{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:18:02Z","timestamp":1789154282287,"version":"build-2803163510"},"reference-count":25,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T00:00:00Z","timestamp":1637107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81800390"],"award-info":[{"award-number":["81800390"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Research and Development Program of Shaanxi","award":["2020KW-049, 2021KWZ-25, S2020-YF-GHMS-0014, 2017SF-085, 2020GXLH-Y-015"],"award-info":[{"award-number":["2020KW-049, 2021KWZ-25, S2020-YF-GHMS-0014, 2017SF-085, 2020GXLH-Y-015"]}]},{"name":"the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University","award":["XJTU1AF-CRF-2018-025"],"award-info":[{"award-number":["XJTU1AF-CRF-2018-025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Recent metabolomics studies have found circulatory metabolism alterations in patients with asthma, indicating that altered metabolites played a significant role in asthma. However, the regulatory mechanisms in asthma, especially in young chronic persistent asthma remain underexplored. Methods: In this study, a prospective cohort of 162 patients diagnosed of asthma admitted to the First Affiliated Hospital of Xi\u2019an Jiaotong University from January 2018 to December 2019 was used to perform a nested case-control study. Among them, we included 30 patients with chronic persistent asthma between 20 to 35 years old; 30 health control with evenly distributed age and sex were then recruited. Nontargeted metabolomics was applied to identify serum metabolic profiles and altered metabolic pathways. Results: In vitro, human bronchial epithelial cells (HBECs) line BEAS-2B with the addition of L-citrulline and\/or asymmetric dimethylarginine (ADMA) model was utilized and the concentrations of nitric oxide (NO) metabolites were tested to evaluate the therapeutic potential of L-citrulline. The young patients with chronic persistent asthma displayed dysregulated serum metabolic profiles, especially enriched in arginine metabolism. The ratio of L-citrulline to ornithine is associated with blood eosinophil count. In vitro, adding L-citrulline could reverse ADMA-mediated reduction of NOx at lower L-arginine concentration (25 \u03bcM), but was ineffective in the higher L-arginine concentration (100 \u03bcM) media. Conclusions: The arginine metabolism balance is of vital importance during the pathogenesis and progression of chronic asthma. L-citrulline could be a powerful approach to restore airway NO production, potentially exhibiting therapeutic benefits among young patients with chronic asthma.<\/jats:p>","DOI":"10.3390\/nu13114116","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T09:16:11Z","timestamp":1637140571000},"page":"4116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Dysregulated Arginine Metabolism in Young Patients with Chronic Persistent Asthma and in Human Bronchial Epithelial Cells"],"prefix":"10.3390","volume":"13","author":[{"given":"Bo","family":"Zhou","sequence":"first","affiliation":[{"name":"Respirotory Department, The First Affiliated Hospital of Xi\u2019an Jiaotong University, No. 277 W. Yanta Road, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulinigaer Tuerhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, The First Affiliated Hospital of Xi\u2019an Jiaotong University, No. 277 W. Yanta Road, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Biobank, First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyun","family":"Guo","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, The First Affiliated Hospital of Xi\u2019an Jiaotong University, No. 277 W. Yanta Road, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Liu","sequence":"additional","affiliation":[{"name":"Diagnostic Department, The First Affiliated Hospital of Xi\u2019an Jiaotong University, No. 277 W. Yanta Road, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqing","family":"She","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, The First Affiliated Hospital of Xi\u2019an Jiaotong University, No. 277 W. 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Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2500\/aap.2014.35.3777","article-title":"Altered L-arginine metabolism in children with controlled asthma","volume":"35","author":"Kraj","year":"2014","journal-title":"Allergy Asthma Proc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/bcpt.12686","article-title":"Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation","volume":"120","author":"Bo","year":"2017","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"117318","DOI":"10.1016\/j.saa.2019.117318","article-title":"Twisted intramolecular charge transfer (TICT) based fluorescent probe for lighting up serum albumin with high sensitivity in physiological conditions","volume":"223","author":"Zhang","year":"2019","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1042\/CS20180247","article-title":"Targeting amino acids metabolic profile to identify novel metabolic characteristics in atrial fibrillation","volume":"132","author":"She","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5236267","DOI":"10.1155\/2018\/5236267","article-title":"Correlation of Triiodothyronine Level with In-Hospital Cardiac Function and Long-Term Prognosis in Patients with Acute Myocardial Infarction","volume":"2018","author":"She","year":"2018","journal-title":"Dis. Markers"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12933-017-0578-7","article-title":"Hemoglobin A1c is associated with severity of coronary artery stenosis but not with long term clinical outcomes in diabetic and nondiabetic patients with acute myocardial infarction undergoing primary angioplasty","volume":"16","author":"She","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1183\/09031936.00124009","article-title":"Measuring asthma control: A comparison of three classification systems","volume":"36","author":"Reddel","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4844","DOI":"10.1021\/pr9004162","article-title":"Serum metabolite profiling of human colorectal cancer using GC-TOFMS and UPLC-QTOFMS","volume":"8","author":"Qiu","year":"2009","journal-title":"J. Proteome Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17017","DOI":"10.1073\/pnas.1315558110","article-title":"Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China","volume":"110","author":"Wang","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6619","DOI":"10.1021\/ac300898h","article-title":"ADAP-GC 2.0: Deconvolution of coeluting metabolites from GC\/TOF-MS data for metabolomics studies","volume":"84","author":"Ni","year":"2012","journal-title":"Anal. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkp1002","article-title":"SMPDB: The Small Molecule Pathway Database","volume":"38","author":"Frolkis","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D478","DOI":"10.1093\/nar\/gkt1067","article-title":"SMPDB 2.0: Big improvements to the Small Molecule Pathway Database","volume":"42","author":"Jewison","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"e131733","DOI":"10.1172\/jci.insight.131733","article-title":"L-Citrulline increases nitric oxide and improves control in obese asthmatics","volume":"4","author":"Holguin","year":"2019","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"685","DOI":"10.2147\/JAA.S307549","article-title":"Review\u2014Nutraceuticals Can Target Asthmatic Bronchoconstriction: NADPH Oxidase-Dependent Oxidative Stress, RhoA and Calcium Dynamics","volume":"14","author":"McCarty","year":"2021","journal-title":"J. Asthma Allergy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"627503","DOI":"10.3389\/fphar.2021.627503","article-title":"Arginine Therapy for Lung Diseases","volume":"12","author":"Scott","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.jaci.2009.10.065","article-title":"Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma","volume":"125","author":"Mabalirajan","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"L911","DOI":"10.1152\/ajplung.00025.2009","article-title":"Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma","volume":"296","author":"North","year":"2009","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1165\/rcmb.2012-0323OC","article-title":"Increased ornithine-derived polyamines cause airway hyperresponsiveness in a mouse model of asthma","volume":"48","author":"North","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1136\/thx.2003.014894","article-title":"Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath","volume":"59","author":"Lane","year":"2004","journal-title":"Thorax"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1165\/rcmb.2006-0329SM","article-title":"Oxidative-nitrosative stress and post-translational protein modifications: Implications to lung structure-function relations. Arginase modulates NF-kappaB activity via a nitric oxide-dependent mechanism","volume":"36","author":"Ckless","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/11\/4116\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:31:28Z","timestamp":1760167888000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/11\/4116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,17]]},"references-count":25,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["nu13114116"],"URL":"https:\/\/doi.org\/10.3390\/nu13114116","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-567567\/v1","asserted-by":"object"}]},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,17]]}}}