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https://www.readbyqxmd.com/read/28290219/2-crisaborole-topical-ointment-for-the-treatment-of-mild-to-moderate-atopic-dermatitis
#1
Alice C Cheape, Dedee F Murrell
Crisaborole 2% topical ointment is an anti-inflammatory, non-steroidal phosphodiesterase 4 inhibitor which is currently under investigation for its potential role in the treatment of atopic dermatitis and psoriasis. Areas covered: So far, 7 trials have been completed in atopic dermatitis. The 2% strength appeared to be the superior dosing regimen. Pruritus improved significantly within one week. The improvements in objective efficacy assessments in crisaborole-treated patients were also statistically significant compared to the vehicle...
March 14, 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/28283561/alteration-of-neuronal-excitability-and-short-term-synaptic-plasticity-in-the-prefrontal-cortex-of-a-mouse-model-of-mental-illness
#2
Gregg W Crabtree, Ziyi Sun, Mirna Kvajo, Jantine Ac Broek, Karine Fénelon, Heather McKellar, Lan Xiao, Bin Xu, Sabine Bahn, James M O'Donnell, Joseph A Gogos
Employing a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyper-excitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release...
March 10, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28281360/bioactive-triterpenoids-from-the-leaves-of-eriobotrya-japonica-as-the-natural-pde4-inhibitors
#3
Bing-Xin Tan, Lu Yang, Yi-You Huang, Yun-Yun Chen, Guang-Tian Peng, Si Yu, Yi-Nuo Wu, Hai-Bin Luo, Xi-Xin He
The ethanolic extract of the leaves of Eriobotrya japonica exhibited inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of a new triterpene (1), together with seven known triterpenoids, methyl corosolate (2), ursolic acid (3), oleanolic acid (4), methyl maslinate (5), α-amyin (6), 3β,19α,23-trihydroxy-urs-12-ene (7) and uvaol (8). The structure of compound 1 was established as 3β-hydroxyl-21β-acetoxyl-urs-12-en-28-carboxylate on the basis of interpretation of its 1D and 2D NMR and HR-ESI-MS spectroscopic data...
March 10, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28275263/systemic-sclerosis-antifibrotic-effects-of-pde4-blockade
#4
Sarah Onuora
No abstract text is available yet for this article.
April 2017: Nature Reviews. Rheumatology
https://www.readbyqxmd.com/read/28266741/signaling-and-targeted-therapy-of-inflammatory-cells-in-epidermolysis-bullosa-acquisita
#5
REVIEW
Ralf J Ludwig
Pemphigoid diseases (PD) are chronic and life-threating autoimmune diseases of the skin and mucous membranes. PD are characterized and caused by autoantibodies targeting components of the basement membrane. In the PD epidermolysis bullosa acquisita (EBA) the target autoantigen is type VII collagen. Current treatment options of PD, especially EBA, are limited and are mostly based on systemic immunosuppression. Animal models of PD have greatly advanced our understanding of PD pathogenesis. This has led to the identification of several novel therapeutic targets, including signaling molecules...
March 7, 2017: Experimental Dermatology
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
#6
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/28263187/aggregation-of-scaffolding-protein-disc1-dysregulates-phosphodiesterase-4-in-huntington-s-disease
#7
Motomasa Tanaka, Koko Ishizuka, Yoko Nekooki-Machida, Ryo Endo, Noriko Takashima, Hideyuki Sasaki, Yusuke Komi, Amy Gathercole, Elaine Huston, Kazuhiro Ishii, Kelvin Kai-Wan Hui, Masaru Kurosawa, Sun-Hong Kim, Nobuyuki Nukina, Eiki Takimoto, Miles D Houslay, Akira Sawa
Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice)...
March 6, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28255338/apremilast-in-the-treatment-of-psoriatic-arthritis-a-perspective-review
#8
REVIEW
Michael Reed, David Crosbie
Apremilast is an orally-active small molecule which inhibits phosphodiesterase-4 (PDE4). Clinical trials have demonstrated its efficacy and safety in psoriatic arthritis (PsA) and psoriasis. Established therapeutic options have variable effectiveness across the different domains of psoriatic disease. Whilst biologic therapies have proven to be of significant benefit to many patients, not all patients respond, and others are not eligible or do not tolerate biologic therapy. We review the mechanism of action, pharmacokinetics and clinical trial data with regards to both efficacy and safety for apremilast and consider where this new treatment may be positioned in the treatment of PsA...
February 2017: Therapeutic Advances in Musculoskeletal Disease
https://www.readbyqxmd.com/read/28235598/overexpression-of-phosphodiesterase-4-subtypes-involved-in-surgery-induced-neuroinflammatory-cognitive-dysfunction-in-mice
#9
Wei Wang, Qiang Fu, Xiao-Ying Zhang, Ze-Guo Feng, Hao Zhang, Bo Sui, Yong-Yi Zhang, Wei-Xing Zhao, Zhi-Peng Xu, Wei-Dong Mi
Postoperative cognitive dysfunction (POCD) is characterized by cognitive impairments in patients after surgery. Hippocampal neuroinflammation induced by surgery has been recognized as a pathogenesis of POCD. Phosphodiesterase-4 (PDE4) is an enzyme that specifically hydrolyses cyclic adenosine monophosphate (cAMP), which plays an important role during neuroinflammation and the process of learning and memory. However, the role of PDE4 in the development of POCD remains unclear. Male 14-month-old C57BL/6 mice received carotid artery exposure to mimic POCD...
February 21, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28213862/apremilast-a-review-in-psoriasis-and-psoriatic-arthritis
#10
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...
March 2017: Drugs
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
#11
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/28202289/rolipram-potentiates-bevacizumab-induced-cell-death-in-human-glioblastoma-stem-like-cells
#12
Sara Ramezani, Nasim Vousooghi, Fatemeh Ramezani Kapourchali, Mahmoudreza Hadjighasem, Parisa Hayat, Naser Amini, Mohammad Taghi Joghataei
AIMS: Glioblastoma cancer stem-like cells (GCSCs) promote themselves proliferation by secreting the vascular endothelial growth factor A (VEGFA) in an autocrine manner, positively regulated by phosphodiesterase IV (PDE4). In the current study, we investigated the putative cytotoxic effect of bevacizumab, a VEGFA blocker, alone and in combination with a specific inhibitor of PDE4 called rolipram on GCSCs isolated from human surgical tumor specimen with a focus on PI3K/AKT pathway. MAIN METHODS: CD133+/CD15+ GCSCs were characterized by flow cytometry and expanded in a serum-free primary culture system...
March 15, 2017: Life Sciences
https://www.readbyqxmd.com/read/28201975/selective-inhibition-of-phosphodiesterases-4a-b-c-and-d-isoforms-in-chronic-respiratory-diseases-current-and-future-evidences
#13
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/28196708/design-synthesis-and-biological-evaluation-of-2-4-disubstituted-oxazole-derivatives-as-potential-pde4-inhibitors
#14
Ya-Sheng Li, De-Kun Hu, Dong-Sheng Zhao, Xing-Yu Liu, Hong-Wei Jin, Gao-Peng Song, Zi-Ning Cui, Lian-Hui Zhang
In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4μM) and good selectivity against PDE4B. Meanwhile, compound 4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship study showed the 3,5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity...
February 3, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28159622/the-discovery-complex-crystal-structure-and-recognition-mechanism-of-a-novel-natural-pde4-inhibitor-from-selaginella-pulvinata
#15
Yiyou Huang, Xin Liu, Deyan Wu, Guihua Tang, Zengwei Lai, Xuehua Zheng, Sheng Yin, 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 11nM and 90nM, 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/28154167/in-vivo-knockdown-of-pathogenic-proteins-via-specific-and-nongenetic-iap-dependent-protein-erasers-snipers
#16
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/28132578/safety-evaluation-of-apremilast-for-the-treatment-of-psoriasis
#17
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...
March 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28099820/new-and-developing-non-adrenoreceptor-small-molecule-drugs-for-the-treatment-of-asthma
#18
REVIEW
Neil C Thomson
Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta2-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma. Areas covered: New and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA...
February 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28099816/new-treatment-options-and-emerging-drugs-for-axial-spondyloarthritis-biological-and-targeted-synthetic-agents
#19
REVIEW
Eric Toussirot
Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFα agents, we need new therapeutic options for AS and ax SpA. Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs...
February 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28093982/pde7-selective-and-dual-inhibitors-advances-in-chemical-and-biological-research
#20
Agnieszka Jankowska, Artur Świerczek, Grażyna Chłoń-Rzepa, Maciej Pawłowski, Elżbieta Wyska
Phosphodiesterase 7 (PDE7) is an intracellular enzyme that specifically hydrolyses the second messenger, cyclic-3',5'-adenosine monophosphate (cAMP), into inactive non-cyclic nucleotide, 5'-AMP. To date, many structurally diverse compounds with PDE7 inhibitory properties have been described, including selective PDE7 inhibitors, dual PDE4/PDE7, PDE7/PDE8, and PDE7/GSK-3 inhibitors, and non-selective PDE inhibitors with high affinity for PDE7. Inhibitors of PDE7 provided beneficial effects in animal models of inflammatory and neurological disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and many others...
January 16, 2017: Current Medicinal Chemistry
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