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)

Increasing cellular levels of cAMP inhibit eicosanoid production in the human neutrophil; however, little is known about the effects of cAMP on platelet-activating factor (PAF) biosynthesis in this cell. In the current study, the beta-adrenergic receptor agonist isoproterenol, alone or in combination with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), was used to increase cAMP in neutrophils. The incorporation of [3H]acetate into PAF and the synthesis of leukotrienes in response to ionophore A23187 were significantly inhibited by 10 microM isoproterenol. The inhibitory effect on PAF was potentiated by the addition of 10 microM IBMX. The effects of IBMX were mimicked by rolipram, an inhibitor of the cAMP-specific phosphodiesterase IV. Mass spectrometric analysis of the PAF molecular species in stimulated neutrophils indicated that the combination of isoproterenol and IBMX inhibited (> 50%) ionophore- and fMLP-induced production of PAF. To better understand the mechanism involved in the inhibition of PAF formation, the major biosynthetic steps were examined in the presence and absence of a maximally effective concentration of isoproterenol and IBMX. Isoproterenol alone or in the presence of IBMX had no measurable effect on the ionomycin-induced increase in cytosolic calcium concentration, as assessed by fura-2 fluorescence. Treating intact neutrophils with a combination of isoproterenol and IBMX did not inhibit acetyltransferase activity when assayed in a subsequent broken cell preparation. Finally, increasing cellular cAMP with these drugs did not influence the ability of the neutrophil to catabolize PAF. Phospholipase A2-like activity was assayed in the whole cell by measuring the mobilization of phospholipase A2 products, PAF, lyso PAF, and arachidonic acid, from cellular phosphoglycerides. Treatment of neutrophils with isoproterenol and IBMX significantly reduced the production of lyso PAF and PAF from 1-alkyl-2-arachidonoyl sn-glycero-3-phosphocholine. Similarly, increasing cellular levels of cAMP inhibited the cell's ability to mobilize arachidonic acid upon cell activation. These data suggest that increasing cellular levels of cAMP leads to the inhibition of PAF and leukotriene biosynthesis, at least in part, by regulation of phospholipase A2 activity.
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PMID:Influence of isoproterenol and phosphodiesterase inhibitors on platelet-activating factor biosynthesis in the human neutrophil. 839 98

In isolated inner medullary collecting duct (IMCD) cells requirements for the organic osmolyte glycerophosphorylcholine (GPC) vary with extracellular osmolality. To investigate mechanisms of osmotic adaptation GPC metabolism was studied under different osmotic conditions. In contrast to the GPC precursors choline and phosphatidylcholine (PC) cellular GPC was proportional to the osmolality. Hypotonic decrease in cellular GPC was mediated by fast initial release significantly exceeding the low hypertonic release. In long-term studies the total amount of GPC decreased significantly under hypotonic conditions but remained constant under hypertonic conditions resulting in a significant difference after 15 h. To investigate osmotic influences on GPC synthesis and GPC degradation studies with [methyl-3H]choline were performed. Pulse-chase experiments displayed no significant osmotic differences in PC synthesis or in PC degradation to GPC indicated by a similar specific activity of PC. This suggested that phospholipase A2 (PC degradation) was osmotically insensitive. A small and distinct metabolic PC pool may be responsible for high radioactive labeling of newly synthesized GPC which displayed a significantly higher specific activity under hypotonic conditions accompanied by a decrease in GPC amount. Therefore, a higher activity of glycerophosphorylcholine:choline phosphodiesterase (GPC:choline phosphodiesterase) (GPC degradation) under hypotonic conditions is proposed. Similar conclusions can be drawn from using phosphatidyl[methyl-3H]choline. As further evidence for osmotic regulation of GPC:choline phosphodiesterase the specific activity of choline displayed a significant hypotonic increase with chase time which may be equivalent to increased GPC degradation. Therefore, the in vitro experiments suggest that cellular GPC is regulated by an osmosensitive GPC:choline phosphodiesterase. Such a regulation also seems to be present during long-term in vivo experiments. No evidence was found for a genetic adaptation of GPC:choline phosphodiesterase in vivo.
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PMID:Metabolism of the 'organic osmolyte' glycerophosphorylcholine in isolated rat inner medullary collecting duct cells. II. Regulation by extracellular osmolality. 839 69

By means of CM-Sephadex C-25, DEAE-Sephadex A-50, Sephadex G-200, and Sephadex G-75 chromatographies, a lupus anticoagulant like protein (LALP) from Agkistrodon halys brevicaudus was purified. On SDS-PAGE, the purified LALP had a molecular weight of 25,500 daltons under non-reducing condition and 15,000 daltons under reducing condition. The isoelectric point was pH 5.6. Its N terminal amino acid sequencing revealed a mixture of 2 sequences: DCP(P/S)(D/G)WSSYEGH(C/R)(Q/K). It was devoid of phospholipase A, fibrino(geno)lytic, 5'-nucleotidase, L-amino acid oxidase, phosphomonoesterase, phosphodiesterase and thrombin-like activities, which were found in crude venom. In the presence of LALP, PT, aPTT, and dRVVT of human plasma were markedly prolonged and its effects were concentration-dependent but time-independent. The inhibitory effect of LALP on the plasma clotting time was enhanced by decreasing phospholipid concentration in TTI test. The individual clotting factor activity was not affected by LALP when higher dilutions of LALP-plasma mixture were used for assay. Russell's viper venom time was shortened when high phospholipid confirmatory reagent was used. Therefore, the protein has lupus anticoagulant property.
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PMID:Purification and characterization of lupus anticoagulant like protein from Agkistrodon halys brevicaudus venom. 897 23

Wine has been part of human culture for 6,000 years, serving dietary and socio-religious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high-density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl-CoA derivatives. Polymeric aggregation gives rise, in turn to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low-density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo-oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signalling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans.
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PMID:Wine as a biological fluid: history, production, and role in disease prevention. 929 95

We have demonstrated previously that isolated guinea-pig alveolar macrophages (AM) synthesize type-II phospholipase A2 (PLA2-II) through a tumour necrosis factor-alpha (TNF-alpha)-dependent process. This synthesis is enhanced by lipopolysaccharide (LPS) and accompanied by a release of prostaglandin E2 (PGE2) into the medium. Because agents elevating intracellular cAMP, such as PGE2, have been shown to stimulate PLA2-II expression in various cell types, we investigated the modulation of PLA2-II synthesis by cAMP in AM. Surprisingly, incubation of AM with PGE2, dibutyryl-cAMP, cholera toxin or rolipram (an inhibitor of specific cAMP-phosphodiesterase) inhibited both basal and LPS-stimulated PLA2-II expression. The inhibitory effect of PGE2 was observed at concentrations similar to those released by AM. Moreover, treatment of AM with either aspirin or neutralizing PGE2 monoclonal antibody stimulated PLA2-II synthesis. These effects were closely correlated with the ability of these agents to modulate TNF-alpha release, which was decreased by dibutyryl-cAMP and exogenous PGE2, whereas neutralizing PGE2 antibody markedly increased this release. Hence, in contrast to other cell systems, we report that: (i) agents elevating intracellular cAMP levels down-regulate both basal and LPS-induced PLA2-II synthesis, (ii) prostaglandins exert a negative feedback effect on this synthesis, probably through an elevation of intracellular cAMP levels, and (iii) inhibition of TNF-alpha release may account, at least in part, for the down-regulation of PLA2-II expression by endogenously produced prostaglandins and cAMP-elevating agents.
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PMID:Down-regulation by prostaglandins of type-II phospholipase A2 expression in guinea-pig alveolar macrophages: a possible involvement of cAMP. 946 95

One of the challenges in the therapy with anti-inflammatory drugs is the avoidance of gastrointestinal side effects, which may be achieved by selective inhibition of cyclooxygenase (COX) -2. CGP 28238 is reported with these characteristics inhibiting selectively the COX-2 activity at nanomolar concentrations. However, we report here on a novel action of this compound uncovered during the application of higher concentrations. In rat mesangial cells, CGP 28238 induced the mRNA and the protein of COX-2 as well as those of inducible nitric oxide synthase and soluble phospholipase A2. In the case of COX-2, this stimulation had no effect on the production of COX-2 metabolites because of the effective blockade of the enzyme. In contrast, the level of NO produced by the cells increased in a concentration-dependent manner from 1.2 to 12.5 nmol of nitrite/3 x 10(5) cells. Furthermore, in combination with low doses of IL-1 CGP 28238 superinduced the formation of nitrite. The observed effects were independent of the inhibition of prostaglandin formation, as suggested by the failure of the potent COX inhibitor diclofenac to cause similar effects. Furthermore, the activity and expression of enzymes downstream of the COX step, such as prostacyclin synthase, were unaffected by CGP 28238. The inductive action of CGP 28238 could be blocked by inhibitors for tyrosine kinases and protein kinase A, such as genistein and KT5720, respectively. The increase in intracellular cAMP concentration in rat mesangial cells and the inhibition by CGP 28238 of phosphodiesterase 4 activity with an IC50 value of 23 muM gave a rationale to explain the underlying mechanisms for the induction of the inflammatory response genes COX-2, soluble phospholipase A2 and inducible NO synthase in rat mesangial cells.
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PMID:On the induction of cyclooxygenase-2, inducible nitric oxide synthase and soluble phospholipase A2 in rat mesangial cells by a nonsteroidal anti-inflammatory drug: the role of cyclic AMP. 949 2

Rattlesnake venoms are complex biological products containing potentially autolytic components, and they provide a useful tool for the study of long-term maintenance of enzymes in a competent state, both in vivo and in vitro. To evaluate the stability of venom components, 15 aliquots of freshly extracted venom (from Crotalus molossus molossus) were subjected to 15 different temperature and storage conditions for 1 week and then lyophilized; conditions varied from storage at -80 degrees C (optimal preservation of activities) to dilution (1:24) and storage at 37 degrees C (maximal degradation potential). Effects of different storage conditions were evaluated using SDS-PAGE, metalloprotease zymogram gels, a cricket LD50 assay and enzyme assays (metalloprotease, serine proteases, phosphodiesterase, L-amino acid oxidase and phospholipase A2). Venom samples were remarkably refractive to widely varying conditions; enzyme activities of some samples were variable, particularly L-amino acid oxidase, and one sample treatment showed higher toxicity, but electrophoretic results indicated very little effect on venom proteins. This study suggests that most venom activities should remain stable even if stored or collected under potentially adverse conditions, and freezing samples is not necessarily advantageous. Proteins in the crude venom are not as labile as has been previously thought, and endogenous mechanisms present in the venoms likely inhibit autolysis during long-term storage that occurs in vivo in the gland.
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PMID:Effects of temperature and storage conditions on the electrophoretic, toxic and enzymatic stability of venom components. 953 Aug 14

Venoms from the scorpaeniformes Synanceja trachynis and Gymnapistes marmoratus were quantitatively analyzed for enzymic activity. S. trachynis venom displayed significantly higher hyaluronidase activity than G. marmoratus venom, and G. marmoratus venom displayed significantly higher levels of esterase, acid phosphatase, alkaline phosphatase and phosphodiesterase activity. No detectable quantities of phospholipase A2 activity were found in G. marmoratus venom. SDS-polyacrylamide gel electrophoresis of S. trachynis venom indicated the presence of 6 protein bands (20 kDa-295 kDa). G. marmoratus venom displayed 8 protein bands (11 kDa-109 kDa).
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PMID:Enzyme and biochemical studies of stonefish (Synanceja trachynis) and soldierfish (Gymnapistes marmoratus) venoms. 965 39

Glycerophosphrylocholine (GPC) is a renal medullary compatible organic osmolyte that is derived from choline via phosphatidylcholine, which is catalyzed in part by phospholipase A2 (PLA2) and its degradation by GPC: choline phosphodiesterase (GPC: choline PDE). We found that caffeine elevated intracellular free calcium ([Ca2+]i) and GPC level in cultured MDCK cells, canine kidney epithelial cells, and propose a possible biochemical mechanism. When MDCK cells were incubated for 3 h with 1 to 10 mM caffeine, cellular GPC was elevated in a dose-dependent manner, and this occurred independently of the extracellular osmolality. Caffeine stimulated the rate of [14C]choline incorporation into [14C]GPC and PLA2 activity. Whereas, GPC: choline PDE activity was accompanied by less of increase. These enzyme changes demonstrate the increased net synthesis of MDCK GPC. In order to identify what triggers the PLA2 activation, [Ca2+]i was measured by using a fluorescence dye, Fura-2. Caffeine (10 mM) resulted in a typical transient increase in MDCK [Ca2+]i concentration, and this increase was greatly inhibited by pretreatment of MDCK cells with 10 mM ryanodine for 5 min. Ryanodine (10 mM) also inhibited the caffeine-induced stimulation of PLA2 activity. These findings provide the first evidence that caffeine in MDCK cells causes a ryanodine-inhibitable increase of [Ca2+]i and PLA2 activity, resulting in cellular GPC accumulation.
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PMID:Caffeine causes glycerophosphorylcholine accumulation through ryanodine-inhibitable increase of cellular calcium and activation of phospholipase A2 in cultured MDCK cells. 987 37

In rat aortic rings, the mechanism of potentiating effect of genistein, a tyrosine kinase inhibitor, on the relaxation induced by isoproterenol was examined. Pretreatment of the aortic rings by genistein, but not by daidzein, an inactive analogue of genistein, potentiated the relaxation induced by isoproterenol. Genistein also potentiated the relaxation induced by forskolin, an activator of guanylyl cyclase, and dibutyryl cyclic AMP. In addition, theophylline, an inhibitor of phosphodiesterase, potentiated the relaxation induced by isoproterenol and forskolin. Theophylline partly inhibited the potentiation of isoproterenol-induced relaxation by genistein while it completely inhibited the potentiation of forskolin-induced relaxation by genistein. Iberiotoxin, an inhibitor of Ca-activated K (KCa) channels, partly inhibited the isoproterenol-induced relaxation and the potentiating effect of genistein on the relaxation induced by isoproterenol. Quinacrine (an inhibitor of phospholipase A2), alpha-naphthoflavone (an inhibitor of cytochrome P-450 enzymes), and 8-methoxypsoralen (an inhibitor of cytochrome P-450 enzymes), partly inhibited the potentiating effect of genistein on the isoproterenol-induced relaxation, but metyrapone (an inhibitor of cytochrome P-450 enzymes), indomethacin (an inhibitor of cyclooxygenase), and AA861 (an inhibitor of 5-lipoxygenase) did not. These results suggest that the potentiation of isoproterenol-induced relaxation by genistein may be related to the activities of phosphodiesterase, KCa channels, and cytochrome P-450 enzymes.
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PMID:The potentiating effect of genistein on the relaxation induced by isoproterenol in rat aortic rings. 1048 Jun 54


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