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Phosphodiesterase

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https://www.readbyqxmd.com/read/28108651/roflumilast-and-aquaporin-2-regulation-in-rat-renal-inner-medullary-collecting-duct
#1
Ezigbobiara N Umejiego, Yanhua Wang, Mark A Knepper, Chung-Lin Chou
Roflumilast is a cyclic nucleotide phosphodiesterase inhibitor that is FDA-approved for treatment of chronic obstructive pulmonary disease. With a view toward possible use for treatment of patients with X-linked nephrogenic diabetes insipidus (NDI) due to hemizygous mutations in the V2 vasopressin receptor, this study sought to determine the effect of roflumilast on aquaporin-2 (AQP2) phosphorylation, AQP2 trafficking, and water permeability in the rat inner medullary collecting duct (IMCD). In the presence of the vasopressin analog dDAVP (0...
January 2017: Physiological Reports
https://www.readbyqxmd.com/read/28108255/regular-exercise-promotes-memory-function-and-enhances-hippocampal-neuroplasticity-in-experimental-autoimmune-encephalomyelitis-mice
#2
Tae-Woon Kim, Yun-Hee Sung
Multiple sclerosis (MS) is a progressive condition affecting the central nervous system (CNS), and is characterized by the development of demyelinated lesions and plaques in the brain and spinal cord. Exercise is beneficial against dementia in elderly patients, so we investigated the effects of exercise on memory in relation to hippocampal demyelination and neuroplasticity in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Mice were randomly divided into three groups: Sham, EAE, and EAE and exercise (EAE+EX)...
January 17, 2017: Neuroscience
https://www.readbyqxmd.com/read/28106876/inhibition-of-innate-immune-cytosolic-surveillance-by-an-m-tuberculosis-phosphodiesterase
#3
Ruchi Jain Dey, Bappaditya Dey, Yue Zheng, Laurene S Cheung, Jie Zhou, David Sayre, Pankaj Kumar, Haidan Guo, Gyanu Lamichhane, Herman O Sintim, William R Bishai
Mycobacterium tuberculosis infection leads to cytosolic release of the bacterial cyclic dinucleotide (CDN) c-di-AMP and a host-generated CDN, cGAMP, both of which trigger type I interferon (IFN) expression in a STING-dependent manner. Here we report that M. tuberculosis has developed a mechanism to inhibit STING activation and the type I IFN response via the bacterial phosphodiesterase (PDE) CdnP, which mediates hydrolysis of both bacterial-derived c-di-AMP and host-derived cGAMP. Mutation of cdnP attenuates M...
February 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28105791/the-future-of-pleiotropic-therapy-in-heart-failure-lessons-from-the-benefits-of-exercise-training-on-endothelial-function
#4
REVIEW
Gilles W De Keulenaer, Vincent F M Segers, Faiez Zannad, Dirk L Brutsaert
A novel generation of drugs is introduced in the treatment of heart failure (HF). These drugs, including phosphodiesterase-5 inhibitors, guanylate cyclase stimulators and activators, share the feature that their action is either endothelial-mediated or substitutes for endothelial pathways, in particular the nitric oxide-cyclic guanosine monophosphate pathway, thereby influencing homeostatic balances in virtually each organ system in a pleiotropic fashion. Unfortunately, recent clinical trials with some of these drugs have shown disappointing results, at least in the setting of HF with a preserved ejection fraction...
January 19, 2017: European Journal of Heart Failure
https://www.readbyqxmd.com/read/28105765/phosphodiesterase-5-inhibition-in-heart-failure-with-preserved-ejection-fraction-trading-therapy-for-prevention
#5
EDITORIAL
Marco Guazzi, Loek van Heerebeek, Walter J Paulus
No abstract text is available yet for this article.
January 19, 2017: European Journal of Heart Failure
https://www.readbyqxmd.com/read/28105267/potential-treatment-of-cognitive-impairment-in-schizophrenia-by-phosphodiesterase-2-pde2-inhibitors
#6
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28104755/n-glycosylation-of-human-sphingomyelin-phosphodiesterase-acid-like-3a-smpdl3a-is-essential-for-stability-secretion-and-activity
#7
Mathew Traini, Raani Kumaran, Morten Thaysen-Andersen, Maaike Kockx, Wendy Jessup, Leonard Kritharides
Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a recently identified phosphodiesterase, which is a secreted N -linked glycoprotein. SMPDL3A is highly homologous to acid sphingomyelinase (aSMase), but unlike aSMase can not cleave sphingomyelin. Rather, SMPDL3A hydrolyzes nucleotide tri- and diphosphates and their derivatives. While recent structural studies have shed light on these unexpected substrate preferences, many other aspects of SMPDL3A biology which may give insight into its function in vivo remain obscure...
January 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28103900/gde2-is-essential-for-neuronal-survival-in-the-postnatal-mammalian-spinal-cord
#8
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/28101622/-use-of-vasopressors-and-inotropics-in-cardiogenic-shock
#9
H Lemm, S Dietz, M Janusch, M Buerke
Vasoactive drugs and inotropic agents are important for the hemodynamic management of cardiogenic shock. In this article the use of different vasoactive and ionotropic drugs in cardiogenic shock is presented. Hemodynamic management during cardiogenic shock occurs after initial moderate volume delivery by dobutamine to increase inotropism. If adequate perfusion pressures are not achieved norepinephrine is administered. If a sufficient increase in cardiac performance can still not be achieved by the treatment, administration of levosimendan or phosphodiesterase (PDE) inhibitors may be necessary...
January 18, 2017: Herz
https://www.readbyqxmd.com/read/28099939/type-5-phosphodiesterase-regulates-glioblastoma-multiforme-aggressiveness-and-clinical-outcome
#10
Valeriana Cesarini, Maurizio Martini, Lucia Ricci Vitiani, Giovanni Luca Gravina, Silvia Di Agostino, Grazia Graziani, Quintino Giorgio D'Alessandris, Roberto Pallini, Luigi M Larocca, Pellegrino Rossi, Emmanuele A Jannini, Susanna Dolci
Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients...
January 14, 2017: Oncotarget
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
#11
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
#12
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
#13
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/28093982/pde7-selective-and-dual-inhibitors-advances-in-chemical-and-biological-research
#14
Agnieszka Jankowska, Artur Świerczek, Grażyna Chłoń-Rzepa, Maciej Pawłowski, Elżbieta Wyska
Phosphodiesterase 7 (PDE7) is an intracellular enzyme that specifically hydrolyses the second messenger, cyclic-3',5'-adenosine monophosphate (cAMP), into inactive non-cyclic nucleotide, 5'-AMP. To date, many structurally diverse compounds with PDE7 inhibitory properties have been described, including selective PDE7 inhibitors, dual PDE4/PDE7, PDE7/PDE8, and PDE7/GSK-3 inhibitors, and non-selective PDE inhibitors with high affinity for PDE7. Inhibitors of PDE7 provided beneficial effects in animal models of inflammatory and neurological disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and many others...
16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28092671/pde4d-promotes-fak-mediated-cell-invasion-in-braf-mutated-melanoma
#15
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
#16
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/28090289/an-international-physician-survey-of-chronic-thromboembolic-pulmonary-hypertension-management
#17
Henning Gall, Ioana R Preston, Barbara Hinzmann, Sabina Heinz, David Jenkins, Nick H Kim, Irene Lang
We conducted an international study to evaluate practices in the diagnosis and management of patients with chronic thromboembolic pulmonary hypertension (CTEPH) globally across different regions. Between August and October 2012, CTEPH-treating physicians completed a 15-minute online questionnaire and provided patient record data for their 2-5 most recent patients with CTEPH. Overall, 496 physicians (Europe: 260; United States: 152; Argentina: 52; Japan: 32) completed the questionnaire and provided patient record data for 1,748 patients...
December 2016: Pulmonary Circulation
https://www.readbyqxmd.com/read/28089463/anti-inflammatory-effects-of-the-selective-phosphodiesterase-3-inhibitor-cilostazol-and-antioxidants-enzymatically-modified-isoquercitrin-and-%C3%AE-lipoic-acid-reduce-dextran-sulphate-sodium-induced-colorectal-mucosal-injury-in-mice
#18
Yumi Kangawa, Toshinori Yoshida, Hajime Abe, Yoshiki Seto, Taishi Miyashita, Michi Nakamura, Tohru Kihara, Shim-Mo Hayashi, Makoto Shibutani
Developing effective treatments and preventing inflammatory bowel disease (IBD) are urgent challenges in improving patients' health. It has been suggested that platelet activation and reactive oxidative species generation are involved in the pathogenesis of IBD. We examined the inhibitory effects of a selective phosphodiesterase-3 inhibitor, cilostazol (CZ), and two antioxidants, enzymatically modified isoquercitrin (EMIQ) and α-lipoic acid (ALA), against dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were treated with 0...
January 12, 2017: Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Für Toxikologische Pathologie
https://www.readbyqxmd.com/read/28088261/parquetina-nigrescens-leaves-chemical-profile-and-influence-on-the-physical-and-biochemical-indices-of-sexual-activity-of-male-wistar-rats
#19
Omowumi Titilola Kayode, Musa Toyin Yakubu
OBJECTIVE: The leaves of Parquetina nigrescens have been claimed in folk medicine to be useful for managing sexual dysfunction, but there is inadequate scientific evidence for this claim. This investigation was conducted to assess the effects of aqueous leaf extract of Parquetina nigrescens (AEPN) in rats induced with sexual dysfunction. METHODS: Male rats were allocated into various groups after being induced into sexual dysfunction with paroxetine hydrochloride...
January 2017: Journal of Integrative Medicine
https://www.readbyqxmd.com/read/28087362/clinical-phenotypes-and-outcomes-of-heritable-and-sporadic-pulmonary-veno-occlusive-disease-a-population-based-study
#20
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
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