{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T19:16:21Z","timestamp":1792955781225,"version":"4.5.0"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Systemic inflammation in rheumatoid arthritis (RA) is associated with metabolic changes. We used nuclear magnetic resonance (NMR) spectroscopy\u2013based metabolomics to assess the relationship between an objective measure of systemic inflammation [C-reactive protein (CRP)] and both the serum and urinary metabolome in patients with newly presenting RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Serum (n=126) and urine (n=83) samples were collected at initial presentation from disease modifying anti-rheumatic drug na\u00efve RA patients for metabolomic profile assessment using 1-dimensional <jats:sup>1<\/jats:sup>H-NMR spectroscopy. Metabolomics data were analysed using partial least square regression (PLS-R) and orthogonal projections to latent structure discriminant analysis (OPLS-DA) with cross validation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using PLS-R analysis, a relationship between the level of inflammation, as assessed by CRP, and the serum (p=0.001) and urinary (p&amp;lt;0.001) metabolome was detectable. Likewise, following categorisation of CRP into tertiles, patients in the lowest CRP tertile and the highest CRP tertile were statistically discriminated using OPLS-DA analysis of both serum (p=0.033) and urinary (p&amp;lt;0.001) metabolome. The most highly weighted metabolites for these models included glucose, amino acids, lactate, and citrate. These findings suggest increased glycolysis, perturbation in the citrate cycle, oxidative stress, protein catabolism and increased urea cycle activity are key characteristics of newly presenting RA patients with elevated CRP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study consolidates our understanding of a previously identified relationship between serum metabolite profile and inflammation and provides novel evidence that there is a relationship between urinary metabolite profile and inflammation as measured by CRP. Identification of these metabolic perturbations provides insights into the pathogenesis of RA and may help in the identification of therapeutic targets.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.676105","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T13:50:18Z","timestamp":1632837018000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":49,"title":["Relationship Between Inflammation and Metabolism in Patients With Newly Presenting Rheumatoid Arthritis"],"prefix":"10.3389","volume":"12","author":[{"given":"Gurpreet Singh","family":"Jutley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalvin","family":"Sahota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilfita","family":"Sahbudin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Filer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thurayya","family":"Arayssi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Raza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1186\/s13075-019-2026-4","article-title":"Early Rheumatoid Arthritis Is Characterised by a Distinct and Transient Synovial Fluid Cytokine Profile of T Cell and Stromal Cell Origin","volume":"21","author":"Raza","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"B2","first-page":"1","article-title":"Early Rheumatoid Arthritis \u2013 Is There a Window of Opportunity","volume":"80","author":"Cush","year":"2007","journal-title":"J\u00a0Rheumatol Suppl"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)16676-2","article-title":"Effect of a Treatment Strategy of Tight Control for Rheumatoid Arthritis (the TICORA Study): A Single-Blind Randomised Controlled Trial","volume":"364","author":"Grigor","year":"2004","journal-title":"Lancet (London England)"},{"key":"B4","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/art.24367","article-title":"Patient-Reported Outcomes in a Randomized Trial Comparing Four Different Treatment Strategies in Recent-Onset Rheumatoid Arthritis","volume":"61","author":"van der Kooij","year":"2009","journal-title":"Arthritis Rheum"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e000870","DOI":"10.1136\/rmdopen-2018-000870","article-title":"Window of Opportunity in Rheumatoid Arthritis \u2013 Definitions and Supporting Evidence: From Old to New Perspectives","volume":"5","author":"Burgers","year":"2019","journal-title":"RMD Open"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1136\/heartjnl-2019-316193","article-title":"Cardiovascular Risk Factors and Outcomes in Early Rheumatoid Arthritis: A Population-Based Study","volume":"106","author":"Nikiphorou","year":"2020","journal-title":"Heart"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez409","article-title":"Prognostic Value of Comorbidity Indices and Lung Diseases in Early Rheumatoid Arthritis: A UK Population-Based Study","volume":"59","author":"Nikiphorou","year":"2020","journal-title":"Rheumatology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa125","article-title":"Circulating Plasma Metabolites and Risk of Rheumatoid Arthritis in the Nurses\u2019 Health Study","volume":"59","author":"Chu","year":"2020","journal-title":"Rheumatology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1172\/JCI76012","article-title":"Metabolic Programming and PDHK1 Control CD4+ T Cell Subsets and Inflammation","volume":"125","author":"Gerriets","year":"2015","journal-title":"J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3704","article-title":"De Novo Fatty Acid Synthesis Controls the Fate Between Regulatory T and T Helper 17 Cells","volume":"20","author":"Berod","year":"2014","journal-title":"Nat Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01973","article-title":"Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis","volume":"9","author":"Abboud","year":"2018","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"v3","DOI":"10.1093\/rheumatology\/kes113","article-title":"Understanding the Dynamics: Pathways Involved in the Pathogenesis of Rheumatoid Arthritis","volume":"51","author":"Choy","year":"2012","journal-title":"Rheumatology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1263-7","article-title":"Distinct Fibroblast Subsets Drive Inflammation and Damage in Arthritis","volume":"570","author":"Croft","year":"2019","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60784-3","article-title":"New Therapies for Treatment of Rheumatoid Arthritis","volume":"370","author":"Smolen","year":"2007","journal-title":"Lancet (London England)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965","article-title":"The Pathogenesis of Rheumatoid Arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N Engl J Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208476","article-title":"Dysregulated Bioenergetics: A Key Regulator of Joint Inflammation","volume":"75","author":"Biniecka","year":"2016","journal-title":"Ann Rheum Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00347","article-title":"Metabolic Checkpoints in Rheumatoid Arthritis","volume":"11","author":"Pucino","year":"2020","journal-title":"Front Physiol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/art.38021","article-title":"The Impact of Inflammation on Metabolomic Profiles in Patients With Arthritis","volume":"65","author":"Young","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-017-0974-6","article-title":"Comprehensive Metabolic Profiling of Chronic Low-Grade Inflammation Among Generally Healthy Individuals","volume":"15","author":"Pietzner","year":"2017","journal-title":"BMC Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1186\/s12916-016-0681-8","article-title":"Urine Metabolome Profiling of Immune-Mediated Inflammatory Diseases","volume":"14","author":"Alonso","year":"2016","journal-title":"BMC Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/art.37921","article-title":"Metabolic Profiling Predicts Response to Anti-Tumor Necrosis Factor Alpha Therapy in Patients With Rheumatoid Arthritis","volume":"65","author":"Kapoor","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e0163087","DOI":"10.1371\/journal.pone.0163087","article-title":"Exploring the Inflammatory Metabolomic Profile to Predict Response to TNF-\u03b1 Inhibitors in Rheumatoid Arthritis","volume":"11","author":"Cuppen","year":"2016","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e0138537","DOI":"10.1371\/journal.pone.0138537","article-title":"1h-NMR-Based Metabolomic Study for Identifying Serum Profiles Associated With the Response to Etanercept in Patients With Rheumatoid Arthritis","volume":"10","author":"Priori","year":"2015","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1021\/ac051632c","article-title":"Probabilistic Quotient Normalization as Robust Method to Account for Dilution of Complex Biological Mixtures. Application in 1H NMR Metabonomics","volume":"78","author":"Dieterle","year":"2006","journal-title":"Anal Chem"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e16957","DOI":"10.1371\/journal.pone.0016957","article-title":"The Human Serum Metabolome","volume":"6","author":"Psychogios","year":"2011","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.20276","article-title":"A Biphasic Role of Nuclear Transcription Factor (NF)-kappaB in the Islet Beta-Cell Apoptosis Induced by Interleukin (IL)-1beta","volume":"204","author":"Papaccio","year":"2005","journal-title":"J Cell Physiol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.2010.00282.x","article-title":"Leucine Metabolism in Regulation of Insulin Secretion From Pancreatic Beta Cells","volume":"68","author":"Yang","year":"2010","journal-title":"Nutr Rev"},{"key":"B28","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ab.2008.01.037","article-title":"Optimized Metabolite Extraction From Blood Serum for 1H Nuclear Magnetic Resonance Spectroscopy","volume":"377","author":"Tiziani","year":"2008","journal-title":"Analytical Biochem"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-007-0092-0","article-title":"Validation of a Urine Metabolome Fingerprint in Dog for Phenotypic Classification","volume":"3","author":"Viant","year":"2007","journal-title":"Metabolomics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.09.092","article-title":"Improved Methods for the Acquisition and Interpretation of NMR Metabolomic Data","volume":"310","author":"Viant","year":"2003","journal-title":"Biochem Biophys Res Commun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-366","article-title":"MetaboLab\u2013advanced NMR Data Processing and Analysis for Metabolomics","volume":"12","author":"Ludwig","year":"2011","journal-title":"BMC Bioinf"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e73076","DOI":"10.1371\/journal.pone.0073076","article-title":"The Human Urine Metabolome","volume":"8","author":"Bouatra","year":"2013","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.1021\/bk-1977-0052.ch012","article-title":"SIMCA: A Method for Analyzing Chemical Data in Terms of Similarity and Analogy","volume-title":"Chemometrics: Theory and Application","author":"Wold","year":"1977"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemolab.2004.01.003","article-title":"Application of LS-SVM to Non-Linear Phenomena in NIR Spectroscopy: Development of a Robust and Portable Sensor for Acidity Prediction in Grapes","volume":"71","author":"Chauchard","year":"2004","journal-title":"Chemometrics Intelligent Lab Syst"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nature11708","article-title":"Metabolic Phenotyping in Clinical and Surgical Environments","volume":"491","author":"Nicholson","year":"2012","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.chemolab.2008.08.004","article-title":"Biomarker Discovery in Mass Spectral Profiles by Means of Selectivity Ratio Plot","volume":"95","author":"Rajalahti","year":"2009","journal-title":"Chemometrics Intelligent Lab Syst"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1021\/ac060209g","article-title":"Targeted Profiling: Quantitative Analysis of 1H NMR Metabolomics Data","volume":"78","author":"Weljie","year":"2006","journal-title":"Analytical Chem"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1089","article-title":"HMDB 4.0: The Human Metabolome Database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty528","article-title":"MetaboAnalystR: An R Package for Flexible and Reproducible Analysis of Metabolomics Data","volume":"34","author":"Chong","year":"2018","journal-title":"Bioinf (Oxford England)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr001","article-title":"MBRole: Enrichment Analysis of Metabolomic Data","volume":"27","author":"Chagoyen","year":"2011","journal-title":"Bioinf (Oxford England)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.trac.2017.07.009","article-title":"Quantification of Lipoprotein Profiles by Nuclear Magnetic Resonance Spectroscopy and Multivariate Data Analysis","volume":"94","author":"Aru","year":"2017","journal-title":"TrAC Trends Anal Chem"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0567-8","article-title":"Genetic Studies of Urinary Metabolites Illuminate Mechanisms of Detoxification and Excretion in Humans","volume":"52","author":"Schlosser","year":"2020","journal-title":"Nat Genet"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.08.021","article-title":"An Overview of Renal Metabolomics","volume":"91","author":"Kalim","year":"2017","journal-title":"Kidney Int"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1007\/s00216-016-0074-z","article-title":"NMR-Based Metabolomic Approach to Study Urine Samples of Chronic Inflammatory Rheumatic Disease Patients","author":"Vignoli","year":"2017","journal-title":"Anal Bioanal Chem"},{"key":"B45","doi-asserted-by":"publisher","first-page":"92","DOI":"10.2174\/2213235X130108","article-title":"Multivariate Analysis in Metabolomics","volume":"1","author":"Worley","year":"2013","journal-title":"Curr Metabolomics"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1042\/bj1190293","article-title":"Biological Activity and the 3-Methylhistidine Content of Actin and Myosin","volume":"119","author":"Johnson","year":"1970","journal-title":"Biochem J"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(67)90229-X","article-title":"3-Methylhistidine, a Component of Actin","volume":"26","author":"Asatoor","year":"1967","journal-title":"Biochem Biophys Res Commun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/223300a0","article-title":"In Vitro Methylation of Muscle Proteins","volume":"223","author":"Hardy","year":"1969","journal-title":"Nature"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1042\/cs0560341","article-title":"Age-Dependent Changes in the Rate of Myofibrillar Protein Degradation in Humans as Assessed by 3-Methylhistidine and Creatinine Excretion","volume":"56","author":"Tomas","year":"1979","journal-title":"Clin Sci (London Engl 1979)"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.051755","article-title":"Influence of Age and Resistance Exercise on Human Skeletal Muscle Proteolysis: A Microdialysis Approach","volume":"554","author":"Trappe","year":"2004","journal-title":"J Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880060605","article-title":"Content of Methylhistidines in Normal and Pathological Human Skeletal Muscles","volume":"6","author":"Mussini","year":"1983","journal-title":"Muscle Nerve"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880040111","article-title":"Increased Rates of Myofibrillar Protein Breakdown in Muscle-Wasting Diseases","volume":"4","author":"Warnes","year":"1981","journal-title":"Muscle Nerve"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(75)90084-0","article-title":"Metabolism of 3-Methylhistidine in Man","volume":"24","author":"Long","year":"1975","journal-title":"Metab: Clin Exp"},{"key":"B54","doi-asserted-by":"publisher","first-page":"52s","DOI":"10.1183\/09031936.03.00004608","article-title":"Muscle Wasting and Changes in Muscle Protein Metabolism in Chronic Obstructive Pulmonary Disease","volume":"46","author":"Jagoe","year":"2003","journal-title":"Eur Respir J Supplement"},{"key":"B55","doi-asserted-by":"publisher","first-page":"G7","DOI":"10.1152\/ajpgi.1997.273.1.G7","article-title":"GSH Transport in Mitochondria: Defense Against TNF-Induced Oxidative Stress and Alcohol-Induced Defect","volume":"273","author":"Fernandez-Checa","year":"1997","journal-title":"Am J Physiol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2006.04570.x","article-title":"Mitochondrial Glutathione: Hepatocellular Survival-Death Switch","author":"Garcia-Ruiz","year":"2006","journal-title":"J Gastroenterol Hepatol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00416.2012","article-title":"Regulation of Urea Synthesis During the Acute-Phase Response in Rats","volume":"304","author":"Thomsen","year":"2013","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"241738","DOI":"10.1155\/2015\/241738","article-title":"Cytokines Modulate the \u201cImmune-Metabolism\u201d Interactions During Beh\u00e7et Disease: Effect on Arginine Metabolism","volume":"2015","author":"Belguendouz","year":"2015","journal-title":"Int J Inflammation"},{"key":"B59","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1023\/A:1021695625457","article-title":"The Urea Cycle in the Liver of Arthritic Rats","volume":"243","author":"Yassuda Filho","year":"2003","journal-title":"Mol Cell Biochem"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00420","article-title":"Metabolic Reprograming in Macrophage Polarization","volume":"5","author":"Galv\u00e1n-Pe\u00f1a","year":"2014","journal-title":"Front Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00141","article-title":"A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation","volume":"9","author":"Williams","year":"2018","journal-title":"Front Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2013.11.008","article-title":"Succinate: A Metabolic Signal in Inflammation","volume":"24","author":"Mills","year":"2014","journal-title":"Trends Cell Biol"},{"key":"B63","doi-asserted-by":"publisher","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":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/nature05485","article-title":"Inflammation and Metabolic Disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"B65","doi-asserted-by":"publisher","first-page":"79","DOI":"10.4149\/gpb_2010_01_79","article-title":"Alterations in Adipocyte Glucose Transporter GLUT4 and Circulating Adiponectin and Visfatin in Rat Adjuvant Induced Arthritis","volume":"29","author":"Jurcovicova","year":"2010","journal-title":"Gen Physiol Biophys"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-0692","article-title":"Interleukin-1beta-Induced Insulin Resistance in Adipocytes Through Down-Regulation of Insulin Receptor Substrate-1 Expression","volume":"148","author":"Jager","year":"2007","journal-title":"Endocrinology"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1677\/JOE-07-0306","article-title":"Pro-Inflammatory Cytokines Increase Glucose, Alanine and Triacylglycerol Utilization But Inhibit Insulin Secretion in a Clonal Pancreatic Beta-Cell Line","volume":"195","author":"Kiely","year":"2007","journal-title":"J Endocrinol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2015.1083861","article-title":"Recent Advances in Understanding Xenotransplantation: Implications for the Clinic","volume":"11","author":"Cooper","year":"2015","journal-title":"Expert Rev Clin Immunol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.taap.2008.11.007","article-title":"Sulforaphane Protects Against Cytokine- and Streptozotocin-Induced Beta-Cell Damage by Suppressing the NF-kappaB Pathway","volume":"235","author":"Song","year":"2009","journal-title":"Toxicol Appl Pharmacol"},{"key":"B70","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1158\/jcr.1925.148","article-title":"The Metabolism of Carcinoma Cells","volume":"9","author":"Warburg","year":"1925","journal-title":"J Cancer Res"},{"key":"B71","doi-asserted-by":"publisher","first-page":"e1002202","DOI":"10.1371\/journal.pbio.1002202","article-title":"Lactate Regulates Metabolic and Pro-Inflammatory Circuits in Control of T Cell Migration and Effector Functions","volume":"13","author":"Haas","year":"2015","journal-title":"PloS Biol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-07-035972","article-title":"Inhibitory Effect of Tumor Cell-Derived Lactic Acid on Human T Cells","volume":"109","author":"Fischer","year":"2007","journal-title":"Blood"},{"key":"B73","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.cmet.2019.10.004","article-title":"Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4(+) T Cell Metabolic Rewiring","volume":"30","author":"Pucino","year":"2019","journal-title":"Cell Metab"},{"key":"B74","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1186\/s12916-018-1190-8","article-title":"Determinants of the Urinary and Serum Metabolome in Children From Six European Populations","volume":"16","author":"Lau","year":"2018","journal-title":"BMC Med"},{"key":"B75","doi-asserted-by":"publisher","first-page":"e86223","DOI":"10.1371\/journal.pone.0086223","article-title":"Mealtime, Temporal, and Daily Variability of the Human Urinary and Plasma Metabolomes in a Tightly Controlled Environment","volume":"9","author":"Kim","year":"2014","journal-title":"PloS One"},{"key":"B76","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4939-2377-9_13","article-title":"The Strengths and Weaknesses of NMR Spectroscopy and Mass Spectrometry With Particular Focus on Metabolomics Research","volume-title":"Metabonomics: Methods and Protocols","author":"Emwas","year":"2015"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.676105\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T13:50:37Z","timestamp":1632837037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.676105\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":76,"alternative-id":["10.3389\/fimmu.2021.676105"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.676105","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,28]]},"article-number":"676105"}}