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      Discovery of bioactive nitrated lipids and nitro-lipid-protein adducts using mass spectrometry-based approaches

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          Abstract

          Nitro-fatty acids (NO 2-FA) undergo reversible Michael adduction reactions with cysteine and histidine residues leading to the post-translational modification (PTM) of proteins. This electrophilic character of NO 2-FA is strictly related to their biological roles. The NO 2-FA-induced PTM of signaling proteins can lead to modifications in protein structure, function, and subcellular localization. The nitro lipid-protein adducts trigger a series of downstream signaling events that culminates with anti-inflammatory, anti-hypertensive, and cytoprotective effects mediated by NO 2-FA. These lipoxidation adducts have been detected and characterized both in model systems and in biological samples by using mass spectrometry (MS)-based approaches. These MS approaches allow to unequivocally identify the adduct together with the targeted residue of modification. The identification of the modified proteins allows inferring on the possible impact of the NO 2-FA-induced modification. This review will focus on MS-based approaches as valuable tools to identify NO 2-FA-protein adducts and to unveil the biological effect of this lipoxidation adducts.

          Highlights

          • Nitro-fatty acids (NO 2-FA) are endogenous bioactive lipids.

          • NO 2-FA form reversible Michael adducts with proteins leading to PTMs.

          • Adduction of NO 2-FA with proteins culminates to anti-inflammatory, anti-hypertensive, and cytoprotective effects.

          • Mass spectrometry (MS)-based approaches allows to identify NO 2-FA-protein adducts and to unveil their biological effects.

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          Most cited references112

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          Protein carbonylation as a major hallmark of oxidative damage: update of analytical strategies.

          Protein carbonylation, one of the most harmful irreversible oxidative protein modifications, is considered as a major hallmark of oxidative stress-related disorders. Protein carbonyl measurements are often performed to assess the extent of oxidative stress in the context of cellular damage, aging and several age-related disorders. A wide variety of analytical techniques are available to detect and quantify protein-bound carbonyls generated by metal-catalyzed oxidation, lipid peroxidation or glycation/glycoxidation. Here we review current analytical approaches for protein carbonyl detection with a special focus on mass spectrometry-based techniques. The utility of several carbonyl-derivatization reagents, enrichment protocols and especially advanced mass spectrometry techniques are compared and discussed in detail. Furthermore, the mechanisms and biology of protein carbonylation are summarized based on recent high-throughput proteomics data. Copyright © 2013 Wiley Periodicals, Inc.
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            Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling

            Significance Several chronic inflammatory conditions have recently been shown to depend on abnormally high activity of the signaling protein stimulator of IFN genes (STING). These conditions include examples from systemic lupus erythematosus, Aicardi–Goutiéres syndrome, and STING-associated vasculopathy with onset in infancy. The involvement of STING in these diseases points to an unmet demand to identify inhibitors of STING signaling, which could form the basis of anti-STING therapeutics. With this report, we identify distinct endogenously formed lipid species as potent inhibitors of STING signaling—and propose that these lipids could have pharmaceutical potential for treatment of STING-dependent inflammatory diseases.
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              Nitrated fatty acids: Endogenous anti-inflammatory signaling mediators.

              Nitroalkene derivatives of linoleic acid (LNO2) and oleic acid (OA-NO2) are present; however, their biological functions remain to be fully defined. Herein, we report that LNO2 and OA-NO2 inhibit lipopolysaccharide-induced secretion of proinflammatory cytokines in macrophages independent of nitric oxide formation, peroxisome proliferator-activated receptor-gamma activation, or induction of heme oxygenase-1 expression. The electrophilic nature of fatty acid nitroalkene derivatives resulted in alkylation of recombinant NF-kappaB p65 protein in vitro and a similar reaction with p65 in intact macrophages. The nitroalkylation of p65 by fatty acid nitroalkene derivatives inhibited DNA binding activity and repressed NF-kappaB-dependent target gene expression. Moreover, nitroalkenes inhibited endothelial tumor necrosis factor-alpha-induced vascular cell adhesion molecule 1 expression and monocyte rolling and adhesion. These observations indicate that nitroalkenes such as LNO2 and OA-NO2, derived from reactions of unsaturated fatty acids and oxides of nitrogen, are a class of endogenous anti-inflammatory mediators.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                14 January 2019
                May 2019
                14 January 2019
                : 23
                : 101106
                Affiliations
                [a ]Centro de Espectrometria de Massa, Departamento de Química & QOPNA, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
                [b ]Departamento de Química & CESAM & ECOMARE, Universidade de Aveiro, 3810-193 Aveiro, Portugal
                Author notes
                [* ]Corresponding author at: University of Aveiro Campus Universitário de Santiago 3810-193 Aveiro, Portugal mrd@ 123456ua.pt
                Article
                S2213-2317(18)31024-3 101106
                10.1016/j.redox.2019.101106
                6859590
                30718106
                7710a70c-08f7-420c-a782-0b2c49f8b9eb
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 2 November 2018
                : 8 January 2019
                : 10 January 2019
                Categories
                Lipoxidation in pathophysiology and its assessment by high precision methodology

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