{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T22:19:06Z","timestamp":1776464346082,"version":"3.51.2"},"reference-count":92,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/50006\/2020"],"award-info":[{"award-number":["UIDB\/50006\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/50017\/2020+UIDP\/50017\/2020"],"award-info":[{"award-number":["UIDB\/50017\/2020+UIDP\/50017\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["LISBOA-01-0145-FEDER-402-022125"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-402-022125"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Polish National Agency for Academic Exchange (NAWA)","award":["PPI\/APM\/2018\/00015\/U\/001"],"award-info":[{"award-number":["PPI\/APM\/2018\/00015\/U\/001"]}]},{"name":"Portugal 2020","award":["POCI-01-0247-FEDER-035234"],"award-info":[{"award-number":["POCI-01-0247-FEDER-035234"]}]},{"name":"Portugal 2020","award":["LISBOA-01-0247-FEDER-035234"],"award-info":[{"award-number":["LISBOA-01-0247-FEDER-035234"]}]},{"name":"Portugal 2020","award":["ALG-01-0247-FEDER-035234"],"award-info":[{"award-number":["ALG-01-0247-FEDER-035234"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In recent years, several studies have demonstrated that polyunsaturated fatty acids have strong immunomodulatory properties, altering several functions of macrophages. In the present work, we sought to provide a multi-omic approach combining the analysis of the lipidome, the proteome, and the metabolome of RAW 264.7 macrophages supplemented with phospholipids containing omega-3 (PC 18:0\/22:6; \u03c93-PC) or omega-6 (PC 18:0\/20:4; \u03c96-PC) fatty acids, alone and in the presence of lipopolysaccharide (LPS). Supplementation of macrophages with \u03c93 and \u03c96 phospholipids plus LPS produced a significant reprogramming of the proteome of macrophages and amplified the immune response; it also promoted the expression of anti-inflammatory proteins (e.g., pleckstrin). Supplementation with the \u03c93-PC and \u03c96-PC induced significant changes in the lipidome, with a marked increase in lipid species linked to the inflammatory response, attributed to several pro-inflammatory signalling pathways (e.g., LPCs) but also to the pro-resolving effect of inflammation (e.g., PIs). Finally, the metabolomic analysis demonstrated that supplementation with \u03c93-PC and \u03c96-PC induced the expression of several metabolites with a pronounced inflammatory and anti-inflammatory effect (e.g., succinate). Overall, our data show that supplementation of macrophages with \u03c93-PC and \u03c96-PC effectively modulates the lipidome, proteome, and metabolome of these immune cells, affecting several metabolic pathways involved in the immune response that are triggered by inflammation.<\/jats:p>","DOI":"10.3390\/ijms23042139","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T22:44:47Z","timestamp":1644965087000},"page":"2139","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Multi-Omic Profiling of Macrophages Treated with Phospholipids Containing Omega-3 and Omega-6 Fatty Acids Reveals Complex Immunomodulatory Adaptations at Protein, Lipid and Metabolic Levels"],"prefix":"10.3390","volume":"23","author":[{"given":"Tatiana","family":"Maur\u00edcio","sequence":"first","affiliation":[{"name":"Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6651-3226","authenticated-orcid":false,"given":"Susana","family":"Aveiro","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"GreenCoLab-Green Ocean Association, University of Algarve, 8005-139 Faro, Portugal"}]},{"given":"Sofia","family":"Guedes","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Diana","family":"Lopes","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"CESAM-Centre for Environmental and Marine Studies, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"T\u00e2nia","family":"Melo","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"CESAM-Centre for Environmental and Marine Studies, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-3124","authenticated-orcid":false,"given":"Bruno M.","family":"Neves","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences and Institute of Biomedicine\u2014iBiMED, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5357-3601","authenticated-orcid":false,"given":"Ros\u00e1rio","family":"Domingues","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"CESAM-Centre for Environmental and Marine Studies, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8060-7675","authenticated-orcid":false,"given":"Pedro","family":"Domingues","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, Santiago University Campus, University of Aveiro, 3810-193 Aveiro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.2174\/1568010054022024","article-title":"Macrophages in Inflammation","volume":"4","author":"Fujiwara","year":"2005","journal-title":"Curr. Drug Target-Inflamm. Allergy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/path.2284","article-title":"Macrophage Activation by Endogenous Danger Signals","volume":"214","author":"Zhang","year":"2008","journal-title":"J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez, S., Svahn, S.L., and Johansson, M.E. (2019). Effects of Omega-3 Fatty Acids on Immune Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205028"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1146\/annurev.pharmtox.010909.105812","article-title":"Macrophages and Tissue Injury: Agents of Defense or Destruction?","volume":"51","author":"Laskin","year":"2011","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/imm.12910","article-title":"Implications of Macrophage Polarization in Autoimmunity","volume":"154","author":"Funes","year":"2018","journal-title":"Immunology"},{"key":"ref_6","first-page":"338","article-title":"Macrophage Polarization and Its Role in Cancer","volume":"6","year":"2015","journal-title":"J. Clin. Cell. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1038\/s41467-018-05800-6","article-title":"Resolution of Chronic Inflammatory Disease: Universal and Tissue-Specific Concepts","volume":"9","author":"Schett","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Radzikowska, U., Rinaldi, A.O., \u00c7elebi S\u00f6zener, Z., Karaguzel, D., Wojcik, M., Cypryk, K., Akdis, M., Akdis, C.A., and Sokolowska, M. (2019). The Influence of Dietary Fatty Acids on Immune Responses. Nutrients, 11.","DOI":"10.3390\/nu11122990"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1111\/all.13764","article-title":"EAACI Position Paper: Influence of Dietary Fatty Acids on Asthma, Food Allergy, and Atopic Dermatitis","volume":"74","author":"Venter","year":"2019","journal-title":"Allergy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.clim.2016.09.014","article-title":"Role of the JAK\/STAT Signaling Pathway in Regulation of Innate Immunity in Neuroinflammatory Diseases","volume":"189","author":"Yan","year":"2018","journal-title":"Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1016\/j.ejphar.2011.05.085","article-title":"Fatty Acids and Inflammation: The Cutting Edge between Food and Pharma","volume":"668","author":"Calder","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"D\u2019Angelo, S., Motti, M.L., and Meccariello, R. (2020). \u03c9-3 and \u03c9-6 Polyunsaturated Fatty Acids, Obesity and Cancer. Nutrients, 12.","DOI":"10.3390\/nu12092751"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.lfs.2014.10.014","article-title":"Docosahexaenoic Acid Induces M2 Macrophage Polarization through Peroxisome Proliferator-Activated Receptor \u03b3 Activation","volume":"120","author":"Chang","year":"2015","journal-title":"Life Sci."},{"key":"ref_14","first-page":"1","article-title":"15-Lipoxygenase Metabolites of \u03b1-Linolenic Acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], Mediate Anti-Inflammatory Effects by Inactivating NLRP3 Inflammasome","volume":"14","author":"Kumar","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/j.immuni.2013.05.015","article-title":"Omega-3 Fatty Acids Prevent Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome Activation","volume":"38","author":"Yan","year":"2013","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12604","DOI":"10.1002\/jcb.28527","article-title":"Docosahexaenoic Acid Enhances M2 Macrophage Polarization via the P38 Signaling Pathway and Autophagy","volume":"120","author":"Kawano","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.jnutbio.2009.02.008","article-title":"Anti-Inflammatory Effects of EPA and DHA Are Dependent upon Time and Dose-Response Elements Associated with LPS Stimulation in THP-1-Derived Macrophages","volume":"7","author":"Mullen","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1080\/07315724.2004.10719345","article-title":"Eicosapentaenoic Acid Prevents LPS-Induced TNF-\u03b1 Expression by Preventing NF-\u039aB Activation","volume":"23","author":"Zhao","year":"2004","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44612","DOI":"10.1038\/srep44612","article-title":"Effect of Modulation of PPAR-\u03b3 Activity on Kupffer Cells M1\/M2 Polarization in the Development of Non-Alcoholic Fatty Liver Disease","volume":"7","author":"Luo","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.cell.2010.07.041","article-title":"GPR120 Is an Omega-3 Fatty Acid Receptor Mediating Potent Anti-Inflammatory and Insulin-Sensitizing Effects","volume":"142","author":"Oh","year":"2010","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0899-9007(01)00576-7","article-title":"Modulation of Human Immune and Inflammatory Responses by Dietary Fatty Acids","volume":"17","author":"Kelley","year":"2001","journal-title":"Nutrition"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"396","DOI":"10.3109\/10799893.2014.960933","article-title":"Role of MAPK Signal Pathways in Differentiation Process of M2 Macrophages Induced by High-Ambient Glucose and TGF-\u03921","volume":"35","author":"Su","year":"2015","journal-title":"J. Recept. Signal Transduct."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s10753-009-9157-8","article-title":"Gamma-Linolenic Acid Inhibits Inflammatory Responses by Regulating NF-\u039aB and AP-1 Activation in Lipopolysaccharide-Induced RAW 264.7 Macrophages","volume":"33","author":"Chang","year":"2010","journal-title":"Inflammation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.jnutbio.2009.03.007","article-title":"Enrichment of RAW264.7 Macrophages with Essential 18-Carbon Fatty Acids Affects Both Respiratory Burst and Production of Immune Modulating Cytokines","volume":"21","author":"Walloschke","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7510","DOI":"10.3390\/ijms12117510","article-title":"The Impact of Membrane Lipid Composition on Macrophage Activation in the Immune Defense against Rhodococcus Equi and Pseudomonas Aeruginosa","volume":"12","author":"Schoeniger","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1016\/j.febslet.2006.04.091","article-title":"Fatty Acid Control of Nitric Oxide Production by Macrophages","volume":"580","author":"Scavone","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.atherosclerosis.2012.06.059","article-title":"Omega-6 Polyunsaturated Fatty Acids Prevent Atherosclerosis Development in LDLr-KO Mice, in Spite of Displaying a pro-Inflammatory Profile Similar to Trans Fatty Acids","volume":"224","author":"Machado","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E3240","DOI":"10.1073\/pnas.1521453113","article-title":"CYP450-Derived Oxylipins Mediate Inflammatory Resolution","volume":"113","author":"Gilroy","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.4049\/jimmunol.1801653","article-title":"Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid","volume":"205","author":"Brouwers","year":"2020","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1161\/CIRCULATIONAHA.114.010236","article-title":"Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies","volume":"130","author":"Farvid","year":"2014","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/S2213-8587(17)30307-8","article-title":"Omega-6 Fatty Acid Biomarkers and Incident Type 2 Diabetes: Pooled Analysis of Individual-Level Data for 39,740 Adults from 20 Prospective Cohort Studies","volume":"5","author":"Wu","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.freeradbiomed.2007.04.026","article-title":"Methods to Detect Nitric Oxide and Its Metabolites in Biological Samples","volume":"43","author":"Bryan","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pinto, R.V., Antunes, F., Pires, J., Silva-Herdade, A., and Pinto, M.L. (2020). A Comparison of Different Approaches to Quantify Nitric Oxide Release from NO-Releasing Materials in Relevant Biological Media. Molecules, 25.","DOI":"10.3390\/molecules25112580"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/j.1365-2443.2005.00839.x","article-title":"Modulation of TLR Signalling by the C-Terminal Src Kinase (Csk) in Macrophages","volume":"10","author":"Aki","year":"2005","journal-title":"Genes Cells"},{"key":"ref_35","first-page":"5003","article-title":"Reactive Oxygen Species Produced by the NADPH Oxidase 2 Complex in Monocytes Protect Mice from Bacterial Infections","volume":"188","author":"Pizzolla","year":"2012","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3558","DOI":"10.3389\/fimmu.2021.733918","article-title":"Beyond the Extra Respiration of Phagocytosis: NADPH Oxidase 2 in Adaptive Immunity and Inflammation","volume":"12","author":"Mortimer","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1515\/hsz-2017-0131","article-title":"Catalase, a Remarkable Enzyme: Targeting the Oldest Antioxidant Enzyme to Find a New Cancer Treatment Approach","volume":"398","author":"Glorieux","year":"2017","journal-title":"Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.bbrc.2004.02.060","article-title":"Induction of Cyclooxygenase-2 in Macrophages by Catalase: Role of NF-\u039aB and PI3K Signaling Pathways","volume":"316","author":"Jang","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/0891-5849(96)00178-5","article-title":"Activation of NF\u03baB by the Respiratory Burst of Macrophages","volume":"21","author":"Kaul","year":"1996","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"32124","DOI":"10.1074\/jbc.M203298200","article-title":"The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells *","volume":"277","author":"Guha","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1189\/jlb.0110001","article-title":"Anti-Inflammatory Properties of the PI3K Pathway Are Mediated by IL-10\/DUSP Regulation","volume":"88","author":"Bauer","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.4049\/jimmunol.1601515","article-title":"Akt Signaling Pathway in Macrophage Activation and M1\/M2 Polarization","volume":"198","author":"Vergadi","year":"2017","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0005-2760(91)90015-A","article-title":"Beta Oxidation of Fatty Acids","volume":"1081","author":"Schulz","year":"1991","journal-title":"Biochim. Biophys. Acta BBA\u2014Lipids Lipid Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.3389\/fimmu.2019.02993","article-title":"New Insights on the Role of Lipid Metabolism in the Metabolic Reprogramming of Macrophages","volume":"10","author":"Vidal","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/nm.4153","article-title":"NOX4-Dependent Fatty Acid Oxidation Promotes NLRP3 Inflammasome Activation in Macrophages","volume":"22","author":"Moon","year":"2016","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10858-011-9481-9","article-title":"Role of Aminotransferases in Glutamate Metabolism of Human Erythrocytes","volume":"49","author":"Ellinger","year":"2011","journal-title":"J. Biomol. NMR"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/ni.3796","article-title":"\u03b1-Ketoglutarate Orchestrates Macrophage Activation through Metabolic and Epigenetic Reprogramming","volume":"18","author":"Liu","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/0167-4838(88)90050-7","article-title":"Two biochemically distinct classes of fumarase in Escherichia coli","volume":"954","author":"Woods","year":"1988","journal-title":"Biochimica Biophysica Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.celrep.2017.09.092","article-title":"Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects","volume":"21","author":"Tyrakis","year":"2017","journal-title":"Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1080\/07853890310018458","article-title":"The TCA Cycle and Tumorigenesis: The Examples of Fumarate Hydratase and Succinate Dehydrogenase","volume":"35","author":"Pollard","year":"2003","journal-title":"Ann. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.cmet.2020.08.002","article-title":"The Role of HIF in Immunity and Inflammation","volume":"32","author":"McGettrick","year":"2020","journal-title":"Cell Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1101\/gad.1881410","article-title":"Differential Activation and Antagonistic Function of HIF-{alpha} Isoforms in Macrophages Are Essential for NO Homeostasis","volume":"24","author":"Takeda","year":"2010","journal-title":"Genes Dev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9029327","DOI":"10.1155\/2017\/9029327","article-title":"HIF1\u03b1-Induced Glycolysis Metabolism Is Essential to the Activation of Inflammatory Macrophages","volume":"2017","author":"Wang","year":"2017","journal-title":"Mediators Inflamm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ccr.2011.09.006","article-title":"Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif\/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling","volume":"20","author":"Adam","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate Is an Inflammatory Signal That Induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Harber, K.J., de Goede, K.E., Verberk, S.G.S., Meinster, E., de Vries, H.E., van Weeghel, M., de Winther, M.P.J., and van den Bossche, J. (2020). Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages. Metabolites, 10.","DOI":"10.3390\/metabo10090372"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41590-019-0372-7","article-title":"SUCNR1 Controls an Anti-Inflammatory Program in Macrophages to Regulate the Metabolic Response to Obesity","volume":"20","author":"Keiran","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/S1471-4906(02)02291-3","article-title":"Heme Oxygenase-1: A Novel Anti-Inflammatory Mediator","volume":"23","author":"Ward","year":"2002","journal-title":"Trends Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1074\/jbc.M116.770735","article-title":"Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-Deficient Macrophages","volume":"292","author":"Schmidt","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5514","DOI":"10.4049\/jimmunol.179.8.5514","article-title":"The IFN-Inducible GTPase LRG47 (Irgm1) Negatively Regulates TLR4-Triggered Proinflammatory Cytokine Production and Prevents Endotoxemia","volume":"179","author":"Bafica","year":"2007","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.4049\/jimmunol.0802755","article-title":"The Sequestosome 1\/P62 Attenuates Cytokine Gene Expression in Activated Macrophages by Inhibiting IFN Regulatory Factor 8 and TNF Receptor-Associated Factor 6\/NF-\u039aB Activity","volume":"182","author":"Kim","year":"2009","journal-title":"J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"14485","DOI":"10.1074\/jbc.270.24.14485","article-title":"Pleckstrin Inhibits Phosphoinositide Hydrolysis Initiated by G-Protein-Coupled and Growth Factor Receptors. A ROLE FOR PLECKSTRIN\u2019S PH DOMAINS \u2217","volume":"270","author":"Abrams","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"23317","DOI":"10.1074\/jbc.270.40.23317","article-title":"Protein Kinase C Regulates Pleckstrin by Phosphorylation of Sites Adjacent to the N-Terminal Pleckstrin Homology Domain (\u2217)","volume":"270","author":"Abrams","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"39976","DOI":"10.1074\/jbc.M110.182915","article-title":"A Mouse Macrophage Lipidome","volume":"285","author":"Dennis","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Koganesawa, M., Yamaguchi, M., Samuchiwal, S.K., and Balestrieri, B. (2020). Lipid Profile of Activated Macrophages and Contribution of Group V Phospholipase A (2). Biomolecules, 11.","DOI":"10.3390\/biom11010025"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"11600","DOI":"10.1074\/jbc.RA118.003180","article-title":"Choline Transport Links Macrophage Phospholipid Metabolism and Inflammation","volume":"293","author":"Snider","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.bioorg.2009.09.002","article-title":"Lysophosphatidylethanolamine Is\u2014in Contrast to\u2014Choline\u2014Generated under in Vivo Conditions Exclusively by Phospholipase A2 but Not by Hypochlorous Acid","volume":"37","author":"Schober","year":"2009","journal-title":"Bioorganic Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1016\/j.febslet.2007.08.014","article-title":"Lysophosphatidylethanolamine Stimulates Chemotactic Migration and Cellular Invasion in SK-OV3 Human Ovarian Cancer Cells: Involvement of Pertussis Toxin-Sensitive G-Protein Coupled Receptor","volume":"581","author":"Park","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.immunol.021908.132715","article-title":"The Inflammasomes: Guardians of the Body","volume":"27","author":"Martinon","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1189\/jlb.1206756","article-title":"Caspase-1 Inflammasomes in Infection and Inflammation","volume":"82","author":"Lamkanfi","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Carneiro, A.B., Iaciura, B.M.F., Nohara, L.L., Lopes, C.D., Veas, E.M.C., Mariano, V.S., Bozza, P.T., Lopes, U.G., Atella, G.C., and Almeida, I.C. (2013). Lysophosphatidylcholine Triggers TLR2- and TLR4-Mediated Signaling Pathways but Counteracts LPS-Induced NO Synthesis in Peritoneal Macrophages by Inhibiting NF-\u039aB Translocation and MAPK\/ERK Phosphorylation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076233"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.intimp.2016.07.014","article-title":"Stearoyl Lysophosphatidylcholine Enhances the Phagocytic Ability of Macrophages through the AMP-Activated Protein Kinase\/P38 Mitogen Activated Protein Kinase Pathway","volume":"39","author":"Quan","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1161\/01.RES.87.1.52","article-title":"Lysophosphatidylcholine Activates P38 and P42\/44 Mitogen-Activated Protein Kinases in Monocytic THP-1 Cells, but Only P38 Activation Is Involved in Its Stimulated Chemotaxis","volume":"87","author":"Jing","year":"2000","journal-title":"Circ. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"605","DOI":"10.4049\/jimmunol.0901698","article-title":"Substrate Fate in Activated Macrophages: A Comparison between Innate, Classic, and Alternative Activation","volume":"185","author":"Cuenca","year":"2010","journal-title":"J. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.cell.2016.08.064","article-title":"Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages","volume":"167","author":"Mills","year":"2016","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0022-1759(97)00043-4","article-title":"Assessment of the Alamar Blue Assay for Cellular Growth and Viability in Vitro","volume":"204","author":"Nakayama","year":"1997","journal-title":"J. Immunol. Methods"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0891-5849(98)00074-4","article-title":"Direct Observation of Lipid Hydroperoxides in Phospholipid Vesicles by Electrospray Mass Spectrometry","volume":"25","author":"Spickett","year":"1998","journal-title":"Free Radic. Biol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0003-2697(82)90118-X","article-title":"Analysis of Nitrate, Nitrite, and [15N] Nitrate in Biological Fluids","volume":"126","author":"Green","year":"1982","journal-title":"Anal. Biochem."},{"key":"ref_79","unstructured":"Amado, F., Domingues, M.R., Domingues, P., Ferreira, R., and Vitorino, R. (2013). An\u00e1lise de Prote\u00ednas\u2014Guia do Laborat\u00f3rio, 100Luz. [1st ed.]."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can. J. Biochem. Physiology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0003-2697(70)90343-X","article-title":"Spectrophotometric Determination of Phosphate Esters in the Presence and Absence of Orthophosphate","volume":"36","author":"Bartlett","year":"1970","journal-title":"Anal. Biochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1021\/acs.jproteome.0c01052","article-title":"Plasma Phospholipidomic Profile Differs between Children with Phenylketonuria and Healthy Children","volume":"20","author":"Guerra","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_83","unstructured":"(2021, July 05). Mass Spectrometry-Data Independent Analysis (MS-DIAL). Available online: http:\/\/prime.psc.riken.jp\/compms\/msdial\/main.html."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Pluskal, T., Castillo, S., Villar-Briones, A., and Ore\u0161i\u010d, M. (2010). MZmine 2: Modular Framework for Processing, Visualizing, and Analyzing Mass Spectrometry-Based Molecular Profile Data. BMC Bioinformatics, 11.","DOI":"10.1186\/1471-2105-11-395"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/nprot.2012.024","article-title":"A Positive\/Negative Ion\u2013Switching, Targeted Mass Spectrometry\u2013Based Metabolomics Platform for Bodily Fluids, Cells, and Fresh and Fixed Tissue","volume":"7","author":"Yuan","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_86","unstructured":"(2021, July 08). R: The R Project for Statistical Computing. Available online: https:\/\/www.r-project.org\/."},{"key":"ref_87","unstructured":"(2021, July 08). RStudio: Integrated Development Environment for R. Available online: http:\/\/www.rstudio.com\/."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1214\/10-AOAS341","article-title":"Liquid Chromatography Mass Spectrometry-Based Proteomics: Biological and Technological Aspects","volume":"4","author":"Karpievitch","year":"2010","journal-title":"Ann. Appl. Stat."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1093\/bioinformatics\/btm069","article-title":"PcaMethods\u2014A Bioconductor Package Providing PCA Methods for Incomplete Data","volume":"23","author":"Stacklies","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2009). Ggplot2: Elegant Graphics for Data Analysis., Springer. [2nd ed.].","DOI":"10.1007\/978-0-387-98141-3"},{"key":"ref_91","unstructured":"(2021, July 12). pheatmap: Pretty Heatmaps. Available online: https:\/\/CRAN.R-project.org\/package=pheatmap."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"14.10.1","DOI":"10.1002\/cpbi.11","article-title":"Using MetaboAnalyst 3.0 for Comprehensive Metabolomics Data Analysis","volume":"55","author":"Xia","year":"2016","journal-title":"Curr. Protoc. Bioinforma."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2139\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:19:56Z","timestamp":1760134796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,15]]},"references-count":92,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23042139"],"URL":"https:\/\/doi.org\/10.3390\/ijms23042139","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,15]]}}}