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P R A Heckman, A Blokland, N P Van Goethem, B T J Van Hagen, J Prickaerts
The current study investigated the mediating role of phosphodiesterase type 4 (PDE4) regulated cAMP in the dopaminergic modulation of premature responding (action restraint) in rats. Response inhibition, which includes action restraint, finds its neurobiological origin in cortico-striatal-thalamic circuitry and can be modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cAMP/PKA signaling cascade. Areas in the prefrontal cortex are very sensitive to their neurochemical environment, including catecholamine levels...
May 17, 2018: Behavioural Brain Research
Ibrahim Bedioune, Florence Lefebvre, Patrick Lechêne, Audrey Varin, Valérie Domergue, Michael S Kapiloff, Rodolphe Fischmeister, Grégoire Vandecasteele
Aims: β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. Methods and Results: We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation...
May 3, 2018: Cardiovascular Research
Mariana Ferreira Bizzi, Sergio Veloso Brant Pinheiro, Graeme B Bolger, Junia Ribeiro de Oliveira Longo Schweizer, Alexandre V Giannetti, Mary N Dang, Antonio Ribeiro-Oliveira, Márta Korbonits
Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4...
May 3, 2018: Molecular and Cellular Endocrinology
Marie Helene Schernthaner-Reiter, Giampaolo Trivellin, Constantine A Stratakis
Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause mostly somatotropinomas and/or prolactinomas in a subset of familial isolated pituitary adenomas (FIPA). AIP has been shown to interact with phosphodiesterases (PDEs) and G proteins, suggesting a link to the cyclic AMP (cAMP)-dependent protein kinase (PKA) pathway. Upregulation of PKA is seen in sporadic somatotropinomas that carry GNAS1 mutations, and those in Carney complex that are due to PRKAR1A mutations. To elucidate the mechanism of AIP-dependent pituitary tumorigenesis, we studied potential functional and physical interactions of AIP with PKA's main subunits PRKAR1A (R1α) and PRKACA (Cα)...
May 2, 2018: Human Molecular Genetics
Carlos Duarte Correia, Juliana Oliveira, Ricardo Almir Angnes, Ismat Ullah Khan, Ellen Christine Polo, Gabriel Heerdt, Bruno Servilha, Vitor Silva, Ataualpa Braga
Highly diastereo and enantioselective non-covalent substrate directable Heck desymmetrizations of cyclopentenyl olefins bearing hydroxymethyl and carboxylate functional groups are presented. These conformationally unbiased cyclic olefins underwent effective arylations in yields of up to 97%, diastereoselectivity up to >20:1, and enantiomeric excesses of up to 99%. Non-covalent directing effects were shown to be present in Heck-Matsuda and oxidative Heck reactions allowing the preferential formation of cis-substituted aryl cyclopentenes containing two stereocenters, including quaternary stereocenters...
May 3, 2018: Chemistry: a European Journal
Haoxiao Zuo, Bing Han, Wilfred J Poppinga, Lennard Ringnalda, Loes E M Kistemaker, Andrew J Halayko, Reinoud Gosens, Viacheslav O Nikolaev, Martina Schmidt
BACKGROUND AND PURPOSE: 3', 5'-cyclic adenosine monophosphate (cAMP) is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease (COPD), a lung disease primarily provoked by cigarette smoke (CS), the induction of cAMP-dependent pathways, via inhibition of hydrolyzing phosphodiesterases (PDEs), is a prime therapeutic strategy. Mechanisms that disrupt cAMP signaling in airway cells, in particular regulation of endogenous PDEs are poorly understood...
May 3, 2018: British Journal of Pharmacology
Qun Li, Yucong Peng, Linfeng Fan, Hangzhe Xu, Pingyou He, Shenglong Cao, Jianru Li, Ting Chen, Wu Ruan, Gao Chen
Phosphodiesterase-4 (PDE4) plays a fundamental role in a range of central nervous system (CNS) insults, however, the role of PDE4 in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The current study was designed to investigate the role of PDE4 in EBI after SAH and explore the potential mechanism. The SAH model in Sprague-Dawley rat was established by endovascular perforation process. Rats were randomly divided into: sham group, SAH?+?vehicle group, SAH?+?rolipram (PDE4 inhibitor) group, SAH?+?rolipram?+?sirtinol (SIRT1 inhibitor) group and SAH?+?rolipram+MK2206 (Akt inhibitor) group...
March 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Ambikaipakan Balasubramaniam, Sulaiman Sheriff, Lou Ann Friend, J Howard James
PDE4-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by 6-fold, but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B KO-rats. As reported by us previously, burn injury significantly increased EDL muscle total and myofibrillar proteolysis in WT-rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO-rat with burn injury...
April 25, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Xiaonan Liang, Zheng Yong, Ruibin Su
Opioid-induced respiratory depression is a major obstacle to improving the clinical management of moderate to severe chronic pain. Opioids inhibit neuronal activity via various pathways, including calcium channels, adenylyl cyclase, and potassium channels. Currently, the underlying molecular pathway of opioid-induced respiratory depression is only partially understood. This study aimed to investigate the mechanisms of opioid-induced respiratory depression in vivo by examining the effects of different pharmacological agents on fentanyl-induced respiratory depression...
April 18, 2018: Neuroscience Letters
Lamei Yu, Kuichang Yuan, Byung Mun Park, Suhn Hee Kim
This study aimed to determine the effects of levosimendan, a calcium sensitizer, on atrial contractility and atrial natriuretic peptide (ANP) secretion and its modification in hypertrophied atria. Isolated perfused beating rat atria were used from control and isoproterenol-treated rats. Levosimendan and its metabolite OR-1896 caused a positive inotropic effect and suppressed ANP secretion in rat atria. Similar to levosimendan, the selective phosphodiesterase 3 (PDE3) or PDE4 inhibitor also suppressed ANP secretion...
April 10, 2018: European Journal of Pharmacology
Tommaso Prosdocimi, Luca Mollica, Stefano Donini, Marta S Semrau, Anna Paola Lucarelli, Egidio Aiolfi, Andrea Cavalli, Paola Storici, Silvana Alfei, Chiara Brullo, Olga Bruno, Emilio Parisini
Selected members of the large rolipram-related GEBR family of phosphodiesterase-4 (PDE4) inhibitors have been shown to facilitate long term potentiation (LTP) and improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, little if any structure-activity relationship studies have so far been carried out in order to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone...
April 13, 2018: Biochemistry
Esther Barreiro, Ester Puig-Vilanova, Anna Salazar-Degracia, Sergi Pascual-Guardia, Carme Casadevall, Joaquim Gea
Peripheral muscle weakness and mass loss are characteristic features in severe COPD. We hypothesized that the phosphodiesterase-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 microM roflumilast N-oxide (RNO) for three time-cohorts (1h, 6h, and 24h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting...
April 12, 2018: Journal of Applied Physiology
Rene Blöcher, Karen M Wagner, Raghavender R Gopireddy, Todd R Harris, Hao Wu, Bogdan Barnych, Sung Hee Hwang, Yang K Xiang, Ewgenij Proschak, Christophe Morisseau, Bruce D Hammock
Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of 4 selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood (Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 hours...
April 3, 2018: Journal of Medicinal Chemistry
Giulia Vigone, Leia C Shuhaibar, Jeremy R Egbert, Tracy F Uliasz, Matthew A Movsesian, Laurinda A Jaffe
Luteinizing hormone (LH) acts on the granulosa cells that surround the oocyte in mammalian preovulatory follicles to cause meiotic resumption and ovulation. Both of these responses are mediated primarily by an increase in cAMP in the granulosa cells, and activity of the cAMP phosphodiesterase PDE4 contributes to preventing premature responses. However, 2 other cAMP-specific phosphodiesterases, PDE7 and PDE8, are also expressed at high levels in the granulosa cells, raising the question of whether these phosphodiesterases also contribute to preventing uncontrolled activation of meiotic resumption and ovulation...
March 28, 2018: Endocrinology
Fu-Chao Liu, Huang-Ping Yu, Cheng-Yu Lin, Ahmed O Elzoghby, Tsong-Long Hwang, Jia-You Fang
BACKGROUND: Cilomilast is a phosphodiesterase 4 (PDE4) inhibitor for treating inflammatory lung diseases. This agent has a narrow therapeutic index with significant adverse effects on the nervous system. This study was conducted to entrap cilomilast into PEGylated phosphatidylcholine-rich niosomes (phosphatiosomes) to improve pulmonary delivery via the strong affinity to pulmonary surfactant film. Neutrophils were used as a cell model to test the anti-inflammatory activity of phosphatiosomes...
March 30, 2018: Journal of Nanobiotechnology
Manju Sharma, Corey Levenson, John C Browning, Emily M Becker, Ian Clements, Paul Castella, Michael E Cox
Cyclic adenosine monophosphate phosphodiesterases (PDEs) regulate pro-inflammatory cytokine production. One isoform, PDE4, is overactive in chronic relapsing inflammatory skin diseases: psoriasis and eczema/atopic dermatitis, and in several cancers. East Indian sandalwood oil (EISO) has significant anti-inflammatory properties. Here, we report that 75% of pediatric eczema/atopic dermatitis patients treated with topical EISO formulations achieved a >50% reduction in their Eczema Area and Severity Index score...
2018: Frontiers in Pharmacology
Souvik Dey, Suranjana Goswami, Alaa Eisa, Rahul Bhattacharjee, Cameron Brothag, Douglas Kline, Srinivasan Vijayaraghavan
The multifaceted glycogen synthase kinase (GSK3) has an essential role in sperm and male fertility. Since cyclic AMP (cAMP) plays an important role in sperm function, we investigated whether GSK3 and cAMP pathways may be interrelated. We used GSK3 and soluble adenylyl cyclase (sAC) knockout mice and pharmacological modulators to examine this relationship. Intracellular cAMP levels were found to be significantly lower in sperm lacking GSK3α or GSK3β. A similar outcome was observed when sperm cells were treated with SB216763, a GSK3 inhibitor...
March 25, 2018: Journal of Cellular Physiology
Yefei Pang, Peter Thomas
Natriuretic peptide type C (NPPC) and its receptor, natriuretic peptide receptor 2 (NPR2), have essential roles in maintaining meiotic arrest of oocytes in several mammalian species. However, it is not known if a similar mechanism exists in non-mammalian vertebrates. Using zebrafish as a model, we show that Nppc is expressed in ovarian follicle cells, whereas Npr2 is mainly detected in oocytes. Treatment of intact and defolliculated oocytes with 100 nM NPPC for 6 h caused a large increase in cGMP concentrations, and a significant decrease in oocyte maturation (OM), an effect that was mimicked by treatment with 8-Br-cGMP...
March 22, 2018: General and Comparative Endocrinology
Aya M Almatary, Mohammad A Elmorsy, Walaa M El Husseiny, Khalid B Selim, Magda A-A El-Sayed
A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre-G1 phase, and induced cell death by apoptosis of A549 cells in a caspase-dependent manner...
March 24, 2018: Archiv der Pharmazie
Vicky Pauwelyn, Romain A Lefebvre
Background: As the signal transduction of 5-HT4 receptors on cholinergic neurons innervating smooth muscle is controlled by phosphodiesterase (PDE) 4 in porcine stomach and colon, and human large intestine, the in vivo gastroprokinetic effects of a 5-HT4 receptor agonist might be enhanced by combination with a selective PDE4 inhibitor. The presence of 5-HT4 receptors on cholinergic neurons towards murine gastrointestinal circular muscle was recently shown. If the control of this receptor pathway by PDE4 is also present in mice, this might be a good model for in vivo testing of the combination therapy...
2018: Frontiers in Pharmacology
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