumura, Richard G Pestell, Diane Edelstein, Ida Giardino, Guntram Suske, Vijay P Sarthy, H P HammesAbstract:Abstract Methylglyoxal is a highly reactive dicarbonyl degradation product formed from triose phosphates during glycolysis. Methylglyoxal forms stable adducts primarily with arginine residues of intracellular proteins. The biologic role of this covalent modification in regulating cell function is not known. Here we report that in mouse kidney endothelial cells, high glucose causes increased Methylglyoxal modification of the corepressor mSin3A. Methylglyoxal modification of mSin3A results in increased recruitment of O-GlcNAc-transferase, with consequent increased modification of Sp3 by O-linked N-acetylglucosamine. This modification of Sp3 causes decreased binding to a glucose-responsive GC-box in the angiopoietin-2 (Ang-2) promoter, resulting in increased Ang-2 expression. Increased Ang-2 expression induced by high glucose increased expression of intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 in cells and in kidneys from diabetic mice and sensitized microvascular endothelial cells to the proinflammatory effects of tumor necrosis factor α. This novel mechanism for regulating gene expression may play a role in the pathobiology of diabetic vascular disease.
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increased dicarbonyl metabolism in endothelial cells in hyperglycemia induces anoikis and impairs angiogenesis by rgd and gfoger motif modification
Diabetes, 2006Co-Authors: Darin Dobler, Naila Ahmed, Lijiang Song, Kevin E Eboigbodin, Paul J. ThornalleyAbstract:Chronic vascular disease in diabetes is associated with disruption of extracellular matrix (ECM) interactions with adherent endothelial cells, compromising cell survival and impairing vasculature structure. Loss of functional contact with integrins activates anoikis and impairs angiogenesis. The metabolic dysfunction underlying this vascular damage and disruption is unclear. Here, we show that increased modification of vascular basement membrane type IV collagen by Methylglyoxal, a dicarbonyl glycating agent with increased formation in hyperglycemia, formed arginine-derived hydroimidazolone residues at hotspot modification sites in RGD and GFOGER integrin-binding sites of collagen, causing endothelial cell detachment, anoikis, and inhibition of angiogenesis. Endothelial cells incubated in model hyperglycemia in vitro and experimental diabetes in vivo produced the same modifications of vascular collagen, inducing similar responses. Pharmacological scavenging of Methylglyoxal prevented anoikis and maintained angiogenesis, and inhibition of Methylglyoxal metabolism with a cell permeable glyoxalase I inhibitor provoked these responses in normoglycemia. Thus, increased formation of Methylglyoxal and ECM glycation in hyperglycemia impairs endothelial cell survival and angiogenesis and likely contributes to similar vascular dysfunction in diabetes.
Ramanakoppa H Nagaraj - One of the best experts on this subject based on the ideXlab platform.
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Methylglyoxal derived modifications in lens aging and cataract formation
Investigative Ophthalmology & Visual Science, 1998Co-Authors: Farrukh A Shamsi, Kenneth Lin, Candace Sady, Ramanakoppa H NagarajAbstract:PURPOSE. TO determine whether the Maillard reaction of Methylglyoxal is associated with human lens aging and cataractogenesis and to investigate how glutathione depletion affects Methylglyoxalderived modifications in organ-cultured lenses. METHODS. Antibodies against Methylglyoxal-derived modifications were developed in rabbits and purified by immunoaffinity chromatography. A competitive enzyme-linked immunosorbent assay (ELISA) measured Methylglyoxal-derived products in human lens proteins. Lenses of galactosemic rats grown in organ culture were used to assess the role of glutathione-dependent pathways in Methylglyoxal metabolism and Maillard reactions. RESULTS. Methylglyoxal-derived modifications in the human lens were age dependent, and brunescent lenses had the highest levels of these modifications. Immunofluorescence staining identified antigens distributed throughout the lens, with higher levels in old lenses than in younger ones. Experiments with normal or galactosemic rat lenses grown in organ culture showed that lens proteins do not have an increase in Methylglyoxal-modified proteins when cultured in medium containing 500 /xM Methylglyoxal alone, but they accumulate modified proteins when cultured with DL-glyceraldehyde. Inclusion of 30 mM glucose in the medium marginally increased Methylglyoxal-derived products, but there was no correlation between lens glutathione content and Methylglyoxal-derived modifications. CONCLUSIONS. Methylglyoxal-mediated Maillard reactions that occur in the human lens may play a role in lens aging and cataract formation. Methylglyoxal is probably derived from metabolic pathways within the lens. Decreased glutathione in organ-cultured rat lenses does not significantly influence Methylglyoxal-mediated Maillard reactions. (Invest Ophthalmol Vis Set. 1998;39: 2355-2364)
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protein modification by Methylglyoxal chemical nature and synthetic mechanism of a major fluorescent adduct
Archives of Biochemistry and Biophysics, 1997Co-Authors: Irina N Shipanova, Marcus A Glomb, Ramanakoppa H NagarajAbstract:Abstract The nonenzymatic Maillard reaction of proteins, initiated by the addition of sugars and other aldehydes and ketones, is thought to be an important mechanism in aging and the pathogenesis of diabetic complications. The α-dicarbonyl compounds are considered to be key intermediates in this reaction. Methylglyoxal (MG) (pyruvaldehyde), a physiological α-dicarbonyl compound, has been shown to modify proteins both in vitro and in vivo. Here we describe a novel fluorescent pyrimidine, N -δ-(5-hydroxy-4,6-dimethylpyrimidine-2-yl)- l -ornithine (argpyrimidine), formed from the Maillard reaction of MG with N -α- t -BOC-arginine. We find that the fluorescence spectrum of argpyrimidine is similar to that of Methylglyoxal-modified proteins, suggesting that it is a major product in such modified proteins. HPLC-quantification of argpyrimidine in proteins incubated with Methylglyoxal revealed a time-dependent formation. We detected significant amounts of argpyrimidine in incubations of N -α- t -BOC-arginine with micromolar concentrations of MG, and we find that various sugars and ascorbic acid serve as precursors. Our studies indicate that argpyrimidine is synthesized through an intermediate 3-hydroxypentane-2,4-dione and provide a chemical basis for fluorescence in proteins modified by Methylglyoxal. We suggest that enhanced intrinsic fluorescence in diabetic proteins may be due, in part, to Methylglyoxal-mediated Maillard reactions.
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protein cross linking by the maillard reaction isolation characterization and in vivo detection of a lysine lysine cross link derived from Methylglyoxal
Journal of Biological Chemistry, 1996Co-Authors: Ramanakoppa H Nagaraj, Irina N Shipanova, Frederick M FaustAbstract:The Maillard reaction, initiated by nonenzymatic glycosylation of amino groups on proteins by reducing sugars, has been studied for its potential role in aging and the complications of diabetes. One of the major consequences of the advanced Maillard reaction in proteins is the formation of covalently cross-linked aggregates. The chemical nature of the cross-linking structures is largely unknown. Recently, Methylglyoxal has been shown to be a potential glycating agent in vivo and suggested to be a common intermediate in the Maillard reaction involving glucose. Methylglyoxal can form enzymatically or nonenzymatically from glycolytic intermediates and by retro-aldol cleavage of sugars. Its elevation in tissues in diabetes and its high potency to glycate and cross-link proteins led us to investigate the chemical nature of its advanced Maillard products. Using an approach in which a synthetic model peptide was reacted with Methylglyoxal, we isolated and purified a cross-linked peptide dimer. Characterization of this dimer revealed that the peptides are linked through e amino groups of lysine residues. The actual cross-link was shown to be a methylimidazolium, formed from the reaction of two lysines and two Methylglyoxal molecules. We have named this cross-link imidazolysine. Imidazolysine was detected in proteins by high performance liquid chromatography using a postcolumn derivatization method. Proteins incubated with Methylglyoxal showed a time-dependent formation of imidazolysine. Quantification of imidazolysine in human serum proteins revealed a significant increase (p
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protein cross linking by the maillard reaction isolation characterization and in vivo detection of a lysine lysine cross link derived from Methylglyoxal
Journal of Biological Chemistry, 1996Co-Authors: Ramanakoppa H Nagaraj, Irina N Shipanova, Frederick M FaustAbstract:Abstract The Maillard reaction, initiated by nonenzymatic glycosylation of amino groups on proteins by reducing sugars, has been studied for its potential role in aging and the complications of diabetes. One of the major consequences of the advanced Maillard reaction in proteins is the formation of covalently cross-linked aggregates. The chemical nature of the cross-linking structures is largely unknown. Recently, Methylglyoxal has been shown to be a potential glycating agent in vivo and suggested to be a common intermediate in the Maillard reaction involving glucose. Methylglyoxal can form enzymatically or nonenzymatically from glycolytic intermediates and by retro-aldol cleavage of sugars. Its elevation in tissues in diabetes and its high potency to glycate and cross-link proteins led us to investigate the chemical nature of its advanced Maillard products. Using an approach in which a synthetic model peptide was reacted with Methylglyoxal, we isolated and purified a cross-linked peptide dimer. Characterization of this dimer revealed that the peptides are linked through ϵ amino groups of lysine residues. The actual cross-link was shown to be a methylimidazolium, formed from the reaction of two lysines and two Methylglyoxal molecules. We have named this cross-link imidazolysine. Imidazolysine was detected in proteins by high performance liquid chromatography using a postcolumn derivatization method. Proteins incubated with Methylglyoxal showed a time-dependent formation of imidazolysine. Quantification of imidazolysine in human serum proteins revealed a significant increase (p < 0.05) in diabetic samples (mean ± S.D., 313.8 ± 52.7 pmol/mg protein) when compared with normal samples (261.3 ± 50.4). These values correlated with glycohemoglobin (p < 0.05). These results provide chemical evidence for protein cross-linking by dicarbonyl compounds in vivo.
Naila Ahmed - One of the best experts on this subject based on the ideXlab platform.
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increased dicarbonyl metabolism in endothelial cells in hyperglycemia induces anoikis and impairs angiogenesis by rgd and gfoger motif modification
Diabetes, 2006Co-Authors: Darin Dobler, Naila Ahmed, Lijiang Song, Kevin E Eboigbodin, Paul J. ThornalleyAbstract:Chronic vascular disease in diabetes is associated with disruption of extracellular matrix (ECM) interactions with adherent endothelial cells, compromising cell survival and impairing vasculature structure. Loss of functional contact with integrins activates anoikis and impairs angiogenesis. The metabolic dysfunction underlying this vascular damage and disruption is unclear. Here, we show that increased modification of vascular basement membrane type IV collagen by Methylglyoxal, a dicarbonyl glycating agent with increased formation in hyperglycemia, formed arginine-derived hydroimidazolone residues at hotspot modification sites in RGD and GFOGER integrin-binding sites of collagen, causing endothelial cell detachment, anoikis, and inhibition of angiogenesis. Endothelial cells incubated in model hyperglycemia in vitro and experimental diabetes in vivo produced the same modifications of vascular collagen, inducing similar responses. Pharmacological scavenging of Methylglyoxal prevented anoikis and maintained angiogenesis, and inhibition of Methylglyoxal metabolism with a cell permeable glyoxalase I inhibitor provoked these responses in normoglycemia. Thus, increased formation of Methylglyoxal and ECM glycation in hyperglycemia impairs endothelial cell survival and angiogenesis and likely contributes to similar vascular dysfunction in diabetes.
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Methylglyoxal modification of msin3a links glycolysis to angiopoietin 2 transcription
Cell, 2006Co-Authors: Dachun Yao, Paul J. Thornalley, Naila Ahmed, Tetsuya Taguchi, Takeshi Matsumura, Richard G Pestell, Diane Edelstein, Ida Giardino, Guntram Suske, Vijay P SarthyAbstract:Methylglyoxal is a highly reactive dicarbonyl degradation product formed from triose phosphates during glycolysis. Methylglyoxal forms stable adducts primarily with arginine residues of intracellular proteins. The biologic role of this covalent modification in regulating cell function is not known. Here, we report that in retinal Muller cells, increased glycolytic flux causes increased Methylglyoxal modification of the corepressor mSin3A. Methylglyoxal modification of mSin3A results in increased recruitment of O-GlcNAc transferase to an mSin3A-Sp3 complex, with consequent increased modification of Sp3 by O-linked N-acetylglucosamine. This modification of Sp3 causes decreased binding of the repressor complex to a glucose-responsive GC box in the angiopoietin-2 promoter, resulting in increased Ang-2 expression. A similar mechanism involving Methylglyoxal-modification of other coregulator proteins may play a role in the pathobiology of a variety of conditions associated with changes in Methylglyoxal concentration, including cancer and diabetic vascular disease.
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peptide mapping identifies hotspot site of modification in human serum albumin by Methylglyoxal involved in ligand binding and esterase activity
Journal of Biological Chemistry, 2005Co-Authors: Naila Ahmed, Darin Dobler, Mark K Dean, Paul J. ThornalleyAbstract:Methylglyoxal is a potent glycating agent under physiological conditions. Human serum albumin is modified by Methylglyoxal in vivo. The glycation adducts formed and structural and functional changes induced by Methylglyoxal modification have not been fully disclosed. Methylglyoxal reacted with human serum albumin under physiological conditions to form mainly the hydroimidazolone Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (92% of total modification) with a minor formation of argpyrimidine, Nϵ-(1-carboxyethyl)lysine, and Methylglyoxal lysine dimer. When human serum albumin was modified minimally with Methylglyoxal, tryptic peptide mapping indicated a hotspot of modification at Arg-410 located in drug-binding site II and the active site of albumin-associated esterase activity. Modification of Arg-410 by Methylglyoxal was found in albumin glycated in vivo. Other sites of minor modification were: Arg-114, Arg-186, Arg-218, and Arg-428. Hydroimidazolone formation at Arg-410 inhibited ketoprofen binding and esterase activity; correspondingly, glycation in the presence of ketoprofen inhibited Arg-410 modification and loss of esterase activity. The pH dependence of esterase activity indicated a catalytic group with pKa = 7.9 ± 0.1, assigned to the catalytic base Tyr-411 with the conjugate base stabilized by interaction with the guanidinium group of Arg-410. Modification by Methylglyoxal destabilized Tyr-411 and increased the pKa to 8.8 ± 0.1. Molecular dynamics and modeling studies indicated that hydroimidazolone formation caused structural distortion leading to disruption of arginine-directed hydrogen bonding and loss of electrostatic interactions. Methylglyoxal modification of critical arginine residues, therefore, whether experimental or physiological, is expected to disrupt protein-ligand interactions and inactivate enzyme activity by hydroimidazolone formation.
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Methylglyoxal-Derived Hydroimidazolone Advanced Glycation End-Products of Human Lens Proteins
Investigative ophthalmology & visual science, 2003Co-Authors: Naila Ahmed, Paul J. Thornalley, Jens Dawczynski, Sybille Franke, J. Strobel, Gu¨nter Stein, George M. HaikAbstract:Purpose To determine the concentrations of Methylglyoxal-derived advanced glycation end-products (AGEs), the hydroimidazolones MG-H1 and -H2, in soluble human lens proteins and compare them with the concentrations of other Methylglyoxal-derived AGEs and pentosidine. Methods Lens protein samples were hydrolyzed enzymatically. AGEs were assayed without derivatization by HPLC with tandem mass spectrometry; the fluorescent AGEs argpyrimidine and pentosidine were assayed by fluorometric detection. MG-H1 and -H2 were resolved and assayed by fluorometric detection after derivatization with 6-aminoquinolyl-N-hydroxysuccimidylcarbamate (AQC). Results The Methylglyoxal-derived hydroimidazolones MG-H1 and -H2 were detected and quantified in human lens proteins. AGE concentrations (mean +/- SEM) were: MG-H1 4609 +/- 411 pmol/mg protein, MG-H2 3085 +/- 328 pmol/mg protein, argpyrimidine 205 +/- 19 pmol/mg protein, and pentosidine 0.693 +/- 0.104 pmol/mg protein. The concentration of MG-H1 in human lens protein correlated positively with donor age (correlation coefficient = 0.28, P Conclusions Methylglyoxal hydroimidazolones are quantitatively major AGEs of human lens proteins. These substantial modifications of lens proteins may stimulate further glycation, oxidation, and protein aggregation leading to the formation of cataract.
Christopher J. Adams - One of the best experts on this subject based on the ideXlab platform.
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The origin of Methylglyoxal in New Zealand manuka (Leptospermum scoparium) honey
Carbohydrate research, 2009Co-Authors: Christopher J. Adams, Merilyn Manley-harris, Peter C. MolanAbstract:Methylglyoxal in New Zealand manuka honey has been shown to originate from dihydroxyacetone, which is present in the nectar of manuka flowers in varying amounts. Manuka honey, which was freshly produced by bees, contained low levels of Methylglyoxal and high levels of dihydroxyacetone. Storage of these honeys at 37 degrees C led to a decrease in the dihydroxyacetone content and a related increase in Methylglyoxal. Addition of dihydroxyacetone to clover honey followed by incubation resulted in Methylglyoxal levels similar to those found in manuka honey. Nectar washed from manuka flowers contained high levels of dihydroxyacetone and no detectable Methylglyoxal.
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isolation by hplc and characterisation of the bioactive fraction of new zealand manuka leptospermum scoparium honey
Carbohydrate Research, 2008Co-Authors: Christopher J. Adams, Cherie H Boult, Benjamin J Deadman, Judie M Farr, Megan N C Grainger, Merilyn Manleyharris, Melanie J SnowAbstract:Abstract Using HPLC a fraction of New Zealand manuka honey has been isolated, which gives rise to the non-peroxide antibacterial activity. This fraction proved to be Methylglyoxal, a highly reactive precursor in the formation of advanced glycation endproducts (AGEs). Methylglyoxal concentrations in 49 manuka and 34 non-manuka honey samples were determined using a direct detection method and compared with values obtained using standard o -phenylenediamine derivatisation. Concentrations obtained using both the methods were similar and varied from 38 to 828 mg/kg.
Bernhard H J Juurlink - One of the best experts on this subject based on the ideXlab platform.
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increased Methylglyoxal and oxidative stress in hypertensive rat vascular smooth muscle cells
Hypertension, 2002Co-Authors: Lingyun Wu, Bernhard H J JuurlinkAbstract:Methylglyoxal can yield advanced glycation end products via nonenzymatic glycation of proteins. Whether Methylglyoxal contributes to the pathogenesis of hypertension has not been clear. The aim of the present study was to investigate whether the levels of Methylglyoxal and Methylglyoxal-induced advanced glycation end products were enhanced and whether Methylglyoxal increased oxidative stress, activated nuclear factor–κB (NF-κB), and increased intracellular adhesion molecule-1 (ICAM-1) content in vascular smooth muscle cells from spontaneously hypertensive rats. Basal cellular levels of Methylglyoxal and advanced glycation end products were more than 2-fold higher ( P N -acetylcysteine. Our study demonstrates an elevated Methylglyoxal level and advanced glycation end products in cells from hypertensive rats, and Methylglyoxal increases oxidative stress, activates NF-κB, and enhances ICAM-1 expression. Our findings suggest that that elevated Methylglyoxal and associated oxidative stress possibly contribute to the pathogenesis of hypertension.
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increased Methylglyoxal and oxidative stress in hypertensive rat vascular smooth muscle cells
Hypertension, 2002Co-Authors: Bernhard H J JuurlinkAbstract:Methylglyoxal can yield advanced glycation end products via nonenzymatic glycation of proteins. Whether Methylglyoxal contributes to the pathogenesis of hypertension has not been clear. The aim of the present study was to investigate whether the levels of Methylglyoxal and Methylglyoxal-induced advanced glycation end products were enhanced and whether Methylglyoxal increased oxidative stress, activated nuclear factor-kappaB (NF-kappaB), and increased intracellular adhesion molecule-1 (ICAM-1) content in vascular smooth muscle cells from spontaneously hypertensive rats. Basal cellular levels of Methylglyoxal and advanced glycation end products were more than 2-fold higher (P<0.05) in cells from hypertensive rats than from normotensive Wistar-Kyoto rats. This correlated with levels of oxidative stress and oxidized glutathione that were significantly higher in cells from hypertensive rats, whereas levels of glutathione and activities of glutathione reductase and glutathione peroxidase were significantly lower. Basal levels of nuclearly localized NF-kappaB p65 and ICAM-1 protein expression were higher in cells from hypertensive rats than from normotensive rats. Addition of exogenous Methylglyoxal to the cultures induced a greater increase in oxidative stress and advanced glycation end products in cells from hypertensive rats compared with normotensive rats and significantly decreased the activities of glutathione reductase and glutathione peroxidase in cells of both rat strains. Methylglyoxal activated NF-kappaB p65 and increased ICAM-1 expression in hypertensive cells, which was inhibited by N-acetylcysteine. Our study demonstrates an elevated Methylglyoxal level and advanced glycation end products in cells from hypertensive rats, and Methylglyoxal increases oxidative stress, activates NF-kappaB, and enhances ICAM-1 expression. Our findings suggest that that elevated Methylglyoxal and associated oxidative stress possibly contribute to the pathogenesis of hypertension.
