Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulating cells of the mouse macrophage-like cell line RAW 264.7 with the Ca(2+)-ATPase inhibitor thapsigargin increased histamine production. Thapsigargin increased the levels of histidine decarboxylase (HDC) mRNA at 4 h and the expression of 74-kDa HDC protein at 8 h. PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed the thapsigargin-induced histamine production, the increase in HDC mRNA level and 74-kDa HDC protein expression. In contrast, SB203580, an inhibitor of p38 MAP kinase, showed only a partial inhibition of histamine production. TPA and LPS also induced histamine production in RAW 264.7 cells, and the histamine production induced by TPA or LPS was also inhibited by PD98059, but the effect of SB203580 was partial. The synthetic glucocorticoid dexamethasone inhibited thapsigargin-induced histamine production, 74-kDa HDC protein expression and the activation of p44/p42 MAP kinases. In conclusion, the increase in histamine production in macrophages stimulated with inflammatory stimulants is due to the increased expression of 74-kDa HDC, which is positively regulated by activated p44/p42 MAP kinases. Dexamethasone inhibits thapsigargin-induced HDC protein expression and histamine production by inhibiting the MAP kinase activation.
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PMID:[Regulation of histamine production in macrophages]. 1149 23

The responses of airway epithelium following exposure to neutrophil elastase (NE) were investigated. Human bronchial epithelial cells were explanted on insert surfaces of a modified air-liquid interface culture system to which NE was added to stimulate epithelial cells. PGE2 release significantly increased within 10 min of incubation with NE and peaked 3 h after NE (20 microg/ml) stimulation. This action required proteolytic activity as alpha1-antitrypsin blocked NE-induced PGE2 release. The production of PGE2 was also inhibited by indomethacin; a selective cyclooxygenase (COX)-2 inhibitor, celecoxib; and dexamethasone. Moreover, the mRNA expression for COX-2 relative to that for a housekeeping gene was approximately eightfold that of the unstimulated cells. Dexamethasone inhibited COX-2 gene transcription. We further observed that NE-induced PGE2 release involved activation of p44/42, but not p38, MAP kinases. Such p44/42 MAP kinases were rapidly phosphorylated, with the concentration of phosphorylated p44/42 MAP kinases peaking at 10 min after stimulation and declining in culture at 90 min. The specific p44/42 MAP kinase inhibitor UO126 completely blocked p44/42 phosphorylation and, subsequently, PGE2 production. The airway epithelium may play important bronchoprotective and immunomodulatory roles in chronic neutrophilic inflammation.
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PMID:Neutrophil elastase stimulates human airway epithelial cells to produce PGE2 through activation of p44/42 MAPK and upregulation of cyclooxygenase-2. 1283 84

Multiple Myeloma (MM) is a progressive malignancy with poor prognosis, commonly treated by the use of the glucocorticoid Dexamethasone. Myeloma cells resist Dexamethasone induced apoptosis when exposed to IL-6 or IGF-1, both of which are known to activate several signaling cascades. For the first time, we show the actual contribution of downstream mediators, i.e., activated STAT factors, independent of the contribution of their upstream signaling pathways, on the proliferation and Dexamethasone rescue effects of IL-6 and IGF-1 in Multiple Myeloma. Retroviral transduction of cytokine dependent myeloma cells with activated STAT transcription factor constructs overcomes the cells dependence on cytokines for growth, allowing proliferation even in very low serum levels. However, the rescue of these previously cytokine dependent cells with activated STATs does not result in an increase in resistance to Dexamethasone induced apoptosis. Despite the presence of activated STAT3 and STAT5a, apoptosis is induced upon exposure to micromolar levels of Dexamethasone, and IL-6 or IGF-1 is still required to rescue the cells. The ability of these factors to block apoptosis is abrogated by the addition of PI-3 Kinase specific inhibitors, but not inhibitors that target the MAP Kinase pathway. However, ectopic expression of activated STAT3 results in partial rescue from apoptosis of cells treated with FAS ligand. Our data suggests that mechanisms of resistance to induced apoptosis and cellular proliferation are separate and distinct in cytokine dependent myeloma cells.
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PMID:Activating mutations in STAT3 and STAT5 differentially affect cellular proliferation and apoptotic resistance in multiple myeloma cells. 1497 30

There is growing evidence that impairment in intrarenal oxygenation and hypoxic injury might contribute to the pathogenesis of septic renal failure. An important molecule known to act on the renal microvascular tone and therefore consequently being involved in the regulation of intrarenal oxygen supply is NO. The main production of NO under septic conditions derives from iNOS, an enzyme that can be blocked by dexamethasone (DEX). In an animal model of endotoxin-induced renal failure, we tested the hypothesis that inhibition of iNOS by low-dose DEX would improve an impaired intrarenal oxygenation and kidney function. Twenty-two male Wistar rats received a 30-min intravenous infusion of LPS (2.5 mg/kg) and consecutively developed endotoxemic shock. Two hours later, in 12 animals, fluid resuscitation was initiated. Six rats did not receive resuscitation; four animals served as time control. In addition to the fluid, six animals received a bolus of low-dose DEX (0.1 mg/kg). In these animals, the renal iNOS mRNA expression was significantly suppressed 3 h later. Dexamethasone prevented the appearance of cortical microcirculatory hypoxic areas, improved renal oxygen delivery, and significantly restored oxygen consumption. Besides a significant increase in MAP and renal blood flow, DEX restored kidney function and tubular sodium reabsorption to baseline values. In conclusion, treatment with low-dose DEX in addition to fluid resuscitation reversed endotoxin-induced renal failure associated by an improvement in intrarenal microvascular oxygenation. Therefore, low-dose DEX might have potential application in the prevention of septic acute renal failure.
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PMID:Low-dose dexamethasone-supplemented fluid resuscitation reverses endotoxin-induced acute renal failure and prevents cortical microvascular hypoxia. 1882 49

Anti-inflammatory strategies receive growing attention for their potential to prevent pathological deterioration in disorders such as Parkinson's disease, which is accompanied by inflammatory reactions that might play a critical role in the degeneration of nigral dopaminergic neurons. We investigated the influence of dexamethasone - a potent synthetic member of the glucocorticoids class of steroid hormones that acts as an anti-inflammatory - on the degeneration of the dopaminergic neurons of rats observed after intranigral injection of thrombin, a serine protease that induces inflammation through microglia proliferation and activation. We evaluated tyrosine hydroxylase (TH)-positive neurons as well as astroglial and microglial populations; dexamethasone prevented the loss of astrocytes but was unable to stop microglial proliferation induced by thrombin. Moreover, dexamethasone produced alterations in the levels of nexin and the thrombin receptor PAR-1, and facilitated accumulation of alpha-synuclein induced by thrombin in dopaminergic neurons. Dexamethasone increased oxidative stress and expression of monoamine oxidase A and B, along with changes on different MAP kinases related to degenerative processes, resulting in a bigger loss of dopaminergic neurons after intranigral injection of thrombin in dexamethasone-treated animals. It is interesting to ascertain that inhibition of monoamine oxidase by tranylcypromine prevented neurodegeneration of dopaminergic neurons, thus suggesting that the deleterious effects of dexamethasone might be mediated by monoamine oxidase.
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PMID:Degeneration of dopaminergic neurons induced by thrombin injection in the substantia nigra of the rat is enhanced by dexamethasone: role of monoamine oxidase enzyme. 1996 22

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme situated downstream of cyclo-oxygenase-2, promoting the excessive PGE2 production in inflammation. Dexamethasone is known to suppress mPGES-1 but the mechanisms regulating mPGES-1 expression remain poorly known. MKP-1 is a phosphatase controlling the proinflammatory MAP kinase pathways p38 and JNK, thus limiting the inflammatory responses. We have now investigated the role of MKP-1 and MAP kinases p38 and JNK in the regulation of mPGES-1 expression by dexamethasone. Dexamethasone increased MKP-1 and decreased mPGES-1 expression in J774 macrophages and in peritoneal macrophages from wild-type but not from MKP-1 deficient mice. Dexamethasone also reduced p38 and JNK phosphorylation along with enhancement of MKP-1, while inhibition of JNK reduced mPGES-1 expression. These findings were also translated to in vivo conditions as dexamethasone downregulated mPGES-1 expression in paw inflammation in wild-type but not in MKP-1 deficient mice. In conclusion, dexamethasone was found to downregulate mPGES-1 expression through enhanced MKP-1 expression and reduced JNK phosphorylation in inflammatory conditions. The results extend the understanding on the regulation of mPGES-1 expression and highlight the potential of MKP-1 as an anti-inflammatory drug target.
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PMID:Microsomal Prostaglandin E Synthase-1 Expression in Inflammatory Conditions Is Downregulated by Dexamethasone: Seminal Role of the Regulatory Phosphatase MKP-1. 2898 47