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 development of chronic heart failure (CHF) includes phenotypic changes in a host of homeostatic systems so that, as the disease advances, CHF may be seen as a multi-system disorder with its origins in the heart but embracing many extra-cardiac manifestations. Immunological abnormalities are recognised in this context, in particular, changes in the expression of mediators of the innate immune response. Higher levels of the pro-inflammatory cytokine tumor necrosis factor (TNF) are found in the circulation and in the myocardium of patients with CHF than in controls, and TNF has been implicated in a number of pathophysiological processes that are thought important to the progression of CHF. Therapies directed against this cytokine therefore represent a novel approach to heart failure management. Anti-TNF strategies in CHF may target the mechanisms of immune activation, the intracellular pathways regulating TNF production, or the fate of TNF once it has been released into the circulation. Circulating endotoxin may be an important stimulus to TNF production by circulating monocytes, tissue macrophages and cardiac myocytes in CHF and efforts to limit this phenomenon are of interest. Several established pharmacological therapies for patients with CHF, including angiotensin converting enyzme inhibitors, beta-blockers, and phosphodiesterase inhibitors may modify cellular TNF production by their action on intracellular mechanisms, whereas TNF receptor fusion proteins have been developed that target circulating TNF itself. Patients with New York Heart Association class IV symptoms, those with cardiac cachexia and those with oedematous decompensation of their disease have the highest serum TNF levels and are most likely to benefit most from such a therapeutic approach.
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PMID:Tumour necrosis factor in chronic heart failure: a peripheral view on pathogenesis, clinical manifestations and therapeutic implications. 1115 10

Human airway smooth muscle (HASM) cells release granulocyte macrophage-colony stimulating factor (GM-CSF) and express cyclooxygenase (COX)-2 (resulting in the release of prostaglandin [PG] E2) after stimulation with cytokines. Because COX-2 activity can regulate a number of inflammatory processes, we have assessed its effects, as well as those of agents that modulate cyclic adenosine monophosphate (cAMP), on GM-CSF release by HASM cells. Cells stimulated with a combination of proinflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha each at 10 ng/ml) for 24 h released significant amounts of PGE2 (measured by radioimmunoassay) and GM-CSF (measured by enzyme-linked immunosorbent assay). Indomethacin and other COX-1/COX-2 inhibitors caused concentration-dependent inhibitions of PGE2 concomitantly with increases in GM-CSF formation. Addition of exogenous PGE2 or the beta2-agonist fenoterol, which increase cAMP, to cytokine-treated HASM cells had no effect on GM-CSF release unless COX activity was first blocked with indomethacin. The type 4 phosphodiesterase inhibitors rolipram and SB 207499 both caused concentration-dependent reductions in GM-CSF production. Thus, when HASM cells are activated with cytokines they release PGE2, which acts as a "braking mechanism" to limit the coproduction of GM-CSF. Moreover, agents that elevate cAMP also reduce GM-CSF formation by these cells.
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PMID:Effects of prostaglandin E2 and cAMP elevating drugs on GM-CSF release by cultured human airway smooth muscle cells. Relevance to asthma therapy. 1115 49

Enhanced levels of cyclic AMP (cAMP), resulting from stimulation of adenylyl cyclase through activation of distinct pharmacological receptor systems, have a remarkable impact on the activity of the immune system. Among other responses, production of nitric oxide (NO) is also affected. The effects of cAMP range from stimulation to inhibition (or no effect) of immune-stimulated biosynthesis of NO, with a preponderance of stimulatory interference. cAMP has been shown to be a potent, dual modulator of cytokine expression. It dose-dependently suppresses secretion of major NO up-regulatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). On the other hand, production of IL-10, which is known to regulate the inducible NO synthase (iNOS) activation in both a positive and negative direction, is inversely enhanced. It is suggested that the dual effects of cAMP on NO formation are likely to result from the differences in the concentration ratio of these cytokines. The value of this parameter depends on the type and concentration of cAMP-stable derivatives and cAMP-enhancing agents, such as prostaglandins, beta-adrenoceptor agonists, phosphodiesterase inhibitors, forskolin and cholera toxin. The cytokine ratio may be influenced by dynamically developing multiple down- and up-regulatory feedback circuits among cytokines, NO, and cAMP.
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PMID:Role of cytokines in the modulation of nitric oxide production by cyclic AMP. 1128 42

Cilostazol is a specific inhibitor of cAMP phosphodiesterase, which is used for treatment of ischemic symptoms of peripheral vascular disease. Although cilostazol has antiplatelet and vasodilator properties, its effect on the expression of adhesion molecules in vascular endothelium is not known. In the present investigation, we examined the effect of cilostazol on the expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured vascular endothelial cells. Cilostazol strongly inhibited tumor necrosis factor (TNF)-alpha-induced expression of VCAM-1 protein and its mRNA. In addition, cilostazol reduced TNF-alpha-induced U937 cell adhesion to the vascular endothelial cells. In transient transfection studies, cilostazol inhibited TNF-alpha-induced transcriptional activation of VCAM-1 promoter. Electrophoretic mobility shift assays revealed that cilostazol repressed TNF-alpha-induced increase in binding of the transcription nuclear factor-kappaB (NF-kappaB) to its recognition site of VCAM-1 promoter. Cilostazol, however, failed to prevent nuclear translocation of the NF-kappaB p65 protein. These data indicate that cilostazol repressed VCAM-1 gene transcription in cultured vascular endothelial cells, via inhibiting NF-kappaB binding to its recognition sequence. Since the expression of the adhesion molecule is one of the earliest events occurred in atherogenic process, cilostazol might have the potential to prevent atherosclerosis at least via inhibition of the expression of the adhesion molecule.
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PMID:Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-kappaB binding to its recognition sequence. 1150 Jan 82

Blockade of phosphodiesterase 4 with rolipram reduced the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-5, IL-10, and IL-2 but poorly inhibited cell proliferation and interferon-gamma (IFN-gamma) production by activated human T cells. Addition of dibutyryl cAMP mimicked rolipram inhibitions on proliferation, IL-2, TNF-alpha, and IFN-gamma but not on IL-10 or IL-5 production. Moreover, the inhibitory effects of rolipram on proliferation, IFN-gamma, and TNF-alpha but not of IL-10 production can be prevented by a specific protein kinase A inhibitor. Rolipram and pentoxifylline, a nonspecific phosphodiesterase inhibitor, decreased transcription of IL-2 and TNF-alpha promoters in transiently transfected normal T cells. Moreover, they inhibited the activation of nuclear factor-kappaB (NF-kappaB) and nuclear factor of activated T cells (NFAT) and stimulated activator protein-1 (AP-1) and cAMP response element-binding proteins (CREBs). In contrast, dibutyryl cAMP inhibited NF-kappaB but not NFAT activation. Thus, our data indicate that blockade of phosphodiesterase 4 regulates transcription of a particular cytokine through inhibition of NF-kappaB and NFAT, and stimulation of AP-1 and CREB.
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PMID:Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. 1160 91

In an attempt to elaborate in vitro on a therapeutic strategy that counteracts an inflammatory signal, we previously reported a novel immunopharmacological potential of glutathione, an antioxidant thiol, in regulating inflammatory cytokines. In the present study, we investigated the hypothesis that selective regulation of phosphodiesterases (PDEs), a family of enzymes that controls intracellular cAMP/cGMP degradation, differentially regulates proinflammatory cytokines. Selective PDE1 inhibition (8-methoxymethyl-3-isobutyl-1-methylxanthine) blockaded lipopolysaccharide-endotoxin (LPS)-mediated biosynthesis of interleukin (IL)-6, but this pathway had no inhibitory effect on tumor necrosis factor-alpha (TNF-alpha). Furthermore, inhibition of PDE3 (amrinone) abolished the effect of LPS on IL-6, but attenuated TNF-alpha production. Reversible competitive inhibition of PDE4 (rolipram) exhibited a potent inhibitory effect on IL-6 and a dual, biphasic (excitatory/inhibitory) effect on TNF-alpha secretion. Blockading PDE5 (4-[[3',4'-(methylenedioxy)benzyl] amino]-6-methoxyquinazoline) showed a high potency in reducing IL-6 production, but in a manner similar to the inhibition of PDE4, exhibited a biphasic effect on TNF-alpha biosynthesis. Simultaneous inhibition of PDE5, 6, and 9 (zaprinast), purported to specifically elevate intracellular cGMP, reduced, in a dose-independent manner, IL-6 and TNF-alpha biosynthesis. Finally, nonselective inhibition of PDE by pentoxifylline suppressed LPS-mediated secretion of IL-6 and TNF-alpha. The involvement of specific PDE isoenzymes in differentially regulating LPS-mediated inflammatory cytokine biosynthesis indicates a novel approach to unravel the potential therapeutic targets that these isozymes constitute during the progression of inflammation within the respiratory epithelium.
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PMID:Immunopharmacological potential of selective phosphodiesterase inhibition. I. Differential regulation of lipopolysaccharide-mediated proinflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) biosynthesis in alveolar epithelial cells. 1180 17

Cyclic nucleotide phosphodiesterase (PDE) 3B plays an important role in the antilipolytic action of insulin and, thereby, the release of fatty acids from adipocytes. Increased concentrations of circulating fatty acids as a result of elevated or unrestrained lipolysis cause insulin resistance. The lipolytic action of tumor necrosis factor (TNF)-alpha is thought to be one of the mechanisms by which TNF-alpha induces insulin resistance. Ceramide is the suggested second messenger of TNF-alpha action, and in this study, we used 3T3-L1 adipocytes to investigate the effects of C(2)-ceramide (a short-chain ceramide analog) on the expression and regulation of PDE3B and lipolysis. Incubation of adipocytes with 100 micromol/l C(2)-ceramide (N-acetyl-sphingosine) resulted in a time-dependent decrease of PDE3B activity, accompanied by decreased PDE3B protein expression. C(2)-ceramide, in a time- and dose-dependent manner, stimulated lipolysis, an effect that was blocked by H-89, an inhibitor of protein kinase A. These ceramide effects were prevented by 20 micromol/l troglitazone, an antidiabetic drug. In addition to downregulation of PDE3B, the antilipolytic action of insulin was decreased by ceramide treatment. These results, together with data from other studies on PDE3B and lipolysis in diabetic humans and animals, suggest a novel pathway by which ceramide induces insulin resistance. Furthermore, PDE3B is demonstrated to be a target for troglitazone action in adipocytes.
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PMID:C(2)-ceramide influences the expression and insulin-mediated regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 adipocytes. 1187 60

Pentoxifylline (PTX), a phosphodiesterase inhibitor, is known to downregulate tumor necrosis factor-alpha (TNF-alpha) secretion induced by lipopolysacchride (LPS) and gamma interferon (IFN-gamma). We have had limited success in treating leprosy reactions, including erythema nodosum leprosum (ENL), in which TNF-alpha has been identified as a major proinflammatory cytokine. PTX inhibited production of NO (IC50 approximately equal to 1.0 mg/ml) and TNF-alpha (IC50 approximately equal to 0.05 mg/ml) in a dose-dependent fashion. As little as 0.5 mg/ml of PTX decreased NO production and 0.01 mg/ml of PTX inhibited TNF-alpha production. Western blot analyses demonstrated that iNOS was suppressed by PTX. Northern blot analyses showed significant reduction of TNF-alpha mRNA. We conclude that PTX is an effective inhibitor of lipoarabinomannan (LAM)-induced TNF-alpha production at both the product and transcriptional levels in our macrophage cell line. PTX also showed moderate inhibition of NO at the product level as well as translation of iNOS.
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PMID:Pentoxifylline downregulates nitric oxide and tumor necrosis factor-alpha induced by mycobacterial lipoarabinomannan in a macrophage cell line. 1187 67

We investigated the pharmacology of a new class of phosphodiesterase 4 (PDE4) inhibitor, 6,8-disubstituted 1,7-naphthyridines, by using 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171) as a representative compound and compared its potency with the most advanced PDE4 inhibitor, undergoing clinical trials, Ariflo [cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexanecarboxylic acid)]. NVP-ABE171 inhibited the activity of phosphodiesterase 4A, 4B, 4C, and 4D with respective IC(50) values of 602, 34, 1230, and 1.5 nM. Ariflo was about 40 times less potent. In human cells, NVP-ABE171 inhibited the eosinophil and neutrophil oxidative burst, the release of cytokines by T cells, and the tumor necrosis factor-alpha release from monocytes, in the nanomolar range. Ariflo presented a similar inhibition profile but was 7 to 50 times less potent. In BALB/c mice challenged with lipopolysaccharide, NVP-ABE171 inhibited the airway neutrophil influx and activation with an ED(50) in the range of 3 mg/kg. Ariflo was inactive up to a dose of 10 mg/kg. In ovalbumin sensitized Brown Norway rats, NVP-ABE171 inhibited the lipopolysaccharide-induced airway neutrophil influx and activation (ED(50) of 0.2 mg/kg) and the ovalbumin-induced airway eosinophil influx and activation (ED(50) of 0.1 mg/kg). Ariflo was about 100 times less potent in both models. In the ovalbumin model, NVP-ABE171 had a duration of action of more than 24 h. NVP-ABE171 is a novel PDE4 inhibitor that shows activity both in vitro on human inflammatory cells and in vivo in animal models of lung inflammation. This compound class may have potential for the treatment of airway inflammatory conditions such as asthma and chronic obstructive pulmonary diseases.
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PMID:Pharmacological profile of a novel phosphodiesterase 4 inhibitor, 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171), a 1,7-naphthyridine derivative, with anti-inflammatory activities. 1190 80

Matrix metalloproteinases (MMPs) and transforming growth factor (TGF)-beta are involved in airway remodeling associated with the inflammatory process. In this study, we investigated the effect of RP 73-401 (piclamilast), a selective phosphodiesterase-4 inhibitor, on MMP-9 activity and TGF-beta production in two murine models of acute inflammation. In the first model, the lipopolysaccharide (LPS)-induced increase in neutrophils, MMP-9 activity, and tumor necrosis factor (TNF)-alpha and TGF-beta release in bronchoalveolar lavage (BAL) was significantly reduced by RP 73-401 pretreatment. In contrast, the BAL interleukin (IL)-10 level was decreased by LPS but restored by RP 73-401. IL-10 administration in LPS-exposed mice elicited a significant reduction in BAL neutrophilia, MMP-9 activity, and TNF-alpha release but not in TGF-beta production. In the second model, RP 73-401 inhibited BAL neutrophils but not MMP-9 activity and TGF-beta production that were induced by intranasal TNF-alpha. We demonstrated that RP 73-401 might modulate the expression of airway remodeling-associated mediators such as MMP-9 and TGF-beta and that this effect seemed to be at least partially mediated by the balance between TNF-alpha and IL-10.
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PMID:The selective phosphodiesterase 4 inhibitor RP 73-401 reduced matrix metalloproteinase 9 activity and transforming growth factor-beta release during acute lung injury in mice: the role of the balance between Tumor necrosis factor-alpha and interleukin-10. 1190 82


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