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)

By 2020, chronic obstructive pulmonary disease (COPD) will become the third leading cause of mortality and fifth leading cause of disability worldwide. Although traditionally therapeutic nihilism has dominated the approach to the management of COPD patients, it is becoming increasingly clear that COPD is a highly preventable and treatable condition. Smoking cessation is the most important therapy because it is the only intervention that has been shown to modify the accelerated decline in lung function that is characteristic of COPD. Domiciliary oxygen therapy for those who are hypoxemic at rest results in improved survival. Vaccinations and immunizations against influenza and pneumococcus should be encouraged. Bronchodilators are used for symptomatic relief. Recent introduction of long-acting bronchodilators facilitates good control of dyspnea with once or twice daily dosing. In conjunction with inhaled corticosteroids, they appear to produce added clinical benefits. Pulmonary rehabilitation and lung transplantation are other therapeutic options for select groups of patients. Many promising compounds are in various stages of development as future therapies in COPD. Drugs such as phosphodiesterase 4 inhibitors, tyrosine kinase blockers and peroxisome proliferator-activated gamma receptor agonists show great promise as disease-modifying agents in COPD.
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PMID:Therapeutic options for chronic obstructive pulmonary disease: present and future. 1574 84

Vanadyl(IV) ions (+4 oxidation state of vanadium) and their complexes have been shown to have in vitro insulinomimetic activity and to be effective in treating animals with diabetes mellitus. Although, researchers have proposed many vanadyl compounds for the treatment of diabetes patients, the mode of action of vanadyl compounds remains controversial. In order to evaluate the mode of action of these compounds, we examined the insulinomimetic activity of VOSO4, bis(picolinato)oxovanadyl(IV), and bis(maltolato)oxovanadyl(IV) in the presence of several inhibitors relevant to the glucose metabolism. After confirming that these vanadyl compounds were incorporated in the adipocytes as estimated by ESR method, we evaluated the mode of action by examining free fatty acids (FFA) release in the adipocytes. Inhibition of FFA release by these vanadyl compounds was found to be reversed by the addition of inhibitors, typically by cytochalasin B (glucose transporter 4 (GLUT4) inhibitor), cilostamide (phosphodiesterase inhibitor), HNMPA-(AM)3 (tyrosine kinase inhibitor), and wortmannin (PI3-k inhibitor), indicating that these compounds affect primarily GLUT4 and phosphodiesterase, as named "ensemble mechanism". Based on these results, we suggest that vanadyl compounds act on at least four sites relevant to the glucose metabolism, and on GLUT4 and phosphodiesterase in particular in rat adipocytes, which in turn normalizes the blood glucose levels of diabetic animals. The obtained results provide evidence for the role of vanadyl ion and its complexes in stimulation of the uptake and degeneration of glucose.
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PMID:Possible mode of action for insulinomimetic activity of vanadyl(IV) compounds in adipocytes. 1633 44

In recent years, pulmonary hypertension got into the focus of research due to the development of efficacious medications and the discovery of important pathologic mechanisms of disease. Currently, prostanoids, endothelin receptor antagonists and phosphodiesterase 5 inhibitors are the most important substance groups used for treatment. Substances that are emerging in tumor therapy (tyrosine kinase inhibitors, epidermal growth factor [EGF] und platelet-derived growth factor [PDGF] receptor blockers), vasoactive intestinal peptide (VIP), rho-kinase inhibitors and targeted drugs for endothelial dysfunction will be evaluated as future drugs for pulmonary hypertension. Improving early diagnosis of pulmonary hypertension will be an important task in the future. Both the development of diagnostic methods with increased sensitivity and specificity and a broad awareness program will be necessary to achieve this goal.
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PMID:[Pulmonary hypertension: the future has begun]. 1660 90

Airway epithelial damage is a cardinal feature of chronic asthma. Agents which enhance epithelial repair without triggering uncontrolled fibrosis of the mesenchyme would be predicted to be useful in the management of asthma. We have developed a repeat wound model using mucociliated human bronchial epithelial cell (HBEC) cultures to define the key pathways involved in airway epithelial repair, and to study the effects of potential therapeutic agents on epithelial repair in a chronic setting. We show that repair occurs primarily by cell migration to close a defect; this process requires activation of the EGF receptor (EGFR) and subsequent tyrosine kinase signalling. Migration is accompanied by up-regulation of CD44 in motile cells at the wound margins with proliferation of non-migrating cells adjacent to the wound area. In long-term studies beta2 adrenoceptor agonists and phosphodiesterase (PDE) inhibitors have no effect on repair potential, in contrast chronic treatment with the glucocorticoid dexamethasone extends the lifespan of repeatedly wounded differentiated cultures. We suggest part of the beneficial effects of glucocorticoids in asthma is related to this ability to prolong repair potential following repeated episodes of epithelial injury.
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PMID:Glucocorticoids increase repair potential in a novel in vitro human airway epithelial wounding model. 1678 32

GABA is the inhibitory neurotransmitter in most brain stem nuclei. The properties of release of preloaded [(3)H]GABA were now investigated with slices from the mouse brain stem under normal and ischemic (oxygen and glucose deprivation) conditions, using a superfusion system. The ischemic GABA release increased about fourfold in comparison with normal conditions. The tyrosine kinase inhibitor genistein had no effect on GABA release, while the phospholipase inhibitor quinacrine reduced both the basal and K(+)-evoked release in normoxia and ischemia. The activator of protein kinase C (PKC) 4beta-phorbol 12-myristate 13-acetate had no effects on the releases, whereas the PKC inhibitor chelerythrine reduced the basal release in ischemia. When the cyclic guanosine monophosphate (cGMP) levels were increased by superfusion with zaprinast and other phosphodiesterase inhibitors, GABA release was reduced under normal conditions. The NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine (HA) enhanced the basal and K(+)-stimulated release by acting directly on presynaptic terminals. Under ischemic conditions GABA release was enhanced when cGMP levels were increased by zaprinast. This effect was confirmed by inhibition of the release by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The NO-producing agents SNAP, HA, and sodium nitroprusside potentiated GABA release in ischemia. These effects were reduced by the NO synthase inhibitor N(G)-nitro-L: -arginine, but not by ODQ. The results show that particularly NO and cGMP regulate both normal and ischemic GABA release in the brain stem. Their effects are however complex.
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PMID:Modulation of GABA release by second messenger substances and NO in mouse brain stem slices under normal and ischemic conditions. 1705 71

In addition to combination treatment of pulmonary artery hypertension (PHT) with currently available drug options (endothelin-receptor inhibitors, phosphodiesterase-5 inhibitors, prostanoids). Numerous new drugs of other substance groups are being tested in preclinical and clinical studies. Most of the newly tried drugs use previously identified mechanisms of action that are involved in the development and progression of the underlying vascular disease. This has led to a certain paradigm shift which, in addition to vasodilatation and anti-platelet aggregation treatment, increasingly focuses on antiproliferative effects with the aim of preventing or regressing vascular remodelling. Of particular interest in this connection are tyrosine kinase inhibitors, which inhibit the action of such peptide growth factors as platelet-derived growth factor. Imatinib, one of this class of action, has given promising results in experimental studies and several case reports. Another greatly promising approach in the treatment of PHT are activators and simulators of soluble guanylyl cyclase, which are also currently being investigated in clinical trials.
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PMID:[Future aspects of the treatment of pulmonary arterial hypertension]. 1713 2

The release of the inhibitory neurotransmitter GABA is generally enhanced under potentially cell-damaging conditions. The properties and regulation of preloaded [3H]GABA release from mouse hippocampal slices were now studied in free radical-containing medium in a superfusion system. Free radical production was induced by 0.01% of H2O2 in the medium. H2O2 markedly potentiated GABA release, which was further enhanced about 1.5-fold by K+ stimulation (50 mM). In Ca2+-free media this stimulation was not altered, indicating that the release was mostly Ca2+-independent. Moreover, omission of Na+ increased the release, suggesting that it is mediated by Na+-dependent transporters operating outwards, a conception confirmed by the enhancement with GABA homoexchange. Inhibition of the release with the ion channel inhibitors diisothiocyanostilbene-2,2'-disulphonate and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate indicates that Cl(-) channels also participate in the process. This release was not modified by the adenosine receptor (A1 and A2a) agonists and ionotropic glutamate receptor agonists kainate, N-methy-D: -aspartate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, whereas the agonists of metabotropic glutamate receptors of group I [(S)-3,5-dihydroxyphenylglycine] and of group II [(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate] enhanced it by receptor-mediated mechanisms, the effects being abolished by their respective antagonists. The group III agonist L+-2-amino-4-phosphonobutyrate reduced the evoked GABA release, but this was not affected by the antagonist. Furthermore, the release was reduced by activation of protein kinase C by 4 beta-phorbol 12-myristate 13-acetate and by inhibition of tyrosine kinase by genistein and of phoshoplipase by quinacrine. On the other hand, increasing cGMP levels with the phosphodiesterase inhibitor zaprinast, selective for PDE5, 6 and 9, and NO production with the NO-generating compounds hydroxylamine, sodium nitroprusside and S-nitroso-N-penicillamine enhanced the release. The regulation of GABA release induced by free radical production proved thus to be rather complex. Under potentially cell-damaging conditions, the potentiation of GABA release may be a mechanism to counteract hyperactivity and reduce the effects of excitatory amino acid release. On the other hand, reduction of GABA release could be harmful and contribute to excitotoxic damage and neuronal degeneration.
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PMID:Characteristics of GABA release induced by free radicals in mouse hippocampal slices. 1771 30

Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that PC-1 (membrane [corrected] glycoprotein plasma cell antigen 1; also termed [corrected] ectonucleotide pyrophosphatase phosphodiesterase 1 or ENPP1) [corrected] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. PC-1 binds to the connecting domain of the IR alpha-subunit that is located in residues 485-599. The connecting domain transmits insulin binding in the alpha-subunit to activation of tyrosine kinase activation in the beta-subunit. When PC-1 is overexpressed, it inhibits insulin [corrected]induced IR beta-subunit tyrosine kinase activity. In addition, a polymorphism of PC-1 (K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio [corrected] and nephrovascular diseases. The product of this polymorphism has a 2- to 3-fold increased binding affinity for the IR and is more potent than the wild-type PC-1 protein (K121K) in inhibiting the IR. These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both.
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PMID:The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. 1819 90

In the brain stem glycine is associated with multiple sensory and visceral regulations, being involved in, for instance, cardiovascular, respiratory and auditory functions. We here studied the mechanisms of the release of preloaded [(3)H]glycine from mouse brain stem slices in a superfusion system. A depolarizing concentration of K(+) ions (50 mM) evoked glycine release, but in the absence of Ca(2+) the effect was attenuated, indicating that a part of the evoked release represents Ca(2+)-dependent exocytosis. The Ca(2+)-independent release was enhanced by omission of Na(+) and Cl(-). The stimulatory effect of extracellular glycine confirmed the involvement of transporters functioning in a reverse direction. A part of the release is mediated by Na(+) and Cl(-) channels, since it was inhibited by the inhibitors of these, riluzole and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate, respectively. Glycine release was potentiated by the activation of protein kinase C and diminished by increasing cyclic guanosine monophosphate levels with a phosphodiesterase inhibitor, zaprinast. The release was also modulated by the phospholipase inhibitor quinacrine and the tyrosine kinase inhibitor genistein. Adenosine A(1) receptors likewise regulate glycine release, since it was enhanced by their agonist R(-)N(6)-(2-phenylisopropyl)adenosine, which effect was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine. The ionotropic glutamate receptor agonists N-methyl-D: -aspartate, kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate failed to have any effects contrary to their effects in higher brain regions, e.g., in the hippocampus. The group I and III metabotropic glutamate receptor agonists (S)-3,5-dihydroxyphenylglycine and O-phospho-L: -serine, respectively, increased the release in a receptor-mediated manner. Glycine release in the brain stem was also markedly enhanced by cell-damaging conditions, including hypoxia, hypoglycemia and ischemia.
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PMID:Mechanisms of glycine release in mouse brain stem slices. 1860 Apr 48

Pulmonary arterial hypertension (PAH) is a devastating disease that is characterized by a high mortality. The pathogenesis of PAH is multifactorial. In addition to hereditary factors (e. g., BMPR2 mutations), numerous environmental factors may trigger the onset and progression of the disease. An imbalance between vasoconstrictive and vasodilative factors leads to vasoconstriction in the pulmonary circuit, resulting in an increase of pulmonary vascular resistance and pulmonary artery pressure. Alterations of several signaling pathways (i. e.; endothelin, nitric oxide and prostacyclin pathways) contribute to an increase of pulmonary vascular tone, and these pathways represent the targets of the current therapeutic interventions. However, PAH is increasingly recognized as a chronic proliferative disease particularly of the small pulmonary arteries, that is primarily characterized by morphological changes of the vascular wall ("vascular remodeling"). These changes are particularly induced by peptide growth factors such as platelet-derived growth factor (PDGF) that elicit their signals via activation of membrane-bound receptor tyrosine kinases (RTK). Accordingly, there is both experimental and clinical evidence for a therapeutic efficacy of tyrosine kinase inhibitors (TKI), which provide the basis for "reverse remodeling" strategies and indeed represent a promising novel approach for the treatment of PAH. Epidermal growth factor (EGF), soluble guanylate cyclase (sGC), and phosphodiesterase type 1 (PDE1) may represent additional future target molecules. PAH leads to progressive right heart failure which determines the outcome of PAH patients. The pathomechanisms of right heart failure should therefore also be considered for the development of novel therapeutic concepts.
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PMID:[Novel concepts in the pathobiology of pulmonary arterial hypertension]. 1881 87


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