{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:27:42Z","timestamp":1790706462135,"version":"4.1.0"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T00:00:00Z","timestamp":1706832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Council of the Republic of China","award":["(NSC 98-2320-B-030-003-MY3"],"award-info":[{"award-number":["(NSC 98-2320-B-030-003-MY3"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Introduction<\/jats:title><jats:p>Intestinal ischemia and reperfusion (IIR) injury is closely associated with oxidative stress. Evidence shows that oral supplementation with glutamine and citrulline alleviates IIR-induced jejunal damage. We investigated the effects of a combination of glutamine, citrulline, and antioxidant vitamins on IIR-induced jejunal damage, oxidative stress, and inflammation.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Method<\/jats:title><jats:p>Male Wistar rats that underwent 60 min of superior mesenteric artery occlusion were orally administered glutamine plus citrulline (GC), vitamin C plus E (CE), or a combination of GC and CE 15 min before and 3, 9, and 21 h after reperfusion. Healthy rats without IIR were used as controls.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>After reperfusion for 24 h, rats with IIR showed lower levels of red blood cells, hemoglobin, serum glucose, and jejunal DNA and increased white blood cell counts compared to controls (1-way ANOVA with the least significant difference,<jats:italic>P<\/jats:italic>&lt; 0.05). The IIR-induced decrease in serum albumin and increase in plasma interleukin-6 and jejunal thiobarbituric acid-reactive substances (TBARS) were significantly reversed by GC and\/or CE. The results of the 2-way ANOVA indicated that GC was the main factor that increased jejunal villus height and muscularis DNA, and CE was the main factor that increased jejunal muscularis protein and decreased jejunal proinflammatory cytokine levels and myeloperoxidase activity. In addition, GC and CE are the main factors that decrease plasma proinflammatory cytokine levels and the jejunal apoptotic index.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusion<\/jats:title><jats:p>Oral post-treatment supplementation with glutamine and citrulline, combined with vitamins C and E, may alleviate IIR-induced oxidative stress, inflammation, and jejunal damage.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0298334","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T18:24:38Z","timestamp":1706898278000},"page":"e0298334","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Oral post-treatment supplementation with a combination of glutamine, citrulline, and antioxidant vitamins additively mitigates jejunal damage, oxidative stress, and inflammation in rats with intestinal ischemia and reperfusion"],"prefix":"10.1371","volume":"19","author":[{"given":"Yu-Wen","family":"Chiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Hsing","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2138-1837","authenticated-orcid":true,"given":"Hui-Chen","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"issue":"7","key":"pone.0298334.ref001","first-page":"711","article-title":"Histopathology of human small intestinal and colonic ischemia-reperfusion: Experiences from human ir-models","volume":"34","author":"CA Leenarts","year":"2019","journal-title":"Histol Histopathol"},{"key":"pone.0298334.ref002","doi-asserted-by":"crossref","first-page":"111482","DOI":"10.1016\/j.biopha.2021.111482","article-title":"Intestinal ischemic reperfusion injury: Recommended rats model and comprehensive review for protective strategies","volume":"138","author":"J Wang","year":"2021","journal-title":"Biomed Pharmacother"},{"key":"pone.0298334.ref003","doi-asserted-by":"crossref","first-page":"750731","DOI":"10.3389\/fmed.2021.750731","article-title":"Oxidative stress in intestinal ischemia-reperfusion","volume":"8","author":"G Li","year":"2021","journal-title":"Front Med (Lausanne)"},{"issue":"1","key":"pone.0298334.ref004","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13017-022-00443-x","article-title":"Acute mesenteric ischemia: Updated guidelines of the world society of emergency surgery","volume":"17","author":"M Bala","year":"2022","journal-title":"World J Emerg Surg"},{"issue":"1","key":"pone.0298334.ref005","doi-asserted-by":"crossref","first-page":"e501","DOI":"10.1002\/ams2.501","article-title":"Therapeutic strategies for ischemia reperfusion injury in emergency medicine","volume":"7","author":"H Naito","year":"2020","journal-title":"Acute Med Surg"},{"issue":"1","key":"pone.0298334.ref006","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3945\/jn.110.131888","article-title":"Enteral arginine does not increase superior mesenteric arterial blood flow but induces mucosal growth in neonatal pigs","volume":"141","author":"PJ Puiman","year":"2011","journal-title":"J Nutr"},{"issue":"1","key":"pone.0298334.ref007","doi-asserted-by":"crossref","first-page":"e202000104","DOI":"10.1590\/s0102-865020200010000004","article-title":"Glutamine protects intestine against ischemia-reperfusion injury by alleviating endoplasmic reticulum stress induced apoptosis in rats","volume":"35","author":"H Xu","year":"2020","journal-title":"Acta Cir 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resection","volume":"53","author":"S Osowska","year":"2004","journal-title":"Gut"},{"issue":"1","key":"pone.0298334.ref014","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00726-008-0152-4","article-title":"Amino acids and gut function","volume":"37","author":"WW Wang","year":"2009","journal-title":"Amino Acids"},{"issue":"1","key":"pone.0298334.ref015","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.1365-2125.2007.02990.x","article-title":"Pharmacokinetic and pharmacodynamic properties of oral l-citrulline and l-arginine: Impact on nitric oxide metabolism","volume":"65","author":"E Schwedhelm","year":"2008","journal-title":"Br J Clin Pharmacol"},{"issue":"6","key":"pone.0298334.ref016","first-page":"427","article-title":"Enzymatic antioxidant defence mechanism in rat intestinal tissue is changed after ischemia-reperfusion. Effects of an allopurinol plus antioxidant combination","volume":"42","author":"M Kacmaz","year":"1999","journal-title":"Can J Surg"},{"issue":"2","key":"pone.0298334.ref017","first-page":"241","article-title":"A new, rapid, high-sensitivity analysis of amino acids in food type samples","volume":"70","author":"BA Bidlingmeyer","year":"1987","journal-title":"J Assoc Off Anal Chem"},{"issue":"5","key":"pone.0298334.ref018","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1515\/CCLM.1999.086","article-title":"Determination of ascorbic acid in plasma and urine by high performance liquid chromatography with ultraviolet detection","volume":"37","author":"A Rumelin","year":"1999","journal-title":"Clin Chem Lab Med"},{"issue":"1\u20132","key":"pone.0298334.ref019","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0021-9673(97)00416-0","article-title":"Simultaneous determination of vitamins a and e in rat tissues by high-performance liquid chromatography","volume":"778","author":"C Barbas","year":"1997","journal-title":"J Chromatogr A"},{"issue":"2","key":"pone.0298334.ref020","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"H Ohkawa","year":"1979","journal-title":"Anal Biochem"},{"issue":"2","key":"pone.0298334.ref021","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/0003-2697(80)90165-7","article-title":"A simple, rapid, and sensitive DNA assay procedure","volume":"102","author":"C Labarca","year":"1980","journal-title":"Anal Biochem"},{"issue":"3","key":"pone.0298334.ref022","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00383-004-1318-0","article-title":"Oral arginine improves intestinal recovery following ischemia-reperfusion injury in rat","volume":"21","author":"I Sukhotnik","year":"2005","journal-title":"Pediatr Surg Int"},{"issue":"6","key":"pone.0298334.ref023","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/0016-5085(84)90202-6","article-title":"Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models","volume":"87","author":"JE Krawisz","year":"1984","journal-title":"Gastroenterology"},{"issue":"2","key":"pone.0298334.ref024","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"39","author":"F Faul","year":"2007","journal-title":"Behav Res Methods"},{"issue":"3","key":"pone.0298334.ref025","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s11605-007-0102-6","article-title":"The effect of l-arginine and aprotinin on intestinal ischemia-reperfusion injury","volume":"11","author":"CP Spanos","year":"2007","journal-title":"J Gastrointest Surg"},{"issue":"3","key":"pone.0298334.ref026","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1515\/cclm-2017-0291","article-title":"Diagnosis biomarkers in acute intestinal ischemic injury: So close, yet so far","volume":"56","author":"K Peoc\u2019h","year":"2018","journal-title":"Clin Chem Lab Med"},{"key":"pone.0298334.ref027","doi-asserted-by":"crossref","first-page":"924695","DOI":"10.3389\/fphar.2022.924695","article-title":"Mechanism involved in acute liver injury induced by intestinal ischemia-reperfusion","volume":"13","author":"B Jin","year":"2022","journal-title":"Front Pharmacol"},{"issue":"3","key":"pone.0298334.ref028","doi-asserted-by":"crossref","first-page":"L506","DOI":"10.1152\/ajplung.00017.2009","article-title":"L-citrulline ameliorates chronic hypoxia-induced pulmonary hypertension in newborn piglets","volume":"297","author":"M Ananthakrishnan","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"5","key":"pone.0298334.ref029","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1139\/y11-027","article-title":"Protective effect of l-citrulline against acute gastric mucosal lesions induced by ischemia-reperfusion in rats","volume":"89","author":"L Gou","year":"2011","journal-title":"Can J Physiol Pharmacol"},{"issue":"1","key":"pone.0298334.ref030","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/13510002.2016.1229893","article-title":"The effect of antioxidant supplementation on bacterial translocation after intestinal ischemia and reperfusion","volume":"22","author":"A Tassopoulos","year":"2017","journal-title":"Redox Rep"},{"issue":"4","key":"pone.0298334.ref031","doi-asserted-by":"crossref","first-page":"420","DOI":"10.3109\/19390211.2015.1103828","article-title":"Antioxidant potential of the methanol extract of parquetina nigrescens mediates protection against intestinal ischemia-reperfusion injury in rats","volume":"13","author":"FJ Akinrinmade","year":"2016","journal-title":"Journal of dietary supplements"},{"key":"pone.0298334.ref032","doi-asserted-by":"crossref","first-page":"101292","DOI":"10.1016\/j.redox.2019.101292","article-title":"\u0391-tocopherol preserves cardiac 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