{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T18:50:57Z","timestamp":1755802257102,"version":"3.44.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Chronic small-intestinal mucositis (CIM) is a severe gastrointestinal complication that has limited treatment options. This study investigated the potential therapeutic effects of Daikenchuto (DKT), a traditional medicine, on mitigating methotrexate (MTX)-induced CIM in rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male Sprague-Dawley rats were assigned to four groups: control, MTX, DKT-MTX, and DKT. CIM was induced by intraperitoneal administration of MTX (10\u00a0mg\/kg every 6 days), while DKT (2.7% wt\/wt) was orally administered via feed. The surviving rats were euthanized on day 60. Rat intestinal epithelial cells (IEC-6) were used to examine DKT\u2019s cytoprotective effects <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DKT treatment improved survival, reduced gastrointestinal symptoms, and alleviated histological damage, including villus atrophy and crypt hyperplasia. DKT restored mucosal integrity by enhancing the expression of tight junction proteins (CLDN-3) and nutrient transporters (B0,+AT, EAAT3), and by reducing oxidative stress and epithelial cell death. Furthermore, DKT promoted mucosal angiogenesis, as evidenced by increased expression of CD34, VEGFR2, and VEGFA in both tissues and cells. qRT-PCR confirmed upregulation of genes associated with angiogenesis, barrier repair, and mucosal regeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>DKT exerts protective effects against MTX-induced CIM by enhancing angiogenesis, promoting epithelial regeneration, and restoring mucosal barrier function. These findings suggest DKT as a promising adjunctive therapy for managing chronic intestinal toxicity induced by chemotherapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1623726","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T10:02:56Z","timestamp":1755770576000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Daikenchuto improves methotrexate-induced chronic small intestinal mucositis by promoting angiogenesis"],"prefix":"10.3389","volume":"16","author":[{"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":"Daichi","family":"Sadatomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachiko","family":"Mogami","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":"Tomohiko","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiko","family":"Soyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kengo","family":"Kanetaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weili","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susumu","family":"Eguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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":"Abolmaali","year":"2013","journal-title":"Cancer Chemother. 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