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Sánchez-García S, Jaén RI, Lozano-Rodríguez R, Avendaño-Ortiz J, Pascual‐Iglesias A, Hurtado-Navarro L, López-Collazo E, Boscá L, Prieto P. Lipoxin A 4 levels correlate with severity in a Spanish COVID-19 cohort: potential use of endogenous pro-resolving mediators as biomarkers. Front Immunol 2025; 15:1509188. [PMID: 39916956 PMCID: PMC11798798 DOI: 10.3389/fimmu.2024.1509188] [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: 10/10/2024] [Accepted: 12/27/2024] [Indexed: 02/09/2025] Open
Abstract
Background SARS-CoV-2, the causative virus of the COVID-19 global pandemic, leads to a wide variety of responses among patients. Some of them present a very severe phenotype, while others only experience mild symptoms or are even asymptomatic. This differential prognosis is tightly related to the inflammatory status of the patient. Although WHO declared the end of the emergency, the pandemic caused a great socio-sanitary impact in all countries. Thus, the possible outbreak of new biological diseases in the future makes it necessary to deepen the knowledge of this uncontrolled immune response and look for reliable biomarkers to help us predict its potential health impact. Specialized pro-resolving lipid mediators (SPMs) as lipoxins are endogenous mediators synthesized from arachidonic acid in the resolution stage of any inflammatory process. These lipids have pro-resolving actions in several pathological models, including reducing NF-κB-mediated inflammation, and inducing the antioxidant response through the Nrf-2 pathway. Thus, although a potential relationship has already been suggested between low levels of SPMs and COVID-19 severity, their true role as a predictive biomarker is still unknown. Methods and results In this study, we have analyzed by ELISA the serum levels of lipoxin A4 (LXA4) in a representative Spanish cohort. We found reduced levels in deceased patients when compared to mild or severe patients, concomitant with a decrease in the LXA4 biosynthetic pathway and an increase in its degradation pathway. Furthermore, we have studied the correlation between the levels of this SPM and several pathology indicators, finding a significant correlation between increased LXA4 levels and a better prognosis of the patients. Conclusion We propose to measure systemic LXA4 as a new promising biomarker to predict the survival in patients affected by SARS-CoV-2 and presumably to other viruses that can affect humanity in the future.
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Affiliation(s)
- Sergio Sánchez-García
- Departamento de enfermedades metabólicas e inmunitarias, Instituto de Investigaciones Biomédicas “Sols-Morreale”, Madrid, Spain
| | - Rafael I. Jaén
- Departamento de enfermedades metabólicas e inmunitarias, Instituto de Investigaciones Biomédicas “Sols-Morreale”, Madrid, Spain
| | - Roberto Lozano-Rodríguez
- Innate Immune Response Group, Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Madrid, Spain
| | - José Avendaño-Ortiz
- Microbiology Department, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Alejandro Pascual‐Iglesias
- Innate Immune Response Group, Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Madrid, Spain
| | - Laura Hurtado-Navarro
- Innate Immune Response Group, Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Madrid, Spain
| | - Eduardo López-Collazo
- Innate Immune Response Group, Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Lisardo Boscá
- Departamento de enfermedades metabólicas e inmunitarias, Instituto de Investigaciones Biomédicas “Sols-Morreale”, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Prieto
- Departamento de enfermedades metabólicas e inmunitarias, Instituto de Investigaciones Biomédicas “Sols-Morreale”, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
- Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
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2
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B Gowda SG, Shekhar C, Gowda D, Chen Y, Chiba H, Hui SP. Mass spectrometric approaches in discovering lipid biomarkers for COVID-19 by lipidomics: Future challenges and perspectives. MASS SPECTROMETRY REVIEWS 2024; 43:1041-1065. [PMID: 37102760 DOI: 10.1002/mas.21848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 03/14/2023] [Accepted: 04/17/2023] [Indexed: 05/09/2023]
Abstract
Coronavirus disease 2019 (COVID-19) has emerged as a global health threat and has rapidly spread worldwide. Significant changes in the lipid profile before and after COVID-19 confirmed the significance of lipid metabolism in regulating the response to viral infection. Therefore, understanding the role of lipid metabolism may facilitate the development of new therapeutics for COVID-19. Owing to their high sensitivity and accuracy, mass spectrometry (MS)-based methods are widely used for rapidly identifying and quantifying of thousands of lipid species present in a small amount of sample. To enhance the capabilities of MS for the qualitative and quantitative analysis of lipids, different platforms have been combined to cover a wide range of lipidomes with high sensitivity, specificity, and accuracy. Currently, MS-based technologies are being established as efficient methods for discovering potential diagnostic biomarkers for COVID-19 and related diseases. As the lipidome of the host cell is drastically affected by the viral replication process, investigating lipid profile alterations in patients with COVID-19 and targeting lipid metabolism pathways are considered to be crucial steps in host-directed drug targeting to develop better therapeutic strategies. This review summarizes various MS-based strategies that have been developed for lipidomic analyzes and biomarker discoveries to combat COVID-19 by integrating various other potential approaches using different human samples. Furthermore, this review discusses the challenges in using MS technologies and future perspectives in terms of drug discovery and diagnosis of COVID-19.
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Affiliation(s)
- Siddabasave Gowda B Gowda
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
- Graduate School of Global Food Resources, Hokkaido University, Sapporo, Japan
| | - Chandra Shekhar
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Divyavani Gowda
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Yifan Chen
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Hitoshi Chiba
- Department of Nutrition, Sapporo University of Health Sciences, Sapporo, Japan
| | - Shu-Ping Hui
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
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3
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Costa VV, Resende F, Melo EM, Teixeira MM. Resolution pharmacology and the treatment of infectious diseases. Br J Pharmacol 2024; 181:917-937. [PMID: 38355144 DOI: 10.1111/bph.16323] [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: 06/28/2023] [Revised: 12/06/2023] [Accepted: 12/28/2023] [Indexed: 02/16/2024] Open
Abstract
Inflammation is elicited by the host in response to microbes, and is believed to be essential for protection against infection. However, we have previously hypothesized that excessive or misplaced inflammation may be a major contributor to tissue dysfunction and death associated with viral and bacterial infections. The resolutive phase of inflammation is a necessary condition to achieve homeostasis after acute inflammation. It is possible that targeting inflammation resolution may be beneficial for the host during infection. In this review, we summarize the evidence demonstrating the expression, roles and effects of the best described pro-resolving molecules in the context of bacterial and viral infections. Pro-resolving molecules play a pivotal role in modulating a spectrum of pathways associated with tissue inflammation and damage during both viral and bacterial infections. These molecules offer a blend of anti-inflammatory, pro-resolving and sometimes anti-infective benefits, all the while circumventing the undesired and immune-suppressive unwanted effects associated with glucocorticoids. Whether these beneficial effects will translate into benefits to patients clearly deserve further investigation.
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Affiliation(s)
- Vivian Vasconcelos Costa
- Centro de Pesquisa e Desenvolvimento de Fármacos, Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Filipe Resende
- Centro de Pesquisa e Desenvolvimento de Fármacos, Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Eliza Mathias Melo
- Centro de Pesquisa e Desenvolvimento de Fármacos, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro Martins Teixeira
- Centro de Pesquisa e Desenvolvimento de Fármacos, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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4
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Kariminezhad Z, Rahimi M, Fernandes J, Maltais R, Sancéau JY, Poirier D, Fahmi H, Benderdour M. Development of New Resolvin D1 Analogues for Osteoarthritis Therapy: Acellular and Computational Approaches to Study Their Antioxidant Activities. Antioxidants (Basel) 2024; 13:386. [PMID: 38671833 PMCID: PMC11047542 DOI: 10.3390/antiox13040386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/07/2024] [Accepted: 03/15/2024] [Indexed: 04/28/2024] Open
Abstract
In osteoarthritis (OA), oxidative stress plays a crucial role in maintaining and sustaining cartilage degradation. Current OA management requires a combination of pharmaceutical and non-pharmacological strategies, including intraarticular injections of hyaluronic acid (HA). However, several lines of evidence reported that HA oxidation by reactive oxygen species (ROS) is linked with HA cleavage and fragmentation, resulting in reduced HA viscosity. Resolvin D1 (RvD1) is a lipid mediator that is biosynthesized from omega-3 polyunsaturated fatty acids and is a good candidate with the potential to regulate a panoply of biological processes, including tissue repair, inflammation, oxidative stress, and cell death in OA. Herein, newly designed and synthesized imidazole-derived RvD1 analogues were introduced to compare their potential antioxidant properties with commercially available RvD1. Their antioxidant capacities were investigated by several in vitro chemical assays including oxygen radical absorbance capacity, 2,2-diphenyl-1-picrylhydrazyl radical scavenging, ferric ion reducing antioxidant power, hydroxyl radical scavenging, and HA fragmentation assay. All results proved that imidazole-derived RvD1 analogues showed excellent antioxidant performance compared to RvD1 due to their structural modifications. Interestingly, they scavenged the formed reactive oxygen species (ROS) and protected HA from degradation, as verified by agarose gel electrophoresis and gel permission chromatography. A computational study using Gaussian 09 with DFT calculations and a B3LYP/6-31 G (d, p) basis set was also employed to study the relationship between the antioxidant properties and chemical structures as well as calculation of the molecular structures, frontier orbital energy, molecular electrostatic potential, and bond length. The results showed that the antioxidant activity of our analogues was higher than that of RvD1. In conclusion, the findings suggest that imidazole-derived RvD1 analogues can be good candidates as antioxidant molecules for the treatment of oxidative stress-related diseases like OA. Therefore, they can prolong the longevity of HA in the knee and thus may improve the mobility of the articulation.
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Affiliation(s)
- Zahra Kariminezhad
- Orthopedic Research Laboratory, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, QC H4J 1C5, Canada; (Z.K.); (M.R.); (J.F.)
| | - Mahdi Rahimi
- Orthopedic Research Laboratory, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, QC H4J 1C5, Canada; (Z.K.); (M.R.); (J.F.)
| | - Julio Fernandes
- Orthopedic Research Laboratory, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, QC H4J 1C5, Canada; (Z.K.); (M.R.); (J.F.)
| | - René Maltais
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada; (R.M.); (J.-Y.S.); (D.P.)
| | - Jean-Yves Sancéau
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada; (R.M.); (J.-Y.S.); (D.P.)
| | - Donald Poirier
- Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada; (R.M.); (J.-Y.S.); (D.P.)
- Organic Synthesis Service, Medicinal Chemistry Platform, CHU de Québec Research Center, Université Laval, Québec, QC G1V 4G2, Canada
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montréal, QC H2X 0A9, Canada;
| | - Mohamed Benderdour
- Orthopedic Research Laboratory, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, QC H4J 1C5, Canada; (Z.K.); (M.R.); (J.F.)
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Di Profio E, Risé P, Orlandi L, Zoia E, Pinna C, Sala A, Zuccotti G, Verduci E. Unsaturated fatty acids, omega-3 index and hospitalization in MISC. Prostaglandins Leukot Essent Fatty Acids 2024; 202:102627. [PMID: 38964007 DOI: 10.1016/j.plefa.2024.102627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 06/19/2024] [Accepted: 06/30/2024] [Indexed: 07/06/2024]
Abstract
The growing interest in Omega-3 fatty acids as diagnostic markers or new therapeutic approaches also for COVID-19 disease, led us to investigate the presence of potential correlations between Omega-3 fatty acids' levels in whole blood and days of hospitalization or admission to the paediatric intensive care unit (PICU) in 51 children with MIS-C diagnosis following SARS-CoV-2 infection. A statistically significant negative correlation was observed between days of hospitalization and docosapentaenoic acid (22:5n-3,DPA), docosahexaenoic acid (DHA) and total Omega-3 FA levels. Dividing the study group into quartiles according to Omega-3-Index (O3I), no statistically significant difference was observed with respect to the PICU admission rate. In contrast, the number of days of hospitalization in Q4 (O3I ≥ 2.51 %) was different from the number observed in groups Q1-3 (O3I < 2.51 %), with subjects showing higher O3I needing shorter hospitalizations than the subjects with lower O3I. According to previous study investigating O3I in adults affected by Sars-cov-2 we explored the levels of this nutrients in children with MIS-C. Our exploratory study shows that high DPA, DHA and O3I levels could be effective in reducing the length of hospitalization.
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Affiliation(s)
| | - Patrizia Risé
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
| | - Lara Orlandi
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
| | - Elena Zoia
- Anesthesia and Intensive Care Unit, "Vittore Buzzi" Children's Hospital, 20154 Milan, Italy
| | - Christian Pinna
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
| | - Angelo Sala
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy
| | - Gianvincenzo Zuccotti
- Department of Pediatrics, Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy; Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
| | - Elvira Verduci
- Department of Health Sciences, University of Milan, 20142 Milan, Italy; Metabolic Diseases Unit, Department of Pediatrics, Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy.
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Celik Z, Ozen G, Sunar S, Turkyilmaz S, Turkyilmaz G, Kavala AA, Teskin O, Dogan BSU, Topal G. Effect of specialized pro-resolving lipid mediators in the regulation of vascular tone and inflammation in human saphenous vein. Prostaglandins Other Lipid Mediat 2023; 169:106786. [PMID: 37806440 DOI: 10.1016/j.prostaglandins.2023.106786] [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: 04/13/2023] [Revised: 09/23/2023] [Accepted: 10/05/2023] [Indexed: 10/10/2023]
Abstract
Specialized pro-resolving lipid mediators (SPMs), derived from polyunsaturated fatty acids are important mediators in the resolution of inflammation. Recent studies have focused on the effects of SPMs in cardiovascular health and diseases. However, little is known about the effect SPMs on human vascular tone. Therefore, in this study it is aimed to investigate the effect of various SPMs including resolvin D- and E-series, maresin-1 (MaR1) and lipoxin-A4 (LxA4) on the vascular tone of human isolated saphenous vein (SV) preparations under inflammatory conditions. In addition, we aimed to evaluate the effects of SPMs on the release of pro-inflammatory mediators, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF- α) from human SV. Pretreatment of isolated of human SV with resolvin E1 (RvE1), resolvin D1 (RvD1) and MaR1 (100 nM, 18 h) significantly reduced the contractile responses to thromboxane A2 mimetic, U46619 whereas pretreatment with LxA4 and RvD2 (100 nM, 18 h) had no significant effect on the vascular tone of SV. Moreover, RvE1, RvD1 and MaR1 but not LxA4 and RvD2 (100 nM, 18 h) pretreatment diminished the release of MCP-1 and TNF-α from SV. In conclusion, our findings suggest that pre-treatment with RvE1, RvD1, and MaR1 could have potential benefits in decreasing graft vasospasm and vascular inflammation in SV.
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Affiliation(s)
- Zeynep Celik
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey; Department of Pharmacology, Istanbul University, Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Gulsev Ozen
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey
| | - Seynur Sunar
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey; Department of Pharmacology, Istanbul University, Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Saygın Turkyilmaz
- Department of Cardiovascular Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital Bakirkoy, Istanbul, Turkey
| | - Gulsum Turkyilmaz
- Department of Cardiovascular Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital Bakirkoy, Istanbul, Turkey
| | - Ali Aycan Kavala
- Department of Cardiovascular Surgery, Bakirkoy Dr. Sadi Konuk Education and Research Hospital Bakirkoy, Istanbul, Turkey
| | - Onder Teskin
- Department of Cardiovascular Surgery, Biruni University, Istanbul, Turkey
| | - B Sonmez Uydes Dogan
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey
| | - Gokce Topal
- Department of Pharmacology, Istanbul University Faculty of Pharmacy, Istanbul, Turkey.
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7
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Hamaguchi A, Fukuda H, Fujiwara K, Harada T, Fukushima K, Shuto S, Fujino H. Individual resolvin E family members work distinctly and in a coordinated manner in the resolution of inflammation. Prostaglandins Other Lipid Mediat 2023; 168:106759. [PMID: 37327943 DOI: 10.1016/j.prostaglandins.2023.106759] [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: 03/29/2023] [Revised: 06/02/2023] [Accepted: 06/12/2023] [Indexed: 06/18/2023]
Abstract
Three main E-type resolvins (RvEs): RvE1, RvE2, and RvE3, have roles in the resolution of inflammation as anti-inflammatory activities. To investigate the roles of each RvE in the resolution of inflammation, timing of interleukin (IL)- 10 release and IL-10 receptor expressions, and phagocytosis evoked by each RvE in differentiated human monocytes, macrophage-like U937 cells were examined. Here, we show that RvEs enhance the expression of IL-10, and IL-10 receptor-mediated signaling pathways and IL-10-mediated-signaling-independent resolution of inflammatory effects by activating the phagocytotic function. Thus, RvE2 mainly evoked an IL-10-mediated anti-inflammatory function, whereas RvE3 principally activated phagocytotic activity of macrophages, which may be involved in tissue repair. On the other hand, RvE1 showed both functions, although not prominent but rather acting as a relief mediator that takes over the RvE2 function and passes over to the RvE3 function. Therefore, each RvE may act as an important role/stage-specific mediator in a coordinated manner with other RvEs in the processes of the resolution of inflammation.
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Affiliation(s)
- Ayaka Hamaguchi
- Department of Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Hayato Fukuda
- Laboratory of Organic Chemistry for Drug Development, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Koichi Fujiwara
- Laboratory of Organic Chemistry for Drug Development, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Tomofumi Harada
- Department of Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Keijo Fukushima
- Department of Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Satoshi Shuto
- Laboratory of Organic Chemistry for Drug Development, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
| | - Hiromichi Fujino
- Department of Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan.
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Liu M, He H, Fan F, Qiu L, Zheng F, Guan Y, Yang G, Chen L. Maresin-1 protects against pulmonary arterial hypertension by improving mitochondrial homeostasis through ALXR/HSP90α axis. J Mol Cell Cardiol 2023; 181:15-30. [PMID: 37244057 DOI: 10.1016/j.yjmcc.2023.05.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/10/2023] [Accepted: 05/16/2023] [Indexed: 05/29/2023]
Abstract
AIMS Pulmonary arterial hypertension (PAH) is a progressive and lethal disease characterized by continuous proliferation of pulmonary arterial smooth muscle cell (PASMCs) and increased pulmonary vascular remodeling. Maresin-1 (MaR1) is a member of pro-resolving lipid mediators and exhibits protective effects on various inflammation-related diseases. Here we aimed to study the role of MaR1 in the development and progression of PAH and to explore the underlying mechanisms. METHODS AND RESULTS We evaluated the effect of MaR1 treatment on PAH in both monocrotaline (MCT)-induced rat and hypoxia+SU5416 (HySu)-induced mouse models of pulmonary hypertension (PH). Plasma samples were collected from patients with PAH and rodent PH models to examine MaR1 production. Specific shRNA adenovirus or inhibitors were used to block the function of MaR1 receptors. The data showed that MaR1 significantly prevented the development and blunted the progression of PH in rodents. Blockade of the function of MaR1 receptor ALXR, but not LGR6 or RORα, with BOC-2, abolished the protective effect of MaR1 against PAH development and reduced its therapeutic potential. Mechanistically, we demonstrated that the MaR1/ALXR axis suppressed hypoxia-induced PASMCs proliferation and alleviated pulmonary vascular remodeling by inhibiting mitochondrial accumulation of heat shock protein 90α (HSP90α) and restoring mitophagy. CONCLUSION MaR1 protects against PAH by improving mitochondrial homeostasis through ALXR/HSP90α axis and represents a promising target for PAH prevention and treatment.
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Affiliation(s)
- Min Liu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Huixiang He
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Fenling Fan
- Division of Pulmonary Vascular Disease, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Lejia Qiu
- Health Science Center, East China Normal University, Shanghai 200241, China
| | - Feng Zheng
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Guangrui Yang
- School of Bioengineering, Dalian University of Technology, Dalian 116024, China
| | - Lihong Chen
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Health Science Center, East China Normal University, Shanghai 200241, China.
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9
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Nunes VS, Abrahão O, Rogério AP, Serhan CN. ALX/FPR2 Activation by Stereoisomers of D1 Resolvins Elucidating with Molecular Dynamics Simulation. J Phys Chem B 2023; 127:6479-6486. [PMID: 37428488 PMCID: PMC10528287 DOI: 10.1021/acs.jpcb.3c01787] [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] [Indexed: 07/11/2023]
Abstract
Chronic inflammation contributes to several diseases, but its resolution is driven by specialized pro-resolving mediators (SPM) such as resolvin D1 (RvD1) and its epimer aspirin-triggered resolvin D1 (AT-RvD1), both biosynthesized from ω-3 fatty docosahexaenoic acid (DHA). RvD1 and AT-RvD1 have anti-inflammatory and pro-resolution potentials, and their effects could be mediated by formyl peptide receptor type 2 receptor ALX/FPR2, a G-protein-coupled receptor (GPCR). In this work, we performed 44 μs of molecular dynamics simulations with two complexes: FPR2@AT-RvD1 and FPR2@RvD1. Our results show the following: (i) in the AT-RvD1 simulations, the ALX/FPR2 receptor remained in the active state in 62% of the frames, while in the RVD1 simulations, the receptor remained in the active state in 74% of the frames; (ii) two residues, R201 and R205, of ALX/FPR2 appear, establishing interactions with both resolvins in all simulations (22 in total); (iii) RvD1 hydrogen bonds with R201 and R205 presented higher frequency than AT-RvD1; and (iv) residues R201 and R205 are the two receptor hotspots, demonstrated by the binding free calculations. Such results show that the ALX/FPR2 receptor remained in the active state for longer in the FPR2@RvD1 simulations than in the FPR2@AT-RvD1 simulations.
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Affiliation(s)
- Vinicius S. Nunes
- Laboratório Nacional de Computação Científica, Petrópolis, Rio de Janeiro, Brasil
- Laboratório de Química Computacional Medicinal, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brasil
| | - Odonírio Abrahão
- Laboratório de Química Computacional Medicinal, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brasil
| | - Alexandre P. Rogério
- Laboratório de Imunofarmacologia Experimental, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brasil
| | - Charles N. Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Rasquel-Oliveira FS, Silva MDVD, Martelossi-Cebinelli G, Fattori V, Casagrande R, Verri WA. Specialized Pro-Resolving Lipid Mediators: Endogenous Roles and Pharmacological Activities in Infections. Molecules 2023; 28:5032. [PMID: 37446699 DOI: 10.3390/molecules28135032] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/07/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
During an infection, inflammation mobilizes immune cells to eliminate the pathogen and protect the host. However, inflammation can be detrimental when exacerbated and/or chronic. The resolution phase of the inflammatory process is actively orchestrated by the specialized pro-resolving lipid mediators (SPMs), generated from omega-3 and -6 polyunsaturated fatty acids (PUFAs) that bind to different G-protein coupled receptors to exert their activity. As immunoresolvents, SPMs regulate the influx of leukocytes to the inflammatory site, reduce cytokine and chemokine levels, promote bacterial clearance, inhibit the export of viral transcripts, enhance efferocytosis, stimulate tissue healing, and lower antibiotic requirements. Metabolomic studies have evaluated SPM levels in patients and animals during infection, and temporal regulation of SPMs seems to be essential to properly coordinate a response against the microorganism. In this review, we summarize the current knowledge on SPM biosynthesis and classifications, endogenous production profiles and their effects in animal models of bacterial, viral and parasitic infections.
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Affiliation(s)
- Fernanda S Rasquel-Oliveira
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
| | - Matheus Deroco Veloso da Silva
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
| | - Geovana Martelossi-Cebinelli
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
| | - Victor Fattori
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Rubia Casagrande
- Department of Pharmaceutical Sciences, Center of Health Science, Londrina State University, Londrina 86038-440, Paraná, Brazil
| | - Waldiceu A Verri
- Laboratory of Pain, Inflammation, Neuropathy, and Cancer, Department of Pathology, Center of Biological Sciences, Londrina State University, Londrina 86057-970, Paraná, Brazil
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11
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Grewal T, Buechler C. Adipokines as Diagnostic and Prognostic Markers for the Severity of COVID-19. Biomedicines 2023; 11:1302. [PMID: 37238973 PMCID: PMC10215701 DOI: 10.3390/biomedicines11051302] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/26/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Accumulating evidence implicates obesity as a risk factor for increased severity of disease outcomes in patients infected with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Obesity is associated with adipose tissue dysfunction, which not only predisposes individuals to metabolic complications, but also substantially contributes to low-grade systemic inflammation, altered immune cell composition, and compromised immune function. This seems to impact the susceptibility and outcome of diseases caused by viruses, as obese people appear more vulnerable to developing infections and they recover later from infectious diseases than normal-weight individuals. Based on these findings, increased efforts to identify suitable diagnostic and prognostic markers in obese Coronavirus disease 2019 (COVID-19) patients to predict disease outcomes have been made. This includes the analysis of cytokines secreted from adipose tissues (adipokines), which have multiple regulatory functions in the body; for instance, modulating insulin sensitivity, blood pressure, lipid metabolism, appetite, and fertility. Most relevant in the context of viral infections, adipokines also influence the immune cell number, with consequences for overall immune cell activity and function. Hence, the analysis of the circulating levels of diverse adipokines in patients infected with SARS-CoV-2 have been considered to reveal diagnostic and prognostic COVID-19 markers. This review article summarizes the findings aimed to correlate the circulating levels of adipokines with progression and disease outcomes of COVID-19. Several studies provided insights on chemerin, adiponectin, leptin, resistin, and galectin-3 levels in SARS-CoV-2-infected patients, while limited information is yet available on the adipokines apelin and visfatin in COVID-19. Altogether, current evidence points at circulating galectin-3 and resistin levels being of diagnostic and prognostic value in COVID-19 disease.
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Affiliation(s)
- Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia;
| | - Christa Buechler
- Department of Internal Medicine I, Regensburg University Hospital, 93053 Regensburg, Germany
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12
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Sousa AB, Barbosa JN. The Use of Specialized Pro-Resolving Mediators in Biomaterial-Based Immunomodulation. J Funct Biomater 2023; 14:jfb14040223. [PMID: 37103313 PMCID: PMC10145769 DOI: 10.3390/jfb14040223] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/28/2023] Open
Abstract
The implantation of a biomaterial will lead to the immediate onset of an acute inflammatory response, which is of key importance in shaping the quality of the repair process. However, the return to homeostasis is critical to prevent a chronic inflammatory response that may impair the healing process. The resolution of the inflammatory response is now recognized as an active and highly regulated process, being described as specialized immunoresolvents that have a fundamental role in the termination of the acute inflammatory response. These mediators collectively coined as specialized pro-resolving mediators (SPMs) are a family of endogenous molecules that include lipoxins (Lx), resolvins (Rv), protectins (PD), maresins (Mar), Cysteinyl-SPMs (Cys-SPMs) and n-3 docosapentaenoic acid-derived SPMs (n-3 DPA-derived SPMs). SPMs have important anti-inflammatory and pro-resolutive actions such as decreasing the recruitment of polymorphonuclear leukocytes (PMNs), inducing the recruitment of anti-inflammatory macrophages, and increasing macrophage clearance of apoptotic cells through a process known as efferocytosis. Over the last years, the trend in biomaterials research has shifted towards the engineering of materials that are able to modulate the inflammatory response and thus stimulate appropriate immune responses, the so-called immunomodulatory biomaterials. These materials should be able to modulate the host immune response with the aim of creating a pro-regenerative microenvironment. In this review, we explore the potential of using of SPMs in the development of new immunomodulatory biomaterials and we propose insights for future research in this field.
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Affiliation(s)
- Ana Beatriz Sousa
- i3S-Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Judite N Barbosa
- i3S-Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- INEB-Instituto de Engenharia Biomédica, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
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13
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Palakkott AR, Alneyadi A, Muhammad K, Eid AH, Amiri KMA, Akli Ayoub M, Iratni R. The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling. Vaccines (Basel) 2023; 11:768. [PMID: 37112680 PMCID: PMC10141239 DOI: 10.3390/vaccines11040768] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/11/2023] [Accepted: 03/14/2023] [Indexed: 04/03/2023] Open
Abstract
The coronavirus disease-19 (COVID-19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the molecular and cellular levels, the SARS-CoV-2 uses its envelope glycoprotein, the spike S protein, to infect the target cells in the lungs via binding with their transmembrane receptor, the angiotensin-converting enzyme 2 (ACE2). Here, we wanted to investigate if other molecular targets and pathways may be used by SARS-CoV-2. We investigated the possibility of the spike 1 S protein and its receptor-binding domain (RBD) to target the epidermal growth factor receptor (EGFR) and its downstream signaling pathway in vitro using the lung cancer cell line (A549 cells). Protein expression and phosphorylation were examined upon cell treatment with the recombinant full spike 1 S protein or RBD. We demonstrate for the first time the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical Extracellular signal-regulated kinase1/2 (ERK1/2) and AKT kinases and an increase in survivin expression controlling the survival pathway. Our study suggests the putative implication of EGFR and its related signaling pathways in SARS-CoV-2 infectivity and COVID-19 pathology. This may open new perspectives in the treatment of COVID-19 patients by targeting EGFR.
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Affiliation(s)
- Abdul Rasheed Palakkott
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Aysha Alneyadi
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Khalid Muhammad
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Ali Hussein Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
| | - Khaled M. A. Amiri
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Khalifa Center for Biotechnology and Genetic Engineering, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Mohammed Akli Ayoub
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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14
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Yasmeen N, Selvaraj H, Lakhawat SS, Datta M, Sharma PK, Jain A, Khanna R, Srinivasan J, Kumar V. Possibility of averting cytokine storm in SARS-COV 2 patients using specialized pro-resolving lipid mediators. Biochem Pharmacol 2023; 209:115437. [PMID: 36731803 PMCID: PMC9884647 DOI: 10.1016/j.bcp.2023.115437] [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: 12/02/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023]
Abstract
Fatal "cytokine storms (CS)" observed in critically ill COVID-19 patients are consequences of dysregulated host immune system and over-exuberant inflammatory response. Acute respiratory distress syndrome (ARDS), multi-system organ failure, and eventual death are distinctive symptoms, attributed to higher morbidity and mortality rates among these patients. Consequent efforts to save critical COVID-19 patients via the usage of several novel therapeutic options are put in force. Strategically, drugs being used in such patients are dexamethasone, remdesivir, hydroxychloroquine, etc. along with the approved vaccines. Moreover, it is certain that activation of the resolution process is important for the prevention of chronic diseases. Until recently Inflammation resolution was considered a passive process, rather it's an active biochemical process that can be achieved by the use of specialized pro-resolving mediators (SPMs). These endogenous mediators are an array of atypical lipid metabolites that include Resolvins, lipoxins, maresins, protectins, considered as immunoresolvents, but their role in COVID-19 is ambiguous. Recent evidence from studies such as the randomized clinical trial, in which omega 3 fatty acid was used as supplement to resolve inflammation in COVID-19, suggests that direct supplementation of SPMs or the use of synthetic SPM mimetics (which are still being explored) could enhance the process of resolution by regulating the aberrant inflammatory process and can be useful in pain relief and tissue remodeling. Here we discussed the biosynthesis of SPMs, & their mechanistic pathways contributing to inflammation resolution along with sequence of events leading to CS in COVID-19, with a focus on therapeutic potential of SPMs.
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Affiliation(s)
- Nusrath Yasmeen
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Harikrishnan Selvaraj
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Sudarshan S Lakhawat
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Manali Datta
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Pushpender K Sharma
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Ajay Jain
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Rakhi Khanna
- Rajasthan State Regional Forensic Science Laboratory, Kota, Rajasthan, India
| | | | - Vikram Kumar
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India.
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15
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Kumar V, Yasmeen N, Chaudhary AA, Alawam AS, Al-Zharani M, Suliman Basher N, Harikrishnan S, Goud MD, Pandey A, Lakhawat SS, Sharma PK. Specialized pro-resolving lipid mediators regulate inflammatory macrophages: A paradigm shift from antibiotics to immunotherapy for mitigating COVID-19 pandemic. Front Mol Biosci 2023; 10:1104577. [PMID: 36825200 PMCID: PMC9942001 DOI: 10.3389/fmolb.2023.1104577] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/24/2023] [Indexed: 02/05/2023] Open
Abstract
The most severe clinical manifestations of the horrifying COVID-19 disease, that claimed millions of lives during the pandemic time, were Acute respiratory distress syndrome (ARDS), Coagulopathies, septic shock leading eventually to death. ARDS was a consequence of Cytokine storm. The viral SARS-COV2infection lead to avalanche of cytokines and eicosanoids causing "cytokine storm" and "eicosanoid storm." Cytokine storm is one of the macrophage-derived inflammatory responses triggered by binding of virus particles to ACE2 receptors of alveolar macrophages, arise mainly due to over production of various pro-inflammatory mediators like cytokines, e.g., interleukin (IL)-1, IL-2, and tumor necrosis factor (TNF)- α, causing pulmonary edema, acute respiratory distress, and multi-organ failure. Cytokine storm was regarded as the predictor of severity of the disease and was deemed one of the causes of the high mortality rates due to the COVID-19. The basis of cytokine storm is imbalanced switching between an inflammation increasing - pro-inflammatory (M1) and an inflammation regulating-anti-inflammatory (M2) forms of alveolar macrophages which further deteriorates if opportunistic secondary bacterial infections prevail in the lungs. Lack of sufficient knowledge regarding the virus and its influence on co-morbidities, clinical treatment of the diseases included exorbitant use of antibiotics to mitigate secondary bacterial infections, which led to the unwarranted development of multidrug resistance (MDR) among the population across the globe. Antimicrobial resistance (AMR) needs to be addressed from various perspectives as it may deprive future generations of the basic health immunity. Specialized pro-resolving mediators (SPMs) are generated from the stereoselective enzymatic conversions of essential fatty acids that serve as immune resolvents in controlling acute inflammatory responses. SPMs facilitate the clearance of injured tissue and cell debris, the removal of pathogens, and augment the concentration of anti-inflammatory lipid mediators. The SPMs, e.g., lipoxins, protectins, and resolvins have been implicated in exerting inhibitory influence on with cytokine storm. Experimental evidence suggests that SPMS lower antibiotic requirement. Therefore, in this review potential roles of SPMs in enhancing macrophage polarization, triggering immunological functions, hastening inflammation resolution, subsiding cytokine storm and decreasing antibiotic requirement that can reduce AMR load are discussed.
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Affiliation(s)
- Vikram Kumar
- Amity institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India,*Correspondence: Vikram Kumar,
| | - Nusrath Yasmeen
- Amity institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Abdullah S. Alawam
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Mohammed Al-Zharani
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Nosiba Suliman Basher
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - S. Harikrishnan
- Amity institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | | | - Aishwarya Pandey
- INRS, Eau Terre Environnement Research Centre, Québec, QC, Canada
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16
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Phung HH, Lee CH. Mouse models of nonalcoholic steatohepatitis and their application to new drug development. Arch Pharm Res 2022; 45:761-794. [DOI: 10.1007/s12272-022-01410-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022]
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17
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Janciauskiene S, Tumpara S, Schebb NH, Buettner FFR, Mainka M, Sivaraman K, Immenschuh S, Grau V, Welte T, Olejnicka B. Indirect effect of alpha-1-antitrypsin on endotoxin-induced IL-1β secretion from human PBMCs. Front Pharmacol 2022; 13:995869. [PMID: 36249781 PMCID: PMC9564231 DOI: 10.3389/fphar.2022.995869] [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: 07/16/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Human alpha-1-antitrypsin (AAT) encoded by the SERPINA1 gene, is an acute phase glycoprotein that regulates inflammatory responses via both protease inhibitory and non-inhibitory activities. We previously reported that AAT controls ATP-induced IL-1β release from human mononuclear cells by stimulating the release of small bioactive molecules. In the current study, we aimed to elucidate the identity of these putative effectors released from human PBMCs in response to AAT, which may inhibit the LPS-induced release of IL-1β. We pre-incubated human PBMCs alone or with different preparations of AAT (4 mg/ml) for 30 min at 37°C, 5% CO2, and collected cell supernatants filtered through centrifugal filters (cutoff 3 kDa) to eliminate AAT and other high molecular weight substances. Supernatants passed through the filters were used to culture PBMCs isolated from the autologous or a heterologous donors with or without adding LPS (1 μg/ml) for 6 h. Unexpectedly, supernatants from PBMCs pre-incubated with AAT (Zemaira®), but not with other AAT preparations tested or with oxidized AAT (Zemaira®), lowered the LPS-induced release of IL-1β by about 25%–60% without affecting IL1B mRNA. The reversed-phase liquid chromatography coupled with mass spectrometry did not confirm the hypothesis that small pro-resolving lipid mediators released from PBMCs after exposure to AAT (Zemaira®) are responsible for lowering the LPS-induced IL-1β release. Distinctively from other AAT preparations, AAT (Zemaira®) and supernatants from PBMCs pre-treated with this protein contained high levels of total thiols. In line, mass spectrometry analysis revealed that AAT (Zemaira®) protein contains freer Cys232 than AAT (Prolastin®). Our data show that a free Cys232 in AAT is required for controlling LPS-induced IL-1β release from human PBMCs. Further studies characterizing AAT preparations used to treat patients with inherited AAT deficiency remains of clinical importance.
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Affiliation(s)
- Sabina Janciauskiene
- Department of Respiratory Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
- Department of Experimental Medicine, Lund University, Lund, Sweden
- *Correspondence: Sabina Janciauskiene,
| | - Srinu Tumpara
- Department of Respiratory Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
| | - Nils Helge Schebb
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Falk F. R. Buettner
- Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
| | - Malwina Mainka
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Kokilavani Sivaraman
- Department of Respiratory Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
| | - Stephan Immenschuh
- Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Veronika Grau
- Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, German Center for Lung Research, Giessen, Germany
| | - Tobias Welte
- Department of Respiratory Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
| | - Beata Olejnicka
- Department of Respiratory Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany
- Department of Experimental Medicine, Lund University, Lund, Sweden
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18
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McCarthy CE, Duffney PF, Nogales A, Post CM, Lawrence BP, Martinez-Sobrido L, Thatcher TH, Phipps RP, Sime PJ. Dung biomass smoke exposure impairs resolution of inflammatory responses to influenza infection. Toxicol Appl Pharmacol 2022; 450:116160. [PMID: 35817128 PMCID: PMC10211473 DOI: 10.1016/j.taap.2022.116160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 01/26/2023]
Abstract
Epidemiological studies associate biomass smoke with an increased risk for respiratory infections in children and adults in the developing world, with 500,000 premature deaths each year attributed to biomass smoke-related acute respiratory infections including infections caused by respiratory viruses. Animal dung is a biomass fuel of particular concern because it generates more toxic compounds per amount burned than wood, and is a fuel of last resort for the poorest households. Currently, there is little biological evidence on the effects of dung biomass smoke exposure on immune responses to respiratory viral infections. Here, we investigated the impact of dung biomass exposure on respiratory infection using a mouse model of dung biomass smoke and cultured primary human small airway epithelial cells (SAECs). Mice infected with influenza A virus (IAV) after dung biomass smoke exposure had increased mortality, lung inflammation and virus mRNA levels, and suppressed expression of innate anti-viral mediators compared to air exposed mice. Importantly, there was still significant tissue inflammation 14 days after infection in dung biomass smoke-exposed mice even after inflammation had resolved in air-exposed mice. Dung biomass smoke exposure also suppressed the production of anti-viral cytokines and interferons in cultured SAECs treated with poly(I:C) or IAV. This study shows that dung biomass smoke exposure impairs the immune response to respiratory viruses and contributes to biomass smoke-related susceptibility to respiratory viral infections, likely due to a failure to resolve the inflammatory effects of biomass smoke exposure.
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Affiliation(s)
| | - Parker F Duffney
- United States Environmental Protection Agency, Integrated Health Assessment Branch, Research Triangle Park, NC, USA
| | - Aitor Nogales
- Centro de Investigación en Sanidad Animal (CISA), INIA-CSIC, Madrid, Spain
| | - Christina M Post
- Department of Environmental Medicine, University of Rochester, Rochester NY, New York, United States
| | - B Paige Lawrence
- Department of Environmental Medicine, University of Rochester, Rochester NY, New York, United States
| | | | - Thomas H Thatcher
- Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Patricia J Sime
- Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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19
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LipoxinA4 as a Potential Prognostic Marker of COVID-19. J Lipids 2022; 2022:8527305. [PMID: 35812307 PMCID: PMC9259546 DOI: 10.1155/2022/8527305] [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: 04/05/2022] [Revised: 06/02/2022] [Accepted: 06/14/2022] [Indexed: 11/17/2022] Open
Abstract
This pilot study aimed to determine early changes of LXA4 levels among the hospitalized patients confirmed as COVID-19 cases following the clinical management and its correlation with commonly used inflammatory markers, including erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), and ferritin. Thirty-one adult hospitalized patients infected with the non-severe COVID-19 were included. LXA4 levels were measured at the baseline and 48-72 hours after hospitalization. Accordingly, ESR and CRP levels were collected on the first day of hospitalization. Moreover, the maximum serum ferritin levels were determined during the five days. LXA4 levels significantly increased at 48-72 hours compared to the baseline. ESR, CRP, and ferritin levels were positively correlated with the increased LXA4. In contrast, aging was shown to negatively correlate with the increased LXA4 levels. LXA4 may be known as a valuable marker to assess the treatment response among non-elderly patients with non-severe COVID-19. Furthermore, LXA4 could be considered as a potential treatment option under inflammatory conditions. Further studies are necessary to clarify LXA4 role in COVID-19 pathogenesis, as well as the balance between such pro-resolving mediators and inflammatory parameters.
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20
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Liu M, He H, Chen L. Protective Potential of Maresins in Cardiovascular Diseases. Front Cardiovasc Med 2022; 9:923413. [PMID: 35859590 PMCID: PMC9289265 DOI: 10.3389/fcvm.2022.923413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/02/2022] [Indexed: 11/16/2022] Open
Abstract
Cardiovascular diseases are the leading causes of global mortality. Growing evidence suggests that unresolved inflammation contributes to the chronicity, progression and morbidity of many cardiovascular diseases, thus emphasizing the urgent need to illuminate the mechanisms controlling inflammation and its resolution, for the sake of new effective therapeutic options. Macrophage mediators in resolving inflammation (Maresins) are a family of specialized pro-resolving lipid mediators (SPMs) derived from the ω-3 fatty acid docosahexaenoic acid (DHA). Studies have indicated that Maresins play critical role in initiating the pro-resolving functions of phagocytes, decreasing the magnitude of the overall inflammatory response, and thereby protecting against inflammation-related disorders. In this review, we summarize the detailed actions and the therapeutic potential of Maresins, with a particular emphasis on Maresin-1 (MaR1), in cardiovascular diseases. We hope this review will lead to new avenues to Maresins-based therapies for inflammation-associated cardiovascular diseases.
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21
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Radbakhsh S, Katsiki N, Santos RD, Mikhailidis DP, Mantzoros CS, Sahebkar A. Effects of statins on specialized pro-resolving mediators: An additional pathway leading to resolution of inflammation. Metabolism 2022; 132:155211. [PMID: 35533891 DOI: 10.1016/j.metabol.2022.155211] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/22/2022] [Accepted: 04/23/2022] [Indexed: 11/21/2022]
Abstract
Statins are a class of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Anti-inflammatory and antioxidant properties, as well as improvement of endothelial function and plaque stabilization have also been proposed as parts of the pleiotropic effects of statins. Specialized pro-resolving mediators (SPMs) are endogenous lipid-derived molecules originating from ω-6 and ω-3 polyunsaturated fatty acids, such as arachidonic, docosahexaenoic and eicosapentaenoic acid that trigger and modulate the resolution of inflammation. Impaired SPM biosynthesis can lead to excessive or chronic inflammation and is implicated in the pathogenesis of several diseases. Exogenous administration of SPMs, including lipoxin, maresin, protectin, have been shown to improve both bacterial and viral infections, mainly in preclinical models, thus minimizing inflammation. Statin-triggered-SPM production in several in vitro and in vivo models may represent another anti-inflammatory pathway involving these drugs. This commentary discusses scientific publications on the effects of statins on SPMs and the resolution of inflammation process.
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Affiliation(s)
- Shabnam Radbakhsh
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Niki Katsiki
- First Department of Internal Medicine, Diabetes Center, Division of Endocrinology and Metabolism, AHEPA University Hospital, Thessaloniki, Greece
| | - Raul D Santos
- Lipid Clinic Heart Institute (Incor), University of São Paulo, Medical School Hospital, São Paulo, Brazil
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital campus, University College London, London, UK
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Western Australia, Mashhad, Iran.
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22
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Karimi Z, Oskouie AA, Rezaie F, Ajaminejad F, Marashi SM, Azad TM. The Effect of Influenza Virus on The Metabolism of Peripheral Blood Mononuclear Cells with Metabolomics Approach. J Med Virol 2022; 94:4383-4392. [DOI: 10.1002/jmv.27843] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/27/2022] [Accepted: 05/06/2022] [Indexed: 11/08/2022]
Affiliation(s)
- Zeinab Karimi
- Department of Virology, School of Public Health, Tehran University of Medical ScienceTehranIran
| | - Afsaneh Arefi Oskouie
- Department of Basic, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical SciencesTehranIran
| | - Farhad Rezaie
- Department of Virology, School of Public Health, Tehran University of Medical ScienceTehranIran
| | - Fatemeh Ajaminejad
- Department of Virology, School of Public Health, Tehran University of Medical ScienceTehranIran
| | - Sayed Mahdi Marashi
- Department of Virology, School of Public Health, Tehran University of Medical ScienceTehranIran
| | - Talat Mokhtari Azad
- Department of Virology, School of Public Health, Tehran University of Medical ScienceTehranIran
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23
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Gallo CG, Fiorino S, Posabella G, Antonacci D, Tropeano A, Pausini E, Pausini C, Guarniero T, Hong W, Giampieri E, Corazza I, Loiacono R, Loggi E, de Biase D, Zippi M, Lari F, Zancanaro M. The function of specialized pro-resolving endogenous lipid mediators, vitamins, and other micronutrients in the control of the inflammatory processes: Possible role in patients with SARS-CoV-2 related infection. Prostaglandins Other Lipid Mediat 2022; 159:106619. [PMID: 35032665 PMCID: PMC8752446 DOI: 10.1016/j.prostaglandins.2022.106619] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 02/07/2023]
Abstract
Inflammation is an essential protective response against harmful stimuli, such as invading pathogens, damaged cells, or irritants. Physiological inflammation eliminates pathogens and promotes tissue repair and healing. Effective immune response in humans depends on a tightly regulated balance among inflammatory and anti-inflammatory mechanisms involving both innate and adaptive arms of the immune system. Excessive inflammation can become pathological and induce detrimental effects. If this process is not self-limited, an inappropriate remodeling of the tissues and organs can occur and lead to the onset of chronic degenerative diseases. A wide spectrum of infectious and non-infectious agents may activate the inflammation, via the release of mediators and cytokines by distinct subtypes of lymphocytes and macrophages. Several molecular mechanisms regulate the onset, progression, and resolution of inflammation. All these steps, even the termination of this process, are active and not passive events. In particular, a complex interplay exists between mediators (belonging to the group of Eicosanoids), which induce the beginning of inflammation, such as Prostaglandins (PGE2), Leukotrienes (LT), and thromboxane A2 (TXA2), and molecules which display a key role in counteracting this process and in promoting its proper resolution. The latter group of mediators includes: ω-6 arachidonic acid (AA)-derived metabolites, such as Lipoxins (LXs), ω -3 eicosapentaenoic acid (EPA)-derived mediators, such as E-series Resolvins (RvEs), and ω -3 docosahexaenoic (DHA)-derived mediators, such as D-series Resolvins (RvDs), Protectins (PDs) and Maresins (MaRs). Overall, these mediators are defined as specialized pro-resolving mediators (SPMs). Reduced synthesis of these molecules may lead to uncontrolled inflammation with possible harmful effects. ω-3 fatty acids are widely used in clinical practice as rather inexpensive, safe, readily available supplemental therapy. Taking advantage of this evidence, several researchers are suggesting that SPMs may have beneficial effects in the complementary treatment of patients with severe forms of SARS-CoV-2 related infection, to counteract the "cytokine storm" observed in these individuals. Well-designed and sized trials in patients suffering from COVID-19 with different degrees of severity are needed to investigate the real impact in the clinical practice of this promising therapeutic approach.
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Affiliation(s)
- Claudio G Gallo
- Emilian Physiolaser Therapy Center, Castel S. Pietro Terme, Bologna, Italy.
| | - Sirio Fiorino
- Internal Medicine Unit, Budrio Hospital Azienda USL, Bologna, Italy
| | | | - Donato Antonacci
- Medical Science Department, "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, FG, Italy
| | | | | | | | | | - Wandong Hong
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang, People's Republic of China
| | - Enrico Giampieri
- Experimental, Diagnostic and Specialty Medicine Department, University of Bologna, Bologna, Italy
| | - Ivan Corazza
- Experimental, Diagnostic and Specialty Medicine Department, University of Bologna, Bologna, Italy
| | - Rossella Loiacono
- Internal Medicine Unit, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy
| | - Elisabetta Loggi
- Hepatology Unit, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Maddalena Zippi
- Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, Rome, Italy
| | - Federico Lari
- Internal Medicine Unit, Budrio Hospital Azienda USL, Bologna, Italy
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24
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Kumar M, Yano N, Fedulov AV. Gestational exposure to titanium dioxide, diesel exhaust, and concentrated urban air particles affects levels of specialized pro-resolving mediators in response to allergen in asthma-susceptible neonate lungs. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2022; 85:243-261. [PMID: 34802391 PMCID: PMC8785906 DOI: 10.1080/15287394.2021.2000906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Maternal gestational exposures to traffic and urban air pollutant particulates have been linked to increased risk and/or worsening asthma in children; however, mechanisms underlying this vertical transmission are not entirely understood. It was postulated that gestational particle exposure might affect the ability to elicit specialized proresolving mediator (SPM) responses upon allergen encounter in neonates. Lipidomic profiling of 50 SPMs was performed in lungs of neonates born to mice exposed to concentrated urban air particles (CAP), diesel exhaust particles (DEP), or less immunotoxic titanium dioxide particles (TiO2). While asthma-like phenotypes were induced with identical eosinophilia intensity across neonates of all particle-exposed mothers, levels of LXA4, HEPE and HETE isoforms, and HDoHe were only decreased by CAP and DEP only but not by TiO2. However, RvE2 and RvD1 were inhibited by all particles. In contrast, isomers of Maresin1 and Protectin D1 were variably elevated by CAP and DEP, whereas Protectin DX, PGE2, and TxB2 were increased in all groups. Only Protectin D1/DX, MaR1(n-3,DPA), 5(S),15(S)-DiHETE, PGE2, and RvE3 correlated with eosinophilia but the majority of other analytes, elevated or inhibited, showed no marked correlation with inflammation intensity. Evidence indicates that gestational particle exposure leads to both particle-specific and nonspecific effects on the SPM network.
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Affiliation(s)
- Mohan Kumar
- Alpert Medical School of Brown University. Department of Surgery, Rhode Island Hospital. 593 Eddy Street, Providence, RI, USA. 02903
| | - Naohiro Yano
- Alpert Medical School of Brown University. Department of Surgery, Rhode Island Hospital. 593 Eddy Street, Providence, RI, USA. 02903
| | - Alexey V. Fedulov
- Alpert Medical School of Brown University. Department of Surgery, Rhode Island Hospital. 593 Eddy Street, Providence, RI, USA. 02903
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25
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Scott MA, Woolums AR, Swiderski CE, Thompson AC, Perkins AD, Nanduri B, Karisch BB, Goehl DR. Use of nCounter mRNA profiling to identify at-arrival gene expression patterns for predicting bovine respiratory disease in beef cattle. BMC Vet Res 2022; 18:77. [PMID: 35197051 PMCID: PMC8864212 DOI: 10.1186/s12917-022-03178-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/17/2022] [Indexed: 01/21/2023] Open
Abstract
Background Transcriptomics has identified at-arrival differentially expressed genes associated with bovine respiratory disease (BRD) development; however, their use as prediction molecules necessitates further evaluation. Therefore, we aimed to selectively analyze and corroborate at-arrival mRNA expression from multiple independent populations of beef cattle. In a nested case-control study, we evaluated the expression of 56 mRNA molecules from at-arrival blood samples of 234 cattle across seven populations via NanoString nCounter gene expression profiling. Analysis of mRNA was performed with nSolver Advanced Analysis software (p < 0.05), comparing cattle groups based on the diagnosis of clinical BRD within 28 days of facility arrival (n = 115 Healthy; n = 119 BRD); BRD was further stratified for severity based on frequency of treatment and/or mortality (Treated_1, n = 89; Treated_2+, n = 30). Gene expression homogeneity of variance, receiver operator characteristic (ROC) curve, and decision tree analyses were performed between severity cohorts. Results Increased expression of mRNAs involved in specialized pro-resolving mediator synthesis (ALOX15, HPGD), leukocyte differentiation (LOC100297044, GCSAML, KLF17), and antimicrobial peptide production (CATHL3, GZMB, LTF) were identified in Healthy cattle. BRD cattle possessed increased expression of CFB, and mRNA related to granulocytic processes (DSG1, LRG1, MCF2L) and type-I interferon activity (HERC6, IFI6, ISG15, MX1). Healthy and Treated_1 cattle were similar in terms of gene expression, while Treated_2+ cattle were the most distinct. ROC cutoffs were used to generate an at-arrival treatment decision tree, which classified 90% of Treated_2+ individuals. Conclusions Increased expression of complement factor B, pro-inflammatory, and type I interferon-associated mRNA hallmark the at-arrival expression patterns of cattle that develop severe clinical BRD. Here, we corroborate at-arrival mRNA markers identified in previous transcriptome studies and generate a prediction model to be evaluated in future studies. Further research is necessary to evaluate these expression patterns in a prospective manner. Supplementary Information The online version contains supplementary material available at 10.1186/s12917-022-03178-8.
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Affiliation(s)
- Matthew A Scott
- Veterinary Education, Research, and Outreach Center, Texas A&M University and West Texas A&M University, Canyon, TX, 79015, USA.
| | - Amelia R Woolums
- Department of Pathobiology and Population Medicine, Mississippi State University, Starkville, MS, 39762, USA
| | - Cyprianna E Swiderski
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, 85721, USA
| | - Alexis C Thompson
- Department of Pathobiology and Population Medicine, Mississippi State University, Starkville, MS, 39762, USA
| | - Andy D Perkins
- Department of Computer Science and Engineering, Mississippi State University, Starkville, MS, 39762, USA
| | - Bindu Nanduri
- Department of Comparative Biomedical Sciences, Mississippi State University, Starkville, MS, 39762, USA
| | - Brandi B Karisch
- Department of Animal and Dairy Sciences, Mississippi State University, Starkville, MS, 39762, USA
| | - Dan R Goehl
- Professional Beef Services, LLC, Canton, MO, 63435, USA
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Abstract
Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an ongoing pandemic causing significant morbidity and mortality worldwide. The “cytokine storm” is a critical driving force in severe COVID-19 cases, leading to hyperinflammation, multi-system organ failure, and death. A paradigm shift is emerging in our understanding of the resolution of inflammation from a passive course to an active biochemical process driven by endogenous specialized pro-resolving mediators (SPMs), such as resolvins, protectins, lipoxins, and maresins. SPMs stimulate macrophage-mediated debris clearance and counter pro-inflammatory cytokine production, a process collectively termed as the “resolution of inflammation.” Hyperinflammation is not unique to COVID-19 and also occurs in neoplastic conditions, putting individuals with underlying health conditions such as cancer at elevated risk of severe SARS-CoV-2 infection. Despite approaches to block systemic inflammation, there are no current therapies designed to stimulate the resolution of inflammation in patients with COVID-19 or cancer. A non-immunosuppressive therapeutic approach that reduces the cytokine storm in patients with COVID-19 and cancer is urgently needed. SPMs are potent immunoresolvent and organ-protective lipid autacoids that stimulate the resolution of inflammation, facilitate clearance of infections, reduce thrombus burden, and promote a return to tissue homeostasis. Targeting endogenous lipid mediators, such as SPMs, offers an entirely novel approach to control SARS-CoV-2 infection and cancer by increasing the body’s natural reserve of pro-resolving mediators without overt toxicity or immunosuppression.
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Affiliation(s)
- Chantal Barksdale
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Franciele C Kipper
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Shreya Tripathy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ, 07103, USA
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. .,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
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27
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Fatty Acid Oxidation and Pro-Resolving Lipid Mediators Are Related to Male Infertility. Antioxidants (Basel) 2022; 11:antiox11010107. [PMID: 35052611 PMCID: PMC8773194 DOI: 10.3390/antiox11010107] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/25/2021] [Accepted: 12/29/2021] [Indexed: 02/04/2023] Open
Abstract
Specialized pro-resolving lipid mediators regulate the resolution of acute inflammation. They are formed by enzymatic oxygenation of polyunsaturated fatty acids and are divided into families including lipoxins, resolvins, protectins, and maresins. Resolvin D1 (RvD1), produced by docosahexaenoic acid, exerts anti-inflammatory and pro-resolving activities. This research aimed to investigate the implication of seminal RvD1 in human infertility. Infertile patients (n° 67) were grouped based on pathological reproductive conditions as idiopathic infertility, varicocele, and leukocytospermia; the fourth group was composed of fertile men (n° 18). Sperm characteristics were evaluated by light microscopy (WHO guidelines) and by transmission electron microscopy (TEM). The seminal levels of RvD1 and F2-isoprostane (F2-IsoPs) were dosed. In twenty men (6 fertile men, 8 with varicocele, 6 with leukocytospermia) seminal phospholipase A2, iron, cholesterol, transferrin, estradiol, ferritin, testosterone, and sperm membrane fatty acids were detected. The results indicated that: (i) RvD1 amount was positively correlated with F2-IsoPs and reduced sperm quality; (ii) RvD1 levels were significantly higher in patients with leukocytospermia, varicocele, and idiopathic infertility compared to fertile men; (iii) RvD1 increased along with other markers of oxidative stress and inflammation as fatty acids content and clinical biomarkers. This study suggests a panel of inflammatory markers and lipid mediators for a diagnosis of inflammatory status and a subsequent appropriate therapeutic approach.
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28
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Assessment of Polyunsaturated Fatty Acids on COVID-19-Associated Risk Reduction. REVISTA BRASILEIRA DE FARMACOGNOSIA : ORGAO OFICIAL DA SOCIEDADE BRASILEIRA DE FARMACOGNOSIA 2021; 32:50-64. [PMID: 34876760 PMCID: PMC8638948 DOI: 10.1007/s43450-021-00213-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 10/29/2021] [Indexed: 02/06/2023]
Abstract
Pooled evidence conveys the association between polyunsaturated fatty acids and infectious disease. SARS-CoV-2, an enveloped mRNA virus, was also reported to interact with polyunsaturated fatty acids. The present review explores the possible mode of action, immunology, and consequences of these polyunsaturated fatty acids during the viral infection. Polyunsaturated fatty acids control protein complex formation in lipid rafts associated with the function of two SARS-CoV-2 entry gateways: angiotensin-converting enzyme-2 and cellular protease transmembrane protease serine-2. Therefore, the viral entry can be mitigated by modulating polyunsaturated fatty acids contents in the body. α-Linolenic acid is the precursor of two clinically important eicosanoids eicosapentaenoic acid and docosahexaenoic acid, the members of ω-3 fats. Resolvins, protectins, and maresins derived from docosahexaenoic acid suppress inflammation and augment phagocytosis that lessens microbial loads. Prostaglandins of 3 series, leukotrienes of 5 series, and thromboxane A3 from eicosapentaenoic acid exhibit anti-inflammatory, vasodilatory, and platelet anti-aggregatory effects that may also contribute to the control of pre-existing pulmonary and cardiac diseases. In contrast, ω-6 linoleic acid-derived arachidonic acid increases the prostaglandin G2, lipoxins A4 and B4, and thromboxane A2. These cytokines are pro-inflammatory and enhance the immune response but aggravate the COVID-19 severity. Therefore, the rational intake of ω-3-enriched foods or supplements might lessen the complications in COVID-19 and might be a preventive measure. Graphic Abstract
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29
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Kim HJ, Kim B, Byun HJ, Yu L, Nguyen TM, Nguyen TH, Do PA, Kim EJ, Cheong KA, Kim KS, Huy Phùng H, Rahman M, Jang JY, Rho SB, Kang GJ, Park MK, Lee H, Lee K, Cho J, Han HK, Kim SG, Lee AY, Lee CH. Resolvin D1 Suppresses H 2O 2-Induced Senescence in Fibroblasts by Inducing Autophagy through the miR-1299/ARG2/ARL1 Axis. Antioxidants (Basel) 2021; 10:1924. [PMID: 34943028 PMCID: PMC8750589 DOI: 10.3390/antiox10121924] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/24/2021] [Accepted: 11/28/2021] [Indexed: 12/15/2022] Open
Abstract
ARG2 has been reported to inhibit autophagy in vascular endothelial cells and keratinocytes. However, studies of its mechanism of action, its role in skin fibroblasts, and the possibility of promoting autophagy and inhibiting cellular senescence through ARG2 inhibition are lacking. We induced cellular senescence in dermal fibroblasts by using H2O2. H2O2-induced fibroblast senescence was inhibited upon ARG2 knockdown and promoted upon ARG2 overexpression. The microRNA miR-1299 suppressed ARG2 expression, thereby inhibiting fibroblast senescence, and miR-1299 inhibitors promoted dermal fibroblast senescence by upregulating ARG2. Using yeast two-hybrid assay, we found that ARG2 binds to ARL1. ARL1 knockdown inhibited autophagy and ARL1 overexpression promoted it. Resolvin D1 (RvD1) suppressed ARG2 expression and cellular senescence. These data indicate that ARG2 stimulates dermal fibroblast cell senescence by inhibiting autophagy after interacting with ARL1. In addition, RvD1 appears to promote autophagy and inhibit dermal fibroblast senescence by inhibiting ARG2 expression. Taken together, the miR-1299/ARG2/ARL1 axis emerges as a novel mechanism of the ARG2-induced inhibition of autophagy. Furthermore, these results indicate that miR-1299 and pro-resolving lipids, including RvD1, are likely involved in inhibiting cellular senescence by inducing autophagy.
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Affiliation(s)
- Hyun Ji Kim
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Boram Kim
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Hyung Jung Byun
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Lu Yu
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Tuan Minh Nguyen
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Thi Ha Nguyen
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Phuong Anh Do
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Eun Ji Kim
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Kyung Ah Cheong
- Department of Dermatology, Dongguk University Ilsan Hospital, 814 Siksa-dong, Ilsandong-gu, Goyang-si 10326, Korea; (K.A.C.); (G.J.K.); (A.Y.L.)
| | - Kyung Sung Kim
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Hiệu Huy Phùng
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Mostafizur Rahman
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Ji Yun Jang
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
- National Cancer Center, Goyang 10408, Korea; (S.B.R.); (H.L.)
| | - Seung Bae Rho
- National Cancer Center, Goyang 10408, Korea; (S.B.R.); (H.L.)
| | - Gyeoung Jin Kang
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Mi Kyung Park
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
- National Cancer Center, Goyang 10408, Korea; (S.B.R.); (H.L.)
| | - Ho Lee
- National Cancer Center, Goyang 10408, Korea; (S.B.R.); (H.L.)
| | - Kyeong Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Jungsook Cho
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Hyo Kyung Han
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Sang Geon Kim
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
| | - Ai Young Lee
- Department of Dermatology, Dongguk University Ilsan Hospital, 814 Siksa-dong, Ilsandong-gu, Goyang-si 10326, Korea; (K.A.C.); (G.J.K.); (A.Y.L.)
| | - Chang Hoon Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Korea; (H.J.K.); (B.K.); (H.J.B.); (L.Y.); (T.M.N.); (T.H.N.); (P.A.D.); (K.S.K.); (H.H.P.); (M.R.); (J.Y.J.); (M.K.P.); (K.L.); (J.C.); (H.K.H.); (S.G.K.)
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30
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Panigrahy D, Gilligan MM, Serhan CN, Kashfi K. Resolution of inflammation: An organizing principle in biology and medicine. Pharmacol Ther 2021; 227:107879. [PMID: 33915177 DOI: 10.1016/j.pharmthera.2021.107879] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
The resolution of inflammation has emerged as a critical endogenous process that protects host tissues from prolonged or excessive inflammation that can become chronic. Failure of the resolution of inflammation is a key pathological mechanism that drives the progression of numerous inflammation-driven diseases. Essential polyunsaturated fatty acid (PUFA)-derived autacoid mediators termed 'specialized pro-resolving mediators' (SPMs) regulate endogenous resolution programs by limiting further neutrophil tissue infiltration and stimulating local immune cell (e.g., macrophage)-mediated clearance of apoptotic polymorphonuclear neutrophils, cellular debris, and microbes, as well as counter-regulating eicosanoid/cytokine production. The SPM superfamily encompasses lipoxins, resolvins, protectins, and maresins. Our understanding of the resolution phase of acute inflammation has grown exponentially in the past three decades with the discovery of novel pro-resolving lipid mediators, their pro-efferocytosis mechanisms, and their receptors. Technological advancement has further facilitated lipid mediator metabolipidomic based profiling of healthy and diseased human tissues, highlighting the extraordinary therapeutic potential of SPMs across a broad array of inflammatory diseases including cancer. As current front-line cancer therapies such as surgery, chemotherapy, and radiation may induce various unwanted side effects such as robust pro-inflammatory and pro-tumorigenic host responses, characterizing SPMs and their receptors as novel therapeutic targets may have important implications as a new direction for host-targeted cancer therapy. Here, we discuss the origins of inflammation resolution, key discoveries and the failure of resolution mechanisms in diseases with an emphasis on cancer, and future directions focused on novel therapeutic applications for this exciting and rapidly expanding field.
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Affiliation(s)
- Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Molly M Gilligan
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, City University of New York, School of Medicine, New York, NY 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10016, USA
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31
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Wang L, Li Y, Xu M, Deng Z, Zhao Y, Yang M, Liu Y, Yuan R, Sun Y, Zhang H, Wang H, Qian Z, Kang H. Regulation of Inflammatory Cytokine Storms by Mesenchymal Stem Cells. Front Immunol 2021; 12:726909. [PMID: 34394132 PMCID: PMC8358430 DOI: 10.3389/fimmu.2021.726909] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/14/2021] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been widely used in preclinical and clinical trials for various diseases and have shown great potential in the treatment of sepsis and coronavirus disease (COVID-19). Inflammatory factors play vital roles in the pathogenesis of diseases. The interaction between inflammatory factors is extremely complex. Once the dynamics of inflammatory factors are unbalanced, inflammatory responses and cytokine storm syndrome develop, leading to disease exacerbation and even death. Stem cells have become ideal candidates for the treatment of such diseases due to their immunosuppressive and anti-inflammatory properties. However, the mechanisms by which stem cells affect inflammation and immune regulation are still unclear. This article discusses the therapeutic mechanism and potential value of MSCs in the treatment of sepsis and the novel COVID-19, outlines how MSCs mediate innate and acquired immunity at both the cellular and molecular levels, and described the anti-inflammatory mechanisms and related molecular pathways. Finally, we review the safety and efficacy of stem cell therapy in these two diseases at the preclinical and clinical levels.
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Affiliation(s)
- Lu Wang
- Medical School of Chinese PLA, Beijing, China.,Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yun Li
- Medical School of Chinese PLA, Beijing, China.,Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Moyan Xu
- Health Care Office, Chinese PLA General Hospital, Beijing, China
| | - Zihui Deng
- Department of Basic Medicine, Graduate School, Chinese PLA General Hospital, Beijing, China
| | - Yan Zhao
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Mengmeng Yang
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuyan Liu
- Medical School of Chinese PLA, Beijing, China.,Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Rui Yuan
- Medical School of Chinese PLA, Beijing, China.,Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yan Sun
- School of Public Health, Capital Medical University, Beijing, China
| | - Hao Zhang
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
| | - Heming Wang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Zhirong Qian
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Hongjun Kang
- Medical School of Chinese PLA, Beijing, China.,Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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32
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Land WG. Role of DAMPs in respiratory virus-induced acute respiratory distress syndrome-with a preliminary reference to SARS-CoV-2 pneumonia. Genes Immun 2021; 22:141-160. [PMID: 34140652 PMCID: PMC8210526 DOI: 10.1038/s41435-021-00140-w] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/28/2021] [Accepted: 05/25/2021] [Indexed: 02/05/2023]
Abstract
When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.
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Affiliation(s)
- Walter Gottlieb Land
- German Academy for Transplantation Medicine, Munich, Germany.
- Molecular ImmunoRheumatology, INSERM UMR_S1109, Laboratory of Excellence Transplantex, University of Strasbourg, Strasbourg, France.
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An JU, Kim SE, Oh DK. Molecular insights into lipoxygenases for biocatalytic synthesis of diverse lipid mediators. Prog Lipid Res 2021; 83:101110. [PMID: 34144023 DOI: 10.1016/j.plipres.2021.101110] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/11/2021] [Accepted: 06/11/2021] [Indexed: 12/31/2022]
Abstract
Oxylipins derived mainly from C20- and C22-polyunsaturated fatty acids (PUFAs), termed lipid mediators (LMs), are essential signalling messengers involved in human physiological responses associated with homeostasis and healing process for infection and inflammation. Some LMs involved in the resolution of inflammation and infection are termed specialized pro-resolving mediators (SPMs), which are generated by human M2 macrophages or polymorphonuclear leukocytes and have the potential to protect and treat hosts from bacterial and viral infections by phagocytosis activation. Lipoxygenases (LOXs) biosynthesize regio- and stereoselective LMs. Thus, understanding the regio- and stereoselectivities of LOXs for PUFAs at a molecular level is important for the biocatalytic synthesis of diverse LMs. Here, we elucidate the catalytic mechanisms and discuss regio- and stereoselectivities and their changes of LOXs determined by insertion direction and position of the substrate and oxygen at a molecular level for the biosynthesis of diverse human LMs. Recently, the biocatalytic synthesis of PUFAs to human LMs or analogues has been conducted using microbial LOXs. Such microbial LOXs involved in the biosynthesis of LMs are expected to exert significantly higher activity and stability than human LOXs. Diverse regio- and stereoselective LOXs can be obtained from microorganisms, which represent a wealth of genomic sources. We reconstruct the biosynthetic pathways of LOX-catalyzed LMs in humans and other organisms. Furthermore, we suggest the effective methods of biocatalytic synthesis of diverse human LMs from PUFAs or glucose by using microbial LOXs, increasing the stability and activity of LOXs, combining the reactions of LOXs, and constructing metabolic pathways.
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Affiliation(s)
- Jung-Ung An
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea; Synthetic Biology and Bioengineering Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Seong-Eun Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Deok-Kun Oh
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
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