Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrogen oxides (NOx) are important indoor air pollutants and an occupational hazard. Many studies demonstrated that NOx causes lung tissue damage based on the oxidation properties and the free-radical potentials of these gases. In this study we found that NOx delivered as a NO gas-saturated solution induced proliferation of human lung fibroblast MCR-5 cells as evidenced by increasing cell number and S phase distribution. Western data showed that NOx increased the expressions of c-Fos, c-Jun, and signaling kinases including MEKK1, JNK1, and p38 (with induction fold of 3.3, 2.8, and 3.2, respectively) in the cells 12 h after treatment. The levels of phospho-MEKK1 and phospho-JNK1 were also increased. The application of iNOS inhibitor, NAME, partially blocked the activation of MEKK4 and JNK1. These data suggested that JNK and p38 signaling kinases are activated partly by endogenous NO that are generated from NOx-activated iNOS in MRC-5 cells. Therefore, the NOx-induced cell proliferation via activation of MEKK1, JNK1, and p38 might contribute to lung tissue damage caused by NOx pollutants.
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PMID:Induced proliferation of human MRC-5 cells by nitrogen oxides via direct and indirect activation of MEKK1, JNK, and p38 signals. 1207 29

Previously, we showed that increased extracellular tonicity promotes increased type A natriuretic peptide receptor (NPR-A) expression through a p38 MAPKbeta pathway in inner medullary collecting duct cells. The endothelial and inducible nitric-oxide synthase (eNOS and iNOS respectively) genes are also expressed in this nephron segment and are thought to play a role in regulating urinary sodium concentration. We sought to determine whether changes in tonicity might regulate NOS gene expression, and if so, whether these latter changes might be linked mechanistically to the increase in NPR-A gene expression. Increased extracellular tonicity effected a time-dependent reduction in eNOS and iNOS protein levels, eNOS mRNA levels, and eNOS gene promoter activity over the first 8 h of the incubation. Although levels of the eNOS mRNA and promoter activity had returned to normal after 24 h, eNOS protein levels remained low at 24-36 h, and recovery was not complete even at 48 h. The decrease in eNOS expression was signaled in large part through a p38 MAPK-dependent mechanism. Reduction in eNOS expression together with the concomitant decline in intracellular cyclic GMP levels appears to account for a significant portion of the p38 MAPK-dependent osmotic stimulation of NPR-A gene expression noted previously. Collectively, these findings support the existence of a complex regulatory circuitry in the cells of the inner medullary collecting duct linking two independent cyclic GMP-generating signal transduction systems involved in regulation of urinary sodium concentration.
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PMID:Osmoregulation of endothelial nitric-oxide synthase gene expression in inner medullary collecting duct cells. Role in activation of the type A natriuretic peptide receptor. 1208 97

The calcineurin inhibitor cyclosporine A (CsA) modulates leukocyte cytokine production but may also effect nonimmune cells, including microvascular endothelial cells, which regulate the inflammatory process through leukocyte recruitment. We hypothesized that CsA would promote a proinflammatory phenotype in human intestinal microvascular endothelial cells (HIMEC), by inhibiting inducible nitric-oxide synthase (iNOS, NOS2)-derived NO, normally an important mechanism in limiting endothelial activation and leukocyte adhesion. Primary cultures of HIMEC were used to assess CsA effects on endothelial activation, leukocyte interaction, and the expression of iNOS as well as cell adhesion molecules. CsA significantly increased leukocyte binding to activated HIMEC, but paradoxically decreased endothelial expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule-1). In contrast, CsA completely inhibited the expression of iNOS in tumor necrosis factor-alpha/lipopolysaccharide-activated HIMEC. CsA blocked p38 MAPK phosphorylation in activated HIMEC, a key pathway in iNOS expression, but failed to inhibit NFkappaB activation. These studies demonstrate that CsA exerts a proinflammatory effect on HIMEC by blocking iNOS expression. CsA exerts a proinflammatory effect on the microvascular endothelium, and this drug-induced endothelial dysfunction may help explain its lack of efficacy in the long-term treatment of chronically active inflammatory bowel disease.
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PMID:Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS. Paradoxical proinflammatory effect on the microvascular endothelium. 1211 Jun 86

Aspirin [acetylsalicylic acid (ASA)] is an anti-inflammatory drug that protects against cellular injury by inhibiting cyclooxygenases (COX), inducible nitric oxide synthase (iNOS) and p44/42 mitogen-activated protein kinase (p44/42 MAPK), or by preventing translocation of nuclear factor kappaB (NF-kappaB). We studied the effect of ASA pre-treatment on neuronal survival after hypoxia/reoxygenation damage in rat spinal cord (SC) cultures. In this injury model, COX, iNOS and NF-kappaB played no role in the early neuronal death. A 20-h treatment with 3 mm ASA prior to hypoxia/reoxygenation blocked the hypoxia/reoxygenation-induced lactate dehydrogenase (LDH) release from neurons. This neuroprotection was associated with increased phosphorylation of neurofilaments, which are substrates of p44/42 MAPK and cyclin-dependent kinase 5 (Cdk5). PD90859, a p44/42 MAPK inhibitor, had no effect on ASA-induced tolerance, but olomoucine and roscovitine, Cdk5 inhibitors, reduced ASA neuroprotection. Hypoxia/reoxygenation alone reduced both the protein amount and activity of Cdk5, and this reduction was inhibited by pre-treatment with ASA. Moreover, the protein amount of a neuronal Cdk5 activator, p35, recovered after reoxygenation only in ASA-treated samples. The prevention of the loss in Cdk5 activity during reoxygenation was crucial for ASA-induced protection, because co-administration of Cdk5 inhibitors at the onset ofreoxygenation abolished the protection. In conclusion, pre-treatment with ASA induces tolerance against hypoxia/reoxygenation damage in spinal cord cultures by restoring Cdk5 and p35 protein expression.
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PMID:Aspirin provides cyclin-dependent kinase 5-dependent protection against subsequent hypoxia/reoxygenation damage in culture. 1212 33

Mercury is well known to adversely affect the immune system; however, little is known regarding its molecular mechanisms. Macrophages are major producers of nitric oxide (NO) and this signaling molecule is important in the regulation of immune responses. The present study was designed to determine the impact of mercury on NO and cytokine production and to investigate the signaling pathways involved. The murine macrophage cell line J774A.1 was used to study the effects of low-dose inorganic mercury on the production of NO and proinflammatory cytokines. Cells were treated with mercury in the presence or absence of lipopolysaccharide (LPS). Mercury (5-20 microM) dose-dependently decreased the production of NO in LPS-stimulated cells. Concomitant decreases in the expression of inducible nitric oxide synthase (iNOS) mRNA and protein were detected. Treatment of J774A.1 cells with mercury alone did not affect the production of NO nor the expression of iNOS mRNA or protein. Interestingly, mercury alone stimulated the expression of tumor necrosis factor alpha (TNFalpha), and increased LPS-induced TNFalpha and interleukin-6 mRNA expression. Mercury inhibited LPS-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) but had no effect alone. In contrast, mercury activated p38 mitogen-activated protein kinase (p38 MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. These results indicate that mercury suppresses NO synthesis by inhibition of the NF-kappaB pathway and modulates cytokine expression by p38 MAPK activation in J774A.1 macrophage cells.
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PMID:Mercury inhibits nitric oxide production but activates proinflammatory cytokine expression in murine macrophage: differential modulation of NF-kappaB and p38 MAPK signaling pathways. 1217 22

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.
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PMID:Postischemic acute renal failure is reduced by short-term statin treatment in a rat model. 1219 73

We used a chemical genomics approach that includes follow up in parallel syntheses to discover a new class of compounds that selectively suppress glial activation. While the mechanism of action remains to be determined, available data and the experimental approach for discovery indicate that the mechanism includes inhibition of gene regulating protein kinases. Specifically, the increased production of IL-1beta and iNOS in response to various activating stimuli, including Abeta1-42, is suppressed while the production of potentially beneficial responses, such as ApoE production, is not inhibited. The increased production of COX-2 and p38 MAPK activation are also not altered, demonstrating the novel nature of potential therapeutic targets compared to currently available drugs. The chemical scaffold is 3-aminopyridazine (3-AP). This is an attractive scaffold because of its potential for diversification by established, facile chemistries and the prior use of a 3-AP scaffold in other central nervous system targeted therapeutics. Therefore, the potential bioavailability of 3-AP derivatives and the demonstrated cellular selectivity demand that future research address the potential efficacy of selective 3-AP derivatives in animal models of disease.
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PMID:Discovery of new chemical classes of synthetic ligands that suppress neuroinflammatory responses. 1221

Inflammatory processes involving glial cell activation are associated with amyloid plaques and neurofibrillary tangles, the cardinal neuropathological lesions in the brains of Alzheimer's disease (AD) patients, However, it is unclear whether these inflammatory processes occur as a response to neuronal degeneration or might represent more seminal events in the disease process. Some cases of AD are caused by mutations in presenilin-1 (PS1), and it has been shown that PS1 mutations perturb neuronal calcium homeostasis, promote increased production of amyloid beta-peptide (Abeta), and render neurons vulnerable to synaptic dysfunction, excitotoxicity, and apoptosis. Although glial cells express PS1, it is not known if PS1 mutations alter glial cell functions. We now report on studies of glial cells in PS1 mutant knockin mice that demonstrate an adverse effect PS1 mutations in microglial cells. Specifically, PS1 mutant mice exhibit an enhanced inflammatory cytokine response to immune challenge with bacterial lipopolysaccharide (LPS). LPS-induced levels of mRNAs encoding tumor necrosis fctor-alpha (TNFalpha), interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist, and IL-6 are significantly greater in the hippocampus and cerebral cortex of PS1 mutant mice as compared to wild-type mice. In contrast, the cytokine responses to LPS in the spleen is unaffected by the PS1 mutation. Studies of cultured microglia from PS1 mutant and wild-type mice reveal that PS1 is expressed in microglia and that the PS1 mutation confers a heightened sensitivity to LPS, as indicated by superinduction of inducible nitric oxide synthase (NOS) and activation of mitogen-activated protein kinase (MAPK). These findings demonstrate an adverse effect of PS1 mutations on microglial cells that results in their hyperactivation under pro-inflammatory conditions, which may, together with direct effects of mutant PS1 in neurons, contribute to the neurodegenerative process in AD. These findings also have important implications for development of a "vaccine" for the prevention or treatment of AD.
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PMID:Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain. 1223 Mar 3

Advanced glycosylation end products (AGEs) have been implicated in the pathogenesis of diabetic complications. Treatment of RAW 264.7 macrophages with bovine serum albumin (BSA)-derived AGEs caused dose- and time-dependent increases in nitrite production and inducible nitric oxide synthase (iNOS) expression. These effects were blocked by the nuclear factor-kappa B (NF-kappaB) inhibitor, pyrrolidone dithiocarbamate (PDTC). BSA-AGEs also stimulated the translocation of p65 NF-kappaB from cytosol to the nucleus. Electrophoretic mobility shift assay revealed that the NF-kappaB DNA-protein-binding activity was enhanced by AGEs. The tyrosine kinase inhibitor, genistein, the phosphatidylinositol-3-kinase (PI 3-K) inhibitor, LY 294002, the protein kinase C (PKC) inhibitor, Ro 31-8220, and the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 203580, all inhibited AGEs-stimulated iNOS expression, NO release, NF-kappaB translocation and NF-kappaB DNA binding activity. These results suggest that AGEs may activate NF-kappaB via an upstream signaling cascade composed of tyrosine kinase, PI 3-K, PKC, and p38 MAPK, resulting in the induction of iNOS expression in RAW 264.7 macrophages.
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PMID:Advanced glycosylation end products induce NF-kappaB dependent iNOS expression in RAW 264.7 cells. 1224 23

Porphyromonas gingivalis is a Gram-negative periodontopathic bacterium colonizing the oral cavity and its lipopolysaccharide (LPS) is a key factor in the development of periodontitis. We investigated the effect of P. gingivalis LPS on the cellular responses associated with mucin synthesis in sublingual salivary gland acinar cells. Exposure of the acinar cells to the LPS led to a dose-dependent decrease in mucin synthesis and was accompanied by a massive induction in inducible nitric oxide synthase (NOS-2) activity and the increase in NO production, caspase-3 activity and apoptosis. Inhibition of extracellular signal-regulated kinase (ERK) with PD98059 accelerated the LPS-induced decrease in the glycoprotein synthesis and caused further increase in apoptosis and NOS-2 activity, while the blockade of p38 mitogen-activated kinase (MAPK) with SB203580 countered the LPS-induced reduction in the glycoprotein synthesis and obviated the induced increases in NOS-2 and apoptosis. Introduction of NOS-2 inhibitor, L-NAME, not only countered the LPS-induced increase in NO generation, caspase-3 activity and apoptosis, but caused the impedance of the LPS inhibition on mucin synthesis. The findings point to the upregulation in NOS-2 expression by P. gingivalis LPS as a key detrimental culprit affecting salivary mucin synthesis.
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PMID:Porphyromonas gingivalis lipopolysaccharide interferes with salivary mucin synthesis through inducible nitric oxide synthase activation by ERK and p38 kinase. 1237 6


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