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PubMed2006

Glyoxalase I is critical for human retinal capillary pericyte survival under hyperglycemic conditions.

Retinal capillary pericytes undergo premature death, possibly by apoptosis, during the early stages of diabetic retinopathy. The alpha-oxoaldehyde, methylglyoxal (MGO), has been implicated as a cause of cell damage in diabetes. We have investigated the role of MGO and its metabolizing enzyme, glyoxalase I, in high glucose-induced apoptosis (annexin V binding) of human retinal pericyte (HRP). HRP incubated with high glucose (30 mm d-glucose) for 7 days did not undergo apoptosis despite accumulation of MGO. However, treatment with a combination of high glucose and S-p-bromobenzylglutathione cyclopentyl diester, a competitive inhibitor of glyoxalase I, resulted in apoptosis along with a dramatic increase in MGO. Overexpression of glyoxalase I in HRP protected against S-p-bromobenzylglutathione cyclopentyl diester-induced apoptosis under high glucose conditions. Incubation of HRP with high concentrations of MGO resulted in an increase of apoptosis relative to untreated controls. We found an elevation of nitric oxide (NO.) in HRP that was incubated with high glucose when compared with those incubated with either the l-glucose or untreated controls. When HRP were incubated with an NO. donor, DETANONOATE ((Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate), we observed both decreased glyoxalase I expression and activity relative to untreated control cells. Further studies showed that HRP underwent apoptosis when incubated with DETANONOATE and that apoptosis increased further on co-incubation with high glucose. Our findings indicate that glyoxalase I is critical for pericyte survival under hyperglycemic conditions, and its inactivation and/or down-regulation by NO. may contribute to pericyte death by apoptosis during the early stages of diabetic retinopathy.

Adult↗
PubMed2006

Glyoxalase II, a detoxifying enzyme of glycolysis byproduct methylglyoxal and a target of p63 and p73, is a pro-survival factor of the p53 family.

The p53 family proteins are transcription factors and have both common and distinct functions. p53 is a classic tumor suppressor, whereas p63 and p73 have fundamental functions in development. To gain an insight into the functional diversities among the p53 family, target genes specifically regulated by p63 and p73 were examined. Here, we found that the GLX2 gene, which encodes glyoxalase II enzyme, is up-regulated by p63 and p73. Accordingly, a specific responsive element was found in intron 1 of the GLX2 gene, which can be activated and bound by p63 and p73. We also found that, upon overexpression, the cytosolic, but not the mitochondrial, GLX2 inhibits the apoptotic response of a cell to methylglyoxal, a by-product of glycolysis. Likewise, we showed that cells deficient in GLX2 are hypersensitive to methylglyoxal-induced apoptosis. Interestingly, a deficiency in GLX2 also enhances the susceptibility of a cell to DNA damage-induced apoptosis in a p53-dependent manner. These observations reveal a novel link between the p53 family and the glyoxalase system. Given that methylglyoxal is frequently generated under both physiological and pathological conditions, we postulate that GLX2 serves as a pro-survival factor of the p53 family and plays a critical role in the normal development and in the pathogenesis of various human diseases, including cancer, diabetes, and neurodegenerative diseases.

Animals↗
PubMed2006

Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation.

Accumulation of hyperphosphorylated Tau protein as paired helical filaments in pyramidal neurons is a major hallmark of Alzheimer disease. Besides hyperphosphorylation, other modifications of the Tau protein, such as cross-linking, are likely to contribute to the characteristic features of paired helical filaments, including their insolubility and resistance against proteolytic degradation. In this study, we have investigated whether the four reactive carbonyl compounds acrolein, malondialdehyde, glyoxal, and methylglyoxal accelerate the formation of Tau oligomers, thioflavin T-positive aggregates, and fibrils using wild-type and seven pseudophosphorylated mutant Tau proteins. Acrolein and methylglyoxal were the most reactive compounds followed by glyoxal and malondialdehyde in terms of formation of Tau dimers and higher molecular weight oligomers. Furthermore, acrolein and methylglyoxal induced the formation of thioflavin T-fluorescent aggregates in a triple pseudophosphorylation-mimicking mutant to a slightly higher degree than wild-type Tau. Analysis of the Tau aggregates by electron microscopy study showed that formation of fibrils using wild-type Tau and several Tau mutants could be observed with acrolein and methylglyoxal but not with glyoxal and malondialdehyde. Our results suggest that reactive carbonyl compounds, particularly methylglyoxal and acrolein, could accelerate tangle formation in vivo and that this process could be slightly accelerated, at least in the case of methylglyoxal and acrolein, by hyperphosphorylation. Interference with the formation or the reaction of these reactive carbonyl compounds could be a promising way of inhibiting tangle formation and neuronal dysfunction in Alzheimer disease and other tauopathies.

Acrolein↗
PubMed2007

Methylglyoxal inhibits the binding step of collagen phagocytosis.

Bacterial infection-induced fibrosis affects a wide variety of tissues, including the periodontium, but the mechanisms that dysregulate matrix turnover and mediate fibrosis are not defined. Since collagen turnover by phagocytosis is an important pathway for matrix remodeling, we studied the effect of the bacterial and eukaryotic cell metabolite, methylglyoxal (MGO), on the binding step of phagocytosis by periodontal fibroblasts. Type 1 collagen was treated with various concentrations of methylglyoxal, an important glucose metabolite that modifies Arg and Lys residues. The extent of MGO-induced modifications was authenticated by amino acid analysis, solubility, and cross-linking. Cells were incubated with fluorescent beads coated with collagen, and the percentage of phagocytic cells was estimated by flow cytometry. MGO inhibited collagen binding (20% of control for 10 mm MGO) in a time- and concentration-dependent manner. MGO-induced inhibition of binding was prevented by aminoguanidine, which blocks the formation of collagen cross-links. MGO reduced collagen binding strength and blocked intracellular calcium signaling. MGO modified the Arg residue in the critical alpha2beta1 integrin-binding recognition sequence of triple helical collagen peptides, whereas MGO-induced cross-linking of Lys residues played only a small role in binding inhibition. Thus, MGO modifications of Arg residues in collagen could be a key factor in the impaired degradation of collagen that promotes fibrosis in chronic infections, such as periodontitis.

Amino Acids↗
PubMed1999

Immunochemical detection of dicarbonyl-derived imidazolium protein crosslinks in human lenses.

PURPOSE: To determine the formation of imidazolysine, a Maillard reaction derived protein crosslink in the human lens in relation to aging and cataract by immunochemical methods. METHODS: Antibodies against RNase-imidazolysine were raised in rabbits. The antibodies were tested for their specificity for imidazolysine by using various imidazolysine-like compounds and imidazoles. A competitive ELISA tested human lens water-soluble proteins and enzyme-digested water-insoluble proteins for immunoreactivity against the antibodies. RESULTS: The antibodies strongly reacted with structurally related imidazolysine and GOLD (glyoxal-lysine dimer) and thus precluded us from distinguishing imidazolysine from GOLD in the human lens. We assumed that the detected immunoreactivity is due to a combination of GOLD and imidazolysine. The antibodies did not react with histidine. The immunoreactivity in lens proteins was expressed as units of imidazolium crosslinks per unit of protein (1 unit = 1% inhibition of antibody binding to microplate well, 1 unit of protein = approximately 0.3 mg protein). The levels in the water-insoluble proteins were 8.4 +/- 4.5 units (mean +/- SD) and 40.4 +/- 8.5 units per unit of protein in young and old lenses, respectively. Cataractous lenses showed significantly higher levels (58.8 +/- 8.1 units, P < 0.05) when compared to age-matched normal lenses and highest levels were observed in brunescent cataractous lenses (76.6 +/- 13.4 units). The levels were negligible in the water-soluble proteins of young lenses and were 5 to 14-fold lower when compared to the water-insoluble proteins from the same lenses. Western blot analysis of lens proteins showed that the antigens are primarily present in the high molecular weight protein aggregates. CONCLUSIONS: This study provides additional evidence for alpha-dicarbonyl-mediated protein crosslinking in the human lens and suggests that such reactions could play a role in lens aging and cataractogenesis.

Adolescent↗
PubMed2001

High concentrations of glucose induce synthesis of argpyrimidine in retinal endothelial cells.

PURPOSE: To determine if high concentrations of glucose applied to cultured bovine retinal endothelial cells (BRE cells) would result in production of intracellular methylglyoxal (MG), and consequently, the synthesis of MG-derived advanced glycation end products (AGEs). METHODS: BRE cells were incubated with 30 mM D-glucose or 30 mM L-glucose for 7 days. Cells incubated with medium that had 5-mM glucose served as controls. Cells were lysed and the lysate was centrifuged to get a supernatant and a pellet fraction. We measured argpyrimidine, a MG-derived fluorescent AGE in the two fractions by a competitive ELISA using a monoclonal antibody. RESULTS: BRE cells incubated with 30 mM D-glucose produced significantly higher (P < 0.05) levels of intracellular MG than control cells or cells incubated with 30 mM L-glucose. Incubation with 30 mM D-glucose significantly (P < 0.05) enhanced the synthesis of argpyrimidine in both supernatant and pellet fractions when compared to control cells. Immunofluorescence studies confirmed results obtained by ELISA and showed higher levels of argpyrimidine in cells incubated with 30 mM D-glucose. CONCLUSION: These results suggest that MG-mediated protein modification can occur in elevated glucose, and might contribute to endothelial cell changes associated with diabetic retinopathy.

Animals↗
PubMed2002

Immunolocalization and quantification of advanced glycation end products in retinal neovascular membranes and serum: a possible role in ocular neovascularization.

PURPOSE: Earlier studies have revealed the association of advanced glycation end products (AGE) with the pathogenesis of various micro and macro vascular complications. The purpose of the present study is to localize AGEs, namely carboxy methyl lysine (CML-AGE) and methyl glyoxal-derived AGEs (MG-AGE), in retinal neovascular membranes and to quantify them in serum samples. METHODS: Surgically excised retinal neovascular membranes and serum samples obtained from patients with diabetic retinopathy, Eales' disease and nondiabetics were studied. Immunolocalization of AGEs namely CML-AGE and MG-derived AGEs was done using avidin biotin complex method and quantification was done by enzyme linked immunosorbent assay (ELISA). RESULTS: CML-AGE immunoreactivity was detected in all cases of Eales' disease and 61% cases of diabetic retinopathy and none in idiopathic epiretinal membrane (ERM). MG-AGE immunoreactivity was observed in approximately 15% of diabetic retinopathy and none in Eales' disease and and idiopathic ERM. Quantification of AGEs in serum samples revealed statistically significant increased levels of MG-AGE in diabetes, in relation to nondiabetics with idiopathic ERM and CML-AGE in Eales' disease, in relation to diabetics and nondiabetics with idiopathic ERM. CONCLUSION: Results from this study suggest that AGEs formed through glycation and glycoxidation may play an important role in the development of retinal neovascularization. The immunoreactivity of CML-AGEs in neovascular membrane and its increased levels in serum suggest that inspite of the normoglycemic status, glycoxidation and lipid peroxidation due to oxidative stress may trigger retinal neovascularization in Eales' disease, while MG-AGEs in diabetic membrane and serum suggest the role of glycation. Thus the mechanism of neovascularization in different pathological conditions could be different.

Adolescent↗
PubMed2002

Regulation of the glyoxalase pathway in human brain microvascular endothelium: effects of troglitazone and tertiary butylhydroperoxide.

The glyoxalase system, comprised of glyoxalase-I and glyoxalase-II with glutathione as the cofactor, plays an important role in the detoxification of methylglyoxal and other alpha-oxo-aldehydes. Such aldehydes, which increase with hyperglycemia, give rise to advanced glycation end products. The objective of this research was to examine the glyoxalase system in human cerebromicrovascular cells. The hypothesis tested was that this pathway would be regulated by phase 2 enzyme inducers such as t-butylhydroquinone and modulated by the insulin-sensitizing drug troglitazone. Human cerebromicrovascular endothelial cells were cultured and exposed to varying concentrations of t-butylhydroquinone or troglitazone. The activity of glyoxylase-I in human endothelial cells was similar to the activity present in hepatocytes. The phase 2 enzyme inducer t-butylhydroquinone had no effect on the glyoxalase enzymes activities but significantly increased glutathione levels and glutathione reductase activity, indicating that phase 2 enzyme inducers might promote alpha-oxo-aldehyde scavenging. Troglitazone decreased the activities of glyoxalase-I and -II and decreased glyoxalase-I mRNA. Troglitazone had no effect on glutathione levels or on the activity of glutathione reductase or glutathione peroxidase. We conclude that phase 2 enzyme inducers may promote scavenging of alpha-oxoaldehydes in endothelial cells.

Animals↗
PubMed2003

Identification of the binding site of methylglyoxal on glutathione peroxidase: methylglyoxal inhibits glutathione peroxidase activity via binding to glutathione binding sites Arg 184 and 185.

Methylglyoxal (MG), a physiological alpha-dicarbonyl compound is derived from glycolytic intermediates and produced during the Maillard reaction. The Maillard reaction, a non-enzymatic reaction of ketones and aldehydes with amino group of proteins, contributes to the aging of proteins and to complications associated with diabetes. In our previous studies (Che, et al. (1997) "Selective induction of heparin-binding epidermal growth factor-like growth factor by MG and 3-deoxyglucosone in rat aortic smooth muscle cells. The involvement of reactive oxygen species formation and a possible implication for atherogenesis in diabetes". J. Biol. Chem., 272, 18453-18459), we reported that MG elevates intracellular peroxide levels, but the mechanisms for this remain unclear. Here, we report that MG inactivates bovine glutathione peroxidase (GPx), a major antioxidant enzyme, in a dose- and time-dependent manner. The use of BIAM labeling, it was showed that the selenocysteine residue in the active site was intact when GPx was incubated with MG. MALDI-TOF-MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) and protein sequencing examined the possibility that MG modifies arginine residues in GPx. The results show that Arg 184 and Arg 185, located in the glutathione binding site of GPx was irreversively modified by treatment with MG. Reactive dicarbonyl compounds such as 3-deoxyglucosone, glyoxal and phenylglyoxal also inactivated GPx, although the rates for this inactivation varied widely. These data suggest that dicarbonyl compounds are able to directly inactivate GPx, resulting in an increase in intracellular peroxides which are responsible for oxidative cellular damage.

Amino Acid Sequence↗
PubMed2005

In vivo prooxidant state in Werner syndrome (WS): results from three WS patients and two WS heterozygotes.

The hypothesis was tested that Werner syndrome (WS) phenotype might be associated with an in vivo prooxidant state. A set of redox-related endpoints were measured in three WS patients, two of their parents, and 99 controls within a study of some cancer-prone and/or ageing-related genetic disorders. The following analytes were measured: (a) leukocyte 8-hydroxy-2'-deoxyguanosine; (b) glutathione from whole blood, and (c) plasma levels of glyoxal, methylglyoxal, 8-isoprostane, and some plasma antioxidants (uric acid, ascorbic acid, alpha- and gamma-tocopherol). Leukocyte 8-hydroxy-2'-deoxyguanosine levels showed a significant increase in the 3 WS patients vs. 85 controls (p<10(-7)). The disulfide glutathione:glutahione ratio was significantly altered in WS patients (p=0.005). Glyoxal and methylglyoxal levels were significantly increased (p=0.018 and p=0.007, respectively). The plasma levels of uric acid (p=0.002) and ascorbic acid (p=0.003) were also increased significantly in WS patients and in their parents. No significant alterations were found in the plasma levels of alpha- and gamma-tocopherol, nor of 8-isoprostane. This is the first report of in vivo alterations of oxidative stress parameters in WS patients. Further investigations on more extensive study populations are warranted to verify the relevance of an in vivo prooxidant state in WS patients.

8-Hydroxy-2'-Deoxyguanosine↗
PubMedDate not supplied

Oxidation of albumin is enhanced in the presence of uremic toxins.

Albumin has been considered a "sacrificial plasma antioxidant" due to the high reactivity of the protein sulfhydryl groups with oxidants such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). Based on its large quantity and high turnover. It is considered as one of the most important plasma antioxidants for protecting key cellular and regulatory proteins. Since hemodialysis patients have lower overall levels of albumin and possible protein modifications due to uremic toxins, we investigated whether modifications by various uremic toxins would affect the susceptibility of albumin to an oxidative challenge. We incubated bovine serum albumin in the presence of carboxymethyllysine (CML) (10 micromol/L(-1) mmol/L), methyl glyoxal (50 micromol/L(-5) mmol/L), p-cresol (100 micromol/L-10 mmol/L) or hippuric acid (200 micromol/L-20 mmol/L) for 16 hours at 37 degrees C and then subsequently added 0.5 mmol/L(-1) mmol of H2O2/HOCl. We measured the extent of protein modification by the loss of protein sulfhydryl groups, dityrosine formation and the formation of advanced oxidation protein products (AOPP). Incubation of albumin with the uremic toxins caused a loss of protein sulfhydryl groups and an increase in dityrosines and AOPP. The presence of uremic toxins had no effect on the loss of protein sulfhydryl groups after addition of H2O2/HOCl; however, low levels of CML, p-cresol and methyl glyoxal inhibited the formation of AOPP and dityrosines. We suggest that uremic toxins may possibly play a role in mediating free radical initiated protein damage.

Albumins↗
PubMed1989

Effects of glyoxal and methylglyoxal administration on gastric carcinogenesis in Wistar rats after initiation with N-methyl-N'-nitro-N-nitrosoguanidine.

Glyoxal and methylglyoxal were tested for tumor-promoting potential in a two-stage stomach carcinogenesis model. Male outbred Wistar rats were initially given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water (100 mg/l) along with a 10% sodium chloride dietary supplement for 8 weeks. Thereafter, they were returned to basal diet and maintained on drinking water containing no addition or either 0.5% glyoxal or 0.25% methylglyoxal for 32 weeks and then killed for necropsy and histological examination at week 40. Glyoxal treatment significantly increased the incidence of adenocarcinomas in the pylorus of the glandular stomach of rats pretreated with MNNG and sodium chloride. Furthermore, although methylglyoxal did not enhance the development of adenocarcinomas, the incidence of hyperplasias in the pylorus was significantly increased. The results indicate that glyoxal exerts tumor promoting activity on rat glandular stomach carcinogenesis and that methylglyoxal might also have promoting potential.

Aldehydes↗
PubMed1990

Genotoxicity of methylglyoxal: cytogenetic damage in human lymphocytes in vitro and in intestinal cells of mice.

The mutagenic activity of methylglyoxal (MG) was assayed in vitro in human lymphocytes [induction of chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and micronuclei] both in the presence and in the absence of metabolic activation (S9 mix). The Ames/microsome test was performed with the Salmonella typhimurium strains considered more responsive (TA102 and TA104). Positive results were obtained for all the genetic endpoints analysed. In human lymphocytes the activity of MG is decreased by the presence of S9 mix. In the in vivo studies, the metaphase analysis in the ileum and duodenum cells of mice treated per os with MG (400 and 600 mg/kg body wt) gave negative results for CA induction, while only a weak increase of SCE in duodenum cells at the higher dose was obtained. Dimethylhydrazine (25 mg/kg body wt), as positive control, was clearly active in inducing both CAs and SCEs in the same intestinal tissues.

Aldehydes↗
PubMed1994

Development of a 32P-postlabelling method for the analysis of 2'-deoxyguanosine-3'-monophosphate and DNA adducts of methylglyoxal.

A 32P-postlabelling assay was developed for the analysis of adducts arising from the reaction of 2'-deoxyguanosine-3'-monophosphate with the 1,2-dicarbonyl compound methylglyoxal, a major mutagen in several foodstuffs, in particular, instant and brewed coffee. The 32P-postlabelling reaction was optimized by testing various parameters such as the kinetics of phosphorylation by T4 polynucleotide kinase, substrate concentration-dependent labelling efficiency and the concentration of the various ingredients of the phosphorylation reaction. The sensitivity to the 3'-monophosphate dephosphorylation activity of nuclease P1 was also studied. Four isomeric reaction products were separated by HPLC, structurally characterized and identified as 3-(2'-deoxy-beta-D-erythro-pentafuranosyl)-6,7-dihydro-6,7-dihydro xy-6- methylimidazo[2,3-b]purine-9(8H)one. The same adducts could be detected from calf thymus DNA that had been reacted in vitro with methylglyoxal. DNA adducts were isolated after enzymatic digestion to mononucleotides followed by nuclease P1 digestion of normal nucleotides. The total level of methylglyoxal-DNA adducts obtained was 5.7 +/- 1.7 (n = 15) adducts/10(6) nucleotides. The 32P-postlabelling method was further validated by the detection of adducts of methylglyoxal in DNA from freshly isolated and stimulated human lymphocytes exposed in vitro. The concentrations of the adducts detected in these samples were 8.2 +/- 0.9 (n = 3) adducts/10(7) nucleotides and 1.5 +/- 0.1 (n = 3) adducts/10(6) nucleotides after treatment with 1.5 and 3.0 mM methylglyoxal respectively.

Animals↗
PubMed1998

Adaptive response of human melanoma cells to methylglyoxal injury.

The effects of methylglyoxal on the growth of a line of human melanoma cells are investigated. Methylglyoxal inhibits cell growth in a dose-dependent manner and causes an increase in glyceraldehyde 3-phosphate dehydrogenase, and glyoxalase 1 and glyoxalase 2 specific activities. The cellular response to increasing concentrations of methylglyoxal in the culture medium is also studied by measuring L-lactate production, reduced-oxidized glutathione levels and apoptotic cell death. Methylglyoxal seems to promote a change of cell population phenotypic repertoire toward a more monomorphic phenotype. In conclusion, methylglyoxal seems to induce an enzymatic cellular response that lowers methylglyoxal levels and selects the most resistant cells.

Apoptosis↗
PubMed1985

Induction of ornithine decarboxylase and DNA synthesis in rat stomach mucosa by methylglyoxal.

Administration of methylglyoxal at doses of 300-600 mg/kg body weight by gastric tube to male F344 rats induced 100-fold increase in ornithine decarboxylase activity (formation of 682 pmol CO2/30 min/mg protein) within 7 h, 26-fold increase in DNA synthesis (incorporation of 17 800 d.p.m. of [3H]thymidine/microgram DNA) within 16 h, 16-fold increase in the labeling index of S-phase cells (increase from 1.7 to 26.5) within 16 h, and apparent unscheduled DNA synthesis within 2 h in the glandular stomach mucosa. These results suggest that methylglyoxal has potential promoter activity and may also have initiating activity in carcinogenesis in the glandular stomach.

Aldehydes↗
PubMed1985

Methylglyoxal-induced DNA-protein cross-links and cytotoxicity in Chinese hamster ovary cells.

The technique of alkaline elution was applied to study the capacity of methylglyoxal to induce DNA damage and repair in Chinese hamster ovary cells. DNA cross-linking was observed after a 90-min exposure to a subtoxic dose (1.5 mM), and the cross-links were fully repaired by 24 h. The cross-linking appeared to be DNA-protein in nature, since proteinase treatment removed the effect. When the same cells were exposed to methylglyoxal in the presence of a rat liver metabolic system, both cytotoxicity and cross-linking frequency were significantly reduced.

Aldehydes↗