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At least 703 records · Page 39Linked to original sources
PubMed2004

Methylglyoxal induces apoptosis mediated by reactive oxygen species in bovine retinal pericytes.

One of the histopathologic hallmarks of early diabetic retinopathy is the loss of pericytes. Evidences suggest that the pericyte loss in vivo is mediated by apoptosis. However, the underlying cause of pericyte apoptosis is not fully understood. This study investigated the influence of methylglyoxal (MGO), a reactive alpha-dicarbonyl compound of glucose metabolism, on apoptotic cell death in bovine retinal pericytes. Analysis of internucleosomal DNA fragmentation by ELISA showed that MGO (200 to 800 microM) induced apoptosis in a concentration-dependent manner. Intracellular reactive oxygen species were generated earlier and the antioxidant, N-acetyl cysteine, inhibited the MGO-induced apoptosis. NF-kappaB activation and increased caspase-3 activity were detected. Apoptosis was also inhibited by the caspase-3 inhibitor, Z-DEVD-fmk, or the NF-kappaB inhibitor, pyrrolidine dithiocarbamate. These data suggest that elevated MGO levels observed in diabetes may cause apoptosis in bovine retinal pericytes through an oxidative stress mechanism and suggests that the nuclear activation of NF-kappaB are involved in the apoptotic process.

Acetylcysteine↗
PubMed1987

Polyamine metabolism as a target for growth inhibition of Acanthamoeba culbertsoni.

Alpha-difluoromethylornithine had no inhibitory effect on the growth of Acanthamoeba culbertsoni, while methylglyoxal bis(guanyl-hydrazone) and sinefungin completely blocked amebic growth at 2.5 mM and 5 micrograms/ml concentrations, respectively. Cyclohexylamine caused only partial inhibition of amebic growth at 50-200 microM concentrations. Methylglyoxal bis(guanyl-hydrazone) inhibited S-adenosylmethionine decarboxylase of A. culbertsoni indicating this enzyme to be the target for its antiamebic action. This enzyme was, however, not inhibited by sinefungin, suggesting an alternative target for growth inhibition by this compound.

Acanthamoeba↗
PubMed2006

Oxidative modification of human ceruloplasmin by methylglyoxal: an in vitro study.

Methylglyoxal (MG) is an endogenous physiological metabolite which is present in increased concentrations in diabetics. MG reacts with the amino acids of proteins to form advanced glycation end products. In this in vitro study, we investigated the effect of MG on the structure and function of ceruloplasmin (CP) a serum oxidase carrier of copper ions in the human. When CP was incubated with MG, the protein showed increased electrophoretic mobility which represented the aggregates at a high concentration of MG (100 mM). MG-mediated CP aggregation led to the loss of enzymatic activity and the release of copper ions from the protein. Radical scavengers and copper ion chelators significantly prevented CP aggregation. CP is an important protein that circulates in plasma as a major copper transport protein. It is suggested that oxidative damage of CP by MG may induce perturbations of the copper transport system and subsequently lead to harmful intracellular condition. The proposed mechanism, in part, may provide an explanation for the deterioration of organs in the diabetic patient.

Cation Transport Proteins↗
PubMedDate not supplied

Induction of 1,2-dicarbonyl compounds, intermediates in the formation of advanced glycation end-products, during heat-sterilization of glucose-based peritoneal dialysis fluids.

OBJECTIVE: To study the presence of 1,2-dicarbonyl compounds in peritoneal dialysis (PD) fluids, their concentration in effluents with increasing dwell time, and their role in the formation of advanced glycation end-products (AGEs). MEASUREMENTS: Dicarbonyl compounds in heat- and filter-sterilized PD fluids were quantified by reverse-phase high performance liquid chromatography (HPLC) after derivatization to dimethoxyquinoxaline derivatives. Kinetics of the in vitro formation of AGEs upon incubation of 1,2-dicarbonyl compounds or PD fluids with albumin, with or without aminoguanidine, were measured by AGE fluorescence (excitation/emission wavelengths of 350 nm/430 nm). PATIENTS: AGEs and dicarbonyl compounds were measured in effluents collected from standardized 4-hour dwells from 8 continuous cycling peritoneal dialysis patients. RESULTS: In PD fluids, 3-deoxyglucosone (3-DG) has been identified as the major dicarbonyl compound formed during the process of heat sterilization. The process also formed glyoxal (GO) and methylglyoxal (MGO), with the amount of 3-DG being approximately 25-60 times higher than GO and MGO. When incubated with albumin, the identified 1,2-dicarbonyl compounds rapidly formed AGEs. The formation of AGEs was more pronounced in conventional heat-sterilized PD fluids compared with filter-sterilized PD fluids, and was completely inhibited by aminoguanidine. In effluents, the concentration of MGO, GO, and 3-DG decreased with increasing dwell time, with a concomitant increase in AGE fluorescence. CONCLUSIONS: The dicarbonyl compounds 3-DG, MGO, and GO are potent promoters of AGE formation. The presence of these and possibly other dicarbonyl compounds formed during heat sterilization of glucose-based PD fluids is, to a large extent, responsible for the in vitroAGE formation by these fluids, as evidenced by the speed of AGE formation in PD fluids and the complete inhibition by aminoguanidine. Because 3-DG, MGO, and GO are rapidly cleared from PD fluids during dialysis, these compounds may contribute to the in vivo AGE formation in PD patients.

Adult↗
PubMed1999

Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose.

The glycation of proteins by glucose has been linked to the development of diabetic complications and other diseases. Early glycation is thought to involve the reaction of glucose with N-terminal and lysyl side chain amino groups to form Schiff's base and fructosamine adducts. The formation of the alpha-oxoaldehydes, glyoxal, methylglyoxal and 3-deoxyglucosone, in early glycation was investigated. Glucose (50 mM) degraded slowly at pH 7.4 and 37 degrees C to form glyoxal, methylglyoxal and 3-deoxyglucosone throughout a 3-week incubation period. Addition of t-BOC-lysine and human serum albumin increased the rate of formation of alpha-oxoaldehydes - except glyoxal and methylglyoxal concentrations were low with albumin, as expected from the high reactivity of glyoxal and methylglyoxal with arginine residues. The degradation of fructosyl-lysine also formed glyoxal, methylglyoxal and 3-deoxyglucosone. alpha-Oxoaldehyde formation was dependent on the concentration of phosphate buffer and availability of trace metal ions. This suggests that alpha-oxoaldehydes were formed in early glycation from the degradation of glucose and Schiff's base adduct. Since alpha-oxoaldehydes are important precursors of advanced glycation adducts, these adducts may be formed from early and advanced glycation processes. Short periods of hyperglycaemia, as occur in impaired glucose tolerance, may be sufficient to increase the concentrations of alpha-oxoaldehydes in vivo.

Deoxyglucose↗
PubMed1998

Aldehyde induced hypertension in rats: prevention by N-acetyl cysteine.

Methylglyoxal, a highly reactive endogenous aldehyde is formed in the tissue of humans and animals as an intermediate of glucose and fructose metabolism. N-acetyl cysteine (NAC), an analogue of the dietary amino acid cysteine, binds aldehydes thus preventing their damaging effect on physiological proteins. We measured systolic blood pressure (SBP), platelet [Ca2+]i, circulating nitric oxide levels, tissue aldehyde conjugates and renal vascular changes in chronic methyglyoxal treated Wistar-Kyoto (WKY) rats and examined the effect of NAC in the diet on these parameters. Animals, age seven weeks, were divided into three groups of six animals each and were treated as follows: WKY-control (chow diet and normal drinking water); WKY-methylglyoxal (chow diet and methyglyoxal in drinking water); WKY-methyglyoxal + NAC (1.5% NAC in diet and methylglyoxal in drinking water) for the next 18 weeks. Methylgyoxal in drinking water was given at a concentration of 0.2% during weeks 0-5; 0.4%, weeks 6-10; and 0.8%, weeks 11-18. After 18 weeks systolic blood pressure, platelet [Ca2+]i and kidney aldehyde conjugates were significantly higher and serum nitric oxide levels lower in methylglyoxal treated rats. Methylglyoxal treated rats also showed smooth muscle cell hyperplasia in the small artery and arterioles of the kidney. N-acetyl cysteine, an aldehyde binding thiol compound, prevented these changes.

Acetylcysteine↗
PubMed1975

Short induction treatment in acute granulocytic leukemia.

Short treatment with four cytostatics in acute granulocytic leukemia induced aplasia and reduction of total leukemic cells in 50 over 59 patients. Complete remission occured in 30 and 20 died with infectious complications during induction. Short induction treatment allowed a reduction of induction period and so a reduction of high risk period of induction before completion of complete remission.

Adolescent↗
PubMed2000

Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo.

BACKGROUND: The Maillard reaction that leads to the formation of advanced glycation end-products (AGE) plays an important role in the pathogenesis of angiopathy in diabetic patients and in the aging process. Recently, it was proposed that AGE were not only created by glucose, but also by dicarbonyl compounds derived from the Maillard reaction, autoxidation of sugars and other metabolic pathways of glucose. In this study, we developed four types of non-carboxymethyllysine (CML) anti-AGE antibodies that recognized proteins modified by incubation with short chain sugars and dicarbonyl compounds. MATERIALS AND METHODS: AGE-modified serum albumins were prepared by incubation of rabbit serum albumin with glyceraldehyde, glycolaldehyde, methylglyoxal or glyoxal. After immunization of rabbits, four types of AGE-specific antisera were obtained that were specific for the AGE modification. To separate non-CML AGE antibodies (Ab) (non-CML AGE-Ab-2, -3, -4, and -5), these anti-AGE antisera were subjected to affinity chromatography on a matrix coupled with four kinds of AGE bovine serum albumin (BSA) or CML-BSA. These non-CML AGE antibodies were used to investigate the AGE content of serum obtained from diabetic patients on hemodialysis. RESULTS: Characterization of the four types of non-CML AGE antibodies obtained by immunoaffinity chromatography was performed by competitive ELISA and immunoblot analysis. Non-CML AGE-Ab-2 crossreacted with the protein modified by glyceraldehyde or glycolaldehyde. Non-CML AGE-Ab-3 and -Ab-4 specifically cross-reacted with protein modified by glycolaldehyde and methylglyoxal, respectively. NonCML AGE-Ab-5 cross-reacted with protein modified with glyoxal as well as methylglyoxal and glycolaldehyde. Three kinds of non-CML AGE (AGE-2, -4, and -5) were detected in diabetic serum as three peaks with apparent molecular weights of 200, 1.15, and 0.85 kD; whereas, AGE-3 was detected as two peaks with apparent molecular weights of 200 and 0.85 kD. CONCLUSION: We propose that various types of non-CML AGE are formed by the Maillard reaction, sugar autoxidation and sugar metabolism. These antibodies enable us to identify such compounds created by the Maillard reaction in vivo.

Animals↗
PubMed2000

Carnosine and protein carbonyl groups: a possible relationship.

Carnosine has been shown to react with low-molecular-weight aldehydes and ketones and has been proposed as a naturally occurring anti-glycating agent. It is suggested here that carnosine can also react with ("carnosinylate") proteins bearing carbonyl groups, and evidence supporting this idea is presented. Accumulation of protein carbonyl groups is associated with cellular ageing resulting from the effects of reactive oxygen species, reducing sugars, and other reactive aldehydes and ketones. Carnosine has been shown to delay senescence and promote formation of a more juvenile phenotype in cultured human fibroblasts. It is speculated that carnosine may intracellularly suppress the deleterious effects of protein carbonyls by reacting with them to form protein-carbonyl-carnosine adducts, i.e., "carnosinylated" proteins. Various fates of the carnosinylated proteins are discussed including formation of inert lipofuscin and proteolysis via proteosome and RAGE activities. It is proposed that the anti-ageing and rejuvenating effects of carnosine are more readily explainable by its ability to react with protein carbonyls than its well-documented antioxidant activity.

Aldehydes↗
PubMed2001

Effect of methylglyoxal on mouse embryogenesis.

BACKGROUND: Methylglyoxal (MG), a highly active and mutagenetic compound, has been found widely in a variety of foods and beverages. We investigated the effect of MG on mouse embryo development in-vitro. METHODS: Two-cell mouse embryos were divided into six groups according to the MG concentration in the culture medium: Group 1 (control group). 0 mM; Group 2, 10(-4) mM; Group 3, 10(-3) mM; Group 4, 10(-2) mM; Group 5, 10(-1) mM; Group 6, 1 mM. Embryo development and cleavage were compared every day for 5 days. RESULTS: The percentages of embryos reaching blastocyst/hatching stages were as follows: Group 1, 66.8%/34.2%; Group 2, 67.9%/38.7%; Group 3, 56.2%/31.5%; Group 4, 39.4%/14.1%; Group 5, 11.4%/10.2%; Group 6, 0%/0%. Higher MG concentrations (> or = 10(-2) mM) were associated with morphological aberrations and blocked development of embryos. CONCLUSION: The cutoff value of MG concentration on the mouse embryo development in-vitro is 10(-2) mM. An increased risk of embryotoxicity occurs with MG concentrations > or = 10(-2) mM in vitro. There were no significant effects on the growth rate at MG concentrations of 10(-3) and 10(-4) mM.

Animals↗
PubMed2001

Sodium sulfite and N-acetylcysteine: new additives to dialysate for inhibiting formation of glucose degradation products and advanced glycation end-products.

The present study evaluated the inhibiting effect of various chemicals on the advanced glycation end-product (AGEs) cross-linking caused in protein by glucose degradation products (GDPs). We evaluated a few dozen organic and inorganic chemicals--in addition to previously reported AGE inhibitors, such as thiazolium derivatives and aminoguanidine--for their inhibiting effect. Collagen IV (from human placenta) or human serum albumin (HSA) was incubated with an AGE accelerator and one of the selected chemicals in phosphate buffer solution at 37 degrees C for as long as 14 days. Fluorescence intensity (440 nm) was determined after a given incubation time. Among 36 chemicals tested, 8 new chemicals and 5 previously known AGE inhibitors significantly suppressed the increase in fluorescence intensity seen after incubation of HSA with methylglyoxal. We believe that 6 chemicals may effectively quench GDPs and inhibit AGE cross-link formation, in a manner different from that of aminoguanidine and thiazolium.

Acetylcysteine↗
PubMed1975

Changes of certain pharmacological and biochemical indices in acute methylglyoxal poisoning.

Methylglyoxal in doses over 25 mg/kg injected intravenously in cats and rabbits produces distinct changes in the cardiovascular and respiratory systems, but has no effect on respiration or circulation when injected intraperitoneally even in doses up to 1 g/kg. The effect of MG on blood pressure depends on the species of the animal. The effects of MG are dose-related and dependent on the route of its administration. Biochemical studies showed a significant rise in serum activities of creatine kinase (EC 2-7-3-2), lactate dehydrogenase (EC 1-1-1-27) and aspartate aminotransferase (EC 2-6-1-1-) after intraperitoneal injection of MG in the dose of 200 mg/kg in rabbits and 500 mg/kg in rats. The observed changes probably indicate damage of muscle tissue by MG, presumably as a result of low content of one of the glyoxalases in the muscles of the experimental animals. Elevation of glucose levels by MG was probably an adrenergic effect. These biochemical changes can serve to evaluate toxicity of MG preparations, which exhibit variations probably owing to varying degree of polymerization.

Alanine Transaminase↗
PubMed1976

Effect of methyl glyoxal on infectivity and antigenicity of foot-and-mouth disease virus.

The inactivating effect of methyl glyoxal on foot-and-mouth disease (FMD) virus was studied. The rate of inactivation depended upon the drug concentration, incubation temperature and pH of the medium. RNA recovered from the inactivated virus was not infectious. The complement-fixing activity of the virus was not reduced by methyl glyoxal treatment. The antigenicity of inactivated virus preparations determined by levels of virus neutralizing antibody in the blood sera of immunized white rats and rabbits was not inferior to that of the initial uninactivated virus.

Aldehydes↗
PubMedDate not supplied

Early glycated albumin, but not advanced glycated albumin, methylglyoxal, or 3-deoxyglucosone increases the expression of PAI-1 in human peritoneal mesothelial cells.

OBJECTIVE: The continuous contact of glucose-containing peritoneal dialysis (PD) fluids with the peritoneum results in the intraperitoneal formation of early and advanced glycation end-products. This nonenzymatic glycation of proteins may cause morphological and functional alterations to the peritoneum, which may contribute to patient dropout from PD therapy. Because fibrinolytic system components have been demonstrated to play an important role in the balance of intraperitoneal generation and degradation of fibrin, we studied the effect of early and advanced glycated human serum albumin, methylglyoxal, and 3-deoxyglucosone on the synthesis of tissue-type plasminogen activator (tPA), as well as its specific inhibitor (PAI-1), in human peritoneal mesothelial cells (HPMC). METHODS: Antigen concentrations in the supernatants of cultured HPMC were measured by ELISA. Northern blot analysis was conducted for mRNA expression. Electrophoretic mobility shift assays were applied to demonstrate the involvement of the transcription factors nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1) in signal transduction. RESULTS: Incubation of HPMC with early glycated albumin (GHSA) resulted in a time- and concentration-dependent increase in PAI-1 mRNA expression and antigen secretion. In contrast, no changes in PAI-1 synthesis occurred after stimulation with either the 1,2-dicarbonyl compounds methylglyoxal and 3-deoxyglucosone, or with late advanced glycation end-products. tPA synthesis was not affected by any of the tested components. Furthermore, HPMC exposed to GHSA induced NF-kappaB and AP-1 DNA binding activity, suggesting that GHSA-induced overexpression of PAI-1 is transcriptionally regulated by both transcription factors. CONCLUSIONS: We conclude that Amadori modified glycated albumin upregulates PAI-1 synthesis in HPMC, possibly mediated through the activation of the transcription factors NF-kappaB and AP-1. The present data support the clinical relevance of the formation of glycated proteins and their involvement in pathological processes in PD patients. Thus, glycated albumin may contribute to an imbalance between intraperitoneal formation and degradation of fibrin that causes peritoneal structural alterations, with subsequent membrane failure.

Albumins↗
PubMed2001

Protein glycation: creation of catalytic sites for free radical generation.

In a glycation reaction, alpha-dicarbonyl compounds such as deoxyglucosone, methylglyoxal, and glyoxal are more reactive than the parent sugars with respect to their ability to react with amino groups of proteins to form inter- and intramolecular cross-links of proteins, stable end products called advanced Maillard products or advanced end products (AGEs). The AGEs, which are irreversibly formed, accumulate with aging, atherosclerosis, and diabetes mellitus, and are especially associated with long-lived proteins such as collagens, lens crystallins, and nerve proteins. It was suggested that the formation of AGEs not only modifies protein properites but also induces biological damage in vivo. In this report, we summerize results obtained from our studies for (1) identifying the structure of the cross-linked radical species formed in the model system-the reaction between alpha-dicarbonyl methylglyoxal with amino acids, and (2) the reactivity of the radical center of the protein created by the similar reaction. These results indicate that glycation of protein generates active centers for catalyzing one-electron oxidation-reduction reactions. This active center, which exhibits enzyme-like character, is suggested to be the cross-linked Schiff-based radical cation of the protein. It mimics the characteristics of the metal-catalyzed oxidation system. These results together indicate that glycated proteins accumulated in vivo provide stable active sites for catalyzing the formation of free redicals.

Aging↗
PubMed2003

Modification and inactivation of human Cu,Zn-superoxide dismutase by methylglyoxal.

Methylglyoxal (MG) has been identified as an intermediate in non-enzymatic glycation, and increased levels have been reported in patients with diabetes. In this study, the effect of MG on the structure and function of human Cu,Zn-superoxide dismutase (SOD) was investigated. MG modifies Cu,Zn-SOD, as indicated by the formation of fluorescent products. When Cu, Zn-SOD was incubated with MG, covalent crosslinking of the protein increased progressively. MG-mediated modification of Cu,Zn-SOD led to loss of enzymatic activity and release of copper ions from the protein. Radical scavengers inhibited the crosslinking of Cu,Zn-SOD. When Cu,Zn-SOD that had been exposed to MG was analyzed, glycine, histidine, lysine, and valine residues were found to be particularly sensitive. It is suggested that oxidative damage to Cu,Zn-SOD by MG may perturb cellular antioxidant defense systems and damage cells. This effect may account, in part, for organ deterioration in diabetes.

Cross-Linking Reagents↗