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)

High-oleic peanuts are known for a high content of oleic fatty acid. However, it is not known whether high-oleic peanuts are different from normal chemistry peanuts in levels of allergenicity and end-product adducts (i.e., products cross-linked with proteins). For this purpose, four different peanut cultivars (Florunner, Georgia Green, NC 9, and NC 2) were evaluated and compared with high-oleic peanuts (SunOleic 97R). Adducts such as AGE/CML from Maillard reactions and MDA/HNE from lipid oxidation were determined, respectively, in ELISA, using polyclonal antibodies. Allergenicity was determined based on IgE binding and T-cell proliferation. Results showed that raw high-oleic peanuts were not different from normal peanuts in adduct levels. After roasting, CML and HNE levels remained unchanged, but an increased and similar amounts of AGE adducts were found in all peanuts. MDA also increased but not in high-oleic peanuts. This suggests that high-oleic peanuts are more stable to lipid oxidation than others during heating. Despite this, high-oleic peanuts did not differ from normal peanuts in IgE binding and T-cell proliferation. It was concluded that a high content of oleic fatty acid has no effect on peanut allergenicity and that high-oleic peanuts do not give a higher or lower risk of allergy than normal peanuts.
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PMID:High-oleic peanuts are not different from normal peanuts in allergenic properties. 1182 61

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

Hyperglycemia increases oxidative stress in various tissues and leads to diabetic cardiovascular complication. Dyslipidemia, such as an increase in oxidized low-density lipoprotein (LDL), is well recognized in diabetic patients with hyperglycemia. However, the mechanism by which hyperglycemia causes the increased LDL oxidation remains unclear. Albumin is the most abundant protein in the circulation, and can function as an antioxidant. Therefore, we examined whether glycoxidative modification inhibits the antioxidant activity of albumin to LDL oxidation and clarified the mechanism by which this modification may suppress its antioxidant activity. Human serum albumin (HSA) was incubated in phosphate-buffered saline with and without glucose at 37 degrees C for up to 8 weeks under aerobic conditions (referred to as glycoxidation (goHSA) and oxidation (oHSA), respectively). Metal chelator-treated, nonoxidative HSA (chHSA) and freshly prepared HSA (fHSA) were used as controls. N(epsilon)-(carboxymethyl)lysine (CML), a glycoxidative product, was determined by enzyme-linked immunosorbent assay. Oxidation was estimated by measuring the thiols of the HSA molecule. Copper-mediated oxidation of LDL was conducted in the presence or absence of modified HSAs at 37 degrees C for 6 days. Malondialdehyde and negative charge of LDL were measured. To clarify the mechanism of reduced antioxidant activity of HSA, we examined firstly the binding activity of modified HSAs to copper, and secondly the effects of free radical scavengers on the formation of malondialdehyde. CML was formed in goHSA in a time- and concentration-dependent manner. Both goHSA and oHSA significantly decreased the contents of free thiol groups compared to ch- and fHSAs. The antioxidant activity of goHSA to LDL oxidation was the lowest among various modified HSAs. The oHSA showed a moderate decrease in antioxidant activity. The binding activity of go- and oHSAs to copper was lower than that of ch- and fHSAs. The formation of MDA from LDL oxidation in the presence of goHSA was completely inhibited by Tiron (1,2-dihydroxy-3,5-benzenedisulfonic acid) and superoxide dismutase. In contrast, catalase and mannitol had no effect. Our results indicate that in vitro glycoxidation of HSA induced a marked loss of antioxidant activity of this molecule to copper-mediated oxidation of LDL, which may be caused by the generation of superoxide.
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PMID:Contribution of superoxide to reduced antioxidant activity of glycoxidative serum albumin. 1243 98

Humans and laboratory animals recognize human modified LDL as immunogenic. Immune complexes (ICs) isolated from human sera contain malondialdehyde-modified LDL (MDA-LDL) and N (epsilon)(carboxymethyl)lysine-modified LDL (CML-LDL) as well as antibodies reacting with MDA-LDL, copper-oxidized LDL (OxLDL), CML-LDL, and advanced glycosylation end product (AGE)-modified LDL. OxLDL and AGE-LDL antibodies isolated from human sera recognize the same LDL modifications and do not react with modified non-LDL proteins. Rabbit antibodies have different reactivity patterns: MDA-LDL antibodies react strongly with MDA-LDL and MDA-BSA but weakly with OxLDL; OxLDL antibodies react strongly with OxLDL and weakly with MDA-LDL; CML-LDL antibodies react with CML-LDL > CML-BSA > AGE-LDL > OxLDL; AGE-LDL antibodies react strongly with AGE-LDL, react weakly with OxLDL, and do not react with CML-LDL. Thus, human and rabbit antibodies seem to recognize different epitopes. Capture assays carried out with all rabbit antibodies showed binding of apolipoprotein B-rich lipoproteins isolated from ICs, suggesting that laboratory-generated epitopes are expressed by in vivo-modified LDL, although they are not necessarily recognized by the human immune system. Thus, the definition of immunogenic forms of modified LDL eliciting human autoimmune responses requires the isolation and characterization of autoantibodies and modified LDL from human samples, whereas rabbit antibodies can be used to detect in vivo-modified human LDL.
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PMID:Definition of the immunogenic forms of modified human LDL recognized by human autoantibodies and by rabbit hyperimmune antibodies. 1525 97

STI571, a specific tyrosine kinase inhibitor, exhibits a substantial therapeutic activity in patients with chronic myeloid leukaemia and gastrointestinal stromal tumors. In this study we examined the activity of STI571 on the growth and invasiveness of three human epithelial breast cancer cell lines of low (MCF-7) and high (ZR-75-1 and MDA-MB-231) invasive potential. Growth of all cell lines in serum-containing medium was significantly inhibited by STI571 in a dose-dependent manner, with an average IC50 of approximately 5-6 microM. Flow cytometric analysis revealed that this effect is characterized by an accumulation of all breast cancer cell types tested in the G2/M-phase of the cell cycle with a concomitant decrease of the percentage of cells in the S-phase. Interestingly, no increase in apoptosis was observed, indicating that the effect of this kinase inhibitor is cytostatic rather than cytotoxic. In addition, STI571 exerts a significant inhibition effect on the invasion of the highly invasive breast cancer cell lines ZR-75-1 and MDA-MB-231. These results encourage further preclinical investigations on the mechanisms underlying the inhibitory effects of STI571, which may be of great value in breast cancer treatment.
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PMID:STI571 as a potent inhibitor of growth and invasiveness of human epithelial breast cancer cells. 1527 8

The effective microorganism (EM-X) fermentation extract is derived from rice bran and seaweed extract. It has been shown to possess anti-oxidation activity both in vitro and in vivo. To our knowledge, the possible in vitro anti-cancer potential of EM-X has not been demonstrated. Here we showed that the double concentrate of EM-X (EM-X2) at concentrations of 20-30% by volume, had growth inhibitory activity on MDA-MB231 breast cancer cell line and K-562 chronic myelogenous leukaemia cell lines by [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2-H-tetrazolium, inner salt] (MTS) assay. No characteristic features of apoptosis could be observed morphologically. Colony formation assay illustrated that both MDA-MB231 breast cancer and K-562 CML cells lost part of their regeneration potential after treatment with EM-X2 at 30% concentration by volume for 24 h. At these concentrations, only slight growth inhibitory effect was observed in 293 human kidney fibroblast cells and in three non-malignant bone marrows. Intracellular nitro blue tetrazolium (NBT) reduction assay showed that both MDA-MB231 breast cancer and K-562 CML cells had about 30% reduction of intracellular NBT after incubation with 30% of EM-X2. Increased activity of superoxide dismutase (SOD) could be detected from both MDA-MB231 and K-562 cell lines after incubating with 30% of EM-X2. Taken together, our data suggested that EM-X could inhibit growth and reduce the regeneration potential of cancer cells, possibly through its antioxidation activity.
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PMID:Growth inhibitory potential of effective microorganism fermentation extract (EM-X) on cancer cells. 1549 67

BAY 43-9006, a multikinase inhibitor that targets Raf, prevents tumor cell proliferation in vitro and inhibits diverse human tumor xenografts in vivo. The mechanism of action of BAY 43-9006 remains incompletely defined. In the present study, the effects of BAY 43-9006 on the antiapoptotic Bcl-2 family member Mcl-1 were examined. Treatment of A549 lung cancer cells with BAY 43-9006 diminished Mcl-1 levels in a time- and dose-dependent manner without affecting other Bcl-2 family members. Similar BAY 43-9006-induced Mcl-1 downregulation was observed in ACHN (renal cell), HT-29 (colon), MDA-MB-231 (breast), KMCH (cholangiocarcinoma), Jurkat (acute T-cell leukemia), K562 (chronic myelogenous leukemia) and MEC-2 (chronic lymphocytic leukemia) cells. Mcl-1 mRNA levels did not change in BAY 43-9006-treated cells. Instead, BAY 43-9006 enhanced proteasome-mediated Mcl-1 degradation. This Mcl-1 downregulation was followed by mitochondrial cytochrome c release and caspase activation as well as enhanced sensitivity to other proapoptotic agents. The caspase inhibitor Boc-D-fmk inhibited BAY 43-9006-induced caspase activation but not cytochrome c release. In contrast, Mcl-1 overexpression inhibited cytochrome c release and other features of BAY 43-9006-induced apoptosis. Conversely, Mcl-1 downregulation by short hairpin RNA enhanced BAY 43-9006-induced apoptosis. Collectively, these findings demonstrate that drug-induced Mcl-1 downregulation contributes to the proapoptotic effects of BAY 43-9006.
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PMID:The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. 1600 48

This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted.
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PMID:Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. 1698 72

FB2 is a novel Abl/Src dual tyrosine kinase inhibitor which is designed to overcome imatinib resistance. Besides imatinib-sensitive cell lines (K562), FB2 significantly inhibited the growth of imatinib-resistant cell lines of different resistance mechanisms (K562/G5.0 and K562/G01), and decreased the expression of autophosphorylation of Bcr/Abl, c-Src and Lyn kinases on them. It also inhibited the proliferation of Src over activated cells DU145 and MDA-MB-231. Furthermore, FB2 potently prolonged the survival time of non-obese diabetic/severe combined immunodeficient mice harboured K562/G5.0 cells. These results indicated that FB2, an Abl/Src dual tyrosine kinase inhibitor, is a promising candidate for imatinib-resistant CML and Src over activated cancer.
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PMID:Activity of FB2, a novel dual Abl/Src tyrosine kinase inhibitor, against imatinib-resistant chronic myeloid leukemia in vivo and in vitro. 1934 30


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