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PubMed2000

Effect of dwell time on carbonyl stress using icodextrin and amino acid peritoneal dialysis fluids.

BACKGROUND: Deterioration of the peritoneal membrane limits the technical survival of peritoneal dialysis (PD). Advanced glycation of the membrane has been incriminated in this evolution. Advanced glycation end products (AGEs) develop under the influence of glucose and of its degradation products, mainly reactive carbonyl compounds (RCOs) such as glyoxal (GO), methylglyoxal (MGO), and 3-deoxyglucosone (3-DG). The present study was undertaken to evaluate the impact of recently developed glucose-free PD fluids on AGE generation. METHODS: Recently developed glucose-free PD fluids containing either icodextrin or amino acids were investigated. GO, MGO, and 3-DG [high-performance liquid chromatography (HPLC)] and total RCOs (spectrophotometry) were measured in fresh solutions and in effluents after various dwell duration. The AGE formation potential of PD fluids and effluents was assessed by incubation at 37 degrees C, for one week, with bovine serum albumin and by the eventual measurement of pentosidine (HPLC) and Nepsilon-carboxymethyllysine (CML; gas chromatography/mass spectrometry). RESULTS: GO, MGO, and 3-DG (P < 0. 001) as well as total RCOs levels (P < 0.01) were significantly lower in icodextrin and amino acid PD fluid than in commercial, heat-sterilized, 1.36% glucose PD fluid. Pentosidine and CML generation were also significantly lower (P < 0.001) in icodextrin and amino acid PD fluid than in conventional 1.36% glucose PD fluid. The levels of total RCOs, however, increased in icodextrin and amino acid PD fluid effluents with dwell time. AGE formation potential rose accordingly, as demonstrated by a parallel increase in the generation of pentosidine and CML during incubation of PD effluents. CONCLUSION: The present data demonstrate lower RCO contents and AGE formation potential in fresh icodextrin and amino acid PD fluids than in fresh heat-sterilized glucose PD fluids. However, this difference decreases progressively during dwell time, mainly as a result of the influx of total RCOs.

Aged↗

PubMed2002

Efficient in vitro lowering of carbonyl stress by the glyoxalase system in conventional glucose peritoneal dialysis fluid.

BACKGROUND: Reactive carbonyl compounds (RCOs) present in heat-sterilized peritoneal dialysis (PD) fluid have been incriminated in the progressive deterioration of the peritoneal membrane observed in long-term PD patients. The present study utilized the glyoxalase I (GLO I) system as a new approach to lower in vitro the peritoneal fluid content of RCOs such as methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG). METHODS: GO, MGO, and 3-DG solutions or conventional glucose PD fluids were incubated in vitro with various RCO lowering compounds. The evolution of GO, MGO, and 3-DG levels was monitored by high-performance liquid chromatography. The tested compounds included aminoguanidine and glutathione (GSH), alone or together with GLO I. The human GLO I gene was overexpressed in Chinese hamster ovary (CHO) cells, or ubiquitously in transgenic mice. Cell supernatant of the CHO transfectant and protein extracts of various organs of the transgenic mice were also tested. RESULTS: Aminoguanidine incubated with MGO/GO/3-DG mixtures, promptly reduced RCO levels. GSH alone had a similar but milder and slower effect. Together with GLO I, it promptly decreased GO and MGO levels but was less efficient toward 3-DG. After incubation with glucose PD fluid, GSH together with GLO I had the same effect on MGO, GO, and 3-DG levels. Addition of transfected cell supernatant or tissue extracts overexpressing GLO I, together with GSH to either GO, MGO, or 3-DG solutions, promptly and markedly reduced GO and MGO but not 3-DG levels. CONCLUSIONS: GLO I together with GSH efficiently lowers glucose-derived RCOs, especially GO and MGO, both in conventional glucose PD fluids and in RCO solutions. The fact that genetically manipulated cells overexpressing GLO I activity have a similar effect suggests that maneuvers raising GLO I activity in peritoneal cells or in the peritoneal cavity might help prevent the deleterious effects of the peritoneal carbonyl stress in PD patients. The clinical relevance of this approach is yet to be documented.

Animals↗

PubMed2003

Glucose degradation products in PD fluids: do they disappear from the peritoneal cavity and enter the systemic circulation?

BACKGROUND: Glucose degradation products (GDP) are generated in peritoneal dialysis (PD) fluid during heat sterilization and storage. They are thought to adversely affect the peritoneal membrane. The fate of GDP within the peritoneal cavity has not been well characterized. METHODS: A clinical study was designed to determine (1). whether during the dwell in the peritoneal cavity GDP concentration decreases in the PD fluid as assessed by ex vivo formation of AGE; (2). whether exposure to GDP-containing PD fluids increases plasma fluorescence (as an index of plasma AGE concentration) as well as plasma carboxymethyllysine (CML) concentration; and (3). whether exposure to GDP-containing PD fluids adversely affects glycoprotein CA 125 concentration. A two-group crossover design was adopted comprising two consecutive observation periods of eight weeks each. Stable PD patients were exposed in random order either to conventional PD fluid (heat sterilized at pH 5.5) and subsequently to PD test fluid (or the 2 fluids in reverse order). The PD test fluid was sterilized using a multicompartment bag system separating highly concentrated glucose at pH 3 from the buffer solution. Conventional and test fluids differed with respect to concentrations of GDP, that is, 3-deoxyglucosone (118 vs. 12.3 micromol/L), methylglyoxal (5.3 micromol/L vs. below detection threshold), 3, 4-dideoxyglucosone-3-ene (10 micromol/L vs. below detection threshold) and acetaldehyde (226 vs. <1 micromol/L). RESULTS: The following results were obtained. First, methylglyoxal disappeared completely as early as two hours after intraperitoneal instillation of conventional PD fluid. Second, when spent conventional dialysate was recovered after a two hour and particularly an eight hour dwell and subsequently incubated ex vivo with 40 mg of human serum albumin, there was a continuous decrease of AGE-forming capacity, that is, less generation of fluorescence (AGE) and pyrraline (non-fluorescent Amadori product), and an increase of advanced oxidation protein products (AOPP) in the spent dialysate. Third, plasma fluorescence (exc. 350/em. 430 nm) as an index of circulating AGE compounds as well as plasma CML concentrations were significantly higher in the conventional PD fluid period versus low GDP PD fluid period. Fourth, CA 125 concentrations in spent dialysate were higher during the low GDP PD fluid period compared to the conventional PD fluid period. CONCLUSION: Conventional PD fluid undergoes modifications during intraperitoneal dwell with a loss of AGE forming capacity, suggesting breakdown, precipitation or resorption of GDP in vivo. This is accompanied by an increase in plasma AGE compounds.

Adult↗

PubMed2003

Methylglyoxal induces apoptosis through activation of p38 mitogen-activated protein kinase in rat mesangial cells.

BACKGROUND: The formation of methylglyoxal (MG), a highly reactive dicarbonyl compound, is accelerated through several pathways, including the glycation reaction under diabetic conditions, presumably contributing to tissue injury in diabetes. On the other hand, apoptotic cell death of glomerular cells has been suggested to play a role in the development of glomerulosclerosis in various types of glomerular injuries. We therefore examined whether MG was capable of inducing apoptosis in rat mesangial cells to address the possible mechanism by which hyperglycemia-related products accelerated pathologic changes in diabetic glomerulosclerosis. METHODS: Rat mesangial cells were incubated with 0 to 400 micromol/L MG, followed by the detection of apoptosis by both TUNEL method and electrophoretic analysis for DNA fragmentation. In addition, we investigated intracellular mechanisms mediating MG-induced apoptosis, focusing especially on the p38 mitogen-activated protein kinase (MAPK) pathway. RESULTS: MG induced apoptosis in rat mesangial cells in a dose-dependent manner and was accompanied by the activation of p38alpha isoform. Aminoguanidine and N-acetyl-l-cysteine inhibited the MG-induced p38 MAPK activation, as well as apoptosis in rat mesangial cells, suggesting the involvement of oxidative stress in these phenomena. SB203580, a specific inhibitor of p38 MAPK also suppressed the MG-induced apoptosis in rat mesangial cells. CONCLUSIONS: These results suggest a potential role for MG in glomerular injury through p38 MAPK activation under diabetic conditions and may serve as a novel insight into the therapeutic strategies for diabetic nephropathy.

Animals↗

PubMed2001

Low-density lipoprotein (LDL)-induced monocyte-endothelial cell adhesion, soluble cell adhesion molecules, and autoantibodies to oxidized-LDL in chronic renal failure patients on dialysis therapy.

Premature atherosclerosis is a major cause of morbidity and mortality in chronic renal failure patients undergoing dialysis. In this study, we compared autoantibodies to oxidized low-density lipoprotein (OX-LDL), soluble cell adhesion molecules (CAMs), and the effect of both LDL and OX-LDL on monocyte endothelial cell adhesion in chronic renal failure patients on hemodialysis (HD, n = 16) and peritoneal dialysis (PD, n = 17) compared with matched healthy control subjects (C, n = 17). In addition, we studied the effect of supplementation with RRR-alpha-tocopherol (AT) 800 IU/d for 12 weeks on the above measures. LDL and OX-LDL induced adhesion of U937 cells to cultured endothelium, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble E-selectin (sE-selectin); autoantibodies to OX-LDL and markers of lipid peroxidation were determined before and after AT supplementation. Native LDL from PD patients induced greater monocyte-endothelial cell adhesion than LDL from C subjects (43.8% +/- 17.0% v25.3% +/- 17.7%, respectively, P = .0028). OX-LDL from chronic renal failure patients on both PD and HD stimulated greater adhesion than OX-LDL from the C subjects (68.0% +/- 18.5% and 57.6% +/- 15.1% v 40.9% +/- 17.3%, respectively, P < .01); OX-LDL from PD patients induced greater adhesion than that from HD patients (P < .01). Plasma methylglyoxal levels were significantly increased in both HD and PD groups, with higher levels in the HD group. Chronic renal failure patients on HD and PD also had higher levels of plasma sVCAM-1 and sE-selectin than C subjects (P < .01), indicating endothelial activation. Titers of autoantibodies to OX-LDL were not elevated in renal failure patients. Supplementation with AT 800 IU/d for 12 weeks, while resulting in significant enrichment with AT in LDL, did not have a significant effect on any of the parameters studied. This study makes the novel observation that the LDL of chronic renal failure patients on HD and PD appears to be potentially more atherogenic, since it induces greater monocyte-endothelial cell adhesion.

Adult↗

PubMed2003

Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes.

A time-delayed fluorescence immunoassay was developed for the determination of serum levels of methylglyoxal (MG)-derived hydroimidazolone using a monoclonal antiserum raised against Nalpha-acetyl-Ndelta-(5-hydro-5-methyl)-4-imidazolone, Europium-labeled anti-mouse IgG antiserum as indicator, and MG modified bovine serum albumin (BSA) as standard. Serum levels of hydroimidazolone were measured in 45 patients with type 2 diabetes aged 59.4 +/- 6.1 (mean +/- SD) years and with duration of diabetes of 7.3 +/- 3.1 years, and in 19 nondiabetic controls aged 56.3 +/- 4.3 years. The serum levels of hydroimidazolone were significantly higher in patients compared to controls: median, 3.0 (5-95 percentile, 1.6 to 5.4) U/mg protein versus 1.9 (1.2 to 2.8) U/mg protein (P =.0005). Significant positive correlations were observed between the serum levels of hydroimidazolone and serum levels of advanced glycation end products (AGEs), measured with a polyclonal anti-AGE antibody: r = 0.59 for patients (P <.0001), and r = 0.65 for controls (P =.002). Similarly, significant correlations were also found between serum levels of hydroimidazolone and N(epsilon)-(carboxymethyl)-lysine (CML): r = 0.36 in patients and r = 0.55 for controls (both P =.02). Serum hydroimidazolone levels did not correlate with fasting plasma glucose or hemoglobin A(1c) (HbA(1c)) levels. The observed differences between patients with diabetes and nondiabetic controls seem to be comparable to differences measured for other AGE compounds.

Diabetes Mellitus, Type 2↗

PubMed2002

Tumor necrosis factor-induced modulation of glyoxalase I activities through phosphorylation by PKA results in cell death and is accompanied by the formation of a specific methylglyoxal-derived AGE.

Tumor necrosis factor (TNF)-induced cell death in the fibrosarcoma cell line L929 is a caspase-independent process that is characterized by increased production of reactive oxygen species (ROS) in the mitochondria. To elucidate this ROS-dependent cell death pathway, a comparative study of the phosphoproteins present in TNF-treated and control cells was performed. Here we report that TNF induces an increased phosphorylation of glyoxalase I that is mediated by protein kinase A and required for cell death. We also show that TNF induces a substantial increase in intracellular levels of methylglyoxal (MG) that leads to the formation of a specific MG-derived advanced glycation end product and that this formation occurs as a consequence of increased ROS production. These data indicate that MG modification of proteins is a targeted process and that MG may thus function as a signal molecule during the regulation of cell death. Furthermore, we provide evidence that the TNF-induced phosphorylation of glyoxalase I is not involved in detoxification of MG by means of the glyoxalase system, but that phosphorylated glyoxalase I is on the pathway leading to the formation of a specific MG-derived advanced glycation end product.

Animals↗

PubMed2004

A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major.

Glyoxalase I forms part of the glyoxalase pathway that detoxifies reactive aldehydes such as methylglyoxal, using the spontaneously formed glutathione hemithioacetal as substrate. All known eukaryotic enzymes contain zinc as their metal cofactor, whereas the Escherichia coli glyoxalase I contains nickel. Database mining and sequence analysis identified putative glyoxalase I genes in the eukaryotic human parasites Leishmania major, Leishmania infantum, and Trypanosoma cruzi, with highest similarity to the cyanobacterial enzymes. Characterization of recombinant L. major glyoxalase I showed it to be unique among the eukaryotic enzymes in sharing the dependence of the E. coli enzyme on nickel. The parasite enzyme showed little activity with glutathione hemithioacetal substrates but was 200-fold more active with hemithioacetals formed from the unique trypanosomatid thiol trypanothione. L. major glyoxalase I also was insensitive to glutathione derivatives that are potent inhibitors of all other characterized glyoxalase I enzymes. This substrate specificity is distinct from that of the human enzyme and is reflected in the modification in the L. major sequence of a region of the human protein that interacts with the glycyl-carboxyl moiety of glutathione, a group that is conjugated to spermidine in trypanothione. This trypanothione-dependent glyoxalase I is therefore an attractive focus for additional biochemical and genetic investigation as a possible target for rational drug design.

Amino Acid Sequence↗

PubMed2006

wasted away, a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death.

To identify genes required for maintaining neuronal viability, we screened our collection of Drosophila temperature-sensitive paralytic mutants for those exhibiting shortened lifespan and neurodegeneration. Here, we describe the characterization of wasted away (wstd), a recessive, hypomorphic mutation that causes progressive motor impairment, vacuolar neuropathology, and severely reduced lifespan. We demonstrate that the affected gene encodes the glycolytic enzyme, triosephosphate isomerase (Tpi). Mutations causing Tpi deficiency in humans are also characterized by progressive neurological dysfunction, neurodegeneration, and early death. In Tpi-deficient flies and humans, a decrease in ATP levels did not appear to cause the observed phenotypes because ATP levels remained normal. We also found no genetic evidence that the mutant Drosophila Tpi was misfolded or involved in aberrant protein-protein associations. Instead, we favor the hypothesis that mutations in Tpi lead to an accumulation of methylglyoxal and the consequent enhanced production of advanced glycation end products, which are ultimately responsible for the death and dysfunction of Tpi-deficient neurons. Our results highlight an essential protective role of Tpi and support the idea that advanced glycation end products may also contribute to pathogenesis of other neurological disorders.

Animals↗

PubMed2003

Genetic engineering of the glyoxalase pathway in tobacco leads to enhanced salinity tolerance.

The glyoxalase pathway involving glyoxalase I (gly I) and glyoxalase II (gly II) enzymes is required for glutathione-based detoxification of methylglyoxal. We had earlier indicated the potential of gly I as a probable candidate gene in conferring salinity tolerance. We report here that overexpression of gly I+II together confers improved salinity tolerance, thus offering another effective strategy for manipulating stress tolerance in crop plants. We have overexpressed the gly II gene either alone in untransformed plants or with gly I transgenic background. Both types of these transgenic plants stably expressed the foreign protein, and the enzyme activity was also higher. Compared with nontransformants, several independent gly II transgenic lines showed improved capability for tolerating exposure to high methylglyoxal and NaCl concentration and were able to grow, flower, and set normal viable seeds under continuous salinity stress conditions. Importantly, the double transgenic lines always showed a better response than either of the single gene-transformed lines and WT plants under salinity stress. Ionic measurements revealed higher accumulation of Na+ and K+ in old leaves and negligible accumulation of Na+ in seeds of transgenic lines as compared with the WT plants. Comparison of various growth parameters and seed production demonstrated that there is hardly any yield penalty in the double transgenics under nonstress conditions and that these plants suffered only 5% loss in total productivity when grown in 200 mM NaCl. These findings establish the potential of manipulation of the glyoxalase pathway for increased salinity tolerance without affecting yield in crop plants.

Blotting, Southern↗

PubMed2002

Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy.

Diet is a major environmental source of proinflammatory AGEs (heat-generated advanced glycation end products); its impact in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with 5-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a 2-week crossover and 13 in a 6-week study. After 2 weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-alphabeta-actin mRNA ratio was 1.4 +/- 0.5 on H-AGE and 0.9 +/- 0.5 on L-AGE (P = 0.05), whereas serum vascular adhesion molecule-1 was 1,108 +/- 429 and 698 +/- 347 ngml (P = 0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear cell tumor necrosis factor-alpha rose by 86.3% (P = 0.006) and declined by 20% (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H-AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H-AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.

Biomarkers↗

PubMed1975

Interaction of glyoxal and methylglyoxal with biogenic amines.

Glyoxal and methylglyoxal interact with biogenic amines and form biologically active free radicals. Electron spin resonance absorption of the radical at room temperature is characterized by a signal at g equals 2.004 with peak-to-peak width of 29 G. An optical absorption at 400 nm with molar absorptivity of 23,000 accompanies the formation of the radical. The dry powdered preparation of the same reaction, which is considered to be the seconardy product, gives an electron spin resonance signal much narrower and 1/200 in intensity compared with the one in solution. Similarly the 400 nm absorption intensity is 1/8 that of the primary product. Possible biological significance of the primary and the secondary product, in relation to muscular dystrophy and photophosphorylation, is discussed.

Aldehydes↗

PubMed1977

Electronic properties of the casein-methylglyoxal complex.

Measurements of the electron spin resonance, direct current conductivity, microwave permittivity, and electronic transference number are reported for the brown casein-methylglyoxal complex. Compared with normal white casein, the colored casein complex exhibits an increased electronic activity. This is considered to arise from the electron-accepting action of the methylglyoxal in separating electronic charge from an otherwise completely occupied electronic ground state of the casein macromolecule.

Aldehydes↗

PubMed1977

The living state and cancer.

Complex living structures developed on our globe after the appearance of light and oxygen. In functions of these structures, solid state phenomena play a major role. The structural proteins were made into radicals by doping, the covalent incorporation of electron acceptors. This lent mobility to their electrons and a subtle reactivity to their molecules. Cancer is unable to go into the radical state.

Aldehydes↗

PubMed1978

Electronic properties of some protein--methylglyoxal complexes.

Steady-state conductivity measurements and dielectric measurements in the frequency range 10(-5) to 100 Hz are reported for samples of bovine serum albumin, casein, and lysozyme complexed with methylglyoxal. Compared with the untreated proteins, the brown complexed proteins exhibit an increased conductivity and free electron spin density, together with a low-frequency dielectric dispersion. These results can be taken as evidence that the interaction with methylglyoxal results in the proteins possessing an increased electronic activity associated with the creation of mobile electron holes within the valence band states of the protein molecules.

Aldehydes↗

PubMed1978

Isolation of methylglyoxal from liver.

Acetaldehyde and methylglyoxal were shown to be present in liver bound to protein. They were isolated in the form of 2,4-dinitrophenylhydrazones and osazones, respectively. The NMR spectrum of pure methylglyoxal was recorded.

Aldehydes↗

PubMed1979

Quantum chemical calculations of model systems for ascorbic acid adducts with Schiff bases of lysine side chains: possibility of internal charge transfer in proteins.

Ab initio self-consistent field calculations for neutral and cationic ascorbic acid and model compounds have been performed. Furthermore, the bicyclic addition products of alpha-hydroxytetronic acid with methylglyoxal and with the Schiff base formed between methylglyoxal and methylamine have been calculated, again in their neutral and cationic forms, respectively. The results indicate that the investigated cations can act as strong electron acceptors. With the help of space-filling molecular models it has been demonstrated that such conformations of the Schiff base formed between the primary amino group of lysine side chains in proteins and the ascorbic acid methylglyoxal acetal are possible in which the lactone carbonyl group comes near to the N atoms of the peptide groups, so that charge can be transferred between these subunits.

Ascorbic Acid↗

PubMed1980

Spectroscopic studies of the protein-methylglyoxal adduct.

Spectroscopic measurements are reported for the effects of pH, time, solvent, and chemical modification of arginine and lysine side chains on the reaction of proteins with methylglyoxal. The reaction responsible for the appearance of a brown coloration and increased submolecular electronic activity in the proteins involves the epsilon-amino groups of the lysine residues. It is concluded that the primary step in the reaction involves the formation of a Schiff base linkage between the lysine side chain and methylglyoxal. These findings reaffirm the concept that, by the formation of Schiff bases, aldehydes can act as electron acceptors in charge transfer interactions with proteins.

Aldehydes↗