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)

Recent studies have demonstrated a marked increase in the level of advanced glycation end products (AGEs) in the plasma, skin and amyloid fibrils of hemodialysis (HD) patients. The presence of AGEs in (beta2m) forming amyloid fibrils has been established in a previous immunochemical study relying on a monoclonal anti-AGE antibody. In the present study, Western blot analysis and immunohistochemistry reveal that the epitope recognized by this antibody is N epsilon-(carboxymethyl)lysine (CML) and that CML is one of the AGE structures present in amyloid fibrils. Thus, two AGE structures, CML and pentosidine, are now recognized in dialysis-related amyloidosis. AGE accumulation in uremia is not accounted for by elevated glucose levels. Since CML and pentosidine formation are closely linked to oxidative processes, we tested the hypothesis that a high oxidative stress enhanced AGE formation in HD patients. We focused on ascorbic acid (AA) because AA is easily oxidized under oxidative stress and its oxidized form (oxiAA) is a source of CML and pentosidine. In vitro incubation of beta2m with AA under atmospheric oxygen resulted in: (1) the rapid appearance of characteristic physicochemical properties of AGEs (brown color, fluorescence, polymerization tendency); (2) the transformation of beta2m into AGE-modified beta2m recognized by a specific monoclonal antibody; and (3) the accelerated formation of CML in beta2m and beta2m-peptide, recognized by mass spectrometry. A similar in vitro incubation of human serum albumin disclosed a parallel production of pentosidine measured by high-performance liquid chromatographic assay. In HD patients, the degree of AA oxidation, assessed as the ratio of oxiAA to total ascorbate, was more than twice as high as that of normal subjects (0.87 +/- 0.16 vs. 0.35 +/- 0.11, P < 0.0001), suggesting the presence of an increased oxidative stress. Interestingly, plasma level of oxiAA was correlated with the plasma levels of protein linked (P < 0.01, r2 = 0.25) and free (P < 0.05, r2 = 0.22) pentosidine. Altogether these results demonstrate that AGE, that is, CML and pentosidine, production is accelerated under oxidative stress, even in the absence of glucose. They suggest that, in uremia, CML and pentosidine production is determined both by an increased oxidative stress and the availability of precursors such as oxiAA. Finally, both CML and pentosidine contribute to the AGEs present in dialysis-related amyloid fibrils.
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PMID:Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. 908 83

Long-term incubation of proteins with glucose leads to the formation of advanced glycation end products (AGEs), which are characterized by fluorescence, brown color, and cross-linking. Formation of AGEs in vitro requires oxygen and is dependent on transition metal-catalyzed oxidation of glucose or Amadori products. AGEs are thought to be involved in aging and age-enhanced diseases such as diabetic complications, atherosclerosis, dialysis-related amyloidosis, and Alzheimer's disease. Chronic exposure of the skin to sunlight induces hyperplasia of the elastic tissue in the upper dermis known as actinic elastosis. Herein we used a monoclonal anti-AGE antibody (6D12) whose epitope is N(epsilon)-(carboxymethyl)lysine (CML), one of the glycoxidation products of AGEs, and demonstrated that the lesions of actinic elastosis were modified by CML. Further immunohistochemical and immunoelectron microscopic examination with 6D12 demonstrated CML accumulates predominantly in elastic fibers especially in the amorphous electron-dense materials corresponding to photo-induced degenerated area rather than the electron-lucent region. Immunochemical analyses with enzyme-linked immunosorbent assay (ELISA) of elastase-soluble fractions demonstrated that the CML levels of the sun-exposed area were significantly higher than those of the sun-unexposed area. We conclude that ultraviolet-induced oxidation may accelerate CML formation in actinic elastosis of photoaged skin.
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PMID:Photo-enhanced modification of human skin elastin in actinic elastosis by N(epsilon)-(carboxymethyl)lysine, one of the glycoxidation products of the Maillard reaction. 912 35

Recent studies demonstrated N epsilon-(carboxymethyl)lysine (CML) in several tissue proteins. Incubation of proteins with glucose leads through a Schiff base to Amadori products. Oxidative cleavage of Amadori products is considered as a major route to CML formation in vivo, whereas it is not known which reactive oxygen species (ROS) is involved. The present study is undertaken to identify such a ROS. We prepared heavily glycated human serum albumin (HSA) which contained a high level of Amadori products, but an undetectable level of CML. Incubation of glycated HSA with FeCl2, but not with H2O2, led to CML formation which was enhanced by H2O2, but inhibited by catalase or mannitol, whereas superoxide dismutase had no effect. Similar data were obtained by experiments using Boc-fructose-lysine as a model Amadori compound. These data indicate that hydroxyl radical generated by the reaction of Fe2+ with H2O2 mediates CML formation from Amadori compounds.
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PMID:Hydroxyl radical mediates N epsilon-(carboxymethyl)lysine formation from Amadori product. 916 83

Advanced glycation end-products and glycoxidation products, such as Nepsilon-(carboxymethyl)lysine (CML) and pentosidine, accumulate in long-lived tissue proteins with age and are implicated in the aging of tissue proteins and in the development of pathology in diabetes, atherosclerosis and other diseases. In this paper we describe a new advanced glycation end-product, Nepsilon-(carboxyethyl)lysine (CEL), which is formed during the reaction of methylglyoxal with lysine residues in model compounds and in the proteins RNase and collagen. CEL was also detected in human lens proteins at a concentration similar to that of CML, and increased with age in parallel with the concentration of CML. Although CEL was formed in highest yields during the reaction of methylglyoxal and triose phosphates with lysine and protein, it was also formed in reactions of pentoses, ascorbate and other sugars with lysine and RNase. We propose that levels of CML and CEL and their ratio to one another in tissue proteins and in urine will provide an index of glyoxal and methylglyoxal concentrations in tissues, alterations in glutathione homoeostasis and dicarbonyl metabolism in disease, and sources of advanced glycation end-products in tissue proteins in aging and disease.
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PMID:N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins. 918 19

It is likely that leukemia results, at least in part, from mutations that lead to a block in the normal process of differentiation. A defined region of the cytoplasmic domain of the granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for maturation or differentiation of myeloid progenitor cells. Mutations in this region have been found in some patients with severe congenital neutropenia (SCN) who subsequently evolved to acute myeloid leukemia (AML). To determine if mutations of the G-CSF-R are more widespread in hematological malignancies, we have investigated a total of 47 patients, including 29 patients with blast crisis of chronic myeloid leukemia (CML-BC) and 18 patients with de novo acute leukemia as well as 19 normal controls, by RT-PCR and SSCP analysis. Two point mutations were found in a single individual with secondary AML (FAB type M1). The first was heterozygous and is predicted to replace the normal glutamine at position 718 with a stop codon, leading to a truncated protein. An identical mutation has been described previously and shown to act in a dominant negative manner. The second mutation was homozygous and would substitute a lysine for the normal glutamic acid at position 785. No mutations were found in any other patient or control samples. We conclude that mutations in the cytoplasmic domain of the G-CSF-R are infrequent in CML-BC or acute leukemia but may contribute to malignant transformation in some cases.
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PMID:Rarity of dominant-negative mutations of the G-CSF receptor in patients with blast crisis of chronic myeloid leukemia or de novo acute leukemia. 920 82

Nepsilon-(Carboxymethyl)lysine (CML) is a stable chemical modification of proteins formed from both carbohydrates and lipids during autoxidation reactions. We hypothesized that carboxymethyl lipids such as (carboxymethyl)phosphatidylethanolamine (carboxymethyl-PE) would also be formed in these reactions, and we therefore developed a gas chromatography-mass spectrometry assay for quantification of carboxymethylethanolamine (CME) following hydrolysis of phospholipids. In vitro, CME was formed during glycation of dioleoyl-PE under air and from linoleoylpalmitoyl-PE, but not from dioleoyl-PE, in the absence of glucose. In vivo, CME was detected in lipid extracts of red blood cell membranes, approximately 0.14 mmol of CME/mol of ethanolamine, from control and diabetic subjects, (n = 22, p >> 0.5). Levels of CML in erythrocyte membrane proteins were approximately 0.2 mmol/mol of lysine for both control and diabetic subjects (p >> 0.5). For this group of diabetic subjects there was no indication of increased oxidative modification of either lipid or protein components of red cell membranes. CME was also detected in fasting urine at 2-3 nmol/mg of creatinine in control and diabetic subjects (p = 0.085). CME inhibited detection of advanced glycation end product (AGE)-modified protein in a competitive enzyme-linked immunosorbent assay using an anti-AGE antibody previously shown to recognize CML, suggesting that carboxymethyl-PE may be a component of AGE lipids detected in AGE low density lipoprotein. Measurement of levels of CME in blood, tissues, and urine should be useful for assessing oxidative damage to membrane lipids during aging and in disease.
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PMID:Carboxymethylethanolamine, a biomarker of phospholipid modification during the maillard reaction in vivo. 921 92

Advanced glycation end products (AGEs) such as pentosidine and N epsilon-(carboxymethyl)lysine (CML) have been traditionally quantified by HPLC or gas chromatography--mass spectrometry (GC/MS). Enzyme-linked immunosorbent assays (ELISA) have been introduced as a convenient alternative to simplify the detection and measurement of AGEs in proteins and tissues, but some of these studies are limited by the lack of information on the structure of the epitopes recognized by antibodies to AGE-proteins. In this work we demonstrate that an antibody used in a previous study, reporting increased levels of AGEs in patients with diabetes or on continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD), recognizes CML as its major epitope. We also show that there is a significant correlation between the concentration of AGEs in serum measured by ELISA and a GC/MS assay for CML in serum proteins. Both analyses yielded comparable results, with patients on CAPD and HD having about threefold higher AGE- or CML-concentrations in their serum. Our data suggest that ELISA assays for CML should be useful for the clinical measurement of AGEs in serum proteins.
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PMID:Technical note. The serum concentration of the advanced glycation end-product N epsilon-(carboxymethyl)lysine is increased in uremia. 932 46

Advanced glycation end products (AGEs) include a variety of protein adducts whose accumulation alters the structure and function of tissue proteins and stimulates cellular responses. They have been implicated in tissue damage associated with diabetic complications. To assess the possible link between AGE accumulation and the development of diabetic nephropathy (DN), we have examined the immunohistochemical localization of various AGE structures postulated to date, i.e., pentosidine, Nepsilon-(carboxymethyl)lysine (CML), and pyrraline, in diabetic and control kidneys. CML and pentosidine accumulate in the expanded mesangial matrix and thickened glomerular capillary walls of early DN and in nodular lesions and arterial walls of advanced DN, but were absent in control kidneys. By contrast, pyrraline was not found within diabetic glomeruli but was detected in the interstitial connective tissue of both normal and diabetic kidneys. Although the distribution of pyrraline was topographically identical to type III collagen, distribution of pentosidine and CML was not specific for collagen type, suggesting that difference in matrix protein composition per se could not explain heterogeneous AGE localization. Since oxidation is linked closely to the formation of pentosidine and CML, we also immunostained malondialdehyde (MDA), a lipid peroxidation product whose formation is accelerated by oxidative stress, assuming that local oxidative stress may serve as a mechanism of pentosidine and CML accumulation. Consistent with our assumption, diabetic nodular lesions were stained positive for MDA. These findings show that AGE localization in DN varies according to AGE structure, and suggest that the colocalization of markers of glycoxidation (pentosidine and CML) with a marker of lipid peroxidation reflects a local oxidative stress in association with the pathogenesis of diabetic glomerular lesions. Thus, glycoxidation markers may serve as useful biomarkers of oxidative damage in DN.
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PMID:Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. 939 45

Glycation and subsequent Maillard or browning reactions of glycated proteins, leading to the formation of advanced glycation end products (AGEs), are involved in the chemical modification of proteins during normal aging and have been implicated in the pathogenesis of diabetic complications. Oxidative conditions accelerate the browning of proteins by glucose, and AGE proteins also induce oxidative stress responses in cells bearing AGE receptors. These observations have led to the hypothesis that glycation-induced pathology results from a cycle of oxidative stress, increased chemical modification of proteins via the Maillard reaction, and further AGE-dependent oxidative stress. Here we show that the preparation of AGE-collagen by incubation with glucose under oxidative conditions in vitro leads not only to glycation and formation of the glycoxidation product Nepsilon-(carboxymethyl)lysine (CML), but also to the formation of amino acid oxidation products on protein, including m-tyrosine, dityrosine, dopa, and valine and leucine hydroperoxides. The formation of both CML and amino acid oxidation products was prevented by anaerobic, anti-oxidative conditions. Amino acid oxidation products were also formed when glycated collagen, prepared under anti-oxidative conditions, was allowed to incubate under aerobic conditions that led to the formation of CML. These experiments demonstrate that amino acid oxidation products are formed in proteins during glycoxidation reactions and suggest that reactive oxygen species formed by redox cycling of dopa or by the metal-catalysed decomposition of amino acid hydroperoxides, rather than by redox activity or reactive oxygen production by AGEs on protein, might contribute to the induction of oxidative stress by AGE proteins.
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PMID:Presence of dopa and amino acid hydroperoxides in proteins modified with advanced glycation end products (AGEs): amino acid oxidation products as a possible source of oxidative stress induced by AGE proteins. 946 15

Nepsilon-(carboxymethyl)lysine (CML) is known to be formed by oxidative cleavage of Amadori products between C-2 and C-3 of the carbohydrate chain. We report here that CML formation from Amadori compounds is highly accelerated under alkaline conditions. Incubation of glycated human serum albumin (HSA) in 0.1 N NaOH led to the formation of CML whereas glycated HSA reduced by NaCNBH3 or non-glycated HSA did not generate CML. Nalpha-t-butyloxycarbonyl-Nepsilon-fructoselysine (Boc-FL), a model compound of Amadori product, was converted to CML under alkaline conditions. CML level of human sera (n=224) preincubated with 0.1 N NaOH correlated well with glycated albumin value (r=0.912) and hemoglobin A1c (r=0.797).
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PMID:Conversion of Amadori product of Maillard reaction to Nepsilon-(carboxymethyl)lysine in alkaline condition. 955 79


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