{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:09:17Z","timestamp":1776748157931,"version":"3.51.2"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Japan Society for the Promotion of Science and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ischemia reperfusion injury (IRI) during liver-metastasis resection for treatment of colon cancer may increase the risk of further metastasis. Peroxisome proliferator-activated receptor-\u03b3 (PPAR\u03b3) activation has been observed to exert a protective effect against IRI and IRI-induced metastasis of hepatocellular carcinoma. The present study aimed to investigate the effect of the PPAR\u03b3 agonist pioglitazone on tumor metastasis and liver injury following IRI in a mouse model of colon cancer. Pioglitazone (30\u00a0mg\/kg weight) was administered orally 1.5\u00a0h before and 2\u00a0h after the initiation of ischemia and was orally administrated daily to mice from day 0\u201321. SL4-cancer cells expressing red fluorescent protein (SL4-RFP) (1\u2009\u00d7\u200910<jats:sup>6<\/jats:sup>) were injected into the spleen. Fifteen minutes after injection, the hepatoduodenal ligament was clamped with a vessel clip, and released 5\u00a0min later. Liver, blood and tumor samples were taken from mice in order to determine if inflammation was induced by IRI. The effect of pioglitazone on liver metastasis was assessed. Furthermore, the effect of pioglitazone to control the inflammatory response during IRI progression was examined. Liver metastasis along with MMP-9 activation and the production of inflammatory cytokines were resistant to pioglitazone. Our results indicate that liver metastasis and associated inflammation in mice were resistant to pioglitazone.<\/jats:p>","DOI":"10.1038\/s41598-020-75210-6","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T11:02:54Z","timestamp":1603969374000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ischemia reperfusion-induced metastasis is resistant to PPAR\u03b3 agonist pioglitazone in a murine model of colon cancer"],"prefix":"10.1038","volume":"10","author":[{"given":"Yoshihiko","family":"Tashiro","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroto","family":"Nishino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihiko","family":"Sugisawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasunari","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachiko","family":"Inubushi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiko","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shree Ram","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Bouvet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert M.","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"75210_CR1","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1097\/SLA.0b013e3181fc08ca","volume":"253","author":"S Agrawal","year":"2011","unstructured":"Agrawal, S. & Belghiti, J. Oncologic resection for malignant tumors of the liver. Ann. Surg. 253, 656\u2013665 (2011).","journal-title":"Ann. Surg."},{"key":"75210_CR2","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1002\/bjs.7176","volume":"97","author":"R Bahde","year":"2010","unstructured":"Bahde, R. & Spiegel, H. U. Hepatic ischaemia-reperfusion injury from bench to bedside. Br. J. Surg. 97, 1461\u20131475 (2010).","journal-title":"Br. J. Surg."},{"key":"75210_CR3","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1189\/jlb.0805468","volume":"79","author":"A Khandoga","year":"2006","unstructured":"Khandoga, A. et al. Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver. J. Leukoc. Biol. 79, 1295\u20131305 (2006).","journal-title":"J. Leukoc. Biol."},{"key":"75210_CR4","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/S0022-4804(03)00082-9","volume":"111","author":"M Yoshida","year":"2003","unstructured":"Yoshida, M. et al. Intermittent hepatic ischemia-reperfusion minimizes liver metastasis in rats. J. Surg. Res. 111, 255\u2013260 (2003).","journal-title":"J. Surg. Res."},{"key":"75210_CR5","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.bbrc.2008.12.181","volume":"380","author":"SR Lee","year":"2009","unstructured":"Lee, S. R., Kim, H. Y., Hong, J. S., Baek, W. K. & Park, J. W. PPARgamma agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia. Biochem. Biophys. Res. Commun. 380, 17\u201321 (2009).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"75210_CR6","doi-asserted-by":"publisher","first-page":"11293","DOI":"10.1158\/0008-5472.CAN-06-2662","volume":"66","author":"M Bouvet","year":"2006","unstructured":"Lim, C., et al. Hepatic ischemia-reperfusion increases circulating bone marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases. J. Surg. Res. 184, 888\u2013897 (2013).","journal-title":"Cancer. Res."},{"key":"75210_CR7","first-page":"4647","volume":"35","author":"T Matsumoto","year":"2015","unstructured":"Tsuda, T., Horio, F., Kitoh, J. & Osawa, T. Protective effects of dietary cyanidin 3-O-beta-D-glucoside on liver ischemia-reperfusion injury in rats. Arch. Biochem. Biophys. 368, 361\u2013366 (1999).","journal-title":"Anticancer. Res."},{"key":"75210_CR8","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/nprot.2006.109","volume":"1","author":"RM Hoffman","year":"2006","unstructured":"Liu, Y. I., Liu, Z., Chen, Y., Xu, K. & Dong, J. PPARgamma activation reduces ischemia\/reperfusion-induced metastasis in a murine model of hepatocellular carcinoma. Exp. Ther. Med. 11, 387\u2013396 (2016).","journal-title":"Nat. Protoc."},{"key":"75210_CR9","doi-asserted-by":"publisher","first-page":"5195","DOI":"10.1158\/0008-5472.CAN-06-4590","volume":"67","author":"M Yang","year":"2007","unstructured":"Choi, I. K., Kim, Y. H., Kim, J. S. & Seo, J. H. PPAR-gamma ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo. Invest. New. Drugs. 26, 283\u2013288 (2008).","journal-title":"Cancer. Res."},{"key":"75210_CR10","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1016\/j.jss.2013.04.069","volume":"184","author":"C Lim","year":"2013","unstructured":"Sarraf, P. et al. Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat. Med. 4, 1046\u20131052 (1998).","journal-title":"J. Surg. Res."},{"key":"75210_CR11","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1006\/abbi.1999.1311","volume":"368","author":"T Tsuda","year":"1999","unstructured":"Osawa, E. et al. Peroxisome proliferator-activated receptor gamma ligands suppress colon carcinogenesis induced by azoxymethane in mice. Gastroenterology 124, 36\u2013367 (2003).","journal-title":"Arch. Biochem. Biophys."},{"key":"75210_CR12","doi-asserted-by":"publisher","first-page":"387","DOI":"10.3892\/etm.2015.2934","volume":"11","author":"YI Liu","year":"2016","unstructured":"Takano, S. et al. Pioglitazone, a ligand for peroxisome proliferator-activated receptor-gamma acts as an inhibitor of colon cancer liver metastasis. Anticancer. Res. 28, 3593\u20133599 (2008).","journal-title":"Exp. Ther. Med."},{"key":"75210_CR13","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1007\/s10637-007-9108-x","volume":"26","author":"IK Choi","year":"2008","unstructured":"Lefebvre, A. M. et al. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL\/6J-APCMin\/+ mice. Nat. Med. 4, 1053\u20131057 (1998).","journal-title":"Invest. New. Drugs."},{"key":"75210_CR14","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1038\/2030","volume":"4","author":"P Sarraf","year":"1998","unstructured":"Saez, E. et al. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat. Med. 4, 1058\u20131061 (1998).","journal-title":"Nat. Med."},{"key":"75210_CR15","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1053\/gast.2003.50067","volume":"124","author":"E Osawa","year":"2003","unstructured":"Yang, K. et al. Peroxisome proliferator-activated receptor gamma agonist troglitazone induces colon tumors in normal C57BL\/6J mice and enhances colonic carcinogenesis in Apc1638 N\/+ Mlh1+\/- double mutant mice. Int. J. Cancer. 116, 495\u2013499 (2005).","journal-title":"Gastroenterology"},{"key":"75210_CR16","first-page":"3593","volume":"28","author":"S Takano","year":"2008","unstructured":"Elshazly, S. & Soliman, E. PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia\/reperfusion injury. Toxicol. Appl. Pharmacol. 362, 86\u201394 (2019).","journal-title":"Anticancer. Res."},{"key":"75210_CR17","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1038\/2036","volume":"4","author":"AM Lefebvre","year":"1998","unstructured":"Akahori, T. et al. Importance of peroxisome proliferator-activated receptor-gamma in hepatic ischemia\/reperfusion injury in mice. J. Hepatol. 47, 784\u2013792 (2007).","journal-title":"Nat. Med."},{"key":"75210_CR18","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1038\/2042","volume":"4","author":"E Saez","year":"1998","unstructured":"Higuchi, T. et al. Pioglitazone, an agonist of PPAR\u03b3, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression. Biomed. Pharmacother. 118, 109356 (2019).","journal-title":"Nat. Med."},{"key":"75210_CR19","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1002\/ijc.21018","volume":"116","author":"K Yang","year":"2005","unstructured":"Higuchi, T. et al. PPAR\u03b3 Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model. Cancer Genomics Proteomics 17, 35\u201340 (2020).","journal-title":"Int. J. Cancer."},{"key":"75210_CR20","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.taap.2018.10.022","volume":"362","author":"S Elshazly","year":"2019","unstructured":"Bouvet, M. et al. In vivo color-coded imaging of the interaction of colon cancer cells and splenocytes in the formation of liver metastases. Cancer. Res. 66, 11293\u201311297 (2006).","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"75210_CR21","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.jhep.2007.07.030","volume":"47","author":"T Akahori","year":"2007","unstructured":"Matsumoto, T. et al. A color-coded imageable syngeneic mouse model of stromal-cell recruitment by metastatic lymphoma. Anticancer. Res. 35, 4647\u20134654 (2015).","journal-title":"J. Hepatol."},{"key":"75210_CR22","doi-asserted-by":"publisher","first-page":"109356","DOI":"10.1016\/j.biopha.2019.109356","volume":"118","author":"T Higuchi","year":"2019","unstructured":"Hoffman, R. M. & Yang, M. Subcellular imaging in the live mouse. Nat. Protoc. 1, 775\u2013782 (2006).","journal-title":"Biomed. Pharmacother."},{"key":"75210_CR23","doi-asserted-by":"publisher","first-page":"35","DOI":"10.21873\/cgp.20165","volume":"17","author":"T Higuchi","year":"2020","unstructured":"Yang, M., Jiang, P. & Hoffman, R. M. Whole-body subcellular multicolor imaging of tumor-host interaction and drug response in real time. Cancer. Res. 67, 5195\u20135200 (2007).","journal-title":"Cancer Genomics Proteomics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75210-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75210-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75210-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T22:20:41Z","timestamp":1670365241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-75210-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,29]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["75210"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-75210-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,29]]},"assertion":[{"value":"26 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18565"}}