{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:45:31Z","timestamp":1786977931699,"version":"build-2736575974"},"reference-count":52,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T00:00:00Z","timestamp":1612828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K07099"],"award-info":[{"award-number":["19K07099"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>MicroRNAs (miRNA) have received considerable attention as potential biomarkers for drug\u2010induced liver injury. We recently reported that the plasma levels of miR\u2010143\u20103p and miR\u2010218a\u20105p increased in severe cholestasis in rats. This study aimed to investigate whether these miRNAs increase in a severity\u2010dependent manner and to elucidate their pathophysiological roles in cholestasis. Male Sprague\u2013Dawley rats were orally administered different doses of \u03b1\u2010naphthylisothiocyanate or 4,4\u2010methylenedianiline to induce acute cholestasis. They were also orally administered acetaminophen or thioacetamide to induce hepatocellular injury. We found that plasma miR\u2010143\u20103p and miR\u2010218a\u20105p levels increased in a dose\u2010dependent manner in cholestatic rats but not in hepatocellular injury. Bioinformatic analysis provided putative target genes of hsa\u2010miR\u2010218\u20105p, rno\u2010miR\u2010218a\u20105p, and mmu\u2010miR\u2010218\u20105p, among which GNAI2, PPP1CB, and PPP2R5A were experimentally validated as their direct target genes in human cholangiocyte line MMNK\u20101. Proliferation of MMNK\u20101 cells was significantly suppressed after overexpression of miR\u2010218\u20105p and transduction of siRNAs for GNAI2, PPP1CB, and PPP2R5A. In the cholestatic livers of rats, Ppp1cb and Ppp2r5a expression levels decreased, whereas Gnai2 expression levels increased compared with those in vehicle\u2010treated rats, suggesting that Ppp1cb and Ppp2r5a may be under the control of miR\u2010218a\u20105p in vivo. In conclusion, our data suggest that miR\u2010218(a)\u20105p is involved in the suppression of cholangiocyte proliferation by inhibiting the expression of PPP1CB and PPP2R5A, thereby contributing to the pathogenesis of cholestasis; and miR\u2010218a\u20105p leaks into the plasma probably from damaged cholangiocytes in a severity\u2010dependent manner in rats. Therefore, miR\u2010218a\u20105p overexpression could be one of the underlying mechanisms of acute cholestatic liver injury in rats.<\/jats:p>","DOI":"10.1002\/jat.4144","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T19:41:59Z","timestamp":1612986119000},"page":"1537-1552","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Plasma miR\u2010218a\u20105p as a biomarker for acute cholestatic liver injury in rats and investigation of its pathophysiological roles"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8684-601X","authenticated-orcid":false,"given":"Shingo","family":"Oda","sequence":"first","affiliation":[{"name":"Department of Drug Safety Sciences, Division of Clinical Pharmacology Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Hirabuki","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Sciences, Division of Clinical Pharmacology Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiki","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Sciences, Division of Clinical Pharmacology Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Kagawa","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Sciences, Division of Clinical Pharmacology Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3239-2817","authenticated-orcid":false,"given":"Tsuyoshi","family":"Yokoi","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Sciences, Division of Clinical Pharmacology Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.05005"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.58"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840200231"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019055108"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.93101130"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12144"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-5220-x"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00013.2003"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4309"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(01)00459-0"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2011.05.002"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200932010-00005"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.082701.108"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0045-7"},{"key":"e_1_2_7_16_1","first-page":"685","article-title":"Experimental cholangitis due to alpha\u2010naphthyl\u2010isothiocyanate (ANIT)","volume":"40","author":"Goldfarb S.","year":"1962","journal-title":"American Journal of Pathology"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx3002719"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfw090"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.184"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24691"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1586\/17512433.2014.904201"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0188910"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0020363"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfy200"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfg125"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2641"},{"key":"e_1_2_7_27_1","unstructured":"Lala V. 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