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)

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.
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PMID:A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. 1207 Mar 53

Chronic lymphocytic leukemia therapy has changed dramatically over the past decade, with recent studies supporting the use of fludarabine as the initial therapy for symptomatic disease. New findings relative to the use of fludarabine and complications arising from this therapy are reviewed. Exciting combination approaches using monoclonal antibodies such as rituximab or Campath-1H in combination with fludarabine offer the opportunity to improve the complete response rate further in chronic lymphocytic leukemia. Furthermore, the field of experimental therapeutics for chronic lymphocytic leukemia was advanced by the description of a new mouse model of human chronic lymphocytic leukemia and identification of several disrupted signal transduction pathways in this disease. The description of therapies that target AKT, protein kinase C, phosphodiesterase 4, mammalian target of rapamycin, histone deacetylase, and methyltransferase offer the opportunity to utilize molecularly targeted therapy for this disease. Such targeted approaches offer hope that we might be on the threshold to changing the natural history of chronic lymphocytic leukemia.
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PMID:Advances in the therapy of chronic lymphocytic leukemia. 1279 36

Chronic obstructive pulmonary disease (COPD) is a common, smoking-related, severe respiratory condition characterised by progressive, irreversible airflow limitation. Current treatment of COPD is symptomatic, with no drugs capable of halting the relentless progression of airflow obstruction. Better understanding of the airway inflammation, oxidative stress and alveolar destruction that characterise COPD has delineated new disease targets, with consequent identification of novel compounds with therapeutic potential. These new drugs include aids to smoking cessation (e.g. bupropion) and improvements to existing therapies, for example long-acting rather than short-acting bronchodilators, as well as combination therapy. New antiproteases include acyl-enzyme and transition state inhibitors of neutrophil elastase (e.g. sivelestat and ONO-6818), matrix metalloprotease inhibitors (e.g. batimastat), cathepsin inhibitors and peptide protease inhibitors (e.g. DX-890 [EPI-HNE-4] and trappin-2). New antioxidants include superoxide dismutase mimetics (e.g. AEOL-10113) and spin trap compounds (e.g. N-tert-butyl-alpha-phenylnitrone). New anti-inflammatory interventions include phosphodiesterase-4 inhibitors (e.g. cilomilast), inhibitors of tumour necrosis factor-alpha (e.g. humanised monoclonal antibodies), adenosine A(2a) receptor agonists (e.g. CGS-21680), adhesion molecule inhibitors (e.g. bimosiamose [TBC1269]), inhibitors of nuclear factor-kappaB (e.g. the naturally occurring compounds hypoestoxide and (-)-epigallocatechin-3-gallate) and activators of histone deacetylase (e.g. theophylline). There are also selective inhibitors of specific extracellular mediators such as chemokines (e.g. CXCR2 and CCR2 antagonists) and leukotriene B(4) (e.g. SB201146), and of intracellular signal transduction molecules such as p38 mitogen activated protein kinase (e.g. RWJ67657) and phosphoinositide 3-kinase. Retinoids may be one of the few potential treatments capable of reversing alveolar destruction in COPD, and a number of compounds are in clinical trial (e.g. all-trans-retinoic acid). Talniflumate (MSI-1995), an inhibitor of human calcium-activated chloride channels, has been developed to treat mucous hypersecretion. In addition, the purinoceptor P2Y(2) receptor agonist diquafosol (INS365) is undergoing clinical trials to increase mucus clearance. The challenge to transferral of these new compounds from preclinical research to disease management is the design of effective clinical trials. The current scarcity of well characterised surrogate markers predicts that long-term studies in large numbers of patients will be needed to monitor changes in disease progression.
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PMID:Therapy for chronic obstructive pulmonary disease in the 21st century. 1296 14

The enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT), a member of the nucleotidyltransferase alpha/beta phosphodiesterase superfamily, catalyzes the reaction NMN + ATP = NAD + PPi, representing the final step in the biosynthesis of NAD, a molecule playing a fundamental role as a cofactor in cellular redox reactions. NAD also serves as the substrate for reactions involved in important regulatory roles, such as protein covalent modifications, like ADP-ribosylation reactions, as well as Sir2 histone deacetylase, a recently discovered class of enzymes involved in the regulation of gene silencing. This overview describes the most recent findings on NMNATs from bacteria, archaea, yeast, animal and human sources, with detailed consideration of their major kinetic, molecular and structural features. On this regard, the different characteristics exhibited by the enzyme from the various species are highlighted. The possibility that NMNAT may represent an interesting candidate as a target for the rational design of selective chemotherapeutic agents has been suggested.
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PMID:Structure and function of nicotinamide mononucleotide adenylyltransferase. 1507 71

Although theophylline has side effects when used in bronchodilator doses, increasing evidence shows that it has significant antiinflammatory effects in chronic obstructive pulmonary disease at lower plasma concentrations. These antiinflammatory effects are unlikely to be accounted for by phosphodiesterase inhibition or adenosine receptor antagonism, which require higher concentrations. There is now evidence that theophylline at low therapeutic concentrations is an activator of histone deacetylases and that this activation enhances the antiinflammatory effect of corticosteroids. There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance. Theophylline has been shown to restore steroid sensitivity in vitro. The effect of theophylline on histone deacetylase activity appears to be enhanced by oxidative stress. The mechanism whereby theophylline activates histone deacetylase is not yet known, but it does not involve other known actions of theophylline that account for its side effects. Better understanding of the molecular basis for the action of theophylline might lead to the development of novel drugs.
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PMID:Theophylline in chronic obstructive pulmonary disease: new horizons. 1626 58

For a number of patients with bipolar disorder, current pharmacotherapy is generally insufficient. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability, and significant medical and psychiatric comorbidity. Drug development for bipolar disorder may occur through one of two approaches: the first is by understanding the therapeutically relevant biochemical targets of currently effective medications. Two promising direct targets of lithium and valproate are glycogen synthase kinase-3 and histone deacetylase. The second path results from our understanding that severe mood disorders, although not classical neurodegenerative disorders, are associated with regional impairments of structural plasticity and cellular resilience. This suggests that effective treatments will need to provide both trophic and neurochemical support, which serves to enhance and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of mood disorders include inhibitors of glutamate release, N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid potentiators, cyclic adenosine monophosphate phosphodiesterase inhibitors, and glucocorticoid receptor antagonists.
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PMID:Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. 1648 91

Theophylline has been relegated to a second- or even third-line therapy in the treatment of asthma and chronic obstructive pulmonary disease (COPD), behind glucocorticosteroids and beta2-agonists, although recent findings have suggested that theophylline possesses anti-inflammatory and immunomodulatory effects in addition to its well-recognized effects as a bronchodilator. In part, theophylline has fallen out of favor because of its adverse side-effect profile, and this has led to the search for more effective and safer drugs based on the knowledge that theophylline is orally active and that it is a nonselective phosphodiesterase (PDE) inhibitor. This has led to the development of selective PDE4 inhibitors, originally designed for depression, for the treatment of both COPD and asthma. Such drugs have shown clinical efficacy in the treatment of respiratory disease while having a considerably safer side-effect profile in comparison with theophylline, particularly because there are no reported drug interactions with PDE4 inhibitors, a feature that complicates the use of theophylline. In addition, it is also becoming increasingly apparent that theophylline is not working solely through PDE inhibition, as formerly assumed, and that this drug has other relevant pharmacologic activities that are likely to contribute to its efficacy, such as adenosine receptor antagonism and induction of histone deacetylase. Thus, the introduction of PDE4 inhibitors represents an entirely new class of drugs for the treatment of respiratory disease.
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PMID:Are phosphodiesterase 4 inhibitors just more theophylline? 1675 Sep 81

Increased neutrophils are a feature of airway inflammation in patients with chronic obstructive pulmonary disease and in some patients with asthma, particularly patients with more severe disease, during exacerbations and with cigarette smoking. Because neutrophilic inflammation may be detrimental, there are several new approaches to inhibiting neutrophilic inflammation. Neutrophilic inflammation is resistant or poorly responsive to corticosteroids, so different anti-inflammatory approaches are needed. Blocking neutrophil chemotactic factors such as leukotriene B(4) and IL-8 and related cysteine-X-cysteine chemokines by blocking receptor for leukotriene B(4) 1 and receptor for cysteine-X-cysteine chemokines 2 receptors is an approach that is currently being investigated. Other approaches include blocking adhesion molecules such as E-selectin. Inhibiting phosphodiesterase-4, nuclear factor-kappaB, or p38 mitogen-activated protein kinase is another approach that inhibits the production of cysteine-X-cysteine chemokines. Antioxidants, long-acting beta(2)-agonists, and activators of histone deacetylase may also be effective.
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PMID:New molecular targets for the treatment of neutrophilic diseases. 1735 33

The mainstay of current drug therapy is long-acting bronchodilators; several longer acting inhaled beta(2)-agonists and muscarinic antagonists (and combinations) are now in development. No treatments have so far been shown to reduce the progression or suppress the inflammation of COPD. With better understanding of the inflammatory and destructive processes in the pathophysiology of COPD, several new targets have been identified. Several mediator antagonists tested in COPD patients have so far been disappointing, but CXC receptor 2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad-spectrum antiinflammatory drugs, including inhibitors of the enzymes phosphodiesterase 4, p38 mitogen-activated protein kinase, nuclear factor-kappaB, and phosphoinositide-3-kinase-gamma, may be more effective, but the side effects will be a major limitation so that inhaled delivery may be necessary. Perhaps the most promising approach is the reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by theophylline-like drugs, more effective antioxidants, and nonantibiotic macrolide agents.
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PMID:Emerging pharmacotherapies for COPD. 1905 58

Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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PMID:Glucocorticoid resistance in inflammatory diseases. 1948 16


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