Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P51812 (mitogen-activated protein)
10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The age-related impairment in long-term potentiation in the rat dentate gyrus is coupled with an increase in the proinflammatory cytokine, interleukin-1beta (IL-1beta). It is possible that this increase in IL-1beta might be a consequence of the age-related increase in reactive oxygen species production in hippocampal tissue. In this study we set out to identify the underlying cause of the age-related increase in reactive oxygen species production and to establish whether any consequences of such a change might impact on the ability of aged rats to sustain long-term potentiation (LTP). We report that there was an age-related increase in the activity of superoxide dismutase but no parallel increases in activities of glutathione peroxidase or catalase, while age-related decreases in the concentration of the scavengers, vitamins E and C and glutathione were also observed. We propose that these compromises in antioxidative strategies may result in an increase in reactive oxygen species production. The data described indicate that IL-1beta and H2O2 increase the activity of two stress-activated mitogen-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 in vitro, while age-related increases in both kinases were observed. We propose that the endogenous increase in these parameters which occurs with age induces the increase in activity of the stress-activated kinases, which in turn impacts on the ability of the aged rat to sustain LTP.
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PMID:Age-related impairment in LTP is accompanied by enhanced activity of stress-activated protein kinases: analysis of underlying mechanisms. 1065 89

Reactive oxygen species (ROS) have emerged as important signaling molecules in the regulation of various cellular processes. In our study, we investigated the effect of a wide range of ROS on Chinese hamster lung fibroblast (V79) cell proliferation. Treatment with H2O2 (100 microM), superoxide anion (generated by 1 mM xanthine and 1 mU/ml xanthine oxidase), menadione, and phenazine methosulfate increased the cell proliferation by approximately 50%. Moreover, a similar result was observed after partial inhibition of superoxide dismutase (SOD) and glutathione peroxidase. This upregulation of cell proliferation was suppressed by pretreatment with hydroxyl radical scavengers and iron chelating agents. In addition to ROS, treatment with exogenous catalase and SOD mimic (MnTMPyP) suppressed the normal cell proliferation. Short-term exposure of the cells to 100 microM H2O2 was sufficient to induce proliferation, which indicated that activation of the signaling pathway is important as an early event. Accordingly, we assessed the ability of H2O2 to activate mitogen-activated protein kinases (MAPK). Jun-N-terminal kinase (JNK) and p38 MAPK were both rapidly and transiently activated by 100 microM H2O2, with maximal activation 30 min after treatment. However, the activity of extracellular signal-regulated kinase (ERK) was not changed. Pretreatment with SB203580 and SB202190, specific inhibitors of p38 MAPK, reduced the cell proliferation induced by H2O2. The activation of both JNK and p38 MAPK was also suppressed by pretreatment with hydroxyl radical scavenger and iron chelating agents. Our results suggest that the trace metal-driven Fenton reaction is a central mechanism that underlies cell proliferation and MAPK activation.
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PMID:Effects of reactive oxygen species on proliferation of Chinese hamster lung fibroblast (V79) cells. 1129 67

Reactive oxygen species have been shown to play important roles in v-Ha-Ras mitogenic signaling. We hypothesized that v-Ha-Ras overexpression would induce superoxide production, and therefore modify expression of the primary antioxidant enzyme system. We have demonstrated that immortal rat kidney epithelial cells stably transduced with constitutively active v-Ha-ras produced significantly larger amounts of superoxide radical than wild-type or vector-transfected control cells. The levels of the primary antioxidant enzymes copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase were increased in the superoxide-overproducing cells. DNA-binding activities of the transcription factors activator protein-1, activator protein-2, and nuclear factor-kappaB were all enhanced in the superoxide-overproducing cells. These v-Ha-ras transduced cells also had a shortened cell doubling time and higher plating efficiency, and displayed greater constitutive levels of phosphorylated mitogen-activated protein kinases. These data demonstrate that v-Ha-Ras overexpression increases superoxide production and this apparently affects a wide variety of cell signaling and redox systems.
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PMID:V-Ha-Ras overexpression induces superoxide production and alters levels of primary antioxidant enzymes. 1155 55

1: Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one) is a selenoorganic compound exhibiting both glutathione peroxidase activity and antioxidant activity. Although it has been reported that ebselen is effective for oxidative stress-induced neuronal damage both in vivo and clinically, the precise mechanisms of the efficacy have not yet been elucidated. Thus, we hypothesized that ebselen may affect reactive oxygen species-induced mitogen-activated protein (MAP) kinase activation in cultured PC12 cells. 2: Our findings showed that hydrogen peroxide (H(2)O(2)) stimulated rapid and significant activation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 in PC12 cells, which is a model of catecholamine-containing neurons. 3: H(2)O(2)-induced JNK activation was inhibited by ebselen, whereas ERK1/2 and p38 activation by H(2)O(2) were not affected by ebselen. 4: Inhibition by ebselen of H(2)O(2)-induced hydroxyl radical generation in PC12 cells was observed using electron paramagnetic resonance measurements. Ebselen also inhibited H(2)O(2)-induced increases in DNA binding activity of activator protein-1 (AP-1), a downstream transcription factor of JNK, composed of the c-Jun homo/heterodimer. 5: Finally, pretreatment of cells with ebselen resulted in a significant recovery from cell death including apoptosis by H(2)O(2) in PC12 cells. 6 These findings suggest that ebselen attenuates oxidative stress-induced neuronal cell death through the inhibition of the JNK and AP-1 signalling pathway. Thus, inhibition of JNK by ebselen may imply its usefulness for treatment of ischaemic cerebral diseases relevant to neuronal cell death.
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PMID:Ebselen attenuates oxidative stress-induced apoptosis via the inhibition of the c-Jun N-terminal kinase and activator protein-1 signalling pathway in PC12 cells. 1214 2

Under conditions where apoptosis is prevented, peroxides disrupt the endothelial monolayer by inducing cytoskeletal rearrangements, cell retraction and formation of arrays of membrane blebs. In human umbilical vein endothelial cells (HUVEC), the H(2)O(2)-induced membrane blebbing was found to be a transient process executed by two parallel signaling mechanisms: (i) mobilization of cytosolic [Ca(2+)](i) through a pathway requiring oxidation of reduced glutathione (GSH), and (ii) activation of p38 mitogen-activated protein kinases (MAPK) independently of GSH oxidation and Ca(2+) mobilization. In the HUVEC, membrane blebbing was thus blocked by inhibition of GSH oxidation, Ca(2+) mobilization or p38 MAPK activation. Stimulation of GSH peroxidation with ebselen potentiated the H(2)O(2)-induced oscillating Ca(2+) response and the bleb formation, but not p38 phosphorylation. Chelation of [Ca(2+)](i) abolished the blebbing process but not p38 activation. In addition, in the GSH peroxidase-resistant cell line ECV304, H(2)O(2) was unable to promote membrane blebbing or significant Ca(2+) release, while p38 became phosphorylated. However, [Ca(2+)](i) was increased and blebs were formed, when the ECV304 were treated with ebselen before H(2)O(2). Together, this leads to a model where oxidative stress, through both Ca(2+)-dependent and p38 kinase-mediated phosphorylation events, causes reassembly of the actin cytoskeleton and subsequent appearance of membrane blebs at the plasma membrane.
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PMID:Glutathione oxidation in calcium- and p38 MAPK-dependent membrane blebbing of endothelial cells. 1218 63

Ebselen (2-phenyl-1, 2-benzisoselenazol-3[2H]-one) is a seleno-organic compound exhibiting both glutathione peroxidase and antioxidant activity. Although it has been reported that ebselen is effective against hydrogen peroxide (H(2)O(2))-induced cell death in several cell types, its effect on endothelial cell damage has not yet been elucidated. In the present study, we examined the effect of ebselen on H(2)O(2)-induced human umbilical vein endothelial cells (HUVECs) death, and its intracellular mechanism. Our findings showed that pretreatment of HUVECs with ebselen resulted in a significant recovery from H(2)O(2)-induced cell death in a concentration-dependent manner. In addition to the inhibition of lactate dehydrogenase (LDH) leakage, ebselen inhibited H(2)O(2)-induced cytochrome c release and caspase-3 activation and the resultant apoptosis in HUVECs. Moreover, it was observed that H(2)O(2) significantly stimulated activation of mitogen-activated protein (MAP) kinases, i.e., p38 MAP kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2). Ebselen inhibited H(2)O(2)-induced p38 MAP kinase, but not JNK or ERK1/2 activation. Furthermore, SB203580 (4-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-5-[4-pyridyl]-1H-imidazole), a specific p38 MAP kinase inhibitor, inhibited H(2)O(2)-induced p38 MAP kinase phosphorylation, cytochrome c release, caspase-3 activation, as well as cell death in HUVECs. These findings suggest that ebselen attenuates H(2)O(2)-induced endothelial cell death through the inhibition of signaling pathways mediated by p38 MAP kinase, caspase-3, and cytochrome c release. Thus, inhibition of p38 MAP kinase by ebselen may imply its usefulness for prevention and/or treatment of endothelial cell dysfunction, which was suggested to be the first step in the development of atherosclerosis.
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PMID:Ebselen inhibits p38 mitogen-activated protein kinase-mediated endothelial cell death by hydrogen peroxide. 1475 32

Results are presented which support the hypothesis that adequate steady-state levels of hydrogen peroxide (H2O2) are required to overcome the effects of high catalase and glutathione peroxidase (GPx) expression for p38 mitogen-activated protein (MAP) kinase activation and tumor necrosis factor (TNF)-alpha gene expression in human alveolar macrophages stimulated with asbestos. We found significant differences in the types and amounts of reactive oxygen species generated in human blood monocytes compared with human alveolar macrophages. This difference in reactive oxygen species production is related, in part, to the differences in antioxidant enzyme expression and activity. Most importantly, catalase and GPx activities were significantly increased in alveolar macrophages compared with blood monocytes. Asbestos activated the p38 MAP kinase and induced TNF-alpha gene expression only in blood monocytes. Increasing the steady-state levels of H2O2 by using polyethylene glycol superoxide dismutase, an antioxidant that crosses the cell membrane, or aminotriazole, an irreversible inhibitor of catalase, allowed the p38 MAP kinase to be activated in alveolar macrophages. In addition, asbestos-stimulated macrophages cultured with polyethylene glycol superoxide dismutase had a significant increase in gene expression mediated by the TNF-alpha promoter. These results demonstrate that high catalase and GPx activity in human alveolar macrophages limits the effectiveness of H2O2 to act as a mediator of inflammatory gene expression.
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PMID:High levels of catalase and glutathione peroxidase activity dampen H2O2 signaling in human alveolar macrophages. 1496 75

Mitochondria were classically recognized as the organelles that produce the energy required to drive the endergonic processes of cell life, but now they are considered as the most important cellular source of free radicals, as the main target for free radical regulatory and toxic actions, and as the source of signaling molecules that command cell cycle, proliferation and apoptosis. The progress in the knowledge of mitochondrial functions in the last decades is reviewed. The mitochondrial production of the primary free radicals superoxide anion (O(2)(-)) and nitric oxide (NO), as well as of the termination products H(2)O(2) (hydrogen peroxide) and peroxynitrite (ONOO(-)), is described. A network of intramitochondrial antioxidants consisting of the enzymes Mn-superoxide dismutase and glutathione peroxidase and of the reductants NADH(2), ubiquinol and reduced glutathione, is operative in minimizing the potentially harmful effects of O(2)(-), NO, H(2)O(2) and ONOO(-). Nitric oxide and H(2)O(2) participate in cell signaling, through narrow concentration ranges that signal for opposite cellular situations, i.e., proliferation or apoptosis. A mechanism involving mitogen-activated protein kinases is described. The role of mitochondria in apoptosis is well established through the mitochondrion-dependent pathways of cell death, that includes increased NO production, loss of membrane potential, appearance of dysfunctional mitochondria, cytochrome c release and opening of the voltage-dependent anion channel of the outer membrane.
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PMID:Mitochondrial free radical production and cell signaling. 1505 13

Diseases such as hypertension, atherosclerosis and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many stimuli influence cellular changes, including mechanical forces, such as shear stress, and vasoactive agents, of which angiotensin II (Ang II) appears to be amongst the most important. Ang II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive oxygen species (ROS). Mechanical forces, comprising both unidirectional laminar and oscillatory shear, are increasingly being recognized as important inducers of vascular NO and ROS generation. In general, laminar flow is associated with upregulation of eNOS and NO production and increased expression of antioxidants glutathione peroxidase and superoxide dismutase, thereby promoting a healthy vascular wall and protecting against oxidative vascular injury. On the other hand, oscillatory shear is linked to increased ROS production with consequent oxidative damage, as occurs in hypertension. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca(2+) concentration, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, low concentrations of intracellular ROS play an important role in normal redox signaling involved in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review describes some of the redox-sensitive signaling pathways that are involved in the functional and structural vascular changes associated with hypertension.
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PMID:Redox signaling in hypertension. 1676 37

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has potent effects in the brain as a free radical scavenger in ischemia-reperfusion (IR) injuries. However, whether this free radical scavenger can prevent myocardial injury after cerebral IR is not clear. The aim of the present study was to investigate the effect of edaravone against oxidative damage in brain-to-heart signaling triggered by IR injury and its possible mechanism. In this study, the expression of glutathione peroxidase (GSHPx) and protein carbonyl content was examined to evaluate oxidative stress. The activation of mitogen-activated protein kinases (MAPKs) was also examined. Terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) analysis was performed to estimate cardiomyocytes cell death. After edaravone treatment there was a mild increase in activities of GSHPx in cardiomyocytes; however, there was a decrease in protein carbonyl content. p38 MAPK activity was inhibited by edaravone treatment in comparison with the vehicle group in myocardium. These results were further complemented by a significant reduction of TUNEL-positive cells in the heart sections. Our results demonstrate that edaravone provides ameliorative effects in the myocardium after cerebral IR injury by differentially modulating MAPK's activity, thus reducing the oxidative stress state.
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PMID:Effects of edaravone in heart of aged rats after cerebral ischemia-reperfusion injury. 1732 38


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