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)

The plasma membranes of bovine adrenal chromaffin cells were isolated and the activities of enzymes involved in arachidonic acid liberation were investigated. Only a minute activity of phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4) could be detected using externally added phosphatidylcholine (PC) and phosphatidylethanolamine (PE) as substrate. When membranes were treated with exogenous phospholipase C (orthophosphoric acid diester phosphohydrolase, EC 3.1.4.1) there was a liberation of free fatty acids from the sn-2 position of PC. The enzyme responsible for this effect could be demonstrated to be a diacylglycerol lipase (glycerol ester hydrolase, EC 3.1.1.3) localized in the plasma membrane. Using phosphatidylinositol (PI) as a substrate, it was found that an endogenous phospholipase C exists which co-purifies with the membrane preparation. The produced diacylglycerol is subsequently hydrolyzed by diacylglycerol lipase liberating arachidonic acid. The two enzymes, phospholipase C and diacylglycerol lipase were characterized. Phospholipase C was found to be calcium dependent and PI specific, showing an activity of 60 pmol/micrograms protein per h (1.2 mM Ca2+), whereas the diacylglycerol lipase was calcium independent hydrolyzing diacylglycerol at a rate of 7.2 pmol/micrograms protein per h. The lipase but not the phospholipase C was inhibited 50% by 1.7 mM para-bromophenacylbromide.
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PMID:Phospholipase C and diacylglycerol lipase activities associated with plasma membranes of chromaffin cells isolated from bovine adrenal medulla. 308 88

A model for the regulation of erythropoietin production has been presented. This model proposes that a primary O2-sensing reaction in the kidney is initiated by a decrease in ambient PO2, a rapid decrease in gas exchange in the lung, a diminished oxygen-carrying capacity of hemoglobin, a molecular deprivation of oxygen, or a decrease in renal blood flow. It is proposed that the primary oxygen-sensing reaction may trigger the release of several mediators that stimulate adenylate cyclase through a receptor-activated stimulation of a G protein in the renal cell membrane. Some of the agents that are thought to be released during hypoxia, which may trigger this cascade, are adenosine (A2 activation), eicosanoids (PGE2, PGI2, and 6-keto PGE1), oxygen-free radicals (superoxide and H2O2), and catecholamines with beta-2 adrenergic receptor agonist properties. The activation of adenylate cyclase generates cyclic AMP, which activates protein kinase A, leading to the production of a phosphoprotein that, in turn, activates a nuclear protein involved in transcription and/or translation for erythropoietin biosynthesis and/or secretion. A second part of this model concerns the effect of hypoxia on a renal cell membrane phosphodiesterase and the generation of inositol triphosphate and diacylglycerol. Diacylglycerol may interact with diacylglycerol lipase to generate arachidonic acid, which, together with arachidonic acid generated by the interaction of phospholipase A2 on membrane phospholipids, produces eicosanoids. Eicosanoids may play a secondary role in Ep production/secretion. The model further proposes that calcium levels in both renal and liver cells may be important in regulating erythropoietin biosynthesis and/or secretion. It is proposed that an increase in intracellular calcium leads to the inhibition of erythropoietin biosynthesis and/or secretion and a decrease in intracellular calcium increases erythropoietin production. The specific mechanism by which calcium regulates erythropoietin biosynthesis and secretion is not well understood. However, a good correlation is seen with several agents that decrease intracellular calcium and increase erythropoietin production as well as with other agents that increase intracellular calcium and decrease erythropoietin production. When inositol triphosphate levels are increased, an increase in the mobilization of intracellular calcium from the endoplasmic reticulum or another intracellular pool occurs. This increased intracellular calcium probably activates a calcium calmodulin kinase and produces a phosphoprotein that inhibits erythropoietin production/secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacologic modulation of erythropoietin production. 328 82

Young swine (28 days of age) were fed an isocaloric and isonitrogenous diet with either a high fat or a low fat content for 3 to 4 weeks. The adipose tissue lipolytic rate was higher in the group fed the high fat diet. However, there was no effect of diet on the activities of several of the enzymes controlling the lipolytic process, i.e., adenylate cyclase, phosphodiesterase and hormone-sensitive lipase. No effect of diet on the activity of lipoprotein lipase was detected. Fasting for 72 hr, but not for 24 or 48 hr, caused an increase in the lipolytic rate. There was also a decrease in cell size after a 72-hr fast (P greater than .05) such that the increased rate was not significant when the data were expressed on a cell basis. Inexplicable transient changes in adenylate cyclase activity, as well as a decrease in the activity of the low affinity phosphodiesterase (doubtful physiological significance), were detected during starvation. Starvation depressed the adipose tissue lipoprotein lipase activity but had no effect on the hormone-sensitive lipase activity.
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PMID:Effect of nutritional status on swine adipose tissue lipolytic activities. 627 20

1. A rat brain supernatant and microsomal fraction contained a phospholipase A1 enzyme which hydrolysed phosphatidylinositol at pH 8 in the absence of calcium. Triolein and phosphatidylcholine were not attacked under the same incubation conditions. 2. No evidence could be obtained for a phospholipase A2 in the microsomal preparation, and in the presence of Ca2+ the release of fatty acid observed was due to phosphatidylinositol phosphodiesterase followed by diacylglycerol lipase action. 3. Brain phosphatidylinositol phosphodiesterase showed extensive activity in the alkaline range (7-8.5) as well as at pH 5-5.5. The activity at higher pH values required higher calcium concentrations and disappeared on purification of the soluble enzyme by ammonium sulphate fractionation. 4. In general the ratio between inositol 1,2-(cyclic)phosphate and inositol 1-phosphate produced by phosphodiesterase action decreased with increasing pH.
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PMID:The catabolism of phosphatidylinisitol by an EDTA-insensitive phospholipase A1 and calcium-dependent phosphatidylinositol phosphodiesterase in rat brain. 627 69

In this study, the effects of caffeine on lipoprotein lipase (LPL) gene expression were investigated in the 3T3-F442A preadipocyte cell line during the adipocyte differentiation process by determining LPL enzymatic activity and its messenger RNA (mRNA) level. The results demonstrate that caffeine acts on the gene expression of LPL, an early marker of adipocyte differentiation. It has a biphasic action: it increases gene expression in terms of mRNA when it is added to preadipocytes during the early stage of differentiation, but this is accompanied by a reduction of enzymatic activity. On the other hand, when caffeine is added for long periods during differentiation and/or when it is added to mature adipocytes, it induces marked inhibition of mRNA levels, correlated with a marked reduction of secreted enzymatic activity. The inhibitory effect of caffeine on LPL mRNA level can be reproduced by theophylline, a phosphodiesterase inhibitor, and by dibutyryl cyclic AMP, a non-metabolizable analog of cyclic AMP. However, the effect of caffeine and theophylline lasts longer than that of cyclic AMP, suggesting that a mechanism other than inhibition of cyclic AMP hydrolysis may be involved in the action of caffeine.
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PMID:Effects of caffeine on lipoprotein lipase gene expression during the adipocyte differentiation process. 962 92

Astilbin, a dihydroflavonol rhamnoside isolated from the leaves of Engelhardtia chrysolepis, enhanced the vanadate-stimulated release of lipoprotein lipase (LPL) activity from rat isolated fat pads. N-[2-(Methyl-amino)ethyl]-5-isoquinolinesulfonamide (H-8), a potent inhibitor of cAMP-dependent protein kinase (PKA), markedly inhibited the enhancement by astilbin. Lipolysis in the fat pads was stimulated by astilbin alone in a dose-dependent manner and this stimulation was suppressed in the presence of vanadate, probably due to its antilipolytic action. A significant enhancement by astilbin was observed with increasing effects of vanadate on cAMP content in the fat pads and on cAMP phosphodiesterase (PDE) activity in the particulate fraction although astilbin alone showed only a slight increase in the cellular cAMP content and PDE activity. Astilbin may enhance the vanadate-stimulated release of LPL activity through a synergistic effect on an increase in the cellular cAMP content produced by vanadate accompanied by more potent activation of PKA.
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PMID:Enhancement of the vanadate-stimulated release of lipoprotein lipase activity by astilbin from the leaves of Engelhardtia chrysolepis. 963 10

The action of lipoprotein lipase on chylomicrons (CM) and very low density lipoproteins (VLDL) produces remnant lipoproteins (RLP) which are rich in triglycerides, cholesterol and apolipoprotein E (apo E). Apo E serves as a ligand for uptake of RLP by macrophages, platelets, endothelial cells and other cells expressing the LDL-receptor or the remnant receptor, thus having a major role in the clearance of plasma cholesterol and triglycerides, but at the same time, uptake of apo E-bearing RLP can profoundly alter the physiology of these cells and promote atherosclerosis. Like RLP, blood platelets also have roles in atherosclerosis and thrombosis, hence it is likely that RLP influence platelet activity as well. RLP derived from normal human plasma VLDL and CM were prepared using two monoclonal antibodies, anti-apo B-100 (JI-H) and anti-apo A-I (H-12) coupled to Sepharose 4B gel to form an immunoaffinity column. Lipoproteins containing apo B-100 including VLDL and LDL adsorb to (JI-H)-gel, while CM and HDL with apo A-I adsorb to (H-12)-gel. The particles in the unbound fraction (RLP) are rich in apo B-48, apo E and apo B-100 containing particles with multiple molecules of apo E. The RLP fraction with a total triglyceride of 14+/-3.2 mg/ml; cholesterol, 0.39+/-0.1 mg/ml and protein, 0.78+/-0.24 mg/ml (n=19) was added to aliquots of blood of man, rabbits, guinea pigs, mice, and rats at protein equivalents of 0.98 to 78 microg/ml blood and agitated gently at 37 degrees C for 40 sec. Platelet aggregation was measured as a fall in single platelet count. RLP induced aggregation of platelets in man (p<0.005) rabbit (p<0.0005), guinea pig (p<0.002) and mouse (p<0.0001), but no RLP induced platelet aggregation was observed in the rat blood. Scanning electron microscopy revealed that in the presence of RLP, platelets had adhered to and formed aggregates on red cells. The platelet response to RLP was inhibited by apyrase known to scavenge ADP, by 5 microM 2-chloroadenosine, a platelet ADP receptor antagonist and by 3.4 microM cilostazol, a phosphodiesterase type III inhibitor known to raise cyclic AMP level in platelets. It is thought that RLP cause leakage of ADP from red cells which then mediates platelet aggregation.
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PMID:Adenosine 5'-diphosphate as a factor in platelet aggregation induced by human plasma remnant lipoproteins. 974 29

Cilostazol, a selective type III phosphodiesterase inhibitor, has antiplatelet and vasodilating effects. In this study, the effects of cilostazol on lipid metabolism and lipoprotein lipase (LPL) activity were studied in rats. Cilostazol was administered orally at doses of 30 or 100 mg/kg twice a day for 1-2 weeks to rats. Cilostazol decreased the serum triglyceride level in normolipidemic rats. The serum triglyceride level was reduced and HDL cholesterol level was increased by cilostazol in streptozotocin (STZ)-induced diabetic rats. The disappearance of exogenous triglyceride was accelerated by cilostazol in normolipidemic rats. Cilostazol increased post-heparin plasma LPL activity but had no effect on hepatic triglyceride lipase activity in STZ-induced diabetic rats. Cilostazol also increased LPL activity in the heart in STZ-induced diabetic rats. These findings suggest that an increase in LPL activity is responsible for the serum triglyceride lowering and HDL cholesterol elevating effects of cilostazol in rats.
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PMID:Cilostazol, a selective type III phosphodiesterase inhibitor, decreases triglyceride and increases HDL cholesterol levels by increasing lipoprotein lipase activity in rats. 1099 57

The action of lipoprotein lipase on chylomicrons (CM) and very low density lipoproteins (VLDL) produces remnant lipoproteins (RLP) that are rich in triglycerides, cholesterol and apolipoprotein E (apo E). Apo E serves as a ligand for the LDL receptor and mediates uptake of RLP by macrophages, vascular wall and other cells that express the LDL receptor. Uptake of RLP can profoundly alter the physiology of cells and promote atherosclerosis and thrombosis. Like RLP, blood platelets also have roles in atherosclerosis and thrombosis; hence it is likely that RLP can influence platelet activity as well. Platelet aggregation was assessed by measuring the loss of single platelets. Apo E3/3-rich RLP derived from normal human plasma VLDL and CM were prepared by an immunoseparation method. At 2.5 to 10 microliters, RLP induced platelet aggregation that increased with the dose of RLP, but decreased it at 25 to 200 microliters. Unlike apo E3/3-rich RLP, apo E4/3 (heterozygous phenotype) rich RLP caused platelet aggregation in a dose-dependent manner, without producing a bell-shape dose-response relationship. Scanning electron microscopy revealed that activated platelets had adhered to and formed aggregates on the red cell membrane. The platelet response was unaffected by aspirin, but was inhibited by apyrase (an ADP scavenger), 2-chloroadenosine (a platelet ADP-receptor antagonist) and cilostazol, a phosphodiesterase type III inhibitor. It is thought that RLP cause leakage of ADP from red cells, which then mediates platelet aggregation.
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PMID:[Aggregation of human blood platelets by remnant-like lipoprotein particles]. 1121 76

Cilostazol, a novel oral phosphodiesterase inhibitor, has shown consistent improvement in exercise tolerance in patients with intermittent claudication (IC). In addition to this effect, cilostazol has previously been shown to have beneficial effects on the dyslipidemia, i.e., combination of high triglycerides with low high-density-lipoprotein cholesterol (HDL-C) levels. Interleukin-6 (IL-6) suppresses the activity of lipoprotein lipase, which modulates the metabolism of triglycerides and HDL-C. To determine whether a reduction of IL-6 contributes to the improvement of lipid profiles, we prospectively investigated the effect of cilostazol (n=16, 100 mg, twice daily) on the changes of lipid profiles and on the association with the changes of IL-6 compared with those of pentoxifylline (n=16, 400 mg, bid) in patients with IC. After eight weeks of administration of cilostazol to patients with IC, walking distances were increased, associated with a 29% decrease in plasma triglycerides and a 13% increase in HDL-C. No significant changes of lipid profiles in the pentoxifylline and placebo groups were observed although a similar improvement in walking distances was achieved in the pentoxifylline group. IL-6 levels were significantly reduced in patients receiving cilostazol as compared with those receiving placebo or pentoxifylline. The cilostazol-induced changes in the IL-6 were positively related to those of triglycerides in the cilostazol group (r=0.63, P<0.05) and negatively related to those of HDL-C (r=-0.55, P<0.05). These findings suggest that in addition to consistent improvement of exercise tolerance, cilostazol may improve lipid profiles by reducing IL-6 release. However, pentoxifylline did not affect lipid profiles although a similar improvement of maximal walking distance (MWD) was achieved.
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PMID:Differential lipogenic effects of cilostazol and pentoxifylline in patients with intermittent claudication: potential role for interleukin-6. 1158 28


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