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https://www.readbyqxmd.com/read/29743346/pgd2-dp2-receptor-activation-promotes-severe-viral-bronchiolitis-by-suppressing-ifn-%C3%AE-production
#1
Rhiannon B Werder, Jason P Lynch, Jennifer C Simpson, Vivian Zhang, Nick H Hodge, Matthew Poh, Elizabeth Forbes-Blom, Christina Kulis, Mark L Smythe, John W Upham, Kirsten Spann, Mark L Everard, Simon Phipps
Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls...
May 9, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29679483/prostaglandin-fp-receptor-antagonists-discovery-pharmacological-characterization-and-therapeutic-utility
#2
REVIEW
Najam A Sharif, Peter G Klimko
In contrast to the availability of potent and selective antagonists of several prostaglandin (PG) receptor types (including DP1 , DP2 , EP, and TP receptors), there has been a paucity of well-characterized, selective FP-receptor antagonists. The earliest ones included dimethyl amide and dimethyl amine derivatives of PGF2α , but these have failed to gain prominence. The fluorinated PGF2α analogs, AL-8810 and AL-3138, were subsequently discovered as competitive and non-competitive FP-receptor antagonists, respectively...
April 21, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29607536/dp1-receptor-signaling-prevents-the-onset-of-intrinsic-apoptosis-in-eosinophils-and-functions-as-a-transcriptional-modulator
#3
Miriam Peinhaupt, David Roula, Anna Theiler, Miriam Sedej, Rudolf Schicho, Gunther Marsche, Eva M Sturm, Ian Sabroe, Marc E Rothenberg, Akos Heinemann
Prostaglandin (PG) D2 is the ligand for the G-protein coupled receptors DP1 (D-type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro-inflammatory effects of DP2...
April 1, 2018: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29439547/prostaglandin-d2-mediated-dp2-and-akt-signal-regulate-the-activation-of-androgen-receptors-in-human-dermal-papilla-cells
#4
Kwan Ho Jeong, Ji Hee Jung, Jung Eun Kim, Hoon Kang
Prostaglandin D2 (PGD2) and prostaglandin D2 receptor 2 (DP2) is known to be an important factor in androgenetic alopecia (AGA). However, the effect of PGD2 in human dermal papilla cells (hDPCs) is not fully understood. The function of PGD2-induced expression of the androgen receptor (AR), DP2, and AKT (protein kinase B) signal were examined by using real time-PCR (qRT-PCR), western blot analysis, immunocytochemistry (ICC), and siRNA transfection system. PGD2 stimulated AR expression and AKT signaling through DP2...
February 12, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29363343/fevipiprant-in-the-treatment-of-asthma
#5
REVIEW
Christobelle White, Adam Wright, Christopher Brightling
Asthma is common and in many, particularly those with more severe disease, there remains a substantial unmet need. Success with biologics targeting eosinophilic inflammation underscore the value of treating inflammation in asthma beyond corticosteroids. Fevipiprant (QAW039) is an oral treatment for asthma. It competitively and reversibly antagonises the prostaglandin D2 receptor 2 (DP2) expressed on inflammatory and structural cells. Areas covered: We reviewed fevipiprant's mode of action and efficacy against other current and emerging pharmacological interventions for moderate-to-severe asthma...
February 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29217623/prostaglandins-d-2-and-e-2-have-opposite-effects-on-alveolar-macrophages-infected-with-histoplasma-capsulatum
#6
Priscilla A T Pereira, Patrícia A Assis, Morgana K B Prado, Simone G Ramos, David M Aronoff, Francisco W G de Paula-Silva, Carlos A Sorgi, Lúcia H Faccioli
Prostaglandin E2 (PGE2 ) suppresses macrophage effector mechanisms; however, little is known about the function of PGD2 in infected alveolar macrophages (AMs). Using serum-opsonized Histoplasma capsulatum (Ops- H. capsulatum ) in vitro, we demonstrated that AMs produced PGE2 and PGD2 in a time-dependent manner, with PGE2 levels exceeding those of PGD2 by 48 h postinfection. Comparison of the effects of both exogenous PGs on AMs revealed that PGD2 increased phagocytosis and killing through the chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes receptor, whereas PGE2 had opposite effects, through E prostanoid (EP) receptor 2 (EP2)/EP4-dependent mechanisms...
February 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/28947949/correction-to-discovery-of-fevipiprant-nvp-qaw039-a-potent-and-selective-dp2-receptor-antagonist-for-treatment-of-asthma
#7
David A Sandham, Lucy Barker, Lyndon Brown, Zarin Brown, David Budd, Steven J Charlton, Devnandan Chatterjee, Brian Cox, Gerald Dubois, Nicholas Duggan, Edward Hall, Julia Hatto, Catherine Leblanc, Janet Maas, Jodie Manini, Rachael Profit, Darren Riddy, Catherine Ritchie, Bindi Sohal, Duncan Shaw, Rowan Stringer, David A Sykes, Matthew Thomas, Katharine L Turner, Simon J Watson, Ryan West, Elisabeth Willard, Gareth Williams, Jennifer Willis
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].
September 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28838980/fevipiprant-an-oral-prostaglandin-dp2-receptor-crth2-antagonist-in-allergic-asthma-uncontrolled-on-low-dose-inhaled-corticosteroids
#8
Eric D Bateman, Alfredo G Guerreros, Florian Brockhaus, Björn Holzhauer, Abhijit Pethe, Richard A Kay, Robert G Townley
Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d) or twice-daily (2, 25, 75 or 150 mg b.i.d) fevipiprant (n=782), montelukast 10 mg q.d (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.dFevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0...
August 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28818625/the-therapeutic-potential-of-crth2-dp2-beyond-allergy-and-asthma
#9
REVIEW
Katharina Jandl, Akos Heinemann
Prostaglandin (PG) D2 has been in the focus of research for quite a long time, but its biological effects and its roles in human disease are still not fully characterized. When in 2001 a second major PGD2 receptor termed chemoattractant receptor homologue expressed on Th2 cells (CRTH2; alternative name DP2) was discovered, diverse investigations started to shed more light on the complex and often controversial actions of the prostaglandin. With various immunomodulating effects, such as induction of migration, activation, and cytokine release of leukocytes observed both in vivo and in vitro, CRTH2 has emerged as a promising target for the treatment of allergic diseases...
November 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28770200/prostaglandins-and-their-receptors-in-eosinophil-function-and-as-therapeutic-targets
#10
REVIEW
Miriam Peinhaupt, Eva M Sturm, Akos Heinemann
Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28628857/identification-of-b-and-t-cell-epitope-based-peptide-vaccine-from-igf-1-receptor-in-breast-cancer
#11
Manijeh Mahdavi, Violaine Moreau, Majid Kheirollahi
The insulin-like growth factor-1 receptor (IGF-1R) plays a key role in proliferation, growth, differentiation, and development of several human malignancies including breast and pancreatic adenocarcinoma. IGF-1R targeted immunotherapeutic approaches are particularly attractive, as they may potentially elicit even stronger antitumor responses than traditional targeted approaches. Cancer peptide vaccines can produce immunologic responses against cancer cells by triggering helper T cell (Th) or cytotoxic T cells (CTL) in association with Major Histocompatibility Complex (MHC) class I or II molecules on the cell surface of antigen presenting cells...
August 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28623133/prostaglandin-d-2-enhances-lipid-accumulation-through-suppression-of-lipolysis-via-dp2-crth2-receptors-in-adipocytes
#12
Eri Wakai, Kosuke Aritake, Yoshihiro Urade, Ko Fujimori
Prostaglandin (PG) D2 enhanced lipid accumulation in adipocytes. However, its molecular mechanism remains unclear. In this study, we investigated the regulatory mechanisms of PGD2 -elevated lipid accumulation in mouse adipocytic 3T3-L1 cells. The Gi-coupled DP2 (CRTH2) receptors (DP2R), one of the two-types of PGD2 receptors were dominantly expressed in adipocytes. A DP2R antagonist, CAY10595, but not DP1 receptor antagonist, BWA868C cleared the PGD2 -elevated intracellular triglyceride level. While, a DP2R agonist, 15R-15-methyl PGD2 (15R) increased the mRNA levels of the adipogenic and lipogenic genes, and decreased the glycerol release level...
August 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28612233/targeting-the-pgd2-crth2-dp1-signaling-pathway-in-asthma-and-allergic-disease-current-status-and-future-perspectives
#13
Maciej Kupczyk, Piotr Kuna
Prostaglandin D2 (PGD2) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD2 are mediated by D-prostanoid (DP1), CRTH2 (DP2), and thromboxane prostanoid (TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th2) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th2-type cytokines (interleukin [IL]-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils...
August 2017: Drugs
https://www.readbyqxmd.com/read/28602634/dp1-receptor-agonist-bw245c-inhibits-diet-induced-obesity-in-apoe-mice
#14
Sunil Kumar, Thomas Palaia, Christopher Hall, Louis Ragolia
BACKGROUND/OBJECTIVE: Lipocalin Prostaglandin D2 synthase (LPGDS) contributes to the production of PGD2, which has been associated with adipogenesis. In this study, we aimed to investigate the role of PGD2 on obesity through its DP1 and DP2 receptor signaling using intraperitoneal injection of their respective agonists and antagonists. METHODS: ApoE(-/-) mice were divided into five groups: vehicle control (n=5), DP1 receptor agonist (n=5), DP1 receptor antagonist (n=5), DP2 receptor agonist (n=5), and DP2 receptor antagonist (n=5), and the study was carried out for 10 weeks...
June 8, 2017: Obesity Research & Clinical Practice
https://www.readbyqxmd.com/read/28523115/discovery-of-fevipiprant-nvp-qaw039-a-potent-and-selective-dp2-receptor-antagonist-for-treatment-of-asthma
#15
David A Sandham, Lucy Barker, Lyndon Brown, Zarin Brown, David Budd, Steven J Charlton, Devnandan Chatterjee, Brian Cox, Gerald Dubois, Nicholas Duggan, Edward Hall, Julia Hatto, Janet Maas, Jodie Manini, Rachael Profit, Darren Riddy, Catherine Ritchie, Bindi Sohal, Duncan Shaw, Rowan Stringer, David A Sykes, Matthew Thomas, Katharine L Turner, Simon J Watson, Ryan West, Elisabeth Willard, Gareth Williams, Jennifer Willis
Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.
May 11, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28442499/absorption-distribution-metabolism-and-excretion-of-the-oral-prostaglandin-d2-receptor-2-antagonist-fevipiprant-qaw039-in-healthy-volunteers-and-in-vitro
#16
David Pearson, H Markus Weiss, Yi Jin, Jan Jaap van Lier, Veit J Erpenbeck, Ulrike Glaenzel, Peter End, Ralph Woessner, Fabian Eggimann, Gian Camenisch
Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2 ; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14 C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding...
July 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28394950/generation-and-characterization-of-an-antagonistic-monoclonal-antibody-against-an-extracellular-domain-of-mouse-dp2-crth2-gpr44-receptors-for-prostaglandin-d2
#17
Nanae Nagata, Hiroko Iwanari, Hidetoshi Kumagai, Osamu Kusano-Arai, Yuichi Ikeda, Kosuke Aritake, Takao Hamakubo, Yoshihiro Urade
Prostaglandin D2 (PGD2) is a lipid mediator involved in sleep regulation and inflammation. PGD2 interacts with 2 types of G protein-coupled receptors, DP1 and DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on T helper type 2 cells)/GPR44 to show a variety of biological effects. DP1 activation leads to Gs-mediated elevation of the intracellular cAMP level, whereas activation of DP2 decreases this level via the Gi pathway; and it also induces G protein-independent, arrestin-mediated cellular responses...
2017: PloS One
https://www.readbyqxmd.com/read/28091621/differential-susceptibility-and-maturation-of-thymocyte-subsets-during-salmonella-typhimurium-infection-insights-on-the-roles-of-glucocorticoids-and-interferon-gamma
#18
Shamik Majumdar, Mukta Deobagkar-Lele, Vasista Adiga, Abinaya Raghavan, Nitin Wadhwa, Syed Moiz Ahmed, Supriya Rajendra Rananaware, Subhashish Chakraborty, Omana Joy, Dipankar Nandi
The thymus is known to atrophy during infections; however, a systematic study of changes in thymocyte subpopulations has not been performed. This aspect was investigated, using multi-color flow cytometry, during oral infection of mice with Salmonella Typhimurium (S. Typhimurium). The major highlights are: First, a block in the developmental pathway of CD4(-)CD8(-) double negative (DN) thymocytes is observed. Second, CD4(+)CD8(+) double positive (DP) thymocytes, mainly in the DP1 (CD5(lo)CD3(lo)) and DP2 (CD5(hi)CD3(int)), but not DP3 (CD5(int)CD3(hi)), subsets are reduced...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28076322/aeroallergen-der-p-2-promotes-motility-of-human-non-small-cell-lung-cancer-cells-via-toll-like-receptor-mediated-up-regulation-of-urokinase-type-plasminogen-activator-and-integrin-focal-adhesion-kinase-signaling
#19
Chun-Hsiang Lin, Hui-Han Lin, Cheng-Yi Kuo, Shao-Hsuan Kao
House dust mite (HDM) allergens are one of the major causes leading to respiratory hypersensitiveness and airway remodeling. Here we hypothesized that a major HDM allergen Der p 2 could increase cell motility and invasiveness of non-small cell lung cancer (NSCLC) cells. Our results showed that low dose (1 and 3 μg/mL) recombinant Der p 2 protein (DP2) enhanced the migration and invasiveness of human NSCLC cell A549, H1299 and CL1-5, but nonsignificantly altered their growth. Further investigation revealed that integrin αV level was increased and its downstream signaling including focal adhesion kinase (FAK) and paxillin were activated in A549 cells exposed to DP2...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/27898338/effect-of-pgd2-on-middle-meningeal-artery-and-mrna-expression-profile-of-l-pgd2-synthase-and-dp-receptors-in-trigeminovascular-system-and-other-pain-processing-structures-in-rat-brain
#20
Aysegül Sekeroglu, Julie Mie Jacobsen, Inger Jansen-Olesen, Saurabh Gupta, Majid Sheykhzade, Jes Olesen, Deepak K Bhatt
BACKGROUND: Prostaglandins (PGs), particularly prostaglandin D2 (PGD2), E2 (PGE2), and I2 (PGI2), are considered to play a role in migraine pain. In humans, infusion of PGD2 causes lesser headache as compared to infusion of PGE2 and PGI2. Follow-up studies in rats have shown that infusion of PGE2 and PGI2 dilate the middle meningeal artery (MMA), and mRNA for PGE2 and PGI2 receptors is present in rat trigeminovascular system (TVS) and in the brain structures associated with pain. In the present study, we have characterized the dilatory effect of PGD2 on rat MMA and studied the relative mRNA expression of PGD2 receptors and lipocalin-type of PGD2 synthase (L-PGDS)...
February 2017: Pharmacological Reports: PR
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