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)

Erythrocytes are the most abundant cells in blood and carry out the vital function of oxygen transport. These cells lack nuclei and do not synthesise new proteins. Their cellular responses are modulated entirely by post-translational modifications in existing proteins. Phosphorylation mediated by protein kinase C (PKC) plays a significant role in red cell physiology. To date PKC alpha and zeta are the only isoforms reported to be expressed in erythrocytes. Upon activation they influence cytoskeletal integrity and erythrocyte functions. In this study we report for the first time the presence of PKC iota and PKC mu in addition to PKC alpha and zeta in human erythrocytes. All isoforms were present only in the cytosolic fraction. PKC alpha was the only isoform that translocated to the membrane upon stimulation with phorbol myristate acetate (PMA). It could thus mediate several of the reported PMA-regulated membrane modifications. Investigations on alterations in PMA-mediated phosphorylation of erythrocyte skeletal components in disorders such as chronic myeloid leukaemia can now focus on PKC alpha, which is the only isoform in erythrocytes, which translocates to the membrane on stimulation of the cells.
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PMID:Protein kinase C isoforms in human erythrocytes. 1166 2

The accumulation of advanced glycation end products (AGEs) in the tissue and serum of subjects with diabetes has been linked to the pathogenesis of vascular complications. Because diabetes may be also complicated by increased susceptibility to recurrent infection, we investigated the effects of AGEs on human neutrophils, because their burst of activity immediately upon engagement of pathogens or other inflammatory triggers is critical to host response. We demonstrate the presence of receptor for advanced glycation end products (RAGE) at the message and protein levels. We also demonstrate that AGE albumin (but not control albumin) binds with high affinity to human neutrophils (K(d) of 3.7 +/- 0.4 nM). The binding was blocked almost completely by excess soluble RAGE, anti-RAGE antibodies, or antibodies to CML-modified albumin. AGE albumin induced a dose-dependent increase in intracellular-free calcium as well as actin polymerization. Further, AGE albumin inhibited transendothelial migration and Staphylococcus aureus-induced but not fMLP-induced production of reactive oxygen metabolite. Moreover, although AGE albumin enhanced neutrophil phagocytosis of S. aureus, it inhibited bacterial killing. We conclude that functional RAGE is present on the plasma membrane of human neutrophils and is linked to Ca(2)(+) and actin polymerization, and engagement of RAGE impairs neutrophil functions.
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PMID:RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs). 1186 81

Advanced glycation end products (AGEs) are believed to play an important role in the development of angiopathy in diabetes mellitus. Previous reports suggested a correlation between accumulation of AGEs and production of vascular endothelial growth factor (VEGF) in human diabetic retina. However, the mechanisms involved were not revealed. In this study, we investigated the transcriptional regulation of the expression of vascular endothelial growth factor (VEGF) by AGEs, and possible involvement of reactive oxygen species (ROS) in the induction. We employed an AGE of bovine serum albumin (BSA) prepared by an incubation of BSA with D-glucose for 40 weeks and N(epsilon)-(carboxymethyl)lysine (CML), a major AGE. The expression of VEGF was induced by CML-BSA in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the DNA-binding activity of activator protein-1 (AP-1). Promoter assay showed that the induction of VEGF was dependent on AP-1. The activity of Ras/Raf-1/MEK/ERK1/2 was involved in the CML-BSA-stimulated signaling pathways to activate the AP-1 transcription with a peak at 1 h. AGE-BSA also induced VEGF mediated by AP-1, however, there was a difference of effect between AGE-BSA and CML-BSA in the activation of AP-1. AGE-BSA-stimulated AP-1 activity showed a peak at 5 h, which paralleled the formation of ROS. Reduction of AGE-BSA with NaBH(4) or addition of vitamin E attenuated the AGE-BSA-stimulated signaling pathways leading to the same pattern as for CML-BSA-stimulated signals. These results suggest an important role for AGEs in stimulation of the development of angiogenesis observed in diabetic complications, and that ROS accelerates the AGE-stimulated VEGF expression.
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PMID:Reactive oxygen species accelerate production of vascular endothelial growth factor by advanced glycation end products in RAW264.7 mouse macrophages. 1193 95

Iron-storage diseases are believed to cause organ damage through generation of reactive oxygen species. Using a murine model of iron overload, we found that hepatic iron stores increased logarithmically during 3 weeks of chronic intraperitoneal administration of iron dextran, while hepatic glutathione peroxidase activity declined linearly by approximately 50% during the same period. Plasma concentrations of aliphatic aldehydes increased by 2- to 3-fold, and plasma malondialdehyde (MDA) by 6-fold. Modification of total liver protein by products of lipid peroxidation, including MDA-lysine, 4-hydroxynonenal-lysine, and N(epsilon)-(carboxymethyl)lysine (CML), increased by approximately 3-fold, while levels of the protein oxidation marker, methionine sulfoxide (MetSO), were unchanged. Skin collagen was resistant to modification until the third week, when 2- to 3-fold increases in both CML and MetSO were observed. Our results document that iron overload increases lipid peroxidation, with concomitant increases in reactive aldehydes in plasma and chemical modification of tissue proteins. CML was a sensitive indicator of hepatocellular oxidative stress, compared to MetSO, while extensive modification of extracellular skin collagen was not observed until the late stages of iron overload and oxidative stress. These observations provide direct evidence for the contribution of reactive oxygen species, lipid peroxidation, and reactive carbonyl intermediates to the pathogenesis of iron-overload diseases.
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PMID:Lipid peroxidation and protein modification in a mouse model of chronic iron overload. 1197

The present investigation studies the effect of aging, short-term and long-term caloric restriction on four different markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins: protein carbonyls (measured by ELISA); Nepsilon-(carboxyethyl)lysine (CEL), Nepsilon-(carboxymethyl)lysine (CML), and Nepsilon-(malondialdehyde)lysine (MDA-lys) measured by gas chromatography/mass spectrometry. Aging increased the steady state level of CML in rat heart mitochondria without changing the levels of the other three markers of protein damage. Short-term caloric restriction (six weeks) did not change any of the parameters measured. However, long-term (one year) caloric restriction decreased CEL and MDA-lys in heart mitochondria and did not change protein carbonyls and CML levels. The decrease in MDA-lys was not due to changes in the sensitivity of mitochondrial lipids to peroxidation since the measurements of the fatty acid composition showed that the total number of fatty acid double bonds was not changed by caloric restriction. The decrease in CEL and MDA-lys in caloric restriction agrees with the previously and consistently described finding that caloric restriction agrees with the previously and consistently described finding that caloric restriction lowers the rate of generation of reactive oxygen species (ROS) in rodent heart mitochondria, although in the case of CEL a caloric restriction-induced lowering of glycaemia can also be involved. The CEL and MDA-lys results support the notion that caloric restriction decreases oxidative stress-derived damage to heart mitochondrial proteins.
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PMID:Aging increases Nepsilon-(carboxymethyl)lysine and caloric restriction decreases Nepsilon-(carboxyethyl)lysine and Nepsilon-(malondialdehyde)lysine in rat heart mitochondrial proteins. 1199 2

In this investigation the effect of 4 months of 40% restriction of calories on defined markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins was studied. The protein markers assessed were N(epsilon)-(carboxyethyl)lysine (CEL), N(epsilon)-(carboxymethyl)lysine (CML), N(epsilon)-(malondialdehyde)lysine (MDA-lys), and the recently described (PNAS 98:69-74, 2001) main constituents of protein carbonyls glutamic and aminoadipic semialdehydes. All these markers were measured by gas chromatography/mass spectrometry. The results showed that glutamic semialdehyde was present in rat heart mitochondria at levels 20-fold higher than aminoadipic semialdehyde. After 4 months of caloric restriction, the levels of CEL, CML, MDA-lys and glutamic semialdehyde were significantly lower in the mitochondria from caloric restricted animals than in the controls. These decreases were not due to a lower degree of oxidative attack to mitochondrial proteins, since the rate of mitochondrial oxygen radical generation was not modified by 4 months of caloric restriction. The decreases in MDA-lys and CML were not due either to changes in the sensitivity of mitochondrial lipids to peroxidation since measurements of the fatty acid composition showed that the total number of fatty acid double bonds and the peroxidizability index were not changed by caloric restriction. The results globally indicate that caloric restriction during 4 months decreases oxidative stress-derived damage to heart mitochondrial proteins. They also suggest that these decreases are due to an increase in the capacity of the restricted mitochondria to decompose oxidatively modified proteins.
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PMID:Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls. 1242 50

Reactive carbonyl species (RCS) are potent mediators of cellular carbonyl stress originating from endogenous chemical processes such as lipid peroxidation and glycation. Skin deterioration as observed in photoaging and diabetes has been linked to accumulative protein damage from glycation, but the effects of carbonyl stress on skin cell genomic integrity are ill defined. In this study, the genotoxic effects of acute carbonyl stress on HaCaT keratinocytes and CF3 fibroblasts were assessed. Administration of the alpha-dicarbonyl compounds glyoxal and methylglyoxal as physiologically relevant RCS inhibited skin cell proliferation, led to intra-cellular protein glycation as evidenced by the accumulation of N(epsilon)-(carboxymethyl)-L-lysine (CML) in histones, and caused extensive DNA strand cleavage as assessed by the comet assay. These effects were prevented by treatment with the carbonyl scavenger D-penicillamine. Both glyoxal and methylglyoxal damaged DNA in intact cells. Glyoxal caused DNA strand breaks while methylglyoxal produced extensive DNA-protein cross-linking as evidenced by pronounced nuclear condensation and total suppression of comet formation. Glycation by glyoxal and methylglyoxal resulted in histone cross-linking in vitro and induced oxygen-dependent cleavage of plasmid DNA, which was partly suppressed by the hydroxyl scavenger mannitol. We suggest that a chemical mechanism of cellular DNA damage by carbonyl stress occurs in which histone glycoxidation is followed by reactive oxygen induced DNA stand breaks. The genotoxic potential of RCS in cultured skin cells and its suppression by a carbonyl scavenger as described in this study have implications for skin damage and carcinogenesis and its prevention by agents selective for carbonyl stress.
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PMID:DNA damage by carbonyl stress in human skin cells. 1251 11

Normal aerobic metabolism is associated with the production of reactive oxygen species (ROS) and, consequently, the induction of apoptosis and necrosis. The cell death response to oxidative stress is thought to contribute to aging, neurological degeneration, and other disorders. ROS-induced apoptosis and necrosis involves activation of the cytoplasmic c-Abl tyrosine kinase and thereby signaling to mitochondria. Herein, we show that STI571, an inhibitor of Bcr-Abl in chronic myelogenous leukemia, blocks activation of c-Abl in the response of mouse embryo fibroblasts and human U-937 myeloid leukemia cells to hydrogen peroxide (H(2)O(2)). Immunofluorescence microscopy and subcellular fractionation studies demonstrate that STI571 decreases H(2)O(2)-induced targeting of c-Abl to mitochondria in the two cell types by 59 to 85%. The results also show that STI571 attenuates H(2)O(2)-induced loss of the mitochondrial transmembrane potential. In concert with these effects, STI571 inhibits the death response to H(2)O(2) exposure by 40 to 80% depending on the cell type. These findings indicate that inhibition of c-Abl signaling by STI571 attenuates mitochondrial dysfunction and cell death in the cellular response to oxidative stress.
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PMID:Abrogation of the cell death response to oxidative stress by the c-Abl tyrosine kinase inhibitor STI571. 1252 98

Aging is accompanied by a gradual deterioration of cell functions. Mitochondrial dysfunction and accumulation of protein damage have been proposed to contribute to this process. The present study was carried out to examine the effects of aging in mitochondrial matrix isolated from rat liver. The activity of Lon protease, an enzyme implicated in the degradation of abnormal matrix proteins, was measured and the accumulation of oxidation and glycoxidation (Nepsilon-carboxymethyllysine, CML) products was monitored using immunochemical assays. The function of isolated mitochondria was assessed by measuring respiratory chain activity. Mitochondria from aged (27 months) rats exhibited the same rate of oxygen consumption as those from adult (10 months) rats without any change in coupling efficiency. At the same time, the ATP-stimulated Lon protease activity, measured as fluorescent peptides released, markedly decreased from 10-month-old rats (1.15 +/- 0.15 FU x micro g protein-1 x h-1) to 27-month-old-rats (0.59 +/- 0.08 FU x micro g protein-1 x h-1). In parallel with this decrease in activity, oxidized proteins accumulated in the matrix upon aging while the CML-modified protein content assessed by ELISA significantly increased by 52% from 10 months (11.71 +/- 0.61 pmol CML x micro g protein-1) to 27 months (17.81 +/- 1.83 pmol CML x micro g protein-1). These results indicate that the accumulation of deleterious oxidized and carboxymethylated proteins in the matrix concomitant with loss of the Lon protease activity may affect the ability of aging mitochondria to respond to additional stress.
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PMID:Changes in rat liver mitochondria with aging. Lon protease-like reactivity and N(epsilon)-carboxymethyllysine accumulation in the matrix. 1275 49

The transcription factor Bach2, a member of the CNC family of proteins, binds to the Maf recognition element (MARE) by forming homodimers or dimerizing with small Maf transcription factors. Bach2-expressing cells show reduced proliferation and undergo spontaneous cell death. The inhibition of BCR/ABL tyrosine kinase activity by STI571 in chronic myeloid leukemia (CML) cell lines and CD34+ cells from patients with CML in lymphoid crisis results in induction of BACH2 expression. We show here that BACH2 modifies the in vitro cytotoxicity of anticancer drugs. The cytotoxic effects of commonly used anticancer agents were studied by overexpression of BACH2 in RAJI lymphoid cells, a cell line that does not express endogenous BACH2. Cell growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Clones overexpressing BACH2 were more sensitive to etoposide, doxorubicin, and cytarabine than control RAJI cells, whereas there were no significant differences in the sensitivity of either cells to methotrexate or vincristine. Interestingly, we found that the former drugs were oxidative stressors that induced the nuclear accumulation of BACH2. In contrast, methotrexate or vincristine did not induce production of intracellular reactive oxygen species (ROS) and nuclear accumulation of BACH2. These results, coupled with our previous data showing that BACH2 promotes oxidative stress-induced cell death, suggest that combination chemotherapy involving STI571 and anticancer drugs that produce ROS may be of benefit in the treatment of Philadelphia chromosome 1 (Ph1)-positive leukemia.
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PMID:B-cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs. 1282 6


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