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Phosphodiesterase 4

Christian Viniol, Claus F Vogelmeier
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. While COPD is a mainly chronic disease, a substantial number of patients suffer from exacerbations. Severe exacerbations are related to a significantly worse survival outcome. This review summarises the current knowledge on the different aspects of COPD exacerbations. The impact of risk factors and triggers such as smoking, severe airflow limitation, bronchiectasis, bacterial and viral infections and comorbidities is discussed...
March 31, 2018: European Respiratory Review: An Official Journal of the European Respiratory Society
L V Tat'yanenko, N A Sanina, O V Dobrokhotova, A I Kotelnikov, N S Goryachev, I I Pihteleva, G I Kozub, T A Kondrateva
The effect of iron nitrosyl complexes, NO donors, of a general formula [Fe2 (L)2 (NO)4 ] with functional sulfur-containing ligands (L-3-nitro-phenol-2-yl, 4-nitro-phenol-2-yl, or 1-methyl-tetrazol-5-yl) on the activity of sarcoplasmic reticulum Ca2+ -ATPase and cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) was studied. The test complexes uncoupled the hydrolytic and transport functions of Ca2+ - ATPase, thus disturbing the balance of Ca2+ ions in cells, which may affect the formation of thrombi and adhesion of metastatic cells to the endothelium of capillaries...
January 2018: Doklady. Biochemistry and Biophysics
Nahla Reda Sarhan, Nesreen Moustafa Omar
Tadalafil (Cialis) is one of the most commonly used phosphodiesterase type5 (PDE5) inhibitors. This work aimed to analyze the histological and ultrastructural changes provoked by chronic tadalafil administration in the rat retina, correlate between such changes and PDE5 immunoexpression and to evaluate the possible reversibility of these changes. Thirty Sprague Dawley male rats were randomly distributed into 3 groups. Control group; given 1 ml distilled water daily for 6 weeks. Tadalafil group; given tadalafil in a daily dose of 2...
March 8, 2018: Acta Histochemica
Tsuneya Ikezu, Cidi Chen, Annina M DeLeo, Ella Zeldich, M Daniele Fallin, Nicholas M Kanaan, Kathryn L Lunetta, Carmela R Abraham, Mark W Logue, Lindsay A Farrer
We studied the effect of two rare mutations (rs144662445 and rs149979685) in the A-kinase anchoring protein 9 (AKAP9) gene, previously associated with Alzheimer disease (AD) in African Americans (AA), on post-translational modifications of AD-related pathogenic molecules, amyloid precursor protein (APP) and microtubule-associated protein Tau using lymphoblastoid cell lines (LCLs) from 11 AA subjects with at least one AKAP9 mutation and 17 AA subjects lacking these mutations. LCLs were transduced by viral vectors expressing causative AD mutations in APP or human full-length wild type Tau...
March 7, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Jihyun Youm, Hyunyong Lee, Youngwoo Choi, Joobyoung Yoon
Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti-asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A-activated spleen cells and polarized Th2 cells...
March 7, 2018: Journal of Cellular and Molecular Medicine
Wei Liu, Patrick J Antonelli, Philipp Dahm, Tobias Gerhard, Joseph A C Delaney, Richard Segal, Stephen Crystal, Almut G Winterstein
PURPOSE: The objective of the study was to determine the risk of sudden sensorineural hearing loss (SNHL) associated with use of phosphodiesterase type 5 (PDE5) inhibitors. METHODS: We conducted a retrospective cohort study in the MarketScan Commercial Claims and Encounters Database including adult men who initiated a PDE5 inhibitor (n = 377,722) and 1,957,233 nonusers between 1998 and 2007. Periods of drug exposure were assessed on a weekly basis based on pharmacy billing records, assuming use of 1 dose per week (current use)...
March 7, 2018: Pharmacoepidemiology and Drug Safety
Neema S Patel, Jennifer Klett, Katy Pilarzyk, Dong Ik Lee, David Kass, Frank S Menniti, Michy P Kelly
3',5'-Cyclic nucleotide phosphodiesterases (PDEs) degrade 3',5' cyclic adenonosine monophosphate (cAMP) and 3',5' cyclic guanosine monophosphate (cGMP), with PDE9A having the highest affinity for cGMP. We show PDE9A6 and 3 novel PDE9 isoforms (PDE9X-100, PDE9X-120, and PDE9X-175) are reliably detected in the brain and lung of mice, whereas PDE9A2 and other isoforms are found elsewhere. PDE9A localizes to the membrane in all organs except the bladder, where it is cytosolic. Brain additionally shows PDE9 in the nuclear fraction...
February 5, 2018: Neurobiology of Aging
Richard S Roberts, Sara Sevilla, Manel Ferrer, Joan Taltavull, Begoña Hernández, Victor Segarra, Jordi Gracia, Martin D Lehner, Amadeu Gavaldà, Míriam Andrés, Judit Cabedo, Dolors Vilella, Peter Eichhorn, Elena Calama, Carla Carcasona, Montserrat Miralpeix
Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with sub-nanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration...
March 5, 2018: Journal of Medicinal Chemistry
Jian Luo, Ling Yang, Jing Yang, Dan Yang, Bi-Cui Liu, Dan Liu, Bin-Miao Liang, Chun-Tao Liu
Phosphodiesterase 4 (PDE4) inhibitors are a novel medication approved for airway inflammatory diseases including chronic obstructive pulmonary disease. Their role and application in asthma are controversial and not defined. A comprehensive search was performed in major databases (1946-2016) using the keywords: 'phosphodiesterase 4 inhibitor' or 'roflumilast' and 'asthma'. Placebo-controlled trials reporting lung function, airway hyperresponsiveness by direct challenge, asthma control and exacerbations, and adverse events were included...
March 4, 2018: Respirology: Official Journal of the Asian Pacific Society of Respirology
Lin Chen, Gui-Hua Tang, Fu-Liang Guo, Wei Li, Jun-Sheng Zhang, Bo Liu, Sheng Yin
A pair of undescribed bicoumarin enantiomers, (P)/(M)-corinepalensin A, two undescribed prenylated coumarins, corinepalensins B and C, along with ten known coumarins were isolated from the twigs of Coriaria nepalensis. (P)/(M)-corinepalensin A feature a rare C-5C-5' axially chiral linkage between two prenylated coumarin monomers. Their structures were determined by a combination of spectroscopic methods, single crystal X-ray diffraction, and ECD calculations. All isolates were evaluated for the inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease...
February 28, 2018: Phytochemistry
Susann Schröder, Barbara Wenzel, Winnie Deuther-Conrad, Rodrigo Teodoro, Mathias Kranz, Matthias Scheunemann, Ute Egerland, Norbert Höfgen, Detlef Briel, Jörg Steinbach, Peter Brust
Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the18 F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18 F])fluoroethoxy)-7-methylimidazo[5,1- c ]pyrido[2,3- e ][1,2,4]triazine (([18 F]) TA5 ). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3...
March 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Mervat Z Mohamed, Heba M Hafez, Nagwa M Zenhom, Hanaa Hassanein Mohammed
AIMS: Male infertility prevalence is higher in diabetic patients. Those patients exhibit testicular oxidative damage due to sustained hyperglycemia and inflammation. The study has investigated the efficacy of cilostazol, a phosphodiesterase 3 inhibitor, on testicular damage of diabetic rats. MAIN METHODS: Streptozotocin-induced diabetes in rats was used as a model. Six control male rats and 24 diabetic male rats were divided into the following: diabetic, cilostazol at low dose, cilostazol at high dose, and sildenafil treated rat groups...
February 26, 2018: Life Sciences
Yoichi Kadoh, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Kenji Omori, Jun Kotera, Takashi Sasaki, Tamaki Kobayashi, Hiroyuki Taniguchi, Yumi Watanabe, Koki Kojima, Toshiaki Sakamoto, Toshiyuki Himiyama, Eiji Kawanishi
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5...
2018: Chemical & Pharmaceutical Bulletin
Michael F Santillo, Mapa S T Mapa
Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase-5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based upon measuring inhibition of PDE5 activity, which is the pharmacological mechanism shared among the adulterants...
February 28, 2018: Drug Testing and Analysis
Yang Fu, Zhaoqing Yu, Shu Liu, Bo Chen, Li Zhu, Zhou Li, Shan-Ho Chou, Jin He
C-di-GMP has been well investigated to play significant roles in the physiology of many Gram-negative bacteria. However, its effect on Gram-positive bacteria is less known. In order to more understand the c-di-GMP functions in Gram-positive bacteria, we have carried out a detailed study on the c-di-GMP-metabolizing enzymes and their physiological functions in Bacillus thuringiensis , a Gram-positive entomopathogenic bacterium that has been applied as an insecticide successfully. We performed a systematic study on the ten putative c-di-GMP-synthesizing enzyme diguanylate cyclases (DGCs) and c-di-GMP-degrading enzyme phosphodiesterases (PDEs) in B...
2018: Frontiers in Microbiology
Deborah Kim, Kyung Min Lee, Marc R Freiman, W Ryan Powell, Elizabeth S Klings, Seppo Rinne, Donald Miller, Adam J Rose, Renda Soylemez Wiener
RATIONALE: Care of patients with pulmonary hypertension (PH) is complex. While pulmonary vasodilators are effective for Group 1 PH, clinical guidelines and the Choosing Wisely Campaign recommend against routine use for Groups 2 and 3 PH (the most common types of PH) due to a lack of benefit, potential for harm, and high cost ($10,000-$13,000 per patient per year treated). Little is known about how these medications are used in practice. OBJECTIVE(S): To determine national patterns of phosphodiesterase-5-inhibitor (PDE5i) prescribing for PH in the Veterans Health Administration (VA)...
February 27, 2018: Annals of the American Thoracic Society
Jiahong Zhong, Hui Yu, Chang Huang, Qiuping Zhong, Yaping Chen, Jinfeng Xie, Zhongzhen Zhou, Jiangping Xu, Haitao Wang
Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+ ) were examined in SH-SY5Y cells...
February 14, 2018: Redox Biology
Paradorn Muangnil, Saravut Satitsri, Kwanruthai Tadpetch, Patchreenart Saparpakorn, Varanuj Chatsudthipong, Supa Hannongbua, Vatcharin Rukachaisirikul, Chatchai Muanprasat
Overstimulation of CFTR-mediated Cl- secretion plays an important role in the pathogenesis of secretory diarrheas, which remain an important global health problem. This study aimed to identify inhibitors of CFTR-mediated Cl- secretion from a library of fungus-derived compounds and to evaluate their pharmacological properties and anti-diarrheal utility. We identified zearalenone, 7'-dehydrozearalenone and 8'-hydroxyzearalenone isolated from the seagrass-derived fungus Fusarium sp. PSU-ES123 as inhibitors of CFTR-mediated Cl- secretion in human intestinal epithelial (T84) cells...
February 20, 2018: Biochemical Pharmacology
Yuri A Blednov, Adriana J Da Costa, Tamara Tarbox, Olga Ponomareva, Robert O Messing, R Adron Harris
BACKGROUND: Phosphodiesterase type 4 (PDE4) inhibitors produce widespread anti-inflammatory effects and reduce ethanol consumption in several rodent models. These drugs are potential treatments for several diseases, including central nervous system disorders, but clinical use is limited by their emetic activity. Apremilast is a selective PDE4 inhibitor with fewer gastrointestinal side effects that is FDA approved for the treatment of psoriasis. METHODS: We measured the acute and chronic effects of apremilast on ethanol consumption in male and female C57BL/6J mice using the continuous and intermittent 24-h two-bottle choice drinking models...
February 22, 2018: Alcoholism, Clinical and Experimental Research
Yuri A Blednov, Adriana J Da Costa, R Adron Harris, Robert O Messing
BACKGROUND: In our companion paper, we reported that the phosphodiesterase type 4 inhibitor apremilast reduced ethanol intake and preference in different drinking models in male and female C57BL/6J mice. In the current study, we measured the effects of apremilast on other behaviors that are correlated with ethanol consumption. METHODS: The effects of apremilast (20 mg/kg) on the following behaviors were studied in male and female C57BL/6J mice: locomotor response to a novel situation; ethanol- or LiCl-induced conditioned taste aversion (CTA) to saccharin; conditioned place preference (CPP) and conditioned place avoidance (CPA) to ethanol; severity of handling-induced convulsions after ethanol administration; ethanol-induced anxiolytic-like behavior in the elevated plus maze; duration of ethanol-induced loss of the righting reflex (LORR); recovery from ethanol-induced motor impairment on the rotarod; and acute functional tolerance (AFT) to ethanol...
February 22, 2018: Alcoholism, Clinical and Experimental Research
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