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David J Titus, Nicole M Wilson, Julie E Freund, Melissa M Carballosa, Kevin E Sikah, Concepcion Furones, W Dalton Dietrich, Mark E Gurney, Coleen M Atkins
UNLABELLED: Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI...
July 6, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Hao Huang, Zeng-Chun Ma, Yu-Guang Wang, Qian Hong, Hong-Ling Tan, Cheng-Rong Xiao, Qian-De Liang, Xiang-Lin Tang, Yue Gao
OBJECTIVE: Phosphodiesterase (PDE) plays an important role in the pathogenesis of Alzheimer's disease (AD). Ferulic acid (FA) has a therapeutic benefit in the treatment of AD. We investigated whether this therapeutic effect is based on the modulation of the PDE/cyclic adenosine monophosphate (cAMP) pathway. In the present study, we investigated whether FA could abrogate Aβ25-35- and lipopolysaccharide-induced cellular damage. MATERIALS AND METHODS: Cell viability, superoxide production, and the levels of inflammatory factors were investigated...
October 2015: International Journal of Clinical Pharmacology and Therapeutics
Bin Wu, Birgit Ohlendorf, Vanessa Oesker, Jutta Wiese, Susann Malien, Rolf Schmaljohann, Johannes F Imhoff
Two new oxaphenalenone dimers, talaromycesone A (1) and talaromycesone B (2), and a new isopentenyl xanthenone, talaroxanthenone (3), together with six known diphenyl ether derivatives, e.g., Δ(1',3'),-1'-dehydroxypenicillide (4), 1',2'-dehydropenicillide (5), vermixocin A (6), vermixocin B (7), 3'-methoxy-1'2'-dehydropenicillide (8), and AS-186c (9), were isolated from the culture broth and mycelia of a marine fungus Talaromyces sp. strain LF458. Compound 2 represents the first example of 1-nor oxaphenalenone dimer carbon skeleton...
February 2015: Marine Biotechnology
Jonny Nachtigall, Andreas Kulik, Soleiman Helaly, Alan T Bull, Michael Goodfellow, Juan A Asenjo, Armin Maier, Jutta Wiese, Johannes F Imhoff, Roderich D Süssmuth, Hans-Peter Fiedler
Three new 22-membered macrolactone antibiotics, atacamycins A-C, were produced by Streptomyces sp. C38, a strain isolated from a hyper-arid soil collected from the Atacama Desert in the north of Chile. The metabolites were discovered in our HPLC-diode array screening and isolated from the mycelium by extraction and chromatographic purification steps. The structures were determined by mass spectrometry and NMR experiments. Atacamycins A, B and C exhibited moderate inhibitory activities against the enzyme phosphodiesterase (PDE-4B2), whereas atacamycin A showed a moderate antiproliferative activity against adeno carcinoma and breast carcinoma cells...
December 2011: Journal of Antibiotics
Leila Gobejishvili, Diana V Avila, David F Barker, Smita Ghare, David Henderson, Guy N Brock, Irina A Kirpich, Swati Joshi-Barve, Sri Prakash L Mokshagundam, Craig J McClain, Shirish Barve
S-Adenosylmethionine (SAM) treatment has anti-inflammatory, cytoprotective effects against endotoxin-induced organ injury. An important component of the anti-inflammatory action of SAM involves down-regulation of the lipopolysaccharide (LPS)-induced transcriptional induction of tumor necrosis factor-α (TNF) expression by monocytes/macrophages. We examined the effect of SAM on expression and activity of LPS-induced up-regulation of phosphodiesterase 4 (PDE4), which regulates cellular cAMP levels and TNF expression...
May 2011: Journal of Pharmacology and Experimental Therapeutics
Elizabeth Borysiewicz, Daniel Fil, Daniel Dlaboga, James M O'Donnell, Gregory W Konat
Cyclic AMP is part of an endogenous mechanism that downregulates inflammatory response, and its intracellular concentration is regulated chiefly by cyclic nucleotide phosphodiesterases type 4. The goal of the present study was to determine whether phosphodiesterases 4 are involved in the inflammatory response of astrocytes mediated by Toll-like receptors. Astrocyte cultures established from newborn rat brain were challenged with lipoteichoic acid, a ligand of Toll-like receptor 2, polyinosinic-polycytidylic acid, a ligand of Toll-like receptor 3, or lipopolysaccharide, a ligand of Toll-like receptor 4...
September 2009: Metabolic Brain Disease
Sha Zhu, Genqing Yang, Xiaolan Yang, Yunsheng Zhao, Xiang Li, Ping Deng, Yanling Xie, Zhiyong Gan, Yin Liu, Zhirong Li, Juan Liao, Ming'an Yu, Fei Liao
Recombinant expression in Escherichia coli of human cyclic nucleotide phosphodiesterase 4B2 (hPDE4B2) fused to maltose-binding-protein (MBP-hPDE4B2) was investigated. hPDE4B2 DNA amplified via nested RT-PCR with total RNAs from U937 cells was ligated with pMAL-p2x. After induction at 18 degrees C for 16 h, soluble MBP-hPDE4B2 was produced in E. coli. MBP-hPDE4B2 after amylose-resin chromatography showed 35% homogeneity, and its Michaelis-Menten constant was 10+/-2 microM (n=3). Rolipram had a dissociation constant of 9+/-2 nM (n=2), and zinc ion was a potent inhibitor...
April 23, 2009: Bioscience, Biotechnology, and Biochemistry
Matthew D Cullen, York-Fong Cheung, Miles D Houslay, Tracy L Hartman, Karen M Watson, Robert W Buckheit, Christophe Pannecouque, Erik De Clercq, Mark Cushman
The alkenyldiarylmethanes (ADAMs) are currently being investigated as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of potential value in the treatment of HIV infection and AIDS. During the course of these studies, a number of ADAM analogues have been identified that protect HIV-infected cells from the cytopathic effects of the virus by an unknown, HIV-1 RT-independent mechanism. Since the phosphodiesterase 4 family is required for HIV infection, the effect of various ADAMs on the activity of PDE4B2 was investigated in an effort to determine if the ADAMs could possibly be targeting phosphodiesterases...
February 15, 2008: Bioorganic & Medicinal Chemistry Letters
Bing Zhu, John Kelly, Lakshmi Vemavarapu, W Joseph Thompson, Samuel J Strada
Regulation of the rolipram-sensitive cAMP-specific phosphodiesterase 4 (PDE4) gene family was studied in rat pulmonary microvascular endothelial cells (RPMVECs). Total PDE4 hydrolysis was increased within 10 min after addition of forskolin (10 microM), reached a maximum at 20-40 min, and then gradually declined in the cells. A similar activation of PDE4 activity was observed using a protein kinase A (PKA) activator, N(6)-monobutyryl cAMP. Both the forskolin and the N(6)-monobutyryl cAMP activated PDE4 activities were blocked by the PKA-specific inhibitor, H89...
August 1, 2004: Biochemical Pharmacology
Jacqueline Arp, Mark G Kirchhof, Miren L Baroja, Steven H Nazarian, Thu A Chau, Craig A Strathdee, Eric H Ball, Joaquín Madrenas
Stimulation of T cells through their antigen receptors (TCRs) causes a transient increase in the intracellular concentration of cyclic AMP (cAMP). However, sustained high levels of cAMP inhibit T-cell responses, suggesting that TCR signaling is coordinated with the activation of cyclic nucleotide phosphodiesterases (PDEs). The molecular basis of such a pathway is unknown. Here we show that TCR-dependent signaling activates PDE4B2 and that this enhances interleukin-2 production. Such an effect requires the regulatory N terminus of PDE4B2 and correlates with partitioning within lipid rafts, early targeting of this PDE to the immunological synapse, and subsequent accumulation in the antipodal pole of the T cell as activation proceeds...
November 2003: Molecular and Cellular Biology
Stéphanie Oger, Céline Méhats, Emmanuelle Dallot, Françoise Ferré, Marie-Josèphe Leroy
Intrauterine infections are important etiological factors of preterm labor. They trigger an increase in proinflammatory cytokines, in particular IL-1beta, that induces a cascade of events resulting in the production of potent effectors of myometrial contractility, such as the prostaglandin E(2) (PGE(2)). Within the smooth muscle cells, contractility is under the control of cAMP content, partly regulated by cAMP-phosphodiesterase 4 (PDE4), the predominant family of PDEs expressed in human myometrium. In the present study, using a model of inflammation of human myometrial cells in culture, we demonstrated that exposing the cells to IL-1beta resulted in a significant up-regulation of PDE4 activity through an increase in PDE4B2 mRNA and protein levels...
December 2002: Journal of Clinical Endocrinology and Metabolism
P Wang, P Wu, K M Ohleth, R W Egan, M M Billah
The type 4 phosphodiesterase (PDE4) is the predominant PDE isozyme in various leukocytes and plays a key role in the regulation of inflammatory cell activation. There are four PDE4 subtypes (A, B, C, and D), and within each subtype, there are multiple variants. Very recently, we found in monocytes that PDE4B gene expression is selectively induced by lipopolysaccharide (LPS) and that the induction is inhibited by interleukin (IL)-10 and IL-4. In this study, we show that the PDE4B gene is constitutively expressed in neutrophils and that this expression remains unaffected by LPS or IL-10...
July 1999: Molecular Pharmacology
R A Allen, M W Merriman, M J Perry, R J Owens
We described the development of a recombinant cell-based system for the characterisation of phosphodiesterase (PDE) 4 isoforms and the evaluation of inhibitors. The Chinese hamster ovary (CHO) cell, which was found to have a low endogenous PDE4 background and no beta-adrenergic receptors (beta-AR), was transiently transfected with beta-AR and various PDE4 isoforms which were expressed as functionally coupled molecules. From correlations of elevation of adenosine 3',5'-cyclic monophosphate in situ and the inhibition of catalytic activity in vitro with the various PDE4 isoforms, it was apparent that PDE4A4, 4B2, 4C2, 4D2, and 4D3 all adopted a high-affinity binding conformation (i...
June 15, 1999: Biochemical Pharmacology
M J Leroy, C Méhats, P Duc-Goiran, G Tanguy, B Robert, E Dallot, T M Mignot, G Grangé, F Ferré
In light of the important role of the second messengers cAMP and cGMP in the mechanism of relaxation in the human myometrium, specific regulation of the phosphodiesterase (PDE) enzymatic system responsible for cyclic nucleotide inactivation is essential. We previously identified in the human myometrium PDE4 cAMP-specific PDE as by far the most abundant isoform. Here we have studied the expression patterns of mRNAs for the four cloned human PDE4 genes in the myometria of pregnant and non-pregnant women. Concurrent expression of the PDE4A, 4B, 4C and 4D genes is demonstrated...
January 1999: Cellular Signalling
M J Perry, J O'Connell, C Walker, T Crabbe, D Baldock, A Russell, S Lumb, Z Huang, D Howat, R Allen, M Merriman, J Walls, T Daniel, B Hughes, F Laliberte, G A Higgs, R J Owens
We present the in vitro characterization of a novel phosphodiesterase type 4 inhibitor, CDP840 (R-[+]-4-[2-¿3-cyclopentyloxy-4-methoxyphenyl¿-2-phenylethyl]pyridine), which has shown efficacy in a phase II allergen challenge study in asthmatics without adverse effects. CDP840 potently inhibits PDE-4 isoenzymes (IC50 2-30 nM) without any effect on PDE-1, 2, 3, 5, and 7 (IC50 > 100 microM). It exhibited no significant selectivity in inhibiting human recombinant isoenzymes PDE-4A, B, C or D and was equally active against the isoenzymes lacking UCR1 (PDE-4B2 and PDE-4D2)...
1998: Cell Biochemistry and Biophysics
M Grange, M Picq, A F Prigent, M Lagarde, G Nemoz
Phosphatidic acid (PA) has been previously shown to activate specifically some of the isoforms of type 4 cylic nucleotide phosphodiesterases (PDE-4) in an acellular system. In the present work, we have investigated the mechanism of PA-activating effect by using a recombinant PA-sensitive isoform, PDE-4D3. The enzyme was specifically activated by acidic phospholipids, but not by zwitterionic phospholipids or anionic detergents. The importance of the role of PA acidic groups in the activation process was confirmed by studying the influence of pH and ionic strength on activation...
1998: Cell Biochemistry and Biophysics
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