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: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of the T47D(A1-2) mammary carcinoma cell line with the nonspecific kinase inhibitor 2-aminopurine (2AP) has an unusual effect on induction of the mouse mammary tumor virus promoter by glucocorticoids. 2AP initially abrogates the dexamethasone-mediated increase, but after about 16-20 h, this effect is reversed, and continued incubation with 2AP potently stimulates the hormone induction. The biphasic kinetics of 2AP action displayed cell specificity. No inhibitory phase was seen in fibroblasts. Cell type specificity is also seen upon treatment of cells with isobutylmethylxanthine (IBMX). Dexamethasone action is inhibited in mammary cells, but potentiated in fibroblasts. Unlike 2AP treatment, IBMX continues to suppress the hormone response through at least 48 h of treatment. IBMX is commonly used as a phosphodiesterase inhibitor, and indeed, it stimulates a cAMP-dependent promoter in both mammary carcinoma cells and fibroblasts. Because elevating cAMP will potentiate dexamethasone-mediated induction in mammary cells, IBMX must be interventing in another pathway that elicits IBMX-dependent suppression of the hormone response. Pharmacological studies suggest that this interaction is not mediated through adenosine receptors, histamine receptors, or imidazoline receptors. The five-member imidazole ring plays a critical role in the suppressive activity; substitutions at the 7 position inhibit suppression. These results give further indication of coupling of steroid receptor action to other cellular signaling pathways. This complex spectrum of interactions may play a central determining role in the tissue specificity of the response to steroid hormones.
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PMID:Modulation of glucocorticoid-regulated transcription by purines: novel characteristics and implications for tissue specificity of steroid responses. 753 78

Glucocorticoids modulate signal transduction mechanisms in a number of cell systems. As the adrenal medulla is exposed to relatively high levels of adrenal cortical glucocorticoids in vivo, particularly during periods of stress, the aim of the present study was to determine whether glucocorticoids modulate cyclic AMP (cAMP) metabolism in an in vitro model of this system, the PC18 cell line. Dexamethasone significantly potentiated cAMP accumulation in response to the adenosine analogue N6-R-phenylisopropyl adenosine (PIA), and in response to forskolin. This effect was both time- and concentration-dependent. Maximal potentiation was observed after 48 h of exposure to 1 microM dexamethasone. Corticosterone and to a lesser extent aldosterone also significantly potentiated PIA-dependent cAMP accumulation. In contrast, estradiol, testosterone, and triiodothyronine had no potentiative effect. Potentiation could be eliminated by coincubation with the protein synthesis inhibitor cycloheximide. In the presence of Ro 20-1724, a cAMP-phosphodiesterase inhibitor, the degree of potentiation of both PIA- and forskolin-dependent cAMP accumulation was significantly decreased by 50-60%. These data suggested that altered cAMP-phosphodiesterase activity may be involved in this response. However, cytosolic and membrane-bound low Km cAMP-phosphodiesterase activity was unchanged in dexamethasone-treated cells compared with controls. Similarly, there were no significant differences in basal, PIA-, forskolin-, or GTP gamma S-stimulated adenylate cyclase activities between groups. These studies indicate that glucocorticoids can potentiate cAMP accumulation in intact PC18 cells. The mechanism underlying this potentiation is likely to be multifactorial, but may be due in part to decreased cAMP catabolism.
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PMID:Modulation of cyclic AMP metabolism by glucocorticoids in PC18 cells. 793 Dec 78

Treatment of mice with rolipram, a phosphodiesterase type 4 inhibitor, selectively modified the acute inflammatory reaction elicited by zymosan administration in 6-day-old mouse air-pouches. Rolipram (1-10 mg kg-1, i.p.) prevented the rise of endogenous tumor necrosis factor-alpha (TNF-alpha) in the lavage fluids (approximately 60% inhibition) induced by zymosan, with no effect upon interleukin-1 alpha levels. This action was not accompanied by changes in neutrophil accumulation, but the amount of elastase released in the lavage fluids was significantly reduced (approximately 50%). Dexamethasone (1.5 mg kg-1, i.v.), used for comparative purposes, significantly reduced the release of TNF-alpha (> 50%), interleukin-1 alpha (> 70%) and cellular infiltration (approximately 50%), but had only a marginal effect on the release of elastase activity. In conclusion, in this murine model of acute inflammation induced by zymosan, rolipram inhibited the endogenous TNF-alpha production at a local site of inflammation, such as the subcutaneous air-pouch, and prevented the full activation of migrated cells.
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PMID:Effect of rolipram in a murine model of acute inflammation: comparison with the corticoid dexamethasone. 856 19

The ability of dexamethasone and prednisolone (corticosteroids), FK506 and cyclosporin A (T cell immunosuppressants), and of nitraquazone and rolipram (phosphodiesterase IV inhibitors) to inhibit cytokine production by stimulated human blood was investigated. Heparinized human blood obtained from normal healthy volunteers was stimulated with phytohemagglutinin (PHA) in the presence or absence of drug. After different incubation times, supernatant levels of interleukin (IL)-2, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon gamma (IFN-gamma) were quantified by ELISA. Dexamethasone strongly inhibited the production of IL-5 (IC50 = 0.004 microM), was less potent against IL-2 and IFN-gamma (IC50 = 0.02-0.05 microM) and showed a relatively weak effect against GM-CSF (IC50 = 0.6 microM). Similarly prednisolone potently suppressed IL-5 generation (IC50 = 0.05 microM), displayed a more modest activity on IL-2 and IFn-gamma (IC50 = 0.2-0.3 microM) and exerted only partial effects (43% inhibition at 1 microM) on GM-CSF). FK506 strongly suppressed the production of IL-2 (IC50 = 0.01 microM) and GM-CSF (IC50 = 0.03 microM), but was inactive (< 30% inhibition at 1 microM) against IL-5 and IFN-gamma. Similarly, cyclosporin A reduced the generation of IL-2 (IC50 = 0.4 microM) and GM-CSF (IC50 = 0.6 microM) while barely affecting the other two cytokines. Nitraquazone and rolipram were most active in reducing the production of IL-5 (IC50 = 0.8 and 1.3 microM, respectively), while their potency against IL-2, GM-CSF and IFN-gamma was 3-6 times lower, with IC50's between 2.4 and 8.0 microM. These data indicate that corticosteroids, T cell immunosuppressants and phosphodiesterase IV inhibitors affect cytokine production by PHA-stimulated human blood cells in a differential and "pharmacotypical'' manner.
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PMID:Cytokine production by phytohemagglutinin-stimulated human blood cells: effects of corticosteroids, T cell immunosuppressants and phosphodiesterase IV inhibitors. 884 99

Deficiencies in cellular cyclic AMP (cAMP) and nitric oxide (NO) production are thought to be involved in the pathogenesis of diabetic neuropathy. We used a human neuroblastoma cell line, SH-SY5Y, to investigate the effect of cilostazol, a specific cAMP phosphodiesterase inhibitor, on NO production and Na+, K+-ATPase activity. SH-SY5Y cells were cultured under 5 or 50 mM glucose for 5-6 days, the cells were then exposed to cilostazol or other chemicals and nitrite, cAMP and Na+, K+-ATPase activity were measured. In cells grown in 50 mM glucose, cilostazol was observed to increase significantly both NO production and cellular cAMP accumulation in a time- and dose-dependent manner. Cilostazol also significantly recovered reduced levels of protein kinase A activity (PKA) in 50 mM glucose. Furthermore, a PKA inhibitor, H-89 significantly suppressed the increase in NO production stimulated by cilostazol, suggesting that cilostazol stimulates NO production by activating PKA. Cilostazol did not affect either sorbitol or myo-inositol concentrations. Dexamethasone, which is known to induce inducible NO synthase, had no effect on NO production stimulated by cilostazol, suggesting that cilostazol stimulates NO production catalyzed by neuronal constitutive NO synthase (ncNOS) in SH-SY5Y cells. L-arginine, which is an NO agonist enhanced Na+, K+-ATPase activity in cells grown in 50 mM glucose, NG-nitro-L-arginine methyl ester (L-NAME), which is an NOS inhibitor inhibited basal Na+, K+-ATPase activity in 5 mM glucose and suppressed the increased enzyme activity induced by cilostazol in 50 mM glucose. The above results confirmed our previous observation that NO regulates Na+, K+-ATPase activity in SH-SY5Y cells and suggest that cilostazol increases Na+, K+-ATPase activity, at least in part, by stimulating NO production. The present results also suggest that cilostazol has a beneficial effect on diabetic neuropathy by improving Na+, K+-ATPase activity via directly increasing cAMP and NO production in nerves.
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PMID:Cilostazol, a cyclic AMP phosphodiesterase inhibitor, stimulates nitric oxide production and sodium potassium adenosine triphosphatase activity in SH-SY5Y human neuroblastoma cells. 1050 60

The effects of the synthetic glucocorticoid dexamethasone on the cAMP content of murine T lymphocyte cell lines has been investigated. Incubation of the 3B4.15 T cell hybrids with dexamethasone results in an average 5-fold increase in intracellular cyclic AMP levels after 6 h of treatment. This phenomenon is abolished in the presence of RU486 and of cycloheximide, indicating that it requires binding of the drug to the intracellular glucocorticoids receptor and de novo protein synthesis. Dexamethasone-induced elevation of intracellular cyclic AMP correlates with both an increase in adenylate cyclase activity and a decrease in phosphodiesterase activity in T cell hybrids. This modulation of cyclic AMP metabolism is independent of serum-derived factors, suggesting that it is not secondary to transmembrane receptor stimulation by an extracellular ligand. We propose that glucocorticoids interfere with the homeostatic control of intracellular cAMP concentration, leading to a sustained increase in the content of this important second messenger in murine T lymphocyte cell lines. This study suggests that elevation of cAMP levels may represent one way by which glucocorticoids modulate the immune response.
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PMID:Dexamethasone increases intracellular cyclic AMP concentration in murine T lymphocyte cell lines. 1109 Jun 57

This study investigated whether a correlation between airway hyperreactivity (AHR), leukocyte influx, and nitric oxide (NO) existed in guinea pigs chronically exposed to lipopolysaccharide (LPS). The effect of the corticosteroid, dexamethasone, or phosphodiesterase-4 (PDE4) inhibitor, rolipram, on these features was studied. Airway function was measured in conscious guinea pigs (specific airways conductance) before and after single, double, or chronic (nine) LPS (30 microg x ml(-1), 1 h) exposures. Airway reactivity to inhaled histamine (1 mM, 20 s) was assessed before and at various times after LPS challenges. Leukocytes and NO metabolites were measured in bronchoalveolar lavage fluid (BALF). AHR occurred at 1 h after a single LPS challenge and was resolved by 4 h. This coincided with reduction and recovery, respectively, of BALF NO levels. The AHR and NO deficiency were extended to 4 h, after a double LPS exposure. Chronic LPS exposures, 48 h apart, initially caused persistent bronchodilations, whereas later exposures produced progressively persistent bronchoconstrictions. There was AHR 24 h after the eighth challenge. Twenty-four hours after the ninth LPS exposure, macrophages, neutrophils, eosinophils, and NO metabolites were elevated in BALF. Dexamethasone (20 mg x kg(-1) i.p.) or rolipram (1 mg x kg(-1) i.p.) prevented single and chronic LPS-induced AHR, the respective deficiency and elevation in NO metabolites, and the chronic LPS-induced leukocyte influx. Dexamethasone exacerbated, whereas rolipram reversed, the chronic LPS-induced bronchoconstrictions. This study demonstrates for the first time that chronic LPS causes persistent bronchoconstriction, neutrophilic inflammation, AHR, and NO overproduction in guinea pig airways. These rolipram-sensitive features suggest the potential of PDE4 inhibitors in airway disease.
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PMID:Chronic lipopolysaccharide exposure on airway function, cell infiltration, and nitric oxide generation in conscious guinea pigs: effect of rolipram and dexamethasone. 1140 55

The effects of chronic exposures (nine, 48 h apart) of conscious guinea pigs to lipopolysaccharide (LPS) (30 microg. ml(-1), 1 h) on airway function, airway histology (in particular, goblet cell numbers), and inflammatory cell infiltration of the lungs were examined as a model of chronic inflammatory lung disease, such as chronic obstructive pulmonary disease. The sensitivity of these parameters to treatment with the corticosteroid, dexamethasone, or the phosphodiesterase-4 (PDE4) inhibitor, rolipram, was determined. As the number of LPS exposures increased, there was a progressively persistent bronchoconstriction after each exposure. After nine LPS exposures, there was evidence on histological examination of airway infiltration of, predominantly, neutrophils in perivascular, peribronchial, and alveolar tissues. After chronic LPS exposure, the airway epithelium possessed a marked goblet cell hyperplasia and evidence of inflammatory edema, features contributory to reduced airway caliber. Treatment with dexamethasone (20 mg. kg(-1)) or rolipram (1 mg. kg(-1)), administered (i.p.) 24 and 0.5 h before exposure and 24 and 47 h after each subsequent exposure, attenuated the inflammatory cell infiltration into the airway, goblet cell hyperplasia, and inflammatory edema. Dexamethasone exacerbated, whereas rolipram reversed, the chronic LPS-induced bronchoconstrictions. This study demonstrates that chronic LPS causes persistent bronchoconstriction, neutrophilic airway inflammation, goblet cell hyperplasia, and edema. These rolipram-sensitive features suggest the potential of PDE4 inhibitors in chronic inflammatory lung diseases.
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PMID:Goblet cell hyperplasia, airway function, and leukocyte infiltration after chronic lipopolysaccharide exposure in conscious Guinea pigs: effects of rolipram and dexamethasone. 1213 Jul 48

Metabonomics is the evaluation of the multiparametric metabolic response of biological systems to pathophysiological stimuli. High-resolution nuclear magnetic resonance (NMR) spectroscopy of biofluids coupled with pattern recognition-based chemometric analysis is an emerging approach to the study of metabonomics and may be used for the prediction of toxicity in vivo and for identification of surrogate markers of toxicity. Previously, we established that metabonomic analysis of urine samples has significant potential for identification of phosphodiesterase type 4 (PDE-4) inhibitor-induced vascular lesions in rats. It was not clear, however, whether the observed changes in metabonomics profile were related mechanistically to the pathogenesis of these vascular lesions or whether these changes were reflective primarily of the ensuing inflammatory response. In the present study, dexamethasone was used to suppress inflammation associated with vascular lesions induced in rats by the PDE-4 inhibitor CI-1018 and urine samples were evaluated for resultant changes in metabonomic profile. Female Wistar rats were given CI-1018 by gavage at 750 mg/kg with or without concurrent intraperitoneal administration of dexamethasone at 1 mg/kg for 4 days. Dexamethasone induced a characteristic lymphoid depletion and lymphocytolysis but no evidence of vascular lesions. Rats dosed with CI-1018 had mild vascular changes in liver and/or marked vascular lesions in mesentery characterized by medial necrosis, hemorrhage, and/or edema accompanied by perivascular mixed inflammatory cell infiltrates. Inflammatory infiltrates associated with these lesions were eliminated in rats given dexamethasone, yet minimal medial smooth muscle necrosis and degeneration still occurred, suggestive of etiologic changes rather than effects secondary to the inflammatory response. Principle component analysis of urine NMR spectra produced a clear pattern separation within 48 to 72 h between CI-1018-treated rats with vascular lesions and vehicle controls or rats given dexamethasone alone. There was no pattern separation, however, between rats given CI-1018 alone and rats given CI-1018 and dexamethasone concurrently, suggesting that CI-1018-induced urine spectral changes were associated with the vascular lesions, yet were independent of the inflammatory response. These findings provide new insight into the mechanism(s) of PDE inhibitor-induced vasculitis and support the potential use of metabonomics for developing reliable noninvasive methods for detecting vascular changes in rats.
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PMID:Effect of dexamethasone on the metabonomics profile associated with phosphodiesterase inhibitor-induced vascular lesions in rats. 1238 50

This study investigated whether a correlation between leukocyte-derived elastolytic activity, alveolar epithelial type-1 cell damage, and leukocyte infiltration of the airways existed in guinea-pigs chronically exposed to inhaled lipopolysaccharide (LPS). The airway pathology of this model, notably the neutrophilia, resembles chronic obstructive pulmonary disease (COPD). The effect of the corticosteroid, dexamethasone, or the phosphodiesterase-4 (PDE4)-inhibitor, rolipram, on these features was studied. Conscious guinea-pigs were exposed for 1 h to single or repeated (nine) doses of LPS (30 microg ml(-1)). Dexamethasone (20 mg kg(-1), ip) or rolipram (1 mg kg(-1), ip) was administered 24 and 0.5 h before the first exposure and daily thereafter. Bronchoalveolar lavage fluid (BALF) was removed and elastolytic activity determined as the elastase-like release of Congo Red from impregnated elastin. The presence of the specific epithelial cell type-1 protein (40-42 kDa) RT1(40) in BALF was identified by Western blotting using a rat monoclonal antibody and semi-quantified by dot-blot analysis. The antibody was found to identify guinea-pig RT1(40). BALF inflammatory cells, particularly neutrophils and macrophages, and elastolytic activity were increased in chronic LPS-exposed guinea-pigs, the latter by 90%. Chronic LPS exposure also increased (10.5-fold) RT1(40) levels, indicating significant alveolar epithelial type-1 cell damage. Dexamethasone or rolipram treatment reduced the influx of inflammatory cells, the elastolytic activity (by 40% and 38%, respectively), and RT1(40) levels (by 50% and 57%, respectively). In conclusion, chronic LPS-exposed guinea-pigs, like COPD, exhibit elastolytic lung damage. This was prevented by a PDE4 inhibitor and supports their development for suppressing this leukocyte-mediated pathology.
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PMID:Elastolytic activity and alveolar epithelial type-1 cell damage after chronic LPS inhalation: effects of dexamethasone and rolipram. 1612 18


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