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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
#1
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
#2
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/28753652/the-phosphodiesterase-inhibitor-ibudilast-attenuates-neuroinflammation-in-the-mptp-model-of-parkinson-s-disease
#3
Joanna Schwenkgrub, Malgorzata Zaremba, Ilona Joniec-Maciejak, Agnieszka Cudna, Dagmara Mirowska-Guzel, Iwona Kurkowska-Jastrzębska
BACKGROUND/AIMS: Since the degeneration of the nigrostriatal dopaminergic pathway in Parkinson's disease (PD) is associated with the inflammation process and decreased levels of cyclic nucleotides, inhibition of up-regulated cyclic nucleotide phosphodiesterases (PDEs) appears to be a promising therapeutic strategy. We used ibudilast (IBD), a non-selective PDE3,4,10,11 inhibitor, due to the abundant PDE 4 and 10 expression in the striatum. The present study for the first time examined the efficacy of IBD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD...
2017: PloS One
https://www.readbyqxmd.com/read/28737056/quantification-of-human-brain-pde4-occupancy-by-gsk356278-a-11-c-r-rolipram-pet-study
#4
Jasper van der Aart, Cristian Salinas, Rahul Dimber, Sabina Pampols-Maso, Ashley A Weekes, John Tonkyn, Frank A Gray, Jan Passchier, Roger N Gunn, Eugenii A Rabiner
We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [(11)C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28709568/current-and-emerging-topical-therapies-for-atopic-dermatitis
#5
Jeremy Udkoff, Andrea Waldman, Jusleen Ahluwalia, Jenna Borok, Lawrence F Eichenfield
The pathogenesis of atopic dermatitis (AD) involves epidermal barrier dysfunction and T helper cell type 2 (Th2) lymphocyte-driven inflammation. Cytokines, such as interleukin 4 (IL-4) and IL-13, are important in this reaction. They stimulate B cells to produce immunoglobulin E, causing atopic disease. This process has been well characterized, and new therapies for AD, such as phosphodiesterase 4 (PDE-4) inhibitors, Th2-expressed chemoattractant receptor-homologous molecule antagonists, and Janus kinase inhibitors, work by antagonizing this cellular pathway...
July 2017: Clinics in Dermatology
https://www.readbyqxmd.com/read/28706457/relaxant-and-anti-inflammatory-effect-of-two-thalidomide-analogs-as-pde-4-inhibitors-in-pregnant-rat-uterus
#6
Víctor Manuel Muñoz-Pérez, Eduardo Fernández-Martínez, Héctor Ponce-Monter, Mario I Ortiz
The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K(+)-induced tonic, and Ca(2+)-induced contractions...
July 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28613871/discovery-of-n-4-5-4-fluorophenyl-3-methyl-2-methylsulfanyl-3h-imidazol-4-yl-pyridin-2-yl-acetamide-cbs-3595-a-dual-p38%C3%AE-mapk-pde-4-inhibitor-with-activity-against-tnf%C3%AE-related-diseases
#7
Wolfgang Albrecht, Anke Unger, Silke M Bauer, Stefan A Laufer
The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release...
June 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28554321/phosphodiesterase-4-inhibitors-in-immune-mediated-diseases-mode-of-action-clinical-applications-current-and-future-perspectives
#8
Lazaros I Sakkas, Athanasios Mavropoulos, Dimitrios P Bogdanos
Phosphodiesterase (PDE) 4 is a superfamily of enzymes that catalyze the hydrolysis of cyclic adenosine 3',5'-monophosphate (cAMP), an intracellular second messenger and regulator of a wide array of genes and proteins. Increased levels of intracellular cAMP lead to activation of genes but also to inhibition of nuclear factor-kappa B, involved in pro-inflammatory responses. By increasing cAMP levels, PDE4 inhibitors, such as apremilast, reduced production of pro-inflammatory TNFα, IFNγ, and IL-17 and increased production of anti-inflammatory IL-10 in lipopolysaccharide-stimulated peripheral blood mononuclear cells, and in patients with psoriatic arthritis (PsA)...
May 29, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28515693/rolipram-improves-outcome-in-a-rat-model-of-infant-sepsis-induced-cardiorenal-syndrome
#9
Clark R Sims, Sharda P Singh, Shengyu Mu, Neriman Gokden, Dala Zakaria, Trung C Nguyen, Philip R Mayeux
While the mortality rate associated with sepsis in children has fallen over the years, it still remains unacceptably high. The development of both acute cardiac dysfunction and acute kidney injury during severe sepsis is categorized as type 5 cardiorenal syndrome (CRS) and is poorly understood in infants. To address this lack of understanding and the need for an appropriate animal model in which to conduct relevant preclinical studies, we developed a model of infant sepsis-induced CRS in rat pups then evaluated the therapeutic potential of the phosphodiesterase (PDE) 4 inhibitor, rolipram...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28414142/doxofylline-does-not-increase-formoterol-induced-camp-nor-mkp-1-expression-in-asm-cells-resulting-in-lack-of-anti-inflammatory-effect
#10
Brijeshkumar S Patel, Michael J Kugel, Gina Baehring, Alaina J Ammit
The xanthine doxofylline has been examined in clinical trials and shown to have efficacy and greater tolerability than theophylline in asthma and chronic obstructive pulmonary disease. The 'novofylline' doxofylline has demonstrated bronchodilatory and anti-inflammatory actions in in vivo and ex vivo experimental models of respiratory disease. However, there are limited studies in vitro. We address this herein and examine whether doxofylline has anti-inflammatory impact on primary cultures of airway smooth muscle (ASM) cells...
August 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28330503/caffeine-modulates-glucocorticoid-induced-expression-of-ctgf-in-lung-epithelial-cells-and-fibroblasts
#11
Markus Fehrholz, Kirsten Glaser, Christian P Speer, Silvia Seidenspinner, Barbara Ottensmeier, Steffen Kunzmann
BACKGROUND: Although caffeine and glucocorticoids are frequently used to treat chronic lung disease in preterm neonates, potential interactions are largely unknown. While anti-inflammatory effects of glucocorticoids are well defined, their impact on airway remodeling is less characterized. Caffeine has been ascribed to positive effects on airway inflammation as well as remodeling. Connective tissue growth factor (CTGF, CCN2) plays a key role in airway remodeling and has been implicated in the pathogenesis of chronic lung diseases such as bronchopulmonary dysplasia (BPD) in preterm infants...
March 23, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28263828/6-hydroxy-5-7-dimethoxy-flavone-suppresses-the-neutrophil-respiratory-burst-via-selective-pde4-inhibition-to-ameliorate-acute-lung-injury
#12
Yung-Fong Tsai, Tzu-Chi Chu, Wen-Yi Chang, Yang-Chang Wu, Fang-Rong Chang, Shun-Chin Yang, Tung-Ying Wu, Yu-Ming Hsu, Chun-Yu Chen, Shih-Hsin Chang, Tsong-Long Hwang
Over-activated neutrophils produce enormous oxidative stress and play a key role in the development of acute and chronic inflammatory diseases. 6-Hydroxy-5,7-dimethoxy-flavone (UFM24), a flavone isolated from the Annonaceae Uvaria flexuosa, showed inhibitory effects on human neutrophil activation and salutary effects on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. UFM24 potently inhibited superoxide anion (O2(•-)) generation, reactive oxidants, and CD11b expression, but not elastase release, in N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils...
March 3, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28167453/the-role-of-%C3%AE-arrestin-2-on-fear-anxious-related-memory-in-a-rat-model-of-post-traumatic-stress-disorder
#13
Jinlan Ding, Fang Han, Lili Wen, Bing Xiao, Yuxiu Shi
BACKGROUND: Post-traumatic stress disorder (PTSD) can be categorised as a disorder of dysregulated fear processing. In the formation and development of PTSD, whether fear/anxious-related memory is regulated by β-arrestin-2, and happened along the signal transduction pathways remains unknown. METHOD: We used single prolonged stress (SPS) as the animal model of PTSD. Next, elevated plus maze tests (EPM) was performed to examine fear/anxious memory- related behaviors...
April 15, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28152479/inhibitor-of-phosphodiestearse-4-improves-memory-deficits-oxidative-stress-neuroinflammation-and-neuropathological-alterations-in-mouse-models-of-dementia-of-alzheimer-s-type
#14
Amit Kumar, Nirmal Singh
The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation...
April 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28046551/we-ab-bra-09-registration-of-preoperative-mri-to-intraoperative-radiographs-for-automatic-vertebral-target-localization
#15
T De Silva, A Uneri, M Ketcha, S Reaungamornrat, J Goerres, S Vogt, G Kleinszig, J Wolinsky, J H Siewerdsen
PURPOSE: Accurate localization of target vertebrae is essential to safe, effective spine surgery, but wrong-level surgery occurs with surprisingly high frequency. Recent research yielded the "LevelCheck" method for 3D-2D registration of preoperative CT to intraoperative radiographs, providing decision support for level localization. We report a new method (MR-LevelCheck) to perform 3D-2D registration based on preoperative MRI, presenting a solution for the increasingly common scenario in which MRI (not CT) is used for preoperative planning...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/27766379/aryl-1-3-5-triazine-ligands-of-histamine-h4-receptor-attenuate-inflammatory-and-nociceptive-response-to-carrageen-zymosan-and-lipopolysaccharide
#16
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...
January 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/27739411/inhibition-of-uterine-contractility-by-thalidomide-analogs-via-phosphodiesterase-4-inhibition-and-calcium-entry-blockade
#17
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
https://www.readbyqxmd.com/read/27735066/anti-inflammatory-therapies-in-atopic-dermatitis
#18
REVIEW
A Heratizadeh, T Werfel
The pathogenesis of atopic dermatitis (AD) is multifactorial 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 'breakthrough' in the treatment of AD...
December 2016: Allergy
https://www.readbyqxmd.com/read/27713015/in-vivo-effective-dibenzo-b-d-furan-1-yl-thiazoles-as-novel-pde-4-inhibitors
#19
Gopalan Balasubramanian, Sukunath Narayanan, Lavanya Andiappan, Thirunavukkarasu Sappanimuthu, Saravanan Thirunavukkarasu, Shamundeeswari Sundaram, Saravanakumar Natarajan, Naresh Sivaraman, Sridharan Rajagopal, Fakrudeen Ali Ahamed Nazumudeen, Sanjeev Saxena, Santosh L Vishwakarma, Shridhar Narayanan, Ganapavarapu V R Sharma, Chidambaram V Srinivasan, Narasimhan Kilambi
Herein we report the synthesis, PDE-4B and TNF-α inhibitory activities of a few dibenzo[b,d]furan-1-yl-thiazole derivatives. The hydroxycyclohexanol amide derivatives 14, 18, 24, 29, 31 and 33 exhibited promising in vitro PDE-4B and TNF-α inhibitory activities. Compound 24 showed good systemic availability in preclinical animal models and was also found to be non-toxic (exploratory mutagenicity test). Further it exhibited promising results in in vivo asthma/COPD and Uveitis models.
November 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27695125/synthesis-pharmacological-profile-and-docking-studies-of-new-sulfonamides-designed-as-phosphodiesterase-4-inhibitors
#20
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
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