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https://www.readbyqxmd.com/read/28438557/the-isozyme-selective-phosphodiesterase-4-inhibitor-abi-4-attenuates-the-effects-of-lipopolysaccharide-in-human-cells-and-rodent-models-of-peripheral-and-cns-inflammation
#1
Joseph R Hedde, Ashley N Hanks, Christopher J Schmidt, Zoë A Hughes
Inhibitors of phosphodiesterase-4 (PDE4) have been approved for the treatment of inflammatory disorders, but are associated with dose-limiting nausea and vomiting. These side effects are hypothesized to be mediated by inhibition of the PDE4D isozyme. Here we demonstrate the anti-inflammatory effects of the novel brain penetrant PDE4D-sparing PDE4 inhibitor, ABI-4. ABI-4 was a potent (EC50 ∼14 nM) inhibitor of lipopolysaccharide (LPS) induced TNF-α release from mouse microglia and human PBMCs. ABI-4 (0.32 mg/kg) blocked LPS-induced release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in blood and brain of mice...
April 21, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28432317/psiguajadials-a-k-unusual-psidium-meroterpenoids-as-phosphodiesterase-4-inhibitors-from-the-leaves-of-psidium-guajava
#2
Gui-Hua Tang, Zhen Dong, Yan-Qiong Guo, Zhong-Bin Cheng, Chu-Jun Zhou, Sheng Yin
Bioassay-guided fractionation of the ethanolic extract of the leaves of Psidium guajava led to the isolation of 11 new Psidium meroterpenoids, psiguajadials A-K (1-11), along with 17 known ones (12-28). Their structures and absolute configurations were elucidated by spectroscopic methods and comparison of experimental and calculated ECD. Compounds 1 and 2 represent two unprecedented skeletons of 3,5-diformyl-benzyl phloroglucinol-coupled sesquiterpenoid, while 3 is the first example of Psidium meroterpenoids coupling via an oxepane ring...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28416366/2-year-animal-carcinogenicity-results-for-crisaborole-a-novel-phosphodiesterase-4-inhibitor-for-atopic-dermatitis
#3
Vic Ciaravino, Dina Coronado, Cheryl Lanphear, Sanjay Chanda
BACKGROUND: Crisaborole is a novel, topical nonsteroidal, anti-inflammatory, phosphodiesterase 4 (PDE4) inhibitor for the treatment of mild to moderate atopic dermatitis. OBJECTIVE: As part of a nonclinical safety testing program, these 2-year studies tested the carcinogenic potential of crisaborole. METHODS: Crisaborole ointment, 2%, 5%, or 7%, was applied once daily topically to mice, and crisaborole was administered orally to rats at doses of 30, 100, or 300mg/kg/day for up to 104 weeks...
March 30, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28405029/protein-kinase-enzymes-in-the-human-vagina-relation-to-key-mediators-of-the-cyclic-amp-and-cyclic-gmp-pathways
#4
S Ückert, J Sonnenberg, J E Sonnenberg, W Kauffels, K Albrecht, M A Kuczyk, P Hedlund
Aside from phosphodiesterase (PDE) isoenzymes, protein kinases (cAK=cyclic AMP-binding protein kinase, cGK=cyclic GMP-binding protein kinase) have also been identified as important receptors for cyclic nucleotides. A significance of protein kinases in the control of the function of the male and female reproductive tract has been suggested; however, up until today, only a few approaches have addressed these enzymes in female genital tissues. The present study aimed to investigate by means of biochemical and immunohistochemical methods the expression of cAK and cGK...
April 13, 2017: International Journal of Impotence Research
https://www.readbyqxmd.com/read/28402318/memory-enhancing-effects-of-gebr-32a-a-new-pde4d-inhibitor-holding-promise-for-the-treatment-of-alzheimer-s-disease
#5
Roberta Ricciarelli, Chiara Brullo, Jos Prickaerts, Ottavio Arancio, Carla Villa, Claudia Rebosio, Elisa Calcagno, Matilde Balbi, Britt T J van Hagen, Elentina K Argyrousi, Hong Zhang, Maria Adelaide Pronzato, Olga Bruno, Ernesto Fedele
Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses...
April 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28389413/influence-of-cell-confluence-on-the-camp-signalling-pathway-in-vascular-smooth-muscle-cells
#6
M Belacel-Ouari, L Zhang, F Hubert, R Assaly, R Gerbier, R Jockers, F Dauphin, P Lechêne, R Fischmeister, B Manoury, V Leblais
The influence of cell confluence on the β-adrenoceptor (β-AR)/cAMP/phosphodiesterase (PDE) pathway was investigated in cultured rat aortic smooth muscle cells (RASMCs). Cells were plated either at low density (LD: 3·10(3)cells/cm(2)) or high density (HD: 3·10(4)cells/cm(2)) corresponding to non-confluent or confluent cells, respectively, on the day of experiment. β-AR-stimulated cAMP was monitored in real-time using the fluorescence resonance energy transfer (FRET)-based cAMP sensor, Epac2-camps. A brief application (15s) of the β-AR agonist isoprenaline (Iso) induced a typical transient FRET signal, reflecting cAMP production followed by its rapid degradation...
April 4, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28383060/phosphodiesterase-4b-negatively-regulates-endotoxin-activated-interleukin-1-receptor-antagonist-responses-in-macrophages
#7
Jing-Xing Yang, Kou-Chou Hsieh, Yi-Ling Chen, Chien-Kuo Lee, Marco Conti, Tsung-Hsien Chuang, Chin-Pyng Wu, S-L Catherine Jin
Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28378713/the-preparation-characterization-structure-and-dissolution-analysis-of-apremilast-solvatomorphs
#8
Yun Deng Wu, Xiao Lei Zhang, Xiao Hong Liu, Jian Xu, Mei Zhang, Kun Shen, Si Han Zhang, Yong Mei He, Yan Ma, Ai Hua Zhang
Apremilast (AP) {systematic name: (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-acetamidoisoindoline-1,3-dione} is an inhibitor of phosphodieasterase-4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis. The ability of AP to form solvates has been investigated and three solvatomorphs of AP, namely, the AP ethyl acetate hemisolvate, C22H24N2O7S·0.5C4H8O2, the AP toluene hemisolvate, C22H24N2O7S·0.5C7H8, and the AP dichloromethane monosolvate, C22H24N2O7S·CH2Cl2, were obtained...
April 1, 2017: Acta Crystallographica. Section C, Structural Chemistry
https://www.readbyqxmd.com/read/28366471/phosphodiesterase-4-inhibition-restored-hippocampal-long-term-potentiation-after-primary-blast
#9
Edward W Vogel, Fatima N Morales, David F Meaney, Cameron R Bass, Barclay Morrison
Due to recent military conflicts and terrorist attacks, blast-induced traumatic brain injury (bTBI) presents a health concern for military and civilian personnel alike. Although secondary blast (penetrating injury) and tertiary blast (inertia-driven brain deformation) are known to be injurious, the effects of primary blast caused by the supersonic shock wave interacting with the skull and brain remain debated. Our group previously reported that in vitro primary blast exposure reduced long-term potentiation (LTP), the electrophysiological correlate of learning and memory, in rat organotypic hippocampal slice cultures (OHSCs) and that primary blast affects key proteins governing LTP...
March 31, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28339772/heterologous-desensitization-of-cardiac-%C3%AE-adrenergic-signal-via-hormone-induced-%C3%AE-ar-arrestin-pde4-complexes
#10
Qian Shi, Minghui Li, Delphine Mika, Qin Fu, Sungjin Kim, Jason Phan, Ao Shen, Gregoire Vandecasteele, Yang K Xiang
Aims: Cardiac β-adrenergic receptor (βAR) signaling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Methods and results: Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists...
February 21, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28290219/2-crisaborole-topical-ointment-for-the-treatment-of-mild-to-moderate-atopic-dermatitis
#11
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...
April 5, 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
#12
Gregg W Crabtree, Ziyi Sun, Mirna Kvajo, Jantine A C Broek, Karine Fénelon, Heather McKellar, Lan Xiao, Bin Xu, Sabine Bahn, James M O'Donnell, Joseph A Gogos
Using 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 hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V...
April 12, 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
#13
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
#14
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
#15
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
#16
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
#17
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)...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28255338/apremilast-in-the-treatment-of-psoriatic-arthritis-a-perspective-review
#18
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-neuroinflammation-and-cognitive-dysfunction-in-mice
#19
Wei Wang, Xiao-Ying Zhang, Ze-Guo Feng, Dong-Xin Wang, Hao Zhang, Bo Sui, Yong-Yi Zhang, Wei-Xing Zhao, Qiang Fu, Zhi-Peng Xu, Wei-Dong Mi
Postoperative cognitive dysfunction (POCD) is characterized by cognitive impairments in patients after surgery. Hippocampal neuroinflammation induced by surgery is highly associated with 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
#20
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
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