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Phosphodiesterase 4

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https://www.readbyqxmd.com/read/28213862/apremilast-a-review-in-psoriasis-and-psoriatic-arthritis
#1
Gillian M Keating
Apremilast (Otezla(®)) is an orally administered, small molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast 30 mg twice daily reduced the severity of moderate to severe plaque psoriasis in the phase 3 ESTEEM trials, as well as improving difficult-to-treat nail, scalp and palmoplantar psoriasis. Most patient-reported outcomes, including pruritus and the total Dermatology Life Quality Index, also improved to a significantly greater extent with apremilast than with placebo, with significant improvements in pruritus and skin discomfort/pain visual analogue scale scores seen as early as week 2 with apremilast...
February 18, 2017: Drugs
https://www.readbyqxmd.com/read/28213324/qing-hua-granule-induces-glp-1-secretion-via-bitter-taste-receptor-in-db-db-mice
#2
Junyan Li, Jie Xu, Ruifang Hou, Xin Jin, Jingyi Wang, Na Yang, Li Yang, Li Liu, Feng Tao, Hao Lu
Qing-Hua Granule (QHG), the modified formulation of a classical Chinese prescription named Gegen Qinlian Decoction, was clinically employed to treat type 2 diabetes mellitus (T2DM) through regulation of glucagon-like peptide-1 (GLP-1). However, the potential mechanism is unknown. We investigate whether QHG induces GLP-1 secretion via activation of bitter taste receptor (TAS2R) pathway in the gastrointestinal tract of db/db mice. The db/db mice were intragastrically (i.g.) administered QHG (low/medium/high dose) once daily for 8 weeks...
February 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28210757/sildenafil-a-phosphodiesterase-type-5-inhibitor-downregulates-osteopontin-in-human-peripheral-blood-mononuclear-cells
#3
Beata Kaleta, Agnieszka Boguska
The aim of this study was to investigate the ability of sildenafil to regulate osteopontin (OPN) gene and protein in peripheral blood mononuclear cells (PBMCs) from healthy blood donors. OPN is expressed by a wide variety of cell types, including immune cells. OPN functions are linked to various physiological and pathological conditions. Sildenafil is a selective inhibitor of type 5 phosphodiesterase. Sildenafil has recently been found to have immunomodulatory effects in animal models and in studies performed in humans...
February 16, 2017: Archivum Immunologiae et Therapiae Experimentalis
https://www.readbyqxmd.com/read/28209630/inhibition-of-phosphodiesterase-4-pde4-reduces-dermal-fibrosis-by-interfering-with-the-release-of-interleukin-6-from-m2-macrophages
#4
Christiane Maier, Andreas Ramming, Christina Bergmann, Rita Weinkam, Nicolai Kittan, Georg Schett, Jörg H W Distler, Christian Beyer
OBJECTIVES: To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc). METHODS: We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4...
February 16, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28201975/selective-inhibition-of-phosphodiesterases-4a-b-c-and-d-isoforms-in-chronic-respiratory-diseases-current-and-future-evidences
#5
Sonia Contreras, Javier Milara, Esteban Morcillo, Julio Cortijo
Chronic respiratory diseases affect millions of people every day. According to World Health Organization estimates, ~235 million people suffer from asthma, ~64 million suffer from chronic obstructive pulmonary disease (COPD), and millions more suffer from allergic rhinitis around the world. In recent last years, the first phosphodiesterase 4 (PDE4) inhibitor, roflumilast, was approved as a treatment to reduce the risk of exacerbations in stable and severe COPD associated with chronic bronchitis and a history of exacerbations...
February 13, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28194663/cilostazol-use-is-associated-with-reduced-risk-of-dementia-a-nationwide-cohort-study
#6
Shu-Yu Tai, Chen-Yu Chien, Yu-Han Chang, Yuan-Han Yang
Whether antiplatelet agents have a preventive effect on cognitive function remains unknown. We examined the potential association between the use of cilostazol, an antiplatelet agent and cyclic adenosine monophosphate phosphodiesterase 3 inhibitor, and the risk of dementia in an Asian population. Patients initiating cilostazol therapy between 1 January 2004 and 31 December 2009 without a prior history of dementia were identified from Taiwan's National Health Insurance database. Participants were stratified by age, sex, comorbidities, and comedication...
February 13, 2017: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/28191858/impact-of-the-pde4d-gene-polymorphism-and-additional-snp-snp-and-gene-smoking-interaction-on-ischemic-stroke-risk-in-chinese-han-population
#7
Xianxiang Wang, Zhongwu Sun, Yiquan Zhang, Xuefeng Tian, Qingxin Li, Jing Luo
AIMS: To investigate the association between phosphodiesterase 4D gene (PDE4D) gene single nucleotide polymorphisms (SNPs) and ischemic stroke (IS) risk, and impact of additional SNP- SNP and gene- smoking interaction on IS risk in Chinese population. METHODS: A total of 1228 subjects (666 males, 562 females) were selected, including 610 IS patients and 618 control subjects. Logistic regression model was used to examine the association between SNPs in PDE4D gene and IS risk...
February 13, 2017: Neurological Research
https://www.readbyqxmd.com/read/28188129/enhancement-of-fracture-healing-in-the-rat-modulated-by-compounds-that-stimulate-inducible-nitric-oxide-synthase-acceleration-of-fracture-healing-via-inducible-nitric-oxide-synthase
#8
R A Rajfer, A Kilic, A S Neviaser, L M Schulte, S M Hlaing, J Landeros, M G Ferrini, E Ebramzadeh, S-H Park
OBJECTIVES: We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days. MATERIALS AND METHODS: Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail...
February 2017: Bone & Joint Research
https://www.readbyqxmd.com/read/28170448/genome-wide-analysis-identifies-colonic-genes-differentially-associated-with-serum-leptin-and-insulin-concentrations-in-c57bl-6j-mice-fed-a-high-fat-diet
#9
Sung-Eun Kim, Jinsil Choo, Joon Yoon, Jae Ryang Chu, Yun Jung Bae, Seungyeoun Lee, Taesung Park, Mi-Kyung Sung
Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn's disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories) or high-fat diet (HFD, 45% of fat calories) for 8 weeks...
2017: PloS One
https://www.readbyqxmd.com/read/28165743/design-and-synthesis-of-novel-and-selective-phosphodiesterase-2-pde2-inhibitors-for-the-treatment-of-memory-disorders
#10
Laurent Gomez, Mark Eben Massari, Troy Vickers, Graeme Freestone, William F Vernier, Kiev Ly, Rui Xu, Margaret McCarrick, Tami Marrone, Markus Metz, Yingzhou G Yan, Zachary W Yoder, Robert Lemus, Nicola J Broadbent, Richard Barido, Noelle Warren, Kara Schmelzer, David Neul, Dong Lee, Carsten B Andersen, Kristen Sebring, Kathleen Aertgeerts, Xianbo Zhou, Ali Tabatabaei, Marco Peters, J Guy Breitenbucher
A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2 inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2 active site...
February 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28162947/fty720-supplementation-partially-improves-erectile-dysfunction-in-rats-with-streptozotocin-induced-type-1-diabetes-through-inhibition-of-endothelial-dysfunction-and-corporal-fibrosis
#11
Kai Cui, Yajun Ruan, Tao Wang, Ke Rao, Zhong Chen, Shaogang Wang, Jihong Liu
INTRODUCTION: Erectile dysfunction (ED) in patients with diabetes mellitus (DM) seriously affects their quality of life. However, these patients show a poor effect rate for oral phosphodiesterase type 5 inhibitors. Thus, new treatment methods are urgently needed. Fingolimod hydrochloride (FTY720) was approved in 2010 for the treatment of patients with the relapsing-remitting form of multiple sclerosis. AIM: To investigate whether FTY720 supplementation could ameliorate ED induced by DM (DMED)...
February 2, 2017: Journal of Sexual Medicine
https://www.readbyqxmd.com/read/28159622/the-discovery-complex-crystal-structure-and-recognition-mechanism-of-a-novel-natural-pde4-inhibitor-from-selaginella-pulvinata
#12
Yiyou Huang, Xin Liu, Deyan Wu, Guihua Tang, Zengwei Lai, Xuehua Zheng, Yin Sheng, Hai-Bin Luo
Phosphodiesterase-4 (PDE4) is an important drug target for treatment of inflammation-related diseases. Till now, natural PDE4 inhibitors are rare and their co-crystal structures with PDE4 are hardly available. In the present study, selaginpulvilins K and L (1 and 2), two novel fluorene derivatives, were isolated from a traditional Chinese medicine Selaginella pulvinata and exhibited remarkable inhibition against phosphodiesterase-4D (PDE4D) at IC50 11 nM and 90 nM, respectively. Compound 1 also showed a good selectivity across PDE families with the selective fold ranging from 30 to 909...
January 31, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28159537/diethyl-4-4-dihydroxy-8-3-neolign-7-7-dien-9-9-dionate-exhibits-antihypertensive-activity-in-rats-through-increase-in-intracellular-cgmp-level-and-blockade-of-calcium-channels
#13
Arjun Singh, B Sathish Kumar, Sarfaraz Alam, Hina Iqbal, Mohammad Shafiq, Feroz Khan, Arvind S Negi, Kashif Hanif, Debabrata Chanda
We report here the antihypertensive and vasorelaxant potential of some steroidal and non-steroidal compounds identified through a library of compounds. All the novel analogues showed vasorelaxant potential in isolated rat aorta. The most potent lead neolignan1 (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) produced concentration dependent relaxation with [pD2 5.16 ± 0.05; n=16 and Emax 96.97% ± 1.12%; n=16]. The neolignan1 relaxation is independent of endothelium and is sensitive to ODQ (1H-[1, 2, 4] oxadiazolo [4, 3-a] quinoxalin-1-one; a blocker of soluble guanylyl cyclase (sGC) which synthesizes cGMP (cyclic guanosine monophosphate))...
January 31, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28154167/in-vivo-knockdown-of-pathogenic-proteins-via-specific-and-nongenetic-iap-dependent-protein-erasers-snipers
#14
Nobumichi Ohoka, Keiichiro Okuhira, Masahiro Ito, Katsunori Nagai, Norihito Shibata, Takayuki Hattori, Osamu Ujikawa, Kenichiro Shimokawa, Osamu Sano, Ryokichi Koyama, Hisashi Fujita, Mika Teratani, Hirokazu Matsumoto, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
Many diseases, especially cancers, result from aberrant or over-expression of pathogenic proteins. Specific inhibitors against these proteins have shown remarkable therapeutic effects, but are limited mainly to enzymes. An alternative approach that may have utility in drug development relies on selective degradation of pathogenic proteins via small, chimeric molecules linking an E3 ubiquitin ligase to the targeted protein for proteasomal degradation. To this end, we recently developed a protein-knockdown system based on hybrid small-molecule SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers) that recruit inhibitor of apoptosis protein (IAP) ubiquitin ligases to specifically degrade targeted proteins...
February 2, 2017: Journal of Biological Chemistry
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
#15
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...
January 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28139692/control-of-neuropeptide-expression-by-parallel-activity-dependent-pathways-in-caenorhabditis-elegans
#16
Teresa Rojo Romanos, Jakob Gramstrup Petersen, Roger Pocock
Monitoring of neuronal activity within circuits facilitates integrated responses and rapid changes in behavior. We have identified a system in Caenorhabditis elegans where neuropeptide expression is dependent on the ability of the BAG neurons to sense carbon dioxide. In C. elegans, CO2 sensing is predominantly coordinated by the BAG-expressed receptor-type guanylate cyclase GCY-9. GCY-9 binding to CO2 causes accumulation of cyclic GMP and opening of the cGMP-gated TAX-2/TAX-4 cation channels; provoking an integrated downstream cascade that enables C...
January 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28133708/tadalafil-improves-lean-mass-and-endothelial-function-in-nonobese-men-with-mild-ed-luts-in-vivo-and-in-vitro-characterization
#17
Antonio Aversa, Simona Fittipaldi, Davide Francomano, Viviana M Bimonte, Emanuela A Greco, Clara Crescioli, Luigi Di Luigi, Andrea Lenzi, Silvia Migliaccio
PURPOSE: Phosphodiesterase type-5 inhibitor administration in diabetic men with erectile dysfunction (ED) is associated with reduced waist circumference. We evaluated potential effects of daily tadalafil administration on body composition and investigated its possible mechanism(s) of action in C2C12 skeletal muscle cells in vitro. METHODS: Forty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m(2)) complaining mild ED and/or low urinary tract symptoms (LUTS) were randomly assigned to receive tadalafil (TAD) 5 mg/daily (once-a-day=OAD-TAD; n = 23) or 20 mg on-demand (on-demand=OD-TAD; n = 20) for 2 months...
January 30, 2017: Endocrine
https://www.readbyqxmd.com/read/28132591/exploring-pyrazolo-3-4-d-pyrimidine-phosphodiesterase-1-pde1-inhibitors-a-predictive-approach-combining-comparative-validated-multiple-molecular-modeling-techniques
#18
Sk Abdul Amin, Sonam Bhargava, Nilanjan Adhikari, Shovanlal Gayen, Tarun Jha
Phosphodiesterase 1 (PDE1) is a potential target for a number of neurodegenerative disorders such as Schizophrenia, Parkinson's and Alzheimer's diseases. A number of pyrazolo[3,4-d]pyrimidine PDE1 inhibitors were subjected to different molecular modeling techniques [such as regression-based quantitative structure-activity relationship (QSAR): multiple linear regression (MLR), support vector machine (SVM) and artificial neural network (ANN); classification-based QSAR: Bayesian modeling and Recursive partitioning; Monte Carlo based QSAR; Open3DQSAR; pharmacophore mapping and molecular docking analyses] to get a detailed knowledge about the physicochemical and structural requirements for higher inhibitory activity...
January 29, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28132578/safety-evaluation-of-apremilast-for-the-treatment-of-psoriasis
#19
A Dattola, E Del Duca, R Saraceno, T Gramiccia, L Bianchi
Psoriasis (PSo) is a chronic inflammatory skin disease associated with co-morbidities such as hypertension, diabetes, dyslipidemia and metabolic syndrome. It is a typothypical Th1/Th17 disease that affects from 2 to 3% of the world population. Numerous are the drugs that can be used in our clinical practice; the choice of these drugs depends on the characteristics of the patient. Areas covered: Apremilast is the first oral small molecules to receive FDA approval for the treatment of adults with active psoriasis and psoriatic arthritis...
January 30, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28128066/beneficial-effects-of-sildenafil-on-tissue-perfusion-and-inflammation-in-a-murine-model-of-limb-ischemia-and-atherosclerosis
#20
Aggeliki Valatsou, Alexandros Briasoulis, Georgia Vogiatzi, Alsistis Pantopoulou, Evangelos Oikonomou, Antigoni Miliou, Despina Perrea, Dimitris Tousoulis
BACKGROUND: Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has endothelium protective and angiogenic effects. OBJECTIVES: To test if sildenafil improves tissue perfusion and neovascularization and downregulates pro-inflammatory molecules following limb ischemia. METHODS: 30 ApoE-/- male mice, bred with cholesterol rich diet for 4 weeks, were anesthetized and underwent unilateral hind-limb ischemia with ligation of the left femoral artery...
January 26, 2017: Current Vascular Pharmacology
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