{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:29:29Z","timestamp":1790832569363,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The immunological response in bacterial meningitis (BM) causes the formation of reactive oxygen and nitrogen species (ROS, RNS) and activates myeloperoxidase (MPO), an inflammatory enzyme. Thus, structural oxidative and nitrosative damage to proteins and DNA occurs. We aimed to asses these events in the cerebrospinal fluid (CSF) of pediatric BM patients. Phenylalanine (Phe), para-tyrosine (p-Tyr), nucleoside 2\u2032-deoxiguanosine (2dG), and biomarkers of ROS\/RNS-induced protein and DNA oxidation: ortho-tyrosine (o-Tyr), 3-chlorotyrosine (3Cl-Tyr), 3-nitrotyrosine (3NO\u2082-Tyr) and 8-oxo-2\u2032-deoxyguanosine (8OHdG), concentrations were measured by liquid chromatography coupled to tandem mass spectrometry in the initial CSF of 79 children with BM and 10 without BM. All biomarkers, normalized with their corresponding precursors, showed higher median concentrations (p &lt; 0.0001) in BM compared with controls, except 8OHdG\/2dG. The ratios o-Tyr\/Phe, 3Cl-Tyr\/p-Tyr and 3NO\u2082-Tyr\/p-Tyr were 570, 20 and 4.5 times as high, respectively. A significantly higher 3Cl-Tyr\/p-Tyr ratio was found in BM caused by Streptococcus pneumoniae, than by Haemophilus influenzae type b, or Neisseria meningitidis (p = 0.002 for both). In conclusion, biomarkers indicating oxidative damage to proteins distinguished BM patients from non-BM, most clearly the o-Tyr\/Phe ratio. The high 3Cl-Tyr\/p-Tyr ratio in pneumococcal meningitis suggests robust inflammation because 3Cl-Tyr is a marker of MPO activation and, indirectly, of inflammation.<\/jats:p>","DOI":"10.3390\/antiox8100441","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T11:11:16Z","timestamp":1569928276000},"page":"441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Protein Oxidation Biomarkers and Myeloperoxidase Activation in Cerebrospinal Fluid in Childhood Bacterial Meningitis"],"prefix":"10.3390","volume":"8","author":[{"given":"Emilie","family":"Rugemalira","sequence":"first","affiliation":[{"name":"Children\u2019s Hospital, Helsinki University Hospital, Stenb\u00e4ckinkatu 9, 00029 Helsinki, Finland"},{"name":"Faculty of Medicine, University of Helsinki, Yliopistonkatu 4, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0020-361X","authenticated-orcid":false,"given":"Irmeli","family":"Roine","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University Diego Portales, Manuel Rodrigues Sur 333, 8370109 Santiago Region Metropolitana, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6979-2235","authenticated-orcid":false,"given":"Julia","family":"Kuligowski","sequence":"additional","affiliation":[{"name":"Health Research Institute La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7630-0614","authenticated-orcid":false,"given":"\u00c1ngel","family":"S\u00e1nchez-Illana","sequence":"additional","affiliation":[{"name":"Health Research Institute La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 David","family":"Pi\u00f1eiro-Ramos","sequence":"additional","affiliation":[{"name":"Health Research Institute La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sture","family":"Andersson","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Helsinki University Hospital, Stenb\u00e4ckinkatu 9, 00029 Helsinki, Finland"},{"name":"Faculty of Medicine, University of Helsinki, Yliopistonkatu 4, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikki","family":"Peltola","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Helsinki University Hospital, Stenb\u00e4ckinkatu 9, 00029 Helsinki, Finland"},{"name":"Faculty of Medicine, University of Helsinki, Yliopistonkatu 4, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Leite Cruzeiro","sequence":"additional","affiliation":[{"name":"Hospital Pedi\u00e1trico David Bernardino, Rua Amilcar Cabral, Luanda, Angola"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuula","family":"Pelkonen","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, Helsinki University Hospital, Stenb\u00e4ckinkatu 9, 00029 Helsinki, Finland"},{"name":"Faculty of Medicine, University of Helsinki, Yliopistonkatu 4, 00014 Helsinki, Finland"},{"name":"Hospital Pedi\u00e1trico David Bernardino, Rua Amilcar Cabral, Luanda, Angola"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0061-4742","authenticated-orcid":false,"given":"M\u00e1ximo","family":"Vento","sequence":"additional","affiliation":[{"name":"Health Research Institute La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain"},{"name":"Division of Neonatology, University and Polytechnic Hospital La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,1]]},"reference":[{"key":"ref_1","unstructured":"GBD 2015 Child Mortality Collaborators (2016). Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980\u20132015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet, 388, 1725\u20131774."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S1473-3099(10)70048-7","article-title":"Global and regional risk of disabling sequelae from bacterial meningitis: A systematic review and meta-analysis","volume":"10","author":"Edmond","year":"2010","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1097\/WCO.0b013e32833950dd","article-title":"Mechanisms of injury in bacterial meningitis","volume":"23","author":"Gerber","year":"2010","journal-title":"Curr. Opin. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.2217\/fmb.15.43","article-title":"Bacterial meningitis: Insights into pathogenesis and evaluation of new treatment options: A perspective from experimental studies","volume":"10","author":"Liechti","year":"2015","journal-title":"Future Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"371465","DOI":"10.1155\/2013\/371465","article-title":"Role of oxidative stress in the pathophysiology of pneumococcal meningitis","volume":"2013","author":"Barichello","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1146\/annurev-biochem-060815-014442","article-title":"Reactive oxygen species and neutrophil function","volume":"85","author":"Winterbourn","year":"2016","journal-title":"Annu. Rev. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1590\/S0004-282X2012000500011","article-title":"Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches","volume":"70","author":"Barichello","year":"2012","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1073\/pnas.0307446101","article-title":"Nitric oxide, oxidants, and protein tyrosine nitration","volume":"101","author":"Radi","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3164\/jcbn.15-104","article-title":"Neutrophil myeloperoxidase and its substrates: Formation of specific markers and reactive compounds during inflammation","volume":"58","author":"Kato","year":"2016","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1093\/tropej\/fmt013","article-title":"Oxidative stress in children with bacterial meningitis","volume":"59","author":"Srivastava","year":"2013","journal-title":"J. Trop. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1373\/clinchem.2005.061408","article-title":"Biomarkers of oxidative damage in human disease","volume":"52","author":"Rossi","year":"2006","journal-title":"Clin. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kuligowski, J., Torres-Cuevas, I., Quintas, G., Rook, D., van Goudoever, J.B., Cubells, E., Asensi, M., Lliso, I., Nunez, A., and Vento, M. (2014). Assessment of oxidative damage to proteins and DNA in urine of newborn infants by a validated UPLC-MS\/MS approach. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093703"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/S0891-5849(99)00206-3","article-title":"Stable markers of oxidant damage to proteins and their application in the study of human disease","volume":"27","author":"Davies","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.pneurobio.2006.11.008","article-title":"Oxidative stress in pneumococcal meningitis: A future target for adjunctive therapy?","volume":"80","author":"Klein","year":"2006","journal-title":"Prog. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S1473-3099(11)70055-X","article-title":"Slow initial beta-lactam infusion and oral paracetamol to treat childhood bacterial meningitis: A randomised, controlled trial","volume":"11","author":"Pelkonen","year":"2011","journal-title":"Lancet Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.freeradbiomed.2015.09.014","article-title":"Novel biomarkers in amniotic fluid for early assessment of intraamniotic infection","volume":"89","author":"Stefanovic","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.neulet.2017.06.002","article-title":"Temporal changes of oxidative stress markers in Escherichia coli K1-induced experimental meningitis in a neonatal rat model","volume":"653","author":"Giridharan","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1016\/S0024-3205(02)02137-9","article-title":"Oxidant and antioxidant activities in childhood meningitis","volume":"71","author":"Tsukahara","year":"2002","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/02724936.2000.11748119","article-title":"Evaluation of free radical status in CSF in childhood meningitis","volume":"20","author":"Ray","year":"2000","journal-title":"Ann. Trop. Paediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2174\/0929867323666160119094516","article-title":"Role of tyrosine isomers in acute and chronic diseases leading to oxidative stress\u2014A review","volume":"23","author":"Molnar","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/7854_2016_23","article-title":"Mechanisms of inflammation-associated depression: Immune influences on tryptophan and phenylalanine metabolisms","volume":"31","author":"Strasser","year":"2017","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1128\/CMR.00008-11","article-title":"Pathogenesis and pathophysiology of pneumococcal meningitis","volume":"24","author":"Geldhoff","year":"2011","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1086\/533448","article-title":"Influence of admission findings on death and neurological outcome from childhood bacterial meningitis","volume":"46","author":"Roine","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.clinbiochem.2009.09.023","article-title":"Oxidative stress and myeloperoxidase activity during bacterial meningitis: Effects of febrile episodes and the BBB permeability","volume":"43","author":"Miric","year":"2010","journal-title":"Clin. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1007\/s11064-011-0514-2","article-title":"Oxidative stress, cytokine\/chemokine and disruption of blood-brain barrier in neonate rats after meningitis by Streptococcus agalactiae","volume":"36","author":"Barichello","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1212\/WNL.58.2.186","article-title":"Oxidative stress in bacterial meningitis in humans","volume":"58","author":"Kastenbauer","year":"2002","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1179\/135100000101535834","article-title":"Oxidative stress in childhood meningitis: Measurement of 8-hydroxy-2\u2032-deoxyguanosine concentration in cerebrospinal fluid","volume":"5","author":"Tsukahara","year":"2000","journal-title":"Redox Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.aca.2016.01.054","article-title":"Protein-bound tyrosine oxidation, nitration and chlorination by-products assessed by ultraperformance liquid chromatography coupled to tandem mass spectrometry","volume":"913","author":"Kuligowski","year":"2016","journal-title":"Anal. Chim. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.arr.2016.03.005","article-title":"Roles of the tyrosine isomers meta-tyrosine and ortho-tyrosine in oxidative stress","volume":"27","author":"Ipson","year":"2016","journal-title":"Ageing Res. Rev."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/8\/10\/441\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:36Z","timestamp":1760189196000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/8\/10\/441"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,1]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["antiox8100441"],"URL":"https:\/\/doi.org\/10.3390\/antiox8100441","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,1]]}}}