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)

Dipyridamole is a nucleoside transport inhibitor and a non-selective phosphodiesterase inhibitor. However, the mechanisms by which dipyridamole exerts its anti-inflammatory effects are not completely understood. In the present study, we investigated the role of mitogen-activated kinase phosphatase-1 (MKP-1) in dipyridamole's anti-inflammatory effects. We show that dipyridamole inhibited interleukin-6 and monocyte chemoattractant protein-1 secretion, inducible nitric oxide synthase protein expression, nitrite accumulation, and cyclooxygenase-2 (COX-2) induction in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Dipyridamole inhibited the nuclear factor kappa B (NF-kappaB) signaling pathway as demonstrated by inhibition of the inhibitor of NF-kappaB (IkappaB) phosphorylation, IkappaB degradation, p65 translocation from the cytosol to the nucleus, and transcription of the reporter gene. Dipyridamole also inhibited LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) and IkappaB kinase-beta (IKK-beta) activities in RAW 264.7 cells. A p38 MAPK inhibitor, SB 203580, inhibited LPS-stimulated COX-2 expression and IKK-beta activation suggesting that LPS may activate the NF-kappaB signaling pathway via upstream p38 MAPK activation. Furthermore, dipyridamole stimulated transient activation of MKP-1, a potent inhibitor of p38 MAPK function. Knockdown of MKP-1 by transfecting MKP-1 siRNA or inhibition of MKP-1 by the specific inhibitor, triptolide, significantly reduced the inhibitory effects of dipyridamole on COX-2 expression induced by LPS. Taken together, these data suggest that dipyridamole exerts its anti-inflammatory effect via activation of MKP-1, which dephosphorylates and inactivates p38 MAPK. Inactivation of p38 MAPK in turn inhibits IKK-beta activation and subsequently the NF-kappaB signaling pathway that mediates LPS-induced cyclooxygenase-2 expression in RAW 264.7 cells.
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PMID:Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells. 1676 38

In a previous study, we analysed the synthesis and properties of a series of imidazo[1,2-alpha]quinoxalines designed in our laboratory as possible imiquimod analogues. We found that these imidazo[1,2-alpha]quinoxalines were in fact potent inhibitors of phosphodiesterase 4 enzymes (PDE4). PDE4 inhibition normally results in an increase in intracellular cAMP which, in PBMC, induces the suppression of TNF-alpha mRNA transcription and thus cytokine synthesis. Such an effect is antagonistic to that of imiquimod. Furthermore, some TNF-alpha-induced activity, such as cell apoptosis which is dependent on the intracellular cAMP levels might also be affected. Therefore, by counteracting the properties of TNF-alpha and/or its production, the imidazo[1,2-alpha]quinoxalines could be considered as potential anti-inflammatory drugs. The present study was performed to confirm or refute this hypothesis. For this, we characterized the effects of imidazo[1,2-alpha]quinoxalines both on TNF-alpha activity and synthesis in regard to their ability to act as inhibitors of PDE4 (IPDE4). We found that the imidazo[1,2-alpha]quinoxalines dose-dependently prevented the TNF-alpha-triggered death of L929 cells, with the 8-series (-NHCH3 in R4) being the most potent. Moreover, when the effect of the 8-series on TNF-alpha production was investigated using gamma9delta2 T cells, it was observed that these compounds impaired the TCR:CD3-triggered TNF-alpha production. Structure-activity analysis revealed that these properties of the drugs did not coincide with their IPDE4 properties. This prompted further exploration into other signalling mechanisms possibly involved in TNF-alpha action and production, notably the p38 MAPK and the PI3K pathway. We demonstrate here that the imidazo[1,2-alpha]quinoxalines targeted these pathways in a different way: they activated the p38 MAPK pathway whilst inhibiting the PI3K pathway. Such effects on cell signalling could account for the imidazo[1,2-alpha]quinoxalines effects on 1) action and 2) production of TNF-alpha, which define these drugs as potential anti-inflammatory agents.
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PMID:Impairment of TNF-alpha production and action by imidazo[1,2- alpha] quinoxalines, a derivative family which displays potential anti-inflammatory properties. 1702 37

Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) are involved in vascular inflammation. We tested the hypothesis, and explored the underlining mechanisms that cilostazol, a phosphodiesterase 3 inhibitor with antiplatelet and antithrombotic properties, inhibits lipopolysaccharide (LPS)-induced MCP-1 and MMP-9 expression. In a rabbit aorta balloon-injury model, administration of LPS increased macrophage infiltration and MCP-1 and MMP-9 expression; cilostazol supplementation prevented this phenomenon and reduced intimal hyperplasia. In contrast, the reverse zymography showed that cilostazol did not affect TIMP-1 expression in serum. In monocytic THP-1 cells, cilostazol and N6,O2'-dibutyryl-cAMP (dioctanoyl-cAMP, a cAMP analog) dose-dependently inhibited LPS-induced MCP-1 protein expression and MMP-9 activation, but did not affect the tissue inhibitor of metalloproteinase-1. Quantitative real-time polymerase chain reaction (PCR) showed that cilostazol inhibited MCP-1 and MMP-9 mRNA expression. Cilostazol significantly inhibited LPS-induced activation of p38, JNK, and nuclear factor-kappaB, and the respective inhibitors of p38 and JNK greatly reduced the level of LPS-induced MCP-1 and MMP-9, suggesting the involvement of the p38 and JNK pathways. In conclusion, cilostazol administered with LPS in vivo reduced neointimal hyperplasia and macrophage infiltration in the balloon-injured rabbit aorta; in vitro, cilostazol inhibits LPS-induced MCP-1 and MMP-9 expression. These data suggest that cilostazol may play an important role in preventing endotoxin- and injured-mediated vascular inflammation.
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PMID:Cilostazol attenuates MCP-1 and MMP-9 expression in vivo in LPS-administrated balloon-injured rabbit aorta and in vitro in LPS-treated monocytic THP-1 cells. 1751 47

Inhibition of p38 MAPK suppresses the expression of proinflammatory cytokines such as TNF-alpha and IL-1 beta in macrophages and fibroblast-like synoviocytes (FLS). However, there have been no genomewide studies on the gene targets of p38 MAPK signaling in synoviocytes. Microarray technology was applied to generate a comprehensive analysis of all genes regulated by the p38 MAPK signaling pathway in FLS. Gene expression levels were measured with Agilent oligonucleotide microarrays. Four independent sets of mRNA modulated by TNF-alpha and vehicle were used to measure the change of gene expression due to TNF-alpha, and three experiments were done to ascertain the effect of SB-203580, a p38 MAPK inhibitor, on TNF-alpha-induced genes. Microarray data were validated by RT-quantitative polymerase chain reaction. One hundred forty-one significantly expressed genes were more than twofold upregulated by TNF-alpha. Thirty percent of these genes were downregulated by the p38 inhibitor SB-203580, whereas 67% of these genes were not significantly changed. The SB-203580-inhibited genes include proinflammatory cytokines such as interleukins and chemokines, proteases including matrix metallopeptidases, metabolism-related genes such as cyclooxygenases and phosphodiesterase, genes involved in signal transduction, and genes encoding for transcription factors, receptors, and transporters. Approximately one-third of the TNF-alpha-induced genes in FLS are regulated by the p38 MAPK signal pathway, showing that p38 MAPK is a possible target for suppressing proinflammatory gene expressions in rheumatoid arthritis.
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PMID:Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factor-alpha signaling. 1765 67

Chronic obstructive pulmonary disease (COPD) is a global health problem. Being a progressive disease characterized by inflammation and predominantly caused by tobacco smoking, it deteriorates pulmonary and skeletal muscle functioning, and reduces physical behavior, societal participation and quality of life. During the last two decades studies were focused on the airway and systemic inflammation, oxidative stress, and airway and/or parenchymal remodeling. Macrophages, neutrophils and T cells are thought to be important key players, as well as structural cells like fibroblasts, epithelial, endothelial and smooth muscle cells. Mediators and proteins including cytokines, chemokines, growth factors, proteinases, and oxidants seem to be involved differentially in its pathogenesis. Current pharmacological treatments are directed to reducing airway inflammation, boosting the endogenous levels of anti-oxidants and relieving airway contraction and sputum production. Most agents were primarily used for treating asthma. But in contrast to asthma, these treatments are not very effective in COPD. As a result, novel more specifically acting interventional drugs with less side effects are being developed to treat chronic inflammatory diseases, including COPD. This review highlights studies on novel or potential drug antioxidants such as dietary antioxidants supplementation, N-acetyl-L-cysteine, N-acystelyn, endosteine, antioxidant enzyme mimetics, and anti-inflammatory agents like antagonists of cytokines, such as tumor necrosis factor (TNF)-alpha, CXCL8, and CCL2, and inhibitors of signal transduction proteins including phosphodiesterase 4, MAPK p38, P1-3k, and NFkappaB.
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PMID:Future therapeutic treatment of COPD: struggle between oxidants and cytokines. 1822 60

Exposure to hypoxia triggers a variety of adverse effects in the brain that arise from metabolic stress and induce neuron apoptosis. Overexpression of the hypoxia-inducible factor-1alpha (HIF-1alpha) is believed to be a major candidate in orchestrating the cell's defense against stress. To test the impact of HIF-1alpha on apoptosis during chronic hypoxia in vivo, we examined the protective effect of modulating the nitric oxide (NO)/cGMP pathway by sildenafil, a selective inhibitor of phosphodiesterase-5 (PDE-5). Male ICR/CD-1 mice were divided into 3 groups (n = 6/group): normoxic (21% O(2)), hypoxic (9.5% O(2)), and hypoxic with sildenafil (1.4-mg/kg intraperitoneal injections daily). At the end of the 8-day treatment period, the mice were euthanized and cerebral cortex biopsies were harvested for analyses. We found that sildenafil: (1) did not significantly alter the hypoxia-induced weight loss and hemoglobin increase, but did augment plasma nitrates+nitrites and the tissue content of cGMP and phosphorylated (P) NO synthase III; (2) reversed the hypoxia-induced neuron apoptosis (terminal deoxynucleotidyl transferase positivity and double-staining immunofluorescence, P = 0.009), presumably through increased bcl-2/Bax (P = 0.0005); and (3) did not affect HIF-1alpha, but rather blunted the hypoxia-induced increase in P-ERK1/2 (P = 0.0002) and P-p38 (P = 0.004). We conclude that upregulating the NO/cGMP pathway by PDE-5 inhibition during hypoxia reduces neuron apoptosis, regardless of HIF-1alpha, through an interaction involving ERK1/2 and p38.
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PMID:Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of hypoxia-inducible factor-1alpha signaling. 1864 Oct 57

Expression of the anti-inflammatory cytokine IL-10 can be induced either by TLR agonists such as lipopolysaccharide (LPS), or by various endogenous stimuli, in particular those acting via a cAMP-dependent signaling pathway. We have previously reported that the synthetic phospho-ceramide analogue-1 (PCERA-1) increases cAMP level and subsequently down-regulates production of TNFalpha and up-regulates production of IL-10 in LPS-stimulated macrophages. The objective of this study was to determine the mechanism of activity of PCERA-1 and the role of cAMP in LPS-induced IL-10 production. We show here that PCERA-1 induces IL-10 production in synergism with various TLR agonists in mouse RAW264.7 macrophages. Cooperativity is evident both at the mRNA and protein levels. IL-10 production by LPS and PCERA-1 is mediated by the cAMP pathway and by the p38 MAP kinase. Phosphorylation of p38 is cooperatively accomplished by LPS and PCERA-1 or other cAMP inducers. Furthermore, the activity of PCERA-1 can be partially mimicked by a cell-permeable analog of cAMP, and blocked by the protein kinase A (PKA) inhibitor H89. Finally, in the absence of PCERA-1, the residual IL-10 induction by LPS depends on the basal cAMP level as it can be largely elevated by the phosphodiesterase (PDE)-4 inhibitor rolipram. Our results thus indicate that IL-10 induction by LPS critically depends on basal cAMP level, and that a co-stimulus by a TLR agonist and a cAMP-elevating agent results in synergistic PKA-dependent and p38-dependent IL-10 production.
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PMID:Synergistic IL-10 induction by LPS and the ceramide-1-phosphate analog PCERA-1 is mediated by the cAMP and p38 MAP kinase pathways. 1936 73

Increased expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues is a potential factor linking diabetes to restenosis after percutaneous coronary intervention. Recent studies have shown that cilostazol, a selective type 3 phosphodiesterase inhibitor, prevents neointimal hyperplasia and in-stent thrombosis in patients with diabetes after coronary angioplasty and stent implantation. However, the molecular mechanism of this drug has not been fully elucidated. We examined whether cilostazol inhibits PAI-1 expression in vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. We found that cilostazol effectively inhibits angiotensin II-, high glucose- and TGF-beta-stimulated PAI-1 expression in vivo and in vitro. Cilostazol attenuated PAI-1 expression in neointimal regions and inhibited neointimal hyperplasia after balloon injury. Cilostazol inhibited PAI-1 expression by multiple mechanisms including downregulation of TGF-beta, JNK and p38 signaling pathways. Cilostazol also inhibited transactivating activity at the PAI-1 promoter by Smad3, leading to a suppression of PAI-1 gene transcription. Taken together with its antiproliferative effect on VSMCs, this may explain how cilostazol exerts its antithrombogenic effects after angioplasty and stent implantation.
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PMID:Cilostazol inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor expression in artery wall and neointimal region after vascular injury. 1958 29

Epithelial-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-beta1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-beta1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-beta1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and alpha-smooth muscle actin. Interestingly, TGF-beta1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-beta1-stimulated cells. Most importantly, treatment of TGF-beta1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-beta1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-beta1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.
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PMID:Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition: the role of phosphodiesterase 4. 1975 79

Hypercholesterolemia is associated with impaired neovascularization in response to ischemia. Potential mechanisms include defective NO bioactivity and a reduction in the number/function of endothelial progenitor cells (EPCs). Here we tested the hypothesis that sildenafil, a phosphodiesterase 5 inhibitor that increases NO-driven cGMP levels, could stimulate EPC function and improve ischemia-induced neovascularization in hypercholesterolemic conditions. Apolipoprotein E-deficient (ApoE(-/-)) mice were treated (or not treated) with sildenafil (40 mg/kg per day in water), and hindlimb ischemia was surgically induced by femoral artery removal. Sildenafil treatment led to an improved blood flow recovery, an increased capillary density, and a reduction of oxidative stress levels in ischemic muscles at day 7 after surgery. Sildenafil therapy is associated with an increased activation of angiogenic transduction pathways, including Akt, p44/42 mitogen-activated protein kinase, and p38. In vitro, sildenafil increases cellular migration and tubule formation of mature endothelial cells (human umbilical vascular endothelial cells) in a cGMP-dependent manner. In vivo, ApoE(-/-) mice treated with sildenafil exhibit a significant increase in the number of bone marrow-derived EPCs. Moreover, the angiogenic activities of EPCs (migration and adhesion) are significantly improved in ApoE(-/-) mice treated with sildenafil. In summary, this study demonstrates that sildenafil treatment is associated with improved ischemia-induced neovascularization in hypercholesterolemic ApoE(-/-) mice. The mechanisms involve beneficial effects on angiogenic transduction pathways together with an increase in the number and the functional activity of EPCs. Sildenafil could constitute a novel therapeutic strategy to reduce tissue ischemia in atherosclerotic diseases.
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PMID:Sildenafil increases endothelial progenitor cell function and improves ischemia-induced neovascularization in hypercholesterolemic apolipoprotein E-deficient mice. 1977 Apr


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