{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T09:36:32Z","timestamp":1768037792319,"version":"3.49.0"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tsumura Kampo Research Laboratories, Tsumura & Co."}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Daikenchuto (DKT) has positive therapeutic effects on improving various gastrointestinal disorders. The present study investigated whether or not DKT has a potential therapeutic effect on chemotherapy-induced acute small intestinal mucositis (CIM) in a rat model.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Intraperitoneal injection of 10 mg\/kg methotrexate (MTX) every 3 days for a total of 3 doses was used for induction of CIM in a rat model. The MTX and DKT-MTX groups were injected with MTX as above from the first day, and the DKT-MTX and DKT groups were administered 2.7% DKT via the diet at the same time. The rats were euthanized on day 15.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The DKT-MTX group showed an improvement in the body weight and conditions of gastrointestinal disorders as well as increased levels of diamine oxidase in plasma and in the small intestinal villi. The pathology results showed that small intestinal mucosal injury in the DKT-MTX group was less severe than that in the MTX group. Immunohistochemistry for myeloperoxidase and malondialdehyde and quantitative real-time polymerase chain reaction (RT-qPCR) for TGF-\u03b21 and HIF-1\u03b1 showed that DKT attenuated peroxidative damage. The crypts in the DKT-MTX group contained more Ki-67-positive cells than MTX group. The zonula occluden-1 and claudin-3 results showed that DKT promoted repair of the mucosal barrier. RT-qPCR for the amino acid transporters EAAT3 and BO+AT also confirmed that DKT promoted mucosal repair and thus promoted nutrient absorption.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>DKT protected against MTX-induced CIM in a rat model by reducing inflammation, stimulating cell proliferation, and stabilizing the mucosal barrier.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0283626","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T17:50:14Z","timestamp":1680198614000},"page":"e0283626","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Therapeutic effect and mechanism of Daikenchuto in a model of methotrexate-induced acute small intestinal mucositis"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9136-0882","authenticated-orcid":true,"given":"Peilin","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satomi","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiko","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiko","family":"Soyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Hidaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kengo","family":"Kanetaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichiro","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daichi","family":"Sadatomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachiko","family":"Mogami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Fujitsuka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weili","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7876-0152","authenticated-orcid":true,"given":"Susumu","family":"Eguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"pone.0283626.ref001","doi-asserted-by":"crossref","first-page":"681417","DOI":"10.3389\/fphar.2021.681417","article-title":"Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies","volume":"12","author":"D Dahlgren","year":"2021","journal-title":"Front Pharmacol"},{"issue":"Suppl 5","key":"pone.0283626.ref002","doi-asserted-by":"crossref","first-page":"v139","DOI":"10.1093\/annonc\/mdv202","article-title":"Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up","volume":"26","author":"DE Peterson","year":"2015","journal-title":"Ann Oncol"},{"issue":"5","key":"pone.0283626.ref003","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1007\/s00280-012-2062-0","article-title":"A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis","volume":"71","author":"SS Abolmaali","year":"2013","journal-title":"Cancer Chemother Pharmacol"},{"issue":"3","key":"pone.0283626.ref004","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1159\/000356817","article-title":"Life-Threatening Gastrointestinal Mucosal Necrosis during Methotrexate Treatment for Rheumatoid Arthritis","volume":"7","author":"T Tsukada","year":"2013","journal-title":"Case Rep Gastroenterol"},{"issue":"6","key":"pone.0283626.ref005","doi-asserted-by":"crossref","first-page":"G970","DOI":"10.1152\/ajpgi.00043.2010","article-title":"Effect of daikenchuto (TU-100) on gastrointestinal and colonic transit in humans","volume":"298","author":"N Manabe","year":"2010","journal-title":"American journal of physiology Gastrointestinal and liver physiology"},{"key":"pone.0283626.ref006","doi-asserted-by":"crossref","first-page":"146262","DOI":"10.1016\/j.gene.2022.146262","article-title":"Microbiome biomarkers associated with the gut contraction response elicited by the Japanese traditional medicine daikenchuto","volume":"826","author":"Y Wada","year":"2022","journal-title":"Gene"},{"issue":"4","key":"pone.0283626.ref007","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1620\/tjem.230.197","article-title":"Intragastric Dai-Kenchu-To, a Japanese herbal medicine, stimulates colonic motility via transient receptor potential cation channel subfamily V member 1 in dogs","volume":"230","author":"D Kikuchi","year":"2013","journal-title":"Tohoku J Exp Med"},{"issue":"3","key":"pone.0283626.ref008","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1248\/bpb.23.352","article-title":"Effects of Dai-kenchu-to on levels of 5-hydroxytryptamine (serotonin) and vasoactive intestinal peptides in human plasma","volume":"23","author":"T Nagano","year":"2000","journal-title":"Biol Pharm Bull"},{"issue":"6","key":"pone.0283626.ref009","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1002\/jgh3.12410","article-title":"Daikenchuto attenuates visceral pain and suppresses eosinophil infiltration in inflammatory bowel disease in murine models","volume":"4","author":"Y Kogure","year":"2020","journal-title":"JGH Open"},{"issue":"4","key":"pone.0283626.ref010","doi-asserted-by":"crossref","first-page":"G428","DOI":"10.1152\/ajpgi.00356.2012","article-title":"Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine","volume":"304","author":"T Kono","year":"2013","journal-title":"American journal of physiology Gastrointestinal and liver physiology"},{"issue":"1","key":"pone.0283626.ref011","doi-asserted-by":"crossref","first-page":"4580","DOI":"10.1038\/s41598-021-84167-z","article-title":"Growth stimulation of Bifidobacterium from human colon using daikenchuto in an in vitro model of human intestinal microbiota","volume":"11","author":"K Sasaki","year":"2021","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0283626.ref012","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1038\/s41598-018-19550-4","article-title":"Enhanced anastomotic healing by Daikenchuto (TJ-100) in rats","volume":"8","author":"T Wada","year":"2018","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0283626.ref013","doi-asserted-by":"crossref","first-page":"169","DOI":"10.2739\/kurumemedj.MS663005","article-title":"A Pilot Study Evaluating the Effectiveness and Safety of Daikenchuto (TJ-100) for the Treatment of Postoperative Abdominal Pain or Bloating in Patients Undergoing Hepatectomy: Study Protocol for a Randomized, Open, Controlled Trial","volume":"66","author":"S Eguchi","year":"2021","journal-title":"Kurume Med J"},{"issue":"8","key":"pone.0283626.ref014","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1002\/jpen.2076","article-title":"Effect of Daikenchuto for Mechanically Ventilated Patients With Enteral Feeding Intolerance: A Propensity Score-Matched Analysis Using a Nationwide Administrative Inpatient Database","volume":"45","author":"H Ohbe","year":"2021","journal-title":"JPEN J Parenter Enteral Nutr"},{"key":"pone.0283626.ref015","doi-asserted-by":"crossref","first-page":"146266","DOI":"10.1016\/j.gene.2022.146266","article-title":"Distinct effects of TU-100 (daikenchuto) on long-lasting dysbiosis in the small intestine in patients with colorectal cancer and inflammatory bowel disease","volume":"820","author":"T Kono","year":"2022","journal-title":"Gene"},{"issue":"1","key":"pone.0283626.ref016","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s10147-014-0678-2","article-title":"Effect of TU-100, a traditional Japanese medicine, administered after hepatic resection in patients with liver cancer: a multi-center, phase III trial (JFMC40-1001)","volume":"20","author":"M Shimada","year":"2015","journal-title":"Int J Clin Oncol"},{"issue":"10","key":"pone.0283626.ref017","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1007\/s00595-017-1518-6","article-title":"TU-100 exerts a protective effect against bacterial translocation by maintaining the tight junction","volume":"47","author":"C Takasu","year":"2017","journal-title":"Surg Today"},{"issue":"4","key":"pone.0283626.ref018","first-page":"E139","article-title":"Effect of Daikenchuto On Spontaneous Intestinal Tumors in Apc(Min\/+) Mice","volume":"66","author":"L Kong","year":"2021","journal-title":"Kobe J Med Sci"},{"issue":"1","key":"pone.0283626.ref019","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1046\/j.1432-0436.2003.700603.x","article-title":"Identification of a putative intestinal stem cell and early lineage marker; musashi-1","volume":"71","author":"CS Potten","year":"2003","journal-title":"Differentiation"},{"issue":"11","key":"pone.0283626.ref020","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1136\/jcp.2005.031260","article-title":"An approach to duodenal biopsies","volume":"59","author":"S Serra","year":"2006","journal-title":"J Clin Pathol"},{"issue":"5","key":"pone.0283626.ref021","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1111\/j.1365-2141.2009.07765.x","article-title":"Advances in individual prediction of methotrexate toxicity: a review","volume":"146","author":"K. Schmiegelow","year":"2009","journal-title":"Br J Haematol"},{"issue":"12","key":"pone.0283626.ref022","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.ejca.2014.04.014","article-title":"Review of therapeutic drug monitoring of anticancer drugs part 1\u2014cytotoxics","volume":"50","author":"A Paci","year":"2014","journal-title":"Eur J Cancer"},{"key":"pone.0283626.ref023","first-page":"387071","article-title":"Curcumin ameliorates methotrexate-induced nephrotoxicity in rats","volume":"2013","author":"MA Morsy","year":"2013","journal-title":"Adv Pharmacol Sci"},{"issue":"9","key":"pone.0283626.ref024","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1592\/phco.2005.25.9.1271","article-title":"Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: case report and review of the literature","volume":"25","author":"A Perez-Verdia","year":"2005","journal-title":"Pharmacotherapy"},{"issue":"11","key":"pone.0283626.ref025","doi-asserted-by":"crossref","first-page":"584","DOI":"10.5414\/CPP46584","article-title":"Relationship between oral mucositis and high-dose methotrexate therapy in pediatric acute lymphoblastic leukemia","volume":"46","author":"T Maiguma","year":"2008","journal-title":"Int J Clin Pharmacol Ther"},{"issue":"10","key":"pone.0283626.ref026","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s00204-008-0287-9","article-title":"Methotrexate-induced nitrosative stress may play a critical role in small intestinal damage in the rat","volume":"82","author":"VK Kolli","year":"2008","journal-title":"Arch Toxicol"},{"issue":"4","key":"pone.0283626.ref027","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1007\/s10620-012-2437-4","article-title":"Preclinical efficacy of melatonin to reduce methotrexate-induced oxidative stress and small intestinal damage in rats","volume":"58","author":"VK Kolli","year":"2013","journal-title":"Digestive diseases and sciences"},{"issue":"12","key":"pone.0283626.ref028","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1091\/mbc.E14-07-1194","article-title":"HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity","volume":"26","author":"BJ Saeedi","year":"2015","journal-title":"Mol Biol Cell"},{"issue":"3","key":"pone.0283626.ref029","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1177\/1753425917690815","article-title":"TGF-\u03b21 protects intestinal integrity and influences Smads and MAPK signal pathways in IPEC-J2 after TNF-\u03b1 challenge","volume":"23","author":"K Xiao","year":"2017","journal-title":"Innate Immun"},{"issue":"6","key":"pone.0283626.ref030","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00280-010-1253-9","article-title":"Zonula Occludens-1 alterations and enhanced intestinal permeability in methotrexate-treated rats","volume":"66","author":"K Hamada","year":"2010","journal-title":"Cancer Chemother Pharmacol"},{"key":"pone.0283626.ref031","first-page":"10","article-title":"Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease","author":"A Buckley","year":"2018","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"6","key":"pone.0283626.ref032","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1053\/j.gastro.2021.08.047","article-title":"The Tight Junction Protein ZO-1 Is Dispensable for Barrier Function but Critical for Effective Mucosal Repair","volume":"161","author":"WT Kuo","year":"2021","journal-title":"Gastroenterology"},{"issue":"6","key":"pone.0283626.ref033","doi-asserted-by":"crossref","first-page":"C1404","DOI":"10.1152\/ajpcell.00270.2010","article-title":"Redistribution of the tight junction protein ZO-1 during physiological shedding of mouse intestinal epithelial cells","volume":"300","author":"Y Guan","year":"2011","journal-title":"Am J Physiol Cell Physiol"},{"key":"pone.0283626.ref034","article-title":"A prospective study of Daikenchuto on superior mesenteric artery and portal venous blood flows in extremely low birthweight infants","author":"S Watanabe","year":"2022","journal-title":"Research Square"},{"issue":"2","key":"pone.0283626.ref035","first-page":"84","article-title":"Daikenchuto improved perioperative nutritional status of the patients with colorectal cancer: A prospective open-labeled randomized exploratory study","volume":"11","author":"F Fujita","year":"2019","journal-title":"Interv Med Appl Sci"},{"issue":"5","key":"pone.0283626.ref036","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1172\/JCI110881","article-title":"Plasma postheparin diamine oxidase. Sensitive provocative test for quantitating length of acute intestinal mucosal injury in the rat","volume":"71","author":"GD Luk","year":"1983","journal-title":"The Journal of clinical investigation"},{"issue":"2","key":"pone.0283626.ref037","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1007\/s00795-013-0055-7","article-title":"Diamine oxidase as a marker of intestinal mucosal injury and the effect of soluble dietary fiber on gastrointestinal tract toxicity after intravenous 5-fluorouracil treatment in rats","volume":"47","author":"I Fukudome","year":"2014","journal-title":"Med Mol Morphol"},{"issue":"1","key":"pone.0283626.ref038","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1172\/JCI109836","article-title":"Diamine oxidase (histaminase). A circulating marker for rat intestinal mucosal maturation and integrity","volume":"66","author":"GD Luk","year":"1980","journal-title":"The Journal of clinical investigation"},{"issue":"1","key":"pone.0283626.ref039","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0899-9007(01)00715-8","article-title":"Usefulness of soluble dietary fiber for the treatment of diarrhea during enteral nutrition in elderly patients","volume":"18","author":"M Nakao","year":"2002","journal-title":"Nutrition"},{"issue":"2","key":"pone.0283626.ref040","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1177\/0748233713500833","article-title":"Intervention of ginger or propolis ameliorates methotrexate-induced ileum toxicity","volume":"32","author":"M Abdul-Hamid","year":"2016","journal-title":"Toxicol Ind Health"},{"issue":"20","key":"pone.0283626.ref041","article-title":"Antiulcer Activity of Steamed Ginger Extract against Ethanol\/HCl-Induced Gastric Mucosal Injury in Rats","volume":"25","author":"JK Shin","year":"2020","journal-title":"Molecules"},{"issue":"3","key":"pone.0283626.ref042","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/jsfa.11442","article-title":"Ginger and 6-gingerol prevent lipopolysaccharide-induced intestinal barrier damage and liver injury in mice","volume":"102","author":"XX Guo","year":"2022","journal-title":"J Sci Food Agric"},{"key":"pone.0283626.ref043","first-page":"862743","article-title":"Sphingosine kinase-1-dependent and -independent inhibitory effects of zanthoxyli fructus to attenuate the activation of mucosal mast cells and ameliorate food allergies in mice","volume":"2012","author":"X Wang","year":"2012","journal-title":"Evid Based Complement Alternat Med"},{"issue":"49","key":"pone.0283626.ref044","doi-asserted-by":"crossref","first-page":"141","DOI":"10.4103\/0973-1296.196312","article-title":"Depolarizing Effects of Daikenchuto on Interstitial Cells of Cajal from Mouse Small Intestine","volume":"13","author":"H Kim","year":"2017","journal-title":"Pharmacogn Mag"},{"key":"pone.0283626.ref045","doi-asserted-by":"crossref","first-page":"e1983","DOI":"10.7717\/peerj.1983","article-title":"Screening of cytoprotectors against methotrexate-induced cytogenotoxicity from bioactive phytochemicals","volume":"4","author":"S Gu","year":"2016","journal-title":"PeerJ"},{"issue":"10","key":"pone.0283626.ref046","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.jsps.2021.09.007","article-title":"Total ginsenosides promote the IEC-6 cell proliferation via affecting the regulatory mechanism mediated by polyamines","volume":"29","author":"Y Zhu","year":"2021","journal-title":"Saudi Pharm J"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0283626","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T17:50:46Z","timestamp":1680198646000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0283626"}},"subtitle":[],"editor":[{"given":"Muhammad Shahid","family":"Riaz Rajoka","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,30]]},"references-count":46,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0283626","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,30]]}}}