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)

Serum soluble interleukin-6 receptor (sIL-6R) concentrations were measured in 50 patients with plasma cell dyscrasias using a commercially available immunoenzymatic assay kit. There were 40 patients with multiple myeloma (MM), 5 patients with monoclonal gammopathy of undetermined significance (MGUS), 3 patients with solitary plasmacytoma (SPC), 1 patient with chronic myelogenous leukaemia and multiple myeloma (CML/MM), and 1 patient with plasma cell leukaemia (PCL). We found that serum sIL-6R concentrations were higher in MM patients (62.53 +/- 38.85 ng/ml) than in 20 normal volunteers studied (36.75 +/- 13.79 ng/ml) (p < 0.01). The cut-off value of 65 ng/ml seen in 2 of our controls was arbitrarily taken as the upper limit of the control range for serum sIL-6R; according to this criterion, 14 patients with MM (35%), 1 patient with SPC, the unique patient with CML + MM, and the unique patient with PCL had elevated concentrations of the receptor. Patients with MGUS had normal sIL-6R values. In MM patients, serum sIL-6R levels correlated with the clinical phase of the disease: they were elevated in patients with early or late active disease and ranged within normal limits in patients with plateau-phase disease (p < 0.001). Thirteen of 27 patients with active MM had elevated serum sIL-6R values, i.e. 48.1%, but only 1 out of 13 patients with disease in the plateau phase, i.e. 7.7% (p < 0.05). Furthermore, in the entire group of MM patients, serum sIL-6R levels correlated with the concentrations of serum beta 2-microglobulin, (p < 0.02), CRP (p < 0.01), ferritin (p < 0.01) and LDH (p < 0.01), while they did not correlate with disease stage, haemoglobin levels, proportion of marrow myeloma cells, the values of serum IL-6, the levels of serum albumin, or the grade of bone lesions. We conclude that elevated serum sIL-6R levels should be related to the growth of myeloma cells and suggest that serum sIL-6R concentrations may be used as an indicator of disease activity.
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PMID:Serum levels of soluble IL-6 receptor in multiple myeloma as indicator of disease activity. 915 60

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

It has been suggested that in blast crisis (BC) of chronic myeloid leukaemia (CML) the clinical and laboratory features of patients with 'lymphoid' phenotype differ from those of patients with non-lymphoid BC. In order to assess any differences, 97 patients consecutively diagnosed with BC that followed a known chronic phase of CML were analysed. 19 patients had 'lymphoid' BC: in 17 the blasts expressed a B-lineage phenotype: in the remaining two they corresponded to T lymphoblasts. Four cases of B-lineage phenotype BC were considered as biphenotypic, due to the co-expression of myeloperoxidase and one or two other myeloid markers (CD33, CD13 and CD68) on the blast cells; in the other six cases of B-lineage BC the blasts expressed one or both of the myeloid markers CD33 (n = 4) and CD13 (n = 3). Patients with 'lymphoid' BC seldom had an accelerated phase prior to BC (1/19 v 36/78 with non-lymphoid BC, P = 0.002), had less frequent splenomegaly (9/19 v 59/78, P = 0.03) and hepatomegaly (5/19 v 45/78, P = 0.02) and showed a higher degree of marrow blast infiltration (mean value 74 +/- 24% v 38 +/- 23%, P < 0.0001), lesser blood basophilia (2.2 +/- 2.5% v 8.2 +/- 7.8%, P < 0.0001), and higher serum albumin levels (P = 0.001) than those with non-lymphoid BC. 13 patients with 'lymphoid' BC (68.4%) showed a favourable response to chemotherapy regimens including vincristine and prednisone and, overall, 'lymphoid' BC patients survived significantly longer than the remainder (median survival 12 months v 4.7 months, P = 0.006). These results indicate that 'lymphoid' BC of CML has a distinct clinicohaematological profile and confirm the better prognosis of such patients.
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PMID:'Lymphoid' blast crisis of chronic myeloid leukaemia is associated with distinct clinicohaematological features. 945 Aug

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

Aging and age-related diseases are associated with the production of reactive oxygen species which modify lipids, proteins and DNA. Here we hypothesized the glyco- and lipoxidation product N(epsilon)-(carboxymethyl)lysine (CML) in proteins should bind divalent and redox active transition metal binding. CML-rich poly-L-lysine and bovine serum albumin (BSA) were chemically prepared and found to bind non-dialyzable Cu(2+), Zn(2+) and Ca(2+). CML-BSA-copper complexes oxidized ascorbate and depolymerized protein in the presence of H(2)O(2). CML-rich tail tendons implanted for 25 days into the peritoneal cavity of diabetic rats had a 150% increase in copper content and oxidized ascorbate three times faster than controls. CML-rich proteins immunoprecipitated from serum of uremic patients oxidized four times more ascorbate than control and generated spin adducts of DMPO in the presence of H(2)O(2). The chelator DTPA suppressed ascorbate oxidation thereby implicating transition metals in the process. In aging and disease, CML accumulation may result in a deleterious vicious cycle since CML formation itself is catalyzed by lipoxidation and glycoxidation.
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PMID:Protein aging by carboxymethylation of lysines generates sites for divalent metal and redox active copper binding: relevance to diseases of glycoxidative stress. 1040 71

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

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

Long-term incubation of proteins with glucose leads to the formation of advanced glycation end products (AGEs) that are recognized by AGE receptors. Glyoxal, glycolaldehyde (GA), and methylglyoxal are potential intermediates for the formation of AGE structures such as Nomega-(carboxymethyl)lysine (CML). We evaluated the contribution of these aldehydes to the formation of AGE structure(s), particularly the structure important for the receptor-mediated endocytic uptake of AGE proteins by macrophages. GA-modified bovine serum albumin (BSA), methylglyoxal-modified BSA (MG-BSA), and glyoxal-modified BSA (GO-BSA) were prepared, and their physicochemical, immunological, and biologic properties were compared with those of glucose-derived AGE-BSA. CML contents were high in GO-BSA and low in GA-modified BSA (GA-BSA) but did not exist in MG-BSA. The fluorescence patterns of GA-BSA and MG-BSA were similar to those of glucose-derived AGE-BSA but were weak in GO-BSA. Immunochemically, the antibody against non-CML structures of glucose-derived AGE-BSA reacted strongly with GA-BSA and weakly with GO-BSA but did not react with MG-BSA. The negative charge of these ligands increased to a similar extent. However, GA-BSA, but not MG-BSA or GO-BSA, underwent receptor-mediated endocytosis by the macrophage-derived cell line RAW 264.7, which was effectively inhibited by glucose-derived AGE-BSA, acetylated LDL, and oxidized LDL, which are well-known ligands for the macrophage type I and type II class A scavenger receptors (MSR-A). The endocytic uptake of GA-BSA by mouse peritoneal macrophages was also significant, but that by peritoneal macrophages from MSR-A-deficient mice was markedly reduced. Our results suggest that GA serves as an important intermediate for the generation of AGE structure(s) responsible for recognition by MSR-A.
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PMID:Glycolaldehyde, a reactive intermediate for advanced glycation end products, plays an important role in the generation of an active ligand for the macrophage scavenger receptor. 1101 56

Proteins can be chemically modified by sugars by glycation, or the Maillard reaction. The Maillard reaction produces irreversible adducts on proteins that are collectively known as advanced glycation end products, or AGEs. Recent studies indicate that several alpha-dicarbonyl compounds, including glyoxal (GXL), are precursors of AGEs in vivo. We developed antibodies against a GXL-modified protein (GXL-AGE) and purified a mixture of GXL-AGE-specific antibodies by chromatography on GXL-modified bovine serum albumin (BSA-GXL) coupled to EAH-Sepharose. This preparation was then processed on a human serum albumin-carboxymethyllysine (HSA-CML)-NHS-Sepharose to remove CML-specific antibodies. We used the resulting purified antibody in a competitive ELISA to probe GXL-AGEs in vitro and in vivo. We found increasingly greater antibody binding with increasing concentrations of GXL-modified BSA, but the antibody failed to react with either free CML or protein-bound CML. Incubation experiments with BSA revealed that glyceraldehyde, ribose and threose could be precursors of GXL-AGEs as well. Experiments in which GXL was incubated with N-alpha-acetyl amino acids showed that the antibody reacts mostly with lysine modifications. The GXL-derived lysine-lysine crosslinking structure, GOLD was found to be one of the antigenic epitopes for the antibody. Analysis of human plasma proteins revealed significantly higher levels of GXL-AGE antigens in type II diabetic subjects compared with normal controls (P<0.0001). We also found GXL-AGEs in human lens proteins. Bovine aortic endothelial cells cultured for 7 days with 30 mM glucose did not accumulate intracellular GXL-AGEs. These studies underscore the importance of GXL for extracellular AGE formation (except in lens where it is likely to be formed intracellularly) and suggest that changes associated with age and diabetes might be prevented by alteration of GXL-AGE formation.
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PMID:Maillard reactions by alpha-oxoaldehydes: detection of glyoxal-modified proteins. 1101 16

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.
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PMID:Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. 1137 53


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