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)

Changes in the contents of adenine nucleotides, creatine phosphate, inorganic phosphate, creatine, glucose-6-phosphate and glycogen and the activity of adenylate cyclase, creatine kinase, glycogen phosphorylase 31:51-AMP-phosphodiesterase and glycogen synthetase in muscles and of blood catecholamines were studied in adult rats before loading, immediately after the cessation of the muscular activity, and at rest. Adenine nucleotides are established to play a regulatory role in catabolic and anabolic processes nucleotides are established to play a regulatory role in catabolic and anabolic processes related to the muscular activity. It is established that compensation and supercompensation of the working losses of muscular creatine phosphate and glycogen are due to activation of anabolic processes under conditions of higher phosphorylation of the adenylic system.
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PMID:[Dependence of creatine kinase and glycogen synthetase activities of skeletal muscles on state of adenine nucleotide phosphorylation and cAMP metabolism]. 624 97

After the intraperitoneal administration of 0.5 mEq 134 CsCI . kg -1 to mice, the maximum cesium level in the kidney's, heart, lungs and liver was found in the first hour (T 1/2 13 h), in the muscles after 8 h (T 1/2 180 h), in the brain after 24 h (T 1/2 140 h) and in the blood after 24 h. Maximum cesium levels were found in the muscles. Rats excreted about 17% of the administered dose in 24 h and 38% in 144 h. Most of the cesium (about 90%) is excreted in the urine. In rats, equalization of the plasma and RBC cesium levels takes longer than 6h. Cesium transport is not entirely dependent on the ATPase system, as shown by the results given by the crude mitochondrial fraction with a reduced potassium content. Among the various univalent ions studied, the effect of cesium on creatine kinase, 5'-nucleotidase, phosphodiesterase and deaminase activity was the smallest.
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PMID:Distribution of cesium in the organism and its effect on the nucleotide metabolism enzymes. 645 57

alpha-Toxin-permeabilized gastric glands represent a functional model in which acid secretion can be elicited by either adenosine 3',5'-cyclic monophosphate (cAMP) or ATP, with proven morphological and functional transition between resting and secretory states [X. Yao, S. M. Karam, M. Ramilo, Q. Rong, A. Thibodeau, and J. G. Forte. Am. J. Physiol. 271 (Cell Physiol. 40): C61-C73, 1996.] In this study we use alpha-toxin-permeabilized rabbit gastric glands to study energy metabolism and the interplay between nucleotides to support acid secretion, as indicated by the accumulation of aminopyrine (AP). When permeabilized glands were treated with a phosphodiesterase inhibitor, the secretory response to cAMP was inhibited, whereas the secretory response to ATP was potentiated. This implied that 1) ATP provided support not only as an energy source but also as substrate for adenylate cyclase, 2) activation of acid secretion by cAMP needed ATP, and 3) ATP and cAMP exchanged rapidly inside parietal cells. To address these issues, we tested the action of adenine nucleotides in the presence and absence of oxidizable substrates. All adenine nucleotides, including AMP, ADP, ATP, and cAMP, could individually enhance the glandular AP accumulation in the presence of substrates, whereas only a high concentration of ATP (5 mM) was able to support secretory activity in substrate-free buffer. Moreover, ATP could maintain 75-80% of maximal secretory activity in phosphate-free buffer; cAMP alone could not support secretion in phosphate-free buffer. In glands and in H(+)-K(+)-adenosinetriphosphatase-rich gastric microsomes, we showed the operation of adenylate kinase, creatine kinase, and ATP/ADP exchange activities. These enzymes, together with endogenous adenylate cyclase and phosphodiesterase, provide the recycling of nucleotides essential for the viability of alpha-toxin-permeabilized gastric glands and imply the importance of nucleotide recycling for energy metabolism in intact parietal cells.
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PMID:Nucleotide metabolism by gastric glands and H(+)-K(+)-ATPase-enriched membranes. 945 79

The phosphoramidate triester prodrugs of anti-human HIV 2', 3'-dideoxynucleoside analogs (ddN) represent a convenient approach to bypass the first phosphorylation to ddN 5'-monophosphate (ddNMP), resulting in an improved formation of ddN 5'-triphosphate and, hence, higher antiviral efficacy. Although phosphoramidate derivatization markedly increases the anti-HIV activity of 2',3'-didehydro-2', 3'-dideoxythymidine (d4T) in both wild-type and thymidine kinase-deficient CEM cells, the concept is far less successful for the 3'-azido-2',3'-dideoxythymidine (AZT) triesters. We now investigated the metabolism of triester prodrugs of d4T and AZT using pure enzymes or different biological media. The efficiency of the first activation step, mediated by carboxylesterases, consists of the formation of the amino acyl ddNMP metabolite. The efficiency of this step was shown to be dependent on the amino acid, alkyl ester, and ddN moiety. Triesters that showed no conversion to the amino acyl ddNMP accumulated as the phenyl-containing intermediate and had poor, if any, anti-HIV activity. In contrast to the relative stability of the triesters in human serum, carboxylesterase-mediated cleavage of the prodrugs was found to be remarkably high in mouse serum. The subsequent conversion of the amino acyl ddNMP metabolite to ddNMP or ddN was highest in rat liver cytosolic enzyme preparations. Although L-alaninyl-d4TMP was efficiently converted to d4TMP, the main metabolite formed from L-alaninyl-AZTMP was the free nucleoside (AZT), thus explaining why d4T prodrugs, but not AZT prodrugs, retain anti-HIV activity in HIV-infected thymidine kinase-deficient cell cultures. The rat liver phosphoramidase responsible for the formation of ddNMP was shown to be distinct from creatine kinase, alkaline phosphatase, and phosphodiesterase.
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PMID:Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine. 1049 51

Studies in respiratory alkalotic or short-term phosphate deprived rats raised the possibility that in straight portion of proximal tubules (PST) cAMP might be not a mediator of PTH in inhibition of phosphate reabsorption. The present experiments directly compared the sensitivity of Na-dependent phosphate [32P] (Na-Pi) uptake to PTH or cAMP by PCT or PST cells freshly prepared from outer cortex and outer stripe of outer medulla of rat kidney. The purity of the cells was examined by activity of enzymes specific for PST i.e. glutamine synthetase, gamma-glutamyl transpeptidase and creatine kinase, a marker enzyme for medullary thick ascending limb (MTAL) and distal convoluted tubule. Similar inhibition of Na-Pi uptake by 1-34 bPTH by PST and PCT cells was observed: -33.0 and -30.0% (ns), respectively. In contrast, dibutyryl cAMP decreased Na-Pi uptake only by PCT but not by PST cells: -31.0 and -3.6% (p<0.02), respectively. The 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, resulted in slight stimulation of Na-Pi uptake by PST but strong inhibition by PCT cells: 7.8 vs -26.0% (p<0.001). In contrast to PCT in PST cells cAMP seems to play a minor role as a mediator of inhibition of Na-Pi uptake by PTH.
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PMID:Dissociation of parathyroid hormone and cyclic-3', 5'AMP effects on Na-Pi uptake by cells isolated from proximal straight tubules of rat kidney. 1089 2

Myocardial contractile function after cardioplegic arrest is often depressed and an ideal cardioplegic solution has not been developed yet. The aim of this study was to assess the efficacy of phosphodiesterase III inhibitors, amrinone and enoximone, and levosimendan, a novel Ca2+ sensitizing agent, on recovery of hearts after normothermic cardioplegic arrest when added to the St. Thomas' hospital cardioplegic solution. In the control group, isolated guinea pig hearts were perfused in Langendorff apparatus and arrested with standard St. Thomas' solution. In other groups, amrinone (10(-5) mol.L-1), levosimendan (10(-5) mol.L-1), or enoximone (10(-4) mol.L-1) were added to the cardioplegic solution. In all hearts, intraventricular pressure, +dp/dtmax, -dp/dtmax, area under pressure-time curve, heart rate, coronary flow, lactate dehydrogenase and creatine kinase enzyme leakage, and oxygen consumption were measured. In the enoximone group, contractility force and +dp/dtmax, were found to be significantly high in the reperfusion and inotropic periods in comparison with other groups (p < 0.05). -dp/dtmax and area under contractility-time curve values were significantly high in inotropic period in enoximone group (p < 0.05). No statistically significant difference was noted in other groups. Cardioplegic solution enrichment with enoximone augmented mechanic functions in reperfusion period. No positive effect of amrinone or levosimendan was observed in this study.
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PMID:Comparison of enoximone, amrinone, or levosimendan enriched St. Thomas' hospital cardioplegic solutions used for myocardial preservation in isolated guinea pig hearts. 1251 45

We have previously shown that myogenesis induction by Arg8-vasopressin (AVP) in L6 rat myoblasts involves a sustained stimulation of type 4 cAMP-phosphodiesterase. In this model, we observed that a transient cAMP generation occurs in the minutes following AVP addition. Evidence suggests that cAMP generation is due to the prostaglandins produced in response to AVP binding to V1a receptors and subsequent activation of phospholipase A2. The early cAMP increase was effective in activating cAMP-dependent protein kinase (PKA) and increasing phosphorylation of CREB transcription factor. Inhibition of PKA by compound H89 prior to AVP addition led to a significant reduction of expression of the differentiation marker creatine kinase, whereas H89 added 1-5 h after AVP had no significant effect. Furthermore, PKA inhibition 24 h after the beginning of AVP treatment potentiated differentiation. This shows that both an early activation and a later down-regulation of the cAMP pathway are required for AVP induction of myogenesis. Because phosphodiesterase PDE4D3 overexpressed in L6 cells lost its ability to potentiate AVP-induced differentiation when mutated and rendered insensitive to PKA phosphorylation and activation, we hypothesize that the early cAMP increase is required to trigger the down-regulation of cAMP pathway through stimulation of phosphodiesterase.
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PMID:A bimodal modulation of the cAMP pathway is involved in the control of myogenic differentiation in l6 cells. 1450 85

During exercise, defects in calcium (Ca2+) release have been proposed to impair muscle function. Here, we show that during exercise in mice and humans, the major Ca2+ release channel required for excitation-contraction coupling (ECC) in skeletal muscle, the ryanodine receptor (RyR1), is progressively PKA-hyperphosphorylated, S-nitrosylated, and depleted of the phosphodiesterase PDE4D3 and the RyR1 stabilizing subunit calstabin1 (FKBP12), resulting in "leaky" channels that cause decreased exercise tolerance in mice. Mice with skeletal muscle-specific calstabin1 deletion or PDE4D deficiency exhibited significantly impaired exercise capacity. A small molecule (S107) that prevents depletion of calstabin1 from the RyR1 complex improved force generation and exercise capacity, reduced Ca2+-dependent neutral protease calpain activity and plasma creatine kinase levels. Taken together, these data suggest a possible mechanism by which Ca2+ leak via calstabin1-depleted RyR1 channels leads to defective Ca2+ signaling, muscle damage, and impaired exercise capacity.
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PMID:Remodeling of ryanodine receptor complex causes "leaky" channels: a molecular mechanism for decreased exercise capacity. 1826 35

Proteomic analysis of matrix vesicles (MVs) isolated from 17-day-old chicken embryo femurs revealed the presence of creatine kinase. In this report we identified the enzyme functionally and suggest that the enzyme may participate in the synthesis of ATP from ADP and phosphocreatine within the lumen of these organelles. Then, ATP is converted by nucleotide hydrolyzing enzymes such as Na(+), K(+)-ATPase, protein kinase C, or alkaline phosphatase to yield inorganic phosphate (P(i)), a substrate for mineralization. Alternatively, ATP can be hydrolyzed by a nucleoside triphosphate pyrophosphatase phosphodiesterase 1 producing inorganic pyrophosphate (PP(i)), a mineralization inhibitor. In addition, immunochemical evidence indicated that VDAC 2 is present in MVs that may serve as a transporter of nucleotides from the extracellular matrix. We discussed the implications of ATP production and hydrolysis by MVs as regulatory mechanisms for mineralization.
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PMID:Active creatine kinase is present in matrix vesicles isolated from femurs of chicken embryo: Implications for bone mineralization. 2002 5

Scatophagus argus of the family Scatophagidae inflicts painful wounds in fishermen while handling it. The venom induces prominent local tissue damage characterized by pain, edema and necrosis. The pathogenesis of acute muscle damage in gastrocnemius muscle induced by S. argus venom was studied in mice. The inflammatory response induced by S. argus venom in the mice hind paw was studied measuring paw edema. Intramuscular injection of S. argus venom induced motoxicity. The effect of S. argus venom on the cellular components of inflammatory response was investigated. Venom from S. argus were quantitatively analyzed for enzymic and biochemical activity. The biochemical changes induced by the sublethal concentration of S. argus venom and histopathological studies of effect of venom on mice were carried out. Venom induced a rapid increment in serum creatine kinase (CK) and lactate dehydrogenase (LDH) showing the myotoxicity of venom. Concomitant with this a reduction of muscle CK and LDH activity was observed, where as no increment in muscle lactate was detected. Our findings showed that the edematic activity was dose dependent and remained significantly elevated over 48 h after injection. Administration of S. argus venom caused a significant cell accumulation of neutrophils in to peritoneal cavity as well as foot pad up to 24h with maximal being at 4-6h. The venom components analyzed showed the presence of phosphodiesterase, acid phosphatases, alkaline phosphatases, proteinase, and caseinolytic activity. SDS PAGE revealed the presence of major and minor protein bands between 6.5 and 68 kDa. The biochemical changes induced by the sublethal concentration of S. argus venom showed reversible changes in the hematological (blood cell count, hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and platelet count) parameters which were significantly altered at 6 and 24h (GLM repeated measures p<0.05). Serum enzymes such as AST, ALT, ACP, ALP, LDH and urea were altered significantly which in turn confirmed the damage of vital organ tissue.
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PMID:Characterization of biological activity of Scatophagus argus venom. 2060 40


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