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DP2 receptor

Na N Guan, Karl Svennersten, Petra J de Verdier, N Peter Wiklund, Lars E Gustafsson
The proximal urethra and urinary bladder trigone play important roles in continence. We have previously shown that PGD2 is released from guinea pig bladder urothelium/suburothelium and can inhibit detrusor contractile responses. We presently wished to investigate PGD2 actions in guinea pig out-flow region and the distribution of DP1 /DP2 receptors. The effects of PGD2 on urothelium-intact trigone and proximal urethra contractility were studied in organ bath experiments. Expression of DP1 /DP2 receptor proteins was analysed by western blot...
September 23, 2016: Journal of Cellular and Molecular Medicine
Soledad P Rossi, Stefanie Windschüttl, María E Matzkin, Verónica Rey-Ares, Claudio Terradas, Roberto Ponzio, Elisa Puigdomenech, Oscar Levalle, Ricardo S Calandra, Artur Mayerhofer, Mónica B Frungieri
Reactive oxygen species (ROS) regulate testicular function in health and disease. We previously described a prostaglandin D2 (PGD2) system in Sertoli cells. Now, we found that PGD2 increases ROS and hydrogen peroxide (H2O2) generation in murine TM4 Sertoli cells, and also induces antioxidant enzymes expression suggesting that defense systems are triggered as an adaptive stress mechanism that guarantees cell survival. ROS and specially H2O2 may act as second messengers regulating signal transduction pathways and gene expression...
October 15, 2016: Molecular and Cellular Endocrinology
Giuseppe Santini, Nadia Mores, Mario Malerba, Chiara Mondino, Giuseppe Macis, Paolo Montuschi
INTRODUCTION: By activating DP1 and DP2 receptors on immune and non-immune cells, prostaglandin D2 (PGD2), a major metabolic product of cyclo-oxygenase pathway released after IgE-mediated mast cell activation, has pro-inflammatory effects, which are relevant to the pathophysiology of allergic airway disease. At least 15 selective, orally active, DP2 receptor antagonists and one DP1 receptor antagonist (asapiprant) are under development for asthma and/or allergic rhinitis. AREAS COVERED: In this review, the authors cover the pharmacology of PGD2 and PGD2 receptor antagonists and look at the preclinical, phase I and phase II studies with selective DP1 and DP2 receptor antagonists...
June 2016: Expert Opinion on Investigational Drugs
Jie Ma, Qunfang Yang, Yuling Wei, Yang Yang, Chaonan Ji, Xinyue Hu, Shaoshan Mai, Shengnan Kuang, Xiaoyan Tian, Ying Luo, Guojuan Liang, Junqing Yang
In the present study, the agonists and antagonists of DP receptor were used to examine whether the PGD2-DP signaling pathway affects neuronal function. Primary cultured hippocampal neuron was prepared and treated with aluminum maltolate (100 μM) to establish the neuronal damage model. PGD2 and cAMP content was detected by ELISA. L-PGDS and DPs mRNA and protein expression were measured by RT-PCR and Western blotting, respectively. The aluminium-load neuron was treated with the DP1 agonist BW245C, the DP1 antagonist BWA868C, the DP2 agonist DK-PGD2, and the DP2 antagonist CAY10471, respectively...
2016: Scientific Reports
Young-So Yoon, Ye-Ji Lee, Youn-Hee Choi, Young Mi Park, Jihee Lee Kang
Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1...
2016: Scientific Reports
Chintan N Koyani, Kerstin Kitz, Christine Rossmann, Eva Bernhart, Evelyn Huber, Christopher Trummer, Werner Windischhofer, Wolfgang Sattler, Ernst Malle
Despite considerable efforts to improve treatment modalities for osteosarcoma (OS), patient survival remains poor mainly due to pro-survival pathways in OS cells. Among others, prostaglandins (PGs) are the potent regulators of bone homoeostasis and OS pathophysiology. Therefore, the present study aimed to elucidate the impact of 15-deoxy-Δ(12,14)-PGJ2 (15d-PGJ2, a stable PGD2 degradation product) on cell death/cell survival pathways in p53-deficient MG-63 OS cells. Our findings show that 15d-PGJ2 induces generation of reactive oxygen species that promote p38 MAPK activation and subsequent Akt phosphorylation...
March 15, 2016: Biochemical Pharmacology
Katharina Jandl, Elvira Stacher, Zoltán Bálint, Eva Maria Sturm, Jovana Maric, Miriam Peinhaupt, Petra Luschnig, Ida Aringer, Alexander Fauland, Viktoria Konya, Sven-Erik Dahlen, Craig E Wheelock, Dagmar Kratky, Andrea Olschewski, Gunther Marsche, Rufina Schuligoi, Akos Heinemann
BACKGROUND: Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date. OBJECTIVE: We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo...
March 2016: Journal of Allergy and Clinical Immunology
Andrew P Fontenot, Michael T Falta, John W Kappler, Shaodong Dai, Amy S McKee
Chronic beryllium (Be) disease is a granulomatous lung disorder that results from Be exposure in a genetically susceptible host. The disease is characterized by the accumulation of Be-responsive CD4(+) T cells in the lung, and genetic susceptibility is primarily linked to HLA-DPB1 alleles possessing a glutamic acid at position 69 of the β-chain. Recent structural analysis of a Be-specific TCR interacting with a Be-loaded HLA-DP2-peptide complex revealed that Be is coordinated by amino acid residues derived from the HLA-DP2 β-chain and peptide and showed that the TCR does not directly interact with the Be(2+) cation...
January 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jenny W Wang, David F Woodward, Jose L Martos, Clive L Cornell, Robert W Carling, Philip J Kingsley, Lawrence J Marnett
A polypharmacologic approach to prostanoid based anti-inflammatory therapeutics was undertaken in order to exploit both the anti- and proinflammatory properties attributed to the various prostanoid receptors. Multitargeting of selected prostanoid receptors yielded a prototype compound, compound 1 (AGN 211377), that antagonizes prostaglandin D2 receptors (DPs) DP1 (49) and DP2 (558), prostaglandin E2 receptors (EPs) EP1 (266) and EP4 (117), prostaglandin F2α receptor (FP) (61), and thromboxane A2 receptor (TP) (11) while sparing EP2, EP3, and prostaglandin I2 receptors (IPs); Kb values (in nanomoles) are given in parentheses...
January 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Tatsurou Yagami, Hiromi Koma, Yasuhiro Yamamoto
Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity...
September 2016: Molecular Neurobiology
Go Takahashi, Fujio Asanuma, Noriko Suzuki, Maki Hattori, Shingo Sakamoto, Akira Kugimiya, Yasuhiko Tomita, Goro Kuwajima, William M Abraham, Masashi Deguchi, Akinori Arimura, Michitaka Shichijo
Prostaglandin (PG) D2 elicits responses through either the DP1 and/or DP2 receptor. Experimental evidence suggests that stimulation of the DP1 receptor contributes to allergic responses, such that antagonists are considered to be directed therapies for allergic diseases. In this study, we demonstrate the activity of a novel synthetic DP1 receptor antagonist termed asapiprant (S-555739) for the DP1 receptor and other receptors in vitro, and assess the efficacy of asapiprant in several animal models of allergic diseases...
October 15, 2015: European Journal of Pharmacology
M T Falta, A N Tinega, D G Mack, N A Bowerman, F Crawford, J W Kappler, C Pinilla, A P Fontenot
Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4(+) T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (βGlu69), and HLA-DPB1*02:01 is the most prevalent βGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here we characterized the T-cell receptor (TCR) repertoire of Be-responsive CD4(+) T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice...
January 2016: Mucosal Immunology
Sunil Kumar, Thomas Palaia, Christopher E Hall, Louis Ragolia
The objective of the study was to investigate the role of prostaglandin D2 during pregnancy and its mediator Lipocalin-type prostaglandin D2 synthase (L-PGDS) as a predictor of preterm birth (PTB). Transgenic L-PGDS (+/+), L-PGDS (-/-) and C57BL/6 control pregnant mice models were used to determine the effect of DP1 and DP2 receptor antagonists in lipopolysaccharide (LPS)-induced PTB mice. In addition, L-PGDS levels were measured in the cervicovaginal secretions (CVS) of 370 pregnant women using ELISA and further processed for isoform detection using 2-D gel electrophoresis...
April 2015: Prostaglandins & Other Lipid Mediators
M Medani, D Collins, H M Mohan, E Walsh, D C Winter, A W Baird
AIMS: Prostaglandin D2 is released by mast cells and is important in allergies. Its role in gastrointestinal function is not clearly defined. This study aimed to determine the effect of exogenous PGD2 on ion transport in ex vivo normal human colonic mucosa. MATERIALS AND METHODS: Mucosal sheets were mounted in Ussing chambers and voltage clamped to zero electric potential. Ion transport was quantified as changes in short-circuit current. In separate experiments epithelial monolayers or colonic crypts, isolated by calcium chelation, were treated with PGD2 and cAMP levels determined by ELISA or calcium levels were determined by fluorimetry...
February 1, 2015: Life Sciences
Sarah A Maher, Mark A Birrell, John J Adcock, Michael A Wortley, Eric D Dubuis, Sara J Bonvini, Megan S Grace, Maria G Belvisi
Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D2 receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough. We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD2 responses. PGD2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia...
April 2015: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Sally E Stinson, Yassine Amrani, Christopher E Brightling
BACKGROUND: The D prostanoid receptor 2 (DP2; also known as chemoattractant receptor-homologous molecule expressed on TH2 cells) is implicated in the pathogenesis of asthma, but its expression within bronchial biopsy specimens is unknown. OBJECTIVES: We sought to investigate the bronchial submucosal DP2 expression in asthmatic patients and healthy control subjects and to explore its functional role in epithelial cells. METHODS: DP2 protein expression was assessed in bronchial biopsy specimens from asthmatic patients (n = 22) and healthy control subjects (n = 10) by using immunohistochemistry and in primary epithelial cells by using flow cytometry, immunofluorescence, and quantitative RT-PCR...
February 2015: Journal of Allergy and Clinical Immunology
Tae Chul Moon, Eduardo Campos-Alberto, Tsuyoshi Yoshimura, Graeme Bredo, Aja M Rieger, Lakshmi Puttagunta, Daniel R Barreda, A Dean Befus, Lisa Cameron
PGD₂ has long been implicated in allergic diseases. Recent cloning of a second PGD₂ receptor, DP2 (also known as CRTh2), led to a greater understanding of the physiological and pathophysiological implications of PGD₂. PGD₂ signaling through DP1 and DP2 mediates different and often opposite effects in many cell types of the immune system. Although mast cells (MC) are the largest source of PGD₂ in the body, there is little information about their potential expression of DP2 and its functional significance...
2014: PloS One
Brigitte Moniot, Safdar Ujjan, Julien Champagne, Hiroyuki Hirai, Kosuke Aritake, Kinya Nagata, Emeric Dubois, Sabine Nidelet, Masataka Nakamura, Yoshihiro Urade, Francis Poulat, Brigitte Boizet-Bonhoure
Through intercellular signalling, the somatic compartment of the foetal testis is able to program primordial germ cells to undergo spermatogenesis. Fibroblast growth factor 9 and several members of the transforming growth factor β superfamily are involved in this process in the foetal testis, counteracting the induction of meiosis by retinoic acid and activating germinal mitotic arrest. Here, using in vitro and in vivo approaches, we show that prostaglandin D2 (PGD2), which is produced through both L-Pgds and H-Pgds enzymatic activities in the somatic and germ cell compartments of the foetal testis, plays a role in mitotic arrest in male germ cells by activating the expression and nuclear localization of the CDK inhibitor p21(Cip1) and by repressing pluripotency markers...
September 2014: Development
Seisuke Kusano, Mutsuko Kukimoto-Niino, Yoko Satta, Noboru Ohsawa, Tomomi Uchikubo-Kamo, Motoaki Wakiyama, Mariko Ikeda, Takaho Terada, Ken Yamamoto, Yasuharu Nishimura, Mikako Shirouzu, Takehiko Sasazuki, Shigeyuki Yokoyama
The major allergen, Cry j 1, was isolated from Japanese cedar Cryptomeria japonica (Cry j) pollen and was shown to react with immunoglobulin E antibodies in the sera from pollinosis patients. We previously reported that the frequency of HLA-DP5 was significantly higher in pollinosis patients and the immunodominant peptides from Cry j 1 bound to HLA-DP5 to activate Th2 cells. In the present study, we determined the crystal structure of the HLA-DP5 heterodimer in complex with a Cry j 1-derived nine-residue peptide, at 2...
August 26, 2014: Journal of Molecular Biology
Gina M Clayton, Yang Wang, Frances Crawford, Andrey Novikov, Brian T Wimberly, Jeffrey S Kieft, Michael T Falta, Natalie A Bowerman, Philippa Marrack, Andrew P Fontenot, Shaodong Dai, John W Kappler
T-cell-mediated hypersensitivity to metal cations is common in humans. How the T cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T cells to inhaled beryllium. Here, we show that the T cell ligand is created when a Be(2+) cation becomes buried in an HLA-DP2/peptide complex, where it is coordinated by both MHC and peptide acidic amino acids...
July 3, 2014: Cell
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