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

In the present study, we investigated the ability of the tetrapeptide NAc-Ser-Asp-Lys-Pro-OH (AcSDKP), a reported inhibitor of primitive hematopoietic cells, to influence the proliferative behavior of primitive normal and chronic myeloid leukemia (CML) progenitor cells in the adherent layer of long-term cultures (LTCs). Addition of > or = 50 ng/mL of AcSDKP to LTCs of normal cells at the time of the regular weekly half-medium change selectively and reversibly decreased the proportion of high proliferative potential erythroid and granulopoietic progenitors in the adherent layer that were in S-phase without changing their numbers, but had no effect on either the cycling activity or number of analogous (neoplastic) cells in the adherent layer of CML LTCs. Specificity of the effect of AcSDKP on primitive normal progenitors was demonstrated by the finding that a similar addition of either the control peptide, AcSDKE, or 100 ng/mL of tumor necrosis factor-alpha (TNF-alpha, which contains the SDKP sequence), or SDKP itself (at 300 ng/mL) did not inhibit the proliferation of primitive normal progenitors in LTC adherent layers. Incorporation of > or = 30 ng/mL of AcSDKP (but not the related control peptide, AcSDKE) directly into methylcellulose cultures of normal marrow cells resulted in a dose-dependent suppression of colony formation, which was not seen in similar studies with CML marrow or after removal of adherent cells from normal marrow. Additional experiments showed that the inhibitory effect of AcSDKP on primitive normal progenitor cycling in the LTC system could be overcome by the simultaneous addition of macrophage inflammatory protein-1 beta (MIP-1 beta); an antagonist of MIP-1 alpha. The apparent differential effect of AcSDKP on primitive normal and CML progenitors may thus be a secondary consequence of the differential responsiveness of these cells to MIP-1 alpha for another molecule antagonized by MIP-1 beta), whose production or release by adherent marrow cells is inducible by AcSDKP. Such a mechanism may offer a method for obtaining localized increases in vivo of cytokines like MIP-1 alpha, suggesting novel and perhaps less toxic strategies for protecting primitive normal progenitors during repeated treatments with cycle-active chemotherapeutic agents where escalating the dose of drug given would be desirable.
 ...
PMID:The tetrapeptide AcSDKP specifically blocks the cycling of primitive normal but not leukemic progenitors in long-term culture: evidence for an indirect mechanism. 806 44

We investigated the expression of p53 in paraformaldehyde-lysine-periodate fixed normal and chronic myelogenous leukemia (CML) hemopoietic cells with flow cytometry and two monoclonal antibodies, PAb1801 and the mutant-conformation-associated PAb240. With both antibodies p53 proteins were detected in more than 50% of CD34+ cells and in more than 95% neutrophils but were undetectable in the CD34- myeloid precursors. The expression of a p53 protein reactive with PAb240 was closely associated with CD34+/HLA-DR+ cells and with cells in active cell cycle, while the p53 protein recognized by PAb1801 was mainly found in CD34+/HLA-DR- cells and in cells in the G0/G1 phases of the cell cycle. Treatment of chronic-phase CML cells with p53 antisense oligonucleotides resulted in significantly increased numbers of granulocyte-macrophage colony-forming unit colonies in 12 of 17 cases studied. Slightly reduced granulocyte-macrophage colony-forming unit colony numbers were observed in one case and no change in the four others. In eight samples of normal bone marrow cells, treatment with antisense oligonucleotides showed no consistent changes in granulocyte-macrophage colony-forming unit numbers. Our data suggest that the expression of the tumor suppressor p53 is involved in the regulation of both normal and CML hemopoiesis and that the inhibition of p53 expression could modulate the proliferation of CML hemopoietic cells and possibly of normal cells.
 ...
PMID:The involvement of "tumor suppressor" p53 in normal and chronic myelogenous leukemia hemopoiesis. 827 97

To investigate the contribution of glycation and oxidation reactions to the modification of insoluble collagen in aging and diabetes, Maillard reaction products were measured in skin collagen from 39 type 1 diabetic patients and 52 nondiabetic control subjects. Compounds studied included fructoselysine (FL), the initial glycation product, and the glycoxidation products, N epsilon-(carboxymethyl) lysine (CML) and pentosidine, formed during later Maillard reactions. Collagen-linked fluorescence was also studied. In nondiabetic subjects, glycation of collagen (FL content) increased only 33% between 20 and 85 yr of age. In contrast, CML, pentosidine and fluorescence increased five-fold, correlating strongly with age. In diabetic patients, collagen FL was increased threefold compared with nondiabetic subjects, correlating strongly with glycated hemoglobin but not with age. Collagen CML, pentosidine and fluorescence were increased up to twofold in diabetic compared with control patients: this could be explained by the increase in glycation alone, without invoking increased oxidative stress. There were strong correlations among CML, pentosidine and fluorescence in both groups, providing evidence for age-dependent chemical modification of collagen via the Maillard reaction, and acceleration of this process in diabetes. These results support the description of diabetes as a disease characterized by accelerated chemical aging of long-lived tissue proteins.
 ...
PMID:Accumulation of Maillard reaction products in skin collagen in diabetes and aging. 851 58

Glycation, oxidation, and browning of proteins have all been implicated in the development of diabetic complications. We measured the initial Amadori adduct, fructoselysine (FL); two Maillard products, N epsilon-(carboxymethyl) lysine (CML) and pentosidine; and fluorescence (excitation = 328 nm, emission = 378 nm) in skin collagen from 39 type 1 diabetic patients (aged 41.5 +/- 15.3 [17-73] yr; duration of diabetes 17.9 +/- 11.5 [0-46] yr, [mean +/- SD, range]). The measurements were related to the presence of background (n = 9) or proliferative (n = 16) retinopathy; early nephropathy (24-h albumin excretion rate [AER24] > or = 20 micrograms/min; n = 9); and limited joint mobility (LJM; n = 20). FL, CML, pentosidine, and fluorescence increased progressively across diabetic retinopathy (P < 0.05, P < 0.001, P < 0.05, P < 0.01, respectively). FL, CML, pentosidine, and fluorescence were also elevated in patients with early nephropathy (P < 0.05, P < 0.001, P < 0.01, P < 0.01, respectively). There was no association with LJM. Controlling for age, sex, and duration of diabetes using logistic regression, FL and CML were independently associated with retinopathy (FL odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.01-1.12, P < 0.05; CML OR = 6.77, 95% CI = 1.33-34.56, P < 0.05) and with early nephropathy (FL OR = 1.05, 95% CI = 1.01-1.10, P < 0.05; CML OR = 13.44, 95% CI = 2.00-93.30, P < 0.01). The associations between fluorescence and retinopathy and between pentosidine and nephropathy approached significance (P = 0.05). These data show that FL and Maillard products in skin correlate with functional abnormalities in other tissues and suggest that protein glycation and oxidation (glycoxidation) may be implicated in the development of diabetic retinopathy and early nephropathy.
 ...
PMID:Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus. 851 59

A number of cellular transformations are due, in large part, to a single base mutation that alters the function of the expressed protein. Similarly, alterations in the DNA sequence of a gene involved in cell proliferation can have a significant effect on the viability of particular cells, Thus, the capacity to modulate the base sequence of such a gene would be a useful tool for cancer therapeutics. We have developed an experimental strategy that centers around site-specific DNA base mutation or correction using a unique chimeric oligonucleotide. This chimeric molecule has demonstrated higher recombinogenic activities than identical oligonucleotides containing only DNA residues, both in vitro and in vivo. The chimeric molecule is designed to hybridize to a target site within the genome and induce a single base mismatch at the residue targeted for mutation. The DNA structure created at this site is recognized by the host cell's repair system which mediates the correction reaction. The bcr-abl fusion gene, the product of a translocation between human chromosomes 9 and 22, and the cause of chronic myelogenous leukemia (CML) can be targeted for gene correction. This fusion gene is a good choice because (1) it is a unique target in CML; (2) it is a single copy target; (3) the DNA sequence of the fusion gene is unique. The goal of such experiments is to knock-out the fusion gene by changing a glutamine or lysine codon into a stop codon through a chimeric directed DNA repair system.
 ...
PMID:Genomic targeting and genetic conversion in cancer therapy. 860 28

Nepsilon-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was approximately 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML, was also formed during incubation of RNase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.
 ...
PMID:The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. 862 37

Long-term incubation of proteins with glucose leads to the formation of advanced glycation end products (AGE). Recent immunological studies have suggested the potential role of AGE in atherosclerosis, aging, and diabetic complications. We previously prepared a monoclonal (6D12) as well as a polyclonal anti-AGE antibody and proposed the presence of a common AGE structure(s) that may act as a major immunochemical epitope [Horiuchi, S., Araki, N., & Morino, Y. (1991) J. Biol. Chem. 266, 7329-7332]. The purpose of the present study was to determine the major epitope. Amino acid analysis of AGE-proteins indicated that N(epsilon)-(carboxymethyl)lysine (CML) was a major modified lysine residue. Immunologic studies demonstrated the positive reaction of 6D12 not only to all CML-modified proteins tested, but also to BSA modified with several aldehydes known to generate a CML-protein adduct, and a linear correlation between the CML contents of CML-BSA and their immunoreactivity to 6D12 up to approximately 8 mol/mol of protein. Further experiments with CML analogs revealed that the epitope of 6D12 is a CML-protein adduct with an important carbonyl group. In contrast to 6D12, our polyclonal anti-AGE antibody showed a significant but much weaker immunoreactivity to CML-BSA, suggesting that the polyclonal antibody contains two populations, one reactive to CML (CML-PA) and the other unreactive to CML (Non-CML-PA). Non-CML-PA separated from CML-PA by CML-BSA affinity chromatography did not react with all CML-modified preparations, but retained its property to react commonly with AGE preparations obtained from proteins, lysine derivatives, and monoaminocarboxylic acids. Therefore, it is clear that a CML-protein adduct is a major immunological epitope in AGE structures, but there still exist other major epitope(s) expressed commonly in AGE-proteins.
 ...
PMID:N (epsilon)-(carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. 867 12

N(epsilon)-(Carboxymethyl)lysine (CML), a major product of oxidative modification of glycated proteins, has been suggested to represent a general marker of oxidative stress and long-term damage to proteins in aging, atherosclerosis, and diabetes. To investigate the occurrence and distribution of CML in humans an antiserum specifically recognizing protein-bound CML was generated. The oxidative formation of CML from glycated proteins was reduced by lipoic acid, aminoguanidine, superoxide dismutase, catalase, and particularly vitamin E and desferrioxamine. Immunolocalization of CML in skin, lung, heart, kidney, intestine, intervertebral discs, and particularly in arteries provided evidence for an age-dependent increase in CML accumulation in distinct locations, and acceleration of this process in diabetes. Intense staining of the arterial wall and particularly the elastic membrane was found. High levels of CML modification were observed within atherosclerotic plaques and in foam cells. The preferential location of CML immunoreactivity in lesions may indicate the contribution of glycoxidation to the processes occurring in diabetes and aging. Additionally, we found increased CML content in serum proteins in diabetic patients. The strong dependence of CML formation on oxidative conditions together with the increased occurrence of CML in diabetic serum and tissue proteins suggest a role for CML as endogenous biomarker for oxidative damage.
 ...
PMID:Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. 902 79

The amount of advanced glycation end-products (AGE) in tissue proteins increases in diabetes mellitus, and the concentration of a subclass of AGEs, known as glycoxidation products, also increases with chronological age in proteins. The rate of accumulation of glycoxidation products is accelerated in diabetes and age-adjusted concentrations of two glycoxidation products, N epsilon-(carboxymethyl)lysine (CML) and pentosidine, correlate with the severity of complication in diabetic patients. Although AGEs and glycoxidation products are implicated in the development of diabetic complications, these compounds are present at only trace concentrations in tissue proteins and account for only a fraction of the chemical modifications in AGE proteins prepared in vitro. The future of the AGE hypothesis depends on the chemical characterization of a significant fraction of the total AGEs in tissue proteins, a quantitative assessment of their effects on protein structure and function, and an assessment of their role as mediators of biological responses. In this manuscript we describe recent work leading to characterization of new AGEs and glycoxidation products. These compounds include: (1) the imidazolone adduct formed by reaction of 3-deoxyglucosone with arginine residues in protein; (2) N epsilon-(carboxyethyl)lysine, an analogue of CML formed on reaction of methylglyoxal with lysine; (3) glyoxal-lysine dimer; and (4) methyl-glyoxal-lysine dimer, which are imidazolium crosslinks formed by reaction of glyoxal or methylglyoxal with lysine residues in protein. The presence of 3-deoxyglucosone, methylglyoxal and glyoxal in vivo and the formation of the above AGEs in model carbonyl-amine reaction systems suggests that these AGEs are also formed in vivo and contribute to tissue damage resulting from the Maillard reaction.
 ...
PMID:New biomarkers of Maillard reaction damage to proteins. 904 6

Oxidative stress is implicated in the pathogenesis of numerous disease processes including diabetes mellitus, atherosclerosis, ischaemia reperfusion injury and rheumatoid arthritis. Chemical modification of amino acids in protein during lipid peroxidation results in the formation of lipoxidation products which may serve as indicators of oxidative stress in vivo. The focus of the studies described here was initially to identify chemical modifications of protein derived exclusively from lipids in order to assess the role of lipid peroxidative damage in the pathogenesis of disease. Malondialdehye (MDA) and 4-hydroxynonenal (HNE) are well characterized oxidation products of polyunsaturated fatty acids on low-density lipoprotein (LDL) and adducts of these compounds have been detected by immunological means in atherosclerotic plaque. Thus, we first developed gas chromatography-mass spectrometry assays for the Schiff base adduct of MDA to lysine, the lysine-MDA-lysine diimine cross-link and the Michael addition product of HNE to lysine. Using these assays, we showed that the concentrations of all three compounds increased significantly in LDL during metal-catalysed oxidation in vitro. The concentration of the advanced glycation end-product N epsilon-(carboxymethyl)lysine (CML) also increased during LDL oxidation, while that of its putative carbohydrate precursor the Amadori compound N epsilon-(1-deoxyfructose-1-yl)lysine did not change, demonstrating that CML is a marker of both glycoxidation and lipoxidation reactions. These results suggest that MDA and HNE adducts to lysine residues should serve as biomarkers of lipid modification resulting from lipid peroxidation reactions, while CML may serve as a biomarker of general oxidative stress resulting from both carbohydrate and lipid oxidation reactions.
 ...
PMID:Lipoxidation products as biomarkers of oxidative damage to proteins during lipid peroxidation reactions. 904 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>