{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:34:01Z","timestamp":1785803641571,"version":"3.56.0"},"reference-count":28,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gunma University Initiative for Advanced Research"},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K08106"],"award-info":[{"award-number":["23K08106"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K23504"],"award-info":[{"award-number":["24K23504"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K11883"],"award-info":[{"award-number":["24K11883"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K11948"],"award-info":[{"award-number":["25K11948"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K19349"],"award-info":[{"award-number":["24K19349"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxygen nanobubble (NBO2) water is reportedly a promising therapeutic and radiosensitizing agent against solid cancers. However, the significance of nanobubble size in inflammation-associated colorectal carcinogenesis in vivo remains elusive. We investigated whether small NBO2 water exerts stronger preventive effects against colitis and colorectal carcinogenesis in an azoxymethane\/dextran sulfate sodium\u2013induced mouse model of colitis-associated cancer. Differences in particle size between the small and large NBO2 water samples were confirmed by atomic force microscopy. The mice received drinking water containing either small or large sized NBO2 throughout the experiment. Small NBO2 water significantly reduced disease activity index scores, histopathological colitis scores, colonic shortening, CD68-positive inflammatory macrophage density, and tumor numbers. However, body weight, water intake, food intake, and spleen weight were unaffected. Immunohistochemistry revealed that small NBO2 water reduced the percentage of Ki-67-positive tumor cells and the proportions of hypoxia-inducible factor-1\u03b1\u2013positive epithelial and stromal cells, whereas no significant differences were observed in CD8- or forkhead box P3-positive cells. We conclude that nanometer-sized oxygen bubbles prevent inflammation-associated colorectal carcinogenesis, and that particle size is a critical determinant of biological effects. Small amounts of NBO2 water may help control colitis and tumor development by alleviating hypoxia in the tumor microenvironment.<\/jats:p>","DOI":"10.3390\/ijms27041975","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T08:51:09Z","timestamp":1771491069000},"page":"1975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Smaller Oxygen Nanobubbles More Effectively Suppress Colitis and Colon Carcinogenesis than Larger Oxygen Nanobubbles"],"prefix":"10.3390","volume":"27","author":[{"given":"Gendensuren","family":"Dorjkhorloo","sequence":"first","affiliation":[{"name":"Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showamachi, Maebashi 371-8510, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuhisa","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showamachi, Maebashi 371-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6832-4146","authenticated-orcid":false,"given":"Akiharu","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showamachi, Maebashi 371-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of General Surgical Science, Graduate School of Medicine, Gunma University, 3-39-22 Showamachi, Maebashi 371-8510, 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Colloid. Interface Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kyzas, G.Z., and Mitropoulos, A.C. (2021). From bubbles to nanobubbles. Nanomaterials, 11.","DOI":"10.3390\/nano11102592"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1021\/acsnano.6b07478","article-title":"Oxygen nanobubble tracking by light scattering in single cells and tissues","volume":"11","author":"Bhandari","year":"2017","journal-title":"ACS Nano"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Casalegno Gardu\u00f1o, R., and D\u00e4britz, J. (2021). New insights on CD8+ T cells in inflammatory bowel disease and therapeutic approaches. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.738762"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1186\/s12964-023-01386-9","article-title":"Macrophage polarization in inflammatory bowel disease","volume":"21","author":"Zhang","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.3748\/wjg.v22.i7.2195","article-title":"Role of regulatory T cell in the pathogenesis of inflammatory bowel disease","volume":"22","author":"Yamada","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15546","DOI":"10.1002\/jcb.28821","article-title":"Evaluation of antitumor effect of oxygen nanobubble water on breast cancer-bearing BALB\/c mice","volume":"120","author":"Mahjour","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Owen, J., McEwan, C., Nesbitt, H., Bovornchutichai, P., Averre, R., Borden, M., McHale, A.P., Callan, J.F., and Stride, E. (2016). Reducing tumour hypoxia via oral administration of oxygen nanobubbles. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168088"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Gombodorj, N., Yokobori, T., Mutsuki, N., Erkhem-Ochir, B., Okami, H., Asao, T., Saeki, H., Shirabe, K., and Yamanouchi, D. (2022). Effects of ultrafine single-nanometer oxygen bubbles on radiation sensitivity in a tumor-bearing mouse model. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126838"},{"key":"ref_10","first-page":"679","article-title":"Development of single nanometer-sized ultrafine oxygen bubbles to overcome the hypoxia-induced resistance to radiation therapy via the suppression of hypoxia-inducible factor-1\u03b1","volume":"52","author":"Iijima","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.cmet.2020.08.002","article-title":"The role of HIF in immunity and inflammation","volume":"32","author":"McGettrick","year":"2020","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1002\/ijc.29519","article-title":"HIF-1 at the crossroads of hypoxia, inflammation, and cancer","volume":"138","author":"Balamurugan","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1053\/j.gastro.2008.03.009","article-title":"Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade","volume":"134","author":"Shah","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/carcin\/bgu004","article-title":"Inhibition of hypoxia-inducible factors limits tumor progression in a mouse model of colorectal cancer","volume":"35","author":"Shay","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Viafara Garcia, S.M., Khan, M.S., Haidar, Z.S., and Acevedo Cox, J.P. (2023). NanoBubble-mediated oxygenation: Elucidating the underlying molecular mechanisms in hypoxia and mitochondrial-related pathologies. Nanomaterials, 13.","DOI":"10.20944\/preprints202310.0962.v1"},{"key":"ref_16","first-page":"19","article-title":"Cytokine networks in animal models of colitis-associated cancer","volume":"35","author":"Antoniou","year":"2015","journal-title":"Anticancer. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1172\/JCI84430","article-title":"Hypoxia-inducible factors: A central link between inflammation and cancer","volume":"126","author":"Triner","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.1172\/JCI84426","article-title":"Hypoxia-inducible factors: Key regulators of myeloid cells during inflammation","volume":"126","author":"Lin","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.1378\/chest.128.4.2918","article-title":"Microbubbles: Pathophysiology and clinical implications","volume":"128","author":"Barak","year":"2005","journal-title":"Chest"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1136\/jnis-2023-020739","article-title":"Iatrogenic air embolism: Influence of air bubble size on cerebral infarctions in an experimental in vivo and numerical simulation model","volume":"16","author":"Schaefer","year":"2024","journal-title":"J. Neurointerv. Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jcis.2021.11.061","article-title":"Aeration and dissolution behavior of oxygen nanobubbles in water","volume":"609","author":"Xue","year":"2022","journal-title":"J. Colloid. Interface Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Chen, C., Gao, Y., and Zhang, X. (2025). The Existence and Stability Mechanism of Bulk Nanobubbles: A Review. Nanomaterials, 15.","DOI":"10.3390\/nano15040314"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tang, Z., Xiong, D., Song, J., Ye, M., Liu, J., Wang, Z., Zhang, L., and Xiao, X. (2020). Antitumor drug combretastatin-A4 phosphate aggravates the symptoms of dextran sulfate sodium-induced ulcerative colitis in mice. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00339"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102105","DOI":"10.1016\/j.xpro.2023.102105","article-title":"Protocol for colitis-associated colorectal cancer murine model induced by AOM and DSS","volume":"4","author":"Sun","year":"2023","journal-title":"Star. Protoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104938","DOI":"10.1016\/j.yexmp.2024.104938","article-title":"Histomorphological scoring of murine colitis models: A practical guide for the evaluation of colitis and colitis-associated cancer","volume":"140","author":"Remke","year":"2024","journal-title":"Exp. Mol. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s10549-016-3893-x","article-title":"Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer","volume":"158","author":"Aleskandarany","year":"2016","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s00428-018-2297-1","article-title":"High immune cell score predicts improved survival in pancreatic cancer","volume":"472","author":"Tahkola","year":"2018","journal-title":"Virchows Arch."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s00428-019-02549-1","article-title":"Immune cell score in pancreatic cancer-comparison of hotspot and whole-section techniques","volume":"474","author":"Tahkola","year":"2019","journal-title":"Virchows Arch."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1975\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T08:52:59Z","timestamp":1772009579000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1975"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,19]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041975"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041975","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,19]]}}}