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https://www.readbyqxmd.com/read/29454096/jak-stat-inhibitors-and-other-small-molecule-cytokine-antagonists-for-the-treatment-of-allergic-disease
#1
REVIEW
Michael D Howell, Carolyn Fitzsimons, Paul Smith
OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2), and phosphodiesterase 4 (PDE4) inhibitors in allergic disorders. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles included in this review discuss the emerging mechanism of action of small molecule inhibitors and their utilization in atopic dermatitis (AD), asthma, and allergic rhinitis (AR)...
February 14, 2018: Annals of Allergy, Asthma & Immunology
https://www.readbyqxmd.com/read/29449864/seasonal-variation-in-circulating-group-2-innate-lymphoid-cells-in-mugwort-allergic-asthmatics-during-and-outside-pollen-season
#2
Qing Miao, Yan Wang, Yong-Ge Liu, Yi-Xin Ren, Hui Guan, Zhen Li, Wei Xu, Li Xiang
Background: Group 2 innate lymphoid cells (ILC2s) are a newly identified cell population with the potent capability to produce Th2-type cytokines in a non-antigen specific manner. Previous study demonstrated that enhanced circulating ILC2s in cat-allergic patient after experimental allergen challenge, whereas the effects of natural allergen exposure on peripheral ILC2s are still unclear. We therefore examined the variations in circulating ILC2s among asthmatic patients sensitized to different allergens in- and outside- pollen season...
2018: Allergy, Asthma, and Clinical Immunology
https://www.readbyqxmd.com/read/29427987/advances-and-evolving-concepts-in-allergic-asthma
#3
Hui-Ying Tung, Evan Li, Cameron Landers, An Nguyen, Farrah Kheradmand, J Morgan Knight, David B Corry
Allergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis...
February 2018: Seminars in Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29363343/fevipiprant-in-the-treatment-of-asthma
#4
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...
January 24, 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29335338/crth2-promotes-endoplasmic-reticulum-stress-induced-cardiomyocyte-apoptosis-through-m-calpain
#5
Shengkai Zuo, Deping Kong, Chenyao Wang, Jiao Liu, Yuanyang Wang, Qiangyou Wan, Shuai Yan, Jian Zhang, Juan Tang, Qianqian Zhang, Luheng Lyu, Xin Li, Zhixin Shan, Li Qian, Yujun Shen, Ying Yu
Apoptotic death of cardiac myocytes is associated with ischemic heart disease and chemotherapy-induced cardiomyopathy. Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) is highly expressed in the heart. However, its specific role in ischemic cardiomyopathy is not fully understood. Here, we demonstrated that CRTH2 disruption markedly improved cardiac recovery in mice postmyocardial infarction and doxorubicin challenge by suppressing cardiomyocyte apoptosis. Mechanistically, CRTH2 activation specifically facilitated endoplasmic reticulum (ER) stress-induced cardiomyocyte apoptosis via caspase-12-dependent pathway...
January 15, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29296700/il-33-il-25-and-tslp-induce-a-distinct-phenotypic-and-activation-profile-in-human-type-2-innate-lymphoid-cells
#6
Ana Camelo, Guglielmo Rosignoli, Yoichiro Ohne, Ross A Stewart, Catherine Overed-Sayer, Matthew A Sleeman, Richard D May
Innate lymphoid cells (ILCs) represent a distinct branch of the lymphoid lineage composed of 3 major subpopulations: ILC1, ILC2, and ILC3. ILCs are mainly described as tissue-resident cells but can be detected at low levels in human blood. However, unlike mouse ILCs, there is still no consistent methodology to purify and culture these cells that enables in-depth analysis of their intrinsic biology. Here, we describe defined culture conditions for ILC2s, which allowed us to dissect the roles of interleukin 2 (IL-2), IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) individually, or in combination, in modulating ILC2 phenotype and function...
April 11, 2017: Blood Advances
https://www.readbyqxmd.com/read/29276415/crth2-antagonists-in-asthma-current-perspectives
#7
REVIEW
Dave Singh, Arjun Ravi, Thomas Southworth
Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) binds to prostaglandin D2. CRTH2 is expressed on various cell types including eosinophils, mast cells, and basophils. CRTH2 and prostaglandin D2 are involved in allergic inflammation and eosinophil activation. Orally administered CRTH2 antagonists are in clinical development for the treatment of asthma. The biology and clinical trial data indicate that CRTH2 antagonists should be targeted toward eosinophilic asthma. This article reviews the clinical evidence for CRTH2 involvement in asthma pathophysiology and clinical trials of CRTH2 antagonists in asthma...
2017: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/29110986/the-synthesis-of-2-3-6-trisubstituted-1-oxo-1-2-dihydroisoquinolines-as-potent-crth2-antagonists
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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