{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T15:08:43Z","timestamp":1777734523970,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Asthma is a heterogeneous inflammatory airway disease with variable clinical phenotypes. Dysregulation of the arginine\u2013nitric oxide (NO) pathway contributes to airway hyperresponsiveness and endothelial dysfunction, but its role across stages of pediatric asthma remains unclear. In order to replicate real-world clinical heterogeneity, this investigation assessed serum levels of L-arginine, symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA), L-citrulline, and the SDMA\/ADMA ratio in children with managed asthma, asthma exacerbation, upper respiratory tract infections (URTIs), pneumonia, COVID-19, and healthy controls. Discovering stage-specific arginine pathway changes and evaluating their ability to distinguish asthma and asthma exacerbations from other clinically similar respiratory disorders was the primary aim of our research study. Receiver operating characteristic (ROC) analysis demonstrated that the SDMA\/ADMA ratio achieved the strongest individual discriminative performance for distinguishing asthma exacerbation from controlled asthma (AUC: 0.917), while the combined multimarker model incorporating all four metabolites yielded an AUC of 0.983 with a sensitivity of 87.5% and specificity of 95.5%. These results indicate that arginine pathway metabolites, especially the SDMA\/ADMA ratio, may merit additional research as possible markers of acute disease activity in asthma, even though they are exploratory and need external confirmation.<\/jats:p>","DOI":"10.3390\/biom16050631","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:34:42Z","timestamp":1777458882000},"page":"631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Independent Associations Between Arginine-Related Metabolites and Disease Activity in Pediatric Asthma: A Multivariable Biomarker Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8656-9967","authenticated-orcid":false,"given":"Emine Aylin","family":"\u015eenol","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"},{"name":"Department of Pediatric Neurology, School of Medicine, Manisa Celal Bayar University, 45140 Manisa, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5338-9561","authenticated-orcid":false,"given":"\u00d6ner","family":"\u00d6zdemir","sequence":"additional","affiliation":[{"name":"Department of Pediatric Allergy and Immunology, School of Medicine, Sakarya University, 54187 Sakarya, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7399-4929","authenticated-orcid":false,"given":"Aysel","family":"\u00d6zp\u0131nar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"},{"name":"Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3014-748X","authenticated-orcid":false,"given":"Muhittin A.","family":"Serdar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"},{"name":"Department of Medical Biochemistry, School of Medicine, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"ref_1","unstructured":"Global Initiative for Asthma (2025, September 10). Global Strategy for Asthma Management and Prevention. GLOBAL STRATEGY FOR Global Strategy for Asthma Management and Prevention 24_05_22_WMS 2024. Available online: https:\/\/ginasthma.org\/wp-content\/uploads\/2024\/05\/GINA-2024-Strategy-Report-24_05_22_WMS.pdf."},{"key":"ref_2","first-page":"90","article-title":"Asymmetric dimethylarginine and critical illness","volume":"17","author":"Brinkmann","year":"2014","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/bph.14533","article-title":"Nitric oxide synthase enzymology in the 20 years after the Nobel Prize","volume":"176","author":"Stuehr","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/eurheartj\/ehr304","article-title":"Nitric oxide synthases: Regulation and function","volume":"33","author":"Sessa","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Shah, R.J., Tommasi, S., Faull, R., Gleadle, J.M., Mangoni, A.A., and Selvanayagam, J.B. (2021). Arginine Metabolites as Biomarkers of Myocardial Ischaemia, Assessed with Cardiac Magnetic Resonance Imaging in Chronic Kidney Disease. Biomolecules, 11.","DOI":"10.3390\/biom11030416"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1016\/S0140-6736(01)07184-7","article-title":"Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine","volume":"358","author":"Valkonen","year":"2001","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1161\/HYPERTENSIONAHA.108.120352","article-title":"Endogenous nitric oxide synthase inhibitors, arterial hemodynamics, and subclinical vascular disease: The PREVENCION study","volume":"52","author":"Chirinos","year":"2008","journal-title":"Hypertension"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14606","DOI":"10.3390\/ijms131114606","article-title":"Roles of Nitric Oxide and Asymmetric Dimethylarginine in Pregnancy and Fetal Programming","volume":"13","author":"Huang","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S73","DOI":"10.1191\/1358863x05vm597oa","article-title":"ADMA metabolism and clearance","volume":"10","author":"Teerlink","year":"2005","journal-title":"Vasc. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zakrzewicz, D., and Eickelberg, O. (2009). From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulm. Med., 9.","DOI":"10.1186\/1471-2466-9-5"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1093\/infdis\/jiu156","article-title":"Dimethylarginines: Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria","volume":"210","author":"Weinberg","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1080\/07853890500472151","article-title":"Asymmetric dimethylarginine (ADMA): A novel risk marker in cardiovascular medicine and beyond","volume":"38","year":"2006","journal-title":"Ann. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/cea.12802","article-title":"l-citrulline prevents asymmetric dimethylarginine-mediated reductions in nitric oxide and nitrosative stress in primary human airway epithelial cells","volume":"47","author":"Winnica","year":"2017","journal-title":"Clin. Exp. Allergy"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Janaszak-Jasiecka, A., Siekierzycka, A., P\u0142oska, A., Dobrucki, I.T., and Kalinowski, L. (2021). Endothelial Dysfunction Driven by Hypoxia\u2014The Influence of Oxygen Deficiency on NO Bioavailability. Biomolecules, 11.","DOI":"10.3390\/biom11070982"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.aca.2010.08.011","article-title":"Simultaneous quantitative determination of NG,NG-dimethyl-l-arginine or asymmetric dimethylarginine and related pathway\u2019s metabolites in biological fluids by ultrahigh-performance liquid chromatography\/electrospray ionization-tandem mass spectrometry","volume":"677","author":"Chiandetti","year":"2010","journal-title":"Anal. Chim. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1378\/chest.13-0480","article-title":"Asymmetric dimethylarginine: A disease marker for asthma?","volume":"144","author":"Scott","year":"2013","journal-title":"Chest"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.iac.2014.07.007","article-title":"Arginine metabolism in asthma","volume":"34","author":"Scott","year":"2014","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1183\/09031936.00080313","article-title":"Asymmetric dimethylarginine and asthma","volume":"43","author":"Scott","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1164\/rccm.201011-1810OC","article-title":"Asymmetric dimethylarginine is increased in asthma","volume":"184","author":"Scott","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.yjmcc.2012.06.002","article-title":"Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1)","volume":"53","author":"Strobel","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrneph.2011.31","article-title":"The role of asymmetric and symmetric dimethylarginines in renal disease","volume":"7","author":"Schwedhelm","year":"2011","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1164\/rccm.200710-1542OC","article-title":"Alterations of the arginine metabolome in asthma","volume":"178","author":"Lara","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_23","first-page":"1467","article-title":"Association of Asymmetric Dimethylarginine and Endothelial Dysfunction","volume":"41","year":"2003","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_24","first-page":"561","article-title":"ADMA, SDMA, L-Arginine and nitric oxide in allergic pediatric bronchial asthma","volume":"26","author":"Riccioni","year":"2012","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1164\/rccm.200309-1304OC","article-title":"Decreased arginine bioavailability and increased serum arginase activity in asthma","volume":"170","author":"Morris","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_26","first-page":"e137777","article-title":"L-Arginine supplementation in severe asthma","volume":"5","author":"Liao","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"187","DOI":"10.3390\/ph4010187","article-title":"L-arginine supplementation and metabolism in asthma","volume":"4","author":"Kenyon","year":"2011","journal-title":"Pharmaceuticals"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhou, B., Jiang, G.T., Liu, H., Guo, M., Liu, J., and She, J. (2021). Dysregulated arginine metabolism in young patients with chronic persistent asthma and in human bronchial epithelial cells. Nutrients, 13.","DOI":"10.21203\/rs.3.rs-567567\/v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.amsu.2016.05.017","article-title":"Arginine dimethylation products in pediatric patients with chronic kidney disease","volume":"9","author":"Behery","year":"2016","journal-title":"Ann. Med. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"BMI.S38434","DOI":"10.4137\/BMI.S38434","article-title":"Asymmetric Dimethylarginine and Its Relation as a Biomarker in Nephrologic Diseases","volume":"11","author":"Sitar","year":"2016","journal-title":"Biomark. Insights"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"736319","DOI":"10.1155\/2011\/736319","article-title":"Arginase and Arginine Dysregulation in Asthma","volume":"2011","author":"Benson","year":"2011","journal-title":"J. Allergy"},{"key":"ref_32","first-page":"e131733","article-title":"L-Citrulline increases nitric oxide and improves control in obese asthmatics","volume":"4","author":"Holguin","year":"2019","journal-title":"J. Clin. Investig."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/5\/631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T11:11:15Z","timestamp":1777461075000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/5\/631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,24]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["biom16050631"],"URL":"https:\/\/doi.org\/10.3390\/biom16050631","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,24]]}}}