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https://www.readbyqxmd.com/read/28915270/the-single-cyclic-nucleotide-specific-phosphodiesterase-of-the-intestinal-parasite-giardia-lamblia-represents-a-potential-drug-target
#1
Stefan Kunz, Vreni Balmer, Geert Jan Sterk, Michael P Pollastri, Rob Leurs, Norbert Müller, Andrew Hemphill, Cornelia Spycher
BACKGROUND: Giardiasis is an intestinal infection correlated with poverty and poor drinking water quality, and treatment options are limited. According to the Center for Disease Control and Prevention, Giardia infections afflict nearly 33% of people in developing countries, and 2% of the adult population in the developed world. This study describes the single cyclic nucleotide-specific phosphodiesterase (PDE) of G. lamblia and assesses PDE inhibitors as a new generation of anti-giardial drugs...
September 15, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28903860/a-review-of-synthetic-phosphodiesterase-type-5-inhibitors-pde-5i-found-as-adulterants-in-dietary-supplements
#2
REVIEW
Chee-Leong Kee, Xiaowei Ge, Véronique Gilard, Myriam Malet-Martino, Min-Yong Low
To date, there are 80 synthetic PDE-5i found as adulterants in dietary supplements. Analogues of sildenafil remain as the top list with 50 (62%) and are followed by analogues of tadalafil, 21 (26%), analogues of vardenafil, 7 (9%) and others, 2 (3%). The sildenafil group can be sub-categorized into sulphonamide-bonded (24, 48%), acetyl-bonded (11, 22%), carbonyl or thiocarbonyl-bonded (8, 16%) and other types (7, 14%) based on the functional group linked to pyrazolopyrimidine-one moieties. Meanwhile, analogues of tadalafil have become popularly found as adulterants in dietary supplements like beverages and herbal extracts from 2015 to 2016...
August 9, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28895956/atopic-dermatitis-skin-care-and-topical-therapies
#3
David M Fleischer, Jeremy Udkoff, Jenna Borok, Adam Friedman, Noreen Nicol, Jeffrey Bienstock, Peter Lio, Megha M Tollefson, Lawrence F Eichenfield
Atopic dermatitis (AD) pathogenesis is strongly influenced by Type 2 innate lymphoid cell and T-helper cell type 2 lymphocyte-driven inflammation and skin barrier dysfunction. AD therapies attempt to correct this pathology, and guidelines suggest suggest basics of AD therapy, which include repair of the skin barrier through bathing practices and moisturizers, infection control, and further lifestyle modifications to avoid and reduce AD triggers.While some patients' AD may be controlled using these measures, inflammatory eczema including acute flares and maintenance therapy in more severe patients are treated with topical pharmacologic agents such as topical corticosteroids, topical calcineurin inhibitors, and, more recently, topical PDE-4 inhibitors...
September 2017: Seminars in Cutaneous Medicine and Surgery
https://www.readbyqxmd.com/read/28891448/a-special-focus-on-selexipag-treatment-of-pulmonary-arterial-hypertension
#4
Louise Marqvard Sørensen, Markus Wehland, Marcus Krüger, Ulf Simonsen, Mohamed Zakaria Nassef, Manfred Infanger, Daniela Grimm
BACKGROUND: This review focuses on the treatment of pulmonary arterial hypertension (PAH) with selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues. METHODS: We searched the relevant literature and summarized the current clinical trials concerning selexipag and PAH. RESULTS: With only few cases per million, PAH is a rare disease, but when untreated it can be life threatening. PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin (PGI2)...
September 7, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28889301/determining-phosphodiesterase-activity-radioactive-assay
#5
Barbara I Kazmierczak
Cyclic-di-GMP phosphodiesterases (PDEs) catalyze the hydrolysis of the bacterial second messenger c-di-GMP. This protocol describes a sensitive radioactive assay for PDE activity in which substrate and product can be quickly and easily separated by thin-layer chromatography.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28889300/measuring-cyclic-diguanylate-c-di-gmp-specific-phosphodiesterase-activity-using-the-mant-c-di-gmp-assay
#6
Dorit Eli, Trevor E Randall, Henrik Almblad, Joe J Harrison, Ehud Banin
The second messenger, cyclic diguanylate (c-di-GMP), regulates a variety of bacterial cellular and social behaviors. A key determinant of c-di-GMP levels in cells is its degradation by c-di-GMP-specific phosphodiesterases (PDEs). Here, we describe an assay to determine c-di-GMP degradation rates in vitro using 2'-O-(N'-methylanthraniloyl)-cyclic diguanylate (MANT-c-di-GMP). Additionally, a protocol for the production and purification of recombinant Pseudomonas aeruginosa RocR, a c-di-GMP-specific PDE that may serve as a control in MANT-c-di-GMP assays, is provided...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28889299/fluorescent-2-aminopurine-c-di-gmp-and-gpg-analogs-as-pde-probes
#7
Jie Zhou, Clement Opoku-Temeng, Herman O Sintim
c-di-GMP is widely recognized as an important ubiquitous signaling molecule in bacteria. c-di-GMP phosphodiesterases (PDEs) regulate the intracellular concentration of c-di-GMP and some could be potential drug targets. Here, we describe a class of dinucleotide probes suitable for monitoring the enzymatic activities of c-di-GMP PDEs in real time. Such probes contain fluorescent nucleobases and can be readily cleaved by PDEs, resulting in a change in fluorescence. Fluorescent cyclic and linear dinucleotide probes could be used in diverse applications, such as confirming the activity of an expressed PDE or oligoribonuclease (Orns) or identifying inhibitors of PDEs or Orns using high-throughput screening formats...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28889287/spectrophotometric-and-mass-spectroscopic-methods-for-the-quantification-and-kinetic-evaluation-of-in-vitro-c-di-gmp-synthesis
#8
Geoffrey B Severin, Christopher M Waters
The expression and activity of diguanylate cyclase (DGC) and phosphodiesterase (PDE) enzymes are responsible for modulating and maintaining the intracellular concentration of the bacterial second messenger cyclic diguanosine-monophosphate (c-di-GMP). Here, we describe an in vitro method for the spectrophotometric detection and quantification of DGC catalyzed c-di-GMP synthesis through adaptation of the EnzChek(®) Pyrophosphate Assay Kit. We also outline a method for the quantification of c-di-GMP produced in this in vitro reaction using Ultra-Performance Liquid Chromatography tandem Mass Spectrometry (UPLC-MS/MS)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28888986/pde-5-inhibitor-improves-insulin-sensitivity-by-enhancing-mitochondrial-function-in-adipocytes
#9
Hea Min Yu, Hyo Kyun Chung, Koon Soon Kim, Jae Min Lee, Jun Hwa Hong, Kang Seo Park
Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function...
September 6, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28888651/necrotic-enteritis-locus-1-diguanylate-cyclase-and-phosphodiesterase-cyclic-di-gmp-gene-mutation-attenuates-virulence-in-an-avian-necrotic-enteritis-isolate-of-clostridium-perfringens
#10
Valeria R Parreira, Shivani Ojha, Dion Lepp, Iman Mehdizadeh Gohari, Hongzhuan Zhou, Leonardo Susta, Jianhua Gong, John F Prescott
Necrotic enteritis (NE) caused by netB-positive strains of Clostridium perfringens is an important disease of intensively-reared broiler chickens. It is widely controlled by antibiotic use, but this practice that has come under increasing scrutiny and alternative approaches are required. As part of the search for alternative approaches over the last decade, advances have been made in understanding its pathogenesis but much remains to be understood and applied to the control of NE. The objective of this work was to assess the effect on virulence of mutation of the cyclic-di-GMP signaling genes present on the large pathogenicity locus (NELoc-1) in the tcp-encoding conjugative virulence plasmid, pNetB...
September 2017: Veterinary Microbiology
https://www.readbyqxmd.com/read/28887411/age-related-pacemaker-deterioration-is-due-to-impaired-intracellular-and-membrane-mechanisms-insights-from-numerical-modeling
#11
Joachim Behar, Yael Yaniv
Age-related deterioration of pacemaker function has been documented in mammals, including humans. In aged isolated sinoatrial node tissues and cells, reduction in the spontaneous action potential (AP) firing rate was associated with deterioration of intracellular and membrane mechanisms; however, their relative contribution to age-associated deficient pacemaker function is not known. Interestingly, pharmacological interventions that increase posttranslation modification signaling activities can restore the basal and maximal AP firing rate, but the identities of the protein targets responsible for AP firing rate restoration are not known...
September 8, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28885147/quantitative-susceptibility-mapping-qsm-algorithms-mathematical-rationale-and-computational-implementations
#12
Youngwook Kee, Zhe Liu, Liangdong Zhou, Alexey Dimov, Junghun Cho, Ludovic de Rochefort, Jin Keun Seo, Yi Wang
Quantitative susceptibility mapping (QSM) solves the magnetic field-to-magnetization (tissue susceptibility) inverse problem under conditions of noisy and incomplete field data acquired using magnetic resonance imaging. Sophisticated algorithms are, therefore, necessary to treat the ill-posed nature of the problem and are reviewed here. The forward problem is typically presented as an integral form, where the field is the convolution of the dipole kernel and tissue susceptibility distribution. This integral form can be equivalently written as a partial differential equation (PDE)...
September 5, 2017: IEEE Transactions on Bio-medical Engineering
https://www.readbyqxmd.com/read/28870522/poly-i-c-impairs-no-donor-induced-relaxation-by-overexposure-to-no-via-the-nf-kappa-b-inos-pathway-in-rat-superior-mesenteric-arteries
#13
Makoto Ando, Takayuki Matsumoto, Kumiko Taguchi, Tsuneo Kobayashi
Recent studies have suggested a link between vascular dysfunction and innate immune activation including toll-like receptors (TLRs), but the detailed mechanism remains unclear. Here we investigated whether poly (I:C) [a synthetic double-strand RNA recognized by TLR3, melanoma differentiation-associated gene 5 (MDA5), and retinoic acid-inducible gene I (RIG-I)] affected nitric oxide (NO)/cGMP-related vascular relaxation, one of the major cascades of relaxation, in rat superior mesenteric arteries. Using organ-cultured arteries, we found that poly (I:C) (30μg/mL for approximately 1 day) markedly reduced sodium nitroprusside (SNP)-induced relaxation (vs...
September 1, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28869560/targeting-pde10a-gaf-domain-with-small-molecules-a-way-for-allosteric-modulation-with-anti-inflammatory-effects
#14
Ana M García, José Brea, Alejandro González-García, Concepción Pérez, María Isabel Cadavid, María Isabel Loza, Ana Martinez, Carmen Gil
Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agents...
September 4, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28868308/phosphodiesterases-3-and-4-differentially-regulate-the-funny-current-if-in-mouse-sinoatrial-node-myocytes
#15
Joshua R St Clair, Eric D Larson, Emily J Sharpe, Zhandi Liao, Catherine Proenza
Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3',5'-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac "funny current" (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them...
September 2017: Journal of Cardiovascular Development and Disease
https://www.readbyqxmd.com/read/28868120/novel-cilostamide-analogs-phosphodiesterase-3-inhibitors-produce-positive-inotropic-but-differential-lusitropic-and-chronotropic-effects-on-isolated-rat-atria
#16
Azar Hosseini, Reza Shafiee-Nick, Hamid Sadeghian, Heydar Parsaee
OBJECTIVES: Recently, we showed that some new synthetic compounds structurally related to cilostamide (4-(1,2-dihydro-2-oxoquinolin-6-hydroxy)- N-cyclohexyl-N-methylbutanamide), a selective phosphodiesterase 3 (PDE3) inhibitor, produce inotropic effect comparable to that of IBMX (3-isobutyl-1-methylxanthine), a non-selective PDE inhibitor, but with differential chronotropic effect. In this investigation, we compared the pharmacological effects of these compounds as potential cardiotonic agents using the spontaneously beating atria model...
June 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28867658/identification-and-characterization-of-a-potent-and-biologically-active-pde4-7-inhibitor-via-fission-yeast-based-assays
#17
Ana Santos de Medeiros, Arlene R Wyman, Manal A Alaamery, Christina Allain, F Douglas Ivey, Lili Wang, Hai Le, James P Morken, Alawi Habara, Cuong Le, Shuaiying Cui, Adam Lerner, Charles S Hoffman
We previously constructed a collection of fission yeast strains that express various mammalian cyclic nucleotide phosphodiesterases (PDEs) and developed a cell-based high throughput screen (HTS) for small molecule PDE inhibitors. Here we describe a compound, BC54, that is a selective inhibitor of enzymes from the cAMP-specific PDE4 and PDE7 families. Consistent with the biological effect of other PDE4 and PDE7 inhibitors, BC54 displays potent anti-inflammatory properties and is superior to a combination of rolipram (a PDE4 inhibitor) and BRL50481 (a PDE7A inhibitor) for inducing apoptosis in chronic lymphocytic leukemia (CLL) cells...
September 1, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28866603/boundary-control-of-2-d-burgers-pde-an-adaptive-dynamic-programming-approach
#18
Behzad Talaei, Sarangapani Jagannathan, John Singler
In this paper, an adaptive dynamic programming-based near optimal boundary controller is developed for partial differential equations (PDEs) modeled by the uncertain Burgers' equation under Neumann boundary condition in 2-D. Initially, Hamilton-Jacobi-Bellman equation is derived in infinite-dimensional space. Subsequently, a novel neural network (NN) identifier is introduced to approximate the nonlinear dynamics in the 2-D PDE. The optimal control input is derived by online estimation of the value function through an additional NN-based forward-in-time estimation and approximated dynamic model...
August 29, 2017: IEEE Transactions on Neural Networks and Learning Systems
https://www.readbyqxmd.com/read/28859905/atrazine-suppresses-fsh-induced-steroidogenesis-and-lh-dependent-expression-of-ovulatory-genes-through-pde-camp-signaling-pathway-in-human-cumulus-granulosa-cells
#19
Kristina Pogrmic-Majkic, Dragana Samardzija, Natasa Stojkov-Mimic, Jelena Vukosavljevic, Aleksandra Trninic-Pjevic, Vesna Kopitovic, Nebojsa Andric
Atrazine (ATR) alters female reproductive functions in different animal species. Here, we analyzed whether ATR disturbs steroidogenic and ovulatory processes in hormone-stimulated human cumulus granulosa cells and mechanism of its action. Results showed that treatment of human cumulus granulosa cells with 20 μM ATR for 48 h resulted in lower FSH-stimulated estradiol and progesterone production. ATR reduced mRNA levels of aromatase (CYP19A1), steroidogenic acute regulatory protein (STAR) and luteinizing hormone/choriogonadotropin receptor (LHCGR)...
August 28, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28855593/itga1-is-a-pre-malignant-biomarker-that-promotes-therapy-resistance-and-metastatic-potential-in-pancreatic-cancer
#20
Armen Gharibi, Sa La Kim, Justin Molnar, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Julie Hong, Joy Lin, Laurelin Wolfenden, Jonathan A Kelber
Pancreatic ductal adenocarcinoma (PDAC) has single-digit 5-year survival rates at <7%. There is a dire need to improve pre-malignant detection methods and identify new therapeutic targets for abrogating PDAC progression. To this end, we mined our previously published pseudopodium-enriched (PDE) protein/phosphoprotein datasets to identify novel PDAC-specific biomarkers and/or therapeutic targets. We discovered that integrin alpha 1 (ITGA1) is frequently upregulated in pancreatic cancers and associated precursor lesions...
August 30, 2017: Scientific Reports
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