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https://www.readbyqxmd.com/read/29110986/the-synthesis-of-2-3-6-trisubstituted-1-oxo-1-2-dihydroisoquinolines-as-potent-crth2-antagonists
#1
Xianhai Huang, Ashwin Rao, Wei Zhou, Robert Aslanian, Ravi Nargund, Alexei Buevich, Li-Kang Zhang, Hongchen Qiu, Xiaoxin Yang, Charles G Garlisi, Craig Correll, Anandan Palani
New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay...
July 25, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28964637/neuroendocrine-cells-derived-chemokine-vasoactive-intestinal-polypeptide-vip-in-allergic-diseases
#2
REVIEW
Alok K Verma, Murli Manohar, Sathisha Upparahalli Venkateshaiah, Anil Mishra
Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP)...
September 23, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28928446/tumour-derived-pgd2-and-nkp30-b7h6-engagement-drives-an-immunosuppressive-ilc2-mdsc-axis
#3
Sara Trabanelli, Mathieu F Chevalier, Amaia Martinez-Usatorre, Alejandra Gomez-Cadena, Bérengère Salomé, Mariangela Lecciso, Valentina Salvestrini, Grégory Verdeil, Julien Racle, Cristina Papayannidis, Hideaki Morita, Irene Pizzitola, Camille Grandclément, Perrine Bohner, Elena Bruni, Mukul Girotra, Rani Pallavi, Paolo Falvo, Elisabeth Oppliger Leibundgut, Gabriela M Baerlocher, Carmelo Carlo-Stella, Daniela Taurino, Armando Santoro, Orietta Spinelli, Alessandro Rambaldi, Emanuela Giarin, Giuseppe Basso, Cristina Tresoldi, Fabio Ciceri, David Gfeller, Cezmi A Akdis, Luca Mazzarella, Saverio Minucci, Pier Giuseppe Pelicci, Emanuela Marcenaro, Andrew N J McKenzie, Dominique Vanhecke, George Coukos, Domenico Mavilio, Antonio Curti, Laurent Derré, Camilla Jandus
Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28915062/a-recombinant-fragment-of-human-surfactant-protein-d-suppresses-basophil-activation-th2-and-b-cell-responses-in-grass-pollen-induced-allergic-inflammation
#4
Asif S Qaseem, Iesha Singh, Ansar A Pathan, Janice A Layhadi, Rebecca Parkin, Fedina Alexandra, Stephen R Durham, Uday Kishore, Mohamed H Shamji
RATIONALE: rfhSP-D has been shown to suppress house dust mite and Aspergillus fumigatus-induced allergic inflammation in murine models. OBJECTIVES: We sought to elucidate the effect of rfhSP-D on FcεRI and CD23-mediated grass pollen induced allergic inflammatory responses. METHODS: rfhSP-D, containing homotrimeric neck and lectin domains, was expressed in Escherichia coli BL21 (λDE3) pLysS. PBMCs and sera were obtained from grass pollen allergic individuals (n=27)...
September 15, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28888244/new-and-anticipated-therapies-for-severe-asthma
#5
Stephen P Peters, William W Busse
Asthma is frequently undertreated, resulting in a relatively high prevalence of patients with uncontrolled disease, characterized by the presence of symptoms and risk of adverse outcomes. Patients with uncontrolled asthma have a higher risk of morbidity and mortality, underscoring the importance of identifying uncontrolled disease and modifying management plans to improve control. Several assessment tools exist to evaluate control with various cutoff points and measures, but these tools do not reliably correlate with physiological measures and should be considered a supplement to physiological tests...
September 2017: Journal of Allergy and Clinical Immunology in Practice
https://www.readbyqxmd.com/read/28838980/fevipiprant-an-oral-prostaglandin-dp2-receptor-crth2-antagonist-in-allergic-asthma-uncontrolled-on-low-dose-inhaled-corticosteroids
#6
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/28822449/-cytokine-profiles-of-cd4-t-memory-cells-in-asthma-and-their-relationship-with-asthma-severity
#7
C L Du, K Xu, Z H Min, D D Li, H L Yuan, C Liu, Z H Chen
Objective: To study the phenotype of memory CD4(+) T cells in peripheral blood of asthmatics and its relationship with asthma severity. Methods: From Dec 2014 to Aug 2015, thirty-three asthmatics, twenty-six chronic obstructive pulmonary disease (COPD) patients and twenty-two healthy volunteers were enrolled in Respiratory Clinics of Zhongshan Hospital, Fudan University. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood. Cell surface markers (CD45RO, CRTH2, CD62L, and CCR7) and intracellular protein[interleukin (IL)-5, IL-17, interferon (IFN)-γ]staining was performed using flow-cytometric techniques...
August 8, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28818625/the-therapeutic-potential-of-crth2-dp2-beyond-allergy-and-asthma
#8
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...
August 14, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28768806/a-phenotypically-and-functionally-distinct-human-th2-cell-subpopulation-is-associated-with-allergic-disorders
#9
Erik Wambre, Veronique Bajzik, Jonathan H DeLong, Kimberly O'Brien, Quynh-Anh Nguyen, Cate Speake, Vivian H Gersuk, Hannah A DeBerg, Elizabeth Whalen, Chester Ni, Mary Farrington, David Jeong, David Robinson, Peter S Linsley, Brian P Vickery, William W Kwok
Allergen-specific type 2 helper T (TH2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease-causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic TH2 cell types. We have described a subset of human memory TH2 cells confined to atopic individuals that includes all allergen-specific TH2 cells...
August 2, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28761653/individuals-with-obesity-and-type-2-diabetes-have-additional-immune-dysfunction-compared-with-obese-individuals-who-are-metabolically-healthy
#10
Caroline Richard, Michael Wadowski, Susan Goruk, Lisa Cameron, Arya M Sharma, Catherine J Field
OBJECTIVE: The objective of the current study was to compare the responses to different ex vivo immunogenic challenges between immune cells derived from metabolically healthy subjects with obesity and subjects with obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: We recruited 10 metabolically healthy subjects with obesity (Edmonton Obesity Staging System (EOSS) stage 0) and 9 subjects with obesity and type 2 diabetes (EOSS stage 2) aged between 21 years and 70 years and matched for body mass index...
2017: BMJ Open Diabetes Research & Care
https://www.readbyqxmd.com/read/28679671/breast-regression-protein-39-chitinase-3-like-1-promotes-renal-fibrosis-after-kidney-injury-via-activation-of-myofibroblasts
#11
Tinika A Montgomery, Leyuan Xu, Sherene Mason, Amirtha Chinnadurai, Chun Geun Lee, Jack A Elias, Lloyd G Cantley
The normal response to kidney injury includes a robust inflammatory infiltrate of PMNs and macrophages. We previously showed that the small secreted protein breast regression protein-39 (BRP-39), also known as chitinase 3-like 1 (CHI3L1) and encoded by the Chi3l1 gene, is expressed at high levels by macrophages during the early stages of kidney repair and promotes tubular cell survival via IL-13 receptor α2 (IL13Rα2)-mediated signaling. Here, we investigated the role of BRP-39 in profibrotic responses after AKI...
November 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28669561/effects-of-icariin-on-asthma-mouse-model-are-associated-with-regulation-of-prostaglandin-d2-level
#12
J Qiao, S Sun, L Yuan, J Wang
BACKGROUND: We aimed to observe the effect of icariin on an asthma mouse model and explore the potential underlying mechanisms. METHODS: The asthma mouse model was established by ovalbumin (OVA) sensitisation and respiratory syncytial virus (RSV) infection and then treated with icariin. Airway resistance was assessed by whole body plethysmograph. In addition, pathological slides were stained with haematoxylin-eosin, and the peribronchial inflammation was observed microscopically...
June 29, 2017: Allergologia et Immunopathologia
https://www.readbyqxmd.com/read/28623133/prostaglandin-d2-enhances-lipid-accumulation-through-suppression-of-lipolysis-via-dp2-crth2-receptors-in-adipocytes
#13
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/28615072/chemokine-receptor-co-expression-reveals-aberrantly-distributed-th-effector-memory-cells-in-gpa-patients
#14
Lucas L Lintermans, Abraham Rutgers, Coen A Stegeman, Peter Heeringa, Wayel H Abdulahad
BACKGROUND: Persistent expansion of circulating CD4(+) effector memory T cells (TEM) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4(+) TEM cell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4(+) TEM cell subsets based on chemokine receptor expression in peripheral blood of GPA patients...
June 14, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28612233/targeting-the-pgd2-crth2-dp1-signaling-pathway-in-asthma-and-allergic-disease-current-status-and-future-perspectives
#15
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/28609567/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-the-novel-crth2-antagonist-bi-1021958-at-single-oral-doses-in-healthy-men-and-multiple-oral-doses-in-men-and-women-with-well-controlled-asthma
#16
Andy Fowler, Rüdiger Koenen, James Hilbert, Jon Blatchford, Dominik Kappeler, Ewald Benediktus, Chester Wood, Abhya Gupta
BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12)...
November 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28442499/absorption-distribution-metabolism-and-excretion-of-the-oral-prostaglandin-d2-receptor-2-dp2-antagonist-fevipiprant-qaw039-in-healthy-volunteers-and-in-vitro
#17
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...
April 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28433687/steroid-resistance-of-airway-type-2-innate-lymphoid-cells-from-patients-with-severe-asthma-the-role-of-thymic-stromal-lymphopoietin
#18
Sucai Liu, Mukesh Verma, Lidia Michalec, Weimin Liu, Anand Sripada, Donald Rollins, James Good, Yoko Ito, HongWei Chu, Magdalena M Gorska, Richard J Martin, Rafeul Alam
BACKGROUND: Type 2 innate lymphoid cells (ILC2s) represent an important type 2 immune cell. Glucocorticoid regulation of human ILC2s is largely unknown. OBJECTIVE: We sought to assess steroid resistance of human blood and airway ILC2s from asthmatic patients and to examine its mechanism of induction. METHODS: We studied human blood and lung ILC2s from asthmatic patients and control subjects using flow cytometry and ELISA. RESULTS: Dexamethasone inhibited (P = ...
April 20, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28422515/allergen-induced-increases-in-sputum-levels-of-group-2-innate-lymphoid-cells-in-subjects-with-asthma
#19
Ruchong Chen, Steven G Smith, Brittany Salter, Amani El-Gammal, John Paul Oliveria, Caitlin Obminski, Rick Watson, Paul M O'Byrne, Gail M Gauvreau, Roma Sehmi
RATIONALE: Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines, initiate eosinophilic inflammatory responses in murine models of asthma. OBJECTIVES: To investigate the role of ILC2 in allergen-induced airway eosinophilic responses in subjects with atopy and asthma. METHODS: Using a diluent-controlled allergen challenge crossover study, where all subjects (n = 10) developed allergen-induced early and late responses, airway eosinophilia, and increased methacholine airway responsiveness, bone marrow, blood, and sputum samples were collected before and after inhalation challenge...
September 15, 2017: American Journal of Respiratory and Critical Care Medicine
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
#20
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
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