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1
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Liu XR, Li M, Hao QQ, Yu YJ, Liao C, Yu R, Kong DL, Wang Y. Unraveling cysteinyl leukotrienes and their receptors in inflammation through the brain-gut-lung axis. Virulence 2025; 16:2502555. [PMID: 40351036 PMCID: PMC12077450 DOI: 10.1080/21505594.2025.2502555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/14/2025] Open
Abstract
Cysteinyl leukotrienes (CysLTs), as potent lipid inflammatory mediators, play a pivotal role in systemic multi-organ inflammation and inter-organ communication through interactions with their receptors (CysLTRs). However, However, the function of CysLT3R is unclear and lacks a network of cross-organ metabolite interactions, and the clinical use of leukotriene receptor antagonists (LTRAs) has certain limitations. This review systematically synthesizes existing evidence and proposes future directions by clarifying receptor subtype specificity, optimizing targeted therapies, exploring CysLTs' applications in neuroimmunology, and elucidating the dual roles of CysLTs in chronic inflammation. It is indicated that CysLTs activate eosinophils, mast cells, and airway tuft cells, driving type 2 immune responses and mucus secretion in the lungs, thereby exacerbating respiratory diseases such as asthma. In the nervous system, CysLTs aggravate neurodegenerative disorders like cerebral ischemia and Alzheimer's disease by disrupting the blood-brain barrier, promoting glial activation, and inducing neuronal damage. In the gut, CysLTs regulate anti-helminth immunity via the tuft cell-ILC2 pathway and collaborate with prostaglandin D2 (PGD2) to modulate bile excretion and mucosal protection. Furthermore, CysLTs mediate communication through the gut-lung and gut-brain axes via metabolites such as succinate, contributing to cross-organ inflammatory regulation. In conclusion, this review highlights the complex roles of CysLTs in chronic inflammation, providing a theoretical foundation for precise intervention in multi-organ inflammatory diseases, which provides a theoretical framework for precision interventions in multi-organ inflammatory diseases and inspires interdisciplinary breakthroughs.
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Affiliation(s)
- Xiao-Ru Liu
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - Ming Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Qian-Qian Hao
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - Ya-Jie Yu
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - Cai Liao
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - Rui Yu
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
| | - De-Lei Kong
- Department of Respiratory and Critical Care Medicine, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yun Wang
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China
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Jiang M, Xu Y, Luan X, Wu K, Li Z, Xu HE, Zhang S, Jiang Y, Yin W. Structural basis of the cysteinyl leukotriene receptor type 2 activation by LTD4. Proc Natl Acad Sci U S A 2025; 122:e2417148122. [PMID: 40193607 PMCID: PMC12012480 DOI: 10.1073/pnas.2417148122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 02/18/2025] [Indexed: 04/09/2025] Open
Abstract
The G protein-coupled cysteinyl leukotriene receptor CysLT2R plays intricate roles in the physiology and pathogenesis of inflammation-related processes. It has garnered increasing attention as a potential therapeutic target for atopic asthma, brain injury, central nervous system disorders, and various types of cancer. In this study, we present the cryo-electron microscopy structure of the cysteinyl leukotriene D4 (LTD4)-bound human CysLT2R in complex with a Gαq protein, adopting an active conformation at a resolution of 3.15 Å. The structure elucidates a spacious polar pocket designed to accommodate the two branched negative ends of LTD4 and reveals a lateral ligand access route into the orthosteric pocket located on transmembrane domain helix (TM) 4 and 5. Furthermore, our findings highlight the crucial role of transmembrane domain helix 3 in sensing agonist moieties, representing the pivotal mechanism of receptor activation for both CysLT1R and CysLT2R. Collectively, the insights derived from our structural investigation establish a foundation for comprehending CysLT2R activation by its endogenous ligand LTD4, offering a rational basis for the design of drugs targeting CysLT2R.
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Affiliation(s)
- Mengting Jiang
- Lingang Laboratory, Shanghai200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai201210, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing210023, China
| | - Youwei Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Xiaodong Luan
- Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing100730, China
- Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing100730, China
| | - Kai Wu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Zhen Li
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing210023, China
| | - H. Eric Xu
- School of Life Science and Technology, ShanghaiTech University, Shanghai201210, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing210023, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- University of Chinese Academy of Sciences, Beijing100049, China
| | - Shuyang Zhang
- Department of Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing100730, China
- Center for Drug Research and Evaluation, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing100730, China
| | - Yi Jiang
- Lingang Laboratory, Shanghai200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai201210, China
| | - Wanchao Yin
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- University of Chinese Academy of Sciences, Beijing100049, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong528400, China
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3
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Keovilay JA, Howard KC, Taylor KA, Khan S, Wurl SE, Szahaj MK, Sage T, Chandrika NT, Hou C, Tsodikov OV, Gibbins JM, Garneau-Tsodikova S, Kennedy DR. Development of Zafirlukast Analogues for Improved Antithrombotic Activity Through Thiol Isomerase Inhibition. Arterioscler Thromb Vasc Biol 2025; 45:e136-e149. [PMID: 39973747 PMCID: PMC11945546 DOI: 10.1161/atvbaha.124.321579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 02/10/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Thiol isomerases play essential and nonredundant roles in platelet activation, aggregation, and thrombus formation. Thiol isomerase inhibitors have the potential to overcome the 2 major drawbacks of current antithrombotic therapies, as they target both arterial and venous thrombosis without enhancing bleeding risks. Recently, a Food and Drug Administration-approved drug, zafirlukast (ZAF), was shown to be a promising pan-thiol isomerase inhibitor. The objective of this study is to develop analogues of ZAF with optimized thiol isomerase inhibition and antithrombotic activity. METHODS Thirty-five ZAF analogues were tested in an insulin turbidometric assay for thiol isomerase inhibition. Analogues were tested for platelet activation, aggregation, P-selectin expression, and laser-induced thrombosis in mice and compared with the parent compound. RESULTS Of the 35 analogues, 12 retained activity, with 1, compound 21, that demonstrated a greater potency than that of ZAF, 5 had a similar potency to that of ZAF, and 6 had a weaker potency. Analogues demonstrated inhibition of platelet aggregation and P-selectin expression as compared with ZAF, consistent with their potencies. ZAF and compound 21 were shown to be reversible inhibitors of thiol isomerases, and not cytotoxic to cultured, lung, liver, and kidney cells. Finally, in an in vivo assessment of thrombus formation, compound 21 was able to significantly inhibit thrombus formation without affecting bleeding times. CONCLUSIONS A ZAF analogue, compound 21, with properties superior to those of ZAF was synthesized, demonstrating improved inhibition of platelet activation, aggregation, and thrombus formation as compared with the parent ZAF. This approach could yield a promising clinical candidate for treatment and prophylaxis of arterial and venous thrombosis.
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Affiliation(s)
- Justine A. Keovilay
- College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, 01119
- Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, UK, RG6 6EX
| | - Kaitlind C. Howard
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536
| | - Kirk A. Taylor
- Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, UK, RG6 6EX
| | - Sabeeya Khan
- Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, UK, RG6 6EX
| | - Sienna E. Wurl
- College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, 01119
| | - Melanie K. Szahaj
- College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, 01119
| | - Tanya Sage
- Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, UK, RG6 6EX
| | - Nishad Thamban Chandrika
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536
| | - Caixia Hou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536
| | - Oleg V. Tsodikov
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536
| | - Jonathan M. Gibbins
- Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, UK, RG6 6EX
| | - Sylvie Garneau-Tsodikova
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536
| | - Daniel R. Kennedy
- College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, 01119
- Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, UK, RG6 6EX
- Department of Medicine, UMass Chan Medical School-Baystate, Springfield, MA, 01655
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4
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Skevaki C, Tafo P, Bahmer T, Abdo M, Watz H, Pedersen F, Herzmann C, Rabe KF, Renz H, Nockher WA. Differential expression of eicosanoid pathways after whole blood stimulation in asthma patients. World Allergy Organ J 2025; 18:101047. [PMID: 40235674 PMCID: PMC11999605 DOI: 10.1016/j.waojou.2025.101047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/13/2025] [Accepted: 03/12/2025] [Indexed: 04/17/2025] Open
Abstract
Objectives Asthma is a heterogeneous disease regarding its pathophysiology, clinical symptoms, and response to treatment. Eicosanoids are important inflammatory mediators, able to either promote or attenuate the underlying chronic airway inflammation. We compared eicosanoid expression patterns in the blood circulation and in stimulated blood leukocytes of asthma patients to identify differences in eicosanoid release which may be related to airway inflammation. Methods Blood was collected from 198 adult asthmatic patients and 63 healthy controls, participating in the German Center for Lung Research (DZL) ALLIANCE cohort. Eicosanoid release from leukocytes was analyzed using heparinized whole blood after in vitro stimulation with zymosan. Additionally, circulating eicosanoids were measured directly from ethylenediaminetetraacetic acid (EDTA) plasma. Eicosanoids were extracted via solid phase extraction and quantified by high-performance-liquid-chromatography-tandem-mass-spectrometry (HPLC-MS2). Results Eicosanoid levels were low in blood circulation with no significant differences between asthmatics and controls, except for leukotriene E4 (LTE4) which was slightly elevated in asthmatics. After in vitro stimulation we observed an inhibition of prostaglandin and thromboxane biosynthesis only in patients with severe asthma which was related to the regular use of systemic corticosteroids. In contrast, a significant increase was shown for formation of the 5-Lipoxygenase (5-LOX) product LTE4 in steroid-naïve asthmatics with moderate as well as severe disease severity but not in subjects with systemic steroid treatment. Furthermore 15-Hydorxyeicosatetraenoic acid (15-HETE) production was elevated in asthmatic patients with mild-to-moderate disease activity but dropped down in severe asthmatics. Conclusions Profiling of eicosanoid production in stimulated whole blood samples showed a specific biosynthesis pattern of asthmatic patients, which is influenced by the use of systemic corticosteroids.
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Affiliation(s)
- Chrysanthi Skevaki
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps-University Marburg, University of Giessen Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Marburg, Germany
| | - Pavel Tafo
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps-University Marburg, University of Giessen Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Marburg, Germany
| | - Thomas Bahmer
- LungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
- Universitätsklinikum Schleswig-Holstein Campus Kiel, Internal Medicine Department I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Kiel, Germany
| | - Mustafa Abdo
- LungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Henrik Watz
- Pulmonary Research Institute at LungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Frauke Pedersen
- LungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Christian Herzmann
- Forschungszentrum Borstel, Klinisches Studienzentrum, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany
| | - Klaus F. Rabe
- LungenClinic Grosshansdorf GmbH, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps-University Marburg, University of Giessen Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Marburg, Germany
| | - Wolfgang Andreas Nockher
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps-University Marburg, University of Giessen Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Marburg, Germany
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5
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Thompson MD, Chidiac P, Jose PA, Hauser AS, Gorvin CM. Genetic variants of accessory proteins and G proteins in human genetic disease. Crit Rev Clin Lab Sci 2025; 62:113-134. [PMID: 39743506 PMCID: PMC11854058 DOI: 10.1080/10408363.2024.2431853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/14/2024] [Accepted: 11/16/2024] [Indexed: 01/04/2025]
Abstract
We present a series of three articles on the genetics and pharmacogenetics of G protein- coupled receptors (GPCR). In the first article, we discuss genetic variants of the G protein subunits and accessory proteins that are associated with human phenotypes; in the second article, we build upon this to discuss "G protein-coupled receptor (GPCR) gene variants and human genetic disease" and in the third article, we survey "G protein-coupled receptor pharmacogenomics". In the present article, we review the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane in the context of human genetic disease resulting from pathogenic variants of accessory proteins and G proteins. Pathogenic variants of the genes encoding G protein α and β subunits are examined in diverse phenotypes. Variants in the genes encoding accessory proteins that modify or organize G protein coupling have been associated with disease; these include the contribution of variants of the regulator of G protein signaling (RGS) to hypertension; the role of variants of activator of G protein signaling type III in phenotypes such as hypoxia; the contribution of variation at the RGS10 gene to short stature and immunological compromise; and the involvement of variants of G protein-coupled receptor kinases (GRKs), such as GRK4, in hypertension. Variation in genes that encode proteins involved in GPCR signaling are outlined in the context of the changes in structure and function that may be associated with human phenotypes.
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Affiliation(s)
- Miles D. Thompson
- Krembil Brain Institute, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Peter Chidiac
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Pedro A. Jose
- Division of Renal Diseases & Hypertension, Departments of Medicine and Pharmacology/Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Alexander S. Hauser
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Caroline M. Gorvin
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, West Midlands, UK
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Thoma G, Miltz W, Waelchli R, Orain D, Spanka C, Decoret O, Wolf RM, Hurley B, Cheung AK, Sandham DA, Honda A, Tichkule R, Chen X, Patel T, Labbe-Giguere N, Tan KL, Springer C, Manchester J, Culshaw AJ, Hunt P, Srinivas H, Penno CA, Ferrand S, Numao S, Schopfer U, Jäger P, Wack N, Hasler F, Urban B, Sindelar M, Loetscher P, Kiffe M, Ren X, Nicklin P, White K, Subramanian K, Liu H, Growcott EJ, Röhn TA. Discovery of GJG057, a Potent and Highly Selective Inhibitor of Leukotriene C4 Synthase. J Med Chem 2025; 68:4721-4742. [PMID: 39960261 DOI: 10.1021/acs.jmedchem.4c02897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.
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Affiliation(s)
- Gebhard Thoma
- Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Wolfgang Miltz
- Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Rudolf Waelchli
- Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - David Orain
- Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Carsten Spanka
- Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Odile Decoret
- Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Romain M Wolf
- Global Discovery Chemistry, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Brian Hurley
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Atwood K Cheung
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - David A Sandham
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Ayako Honda
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Ritesh Tichkule
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Xin Chen
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Tajesh Patel
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Nancy Labbe-Giguere
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Kian L Tan
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Clayton Springer
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - John Manchester
- Global Discovery Chemistry, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Andrew J Culshaw
- Global Discovery Chemistry, Novartis Horsham Research Centre, Horsham, West Sussex RH12 5AB, U.K
| | - Peter Hunt
- Global Discovery Chemistry, Novartis Horsham Research Centre, Horsham, West Sussex RH12 5AB, U.K
| | - Honnappa Srinivas
- Discovery Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Carlos A Penno
- Discovery Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Sandrine Ferrand
- Discovery Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Shin Numao
- Discovery Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Ulrich Schopfer
- Discovery Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Petra Jäger
- Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Nathalie Wack
- Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Franziska Hasler
- Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Beatrice Urban
- Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Miriam Sindelar
- Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Pius Loetscher
- Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Michael Kiffe
- PK Sciences, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
| | - Xiaojun Ren
- PK Sciences, Biomedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey 07936, United States
| | - Paul Nicklin
- Respiratory Disease Area, Novartis Horsham Research Centre, Horsham, West Sussex RH12 5AB, U.K
| | - Kevin White
- Global Health Disease Area, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Khaushik Subramanian
- Global Health Disease Area, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Haoyuan Liu
- Global Health Disease Area, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Ellena J Growcott
- Global Health Disease Area, Biomedical Research, Novartis Pharmaceuticals, Cambridge, Massachusetts 02139, United States
| | - Till A Röhn
- Immunology Disease Area, Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland
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7
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Liang Y, Zhang Q, Fan Y. Research progress of knee fibrosis after anterior cruciate ligament reconstruction. Front Pharmacol 2024; 15:1493155. [PMID: 39498335 PMCID: PMC11533135 DOI: 10.3389/fphar.2024.1493155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 10/08/2024] [Indexed: 11/07/2024] Open
Abstract
Anterior cruciate ligament (ACL) injury is a common sports injury, and ACL reconstruction is an effective surgery for this trauma. Most cases gain good recovery after surgery, while some patients may experience knee stiffness, which is characterized by joint fibrosis, leading to reduced joint mobility, pain, and dysfunction. Currently, various research studies have been conducted to unveil the mechanisms underlying this condition, identifying pre-, intra-, and post-operative risk factors, and testify the efficacy of different therapeutic methods against it. In this review, we summarize the current progress regarding the advancements in knee fibrosis after ACL reconstruction. The risk factors associated with knee fibrosis are systematically delineated, accompanied by an evaluation of the efficacy of various treatment modalities for both the prevention and mitigation of fibrosis. Furthermore, recommendations for future research directions are proposed, offering a foundational basis for subsequent investigations.
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Affiliation(s)
- YangYang Liang
- Department of Sports Trauma and Arthroscopic Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
| | - QingQing Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
| | - YouFei Fan
- Department of Sports Trauma and Arthroscopic Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
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8
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Sood R, Anoopkumar-Dukie S, Rudrawar S, Hall S. Neuromodulatory effects of leukotriene receptor antagonists: A comprehensive review. Eur J Pharmacol 2024; 978:176755. [PMID: 38909933 DOI: 10.1016/j.ejphar.2024.176755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/09/2024] [Accepted: 06/16/2024] [Indexed: 06/25/2024]
Abstract
Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively treat respiratory conditions by targeting cysteinyl leukotriene receptors, CysLT1 and CysLT2 subtypes. This review explores the multifaceted effects of LTs, extending beyond bronchoconstriction. CysLT receptors are not only present in the respiratory system but are also crucial in neuronal signaling pathways. LTRAs modulate these receptors, influencing downstream signaling, calcium levels, inflammation, and oxidative stress (OS) within neurons hinting at broader implications. Recent studies identify novel molecular targets, sparking interest in repurposing LTRAs for therapeutic use. Clinical trials are investigating their potential in neuroinflammation control, particularly in Alzheimer's disease (AD) and Parkinson's diseases (PD). However, montelukast, a long-standing LTRA since 1998, raises concerns due to neuropsychiatric adverse drug reactions (ADRs). Despite widespread use, understanding montelukast's metabolism and underlying ADR mechanisms remains limited. This review comprehensively examines LTRAs' diverse biological effects, emphasizing non-bronchoconstrictive activities. It also analyses plausible mechanisms behind LTRAs' neuronal effects, offering insights into their potential as neurodegenerative disease modulators. The aim is to inform clinicians, researchers, and pharmaceutical developers about LTRAs' expanding roles, particularly in neuroinflammation control and their promising repurposing for neurodegenerative disease management.
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Affiliation(s)
- Radhika Sood
- School of Pharmacy and Medical Sciences, Griffith University, Queensland, 4222, Australia
| | | | - Santosh Rudrawar
- School of Pharmacy and Medical Sciences, Griffith University, Queensland, 4222, Australia; Institute for Glycomics, Griffith University, Queensland, 4222, Australia
| | - Susan Hall
- School of Pharmacy and Medical Sciences, Griffith University, Queensland, 4222, Australia.
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Mosala P, Mpotje T, Abdel Aziz N, Ndlovu H, Musaigwa F, Nono JK, Brombacher F. Cysteinyl leukotriene receptor-1 as a potential target for host-directed therapy during chronic schistosomiasis in murine model. Front Immunol 2024; 15:1279043. [PMID: 38840916 PMCID: PMC11150569 DOI: 10.3389/fimmu.2024.1279043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 04/25/2024] [Indexed: 06/07/2024] Open
Abstract
Schistosomiasis remains the most devastating neglected tropical disease, affecting over 240 million people world-wide. The disease is caused by the eggs laid by mature female worms that are trapped in host's tissues, resulting in chronic Th2 driven fibrogranulmatous pathology. Although the disease can be treated with a relatively inexpensive drug, praziquantel (PZQ), re-infections remain a major problem in endemic areas. There is a need for new therapeutic drugs and alternative drug treatments for schistosomiasis. The current study hypothesized that cysteinyl leukotrienes (cysLTs) could mediate fibroproliferative pathology during schistosomiasis. Cysteinyl leukotrienes (cysLTs) are potent lipid mediators that are known to be key players in inflammatory diseases, such as asthma and allergic rhinitis. The present study aimed to investigate the role of cysLTR1 during experimental acute and chronic schistosomiasis using cysLTR1-/- mice, as well as the use of cysLTR1 inhibitor (Montelukast) to assess immune responses during chronic Schistosoma mansoni infection. Mice deficient of cysLTR1 and littermate control mice were infected with either high or low dose of Schistosoma mansoni to achieve chronic or acute schistosomiasis, respectively. Hepatic granulomatous inflammation, hepatic fibrosis and IL-4 production in the liver was significantly reduced in mice lacking cysLTR1 during chronic schistosomiasis, while reduced liver pathology was observed during acute schistosomiasis. Pharmacological blockade of cysLTR1 using montelukast in combination with PZQ reduced hepatic inflammation and parasite egg burden in chronically infected mice. Combination therapy led to the expansion of Tregs in chronically infected mice. We show that the disruption of cysLTR1 is dispensable for host survival during schistosomiasis, suggesting an important role cysLTR1 may play during early immunity against schistosomiasis. Our findings revealed that the combination of montelukast and PZQ could be a potential prophylactic treatment for chronic schistosomiasis by reducing fibrogranulomatous pathology in mice. In conclusion, the present study demonstrated that cysLTR1 is a potential target for host-directed therapy to ameliorate fibrogranulomatous pathology in the liver during chronic and acute schistosomiasis in mice.
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Affiliation(s)
- Paballo Mosala
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
| | - Thabo Mpotje
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
| | - Nada Abdel Aziz
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Immuno-Biotechnology Lab, Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Hlumani Ndlovu
- Division of Chemical and System Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Fungai Musaigwa
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
| | - Justin Komguep Nono
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Unit of Immunobiology and Helminth Infections, Laboratory of Molecular Biology and Biotechnology, Institute of Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and Innovation, Yaoundé, Cameroon
| | - Frank Brombacher
- Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Welcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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Ngoufack Azanze E, Mbiantcha M, Madjo KYK, Yousseu NW, Fagni Njoya ZL, Adjouzem CF, Matah Marthe VM, Ateufack G. Markhamia lutea leaves aqueous and ethanolic extract with curative anti-inflammatory activity attenuates paclitaxel toxicity in rat's intestine. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2024; 21:1-13. [PMID: 37207283 DOI: 10.1515/jcim-2023-0017] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 05/05/2023] [Indexed: 05/21/2023]
Abstract
OBJECTIVES Markhamia lutea (M. lutea, Bignoniaceae) is mainly found in tropical/neotropical regions of America, Africa and Asia. The plant's leaves, stems or roots are used to treat anaemia, bloody diarrhoea, parasitic and microbial infections. This study evaluates anti-inflammatory properties (in vitro) of Markhamia lutea and their curative effects on paclitaxel-induced intestinal toxicity (in vivo). METHODS The anti-inflammatory potential of Markhamia lutea was tested over cytokines (TNF-alpha, IL-6, IL-1β, IL-10), reactive oxygen species (ROS) and enzymes (cyclooxygenase and 5-lipoxygenase). While in vivo, intestinal toxicity was induced for 10 days by oral administration of paclitaxel (3 mg/kg, 0.05 mL). Animals in each group were further treated with aqueous (300 mg/kg) and ethanolic (300 mg/kg) leaves extracts of Markhamia lutea during 7 days and clinical symptoms were recorded, hematological, biochemical and histological analysis were subsequently performed. RESULTS In vitro, aqueous (250 μg/mL) and ethanolic (250 μg/mL) extracts of Markhamia lutea inhibited the activities of cyclooxygenase 1 (56.67 % and 69.38 %), cyclooxygenase 2 (50.67 % and 62.81 %) and 5-lipoxygenase (77.33 % and 86.00 %). These extracts inhibited the production of intracellular ROS, extracellular ROS and cell proliferation with maximum IC50 of 30.83 μg/mL, 38.67 μg/mL and 19.05 μg/mL respectively for the aqueous extract, then 25.46 μg/mL, 27.64 μg/mL and 7.34 μg/mL respectively for the ethanolic extract. The extracts also inhibited the production of proinflammatory cytokines (TNFα, IL-1β and IL-6) and stimulated the production of anti-inflammatory cytokines (IL-10). In vivo, after administration of paclitaxel, the aqueous and ethanolic extracts of Markhamia lutea significantly reduced the weight loss, the diarrheal stools and the mass/length intestines ratio of the treated animals compared to the animals of the negative control group. Biochemically, the extracts lead to a significant drop in serum creatinine and alanine aminotransferase levels, followed by a significant increase in alkaline phosphatase. In addition to bringing the haematological parameters back to normal values after disturbance by paclitaxel, the extracts caused tissue regeneration in the treated animals. CONCLUSIONS In vitro, aqueous and ethanolic extracts of Markhamia lutea showed anti-inflammatory properties (inhibition of COX1, COX2, 5-LOX activities, inhibition of ROS production and cell proliferation); in vivo, the same extracts showed curative properties against intestinal toxicity caused by paclitaxel.
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Affiliation(s)
- Elvira Ngoufack Azanze
- Laboratory of Animal Physiology and Phytopharmacology, Faculty of Science, University of Dschang, Douala, Cameroon
| | - Marius Mbiantcha
- Laboratory of Animal Physiology and Phytopharmacology, Faculty of Science, University of Dschang, Douala, Cameroon
| | - Kouam Yacine Karelle Madjo
- Laboratory of Animal Physiology and Phytopharmacology, Faculty of Science, University of Dschang, Douala, Cameroon
| | - Nana Willaim Yousseu
- Laboratory of Biology and Physiology of Animal Organisms, Department of Biology of Animal Organisms, Faculty of Science, The University of Douala Cameroon, Douala, Cameroon
| | - Zenab Linda Fagni Njoya
- Laboratory of Animal Physiology and Phytopharmacology, Faculty of Science, University of Dschang, Douala, Cameroon
| | - Carine Flore Adjouzem
- Laboratory of Animal Physiology and Phytopharmacology, Faculty of Science, University of Dschang, Douala, Cameroon
| | - Vanessa Mba Matah Marthe
- Laboratory of Animal Physiology and Phytopharmacology, Faculty of Science, University of Dschang, Douala, Cameroon
| | - Gilbert Ateufack
- Laboratory of Animal Physiology and Phytopharmacology, Faculty of Science, University of Dschang, Douala, Cameroon
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Luginina A, Gusach A, Lyapina E, Khorn P, Safronova N, Shevtsov M, Dmitirieva D, Dashevskii D, Kotova T, Smirnova E, Borshchevskiy V, Cherezov V, Mishin A. Structural diversity of leukotriene G-protein coupled receptors. J Biol Chem 2023; 299:105247. [PMID: 37703990 PMCID: PMC10570957 DOI: 10.1016/j.jbc.2023.105247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023] Open
Abstract
Dihydroxy acid leukotriene (LTB4) and cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway. While structurally similar, these two types of leukotrienes (LTs) exert their functions through interactions with two distinct G protein-coupled receptor (GPCR) families, BLT and CysLT receptors, which share low sequence similarity and belong to phylogenetically divergent GPCR groups. Selective antagonism of LT receptors has been proposed as a promising strategy for the treatment of many inflammation-related diseases including asthma and chronic obstructive pulmonary disease, rheumatoid arthritis, cystic fibrosis, diabetes, and several types of cancer. Selective CysLT1R antagonists are currently used as antiasthmatic drugs, however, there are no approved drugs targeting CysLT2 and BLT receptors. In this review, we highlight recently published structures of BLT1R and CysLTRs revealing unique structural features of the two receptor families. X-ray and cryo-EM data shed light on their overall conformations, differences in functional motifs involved in receptor activation, and details of the ligand-binding pockets. An unexpected binding mode of the selective antagonist BIIL260 in the BLT1R structure makes it the first example of a compound targeting the sodium-binding site of GPCRs and suggests a novel strategy for the receptor activity modulation. Taken together, these recent structural data reveal dramatic differences in the molecular architecture of the two LT receptor families and pave the way to new therapeutic strategies of selective targeting individual receptors with novel tool compounds obtained by the structure-based drug design approach.
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Affiliation(s)
- Aleksandra Luginina
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Anastasiia Gusach
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Elizaveta Lyapina
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Polina Khorn
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Nadezda Safronova
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Mikhail Shevtsov
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Daria Dmitirieva
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Dmitrii Dashevskii
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Tatiana Kotova
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Ekaterina Smirnova
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Valentin Borshchevskiy
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia; Joint Institute for Nuclear Research, Dubna, Russia
| | - Vadim Cherezov
- Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California, USA.
| | - Alexey Mishin
- Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
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12
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Brunner SM, Schrödl F, Preishuber-Pflügl J, Runge C, Koller A, Lenzhofer M, Reitsamer HA, Trost A. Distribution of the cysteinyl leukotriene system components in the human, rat and mouse eye. Exp Eye Res 2023; 232:109517. [PMID: 37211287 DOI: 10.1016/j.exer.2023.109517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/18/2023] [Indexed: 05/23/2023]
Abstract
The cysteinyl leukotrienes (CysLTs) have important functions in the regulation of inflammation and cellular stress. Blocking the CysLT receptors (CysLTRs) with specific antagonists is beneficial against progression of retinopathies (e.g. diabetic retinopathy, wet AMD). However, the exact cellular localization of the CysLTRs and their endogenous ligands in the eye have not been elucidated in detail yet. It is also not known whether the expression patterns differ between humans and animal models. Therefore, the present study aimed to describe and compare the distribution of two important enzymes in CysLT biosynthesis, 5-lipoxygenase (5-LOX) and 5-lipoxygenase-activating protein (FLAP), and of CysLTR1 and CysLTR2 in healthy human, rat and mouse eyes. Human donor eyes (n = 10) and eyes from adult Sprague Dawley rats (n = 5) and CD1 mice (n = 8) of both sexes were collected. The eyes were fixed in 4% paraformaldehyde and cross-sections were investigated by immunofluorescence with specific antibodies against 5-LOX, FLAP (human tissue only), CysLTR1 and CysLTR2. Flat-mounts of the human choroid were prepared and processed similarly. Expression patterns were assessed and semiquantitatively evaluated using a confocal fluorescence microscope (LSM710, Zeiss). We observed so far unreported expression sites for CysLT system components in various ocular tissues. Overall, we detected expression of 5-LOX, CysLTR1 and CysLTR2 in the human, rat and mouse cornea, conjunctiva, iris, lens, ciliary body, retina and choroid. Importantly, expression profiles of CysLTR1 and CysLTR2 were highly similar between human and rodent eyes. FLAP was expressed in all human ocular tissues except the lens. Largely weak immunoreactivity of FLAP and 5-LOX was observed in a few, yet unidentified, cells of diverse ocular tissues, indicating low levels of CysLT biosynthesis in healthy eyes. CysLTR1 was predominantly detected in ocular epithelial cells, supporting the involvement of CysLTR1 in stress and immune responses. CysLTR2 was predominantly expressed in neuronal structures, suggesting neuromodulatory roles of CysLTR2 in the eye and revealing disparate functions of CysLTRs in ocular tissues. Taken together, we provide a comprehensive protein expression atlas of CysLT system components in the human and rodent eye. While the current study is purely descriptive and therefore does not allow significant functional conclusions yet, it represents an important basis for future studies in diseased ocular tissues in which distribution patterns or expression levels of the CysLT system might be altered. Furthermore, this is the first comprehensive study to elucidate expression patterns of CysLT system components in human and animal models that will help to identify and understand functions of the system as well as mechanisms of action of potential CysLTR ligands in the eye.
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Affiliation(s)
- Susanne M Brunner
- Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
| | - Falk Schrödl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.
| | - Julia Preishuber-Pflügl
- Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
| | - Christian Runge
- Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria; Cornea Eye Bank, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
| | - Andreas Koller
- Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
| | - Markus Lenzhofer
- Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
| | - Herbert A Reitsamer
- Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria; Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
| | - Andrea Trost
- Research Program for Experimental Ophthalmology and Glaucoma Research, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
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13
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Satapathy SR, Ghatak S, Sjölander A. The tumor promoter cysteinyl leukotriene receptor 1 regulates PD-L1 expression in colon cancer cells via the Wnt/β-catenin signaling axis. Cell Commun Signal 2023; 21:138. [PMID: 37316937 DOI: 10.1186/s12964-023-01157-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 05/01/2023] [Indexed: 06/16/2023] Open
Abstract
Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a subset of patients benefit from PD-1/PD-L1 treatment. Previously, we showed that high cysteinyl leukotriene receptor 1 (CysLT1R) levels are associated with poor prognosis in CRC patients. Recently, we have revealed the role of the tumor promoter CysLT1R in drug resistance and stemness in colon cancer (CC) cells. Here, we show the role of the CysLT1R/Wnt/β-catenin signaling axis in the regulation of PD-L1 using both in vitro and in vivo preclinical model systems. Interestingly, we found that both endogenous and IFNγ-induced PD-L1 expression in CC cells is mediated through upregulation of CysLT1R, which enhances Wnt/β-catenin signaling. Therapeutic targeting of CysLT1R with its antagonist montelukast (Mo), as well as CRISPR/Cas9-mediated or doxycycline-inducible functional absence of CysLT1R, negatively regulated PD-L1 expression in CC cells. Interestingly, an anti-PD-L1 neutralizing antibody exhibited stronger effects together with the CysLT1R antagonist in cells (Apcmut or CTNNB1mut) with either endogenous or IFNγ-induced PD-L1 expression. Additionally, mice treated with Mo showed depletion of PD-L1 mRNA and protein. Moreover, in CC cells with combined treatment of a Wnt inhibitor and an anti-PD-L1 antibody was effective only in β-catenin-dependent (APCmut) context. Finally, analysis of public dataset showed positive correlations between the PD-L1 and CysLT1R mRNA levels. These results elucidate a previously underappreciated CysLT1R/Wnt/β-catenin signaling pathway in the context of PD-L1 inhibition in CC, which might be considered for improving the efficacy of anti-PD-L1 therapy in CC patients. Video Abstract.
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Affiliation(s)
- Shakti Ranjan Satapathy
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Center, Lund University, Skåne University Hospital, Jan Waldenströms Gata 35, 205 02, Malmö, Sweden.
| | - Souvik Ghatak
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Center, Lund University, Skåne University Hospital, Jan Waldenströms Gata 35, 205 02, Malmö, Sweden
| | - Anita Sjölander
- Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Center, Lund University, Skåne University Hospital, Jan Waldenströms Gata 35, 205 02, Malmö, Sweden.
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14
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Stanger L, Holinstat M. Bioactive lipid regulation of platelet function, hemostasis, and thrombosis. Pharmacol Ther 2023; 246:108420. [PMID: 37100208 PMCID: PMC11143998 DOI: 10.1016/j.pharmthera.2023.108420] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/15/2023] [Accepted: 04/17/2023] [Indexed: 04/28/2023]
Abstract
Platelets are small, anucleate cells in the blood that play a crucial role in the hemostatic response but are also implicated in the pathophysiology of cardiovascular disease. It is widely appreciated that polyunsaturated fatty acids (PUFAs) play an integral role in the function and regulation of platelets. PUFAs are substrates for oxygenase enzymes cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LOX), 12-lipoxygenase (12-LOX) and 15-lipoxygenase (15-LOX). These enzymes generate oxidized lipids (oxylipins) that exhibit either pro- or anti-thrombotic effects. Although the effects of certain oxylipins, such as thromboxanes and prostaglandins, have been studied for decades, only one oxylipin has been therapeutically targeted to treat cardiovascular disease. In addition to the well-known oxylipins, newer oxylipins that demonstrate activity in the platelet have been discovered, further highlighting the expansive list of bioactive lipids that can be used to develop novel therapeutics. This review outlines the known oxylipins, their activity in the platelet, and current therapeutics that target oxylipin signaling.
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Affiliation(s)
- Livia Stanger
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States of America
| | - Michael Holinstat
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States of America; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, United States of America.
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15
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Abstract
Kidney disease is associated with adverse consequences in many organs beyond the kidney, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies reveal that kidney injury expands the intestinal lymphatics, increases lymphatic flow, and alters the composition of mesenteric lymph. The intestinal lymphatics, like blood vessels, are a route for transporting potentially harmful substances generated by the intestines. The lymphatic architecture and actions are uniquely suited to take up and transport large macromolecules, functions that differentiate them from blood vessels, allowing them to play a distinct role in a variety of physiological and pathological processes. Here, we focus on the mechanisms by which kidney diseases result in deleterious changes in intestinal lymphatics and consider a novel paradigm of a vicious cycle of detrimental organ cross talk. This concept involves kidney injury-induced modulation of intestinal lymphatics that promotes production and distribution of harmful factors, which in turn contributes to disease progression in distant organ systems.
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Affiliation(s)
- Jianyong Zhong
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Annet Kirabo
- Department of Molecular Physiology and Biophysics (A.K.), Vanderbilt University Medical Center, Nashville, TN
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (A.K.)
| | - Hai-Chun Yang
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Agnes B. Fogo
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
- Department of Medicine (A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Elaine L. Shelton
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
| | - Valentina Kon
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
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Korbecki J, Rębacz-Maron E, Kupnicka P, Chlubek D, Baranowska-Bosiacka I. Synthesis and Significance of Arachidonic Acid, a Substrate for Cyclooxygenases, Lipoxygenases, and Cytochrome P450 Pathways in the Tumorigenesis of Glioblastoma Multiforme, Including a Pan-Cancer Comparative Analysis. Cancers (Basel) 2023; 15:cancers15030946. [PMID: 36765904 PMCID: PMC9913267 DOI: 10.3390/cancers15030946] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive gliomas. New and more effective therapeutic approaches are being sought based on studies of the various mechanisms of GBM tumorigenesis, including the synthesis and metabolism of arachidonic acid (ARA), an omega-6 polyunsaturated fatty acid (PUFA). PubMed, GEPIA, and the transcriptomics analysis carried out by Seifert et al. were used in writing this paper. In this paper, we discuss in detail the biosynthesis of this acid in GBM tumors, with a special focus on certain enzymes: fatty acid desaturase (FADS)1, FADS2, and elongation of long-chain fatty acids family member 5 (ELOVL5). We also discuss ARA metabolism, particularly its release from cell membrane phospholipids by phospholipase A2 (cPLA2, iPLA2, and sPLA2) and its processing by cyclooxygenases (COX-1 and COX-2), lipoxygenases (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2), and cytochrome P450. Next, we discuss the significance of lipid mediators synthesized from ARA in GBM cancer processes, including prostaglandins (PGE2, PGD2, and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2)), thromboxane A2 (TxA2), oxo-eicosatetraenoic acids, leukotrienes (LTB4, LTC4, LTD4, and LTE4), lipoxins, and many others. These lipid mediators can increase the proliferation of GBM cancer cells, cause angiogenesis, inhibit the anti-tumor response of the immune system, and be responsible for resistance to treatment.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Ewa Rębacz-Maron
- Department of Ecology and Anthropology, Institute of Biology, University of Szczecin, Wąska 13, 71-415 Szczecin, Poland
| | - Patrycja Kupnicka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland
- Correspondence: ; Tel.: +48-914-661-515
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17
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Figueroa EE, Denton JS. A SWELL time to develop the molecular pharmacology of the volume-regulated anion channel (VRAC). Channels (Austin) 2022; 16:27-36. [PMID: 35114895 PMCID: PMC8820792 DOI: 10.1080/19336950.2022.2033511] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 12/16/2022] Open
Abstract
Newly emerging roles of LRRC8 volume-regulated anion channels (VRAC) raise important questions about the therapeutic potential of VRAC in the treatment of epilepsy, type 2 diabetes, and other human diseases. A critical barrier to evaluating whether VRAC represents a viable drug target is the lack of potent and specific small-molecule inhibitors and activators of the channel. Here we review recent progress in developing the molecular pharmacology of VRAC made by screening a library of FDA-approved drugs for novel channel modulators. We discuss the discovery and characterization of cysteinyl leukotriene receptor antagonists Pranlukast and Zafirlukast as novel VRAC inhibitors, and zinc pyrithione (ZPT), which apparently activates VRAC through a reactive oxygen species (ROS)-dependent mechanism. These ongoing efforts set the stage for developing a pharmacological toolkit for probing the integrative physiology, molecular pharmacology, and therapeutic potential of VRAC.
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Affiliation(s)
- Eric E. Figueroa
- Department of Physiology, University of California San Francisco, San Francisco, CA, USA
- Department of Pharmacology, Vanderbilt University, Vanderbilt Institute of Chemical Biology, Nashville, TN, USA
| | - Jerod S. Denton
- Department of Pharmacology, Vanderbilt University, Vanderbilt Institute of Chemical Biology, Nashville, TN, USA
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
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18
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Fujisawa S, Nagata Y, Suzuki R. Leukotriene D4 accelerates antigen-mediated mast cell responses via the cysteinyl leukotriene 1 receptor. Cell Immunol 2022; 382:104632. [PMID: 36274438 DOI: 10.1016/j.cellimm.2022.104632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/01/2022] [Accepted: 10/11/2022] [Indexed: 01/13/2023]
Abstract
Cysteinyl leukotrienes (CysLTs), released from mast cells (MCs), are important mediators in allergy. Type 1 receptors for CysLTs (CysLT1R) are involved in accelerating IgE-mediated MC activation. In this study, we aimed to elucidate the mechanisms underlying CysLT1R-mediated MC activation. The CysLT1R agonist/antagonist was applied to two types of major MC models-RBL-2H3 cells and bone marrow-derived MCs (BMMCs). The use of CysLT1R and CysLT2R inhibitors revealed that CysLT1R plays a major role in the acceleration of MC activation. The administration of the CysLT1R agonist leukotriene D4 upregulated IgE-mediated Akt and ERK phosphorylation and subsequently enhanced TNF-α expression, suggesting that CysLT1R regulates the downstream pathway of MC activation. However, these observations were not corroborated by CysLT1R knockdown using shRNA, suggesting a differential regulatory mechanism between the temporal and constitutive inhibitions of CysLT. In conclusion, CysLT1R enhances MC activation by accelerating IgE-induced signal transduction, which enables the co-regulation of rapid degranulation and delayed synthesis of inflammatory mediators in MCs.
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Affiliation(s)
- Sakura Fujisawa
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Ishikawa 920-1192, Japan
| | - Yuka Nagata
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Ishikawa 920-1192, Japan
| | - Ryo Suzuki
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Ishikawa 920-1192, Japan.
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19
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Blockade of Platelet CysLT1R Receptor with Zafirlukast Counteracts Platelet Protumoral Action and Prevents Breast Cancer Metastasis to Bone and Lung. Int J Mol Sci 2022; 23:ijms232012221. [PMID: 36293074 PMCID: PMC9603002 DOI: 10.3390/ijms232012221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/06/2022] [Accepted: 10/11/2022] [Indexed: 11/26/2022] Open
Abstract
Metastases are the main cause of death in cancer patients, and platelets are largely known for their contribution in cancer progression. However, targeting platelets is highly challenging given their paramount function in hemostasis. Using a high-throughput screening and platelet-induced breast tumor cell survival (PITCS) assay as endpoint, we identified the widely used anti-asthmatic drugs and cysteinyl leukotriene receptor 1 (CysLT1R) antagonists, zafirlukast and montelukast, as new specific blockers of platelet protumoral action. Here, we show that human MDA-B02 breast cancer cells produce CysLT through mechanisms involving microsomal glutathione-S-transferase 1/2/3 (MGST1/2/3) and that can modulate cancer cell–platelet interactions via platelet–CysLT1R. CysLT1R blockade with zafirlukast decreased platelet aggregation and adhesion on cancer cells and inhibited PITCS, migration, and invasion in vitro. Zafirlukast significantly reduced, by 90%, MDA-B02 cell dissemination to bone in nude mice and reduced by 88% 4T1 spontaneous lung metastasis formation without affecting primary tumor growth. Combined treatment of zafirlukast plus paclitaxel totally inhibited metastasis of 4T1 cells to the lungs. Altogether, our results reveal a novel pathway mediating the crosstalk between cancer cells and platelets and indicate that platelet CysLT1R represents a novel therapeutic target to prevent metastasis without affecting hemostasis.
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20
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Marques CF, Marques MM, Justino GC. Leukotrienes vs. Montelukast—Activity, Metabolism, and Toxicity Hints for Repurposing. Pharmaceuticals (Basel) 2022; 15:ph15091039. [PMID: 36145259 PMCID: PMC9505853 DOI: 10.3390/ph15091039] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/17/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
Increasing environmental distress is associated with a growing asthma incidence; no treatments are available but montelukast (MTK)—an antagonist of the cysteinyl leukotrienes receptor 1—is widely used in the management of symptoms among adults and children. Recently, new molecular targets have been identified and MTK has been proposed for repurposing in other therapeutic applications, with several ongoing clinical trials. The proposed applications include neuroinflammation control, which could be explored in some neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (AD and PD). However, this drug has been associated with an increasing number of reported neuropsychiatric adverse drug reactions (ADRs). Besides, and despite being on the market since 1998, MTK metabolism is still poorly understood and the mechanisms underlying neuropsychiatric ADRs remain unknown. We review the role of MTK as a modulator of leukotriene pathways and systematize the current knowledge about MTK metabolism. Known toxic effects of MTK are discussed, and repurposing applications are presented comprehensively, with a focus on AD and PD.
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Affiliation(s)
- Cátia F. Marques
- Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
| | - Maria Matilde Marques
- Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
- Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
| | - Gonçalo C. Justino
- Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
- Correspondence:
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21
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Carion TW, Wang Y, Stambersky A, Ebrahim AS, Berger EA. A Dual Role for Cysteinyl Leukotriene Receptors in the Pathogenesis of Corneal Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:2331-2342. [PMID: 35470258 PMCID: PMC9117469 DOI: 10.4049/jimmunol.2100474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 03/12/2022] [Indexed: 05/17/2023]
Abstract
Cysteinyl leukotrienes (CysLTs) have been defined as central mediators of inflammation. Despite our extensive understanding of these bioactive lipid mediators in the pathogenesis of diseases such as asthma, allergic rhinitis, and even neurological disorders, information regarding the eye is markedly lacking. As a result, this study examined the expression profiles of two major CysLT receptors, CysLT1 and CysLT2, in the cornea using experimental mouse models of Pseudomonas aeruginosa-induced keratitis with contrasting outcomes: susceptible C57BL/6 (B6) and resistant BALB/c. Postinfection, disparate levels of CysLT receptors were accompanied by distinct expression profiles for select proinflammatory and anti-inflammatory cell surface markers detected on macrophages and polymorphonuclear neutrophils between the two strains. Further, inhibition of either CysLT receptor converted the disease response of both strains, where corneal perforation was prevented in B6 mice, and BALB/c mice fared significantly worse. In addition, receptor antagonist studies revealed changes in inflammatory cell infiltrate phenotypes and an influence on downstream CysLT receptor signaling pathways. Although the B6 mouse model highlights the established proinflammatory activities related to CysLT receptor activation, results generated from BALB/c mice indicate a protective mechanism that may be essential to disease resolution. Further, basal expression levels of CysLT1 and CysLT2 were significantly higher in uninfected corneas of both mouse strains as opposed to during infection, suggestive of a novel role in homeostatic maintenance within the eye. In light of these findings, therapeutic targeting of CysLT receptors extends beyond inhibition of proinflammatory activities and may impact inflammation resolution, as well as corneal surface homeostasis.
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Affiliation(s)
- Thomas W Carion
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI
| | - Yuxin Wang
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI
| | - Ashten Stambersky
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI
| | - Abdul Shukkur Ebrahim
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI
| | - Elizabeth A Berger
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI
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22
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Chen H, Huang W, Li X. Structures of oxysterol sensor EBI2/GPR183, a key regulator of the immune response. Structure 2022; 30:1016-1024.e5. [DOI: 10.1016/j.str.2022.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/23/2022] [Accepted: 04/13/2022] [Indexed: 12/11/2022]
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23
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Wolf C, Smith S, van Wijk SJL. Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells. Int J Mol Sci 2022; 23:ijms23073567. [PMID: 35408930 PMCID: PMC8999127 DOI: 10.3390/ijms23073567] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 02/01/2023] Open
Abstract
Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.
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24
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Fujimori K, Uno S, Kuroda K, Matsumoto C, Maehara T. Leukotriene C 4 synthase is a novel PPARγ target gene, and leukotriene C 4 and D 4 activate adipogenesis through cysteinyl LT1 receptors in adipocytes. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119203. [PMID: 34968576 DOI: 10.1016/j.bbamcr.2021.119203] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 12/07/2021] [Accepted: 12/18/2021] [Indexed: 01/22/2023]
Abstract
Leukotriene (LT) C4 synthase (LTC4S) catalyzes the conversion from LTA4 to LTC4, which is a proinflammatory lipid mediator in asthma and other inflammatory diseases. LTC4 is metabolized to LTD4 and LTE4, all of which are known as cysteinyl (Cys) LTs and exert physiological functions through CysLT receptors. LTC4S is expressed in adipocytes. However, the function of CysLTs and the regulatory mechanism in adipocytes remain unclear. In this study, we investigated the expression of LTC4S and production of CysLTs in murine adipocyte 3T3-L1 cells and their underlying regulatory mechanisms. Expression of LTC4S and production of LTC4 and CysLTs increased during adipogenesis, whereas siRNA-mediated suppression of LTC4S expression repressed adipogenesis by reducing adipogenic gene expression. The CysLT1 receptor, one of the two LTC4 receptors, was expressed in adipocytes. LTC4 and LTD4 increased the intracellular triglyceride levels and adipogenic gene expression, and their enhancement was suppressed by co-treatment with pranlukast, a CysLT1 receptor antagonist. Moreover, the expression profiles of LTC4S gene/protein during adipogenesis resembled those of peroxisome proliferator-activated receptor (PPAR) γ. LTC4S expression was further upregulated by treatment with troglitazone, a PPARγ agonist. Promoter-luciferase and chromatin immunoprecipitation assays showed that PPARγ directly bound to the PPAR response element of the LTC4S gene promoter in adipocytes. These results indicate that the LTC4S gene expression was enhanced by PPARγ, and LTC4 and LTD4 activated adipogenesis through CysLT1 receptors in 3T3-L1 cells. Thus, LTC4S and CysLT1 receptors are novel potential targets for the treatment of obesity.
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Affiliation(s)
- Ko Fujimori
- Department of Pathobiochemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
| | - Saki Uno
- Department of Pathobiochemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
| | - Kyohei Kuroda
- Department of Pathobiochemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
| | - Chihiro Matsumoto
- Department of Pathobiochemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
| | - Toko Maehara
- Department of Pathobiochemistry, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
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25
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Sokolowska M, Rovati GE, Diamant Z, Untersmayr E, Schwarze J, Lukasik Z, Sava F, Angelina A, Palomares O, Akdis C, O'Mahony L, Jesenak M, Pfaar O, Torres MJ, Sanak M, Dahlén S, Woszczek G. Effects of non-steroidal anti-inflammatory drugs and other eicosanoid pathway modifiers on antiviral and allergic responses: EAACI task force on eicosanoids consensus report in times of COVID-19. Allergy 2022; 77:2337-2354. [PMID: 35174512 PMCID: PMC9111413 DOI: 10.1111/all.15258] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/25/2022] [Accepted: 02/11/2022] [Indexed: 11/29/2022]
Abstract
Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti‐inflammatory, antipyretic, and analgesic effects are applied against symptoms of respiratory infections, including SARS‐CoV‐2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID‐19 also revealed the gaps in our understanding of their mechanism of action, selectivity, and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs‐exacerbated respiratory disease (NERD). In this context, the consensus report summarizes currently available knowledge, novel discoveries, and controversies regarding the use of NSAIDs in COVID‐19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID‐19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarize the major knowledge gaps and unmet needs in current eicosanoid research.
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Affiliation(s)
- Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research (SIAF) University of Zurich Davos Switzerland
- Christine Kühne ‐ Center for Allergy Research and Education (CK‐CARE) Davos Switzerland
| | - G Enrico Rovati
- Department of Pharmaceutical Sciences Section of Pharmacology and Biosciences University of Milan Milano Italy
| | - Zuzana Diamant
- Department of Respiratory Medicine and Allergology Skane University Hospital Lund Sweden
- Department Microbiology Immunology and Transplantation Ku Leuven, Catholic University of Leuven Belgium
- Department of Respiratory Medicine First Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic
| | - Eva Untersmayr
- Institute of Pathophysiology and Allergy Research Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna Austria
| | - Jürgen Schwarze
- Child Life and Health and Centre for Inflammation Research The University of Edinburgh Edinburgh UK
| | - Zuzanna Lukasik
- Swiss Institute of Allergy and Asthma Research (SIAF) University of Zurich Davos Switzerland
- VIB Center for Inflammation Research Ghent University Ghent Belgium
| | - Florentina Sava
- London North Genomic Laboratory Hub Great Ormond Street Hospital for Children NHS Foundation Trust London UK
| | - Alba Angelina
- Department of Biochemistry and Molecular Biology School of Chemistry Complutense University Madrid Spain
| | - Oscar Palomares
- Department of Biochemistry and Molecular Biology School of Chemistry Complutense University Madrid Spain
| | - Cezmi Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF) University of Zurich Davos Switzerland
- Christine Kühne ‐ Center for Allergy Research and Education (CK‐CARE) Davos Switzerland
| | - Liam O'Mahony
- Departments of Medicine and Microbiology APC Microbiome IrelandUniversity College Cork Cork Ireland
| | - Milos Jesenak
- Department of Pulmonology and Phthisiology Department of Allergology and Clinical Immunology Department of Pediatrics Jessenius Faculty of Medicine in Martin Comenius University in BratislavaUniversity Teaching Hospital in Martin Slovakia
| | - Oliver Pfaar
- Department of Otorhinolaryngology, Head and Neck Surgery Section of Rhinology and Allergy University Hospital MarburgPhilipps‐Universität Marburg Marburg Germany
| | - María José Torres
- Allergy Unit Málaga Regional University Hospital‐IBIMA‐UMA Málaga Spain
| | - Marek Sanak
- Department of Medicine Jagiellonian University Medical College Krakow Poland
| | - Sven‐Erik Dahlén
- Institute of Environmental Medicine and the Centre for Allergy Research, Karolinska Institute, and the Department of Respiratory Medicine Karolinska University Hospital Stockholm Sweden
| | - Grzegorz Woszczek
- Asthma UK Centre in Allergic Mechanisms of Asthma School of Immunology and Microbial Sciences King's College London London UK
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26
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Pera T, Loblundo C, Penn RB. Pharmacological Management of Asthma and COPD. COMPREHENSIVE PHARMACOLOGY 2022:762-802. [DOI: 10.1016/b978-0-12-820472-6.00095-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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27
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Ualiyeva S, Lemire E, Aviles EC, Wong C, Boyd AA, Lai J, Liu T, Matsumoto I, Barrett NA, Boyce JA, Haber AL, Bankova LG. Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation. Sci Immunol 2021; 6:eabj0474. [PMID: 34932383 DOI: 10.1126/sciimmunol.abj0474] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Saltanat Ualiyeva
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Evan Lemire
- Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
| | - Evelyn C Aviles
- Department of Neurobiology, Harvard Medical School, Boston, MA, USA
| | - Caitlin Wong
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Amelia A Boyd
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Juying Lai
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Tao Liu
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | | | - Nora A Barrett
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Joshua A Boyce
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Adam L Haber
- Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA
| | - Lora G Bankova
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA
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28
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Association between Glucose-6-Phosphate Dehydrogenase Deficiency and Asthma. J Clin Med 2021; 10:jcm10235639. [PMID: 34884340 PMCID: PMC8658649 DOI: 10.3390/jcm10235639] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/27/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Among the determinants contributing to the pathogenesis of asthma, antioxidant genetic factors play a leading role. Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that is competent to detoxify free radicals. Although a relationship between G6PD deficiency and asthma has been previously reported, the literature is still scanty. In this study, we test this hypothesis in a large cohort of patients from Sardinia, Italy. Methods: A retrospective case–control study was performed using data from 11,829 clinical records of outpatients referred to a teaching hospital for a medical visit. In total, 455 cases (asthma-positive) and 11,374 controls (asthma-negative) were compared for G6PD status using multivariable analysis, adjusting for all covariates. Results: Overall, G6PD deficiency was detected in 11.2% of study participants and was associated with an increased risk of asthma (odds ratio (OR) 1.63; 95% confidence interval (CI) 1.27–2.10). Additional variables significantly associated with asthma were female sex (OR 1.66; 95% CI 1.34–2.06), overweight/obesity (OR 1.56; 95% CI 1.27–1.92), smoking (OR 1.44; 95% CI 1.449–3.963), and high socioeconomic status (OR 1.40; 95% CI 1.16–1.70), whereas age was inversely related with asthma (OR 0.49; 95% CI 0.39–0.61). Conclusions: Our study shows that G6PD deficiency is an independent risk for asthma. These findings suggest that G6PD should be assessed in asthmatic patients for better risk stratification.
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29
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Pokhrel S, Gudneppanavar R, Teegala LR, Duah E, Thodeti CK, Paruchuri S. Leukotriene D 4 Upregulates Oxidized Low-Density Lipoprotein Receptor 1 and CD36 to Enhance Oxidized LDL Uptake and Phagocytosis in Macrophages Through Cysteinyl Leukotriene Receptor 1. Front Physiol 2021; 12:756450. [PMID: 34867460 PMCID: PMC8637273 DOI: 10.3389/fphys.2021.756450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/14/2021] [Indexed: 11/20/2022] Open
Abstract
Endothelial permeability, leukocyte attachment, and unregulated oxidized LDL (oxLDL) uptake by macrophages leading to the formation of foam cells are all vital in the initiation and progression of atherosclerosis. During inflammation, several inflammatory mediators regulate this process through the expression of distinct oxLDL binding cell surface receptors on macrophages. We have previously shown that Leukotriene D4 (LTD4) promotes endothelial dysfunction, increasing endothelial permeability and enhancing TNFα-mediated attachment of monocytes to endothelium, which hints at its possible role in atherosclerosis. Here we analyzed the effect of LTD4 on macrophage function. Macrophages mainly express CysLT1R and flux calcium in response to LTD4. Further, LTD4 potentiates phagocytosis in macrophages as revealed by the uptake of zymosan particles. Notably, LTD4 augmented macrophage phagocytosis and oxLDL uptake which is sensitive to MK-571 [Montelukast (MK)], a CysLT1R-specific antagonist. Mechanistically, LTD4 upregulated two receptors central to foam cell formation, oxidized low-density lipoprotein receptor-1 (OLR1/LOX-1), and CD36 in a time and dose-dependent manner. Finally, LTD4 enhanced the secretion of chemokines MCP-1 and MIP1β. Our results suggest that LTD4 contributes to atherosclerosis either through driving foam cell formation or recruitment of immune cells or both. CysLT1R antagonists are safely being used in the treatment of asthma, and the findings from the current study suggest that these can be re-purposed for the treatment of atherosclerosis.
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Affiliation(s)
- Sabita Pokhrel
- Department of Chemistry, University of Akron, Akron, OH, United States
| | | | - Lakshminarayan Reddy Teegala
- Department of Chemistry, University of Akron, Akron, OH, United States
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Ernest Duah
- Department of Chemistry, University of Akron, Akron, OH, United States
| | - Charles K. Thodeti
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, United States
| | - Sailaja Paruchuri
- Department of Chemistry, University of Akron, Akron, OH, United States
- Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
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Cossette C, Miller LA, Ye Q, Chourey S, Reddy CN, Rokach J, Powell WS. Targeting the oxoeicosanoid (OXE) receptor with a selective antagonist inhibits allergen-induced pulmonary inflammation in non-human primates. Br J Pharmacol 2021; 179:322-336. [PMID: 34766334 DOI: 10.1111/bph.15721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 09/06/2021] [Accepted: 10/01/2021] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND AND PURPOSE The 5-lipoxygenase product 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is a potent chemoattractant for eosinophils and neutrophils. However, little is known about its pathophysiological role because of the lack of a rodent ortholog of its OXE receptor. The present study aimed to determine whether the selective OXE receptor antagonist S-Y048 can inhibit allergen-induced pulmonary inflammation in a monkey model of asthma. EXPERIMENTAL APPROACH Monkeys sensitized to house dust mite antigen (HDM) were treated with either vehicle or S-Y048 prior to challenge with aerosolized HDM and bronchoalveolar (BAL) fluid was obtained 24 h later. After six weeks, animals that had initially been treated with vehicle received S-Y048 and vice versa for animals initially treated with S-Y048. Eosinophils and neutrophils in BAL and lung tissue samples were evaluated, as well as mucus-containing cells in bronchi. KEY RESULTS HDM significantly increased the numbers of eosinophils, neutrophils, and macrophages in BAL fluid 24 h after challenge. These responses were all significantly inhibited by S-Y048, which also reduced the numbers of eosinophils and neutrophils in lung tissue 24 h after challenge with HDM. S-Y048 also significantly reduced the numbers of bronchial epithelial cells staining for mucin and MUC5AC after antigen challenge. CONCLUSION AND IMPLICATIONS This study provides the first evidence that 5-oxo-ETE may play an important role in inducing allergen-induced pulmonary inflammation and could also be involved in regulating MUC5AC in goblet cells. OXE receptor antagonists such as S-Y048 may useful therapeutic agents in asthma and other eosinophilic as well as neutrophilic diseases.
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Affiliation(s)
- Chantal Cossette
- Meakins-Christie Laboratories, Centre for Translational Biology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Lisa A Miller
- California National Primate Research Center, University of California, Davis, CA, United States
| | - Qiuji Ye
- Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida, United States.,Present address: Dept. Chemistry, Rice University, Houston, TX, USA
| | - Shishir Chourey
- Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida, United States.,Present address: Chemical Development Dept., Curia Global, Albany, NY, USA
| | - Chintam Nagendra Reddy
- Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida, United States.,Flamma USA LLC, Malvern, PA
| | - Joshua Rokach
- Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida, United States
| | - William S Powell
- Meakins-Christie Laboratories, Centre for Translational Biology, McGill University Health Centre, Montreal, Quebec, Canada
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31
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Trost A, Motloch K, Koller A, Bruckner D, Runge C, Schroedl F, Bogner B, Kaser-Eichberger A, Strohmaier C, Ladek AM, Preishuber-Pfluegl J, Brunner SM, Aigner L, Reitsamer HA. Inhibition of the cysteinyl leukotriene pathways increases survival of RGCs and reduces microglial activation in ocular hypertension. Exp Eye Res 2021; 213:108806. [PMID: 34715090 DOI: 10.1016/j.exer.2021.108806] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/05/2021] [Accepted: 10/21/2021] [Indexed: 10/20/2022]
Abstract
Glaucoma is the second leading cause of blindness worldwide. This multifactorial, neurodegenerative group of diseases is characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible visual impairment and blindness. There is a huge unmet and urging need for the development of new and translatable strategies and treatment options to prevent this progressive loss of RGC. Accumulating evidence points towards a critical role of neuroinflammation, in particular microglial cells, in the pathogenesis of glaucoma. Leukotrienes are mediators of neuroinflammation and are involved in many neurodegenerative diseases. Therefore, we tested the leukotriene receptors CysLT1R/GPR17-selective antagonist Montelukast (MTK) for its efficacy to modulate the reactive state of microglia in order to ameliorate RGCs loss in experimental glaucoma. Ocular hypertension (OHT) was induced unilaterally by injection of 8 μm magnetic microbead (MB) into the anterior chamber of female Brown Norway rats. The contralateral, untreated eye served as control. Successful induction of OHT was verified by daily IOP measurement using a TonoLab rebound tonometer. Simultaneously to OHT induction, one group received daily MTK treatment and the control group vehicle solution by oral gavage. Animals were sacrificed 13-15 days after MB injection. Retina and optic nerves (ON) of OHT and contralateral eyes were analyzed by immunofluorescence with specific markers for RGCs (Brn3a), microglial cells/macrophages (Iba1 and CD68), and cysteinyl leukotriene pathway receptors (CysLT1R and GPR17). Protein labeling was documented by confocal microscopy and analyzed with ImageJ plugins. Further, mRNA expression of genes of the inflammatory and leukotriene pathway was analyzed in retinal tissue. MTK treatment resulted in a short-term IOP reduction at day 2, which dissipated by day 5 of OHT induction in MTK treated animals. Furthermore, MTK treatment resulted in a decreased activation of Iba1+ microglial cells in the retina and ON, and in a significantly increased RGC survival in OHT eyes. Within the retina, GPR17 and CysLT1R expression was demonstrated in single RCGs and in microglial cells respectively. Further, increased mRNA expression of pro-inflammatory genes was detected in OHT induced retinas. In the ON, OHT induction increased the number of GPR17+ cells, showing a trend of reduction following MTK treatment. This study shows for the first time a significantly increased RGC survival in an acute OHT model following treatment with the leukotriene receptor antagonist MTK. These results strongly suggest a neuroprotective effect of MTK and a potential new therapeutic strategy for glaucoma treatment.
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Affiliation(s)
- Andrea Trost
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria.
| | - Karolina Motloch
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Andreas Koller
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Daniela Bruckner
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Christian Runge
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Falk Schroedl
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria; Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Barbara Bogner
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Alexandra Kaser-Eichberger
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria; Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Clemens Strohmaier
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria; Department of Ophthalmology and Optometry, Johannes Kepler University, Linz, Austria
| | - Anja-Maria Ladek
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Julia Preishuber-Pfluegl
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Susanne Maria Brunner
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Austria
| | - Herbert Anton Reitsamer
- University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, Paracelsus Medical University/SALK, 5020, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University Salzburg, Austria
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Biologically active lipids in the regulation of lymphangiogenesis in disease states. Pharmacol Ther 2021; 232:108011. [PMID: 34614423 DOI: 10.1016/j.pharmthera.2021.108011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/31/2021] [Accepted: 09/01/2021] [Indexed: 02/06/2023]
Abstract
Lymphatic vessels have crucial roles in the regulation of interstitial fluids, immune surveillance, and the absorption of dietary fat in the intestine. Lymphatic function is also closely related to the pathogenesis of various disease states such as inflammation, lymphedema, endometriosis, liver dysfunction, and tumor metastasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing lymphatic vessels, is a critical determinant in the above conditions. Although the effect of growth factors on lymphangiogenesis is well-characterized, and biologically active lipids are known to affect smooth muscle contractility and vasoaction, there is accumulating evidence that biologically active lipids are also important inducers of growth factors and cytokines that regulate lymphangiogenesis. This review discusses recent advances in our understanding of biologically active lipids, including arachidonic acid metabolites, sphingosine 1-phosphate, and lysophosphatidic acid, as regulators of lymphangiogenesis, and the emerging importance of the lymphangiogenesis as a therapeutic target.
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da Cunha AA, Silveira JS, Antunes GL, Abreu da Silveira K, Benedetti Gassen R, Vaz Breda R, Márcio Pitrez P. Cysteinyl leukotriene induces eosinophil extracellular trap formation via cysteinyl leukotriene 1 receptor in a murine model of asthma. Exp Lung Res 2021; 47:355-367. [PMID: 34468256 DOI: 10.1080/01902148.2021.1923864] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
PURPOSE Eosinophils are one of the main cells responsible to the inflammatory response in asthma by the release of inflammatory molecules such as cytokines, reactive oxygen species (ROS), cytotoxic granule, eosinophil extracellular trap (EET), and lipid mediators as cysteinyl leukotriene (cysLT). The interconnections between these molecules are not fully understood. Here, we attempted to investigate the cysLT participation in the mechanisms of EET formation in an asthma model of OVA challenge. MATERIALS AND METHODS Before intranasal challenge with OVA, BALB/cJ mice were treated with a 5-lipoxygenase-activating protein (FLAP) inhibitor (MK-886), or with a cysLT1 receptor antagonist (MK-571) and the lung and bronchoalveolar lavage fluid (BALF) were analyzed. RESULTS We showed that OVA-challenged mice treated with MK-886 or MK-571 had a decrease in inflammatory cells, goblet cells hyperplasia, and eosinophil peroxidase (EPO) activity in the airway. However, only OVA-challenged mice treated with MK-571 had an improvement in lung function. Also, treatments with MK-886 or MK-571 decreased Th2 cytokines levels in the airway. Moreover, we observed that OVA-challenged mice treated with MK-886 or MK-571 had a decrease in EET formation in BALF. We also verified that EET release was not due to cell death because the cell viability remained the same among the groups. CONCLUSION We revealed that the decrease in cysLT production or cysLT1 receptor inhibition by MK-886 or/and MK-571 treatments, respectively reduced EET formation in BALF, showing that cysLT regulates the activation process of EET release in asthma.
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Affiliation(s)
| | - Josiane Silva Silveira
- Laboratory of Pediatric Respirology, Infant Center, Medicine School, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Géssica Luana Antunes
- Laboratory of Pediatric Respirology, Infant Center, Medicine School, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Keila Abreu da Silveira
- Laboratory of Pediatric Respirology, Infant Center, Medicine School, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Rodrigo Benedetti Gassen
- Laboratory of Cellular and Molecular Immunology, Science School, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Ricardo Vaz Breda
- Institute of the Brain (BraIns), Medicine School, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
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Eicosanoid receptors as therapeutic targets for asthma. Clin Sci (Lond) 2021; 135:1945-1980. [PMID: 34401905 DOI: 10.1042/cs20190657] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022]
Abstract
Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.
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Alvarez MDL, Lorenzetti F. Role of eicosanoids in liver repair, regeneration and cancer. Biochem Pharmacol 2021; 192:114732. [PMID: 34411565 DOI: 10.1016/j.bcp.2021.114732] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 12/24/2022]
Abstract
Eicosanoids are lipid signaling molecules derived from the oxidation of ω-6 fatty acids, usually arachidonic acid. There are three major pathways, including the cyclooxygenase (COX), lipoxygenase (LOX), and P450 cytochrome epoxygenase (CYP) pathway. Prostanoids, which include prostaglandins (PG) and thromboxanes (Tx), are formed via the COX pathway, leukotrienes (LT) and lipoxins (LX) by the action of 5-LOX, and hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) by CYP. Although eicosanoids are usually associated with pro-inflammatory responses, non-classic eicosanoids, as LX, have anti-inflammatory and pro-resolving properties. Eicosanoids like PGE2, LTB4 and EETs have been involved in promoting liver regeneration after partial hepatectomy. PGE2 and LTB4 have also been reported to participate in the regenerative phase after ischemia and reperfusion (I/R), while cysteinyl leukotrienes (Cys-LT) contribute to the inflammatory process associated with I/R and are also involved in liver fibrosis and cirrhosis. However, LX, another product of 5-LOX, have the opposite effect, acting as pro-resolving mediators in these pathologies. In liver cancer, most studies show that eicosanoids, with the exception of LX, promote the proliferation of hepatocellular carcinoma cells and favor metastasis. This review summarizes the synthesis of different eicosanoids in the liver and discusses key findings from basic research linking eicosanoids to liver repair, regeneration and cancer and the impact of targeting eicosanoid cascade. In addition, studies in patients are presented that explore the potential use of eicosanoids as biomarkers and show correlations between eicosanoid production and the course and prognosis of liver disease.
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Affiliation(s)
- María de Luján Alvarez
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 570 (S2002LRL), Rosario, Argentina; Área Morfología, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipacha 570 (S2002LRL), Rosario, Argentina; Centro de Altos Estudios en Ciencias Humanas y de la Salud (CAECIHS) Sede Regional Rosario, Universidad Abierta Interamericana, Av. Pellegrini 1618 (S2000BUG), Rosario, Argentina.
| | - Florencia Lorenzetti
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, UNR, Suipacha 570 (S2002LRL), Rosario, Argentina
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Giménez-Bastida JA, González-Sarrías A, Laparra-Llopis JM, Schneider C, Espín JC. Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review. Int J Mol Sci 2021; 22:7937. [PMID: 34360703 PMCID: PMC8348464 DOI: 10.3390/ijms22157937] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 12/15/2022] Open
Abstract
5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.
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Affiliation(s)
- Juan Antonio Giménez-Bastida
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
| | - Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
| | - José Moisés Laparra-Llopis
- Group of Molecular Immunonutrition in Cancer, Madrid Institute for Advanced Studies in Food (IMDEA-Food), 28049 Madrid, Spain;
| | - Claus Schneider
- Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA;
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
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Biringer RG. A review of non-prostanoid, eicosanoid receptors: expression, characterization, regulation, and mechanism of action. J Cell Commun Signal 2021; 16:5-46. [PMID: 34173964 DOI: 10.1007/s12079-021-00630-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/07/2021] [Indexed: 11/29/2022] Open
Abstract
Eicosanoid signaling controls a wide range of biological processes from blood pressure homeostasis to inflammation and resolution thereof to the perception of pain and to cell survival itself. Disruption of normal eicosanoid signaling is implicated in numerous disease states. Eicosanoid signaling is facilitated by G-protein-coupled, eicosanoid-specific receptors and the array of associated G-proteins. This review focuses on the expression, characterization, regulation, and mechanism of action of non-prostanoid, eicosanoid receptors.
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Affiliation(s)
- Roger G Biringer
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, 5000 Lakewood Ranch Blvd, Bradenton, FL, 34211, USA.
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Potential Effects of Leukotriene Receptor Antagonist Montelukast in Treatment of Neuroinflammation in Parkinson's Disease. Int J Mol Sci 2021; 22:ijms22115606. [PMID: 34070609 PMCID: PMC8198163 DOI: 10.3390/ijms22115606] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/16/2021] [Accepted: 05/21/2021] [Indexed: 12/11/2022] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder where misfolded alpha-synuclein-enriched aggregates called Lewy bodies are central in pathogenesis. No neuroprotective or disease-modifying treatments are currently available. Parkinson’s disease is considered a multifactorial disease and evidence from multiple patient studies and animal models has shown a significant immune component during the course of the disease, highlighting immunomodulation as a potential treatment strategy. The immune changes occur centrally, involving microglia and astrocytes but also peripherally with changes to the innate and adaptive immune system. Here, we review current understanding of different components of the PD immune response with a particular emphasis on the leukotriene pathway. We will also describe evidence of montelukast, a leukotriene receptor antagonist, as a possible anti-inflammatory treatment for PD.
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Mechanistic insight on the role of leukotriene receptors in ischemic-reperfusion injury. Pharmacol Rep 2021; 73:1240-1254. [PMID: 33818747 DOI: 10.1007/s43440-021-00258-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 02/07/2023]
Abstract
Leukotrienes (LT) are a class of inflammatory mediators produced by the 5-lipoxygenase (5-LO) enzyme from arachidonic acid (AA). We discussed the various LT inhibitors and downstream pathway modulators, such as Mitogen-Activated Protein Kinases (MAPK), Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/Akt), 5'-Adenosine Monophosphate-Activated Protein Kinase (AMPK), Protein Kinase C (PKC), Nitric Oxide (NO), Bradykinin, Early Growth Response-1 (Egr-1), Nuclear Factor-κB (NF-κB), and Tumor Necrosis Factor-Alpha (TNF-α), which in turn regulate various metabolic and physiological processes involving I/R injury. A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the nature and mechanistic interventions of the leukotriene receptor modulations in ischemic injury. In the pathophysiology of I/R injuries, LT has been found to play an important role. I/R injury affects most of the vital organs and is characterized by inflammation, oxidative stress, cell death, and apoptosis leading to morbidity and mortality. sThis present review focuses on the various LT receptors, i.e., CysLT, LTC4, LTD4, and LTE4, involved in developing I/R injury in organs, such as the brain, spinal cord, heart, kidney, liver, and intestine.
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40
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Guillemot-Legris O, Muccioli GG. The oxysterome and its receptors as pharmacological targets in inflammatory diseases. Br J Pharmacol 2021; 179:4917-4940. [PMID: 33817775 DOI: 10.1111/bph.15479] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 03/14/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022] Open
Abstract
Oxysterols have gained attention over the last decades and are now considered as fully fledged bioactive lipids. The study of their levels in several conditions, including atherosclerosis, obesity and neurodegenerative diseases, led to a better understanding of their involvement in (patho)physiological processes such as inflammation and immunity. For instance, the characterization of the cholesterol-7α,25-dihydroxycholesterol/GPR183 axis and its implication in immunity represents an important step in the oxysterome study. Besides this axis, others were identified as important in several inflammatory pathologies (such as colitis, lung inflammation and atherosclerosis). However, the oxysterome is a complex system notably due to a redundancy of metabolic enzymes and a wide range of receptors. Indeed, deciphering oxysterol roles and identifying the potential receptor(s) involved in a given pathology remain challenging. Oxysterol properties are very diverse, but most of them could be connected by a common component: inflammation. Here, we review the implication of oxysterol receptors in inflammatory diseases.
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Affiliation(s)
- Owein Guillemot-Legris
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
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41
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Voisin T, Perner C, Messou MA, Shiers S, Ualiyeva S, Kanaoka Y, Price TJ, Sokol CL, Bankova LG, Austen KF, Chiu IM. The CysLT 2R receptor mediates leukotriene C 4-driven acute and chronic itch. Proc Natl Acad Sci U S A 2021; 118:e2022087118. [PMID: 33753496 PMCID: PMC8020753 DOI: 10.1073/pnas.2022087118] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2-/- mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.
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MESH Headings
- Animals
- Chronic Disease
- Dermatitis, Atopic/chemically induced
- Dermatitis, Atopic/complications
- Dermatitis, Atopic/immunology
- Dermatitis, Atopic/pathology
- Disease Models, Animal
- Ganglia, Spinal/cytology
- Ganglia, Spinal/metabolism
- Humans
- Leukotriene C4/metabolism
- Mice
- Mice, Knockout
- Pruritus/immunology
- Pruritus/pathology
- Receptors, Leukotriene/genetics
- Receptors, Leukotriene/metabolism
- Sensory Receptor Cells/metabolism
- Signal Transduction/immunology
- Skin/innervation
- Skin/pathology
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Affiliation(s)
- Tiphaine Voisin
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115
| | - Caroline Perner
- Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Marie-Angele Messou
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115
| | - Stephanie Shiers
- Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX 75080
| | - Saltanat Ualiyeva
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham & Women's Hospital, Boston, MA 02115
- Department of Medicine, Harvard Medical School, Boston, MA 02115
| | - Yoshihide Kanaoka
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham & Women's Hospital, Boston, MA 02115
- Department of Medicine, Harvard Medical School, Boston, MA 02115
| | - Theodore J Price
- Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX 75080
| | - Caroline L Sokol
- Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Lora G Bankova
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham & Women's Hospital, Boston, MA 02115
- Department of Medicine, Harvard Medical School, Boston, MA 02115
| | - K Frank Austen
- Division of Allergy and Clinical Immunology, Jeff and Penny Vinik Center for Allergic Disease Research, Brigham & Women's Hospital, Boston, MA 02115;
- Department of Medicine, Harvard Medical School, Boston, MA 02115
| | - Isaac M Chiu
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115;
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42
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Michael J, Zirknitzer J, Unger MS, Poupardin R, Rieß T, Paiement N, Zerbe H, Hutter-Paier B, Reitsamer H, Aigner L. The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice. Int J Mol Sci 2021; 22:2782. [PMID: 33803482 PMCID: PMC7967180 DOI: 10.3390/ijms22052782] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/23/2021] [Accepted: 03/02/2021] [Indexed: 12/20/2022] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling-more specifically, the leukotriene receptors-has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.
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Affiliation(s)
- Johanna Michael
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (J.Z.); (M.S.U.); (T.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Julia Zirknitzer
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (J.Z.); (M.S.U.); (T.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Michael Stefan Unger
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (J.Z.); (M.S.U.); (T.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Rodolphe Poupardin
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Tanja Rieß
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (J.Z.); (M.S.U.); (T.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Nadine Paiement
- IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada; (N.P.); (H.Z.)
| | - Horst Zerbe
- IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada; (N.P.); (H.Z.)
| | | | - Herbert Reitsamer
- Research Program for Experimental Ophthalmology, Department of Ophthalmology and Optometry, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (J.Z.); (M.S.U.); (T.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria;
- Austrian Cluster of Tissue Regeneration, 1200 Vienna, Austria
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Han B, Zhang YY, Ye ZQ, Xiao Y, Rasouli J, Wu WC, Ye SM, Guo XY, Zhu L, Rostami A, Wang LB, Zhang Y, Li X. Montelukast alleviates inflammation in experimental autoimmune encephalomyelitis by altering Th17 differentiation in a mouse model. Immunology 2021; 163:185-200. [PMID: 33480040 DOI: 10.1111/imm.13308] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 12/23/2020] [Accepted: 01/04/2021] [Indexed: 12/25/2022] Open
Abstract
Montelukast is a leukotriene receptor antagonist that is known to prevent allergic rhinitis and asthma. Blocking the Cysteinyl leukotriene receptor (CysLTR1), one of the primary receptors of leukotrienes, has been demonstrated to be efficacious in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through disrupting chemotaxis of infiltrating T cells. However, the role of CysLTR1 in the pathogenesis of MS is not well understood. Here, we show that MS patients had higher expression of CysLTR1 in the circulation and central nervous system (CNS). The majority of CD4+ T cells expressed CysLTR1 in MS lesions. Among T-cell subsets, Th17 cells had the highest expression of CysLTR1, and blocking CysLTR1 signalling abrogated their development in vitro. Inhibition of CysLTR1 by montelukast suppressed EAE development in both a prophylactic and therapeutic manner and inhibited myelin loss in EAE mice. Similarly, the in vivo results showed that montelukast inhibited Th17 response in EAE mice and that Th17 cells treated with montelukast had reduced encephalitogenic in adoptive EAE. Our findings strongly suggest that targeting Th17 response by inhibiting CysLTR1 signalling could be a promising therapeutic strategy for the treatment of MS and CNS inflammatory diseases.
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Affiliation(s)
- Bing Han
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Yan-Yan Zhang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Ze-Qing Ye
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Yun Xiao
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Javad Rasouli
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Wen-Cheng Wu
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Su-Min Ye
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Xin-Yue Guo
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Lin Zhu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | | | - Li-Bin Wang
- The General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yuan Zhang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Xing Li
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
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44
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Yonker LM, Barrios J, Mou H, Hurley BP. Untapped Potential: Therapeutically Targeting Eicosanoids and Endocannabinoids in the Lung. Clin Pharmacol Ther 2021; 110:69-81. [PMID: 33423293 DOI: 10.1002/cpt.2165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/20/2020] [Indexed: 02/05/2023]
Abstract
Inflammation of the airway involves the recruitment of highly active immune cells to combat and clear microbes and toxic factors; however, this inflammatory response can result in unintended damage to lung tissue. Tissue damage resulting from inflammation is often mitigated by resolving factors that limit the scope and duration of the inflammatory response. Both inflammatory and resolving processes require the actions of a vast array of lipid mediators that can be rapidly synthesized through a variety of airway resident and infiltrating immune cells. Eicosanoids and endocannabinoids represent two major classes of lipid mediators that share synthetic enzymes and have diverse and overlapping functions. This review seeks to provide a summary of the major bioactive eicosanoids and endocannabinoids, challenges facing researchers that study them, and their roles in modulating inflammation and resolution. With a special emphasis on cystic fibrosis, a variety of therapeutics are discussed that have been explored for their potential anti-inflammatory or proresolving impact toward alleviating excessive airway inflammation and improving lung function.
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Affiliation(s)
- Lael M Yonker
- Massachusetts General Hospital, Department of Pediatrics, Pulmonary Division, Boston, Massachusetts, USA.,Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, USA.,Harvard Medical School, Department of Pediatrics, Boston, Massachusetts, USA
| | - Juliana Barrios
- Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, USA.,Harvard Medical School, Department of Pediatrics, Boston, Massachusetts, USA
| | - Hongmei Mou
- Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, USA.,Harvard Medical School, Department of Pediatrics, Boston, Massachusetts, USA
| | - Bryan P Hurley
- Massachusetts General Hospital, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, USA.,Harvard Medical School, Department of Pediatrics, Boston, Massachusetts, USA
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45
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Wang H, Qin Z, Yan A. Classification models and SAR analysis on CysLT1 receptor antagonists using machine learning algorithms. Mol Divers 2021; 25:1597-1616. [PMID: 33534023 DOI: 10.1007/s11030-020-10165-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/27/2020] [Indexed: 12/21/2022]
Abstract
Cysteinyl leukotrienes 1 (CysLT1) receptor is a promising drug target for rhinitis or other allergic diseases. In our study, we built classification models to predict bioactivities of CysLT1 receptor antagonists. We built a dataset with 503 CysLT1 receptor antagonists which were divided into two groups: highly active molecules (IC50 < 1000 nM) and weakly active molecules (IC50 ≥ 1000 nM). The molecules were characterized by several descriptors including CORINA descriptors, MACCS fingerprints, Morgan fingerprint and molecular SMILES. For CORINA descriptors and two types of fingerprints, we used the random forests (RF) and deep neural networks (DNN) to build models. For molecular SMILES, we used recurrent neural networks (RNN) with the self-attention to build models. The accuracies of test sets for all models reached 85%, and the accuracy of the best model (Model 2C) was 93%. In addition, we made structure-activity relationship (SAR) analyses on CysLT1 receptor antagonists, which were based on the output from the random forest models and RNN model. It was found that highly active antagonists usually contained the common substructures such as tetrazoles, indoles and quinolines. These substructures may improve the bioactivity of the CysLT1 receptor antagonists.
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Affiliation(s)
- Hongzhao Wang
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, University of Chemical Technology, Beijing, People's Republic of China
| | - Zijian Qin
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, University of Chemical Technology, Beijing, People's Republic of China
| | - Aixia Yan
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, University of Chemical Technology, Beijing, People's Republic of China.
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46
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Saier L, Peyruchaud O. Emerging role of cysteinyl LTs in cancer. Br J Pharmacol 2021; 179:5036-5055. [PMID: 33527344 DOI: 10.1111/bph.15402] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/28/2020] [Accepted: 01/23/2021] [Indexed: 01/31/2023] Open
Abstract
Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has been an increased interest in determining how these lipid mediators orchestrate tumour development and metastasis through promoting a pro-tumour micro-environment. Up-regulation of CysLTs receptors and CysLTs production is found in a number of cancers and has been associated with increased tumorigenesis. Understanding the molecular mechanisms underlying the role of CysLTs and their receptors in cancer progression will help investigate the potential of targeting CysLTs signalling for anti-cancer therapy. This review gives an overview of the biological effects of CysLTs and their receptors, along with current knowledge of their regulation and expression. It also provides a recent update on the molecular mechanisms that have been postulated to explain their role in tumorigenesis and on the potential of anti-CysLTs in the treatment of cancer.
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Affiliation(s)
- Lou Saier
- INSERM, Unit 1033, LYOS, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Olivier Peyruchaud
- INSERM, Unit 1033, LYOS, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
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Sokolowska M, Rovati GE, Diamant Z, Untersmayr E, Schwarze J, Lukasik Z, Sava F, Angelina A, Palomares O, Akdis CA, O’Mahony L, Sanak M, Dahlen S, Woszczek G. Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report, part I. Allergy 2021; 76:114-130. [PMID: 32279330 DOI: 10.1111/all.14295] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/13/2020] [Accepted: 03/25/2020] [Indexed: 12/25/2022]
Abstract
Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.
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Affiliation(s)
- Milena Sokolowska
- Swiss Institute of Allergy and Asthma Research University of Zurich Davos Switzerland
- Christine Kühne ‐ Center for Allergy Research and Education (CK‐CARE) Davos Switzerland
| | - G. Enrico Rovati
- Department of Pharmaceutical Sciences University of Milan Milan Italy
| | - Zuzana Diamant
- Department of Respiratory Medicine & Allergology Skane University Hospital Lund Sweden
- Department of Respiratory Medicine First Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic
| | - Eva Untersmayr
- Institute of Pathophysiology and Allergy Research Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna Vienna Austria
| | - Jargen Schwarze
- Child Life and Health and Centre for Inflammation Research The University of Edinburgh Edinburgh UK
| | - Zuzanna Lukasik
- Swiss Institute of Allergy and Asthma Research University of Zurich Davos Switzerland
| | - Florentina Sava
- London North Genomic Laboratory Hub Great Ormond Street Hospital for Children NHS Foundation Trust London UK
| | - Alba Angelina
- Department of Biochemistry and Molecular Biology School of Chemistry Complutense University Madrid Spain
| | - Oscar Palomares
- Department of Biochemistry and Molecular Biology School of Chemistry Complutense University Madrid Spain
| | - Cezmi A. Akdis
- Swiss Institute of Allergy and Asthma Research University of Zurich Davos Switzerland
- Christine Kühne ‐ Center for Allergy Research and Education (CK‐CARE) Davos Switzerland
| | - Liam O’Mahony
- Departments of Medicine and Microbiology APC Microbiome Ireland University College Cork Cork Ireland
| | - Marek Sanak
- Department of Medicine Jagiellonian University Medical College Krakow Poland
| | - Sven‐Erik Dahlen
- Institute of Environmental Medicine Karolinska Institute Stockholm Sweden
- Centre for Allergy Research Karolinska Institute Stockholm Sweden
| | - Grzegorz Woszczek
- MRC/Asthma UK Centre in Allergic Mechanisms of Asthma School of Immunology & Microbial Sciences King's College London London UK
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Michael J, Bessa de Sousa D, Conway J, Gonzalez-Labrada E, Obeid R, Tevini J, Felder T, Hutter-Paier B, Zerbe H, Paiement N, Aigner L. Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice. Pharmaceutics 2020; 13:E12. [PMID: 33374646 PMCID: PMC7822410 DOI: 10.3390/pharmaceutics13010012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 11/30/2022] Open
Abstract
The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low- and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering from dysphagia, for example, seen in patients with neurodegenerative diseases such as Alzheimer's disease, a disease with increasing interest in repurposing of MTK. This, and the need for an improved bioavailability, triggered us to reformulate MTK. Our aim was to develop a mucoadhesive MTK film with good safety and improved pharmacological features, i.e., an improved bioavailability profile in humans as well as in a mouse model of Alzheimer's disease. We tested dissolution of the MTK mucoadhesive film and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I analysis in humans, which included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF). In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose-dependent manner. The mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate Blood-Brain-Barrier (BBB) penetrance in a preclinical model, as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke.
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Affiliation(s)
- Johanna Michael
- Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (D.B.d.S.)
| | - Diana Bessa de Sousa
- Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (D.B.d.S.)
| | - Justin Conway
- IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada; (J.C.); (E.G.-L.); (R.O.); (H.Z.)
| | | | - Rodolphe Obeid
- IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada; (J.C.); (E.G.-L.); (R.O.); (H.Z.)
| | - Julia Tevini
- Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; (J.T.); (T.F.)
| | - Thomas Felder
- Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria; (J.T.); (T.F.)
| | | | - Horst Zerbe
- IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada; (J.C.); (E.G.-L.); (R.O.); (H.Z.)
| | - Nadine Paiement
- IntelgenX Corp., Saint-Laurent, QC H4S 1Y2, Canada; (J.C.); (E.G.-L.); (R.O.); (H.Z.)
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria; (J.M.); (D.B.d.S.)
- QPS Neuropharmacology, 8074 Grambach/Graz, Austria;
- Austrian Cluster of Tissue Regeneration Affiliation, 1200 Vienna, Austria
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Aigner L, Pietrantonio F, Bessa de Sousa DM, Michael J, Schuster D, Reitsamer HA, Zerbe H, Studnicka M. The Leukotriene Receptor Antagonist Montelukast as a Potential COVID-19 Therapeutic. Front Mol Biosci 2020; 7:610132. [PMID: 33392263 PMCID: PMC7773944 DOI: 10.3389/fmolb.2020.610132] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 11/17/2020] [Indexed: 01/08/2023] Open
Abstract
The emergence and global impact of COVID-19 has focused the scientific and medical community on the pivotal influential role of respiratory viruses as causes of severe pneumonia, on the understanding of the underlying pathomechanisms, and on potential treatment for COVID-19. The latter concentrates on four different strategies: (i) antiviral treatments to limit the entry of the virus into the cell and its propagation, (ii) anti-inflammatory treatment to reduce the impact of COVID-19 associated inflammation and cytokine storm, (iii) treatment using cardiovascular medication to reduce COVID-19 associated thrombosis and vascular damage, and (iv) treatment to reduce the COVID-19 associated lung injury. Ideally, effective COVID-19 treatment should target as many of these mechanisms as possible arguing for the search of common denominators as potential drug targets. Leukotrienes and their receptors qualify as such targets: they are lipid mediators of inflammation and tissue damage and well-established targets in respiratory diseases like asthma. Besides their role in inflammation, they are involved in various other aspects of lung pathologies like vascular damage, thrombosis, and fibrotic response, in brain and retinal damages, and in cardiovascular disease. In consequence, leukotriene receptor antagonists might be potential candidates for COVID-19 therapeutics. This review summarizes the current knowledge on the potential involvement of leukotrienes in COVID-19, and the rational for the use of the leukotriene receptor antagonist montelukast as a COVID-19 therapeutic.
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Affiliation(s)
- Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.,Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | | | - Diana Marisa Bessa de Sousa
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.,Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Johanna Michael
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.,Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Daniela Schuster
- Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Herbert Anton Reitsamer
- Department of Ophthalmology and Optometry, University Clinic Salzburg, Paracelsus Medical University, Salzburg, Austria.,Research Program of Experimental Ophthalmology and Glaucoma Research, Paracelsus Medical University Salzburg, Salzburg, Austria
| | | | - Michael Studnicka
- Department of Pulmonary Medicine, University Clinic Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
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McGovern T, Ano S, Farahnak S, McCuaig S, Martin JG. Cellular Source of Cysteinyl Leukotrienes Following Chlorine Exposure. Am J Respir Cell Mol Biol 2020; 63:681-689. [PMID: 32697598 DOI: 10.1165/rcmb.2019-0385oc] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Exposure of mice to high concentrations of chlorine leads to the synthesis of cysteinyl leukotrienes (cysLTs). CysLTs contribute to chlorine-induced airway hyperresponsiveness. The aim of the current study was to determine the cellular source of the cysLTs. To achieve this aim, we exposed mice to 100 ppm of chlorine for 5 minutes. Intranasal instillation of clodronate in liposomes and of diphtheria toxin in CD11c-DTR mice was used to deplete macrophages. CCR2-/- mice were used to assess the contribution of recruited macrophages. Eosinophils and neutrophils were depleted with specific antibodies. Platelet-neutrophil aggregation was prevented with an antibody against P-selectin. The potential roles of phagocytosis of neutrophils by macrophages and of transcellular metabolism between epithelial cells and neutrophils were explored in coculture systems. We found that depletion of neutrophils was the only intervention that inhibited the synthesis of cysLTs at 24 hours after chlorine exposure. Although macrophages did synthesize cysLTs in response to phagocytosis of neutrophils, depletion of macrophages did not reduce the increment in cysLTs triggered by chlorine exposure. However, coculture of airway epithelial cells with neutrophils resulted in a significant increase in the synthesis of cysLTs, dependent on the expression of 5-lipoxygenase by neutrophils. We conclude that cysLT synthesis following chlorine exposure may be dependent on transcellular metabolism by neutrophil-epithelial interactions.
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Affiliation(s)
- Toby McGovern
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre and McGill University, Montreal, Quebec, Canada
| | - Satoshi Ano
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre and McGill University, Montreal, Quebec, Canada
| | - Soroor Farahnak
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre and McGill University, Montreal, Quebec, Canada
| | - Sarah McCuaig
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre and McGill University, Montreal, Quebec, Canada
| | - James G Martin
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre and McGill University, Montreal, Quebec, Canada
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