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Phosphodiesterase 4

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https://www.readbyqxmd.com/read/28103900/gde2-is-essential-for-neuronal-survival-in-the-postnatal-mammalian-spinal-cord
#1
Clinton Cave, Sungjin Park, Marianeli Rodriguez, Mai Nakamura, Ahmet Hoke, Mikhail Pletnikov, Shanthini Sockanathan
BACKGROUND: Glycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane protein that cleaves glycosylphosphatidylinositol (GPI) anchors to regulate GPI-anchored protein activity at the cell surface. In the developing spinal cord, GDE2 utilizes its enzymatic function to regulate the production of specific classes of motor neurons and interneurons; however, GDE2's roles beyond embryonic neurogenesis have yet to be defined. METHOD: Using a panel of histological, immunohistochemical, electrophysiological, behavioral, and biochemistry techniques, we characterized the postnatal Gde2 (-/-) mouse for evidence of degenerative neuropathology...
January 19, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28097089/selective-inhibition-of-phosphodiesterases-4-5-and-9-induces-hsp20-phosphorylation-and-attenuates-amyloid-beta-1-42-mediated-cytotoxicity
#2
Ryan T Cameron, Ellanor Whiteley, Jon P Day, Anna I Parachikova, George S Baillie
Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1-42 (Aβ1-42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisation between the chaperone and Aβ1-42 to significantly decrease the toxic effect of the peptide...
January 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28096287/prediction-models-for-exacerbations-in-patients-with-copd
#3
REVIEW
Beniamino Guerra, Violeta Gaveikaite, Camilla Bianchi, Milo A Puhan
Personalised medicine aims to tailor medical decisions to the individual patient. A possible approach is to stratify patients according to the risk of adverse outcomes such as exacerbations in chronic obstructive pulmonary disease (COPD). Risk-stratified approaches are particularly attractive for drugs like inhaled corticosteroids or phosphodiesterase-4 inhibitors that reduce exacerbations but are associated with harms. However, it is currently not clear which models are best to predict exacerbations in patients with COPD...
January 2017: European Respiratory Review: An Official Journal of the European Respiratory Society
https://www.readbyqxmd.com/read/28094963/four-step-total-synthesis-of-selaginpulvilin-d
#4
Madison J Sowden, Michael S Sherburn
An extremely concise total synthesis of a potent phosphodiesterase-4 inhibitory natural product, selaginpulvilin D, is reported. The synthesis features a one-pot, 3-fold electrophilic aromatic substitution sequence to assemble a 9,9-diarylfluorene core. The approach allows access to useful quantities of a selaginpulvilin natural product for the first time.
January 17, 2017: Organic Letters
https://www.readbyqxmd.com/read/28092671/pde4d-promotes-fak-mediated-cell-invasion-in-braf-mutated-melanoma
#5
J Delyon, A Servy, F Laugier, J André, N Ortonne, M Battistella, S Mourah, A Bensussan, C Lebbé, N Dumaz
The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28091532/development-of-the-neuroimmune-modulator-ibudilast-for-the-treatment-of-alcoholism-a-randomized-placebo-controlled-human-laboratory-trial
#6
Lara A Ray, Spencer Bujarski, Steve Shoptaw, Daniel Jo Roche, Keith Heinzerling, Karen Miotto
Current directions in medication development for alcohol use disorder (AUD) emphasize the need to identify novel molecular targets and efficiently screen new compounds aimed at those targets. Ibudilast (IBUD) is a neuroimmune modulator that inhibits phosphodiesterases -4 and -10 and macrophage migration inhibitory factor and was recently found to reduce alcohol intake in rats by approximately 50%. To advance medications development for AUD, the present study consists of a randomized, crossover, double-blind, placebo-controlled laboratory study of IBUD in non-treatment seeking individuals with current (ie, past month) mild-to-severe AUD...
January 16, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28087362/clinical-phenotypes-and-outcomes-of-heritable-and-sporadic-pulmonary-veno-occlusive-disease-a-population-based-study
#7
David Montani, Barbara Girerd, Xavier Jaïs, Marilyne Levy, David Amar, Laurent Savale, Peter Dorfmüller, Andrei Seferian, Edmund M Lau, Mélanie Eyries, Jérôme Le Pavec, Florence Parent, Damien Bonnet, Florent Soubrier, Elie Fadel, Olivier Sitbon, Gérald Simonneau, Marc Humbert
BACKGROUND: Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the effect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH. METHODS: We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicêtre, University Paris-Sud) with either confirmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases)...
January 10, 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28080219/adipose-tissue-insulin-resistance-in-gestational-diabetes
#8
Batbayar Tumurbaatar, Aaron T Poole, Gayle Olson, Michel Makhlouf, Hanaa S Sallam, Shwetha Thukuntla, Sucharitha Kankanala, Obos Ekhaese, Guillermo Gomez, Manisha Chandalia, Nicola Abate
BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance (IR) and altered glucose-lipid metabolism. We propose that ectonucleotide pyrophosphate phosphodiesterase-1 (ENPP1), a protein known to induce adipocyte IR, is a determinant of GDM. Our objective was to study ENPP1 expression in adipose tissue (AT) of obese pregnant women with or without GDM, as well as glucose tolerance in pregnant transgenic (Tg) mice with AT-specific overexpression of human ENPP1...
January 12, 2017: Metabolic Syndrome and related Disorders
https://www.readbyqxmd.com/read/28074710/canine-spinal-cord-glioma
#9
Daniel R Rissi, Renee Barber, Annabelle Burnum, Andrew D Miller
Spinal cord glioma is uncommonly reported in dogs. We describe the clinicopathologic and diagnostic features of 7 cases of canine spinal cord glioma and briefly review the veterinary literature on this topic. The median age at presentation was 7.2 y. Six females and 1 male were affected and 4 dogs were brachycephalic. The clinical course lasted from 3 d to 12 wk, and clinical signs were progressive and associated with multiple suspected neuroanatomic locations in the spinal cord. Magnetic resonance imaging of 6 cases revealed T2-weighted hyperintense lesions with variable contrast enhancement in the spinal cord...
January 2017: Journal of Veterinary Diagnostic Investigation
https://www.readbyqxmd.com/read/28065587/ffpm-a-pde4-inhibitor-reverses-learning-and-memory-deficits-in-app-ps1-transgenic-mice-via-camp-pka-creb-signaling-and-anti-inflammatory-effects
#10
Haibiao Guo, Yufang Cheng, Canmao Wang, Jingang Wu, Zhengqiang Zou, Bo Niu, Hui Yu, Haitao Wang, Jiangping Xu
Thus far, phosphodiesterase-4 (PDE4) inhibitors have not been approved for application in Alzheimer's disease (AD) in a clinical setting due to severe side effects, such as nausea and vomiting. In this study, we investigated the effect of FFPM, a novel PDE4 inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Pharmacokinetic studies have revealed that FFPM efficiently permeates into the brain, and reached peak values in plasma 2 h after orally dosing...
January 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28062949/can-cyclic-nucleotide-phosphodiesterase-inhibitors-be-drugs-for-parkinson-s-disease
#11
REVIEW
Dominic Ngima Nthenge-Ngumbau, Kochupurackal P Mohanakumar
Parkinson's disease (PD) has no known cure; available therapies are only capable of offering temporary, symptomatic relief to the patients. Varied therapeutic strategies that are clinically used for PD are pharmacological therapies including dopamine replacement therapies (with or without adjuvant), postsynaptic dopamine receptor stimulation, dopamine catabolism inhibitors and also anticholinergics. Surgical therapies like deep brain stimulation and ablative surgical techniques are also employed. Phosphodiesterases (PDEs) are enzymes that degrade the phosphodiester bond in the second messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)...
January 6, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28055196/discovery-of-novel-phosphodiesterase-2a-inhibitors-by-structure-based-virtual-screening-structural-optimization-and-bioassay
#12
Chen Zhang, Ling-Jun Feng, Yiyou Huang, Deyan Wu, Zhe Li, Qian Zhou, Yinuo Wu, Hai-Bin Luo
Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer's disease and pulmonary hypertension. However, most of the current PDE2A inhibitors have moderate selectivity over other PDEs. In the present study, we described the discovery of novel PDE2A inhibitors by structure-based virtual screening combining pharmacophore model screening, molecular docking, molecular dynamics simulations, and bioassay validation. Nine hits out of 30 molecules from the SPECS database (a hit rate of 30%) inhibited PDE2A with affinity less than 50 μM...
January 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28054669/comparison-of-the-pharmacological-profiles-of-selective-pde4b-and-pde4d-inhibitors-in-the-central-nervous-system
#13
Chong Zhang, Ying Xu, Han-Ting Zhang, Mark E Gurney, James M O'Donnell
Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28032424/relationship-between-age-and-erectile-dysfunction-diagnosis-or-treatment-using-real-world-observational-data-in-the-usa
#14
John P Mulhall, Xuemei Luo, Kelly H Zou, Vera Stecher, Aaron Galaznik
AIMS: With self-reporting of erectile dysfunction (ED) in population-based surveys, men with ED may not represent men who are bothered sufficiently to seek an ED diagnosis and treatment. We used real-world observational data to assess: 1) the prevalence of ED diagnosis or treatment by age subgroups; and 2) the relationship of age with ED diagnosis or treatment after controlling for ED-related comorbidities in the USA. METHODS: This cross-sectional study used de-identified claims data (MarketScan(®) databases; primary analysis)...
December 2016: International Journal of Clinical Practice
https://www.readbyqxmd.com/read/28027560/structural-and-functional-state-of-heart-left-ventricle-depending-on-polymorphism-rs966221-phosphodiesterase-4d-gene-in-emergency-workers-of-the-chornobyl-npp-suffering-from-coronary-heart-disease
#15
O Nastina, G Pleskach, N Kursina, O Bazyka, O Makarevich, I Abramenko, A Chumak, D Belyi
OBJECTIVE: This study consisted in examination the features of structural and functional state of the cardiovascular system in emergency workers (EW) of the Chernobyl nuclear power plant (ChNPP) who suffered from coronary heart disease (CHD) and having different genotypes due to polymorphism rs966221 phosphodiesterase 4D (PDE4D) gene. MATERIALS AND METHODS: The study involved 121 EW and 63 non irradiated patients with CHD. Standardized survey included echo doppler cardiography (EchoCG) that was done by Diagnostic Ultrasound System DS N3 (Mindray)...
December 2016: Problemy Radiat︠s︡iĭnoï Medyt︠s︡yny Ta Radiobiolohiï
https://www.readbyqxmd.com/read/28027554/features-of-coronary-heart-disease-development-in-emergency-workers-of-the-chornobyl-accident-depending-on-the-action-of-radiation-and-non-radiation-risk-factors-and-genotypes-of-single-nucleotide-polymorphism-rs966221-of-phosphodiesterase-4d-gene
#16
D Belyi, G Pleskach, O Nastina, G Sidorenko, N Kursina, O Bazyka, O Kovalev, A Chumak, I Abramenko
OBJECTIVE: This study devoted to specific features of coronary heart disease (CHD) development in emergency work ers (EW) of the accident at the Chernobyl nuclear power plant (ChNPP) based on analysis the interaction between radiation and non radiation risk factors and single nucleotide polymorphism (SNP) rs966221 of phosphodiesterase (PDE) 4D gene. METHODS: It was examined 397 men with CHD, including 274 EW of 1986-1987 and 123 non irradiated persons (con trol group) who were 66±10 and 69±11 years old relatively...
December 2016: Problemy Radiat︠s︡iĭnoï Medyt︠s︡yny Ta Radiobiolohiï
https://www.readbyqxmd.com/read/28025994/the-analgesic-effect-of-rolipram-is-associated-with-the-inhibition-of-the-activation-of-the-spinal-astrocytic-jnk-ccl2-pathway-in-bone-cancer-pain
#17
Chi-Hua Guo, Lu Bai, Huang-Hui Wu, Jing Yang, Guo-Hong Cai, Xin Wang, Sheng-Xi Wu, Wei Ma
Bone cancer pain (BCP) is one of the most difficult and intractable tasks for pain management, which is associated with spinal 'neuron-astrocytic' activation. The activation of the c-Jun N-terminal kinase (JNK)/chemokine (C-C motif) ligand (CCL2) signaling pathway has been reported to be critical for neuropathic pain. Rolipram (ROL), a selective phosphodiesterase 4 inhibitor, possesses potent anti-inflammatory and anti-nociceptive activities. The present study aimed to investigate whether the intrathecal administration of ROL has an analgesic effect on BCP in rats, and to assess whether the inhibition of spinal JNK/CCL2 pathway and astrocytic activation are involved in the analgesic effects of ROL...
November 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27997987/long-term-outcome-in-liver-transplantation-candidates-with-portopulmonary-hypertension
#18
Laurent Savale, Caroline Sattler, Audrey Coilly, Filoména Conti, Sébastien Renard, Claire Francoz, Hélène Bouvaist, Cyrille Feray, Patrick Borentain, Xavier Jaïs, David Montani, Florence Parent, Caroline O'Connell, Philippe Hervé, Marc Humbert, Gérald Simonneau, Didier Samuel, Yvon Calmus, Christophe Duvoux, François Durand, Jean Charles Duclos-Vallée, Olivier Sitbon
BACKGROUND: Portopulmonary hypertension (PoPH) is diagnosed in 2-6% of liver transplantation (LT) candidates. OBJECTIVE AND METHODS: To study outcomes of candidates for LT suffering from PoPH. Data were collected retrospectively from a prospective registry. Pulmonary hemodynamic variables were collected at the time of PoPH diagnosis, at last evaluation before LT, within 6 months and beyond 6 months after LT. RESULTS: Forty-nine patients (35 males, 48±8 years) were analysed (median MELD score 20)...
December 20, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27997807/roflumilast-n-oxide-in-combination-with-formoterol-enhances-the-anti-inflammatory-effect-of-dexamethasone-in-asm-cells
#19
Brijeshkumar S Patel, Md Mostafizur Rahman, Gina Baehring, Dikaia Xenaki, Francesca Su-May Tang, Brian G Oliver, Alaina J Ammit
Roflumilast is an orally active phosphodiesterase 4 (PDE4) inhibitor approved for use in chronic obstructive pulmonary disease. Roflumilast N-oxide (RNO) is the active metabolite of roflumilast and has demonstrated anti-inflammatory impact in vivo and in vitro. To date, the effect of RNO on the synthetic function of airway smooth muscle (ASM) cells is unknown. We address this herein and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMP-dependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation...
December 20, 2016: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27993970/identification-of-a-multifunctional-docking-site-on-the-catalytic-unit-of-phosphodiesterase-4-pde4-that-is-utilised-by-multiple-interaction-partners
#20
Kirsty F Houslay, Frank Christian, Ruth MacLeod, David R Adams, Miles D Houslay, George Scott Baillie
Cyclic AMP (cAMP) specific phosphodiesterase-4 (PDE4) enzymes underpin compartmentalised cAMP signalling by localising to distinct signalling complexes. PDE4 long isoforms can be phosphorylated by mitogen-activated protein kinase-activated protein kinase 2 (MK2), which attenuates activation of such enzymes through their phosphorylation by protein kinase A (PKA). Here we show that MK2 interacts directly with PDE4 long isoforms and define the sites of interaction. One is a unique site that locates within the regulatory UCR1 domain and contains a core Phe141, Leu142 and Tyr143 (FLY) cluster (PDE4A5 numbering)...
December 19, 2016: Biochemical Journal
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