{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T05:42:21Z","timestamp":1777873341126,"version":"3.51.4"},"reference-count":51,"publisher":"Frontiers Media SA","issue":"5","license":[{"start":{"date-parts":[[2008,5,1]],"date-time":"2008-05-01T00:00:00Z","timestamp":1209600000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Exp Biol Med (Maywood)"],"published-print":{"date-parts":[[2008,5]]},"abstract":"<jats:p>Hepatocyte apoptosis has been documented in both clinical and experimental alcoholic liver disease. This study was undertaken to examine the effect of dietary zinc supplementation on hepatic apoptosis in mice subjected to a long-term ethanol exposure. Male adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed hepatitis, as indicated by neutrophil infiltration and elevation of hepatic keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) levels. Apoptotic cell death was detected in ethanol-exposed mice by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was confirmed by the increased activities of caspase-3 and -8. Zinc supplementation attenuated alcoholic hepatitis and reduced the number of TUNEL-positive cells in association with inhibition of caspase activities. Ethanol exposure caused oxidative stress, as indicated by reactive oxygen species accumulation, mitochondrial glutathione depletion, and decreased metallothionein levels in the liver, which were suppressed by zinc supplementation. The mRNA levels of tumor necrosis factor (TNF)-\u03b1, TNF-R1, FasL, Fas, Fas-associated factor-1, and caspase-3 in the liver were upregulated by ethanol exposure, which were attenuated by zinc supplementation. Zinc supplementation also prevented ethanol-elevated serum and hepatic TNF-\u03b1 levels and TNF-R1 and Fas proteins in the liver. In conclusion, zinc supplementation prevented hepatocyte apoptosis in mice subjected to long-term ethanol exposure, and the action of zinc is likely through suppression of oxidative stress and death receptor-mediated pathways.<\/jats:p>","DOI":"10.3181\/0710-rm-265","type":"journal-article","created":{"date-parts":[[2008,5,12]],"date-time":"2008-05-12T19:11:21Z","timestamp":1210619481000},"page":"540-548","source":"Crossref","is-referenced-by-count":52,"title":["Zinc Supplementation Inhibits Hepatic Apoptosis in Mice Subjected to a Long-Term Ethanol Exposure"],"prefix":"10.3389","volume":"233","author":[{"given":"Zhanxiang","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine; Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40202; and National Cancer Institute at NIEHS, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine; Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40202; and National Cancer Institute at NIEHS, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenyuan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine; Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40202; and National Cancer Institute at NIEHS, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[{"name":"Department of Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine; Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40202; and National Cancer Institute at NIEHS, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. James","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Medicine and Department of Pharmacology and Toxicology, University of Louisville School of Medicine; Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40202; and National Cancer Institute at NIEHS, Research Triangle Park, North Carolina 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2008,5,1]]},"reference":[{"key":"bibr-R1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)00089-1"},{"key":"bibr-R2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)00047-7"},{"key":"bibr-R3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2004.40009.x"},{"key":"bibr-R4","doi-asserted-by":"publisher","DOI":"10.1097\/00042737-200601000-00005"},{"key":"bibr-R5","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)61699-9"},{"key":"bibr-R6","doi-asserted-by":"publisher","DOI":"10.1177\/153537020322800411"},{"key":"bibr-R7","doi-asserted-by":"publisher","DOI":"10.2741\/1765"},{"key":"bibr-R8","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20957"},{"key":"bibr-R9","doi-asserted-by":"publisher","DOI":"10.1124\/mol.53.4.638"},{"key":"bibr-R10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.1999.tb04025.x"},{"key":"bibr-R11","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)78614-1"},{"key":"bibr-R12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2006.04.013"},{"key":"bibr-R13","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(03)00276-2"},{"key":"bibr-R14","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.12.023"},{"key":"bibr-R15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.1986.tb05149.x"},{"key":"bibr-R16","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2005.07.002"},{"key":"bibr-R17","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62478-9"},{"key":"bibr-R18","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-2797(99)00166-0"},{"key":"bibr-R19","doi-asserted-by":"crossref","unstructured":"Cao J, Bobo JA, Liuzzi JP, Cousins RJ. Effects of intracellular zinc depletion on metallothionein and ZIP2 transporter expression and apoptosis. J Leukoc Biol 70:559\u2013566, 2001.","DOI":"10.1189\/jlb.70.4.559"},{"key":"bibr-R20","doi-asserted-by":"crossref","unstructured":"Bao S, Knoell DL. Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis. Am J Physiol Lung Cell Mol Physiol 290:L433\u2013L441, 2006.","DOI":"10.1152\/ajplung.00341.2005"},{"key":"bibr-R21","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/71.1.81"},{"key":"bibr-R22","unstructured":"Zhou Z, Kang X, Jiang Y, Song Z, Feng W, McClain CJ, Kang YJ. Preservation of hepatocyte nuclear factor-4alpha is associated with zinc protection against TNF-alpha hepatotoxicity in mice. Exp Biol Med 232:622\u2013628, 2007."},{"key":"bibr-R24","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(91)05089-E"},{"key":"bibr-R25","doi-asserted-by":"crossref","unstructured":"Fermandez-Checa JC, Morales A, Colell A, Bellesta A, Rodes J, Kaplowitz N. S-adenosyl-L-methionine prevents both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. Hepatology 21:207\u2013214, 1995.","DOI":"10.1002\/hep.1840210133"},{"key":"bibr-R26","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510310219"},{"key":"bibr-R27","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(93)90029-T"},{"key":"bibr-R28","doi-asserted-by":"publisher","DOI":"10.1046\/j.1525-1373.1999.d01-143.x"},{"key":"bibr-R29","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4838(85)90098-6"},{"key":"bibr-R30","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4274(89)90075-1"},{"key":"bibr-R31","doi-asserted-by":"publisher","DOI":"10.1177\/153537020222700310"},{"key":"bibr-R32","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)61174-1"},{"key":"bibr-R33","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007347"},{"key":"bibr-R34","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007110"},{"key":"bibr-R35","doi-asserted-by":"publisher","DOI":"10.1016\/S0741-8329(04)00056-4"},{"key":"bibr-R36","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1088"},{"key":"bibr-R37","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20412"},{"key":"bibr-R38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2007.05.005"},{"key":"bibr-R39","unstructured":"Zhou Z, Kang X, Jiang Y, Song Z, Feng W, McClain CJ, Kang YJ. Preservation of hepatocyte nuclear factor-4alpha is associated with zinc protection against TNF-alpha hepatotoxicity in mice. Exp Biol Med 232:622\u2013628, 2007."},{"key":"bibr-R40","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.5.1223"},{"key":"bibr-R41","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.32969"},{"key":"bibr-R42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2006.00235.x"},{"key":"bibr-R43","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.12.023"},{"key":"bibr-R44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2003.tb04426.x"},{"key":"bibr-R45","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2000.tb04592.x"},{"key":"bibr-R46","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)01435-9"},{"key":"bibr-R47","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/agh142"},{"key":"bibr-R48","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v12.i12.1895"},{"key":"bibr-R49","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/133.9.2845"},{"key":"bibr-R50","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/86.1.14"},{"key":"bibr-R51","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2005.09.021"},{"key":"bibr-R52","doi-asserted-by":"publisher","DOI":"10.1016\/S0899-9007(99)00090-8"}],"container-title":["Experimental Biology and Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.sagepub.com\/doi\/pdf\/10.3181\/0710-RM-265","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/journals.sagepub.com\/doi\/full-xml\/10.3181\/0710-RM-265","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/journals.sagepub.com\/doi\/pdf\/10.3181\/0710-RM-265","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T17:54:29Z","timestamp":1777571669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ebm-journal.org\/journals\/experimental-biology-and-medicine\/articles\/10.3181\/0710-rm-265\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,5]]},"references-count":51,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2008,5]]}},"alternative-id":["10.3181\/0710-RM-265"],"URL":"https:\/\/doi.org\/10.3181\/0710-rm-265","relation":{},"ISSN":["1535-3702","1535-3699"],"issn-type":[{"value":"1535-3702","type":"print"},{"value":"1535-3699","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,5]]}}}