{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:30:20Z","timestamp":1788834620913,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T00:00:00Z","timestamp":1616716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cell Biology International"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Radiotherapy is a leading treatment for various types of cancer. However, exposure to high\u2010dose ionizing radiation causes acute gastrointestinal injury and gastrointestinal syndrome. This has significant implications for human health, and therefore, radioprotection is a major area of research. Radiation induces the loss of intestinal stem cells; hence, the protection of stem cells expressing LGR5 (a marker of intestinal epithelial stem cells) is a key strategy for the prevention of radiation\u2010induced injury. In this study, we identified valproic acid (VPA) as a potent radioprotector using an intestinal organoid culture system. VPA treatment increased the number of LGR5+ stem cells and organoid regeneration after irradiation. <jats:italic>N<\/jats:italic>\u2010[<jats:italic>N<\/jats:italic>\u2010(3,5\u2010difluorophenacetyl)\u2010<jats:sc>l<\/jats:sc>\u2010alanyl]\u2010<jats:italic>S<\/jats:italic>\u2010phenylglycine <jats:italic>t<\/jats:italic>\u2010butyl ester (DAPT, an inhibitor of NOTCH signaling) blocked the radioprotective effects of VPA, indicating that NOTCH signaling is a likely mechanism underlying the observed effects of VPA. In addition, VPA acted as a radiosensitizer via the inhibition of histone deacetylase (HDAC) in a colorectal cancer organoid. These results demonstrate that VPA exerts strong protective effects on LGR5+ stem cells via NOTCH signaling and that the inhibition of NOTCH signaling reduces these protective effects, providing a basis for the improved management of radiation injury.<\/jats:p>","DOI":"10.1002\/cbin.11591","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T11:04:08Z","timestamp":1615892648000},"page":"1523-1532","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Valproic acid protects intestinal organoids against radiation via NOTCH signaling"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7655-2336","authenticated-orcid":false,"given":"Misun","family":"Park","sequence":"first","affiliation":[{"name":"Department of Radiological &amp; Clinical Research, Korea Cancer Center Hospital Korea Institute of Radiological and Medical Sciences Seoul Korea"},{"name":"Department of Radiological &amp; Medico\u2010Oncological Sciences Korea University of Science and Technology Daejeon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhye","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Radiological &amp; Clinical Research, Korea Cancer Center Hospital Korea Institute of Radiological and Medical Sciences Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heejeong","family":"Youk","sequence":"additional","affiliation":[{"name":"Department of Radiological &amp; Clinical Research, Korea Cancer Center Hospital Korea Institute of Radiological and Medical Sciences Seoul Korea"},{"name":"Laboratory of Biochemistry, School of Life Sciences and Biotechnology Korea University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ui Sup","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Radiological &amp; Clinical Research, Korea Cancer Center Hospital Korea Institute of Radiological and Medical Sciences Seoul Korea"},{"name":"Department of Surgery Korea Institute of Radiological and Medical Sciences Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young\u2010Hoon","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Radiological &amp; Medico\u2010Oncological Sciences Korea University of Science and Technology Daejeon Korea"},{"name":"Division of Radiation Cancer Research Korea Institute of Radiological and Medical Sciences Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Younjoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Radiological &amp; Clinical Research, Korea Cancer Center Hospital Korea Institute of Radiological and Medical Sciences Seoul Korea"},{"name":"Department of Internal Medicine, Korea Cancer Center Hospital Korea Institute of Radiological and Medical Sciences Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2015.04.013"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6603851"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.133132"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.03.012"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/cbr.2009.0629"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1001410407"},{"key":"e_1_2_8_8_1","article-title":"Valproic acid, valproate and Divalproex in the maintenance treatment of bipolar disorder","volume":"10","author":"Cipriani A.","year":"2013","journal-title":"Cochrane Database of Systematic Reviews"},{"issue":"4","key":"e_1_2_8_9_1","first-page":"360","volume":"15","author":"Citrin D.","year":"2010","journal-title":"Radioprotectors and Mitigators of Radiation\u2010Induced Normal Tissue Injury"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/jjco\/hyf095"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.010908.163145"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03589"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00453.2010"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-017-0314-z"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0902014"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.24.6969"},{"issue":"2","key":"e_1_2_8_17_1","first-page":"323","volume":"23","author":"Greenberger J.S.J.I.v","year":"2009","journal-title":"Radioprotection"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.12-8-942"},{"issue":"7","key":"e_1_2_8_19_1","first-page":"2270","volume":"120","author":"Gudkov A. V.","year":"2010","journal-title":"Radioprotection: Smart Games with Death"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21386"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40778-017-0103-7"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.12-6-738"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.107714"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.315"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.11.008"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2088"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183741"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1060191"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10977-9"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.01.005"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00088.2013"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X17666181227165722"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201540188"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-125-7_19"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.07.050"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07935"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep26069"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602309"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.54.11.2188-a"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.070763"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.053"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3744"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI88410"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118857109"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2737"},{"issue":"5","key":"e_1_2_8_46_1","first-page":"384","volume":"2","author":"Yu J.J.T.cr","year":"2013","journal-title":"Intestinal Stem Cell Injury and Protection During Cancer Therapy"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12416"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.5301\/tj.5000347"}],"container-title":["Cell Biology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbin.11591","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cbin.11591","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cbin.11591","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T05:48:56Z","timestamp":1693201736000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cbin.11591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,26]]},"references-count":47,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1002\/cbin.11591"],"URL":"https:\/\/doi.org\/10.1002\/cbin.11591","archive":["Portico"],"relation":{},"ISSN":["1065-6995","1095-8355"],"issn-type":[{"value":"1065-6995","type":"print"},{"value":"1095-8355","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,26]]},"assertion":[{"value":"2020-11-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}