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)

Calmodulin is known to bind to various amphipathic helical peptide sequences, and the calmodulin-peptide binding surface has been shown to be remarkably tolerant sterically. D-Amino acid peptides, therefore, represent potential nonhydrolysable intracellular antagonists of calmodulin. In the present study, synthetic combinatorial libraries have been used to develop novel D-amino acid hexapeptide antagonists to calmodulin-regulated phosphodiesterase activity. Five hexapeptides were identified from a library containing over 52 million sequences. These peptides inhibited cell proliferation both in cell culture using normal rat kidney cells and by injection via the femoral vein following partial hepatectomy of rat liver cells. These hexapeptides showed no toxic effect on the cells. Despite their short length, the identified hexapeptides appear to adopt a partial helical conformation similar to other known calmodulin-binding peptides, as shown by CD spectroscopy in the presence of calmodulin and NMR spectroscopy in DMSO. The present peptides are the shortest peptide calmodulin antagonists reported to date showing potential in vivo activity.
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PMID:Novel, potent calmodulin antagonists derived from an all-D hexapeptide combinatorial library that inhibit in vivo cell proliferation: activity and structural characterization. 1078 31

1. In rats, inhibition of type IV phosphodiesterase (PDE4) attenuates acute renal failure and early (hours) mortality induced by high-dose endotoxin. Because it is unlikely that protection of renal function accounts for improved early survivability, most likely PDE4 inhibition exerts multiple beneficial effects in endotoxaemia and the purpose of the present study was to test this hypothesis. 2. In study 1, we determined, in anaesthetized rats, the effects of endotoxin (30 mg/kg, i.v.) on cardiac performance parameters (heart rate (HR), ventricular peak systolic pressure (VPSP), maximum positive change in left ventricular pressure with respect to time (+dP/dt), maximum negative change in left ventricular pressure with respect to time (-dP/dtmax), ventricular end-diastolic pressure (VEDP), ventricular minimum diastolic pressure (VMDP) and HR-pressure product), plasma catecholamine levels, plasma renin activity (PRA) and plasma levels of inflammatory cytokines (tumour necrosis factor (TNF)-alpha and interleukin (IL)-lbeta). 3. In study 2, we determined, in anaesthetized rats, whether inhibition of PDE4 attenuates lipopolysaccharide (LPS)-induced changes in the aforementioned parameters of heart performance and neurohumoral status. We compared the changes in these parameters induced by endotoxaemia in animals treated with either RO 20-1724 (10 microg/kg per min; a selective PDE4 inhibitor) or its vehicle (DMSO; 1.35 microL/min). 4. At 90 min postadministration, endotoxin significantly increased HR and reduced -dP/dtmax and VEDP and caused a several-fold increase in plasma levels of TNF-alpha, IL-1beta, noradrenaline, adrenaline and PRA. RO20-1724 significantly blunted the endotoxin-induced reduction in -dP/dtmax and decreased endotoxin-induced increases in TNF-alpha and IL-1beta without significantly altering endotoxin-induced changes in HR, VEDP, catecholamine levels and PRA. 5. Results from these studies indicate that, in addition to preserving renal function, PDE4 inhibition attenuates inflammatory cytokine release caused by high-dose endotoxin and may have protective effects on diastolic function in early profound endotoxaemia.
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PMID:Inhibition of cytokine release by and cardiac effects of type IV phosphodiesterase inhibition in early, profound endotoxaemia in vivo. 1102 70

Sildenafil, in nanomolar serum levels, is an effective phosphodiesterase type 5 inhibitor, and facilitates penile erection only during sexual stimulation. However, there is limited information on the pharmacological activity of this agent when tissue levels approach millimolar concentrations following intracavernosal injection. The aim of this study was to investigate whether sildenafil causes penile erection in the absence of active neurogenic input. Organ bath preparations of rabbit penile cavernosal tissue strips were contracted with 1 microM phenylephrine and exposed to increasing concentrations of sildenafil in the absence or presence of the nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME; 0.6 mM). Sildenafil caused dose-dependent relaxation of rabbit cavernosal smooth muscle at high concentrations (>0.1 microM) with little or no effect at concentrations below 0.1 microM. The addition of L-NAME did not affect this response. In a separate protocol, sildenafil dose response determinations were performed in the presence of the guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ; 3 microM) or vehicle (50% dimethyl sulfoxide [DMSO]). Relaxation to sildenafil in the presence of DMSO was significantly enhanced relative to sildenafil alone. ODQ treatment partially attenuated relaxation to sildenafil, but failed to completely inhibit the response. In cavernosal tissue strips, sildenafil elevated basal cyclic guanosine monophosphate (cGMP) levels twofold (0.54 vs. 1.10 pmol/mg prot). To further investigate these observations, anesthetized rabbits were injected intracavernosally with sildenafil (0.3-1.3 mg). In the absence of pelvic nerve stimulation, the magnitude and duration of the intracavernosal pressure increased in a dose-dependent fashion in response to sildenafil, approaching the systemic arterial pressure at higher doses. Intracavernosal administration of L-NAME, at doses that inhibited pelvic nerve stimulated penile erection, did not alter the response to intracavernosal sildenafil at 1.3 mg. Sildenafil, at the doses tested, did not significantly change the systemic arterial pressure. These data suggest that intracavernosal sildenafil, at tissue levels approaching millimolar concentrations, can cause relaxation of vascular smooth muscle and penile erection by a novel mechanism independent of the classical NO/cGMP pathway.
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PMID:Intracavernosal sildenafil facilitates penile erection independent of the nitric oxide pathway. 1145 59

The characteristics and pathogenesis of the cardiovascular toxicity induced by the type III selective phosphodiesterase inhibitor SK&F 95654 were examined in 2 studies. Sprague-Dawley rats received either a single sc injection of 50, 100, or 200 mg/kg SK&F 95654 and were euthanized at 24 hours after administration of the drug (Study 1), or were given a single subcutaneous (sc) injection of 100 mg/kg SK&F 95654 and euthanized at 1, 2, 4, 6, 8,12, 24 hours, or 2 weeks after treatment (Study 2). Control rats received either DMSO or saline. Myocardial lesions and vascular lesions of the mesentery, spleen, and pancreas were seen 24 hours after dosing with either 50,100, or 200 mg/kg SK&F 95654. The frequency and severity of these lesions (evaluated after the 100 mg/kg dose) increased with time over a period of 1 to 24 hours. By 2 weeks, the lesions subsided. Cardiac lesions consisted of myocyte necrosis with hypercontraction bands, inflammatory cell infiltration, interstitial hemorrhage, and interstitial edema. Vascular lesions of the mesentery were most prominent and consisted of vasodilatation and inflammation in the small-sized vessels, arterial medial necrosis and hemorrhage, and venous thrombosis. The vascular lesions included: leukocyte adhesion to endothelial cells, transendothelial migration of leukocytes, and inflammatory cell infiltration into vessel walls. Affected vessels included arteries, terminal arterioles, capillaries, postcapillary venules, and veins. Apoptosis of endothelial and smooth muscle cells was detected in the mesenteric vasculature by both TUNEL assay and electron microscopy. Evidence of endothelial cell activation in the mesenteric arteries and veins was also observed by electron microscopy. Immunohistochemical staining detected enhanced endothelial cell expression of intercellular adhesion molecule- 1 (ICAM- 1) and von Willebrand factor (vWF) in the mesenteric arteries and veins. Mast cells were noted to be more prevalent in affected mesenteric tissue from drug-treated animals. The present findings suggest that apoptosis of endothelial and smooth muscle cells, activation of endothelial cells, recruitment of mast cells, and increased expression of adhesion molecules are important factors to the overall pathogenesis of SK&F 95654-induced vasculitis.
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PMID:SK&F 95654-induced acute cardiovascular toxicity in Sprague-Dawley rats--histopathologic, electron microscopic, and immunohistochemical studies. 1189 Apr 73

Walleye (Stizostedion vitreum) is a species of interest for the diversification of North American aquaculture production, and semen cryopreservation is of particular value to this effort. To test the hypothesis that adjusting semen extender composition and dilution ratio increases sperm quality after thawing, three extenders (Ext1, Ext2, Ext3; all with DMSO as a cryoprotectant) and three dilution ratios (semen/extender: 1:5, 1:9, 1:15) were screened. The best results were obtained when semen was diluted at a 1:15 ratio with Ext 1, Rathbun extender supplemented with 7% DMSO, 4 mg/ml BSA and 7.5 mg/ml ProFam, a soy-based protein (P = 0.05, n = 6). This method resulted in 46 +/- 3% motility of the thawed spermatozoa and a mortality rate of 39 +/- 4% whereas Ext2 and Ext3 resulted in motility rates of only 10 and 5%. respectively. To test an additional hypothesis that phosphodiesterase inhibition improves sperm function, we assessed the fertility of sperm frozen in optimal conditions and thawed in the presence or absence of 5 mM theophylline (n = 5). The best result was achieved in water without theophylline, with fertilization rates ranging from 28.51 +/- 6.84 to 59.02 +/- 1.06% eyed-up stage, and theophylline reduced fertility (P < 0.05). Our data show that Ext1 at a dilution ratio of one part semen to 15 parts extender should be used for walleye semen cryopreservation and that the fertilizing media does not benefit from theophylline supplementation.
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PMID:Comparison of extenders, dilution ratios and theophylline addition on the function of cryopreserved walleye semen. 1204

Phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus thuringiensis catalyzes the hydrolysis of phosphatidylinositol (PI) in a Ca(2+)-independent two-step mechanism: (i) an intramolecular phosphotransferase reaction to form inositol 1,2-(cyclic)-phosphate (cIP), followed by (ii) a cyclic phosphodiesterase activity that converts cIP to inositol 1-phosphate (I-1-P). Moderate amounts of water-miscible organic solvents have previously been shown to dramatically enhance the cyclic phosphodiesterase activity, that is, hydrolysis of cIP. Cosolvents [isopropanol (iPrOH), dimethylsufoxide (DMSO), and dimethylformamide (DMF)] also enhance the phosphotransferase activity of PI-PLC toward PI initially presented in vesicles, monomers, or micelles. Although these water-miscible organic cosolvents caused large changes in PI particle size and distribution (monitored with pyrene-labeled PI fluorescence, 31P NMR spectroscopy, gel filtration, and electron microscopy) that differed with the activating solvent, the change in PI substrate structure in different cosolvents was not correlated with the enhanced catalytic efficiency of PI-PLC toward its substrates. PI-PLC stability was decreased in water/organic cosolvent mixtures (e.g., the T(m) for PI-PLC thermal denaturation decreased linearly with added iPrOH). However, the addition of myo-inositol, a water-soluble inhibitor of PI-PLC, helped stabilize the protein. At 30% iPrOH and 4 degrees C (well below the T(m) for PI-PLC in the presence of iPrOH), cosolvent-induced changes in protein secondary structure were minimal. iPrOH and diheptanoylphosphatidylcholine, each of which activates PI-PLC for cIP hydrolysis, exhibited a synergistic effect for cIP hydrolysis that was not observed with PI as substrate. This behavior is consistent with a mechanism for cosolvent activation that involves changes in active site polarity along with small conformational changes involving the barrel rim tryptophan side chains that have little effect on protein secondary structure.
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PMID:Water-miscible organic cosolvents enhance phosphatidylinositol-specific phospholipase C phosphotransferase as well as phosphodiesterase activity. 1283 83

In isolated cells (vascular smooth muscle, endothelium, platelets), perfused hearts, in vivo experiments, conscious instrumented animals, and in human subjects the induction of tachyphylaxis and tolerance to various exogenous NO-donors was analyzed. Various ways to circumvent tolerance were successfully tested. Different nitrovasodilators were associated with different rates and magnitudes of generation of tolerance and reactive oxygen radicals (ROS) in all models tested, beginning with PETN (pentaerithrityltetranitrate) (lowest rate) and concluding with GTN (highest rate). This pattern was found in all models tested (isolated cells, perfused organs, and in vivo experiments). The observed changes in ROS production in isolated cells were identical to changes in ROS production in vascular smooth muscle, endothelial cells, and platelets. Thus, blood cells such as washed platelets could be used as marker cells to identify induction of tolerance and rise in platelet activity, closely reflecting changes in the rate of tolerance generation to nitrates associated with enhanced oxidant stress (ROS generation). Generation of tachyphylaxis could be suppressed or even avoided by supplementation of appropriate antioxidants (SOD, vitamin C, DMSO, beta-blockers with antioxidant capacity, modulators of prostanoid metabolism such as ASS) in all models tested, including human subjects. Even fully developed tolerance (during non-intermittent GTN-administration) could be reversed by starting an appropriate antioxidant supplementation. This indicates that other potential factors involved in the generation of nitrovasodilator-associated tolerance (reducing the intended vasodilation and the concovactent decreases in blood pressure, namely augmented sympathetic and RAS-activity, changes in the activity of soluble guanylyl cyclase, protein kinase C, phosphodiesterase, etc.) are of minor importance. Thus, the treatment of tolerance under clinical conditions should closely target changes in redox potential and antioxidant capacity.
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PMID:New approaches to overcome tolerance to nitrates. 1297 98

Our aim is to estimate the role of the DMSO on pre-T lymphoid human cells, we have searched the cyclase and phosphodiesterase activity. We have studied the GTPspecific cyclase (G-Case) and have observed an analogous course to that one of the cAMP-PDE, where, in both cases, the differences ratio is approximately 5. For the cyclase activity values it has been found that cAMP neo formed is undeterminable in these cells, for the controls and the treated samples.
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PMID:Cyclase and phosphodiesterase activity on pre-T lymphoid human cells, treated with dimethyl sulfoxide (DMSO). 1557 Dec 37

A phosphodiesterase model with two zinc centers has been synthesized and characterized. The compound, [Zn(2)(L(-)(2H))(AcO)(H(2)O)](PF(6)).2H(2)O (Zn(2)L'), was formed using an "end-off" type compartmental ligand, 2,6-bis{[(2-pyridylmethyl)(2-hydroxyethyl)amino]methyl}-4-methylphenol (L), and zinc acetate dihydrate. The X-ray crystallographic analysis shows that Zn(2)L' contains a mu-acetato-mu-cresolato-dizinc(II) core comprised of a quasi-trigonal bipyramidal Zn and a distorted octahedral Zn, and the distance between them is 3.421 Angstroms which is close to the dizinc distance in related natural metalloenzymes. Phosphodiesterase activity of Zn(2)L' was investigated using bis(4-nitrophenyl) phosphate (BNPP) as the substrate. The pH dependence of the BNPP cleavage in aqueous buffer media shows a sigmoid-shaped pH-k(obs) profile with an inflection point around pH 7.13 which is close to the first pK(a) value of 7.20 for Zn(2)L' obtained from the potentiometric titration. The catalytic rate constant (k(cat)) is 4.60 x 10(-6) s(-1) at pH 7.20 and 50 degrees C which is ca. 10(5)-fold higher than that of the uncatalyzed reaction. The deprotonated alcoholic group appended on Zn(2)L' is responsible for the cleavage reaction. The possible mechanism for the BNPP cleavage promoted by Zn(2)L' is proposed on the basis of kinetic and spectral analysis. The dizinc complex formed in situ in anhydrous DMSO exhibits a similar ability to cleave BNPP. This study provides a less common example for the phosphodiesterase model in which the metal-bound alkoxide is the nucleophile.
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PMID:An asymmetric dizinc phosphodiesterase model with phenolate and carboxylate bridges. 1587 22

Soy isoflavones have been reported to be natural chemopreventive in several types of human cancer. Daidzein and genistein are two main components of soy isoflavones. In our previous study, they were shown to be anti-proliferative and induce cell cycle arrest at S phase of SHZ-88 rat breast cancer cells. We hypothesized that soy isoflavones might exert its anticancer effect by activating cAMP/PKA pathway. The present study was designed to analyze the effect of soy isoflavones on the cAMP/PKA pathway in SHZ-88 cells. Daidzein and genistein were dissolved in DMSO. Cells were treated with 50 mug/ml daidzein and 15 mug/ml genistein, respectively, and with only equal DMSO in the culture medium as control. The cellular cAMP content was tested by radioimmunoassay (RIA). The activity of adenylate cyclase (AC), phosphodiesterase (PDE) and PKA were measured by RIA and (gamma-(32)P) ATP incorporation. Reverse transcript-polymerase chain reaction (RT-PCR) was used to analyze the expression of cAMP response element binding protein (CREB) mRNA of the cells. The results showed that the concentration of cAMP in the cells treated with 50 mug/ml daidzein and 15 mug/ml genistein was significantly increased by 9.5%and 11.0%, respectively, 5 min later (P<0.05), then increased by 31.0%and 40.3%, respectively, 10 min later (P<0.01), compared with that of the control group cells. The activity of AC was not affected during the course of experiment, but that of PDE was decreased to 71.8%and 71.6%, respectively, in the control group 5 min later (P<0.05). The PKA activity was increased to 125.8%and 122.3%, respectively, in the control group 20 min after the cells were treated with daidzein and genistein (P<0.05), and kept at high level till 40 min after treatment. CREB mRNA of the cells treated with daidzein and genistein was increased by 31.6%and 51.1%, respectively, 3 h later (P<0.05), then began to decrease 6 h after treatment. The current study suggests that soy isoflavones activate the cAMP/PKA pathway in SHZ-88 rat breast cancer cells by inhibiting the activity of phosphodiesterase.
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PMID:[Effect of soy isoflavones on cAMP/PKA pathway in breast cancer cells of the rat.]. 1609 2


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