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Phosphodiesterase 4

Da-Shi Qi, Jin-Hao Tao, Lian-Qin Zhang, Mei Wang, Rui Qu, Lian-Qin Zhang, Pei Liu, Jian-Cheng Miu, Jing-Yi Ma, Xin-Yu Mei
Cilostazol(CTL) is a phosphodiesterase inhibitor, which has been widely used as anti-platelet agent. It also has preventive effects on various central nervous system (CNS) diseases, including ischemic stroke, Parkinson's disease and Alzheimer disease. However, the molecular mechanism underlying the protective effects of CTL is still unclear, and whether CTL can prevent I/R induced cognitive deficit has not been reported. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats...
October 18, 2016: Brain Research
K Reich, M Gooderham, L Green, A Bewley, Z Zhang, I Khanskaya, R M Day, J Goncalves, K Shah, V Piguet, J Soung
BACKGROUND: Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has demonstrated efficacy in patients with moderate to severe psoriasis. OBJECTIVE: Evaluate efficacy and safety of apremilast vs. placebo in biologic-naive patients with moderate to severe plaque psoriasis and safety of switching from etanercept to apremilast in a phase IIIb, randomized, double-blind, placebo-controlled study (NCT01690299). METHODS: 250 patients were randomized to placebo (n=84), apremilast 30 mg BID (n=83) or etanercept 50 mg QW (n=83) through Week 16; thereafter, all patients continued or switched to apremilast through Week 104...
October 21, 2016: Journal of the European Academy of Dermatology and Venereology: JEADV
Szczepan Mogilski, Monika Kubacka, Dorota Łażewska, Małgorzata Więcek, Monika Głuch-Lutwin, Małgorzata Tyszka-Czochara, Karolina Bukowska-Strakova, Barbara Filipek, Katarzyna Kieć-Kononowicz
OBJECTIVE AND DESIGN: Histamine H4 receptor (H4R) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of H4R with particular reference to their anti-inflammatory and analgesic activity. MATERIALS AND SUBJECTS: We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test...
October 20, 2016: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
Jeffrey D Cooney, Ricardo C T Aguiar
Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of cyclic-AMP in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases SYK and PI3K, inhibits VEGFA secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets...
October 18, 2016: Blood
Jian-Jun Wen, Xianxiu Wan, John Thacker, Nisha Jain Garg
BACKGROUND: Chagasic cardiomyopathy (CCM) caused by Trypanosoma cruzi (Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM. METHODS AND RESULTS: C57BL/6 mice were infected with Tc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks...
June 2016: JACC. Basic to Translational Science
Peng Luo, Shuo Li, Yitai Chen, Yuwen Luo, Yun Li, Kai Wang, Yuxia Huang, Xin Chen
BACKGROUND: Roflumilast, a phosphodiesterase-4 inhibitor recommended by clinical guideline, is always being used in combination with at least one long-acting bronchodilator in patients with stable chronic obstructive pulmonary disease (COPD). However, there are few evidences about whether the combination of roflumilast and long-acting bronchodilators is safer and more effective in patients with moderate-to-very severe stable COPD. In our study, we investigate the effect and safety of roflumilast combined with long-acting bronchodilators on moderate-to-severe stable COPD patients...
September 2016: Journal of Thoracic Disease
Eduardo Fernández-Martínez, Héctor Ponce-Monter, Luis E Soria-Jasso, Mario I Ortiz, José-Antonio Arias-Montaño, Guillermo Barragán-Ramírez, Cynthia Mayén-García
Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K⁺-induced tonic, and Ca(2+)-induced contractions in isolated pregnant human myometrial tissues...
October 7, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
A Heratizadeh, T Werfel
The pathogenesis of atopic dermatitis (AD) is multi-factorial and complex. Consequently, clinical signs and symptoms vary strongly depending on individually relevant trigger factors and the stage of the disease. So far, treatment of AD was commonly limited to topical treatment or, in more severe cases, to systemic drugs mostly approved for other indications than AD. However, emerging data on new anti-inflammatory agents have been published in the recent years. As these new substances specifically focus on immune responses in AD, these are partially considered as possible "break-through" in the treatment of AD...
October 13, 2016: Allergy
Shan Yu, Aaron D Pearson, Reyna K V Lim, David T Rodgers, Sijia Li, Holly B Parker, Meredith Weglarz, Eric N Hampton, Michael J Bollong, Jiayin Shen, Claudio Zambaldo, Danling Wang, Ashley K Woods, Timothy M Wright, Peter G Schultz, Stephanie A Kazane, Travis S Young, Matthew S Tremblay
Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen...
October 12, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Ana Maria Jorge, Jonathan Schneider, Sandra Unsleber, Nadine Göhring, Christoph Mayer, Andreas Peschel
The facultative pathogen Staphylococcus aureus colonizes the human anterior nares and causes infections of various organ systems. Which carbon, energy, and phosphate sources can be utilized by S. aureus in nutrient-poor habitats has remained largely unknown. We describe that S. aureus secretes a glycerophosphodiesterase (glycerophosphodiester phosphodiesterase, EC, GlpQ, degrading the glycerophosphodiester (GPD) head groups of phospholipids such as human phosphatidylcholine (GroPC). Deletion of glpQ completely abolished the GroPC-degrading activity in S...
October 11, 2016: Molecular Microbiology
M Fujita, E M Richards, M J Niciu, D F Ionescu, S S Zoghbi, J Hong, S Telu, C S Hines, V W Pike, C A Zarate, R B Innis
Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using (11)C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after ~8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). (11)C-(R)-rolipram positron emission tomographic (PET) scans were performed in 44 unmedicated patients during a major depressive episode and 35 healthy controls...
October 11, 2016: Molecular Psychiatry
Hyun Woo Lim, Tae Su Kim, Woo Seok Kang, Chan Il Song, Seunghee Baek, Jong Woo Chung
OBJECTIVE: The aim of this prospective, double-blind, randomized, placebo-controlled study was to evaluate the efficacy of cilostazol, a selective phosphodiesterase 3 inhibitor, in patients with chronic tinnitus. MATERIALS AND METHODS: Adult patients of chronic tinnitus lasting more than 3 months were included. Fifty eligible patients were randomly assigned to either cilostazol or control (placebo) group. The study medication of oral 100-mg cilostazol and a matching placebo were used twice a day for 4 weeks...
August 2016: Journal of International Advanced Otology
Hui Liu, Hongjun Jin, Xuyi Yue, Junbin Han, Hao Yang, Hubert Flores, Yi Su, David Alagille, Joel S Perlmutter, Gilles Tamagnan, Zhude Tu
Phosphodiesterase 10A (PDE10A) inhibitors show therapeutic effects for diseases with striatal pathology. PET radiotracers have been developed to quantify in vivo PDE10A levels and target engagement for therapeutic interventions. The aim of this study was to compare two potent and selective PDE10A radiotracers, [(11)C]TZ1964B and [(18)F]MNI659 in the nonhuman primate (NHP) brain. Double scans in the same cynomolgus monkey on the same day were performed after injection of [(11)C]TZ1964B and [(18)F]MNI659. Specific uptake was determined in two ways: nondisplaceable binding potential (BPND) was calculated using cerebellum as the reference region and the PDE-10A enriched striatum as the target region of interest (ROI); the area under the time-activity curve (AUC) for the striatum to cerebellum ratio was also calculated...
October 2016: Pharmacology Research & Perspectives
Abdullah M Alenizi, Kevin C Zorn, Marc Bienz, Emad Rajih, Pierre Alain Hueber, Naif Al-Hathal, Serge Benayoun, Thierry Lebeau, Assaad El-Hakim
INTRODUCTION: To evaluate erectile function recovery following robotic-assisted radical prostatectomy (RARP) according to preoperative sexual health inventory for men (SHIM) score stratification. MATERIALS AND METHODS: We prospectively collected data on 250 consecutive patients who underwent RARP by a single surgeon between October 2006 and October 2012. Thirty-six patients were excluded because of lack of preoperative SHIM score. All patients had a minimum follow up of 2 years...
October 2016: Canadian Journal of Urology
Katsumi Kadekawa, Tsuyoshi Majima, Naoki Kawamorita, Hiroki Okada, Tsuyoshi Yoshizawa, Kenichi Mori, Pradeep Tyagi, Kimio Sugaya, Naoki Yoshimura
AIMS: In order to clarify whether an alpha1A/D-adrenoceptor (α1 A/D-AR) antagonist, naftopidil, or a phosphodiesterase type 5 (PDE5) inhibitor, tadalafil, prevents bladder wall remodeling after spinal cord injury (SCI), we examined the bladder and urethral activity as well as ischemic and fibrotic changes in the bladder using SCI rats with or without naftopidil or tadalafil treatment. METHODS: Adult female Sprague-Dawley rats were divided into four groups: (1) normal (spinal cord intact); (2) vehicle SCI; (3) naftopidil SCI; and (4) tadalafil SCI groups...
October 4, 2016: Neurourology and Urodynamics
Hao Cheng, Zhifang Wu, Xiaoyun He, Qingzhen Liu, Hongbin Jia, Yan Di, Qing Ji
Phosphodiesterase 4 (PDE4) has four subtypes: PDE4A, PDE4B, PDE4C and PDE4D. The expression of PDE4 subtypes in microglial cells and the specific contribution of each subtype to inflammation remain unclear. In this study, the expression of PDE4 subtypes in primary microglial cells was assayed. Primary microglial cells were then transfected with specific small interfering RNA (siRNA) against each PDE4 subtype. PDE4 subtype A-D knockdown was confirmed by quantitative polymerase chain reaction. Secreted cytokines in the supernatant and intracellular cyclic adenosine monophosphate (cAMP) levels of transfected cells were measured...
October 2016: Experimental and Therapeutic Medicine
Hana Čipčić Paljetak, Linda Tomašković, Mario Matijašić, Mirjana Bukvić, Andrea Fajdetić, Donatella Verbanac, Mihaela Perića
5-LOX - 5-lipoxygenase; ACT - artemisinin-based combination therapies; ADME - absorption, distribution, metabolism and excretion; BAL - broncho alveolar lavage; CABP - community acquired bacterial pneumonia; cAMP - cyclic adenosine monophosphate; CAP - community-acquired pneumonia; CF - cystic fibrosis, BOS bronchiolitis obliterans syndrome; cGMP - cyclic guanosine monophosphate; COPD - chronic obstructive pulmonary disease; COX - cyclooxygenase; DPB - diffuse panbronchiolitis; HDACs - histone deacetylases; IBD - inflammatory bowel disease; IL-1p - interleukin 1p; IL-6 - interleukin 6; MIC - minimal inhibitory concentrations; MLSB - macrolide, lincosamide, streptogramin B; NSAIDs - non-steroidal anti-inflammatory drugs; OVA - ovalbumin; PDE4 - phosphodiesterase 4; PMA - phorbol 12-myristate 13-acetate; RA - rheumatoid arthritis; RTI - respiratory tract infections; SAHA - suberoylanilide hydroxamic acid; SAR - structure-activity-relationship; Th1 - type 1 helper T-cell; TNBS - trinitrobenzene sulfonic acid; TNF-α - tumour necrosis factor α; UN - United Nations, WHO - World Health Organisation...
September 27, 2016: Current Topics in Medicinal Chemistry
Isabelle Karine da Costa Nunes, Everton Tenório de Souza, Suzana Vanessa S Cardozo, Vinicius de Frias Carvalho, Nelilma Correia Romeiro, Patrícia Machado Rodrigues E Silva, Marco Aurélio Martins, Eliezer J Barreiro, Lídia Moreira Lima
Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents...
2016: PloS One
Zhong-Zhen Zhou, Yu-Fang Cheng, Zheng-Qiang Zou, Bing-Chen Ge, Hui Yu, Cang Huang, Hai-Tao Wang, Xue-Mei Yang, Jiang-Ping Xu
Depression involving neuroinflammation is one of the most common disabling and life-threatening psychiatric disorders. Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by their major side effect of emesis. To obtain more selective PDE4 inhibitors with antidepressant and anti-neuroinflammation potential and less side effect of emesis, we designed and synthesized a series of N-alkyl catecholamides by modifying the 4-methoxybenzyl group of our hit compound, FCPE07, with an alkyl side chain...
October 3, 2016: ACS Chemical Neuroscience
Debrabata Chanda, Jesus Prieto-Lloret, Arjun Singh, Hina Iqbal, Pankaj Yadav, Vladimir Snetkov, Philip I Aaronson
BACKGROUND AND PURPOSE: Glabridin is a major flavonoid in Glycyrrhiza glabra (licorice) root, a traditional Asian medicine. Glabridin is reported to have anti-atherogenic, anti-inflammatory and anti-nephritic properties; however its effects on vascular tone remain unexplored. EXPERIMENTAL APPROACH: We examined the effect of glabridin on rat main mesenteric artery using isometric myography and also ELISA to measure cGMP levels. KEY RESULTS: Glabridin (30μM) relaxed arteries pre-constricted with the thromboxane A2 analog U46619 (0...
September 26, 2016: Life Sciences
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