{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:11:28Z","timestamp":1763467888636},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2008,8,18]],"date-time":"2008-08-18T00:00:00Z","timestamp":1219017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2009,1]]},"abstract":"<jats:p><jats:bold>Aim:\u2002<\/jats:bold> The impact of mandatory immunosuppression on liver regeneration after segmental liver transplantation is of clinical importance. FK778, a novel immunosuppressant, inhibits pyrimidine biosynthesis and prevents rejection after organ transplantation in a dose\u2010dependent manner. We investigated the effect of FK778 at a highly effective dose on liver regeneration in a small animal model.<\/jats:p><jats:p><jats:bold>Methods:\u2002<\/jats:bold> Inbred Lewis rats were subjected to 70% partial hepatectomy (PH) and treated with saline (<jats:italic>n<\/jats:italic>\u2003=\u200328), uridine (<jats:italic>n<\/jats:italic>\u2003=\u200316), FK778 alone (<jats:italic>n<\/jats:italic>\u2003=\u200328) or in combination with uridine (<jats:italic>n<\/jats:italic>\u2003=\u200316). FK778 was given intravenously daily at a dose of 25\u2003mg\/kg bodyweight (bw) and uridine was given daily intraperitoneally at a dose of 250\u2003mg\/kg bw. Liver bodyweight ratio (LBR), hepatocyte proliferation index (PI), blood chemistry and morphological analysis were incorporated. PI was determined by Ki\u201067 immunostaining. De Ritis ratio was calculated to assess the extent of liver damage.<\/jats:p><jats:p><jats:bold>Results:\u2002<\/jats:bold> In FK778\u2010treated animals PI was decreased at 24\u2003h and 72\u2003h and LBR was lower at 48\u2003h and 72\u2003h (<jats:italic>P<\/jats:italic>\u2003&lt;\u20030.05) after the PH. In addition, morphological analysis showed confluent central lobular necrosis at 72\u2003h in four of seven animals. Uridine supplementation restored PI, LBR and the de Ritis ratio in FK778\u2010treated animals and no confluent necroses were observed.<\/jats:p><jats:p><jats:bold>Conclusion:\u2002<\/jats:bold> FK778 is antihepatotrophic as well as antiproliferative during rat liver regeneration. Both liver growth and hepatocyte proliferation are completely restored by supplementation with uridine. In addition, supplemental uridine markedly reduces the severity of morphological abnormalities consistent with FK778 toxicity.<\/jats:p>","DOI":"10.1111\/j.1872-034x.2008.00402.x","type":"journal-article","created":{"date-parts":[[2008,8,18]],"date-time":"2008-08-18T14:51:05Z","timestamp":1219071065000},"page":"86-92","source":"Crossref","is-referenced-by-count":5,"title":["Liver regeneration is impaired by FK778 in partially hepatectomized rats, while supplemental uridine restores both liver growth and hepatocyte proliferation"],"prefix":"10.1111","volume":"39","author":[{"given":"Ali\u2010Reza","family":"Biglarnia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Lorant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyon\u2010Soek","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunnar","family":"Tufveson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"T\u00f6tsch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Malag\u00f3","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2008,12,26]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-198803000-00003"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/lt.20182"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.6.1.51"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000063704.19149.E3"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000061787.68121.4D"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3083.1998.00409.x"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.38.22467"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi952168g"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.21.12398"},{"key":"e_1_2_6_11_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.4049\/jimmunol.159.1.22","article-title":"The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms","volume":"159","author":"Elder RT","year":"1997","journal-title":"J Immunol"},{"key":"e_1_2_6_12_2","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.4049\/jimmunol.160.4.1581","article-title":"Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production","volume":"160","author":"Siemasko K","year":"1998","journal-title":"J Immunol"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(80)90007-X"},{"key":"e_1_2_6_14_2","first-page":"4952","article-title":"Effect of inhibitors of the de novo pyrimidine biosynthetic pathway on serum uridine levels in mice","volume":"41","author":"Karle JM","year":"1981","journal-title":"Cancer Res"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000144312.08782.16"},{"key":"e_1_2_6_16_2","first-page":"186","article-title":"Experimental pathology of the liver. 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