Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of ceruloplasmin in the antioxidative process in the brain in a patient with hereditary ceruloplasmin deficiency (HCD). Immunohistochemistry revealed an accumulation of Nepsilon-(carboxymethyl) lysine (CML) in basal ganglia of the HCD brain. In vitro study disclosed that ceruloplasmin inhibited CML formation from glycated proteins through the reaction of Fe2+ with H2O2 by Fenton reaction. These data suggest that ceruloplasmin plays an important role in the protection of neurons against oxidative stress associated with iron metabolism.
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PMID:Hereditary ceruloplasmin deficiency increases advanced glycation end products in the brain. 1044 2

Prolonged incubation of proteins with reducing sugar produces advanced glycation end products (AGEs), which are implicated as factors for aging and diabetic complications. We previously demonstrated the presence of N(epsilon)-(carboxymethyl)lysine (CML), one of the main AGE structures, in human and animal tissues using a monoclonal anti-CML antibody (6D12). These findings suggest that CML structures present in vivo could serve as immunogens to generate autoantibodies. This suggestion was tested in the present study. First, plasma samples from diabetic rats reacted positively with AGE bovine serum albumin (BSA). These reactivities increased with the duration of diabetic states and were inhibited specifically by CML-BSA. Second, a fraction purified from plasma of diabetic patients, which bound to AGE-BSA, showed a positive reaction to CML-BSA and furthermore also to human lens proteins, which are known to undergo CML modification in vivo. Finally, patients with renal failure caused by diabetes or nondiabetic pathologies had a higher autoantibody activity against CML structure than that in normal subjects or diabetic patients without renal failure. These results indicate that CML accumulated in vivo serves as an immunological epitope to generate an autoantibody specific for CML that might be used as a potential marker for diabetic nephropathy or chronic renal failure.
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PMID:Autoantibody against N(epsilon)-(carboxymethyl)lysine: an advanced glycation end product of the Maillard reaction. 1048 Jun 17

Steady state protein modification by carbonyl compounds is related to the rate of carbonyl adduct formation and the half-life of the protein. Thyroid hormones are physiologic modulators of both tissue oxidative stress and protein degradation. The levels of the glycation product N(epsilon)-fructoselysine (FL) and those of the oxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and malondialdehyde-lysine (MDA-lys), identified by GC/MS in liver proteins, decreased significantly in hyperthyroid rats, as well as (less acutely) in hypothyroid animals. Immunoblotting of liver proteins for advanced glycation end-products (AGE) is in agreement with the results obtained by GC/MS. Cytosolic proteolytic activity against carboxymethylated foreign proteins measured in vitro was significantly increased in hypo- and hyperthyroidism. Oxidative damage to DNA, estimated as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG), did not show significant differences between groups. The results suggests that the steady state levels of these markers depend on the levels of thyroid hormones, presumably through their combined effects on the rates of protein degradation and oxidative stress, whereas DNA is more protected from oxidative damage.
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PMID:Thyroid status modulates glycoxidative and lipoxidative modification of tissue proteins. 1051 95

Metal-catalyzed oxidation (MCO) of proteins leads to the conversion of some amino acid residues to carbonyl derivatives, and may result in loss of protein function. It is well documented that reactions with oxidation products of sugars, lipids, and amino acids can lead to the conversion of some lysine residues of proteins to N(epsilon)-(carboxymethyl)lysine (CML) derivatives, and that this increases their metal binding capacity. Because post-translational modifications that enhance their metal binding capacity should also increase their susceptibility to MCO, we have investigated the effect of lysine carboxymethylation on the oxidation of bovine serum albumin (BSA) by the Fe(3+)/ascorbate system. Introduction of approximately 10 or more mol CML/mol BSA led to increased formation of carbonyls and of the specific oxidation products glutamic and adipic semialdehydes. These results support the view that the generation of CML derivatives on proteins may contribute to the oxidative damage that is associated with aging and a number of age-related diseases.
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PMID:Conversion of lysine to N(epsilon)-(carboxymethyl)lysine increases susceptibility of proteins to metal-catalyzed oxidation. 1052 66

Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure, N(epsilon)-(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-kappaB and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component.
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PMID:N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. 1053 86

The goal of this study was to characterize the isotypes and reactivity of human autoantibodies to copper oxidized LDL (oxLDL). Forty-six purified oxLDL antibodies contained immunoglobulins of the three major isotypes, with a predominance of IgG, subclasses 1 and 3. These IgG isotypes are known to interact with FcRgammaI and to activate the complement system and thus are potentially able to activate macrophages and cause foam cell formation. The same purified antibodies were tested for cross-reactivity with malondialdehyde (MDA)-, glycated (Glyc)-, and native (n)LDL and cardiolipin. Absorption with oxLDL resulted in a decrease of reactivity of 77.2 +/- 4.7%. Absorption with MDA-LDL resulted in a wider range of reduction of reactivity values, ranging from 50 to 87%, possibly reflecting differences in the degree of MDA modification. Absorption with Glyc- and nLDL caused a minor decrease in the reactivity of antibodies to oxLDL (5.9 +/- 7.1 and 6.8 +/- 6. 4%, respectively), comparable to the reduction of reactivity (2.1 +/- 4.0%) measured after absorption with transferrin, an irrelevant protein used as a negative control. These results suggest that oxLDL antibodies recognize primarily MDA epitopes. To determine whether purified oxLDL antibodies also recognize other epitopes known to be generated during copper oxidation of LDL, such as 4-hydroxynonenal (HNE)- and N(epsilon)(carboxymethyl)-lysine (CML), two additional sets of experiments were carried out. First, we monitored the formation of CML-, MDA-lysine, and HNE-lysine at different times during copper oxidation of two LDL pools. Both pools showed simultaneous increases in protein modification, as indicated by increasing fluorescence emission at 430 nm, and in immunoreactivity with oxLDL antibodies, coinciding closely with MDA modification of lysine groups. Second, we assessed whether the reactivity of oxLDL antibodies could be blocked by absorption with CML- or HNE-LDL. HNE-LDL did not react with isolated oxLDL antibodies. Highly modified CML-LDL (>90% of lysine residues modified) reduced the reactivity of oxLDL antibodies, but only by 25.5%. Finally, we investigated the possible cross-reactivity of oxLDL antibodies with cardiolipin. Seventeen purified oxLDL antibodies were used in this study, which showed that absorption with oxLDL or nLDL did not affect their reactivity with immobilized cardiolipin.
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PMID:Immunochemical characterization of purified human oxidized low-density lipoprotein antibodies. 1077 7

Although there have been suggestions that the glycation and oxidation of low density lipoprotein (LDL) might increase its atherogenic potential, little is known about the presence of glycoxidative LDL in human atherosclerotic lesions. We developed specific antibodies against different immunological epitopes of AGE structures, including N(epsilon)-(carboxymethyl)lysine-protein adduct (CML), a glycoxidation product, and structure(s) other than CML (nonCML), and a monoclonal antibody against oxidized phosphatidylcholine (oxPC), as an epitope of oxidized LDL. Immunohistochemical analysis demonstrated that the CML- and oxPC-epitopes were accumulated mainly in macrophage-derived foam cells in atherosclerotic lesions, including fatty streaks and atherosclerotic plaques. On the other hand, the nonCML-epitope and apolipoprotein B were localized mainly in extracellular matrices of atherosclerotic lesions. The CML- and oxPC-epitopes were characterized by a model antigen-generating system using the copper ion-induced peroxidation and/or glucose-induced glycation of LDL. The glycoxidation of LDL caused the formation of CML-epitope with increasing concentrations of copper ion and glucose. It was also formed to some extent in LDL incubated with high concentrations (500 mM) of glucose. However, no CML-epitope was observed in oxidized LDL induced by copper ion alone. On the other hand, the formation of oxPC-epitope in LDL was dependent on copper ion-induced peroxidation, but independent of glucose-induced glycation. The addition of chelators, ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, reduced the increase in electrophoretic mobility and TBARS caused by the peroxidation and glycoxidation of LDL, but had no effects on the formation of fructosamine caused by the glycation and glycoxidation of LDL. Chelators as well as aminoguanidine protected the formation of CML-epitope in glycated or glycoxidative LDL. Although the formation of oxPC-epitope was completely inhibited by the addition of chelators, it was partially protected by aminoguanidine. These in vitro results suggest that the glycoxidative modification of LDL may occur in the arterial intima, and may contribute to the development of human atherosclerotic lesions.
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PMID:In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques. 1085 26

The aim of this work was to compare biochemical, two-dimensional biomechanical and calorimetric parameters of diabetic skin vs. control skin. Skin specimens taken from the palms and backs of the hands of aged persons with non-insulin-dependent diabetes mellitus (NIDDM) and of controls (CO) were compared (age range 68-85 years). Only skin specimens from individuals with diabetes mellitus (DM) showed an increased fluorescence specific for the formation of advanced glycation end-products (AGEs) and the presence of tissue AGEs, such as N(e)-(Carboxymethyl)lysine (CML). Differential scanning calorimetry (DSC) revealed an elevation of the heat flow per unit mass during collagen denaturation in diabetic skin samples. However, the temperatures of the heat flow maximum and the onset of the phase transformation were not uniformly altered. Young's moduli were found to be increased in diabetic skin and correlated with AGE-fluorescence and tissue AGEs. The ratio between the Young's moduli, which defines a measure for the degree of anisotropy, was higher for dorsal skins from hands. In dorsal skin specimens from diabetic subjects the degree of anisotropy was more pronounced than in healthy controls. In general, neither of the measured parameters showed any correlation with age. However, E(1) moduli were clearly associated with the duration of diabetes.
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PMID:Differential scanning calorimetry, biochemical, and biomechanical analysis of human skin from individuals with diabetes mellitus. 1086 65

To assess a role for oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS), we analyzed the immunohistochemical localization of 8-hydroxy2'-deoxyguanosine (OHdG) as a nucleic acid oxidation product, acrolein-protein adduct and 4-hydroxy-2-nonenal (HNE)-protein adduct as lipid peroxidation products, Nepsiloncarboxymethyl-lysine (CML) as a lipid peroxidation or protein glycoxidation product, pentosidine as a protein glycoxidation product, and imidazolone and pyrraline as nonoxidative protein glycation products in the spinal cord of three familial ALS patients with superoxide dismutase(SOD 1) A4V mutation, six sporadic ALS patients, and six age-matched control individuals. The spinal cord sections of the control cases did not show any distinct immunoreactivities for these examined products. In the familial ALS cases, intense immunoreactivities for pyrraline and CML were confined to the characteristic Lewy body-like hyaline inclusions, and imidazolone immunoreactivity was located in the cytoplasm of the residual motor neurons. No significant immunoreactivities for other examined products were detected in the familial ALS spinal cords. In the sporadic ALS cases, intense immunoreactivities for pentosidine, CML and HNE-protein adduct were seen in the cytoplasm of the degenerated motor neurons, and OHdG immunoreactivity was located in the cell nuclei of the residual neurons and glial cells. The present results indicate that oxidative reactions are involved in the disease processes of sporadic ALS, while there is no evidence for increased oxidative damage except for CML deposition in the familial ALS spinal cords. Furthermore, it is likely that the accumulation of pyrraline and imidazolone supports a nonoxidative mechanism in SOD1-related motor neuron degeneration.
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PMID:Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. 1096 97

Advanced glycation end products (AGE) contribute to diabetic tissue injury by two major mechanisms, i.e., the alteration of extracellular matrix architecture through nonenzymatic glycation, with formation of protein crosslinks, and the modulation of cellular functions through interactions with specific cell surface receptors, the best characterized of which is the receptor for AGE (RAGE). Recent evidence suggests that the AGE-RAGE interaction may also be promoted by inflammatory processes and oxidative cellular injury. To characterize the distributions of AGE and RAGE in diabetic kidneys and to determine their specificity for diabetic nephropathy, an immunohistochemical analysis of renal biopsies from patients with diabetic nephropathy (n = 26), hypertensive nephrosclerosis (n = 7), idiopathic focal segmental glomerulosclerosis (n = 11), focal sclerosis secondary to obesity (n = 7), and lupus nephritis (n = 11) and from normal control subjects (n = 2) was performed, using affinity-purified antibodies raised to RAGE and two subclasses of AGE, i.e., N(epsilon)-(carboxymethyl)-lysine (CML) and pentosidine (PENT). AGE were detected equally in diffuse and nodular diabetic nephropathy. CML was the major AGE detected in diabetic mesangium (96%), glomerular basement membranes (GBM) (42%), tubular basement membranes (85%), and vessel walls (96%). In diabetic nephropathy, PENT was preferentially located in interstitial collagen (90%) and was less consistently observed in vessel walls (54%), mesangium (77%), GBM (4%), and tubular basement membranes (31%). RAGE was expressed on normal podocytes and was upregulated in diabetic nephropathy. The restriction of RAGE mRNA expression to glomeruli was confirmed by reverse transcription-PCR analysis of microdissected renal tissue compartments. The extent of mesangial and GBM immunoreactivity for CML, but not PENT, was correlated with the severity of diabetic glomerulosclerosis, as assessed pathologically. CML and PENT were also identified in areas of glomerulosclerosis and arteriosclerosis in idiopathic and secondary focal segmental glomerulosclerosis, hypertensive nephrosclerosis, and lupus nephritis. In active lupus nephritis, CML and PENT were detected in the proliferative glomerular tufts and crescents. In conclusion, CML is a major AGE in renal basement membranes in diabetic nephropathy, and its accumulation involves upregulation of RAGE on podocytes. AGE are also accumulated in acute inflammatory glomerulonephritis secondary to systemic lupus erythematosus, possibly via enzymatic oxidation of glomerular matrix proteins.
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PMID:Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. 1096 90


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