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https://www.readbyqxmd.com/read/28937238/effects-of-roflumilast-a-phosphodiesterase-4-inhibitor-on-the-lung-functions-in-a-saline-lavage-induced-model-of-acute-lung-injury
#1
P Kosutova, P Mikolka, M Kolomaznik, S Rezakova, A Calkovska, D Mokra
Acute lung injury (ALI) is associated with deterioration of alveolar-capillary lining and transmigration and activation of inflammatory cells. Whereas a selective phosphodiesterase-4 (PDE4) inhibitor roflumilast has exerted potent anti-inflammatory properties, this study evaluated if its intravenous delivery can influence inflammation, edema formation, and respiratory parameters in rabbits with a lavage-induced model of ALI. ALI was induced by repetitive saline lung lavage (30 ml/kg). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with roflumilast i...
September 22, 2017: Physiological Research
https://www.readbyqxmd.com/read/28924693/phosphodiesterase-4-inhibition-affects-both-the-direct-and-indirect-pathway-an-electrophysiological-study-examining-the-tri-phasic-response-in-the-substantia-nigra-pars-reticulata
#2
P R A Heckman, J V Schweimer, T Sharp, J Prickaerts, A Blokland
Fronto-striatal circuits constitute the neurobiological basis of many neuropsychiatric disorders. Part of the intracellular signaling within these circuits, including its dopaminergic modulation, is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling cascade. Based on the overall expression in human fronto-striatal circuitry, we tested the effects of a cAMP selective phosphodiesterase 4 (PDE4) inhibitor on the tri-phasic response in the dorsomedial substantia nigra pars reticulata (SNr) upon stimulation of the infralimbic cortex in rats...
September 18, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28922692/phosphodiesterase-4-inhibitors-for-chronic-obstructive-pulmonary-disease
#3
REVIEW
Jimmy Chong, Bonnie Leung, Phillippa Poole
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea and a reduction in lung function, quality of life and life expectancy. Apart from smoking cessation, there are no other treatments that slow lung function decline. Roflumilast and cilomilast are oral phosphodiesterase 4 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This is an update of a Cochrane review first published in 2011 and updated in 2013...
September 19, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28903491/use-of-rat-primary-mesenteric-cells-for-the-prediction-of-pde4-inhibitor-drug-induced-vascular-injury
#4
Mark M Gosink, Robert E Chapin, Dean Wilkie, Scott Davenport, Steven W Kumpf, Bradley E Enerson, Christopher Houle, Petra Koza-Taylor, Todd A Wisialowski, Michael P Lawton
Drug-induced vascular injury (DIVI) in preclinical studies can delay, if not terminate, a drug development program. Clinical detection of DIVI can be very difficult as there are no definitive biomarkers known to reliably detect this disorder in all instances. The preclinical identification of DIVI requires detailed microscopic examination of a wide range of tissues although one of the most commonly affected areas in rats is the mesenteric vasculature. The reason for this predisposition of mesenteric arteries in rats as well as the exact mechanism and cell types involved in the initial development of these lesions have not been fully elucidated...
September 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28888661/rational-design-of-conformationally-constrained-oxazolidinone-fused-1-2-3-4-tetrahydroisoquinoline-derivatives-as-potential-pde4-inhibitors
#5
Gaopeng Song, Xiang Zhu, Junhua Li, Dekun Hu, Dongsheng Zhao, Yixian Liao, Juntong Lin, Lian-Hui Zhang, Zi-Ning Cui
Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D...
September 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28887947/therapeutic-pipeline-for-atopic-dermatitis-end-of-the-drought
#6
REVIEW
Amy S Paller, Kenji Kabashima, Thomas Bieber
Until the past year, our therapeutic armamentarium for treating atopic dermatitis (AD) was still primarily topical corticosteroids and, for more severe disease, systemic immunosuppressants. The pipeline of more targeted topical and systemic therapies is expanding based on our growing understanding of the mechanism for AD and is particularly focused on suppressing the skewed immune activation. Most agents are in phase 2 clinical trials. Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, became available in late 2016 in the United States for mild-to-moderate AD, with other PDE4 inhibitors, an agonist of the aryl hydrocarbon receptor, Janus kinase inhibitors, and commensal organisms also in trials for topical application...
September 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28868308/phosphodiesterases-3-and-4-differentially-regulate-the-funny-current-if-in-mouse-sinoatrial-node-myocytes
#7
Joshua R St Clair, Eric D Larson, Emily J Sharpe, Zhandi Liao, Catherine Proenza
Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3',5'-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac "funny current" (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them...
September 2017: Journal of Cardiovascular Development and Disease
https://www.readbyqxmd.com/read/28867658/identification-and-characterization-of-a-potent-and-biologically-active-pde4-7-inhibitor-via-fission-yeast-based-assays
#8
Ana Santos de Medeiros, Arlene R Wyman, Manal A Alaamery, Christina Allain, F Douglas Ivey, Lili Wang, Hai Le, James P Morken, Alawi Habara, Cuong Le, Shuaiying Cui, Adam Lerner, Charles S Hoffman
We previously constructed a collection of fission yeast strains that express various mammalian cyclic nucleotide phosphodiesterases (PDEs) and developed a cell-based high throughput screen (HTS) for small molecule PDE inhibitors. Here we describe a compound, BC54, that is a selective inhibitor of enzymes from the cAMP-specific PDE4 and PDE7 families. Consistent with the biological effect of other PDE4 and PDE7 inhibitors, BC54 displays potent anti-inflammatory properties and is superior to a combination of rolipram (a PDE4 inhibitor) and BRL50481 (a PDE7A inhibitor) for inducing apoptosis in chronic lymphocytic leukemia (CLL) cells...
September 1, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28859905/atrazine-suppresses-fsh-induced-steroidogenesis-and-lh-dependent-expression-of-ovulatory-genes-through-pde-camp-signaling-pathway-in-human-cumulus-granulosa-cells
#9
Kristina Pogrmic-Majkic, Dragana Samardzija, Natasa Stojkov-Mimic, Jelena Vukosavljevic, Aleksandra Trninic-Pjevic, Vesna Kopitovic, Nebojsa Andric
Atrazine (ATR) alters female reproductive functions in different animal species. Here, we analyzed whether ATR disturbs steroidogenic and ovulatory processes in hormone-stimulated human cumulus granulosa cells and mechanism of its action. Results showed that treatment of human cumulus granulosa cells with 20 μM ATR for 48 h resulted in lower FSH-stimulated estradiol and progesterone production. ATR reduced mRNA levels of aromatase (CYP19A1), steroidogenic acute regulatory protein (STAR) and luteinizing hormone/choriogonadotropin receptor (LHCGR)...
August 28, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28836502/inhibition-of-pde4-by-low-doses-of-rolipram-induces-changes-in-lipid-and-protein-components-of-mice-heart
#10
Sevgi Türker-Kaya, İpek Komsuoğlu Celikyurt, Umut Celikyurt, Aygül Kına
There is significant increasing interest in phosphodiesterase-4 (PDE4) inhibition in treatment of cardiovascular diseases. Related with this, research has focused on cellular, biochemical, molecular and structural changes in heart tissue induced by PDE4s inhibitors. However, for their clinical applicability additional studies are still needed. Fourier transform infrared spectroscopy offers promising approach to contribute such issue due to its ability in detection the changes in biomolecules. By utilizing this method, we examined the effects of PDE4 inhibition by rolipram at 0...
August 24, 2017: General Physiology and Biophysics
https://www.readbyqxmd.com/read/28811612/coenzyme-q10-improves-lipid-metabolism-and-ameliorates-obesity-by-regulating-camkii-mediated-pde4-inhibition
#11
Zhe Xu, Jia Huo, Xin Ding, Mu Yang, Lin Li, Jian Dai, Kazunori Hosoe, Hiroshi Kubo, Masayuki Mori, Keiichi Higuchi, Jinko Sawashita
Our recent studies revealed that supplementation with the reduced form of coenzyme Q10 (CoQ10H2) inhibits oxidative stress and slows the process of aging in senescence-accelerated mice. CoQ10H2 inhibits adipocyte differentiation and regulates lipid metabolism. In the present study, we show that dietary supplementation with CoQ10H2 significantly reduced white adipose tissue content and improved the function of brown adipose tissue by regulating expression of lipid metabolism-related factors in KKAy mice, a model of obesity and type 2 diabetes...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28807677/phosphodiesterase-4b-expression-plays-a-major-role-in-alcohol-induced-neuro-inflammation
#12
Diana V Avila, Scott A Myers, JingWen Zhang, Giorgi Kharebava, Craig J McClain, Hee-Yong Kim, Scott R Whittemore, Leila Gobejishvili, Shirish Barve
It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro-inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels...
August 12, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28799255/synergy-between-5-ht4-receptor-stimulation-and-phosphodiesterase-4-inhibition-in-facilitating-acetylcholine-release-in-human-large-intestinal-circular-muscle
#13
V Pauwelyn, W Ceelen, R A Lefebvre
BACKGROUND: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine...
August 10, 2017: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/28798156/phosphodiesterase-4-inhibitor-and-phosphodiesterase-5-inhibitor-combination-therapy-has-antifibrotic-and-anti-inflammatory-effects-in-mdx-mice-with-duchenne-muscular-dystrophy
#14
Yasunori Nio, Masayuki Tanaka, Yoshihiko Hirozane, Yo Muraki, Mitsugi Okawara, Masatoshi Hazama, Takanori Matsuo
Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase (PDE)-4 inhibitors have exhibited antifibrotic effects in human and animal models...
August 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28772081/investigational-phosphodiesterase-inhibitors-in-phase-i-and-phase-ii-clinical-trials-for-alzheimer-s-disease
#15
REVIEW
Jos Prickaerts, Pim R A Heckman, Arjan Blokland
Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD...
September 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28771997/epac1-pde4-and-pkc-protein-expression-and-their-correlation-with-akap95-and-cx43-in-esophagus-cancer-tissues
#16
Zhiyu Guan, Winxin Zhuang, Hui Lei, Dai Wang, Youliang Yao, Dongbei Guo, Qian Sun, Yun Chen, Xiaoyi Chen, Hongyan Lin, Bogang Teng, Yongxing Zhang
BACKGROUND: This study examined the expression of exchange protein directly activated by cAMP1 (Epac1), PDE4, and PKC in esophageal cancer tissues, and analyzed the association of each protein with the pathological parameters of the samples. METHODS: Epac1, PDE4, and PKC protein expression was evaluated by PV-9000 two-step immunohistochemical techniques in 51 esophageal cancer specimens and 10 para-carcinoma tissues. RESULTS: The positive expression rates of Epac1 and PKC in esophageal cancer tissues (62...
August 3, 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/28768120/investigation-of-lung-pharmacokinetic-of-the-novel-pde4-inhibitor-chf6001-in-preclinical-models-evaluation-of-the-preciseinhale-technology
#17
Alessandro Fioni, Ewa Selg, Valentina Cenacchi, Fernando Acevedo, Giandomenico Brogin, Per Gerde, Paola Puccini
BACKGROUND: Preclinical evaluation of new chemical entities (NCEs) designed to be administered by inhalation route requires lung administration to rodents, especially in the discovery phase. Different administration methods have been used until now, but more efforts are required to obtain controlled and reproducible lung deposition when only small amounts of neat powder material are available. METHODS: The PreciseInhale platform used in the present study enables well-controlled powder aerosol exposures with only small amounts of micronized neat material, providing data on inhalation pharmacokinetic (PK) of NCEs at a very early stage...
August 2, 2017: Journal of Aerosol Medicine and Pulmonary Drug Delivery
https://www.readbyqxmd.com/read/28763109/synthesis-of-14-c-and-2-h-labelled-chf6001-a-new-potent-pde4-inhibitor
#18
E Fontana, V Cenacchi, F Pivetti, A Pignatti, T Pazzi, L Bondanza, M Pazzi
A eight steps preparation of (14) C-labelled CHF6001, a potent PDE4 inhibitor in the treatment of respiratory diseases, is described. An overall yield of approximately 9% was obtained starting from copper[(14) C]cyanide. The synthesis of a stable labelled version of CHF6001 is also reported using the commercially available trideuterated bromomethylcyclopropane as starting material.
August 1, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28755423/epac1-pde4-and-pkc-protein-expression-and-their-association-with-akap95-cx43-and-cyclind2-e1-in-breast-cancer-tissues
#19
Ping Huang, Qian Sun, Wenxin Zhuang, Kuan Peng, Dai Wang, Youliang Yao, Dongbei Guo, Lu Zhang, Chuhan Shen, Mengyun Sun, Chaoying Tang, Bogang Teng, Yongxing Zhang
BACKGROUND: This study was conducted to investigate the exchange protein directly activated by cAMP (Epac1), PDE4, and PKC expression in breast cancer tissues, and the correlation between these proteins and AKAP95, Cx43, cyclin D2, and cyclin E1. METHODS: PV-9000 two-step immunohistochemistry was used to analyze protein expression. RESULTS: The positive rate of Epac1 protein expression in breast cancer tissues (58%) was higher than in para-carcinoma tissues (10%) (P < 0...
September 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/28750036/generation-and-phenotypic-characterization-of-pde1a-mutant-mice
#20
Xiaofang Wang, Satsuki Yamada, Wells B LaRiviere, Hong Ye, Jason L Bakeberg, María V Irazabal, Fouad T Chebib, Jan van Deursen, Peter C Harris, Caroline R Sussman, Atta Behfar, Christopher J Ward, Vicente E Torres
It has been proposed that a reduction in intracellular calcium causes an increase in intracellular cAMP and PKA activity through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of phosphodiesterase 1 (PDE1), the main enzymes generating and degrading cAMP in the distal nephron and collecting duct, thus contributing to the development and progression of autosomal dominant polycystic kidney disease (ADPKD). In zebrafish pde1a depletion aggravates and overexpression ameliorates the cystic phenotype...
2017: PloS One
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