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)

Immunological strategies for the detection of N(epsilon)-(carboxymethyl)lysine (CML), one of the major antigenic structures of advanced glycation end products (AGE), are widely applied to demonstrate the contribution of CML to the pathogeneses of diabetic complications and atherosclerosis. Recent studies have indicated that methylglyoxal (MG), which is generated intracellularly through the Embden-Meyerhof and polyol pathways, reacts with proteins to form MG-derived AGE structures such as N(epsilon)-(carboxyethyl)lysine (CEL). In order to accurately measure the CML contents of the proteins by means of an immunochemical method, we prepared CML-specific antibodies since conventionally prepared polyclonal anti-CML antibody and monoclonal anti-CML antibody (6D12) cross-reacted with CEL. To prepare polyclonal CML-specific antibody, CML-keyhole limpet hemocyanin (CML-KLH) were immunized with rabbit and CEL-reactive antibody was removed by CEL-conjugated affinity chromatography. Monoclonal antibody specific for CML (CMS-10) was obtained by immunization with CML-KLH, followed by successive screening according to CML-bovine serum albumin (CML-BSA)-positive but CEL-BSA-negative criteria. Both polyclonal CML-specific antibody and CMS-10 significantly reacted with CML-proteins but not with CEL-proteins. It is likely therefore that these antibodies can recognize the difference of one methyl group between CML and CEL. Moreover, CMS-10 significantly reacted with BSA modified with several aldehydes and its reactivity was highly correlated with the CML content, which was determined by high performance liquid chromatography, whereas 6D12 showed a low correlation. These results indicate that CMS-10 can be used to determine the CML contents of modified proteins in a more specific way.
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PMID:Conventional antibody against Nepsilon-(carboxymethyl)lysine (CML) shows cross-reaction to Nepsilon-(carboxyethyl)lysine (CEL): immunochemical quantification of CML with a specific antibody. 1567 94

Posttranslational modifications, such as advanced glycoxidation and lipoxidation end products (AGE/ALEs), are implicated in the pathogenesis of diabetic complications and atherosclerosis. Recent studies have demonstrated that AGE/ALEs are generated not only in extracellular matrix proteins, but also in intracellular proteins from metabolic intermediates. In this study we investigate the effect of glucose concentration on the formation of the AGE/ALEs, Nepsilon-(carboxymethyl)lysine (CML), Nepsilon-(carboxyethyl)lysine (CEL), S-(carboxymethyl)cysteine (CMC), and S-(2-succinyl)cysteine (2SC) in erythrocytes as a function of glucose concentration. Human erythrocytes (10% hematocrit) were incubated in Dulbecco's modified Eagle's medium (DMEM) containing 5 mM or 30 mM glucose for 5 days at 37 degrees C. Globin was recovered by precipitation with 0.25 M HCl in acetone. Following acid hydrolysis, amino acids were converted to their trifluoroacetyl methyl ester derivatives and analyzed by GC/MS/MS. The CML and CEL content of globin increased in a time- and glucose-dependent manner and also increased 1.3- and 1.8-fold, respectively, in incubations containing 30 mM glucose; whereas CMC and 2SC content did not change during the five-day incubations. Furthermore, CEL content of globin in erythrocytes incubated with 30 mM was the highest in the other AGEs, indicating that methylglyoxal may play a major role in AGE formation in erythrocytes. The erythrocyte system should be useful for cellular screening of the efficacy of inhibitors of AGE/ALE formation.
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PMID:Effect of glucose concentration on formation of AGEs in erythrocytes in vitro. 1603 33

Several lines of evidence suggest that both advanced glycation end products (AGEs) and oxidation processes play key roles in the physiology of aging and age-related pathologies, leading to irreversible proteins modifications in both tissues and the extracellular matrix. Such an accelerated accumulation of these modifications has been reported to be present in several age-related chronic diseases, such as atherosclerosis, diabetes, arthritis, and neurodegenerative diseases. The current literature reveals that the specific inhibition of AGEs may constitute an innovative therapeutic goal. In experimental animals, the use of sartans significantly reduces blood pressure and kidney pentosidine content, improving both histologic renal damage and proteinuria. In this study, 12 subjects who were affected by diabetes mellitus and hypertension were subjected to oral antihypertensive therapy with valsartan (class of sartans) with timed sampling of plasma and urine pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), malondialdehyde, and isoprostanes levels, respectively, at baseline and after both 3 and 6 months, with parallel ongoing evaluation of glycemic control and blood pressure levels. Valsartan elicited a good antihypertensive effect with a 30% decrease in plasma pentosidine levels (P < .05) after 3 months of therapy, followed by a slight increase after 6 months. Urinary pentosidine concentrations exhibited a 40% decrease after 3 months (215 +/- 19 vs 129 +/- 23 nmol/24 h) and a further significant reduction after 6 months of therapy (105 +/- 24 nmol/24 h). Plasma CML levels showed a progressive decrease after 3 months (23.15 +/- 3.215 vs 19.88 +/- 1.684 micromol/mL) and achieved a further slight reduction after 6 months of therapy (19.48 +/- 1.339 micromol/mL); for urinary CML, a statistically significant reduction was gained after the sixth month of therapy (48.51 +/- 5.70 vs 30.30 +/- 2.77 micromol/24 h after 3 months and 27.02 +/- 4.13 micromol/24 h after 6 months; F = 7.62, P < .005). Plasma and urinary concentrations of malondialdehyde were slightly modified by valsartan treatment; the mean levels after both 3 and 6 months did not significantly differ from baseline. Urinary 15-F2t-isoprostanes (2.96 +/- 0.45 ng/24 h) levels displayed a progressive decrease after both 3 (2.27 +/- 0.31 ng/24 h) and 6 months (1.70 +/- 0.23 ng/24 h) with statistical significance achieved only at the end of the study (P < .05). The present data suggest interesting in vivo antiglycation and antioxidation effects of this angiotensin II receptor antagonist with reductions in plasma and urinary pentosidine, plasma CML, and urinary isoprostanes levels. The present study supports an antagonistic role of valsartan in the production of AGEs precursors through the chelation of transition metals and an antioxidant activity that scavenges reactive oxygen species. This property of valsartan may broaden the scope of newly developed pharmacologic inhibitors of advanced glycoxidation.
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PMID:Effects of valsartan therapy on protein glycoxidation. 1714 34

Despite the common use of immunohistochemistry in autopsy tissues, the stability of most proteins over extended time periods is unknown. The robustness of signal for 16 proteins (MMP1, MMP2, MMP3, MMP9, TIMP1, TIMP2, TIMP3, AGER, MSR, SCARB1, OLR1, CD36, LTF, LGALS3, LYZ, and DDOST) and two measures of advanced glycation end products (AGE, CML) was evaluated. Two formalin-fixed, paraffin-embedded human tissue arrays containing 16 tissues each were created to evaluate 48 hr of autolysis in a warm or cold environment. For these classes of proteins, matrix metalloproteinases and their inhibitors, scavenger receptors, and advanced glycation end product receptors, we saw no systematic diminution of signal intensity during a period of 24 hr. Analysis was performed by two independent observers and confirmed for a subset of proteins by digital analysis and Western blotting. We conclude that these classes of proteins degrade slowly and faithfully maintain their immunohistochemistry characteristics over at least a 24-hr time interval in devitalized tissues. This study supports the use of autopsy tissues with short postmortem intervals for immunohistochemical studies for diseases such as diabetic vascular disease, cancer, Alzheimer's disease, atherosclerosis, and other pathological states. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.
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PMID:Robust immunohistochemical staining of several classes of proteins in tissues subjected to autolysis. 1731 10

Advanced glycation end-products (AGE) play a role in the pathogenesis of several diseases, including diabetic complications and atherosclerosis. In atherosclerotic lesions of human aortas, AGE are localized in the extracellular matrix and intracellularly in foam cells. Two interpretations are possible for AGE accumulation inside macrophages, one is endocytic uptake of extracellular AGE-proteins by scavenger receptors; the other is intracellular AGE formation inside the macrophages. In the present study, we determined the pathways involved in AGE accumulation inside macrophages. RAW 264.7 cells, a murine macrophage cell line, incubated with BSA and 1600 mM glucose for 40 weeks, recognized heavily modified AGE- BSA. In contrast, the cells showed no ligand activity for mildly modified AGE-BSA, prepared by incubating BSA with 50 mM glucose for 24 weeks. Nepsilon-(carboxymethyl)lysine (CML)-modified proteins of about 65 kDa were detected in human monocyte-derived macrophages incubated for 7 days with 30 mM glucose and phorbol myristate acetate. Furthermore, CML was generated when glycated protein was incubated with hypochloric acid. Taken together, our results indicate that AGE detected inside foam cells in atherosclerotic lesions are generated intracellularly rather than representing endocytic uptake of extracellular AGE-proteins by scavenger receptors.
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PMID:Investigation of pathways of advanced glycation end-products accumulation in macrophages. 1739 Mar 98

Endothelial function is considered important in the development of cardiovascular diseases and type 2 diabetes. Circulating advanced glycation end-products (AGEs) and dietary components have been shown to affect endothelial function in type 2 diabetics, but determinants of endothelial function in a non-diabetic population are more poorly investigated. Therefore, we investigated relationships between dietary habits, AGEs and endothelial activation in men with isolated metabolic disturbances. Circulating markers of endothelial activation (soluble forms of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and von Willebrand factor) and plasma N epsilon-carboxymethyl-lysine (CML, the predominant AGE in human plasma) were analyzed in a cross-sectional study of 294 healthy men. Individuals completed a 7-day dietary record, and metabolic and inflammatory parameters were determined. NCEP/ATPIII-criteria were used to define the metabolic syndrome. Endothelial activation was higher in individuals with the metabolic syndrome, and was positively related to certain features of the syndrome (insulin, glucose, inflammation and obesity), but not to others (triacylglycerol and blood pressure). Dietary factors were related to endothelial activation, but CML was not. Multivariate analysis revealed energy and alcohol intake, along with insulin and markers of oxidative stress and inflammation, to be positive predictors of endothelial activation. In this cohort of otherwise healthy men, endothelial activation was increased in individuals with the full metabolic syndrome, but not in those with only some of the components of the metabolic syndrome. Insulin resistance, inflammation, oxidative stress, the dietary intake of energy and alcohol, but not plasma CML, predicted endothelial activation in these men.
Atherosclerosis 2007 Dec
PMID:Markers of endothelial activity are related to components of the metabolic syndrome, but not to circulating concentrations of the advanced glycation end-product N epsilon-carboxymethyl-lysine in healthy Swedish men. 1765 51

Although the association between type 2 diabetes mellitus (DM) and cardiovascular diseases is well-documented, current knowledge regarding reasons for the increased prevalence of atherosclerosis in DM is incomplete. Advanced glycosylation end-products (AGE) may play an important role in the development of atherosclerosis in diabetic patients. We examined the effect of the HMG-CoA reductase inhibitor (HMGRI) cerivastatin on serum concentration of AGE-CML in patients with elevated fasting glucose, impaired glucose tolerance or DM. The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n=34) and placebo (n=35). Patients were characterized by combined hyperlipoproteinemia and the preponderance of dense LDL. Primary objective of the study was the effect of cerivastatin on the concentration of dense LDL subfractions. Here we report on the effect of cerivastatin on the concentration of AGE-CML. After 12 weeks of treatment cerivastatin reduced cholesterol, apolipoprotein B, LDL cholesterol and the concentration of dense LDL. Furthermore, cerivastatin significantly lowered the concentration of AGE-CML by 21% ( P=0,005; compared to -7,5% in the placebo group). The effect on AGE-CML was correlated with the reduction in LDL cholesterol (r=0.355, P=0.003) and LDL apoB (r=0.239, P=0.05). In addition to the lipid-lowering effects of HMGRI, the reduction of AGE-CML observed in our study may entail an improvement of the cardiovascular prognosis in patients with chronic hyperglycemia.
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PMID:The HMG-CoA reductase inhibitor cerivastatin lowers advanced glycation end products in patients with type 2 diabetes. 1770 82

In comparison to the general population, individuals with diabetes suffer a 3- to 4-fold increased risk for developing complications of atherosclerosis and vascular insufficiency. This fact should be taken into account to develop a suitable determinant for the early detection of these complications and subsequently reduce the adverse effect of type 2 diabetes. In vitro experiments have shown that the products of glucose auto-oxidation and Amadori adducts are both potential sources of N(epsilon)-(carboxymethyl)lysine (CML). Excessive formation of CML on low density lipoprotein (LDL) has been proposed to be an important mechanism for the dyslipidemia and accelerated atherogenesis observed in patients with type 2 diabetes. It has been postulated that the uptake of CML-LDL by LDL receptors is impaired, thereby decreasing its clearance from the blood circulation. Alternatively, the uptake of these modified LDL particles by scavenger receptors on macrophages and vascular smooth muscle cells (SMCs) and by AGE receptors on endothelial cells, SMCs, and monocytes is highly enhanced and this, in turn, is centrally positioned to contribute to the pathogenesis of diabetic vascular complications especially coronary artery disease. The present review summarizes the up-to-date information on effects and mechanism of type 2 diabetes-associated coronary atherosclerosis induced by CML-LDL modification.
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PMID:N(epsilon)-(Carboxymethyl)lysine and Coronary Atherosclerosis-Associated Low Density Lipoprotein Abnormalities in Type 2 Diabetes: Current Status. 1917 84

N(omega)-Carboxymethyl-arginine (CMA), N(omega)-carboxyethyl-arginine (CEA) and N(delta)-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) have been identified as L-arginine-derived advanced glycation end products (AGEs) formed by non-enzymatic reactions between reducing sugars such as glucose and amino groups in proteins. These AGEs are structurally analogous to endogenous inhibitors of nitric oxide synthases (NOS) including N(G)-monomethyl-L-arginine (L-NMMA) and asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA). Increased plasma levels of these NOS inhibitors, and thus impaired generation of NO in vivo has been associated with the pathogenesis of vascular complications such as kidney failure and atherosclerosis. For these reasons we examined whether L-arginine-derived AGEs inhibit the activities of three L-arginine metabolizing enzymes including three isoforms of NOS (endothelium, neuronal and inducible NOS), dimethylarginine dimethylaminohydrolase (DDAH) that catalyzes the hydrolytic degradation of L-NMMA and ADMA to L-citrulline, and arginase that modulates intracellular L-arginine bioavailability. We found that AGEs inhibited the in vitro activities of endothelium type NOS weakly (IC(50) values of CMA, CEA and MG-H1 were 830, 3870 and 1280 microM, respectively) and were also potential endogenous inhibitors for arginase (IC(50) values of CMA and CML were 1470 and 1060 microM), but were poor inhibitors for DDAH. These results suggest that the tested L-arginine- and L-lysine-derived AGEs appear not to impair NO biosynthesis directly.
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PMID:Inhibition of L-arginine metabolizing enzymes by L-arginine-derived advanced glycation end products. 2021 51

Advanced glycation endproducts (AGEs) are a group of complex and heterogeneous compounds formed from nonenzymatic reactions. The accumulation of AGEs in vivo has been implicated as a major pathogenic process in diabetic complications and other health disorders, such as atherosclerosis and Alzheimer's disease, and normal aging. In this study, we investigate the inhibitory effects of cinnamon bark proanthocyanidins, catechin, epicatechin, and procyanidin B2 on the formation of specific AGE representatives including pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), and methylglyoxal (MGO) derived AGEs. These compounds displayed obvious inhibitory effects on these specific AGEs, which are largely attributed to both their antioxidant activities and carbonyl scavenging capacities. Meanwhile, in terms of their potent MGO scavenging capacities, effects of these proanthocyanidins on insulin signaling pathways interfered by MGO were evaluated in 3T3-L1 adipocytes. According to the results, proanthocyanidins exerted protective effects on glucose consumption impaired by MGO in 3T3-L1 fat cells.
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PMID:Beneficial effects of cinnamon proanthocyanidins on the formation of specific advanced glycation endproducts and methylglyoxal-induced impairment on glucose consumption. 2047 37


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