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      Eicosanoids metabolized through LOX distinguish asthma–COPD overlap from COPD by metabolomics study

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          Abstract

          Background and objective

          The prevalence of asthma is greater than 20% in patients previously diagnosed with COPD. Patients with asthma–COPD overlap (ACO) are at risk of rapid progression of disease and severe exacerbations. However, in some patients with ACO, a clear distinction from COPD is very difficult by using physiological testing techniques. This study aimed to apply a novel metabolomic approach to identify the metabolites in sera in order to distinguish ACO from COPD.

          Methods

          In the study, blood samples were collected from patients with COPD, ACO, and healthy controls. Cholamine derivatization-ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was used to investigate serum metabolites of eicosanoids.

          Results

          A clear intergroup separation existed between the patients with ACO and those with COPD, while ACO tends to have higher serum metabolic levels of eicosanoids. A robust Orthogonal Projections to Latent Structures-Discriminant Analysis (OPLS-DA) model was found for discriminating between ACO and COPD (R2Y =0.81, Q2=0.79). In addition, there is a significant correlation between some metabolites and clinical indicators, such as hydroxyeicosatetraenoic acids (HETEs), hydroperoxyeicosatetraenoic acids (HPETEs) and FEV1/FVC. The higher values of area under the receiver operating characteristic curves (ROC) of HETEs, which were metabolized from HPETEs through lipoxygenase (LOX), indicated that they should be the potential biomarkers to distinguish ACO from COPD.

          Conclusion

          Eicosanoids can clearly discriminate different biochemical metabolic profiles between ACO and COPD. The results possibly provide a new perspective to identify potential biomarkers of ACO and may be helpful for personalized treatment.

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          Most cited references 28

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          Proresolving lipid mediators and mechanisms in the resolution of acute inflammation.

          Inflammatory responses, like all biological cascades, are shaped by a delicate balance between positive and negative feedback loops. It is now clear that in addition to positive and negative checkpoints, the inflammatory cascade rather unexpectedly boasts an additional checkpoint, a family of chemicals that actively promote resolution and tissue repair without compromising host defense. Indeed, the resolution phase of inflammation is just as actively orchestrated and carefully choreographed as its induction and inhibition. In this review, we explore the immunological consequences of omega-3-derived specialized proresolving mediators (SPMs) and discuss their place within what is currently understood of the role of the arachidonic acid-derived prostaglandins, lipoxins, and their natural C15-epimers. We propose that treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation.
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            The implications of human metabolic network topology for disease comorbidity.

            Most diseases are the consequence of the breakdown of cellular processes, but the relationships among genetic/epigenetic defects, the molecular interaction networks underlying them, and the disease phenotypes remain poorly understood. To gain insights into such relationships, here we constructed a bipartite human disease association network in which nodes are diseases and two diseases are linked if mutated enzymes associated with them catalyze adjacent metabolic reactions. We find that connected disease pairs display higher correlated reaction flux rate, corresponding enzyme-encoding gene coexpression, and higher comorbidity than those that have no metabolic link between them. Furthermore, the more connected a disease is to other diseases, the higher is its prevalence and associated mortality rate. The network topology-based approach also helps to uncover potential mechanisms that contribute to their shared pathophysiology. Thus, the structure and modeled function of the human metabolic network can provide insights into disease comorbidity, with potentially important consequences for disease diagnosis and prevention.
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              Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid.

              Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5-lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo-ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                COPD
                copd
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove
                1176-9106
                1178-2005
                06 August 2019
                2019
                : 14
                : 1769-1778
                Affiliations
                [1 ]Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University , Guangzhou, People’s Republic of China
                [2 ]Department of Laboratory Medicine, Shenzhen People's Hospital , Shenzhen, People's Republic of China
                [3 ]State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Taipa, Macao, People’s Republic of China
                [4 ]Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University , Guiyang, Guizhou, People’s Republic of China
                [5 ]Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center , Columbus, OH, USA
                Author notes
                Correspondence: Baoqing SunDepartment of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University , No. 151, Yanjiang West Road, Yuexiu District, Guiyang, Guangzhou510120, People’s Republic of ChinaTel +86 208 306 2865Email sunbaoqing@vip.163.com
                Jian-Lin WuState Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Avenida Wailong, Taipa, Macao999078, People’s Republic of ChinaTel +85 38 897 2406Email jlwu@must.edu.mo
                [*]

                These authors contributed equally to this work

                Article
                207023
                10.2147/COPD.S207023
                6689553
                © 2019 Cai et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 2, References: 33, Pages: 10
                Categories
                Original Research

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