Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the significance of EPH-gestosis, the author measured the blood levels of lipid peroxides, vitamin E, thromboxane B2, and 6-Keto-prostaglandin F1 alpha. The basis for this was presence of lipid metabolism abnormalities in this disease. 1. The serum lipid peroxides level. In severe cases of EPH-gestosis, a significant increase was observed compared with normal pregnant women in the 10th month of gestation. 2. The serum V-E level. In severe cases of EPH-gestosis, there was a tendency to decrease compared with the values for the late stage of pregnancy. 3. The serum TXB2 level. In severe cases of EPH-gestosis, a significant increase was observed compared with normal pregnant women in the 10th month of gestation. 4. The serum 6-Keto-PGF1 alpha level. In severe cases of EPH-gestosis, a significant decrease was observed compared with normal pregnant women in the 10th month of gestation. 5. Relationship to the gestosis index (G-I). a. Elevation of the lipid peroxide level was noted in cases with a G.I. of 5 or higher. b. The V-E level tended to drop in cases with a G.I. of 4 or higher. c. There was a significant difference between the TXB2 levels at G.I.-3 and G.I.-4. d. The level of 6-Keto-PGF1 alpha dropped as the G.I. increased in cases with a G.I. of 4 or higher.
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PMID:Etiology of EPH-gestosis from the viewpoint of dynamics of vasoactive prostanoid, lipid peroxides and vitamin E. 668 85

The present study was undertaken in order to determine the changes in blood levels of lipid peroxide and vitamin E in EPH gestosis. The mean plasma level of lipid peroxide was 0.89 +/- 0.13 nmol/ml for nonpregnant women, while for normal pregnant women it was 2.51 +/- 0.52 nmol/ml, and 4.10 +/- 0.72 nmol/ml for women with EPH gestosis. The mean plasma level of vitamin E was 6.7 +/- 1.0 micrograms/ml for nonpregnant women, while for normal pregnant women it was 14.5 +/- 2.2 micrograms/ml and 12.6 +/- 1.2 micrograms/ml for women with gestosis. The mean red cell level of vitamin E was 3.55 +/- 0.25 micrograms/ml packed red cells in nonpregnant women, while in normal pregnant women it was 2.56 +/- 0.34 micrograms/ml packed cells and 2.90 +/- 0.28 micrograms/ml packed cells for women with EPH gestosis. The mean platelet level of vitamin E was 99 +/- 25 micrograms/g protein for nonpregnant women, while in normal pregnant women it was 232 +/- 24 micrograms/ml protein and 205 +/- 32 micrograms/g protein for women with EPH gestosis. It was shown in this study that in EPH gestosis the plasma level of lipid peroxide increased while the levels of vitamin E which inhibited the formation of lipid peroxide decreased in plasma, red cells and platelets.
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PMID:Changes in blood level of lipid peroxide and vitamin E during pregnancy: clinical significance and relation to the pathogenesis of EPH gestosis. 800 70

Exposure of human keratinocytes to UVA radiation induced an increase in ceramide (CER) intracellular content, with a dose-dependent effect within the range of 4-9 J/cm(2). The production of CER reached a maximum 2 h after UVA irradiation. The increase of CER was proportional to the intracellular content of reactive oxygen species, was prevented by the antioxidant vitamin E, and enhanced by the prooxidant buthionine-sulfoximine, suggesting the involvement of an oxidative stress. UVA decreased both neutral and acid sphingomyelinase activities measured in vitro. A direct cleavage of sphingomyelin to CER by UVA, recently described, was not observed under our experimental conditions. We also show that, downstream of CER, UVA activated the Ser/Thr kinases ERK, JNK, and p38. Since ceramide has been shown to play a role in stress kinase activation, our results provide a possible mechanism for UVA-induced activation of stress kinases via ceramide formation. However, the actual mechanisms whereby CER is produced in cultured cells under UVA exposure remain to be specified.
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PMID:UVA radiation stimulates ceramide production: relationship to oxidative stress and potential role in ERK, JNK, and p38 activation. 1118 Oct 43

RRR-alpha-tocopherol succinate (vitamin E succinate, VES) is a potent, selective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell culture and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK), but not p38, are critical mediators in VES-induced apoptosis of human breast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ERK1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of the substrate glutathione S-transferase-c-Jun and inhibited VES-induced apoptosis. Increased phosphorylation and transactivation activity of nuclear transcription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatments; however, only c-Jun and ATF-2 appear to be involved in VES-induced apoptosis based on antisense blockage experiments. Collectively, these results imply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.
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PMID:Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. 1152 56

Oral administration of rats to L-2-chloropropionate (L-CPA) causes selective necrosis to the granule cell layer of the cerebellum in vivo and to cultured rat cerebellar granule cells in vitro. The present study was conducted to characterize the involvement of reactive oxygen species (ROS) in cell death of L-CPA to rat cerebellar granule cells in vitro. Exposure to L-CPA (0.625-10 mM) produced a concentration dependent increase in formation of 2,7-dichlorofluorescein (DCF) as a measure of formation of ROS. The elevation of ROS was inhibited after incubation of the cells with the ERK-type of MAP kinases inhibitor U0126, the mitochondrial permeability transition pore inhibitor cyclosporin A (CSA), the antioxidant vitamin E, and the spin trap N-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN). Measurements of nitrite (NO(2)) in the cell culture supernatant using the Griess reagent indicate generation of nitric oxide (NO) after exposure to L-CPA. Incubation with L-CPA (10 mM) for 48 hr lead to cell death (90%). When the granule cells were incubated with L-CPA in combination with the inhibitors of free radical production, the cell death was ameliorated. The results show that L-CPA is toxic to granular cells by production of ROS.
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PMID:Toxic effect of L-2-chloropropionate on cultured rat cerebellar granule cells is ameliorated after inhibition of reactive oxygen species formation. 1174 28

In this study, six common tests for measuring antioxidant activity were evaluated by comparing four antioxidants and applying them to beverages (tea and juices): Trolox equivalent antioxidant capacity assay (TEAC I-III assay), Total radical-trapping antioxidant parameter assay (TRAP assay), 2,2-diphenyl-l-picrylhydrazyl assay (DPPH assay), N,N-dimethyl-p-phenylendiamine assay (DMPD assay), Photochemiluminescence assay (PCL assay) and Ferric reducing ability of plasma assay (FRAP assay). The antioxidants included gallic acid representing the group of polyphenols, uric acid as the main antioxidant in human plasma, ascorbic acid as a vitamin widely spread in fruits and Trolox as water soluble vitamin E analogue. The six methods presented can be divided into two groups depending on the oxidising reagent. Five methods use organic radical producers (TEAC I-III, TRAP, DPPH, DMPD, PCL) and one method works with metal ions for oxidation (FRAP). Another difference between these tests is the reaction procedure. Three assays use the delay in oxidation and determine the lag phase as parameter for the antioxidant activity (TEAC I, TRAP, PCL). They determine the delay of radical generation as well as the ability to scavenge the radical. In contrast, the assays TEAC II and III, DPPH, DMPD and FRAP analyse the ability to reduce the radical cation (TEAC II and III, DPPH, DMPD) or the ferric ion (FRAP). The three tests acting by radical reduction use preformed radicals and determine the decrease in absorbance while the FRAP assay measures the formed ferrous ions by increased absorbance. Gallic acid was the strongest antioxidant in all tests with exception of the DMPD assay. In contrast, uric acid and ascorbic acid showed low activity in some assays. Most of the assays determine the antioxidant activity in the micromolar range needing minutes to hours. Only one assay (PCL) is able to analyse the antioxidant activity in the nanomolar range. Black currant juice showed highest antioxidant activity in all tests compared to tea, apple juice and tomato juice. Despite these differences, results of these in vitro assays give an idea of the protective efficacy of secondary plant products. It is strongly recommended to use at least two methods due to the differences between the test systems investigated.
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PMID:Assessment of antioxidant activity by using different in vitro methods. 1199 86

We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a specific cellular stress response program, including sustained activation of the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK. Aplidin-induced apoptosis was only partially blocked by the general caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone and was also sensitive to AG1478 (an EGFR inhibitor), PP2 (an Src inhibitor), and SB203580 (an inhibitor of JNK and p38 MAPK) in MDA-MB-231 cells. Supporting a role for EGFR in Aplidin action, EGFR-deficient mouse embryo fibroblasts underwent apoptosis upon treatment more slowly than wild-type EGFR fibroblasts and also showed delayed JNK and reduced p38 MAPK activation. N-Acetylcysteine and ebselen (but not other antioxidants such as diphenyleneiodonium, Tiron, catalase, ascorbic acid, and vitamin E) reduced EGFR activation by Aplidin. N-Acetylcysteine and PP2 also partially inhibited JNK and p38 MAPK activation. The intracellular level of GSH affected Aplidin action; pretreatment of cells with GSH or N-acetylcysteine inhibited, whereas GSH depletion caused, hyperinduction of EGFR, Src, JNK, and p38 MAPK. Remarkably, Aplidin also induced apoptosis and activated EGFR, JNK, and p38 MAPK in two cell lines (A-498 and ACHN) derived from human renal cancer, a neoplasia that is highly refractory to chemotherapy. These data provide a molecular basis for the anticancer activity of Aplidin.
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PMID:Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. 1241 12

Increased lipid oxidative stress has been recently implicated in the pathogenesis of coronary artery spasm. Small, dense LDL with high susceptibility to oxidation may be linked to the genesis of coronary vasospasm. The relative migratory distance of the predominant densitometric peak of LDL from that of VLDL to that of HDL in a 3% polyacrylamide gel electrophoresis was determined as a measure of LDL particle size in 49 patients with coronary spastic angina (CSA), in 56 patients with stable effort angina and a significant coronary artery stenosis (SEA) and also in 40 control subjects without coronary artery disease (Control). The incidence of detection of small, dense LDL (particle diameter <25.5 nm) or a relative migratory distance above 0.36 was significantly higher in CSA (57%) and also in SEA (39%) than in Control (20%). In SEA, a significantly higher serum level of triglyceride was noted in the subgroup with the small, dense LDL as compared with the subgroup without. In contrast, in CSA, the serum level of triglyceride was not significantly different between the subgroups with and without the small, dense LDL, although significantly lower serum levels of both HDL-cholesterol and alpha-tocopherol were noted in the former. In 16 patients of CSA, the detection of the small, dense LDL was significantly decreased after a >6-month angina-free period (69-->31%). We conclude that patients with coronary spastic angina had smaller LDL particles, associated not with hypertriglyceridemia but low serum levels of both HDL-cholesterol and vitamin E. Dyslipidemia with small, dense LDL may be related to the genesis of coronary vasospasm.
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PMID:Low density lipoprotein particles are small in patients with coronary vasospasm. 1255 40

Chemical-induced oxidative stress to a cell can signal many cellular responses which include proliferation, differentiation, hemeostasis, apoptosis or necrosis. To better understand the underlying molecular mechanisms after exposure to chemicals, we investigated the signal transduction pathways, in particular the mitogen-activated protein kinase (MAPK) pathway and the ICE/Ced-3 protease (caspase) pathway, activated by different agents. Butylated hydroxyanisol (BHA) and its metabolite, t-butyl-hydroquinone (tBHQ), both are well known phenolic antioxidants used in food preservatives, strongly activated c-Jun N-terminal kinase 1 (JNK1) and/or extracellular signal-regulated protein kinase 2 (ERK2) in a dose- and time-dependent fashion. Pretreatment with free radical scavengers N-acetyl-L-cysteine (NAC), glutathione (GSH), or vitamin E, inhibited ERK2 activation and, to a much lesser extent, JNK 1 activation by BHA and tBHQ, implicating the role of oxidative stress. Under conditions where JNK1 and ERK2 were activated, BHA also activated transcription factors nuclear factor kappa B (NF-kappaB), activated-protein-1 (AP-1), and anti-oxidant response element (ARE), leading to induction of genes such as c-jun, and c-fos. At relatively high concentrations, BHA and tBHQ stimulated proteolytic activity of ICE/Ced3 cysteine proteases, and caused apoptosis, which was blocked by pretreatment with NAC. Further increase in concentrations lead to rapid cell death predominantly occurred via necrosis. Some naturally occurring phytochemicals, such as phenylethyl isothiocyanate (PEITC), green tea polyphenols (GTP), and sulfarophane, which have been shown to be potent inducers of Phase II enzymes, also differentially regulated the activities of JNK, ERK, or CPP-32, in a time- and dose-dependent manner. Our data, together with the work of others, enable us to propose a model in which low concentrations of these chemicals (e.g., BHA, PEITC) activate MAPKs leading to induction of gene expression (e.g., c-jun, c-fos, GSI) which may protect the cells against toxic insults and enhance cell survival. At relatively high concentrations, these agents activated both MAPKS, and the ICE/Ced-3 caspase pathway, leading to apoptosis. The exact mechanisms by which MAPK and caspases are activated by these agents are currently unknown, but may involve oxidative modification of glutathione (GSH) and/or protein thiols, and/or generation of secondary messengers, ceramide and calcium, which further activate downstream events. Taken together, our results suggest that chemicals including phenolic antioxidants activate MAPK pathways which may lead to the induction of genes producing protection and survival mechanisms, as well as the ICE/Ced-3 protease pathway, leading to apoptosis. The balancing amongst these pathways may dictate the fate of the cells upon exposure to chemicals.
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PMID:Differential activation of MAPK and ICE/Ced-3 protease in chemical-induced apoptosis. The role of oxidative stress in the regulation of mitogen-activated protein kinases (MAPKs) leading to gene expression and survival or activation of caspases leading to apoptosis. 1267 Dec 99

Ultraviolet irradiation of mammalian cells induces several events that include activation of growth factor receptors and triggering of signal transduction pathway. Most of the UV responses are mediated by the production of reactive oxygen species (ROS) and can be blocked by antioxidants. In this study, we analysed the effect of UVB irradiation at physiologic doses and that of the pro-oxidant agent cumene hydroperoxide (CUH) on the activation of the receptor for keratinocyte growth factor (KGF), a key mediator of epithelial growth and differentiation. Exposure to both UVB (30-150 mJ/cm(2)) and CUH (200 microM of NIH3T3 KGFR (KGF receptors) transfectants caused a rapid tyrosine phosphorylation and activation of KGFR similar to that induced by KGF, and internalization of the activated receptor. The KGFR expression appeared unmodified by the treatments. Ultrastructural observations of both UVB- and CUH-treated cells showed a normal morphology of the plasma membranes and intracellular organelles. The antioxidant N-acetylcysteine inhibited UVB-induced receptor phosphorylation. The generation of an intracellular oxidative stress was detected as a decrease of catalase activity and of vitamin E, and reduced glutathione levels, whereas superoxide dismutase activity was not significantly modified. A peroxidation of polyunsaturated fatty acids of cell membranes was observed after both treatments, associated with the intracellular oxidative stress. Similar biochemical events were observed on NIH3T3 untransfected control cells, suggesting that KGFR activation follows intracellular generation of ROS and is not associated with a scavenging effect. Taken together our results demonstrate that exposure to UVB and to oxidant stimuli induces a rapid intracellular production of ROS, which in turn are capable of triggering KGFR activation and internalization, similar to those induced by KGF.
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PMID:UVB-induced activation and internalization of keratinocyte growth factor receptor. 1271 19


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