{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:37:41Z","timestamp":1792798661547,"version":"4.5.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2018,9,6]],"date-time":"2018-09-06T00:00:00Z","timestamp":1536192000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81670129"],"award-info":[{"award-number":["81670129"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Dig Dis Sci"],"published-print":{"date-parts":[[2018,12]]},"DOI":"10.1007\/s10620-018-5268-0","type":"journal-article","created":{"date-parts":[[2018,9,6]],"date-time":"2018-09-06T06:05:02Z","timestamp":1536213902000},"page":"3398-3408","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":112,"title":["Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the Nf-\u03baB Pathway"],"prefix":"10.1007","volume":"63","author":[{"given":"Qiang","family":"Ou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6308-151X","authenticated-orcid":false,"given":"Xiaolin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,6]]},"reference":[{"key":"5268_CR1","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1586\/egh.11.21","volume":"5","author":"RC Harmon","year":"2011","unstructured":"Harmon RC, Tiniakos DG, Argo CK. Inflammation in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5:189\u2013200.","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"5268_CR2","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/S1665-2681(19)31820-4","volume":"8","author":"S Bellentani","year":"2009","unstructured":"Bellentani S, Marino M. Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol. 2009;8:S4\u2013S8.","journal-title":"Ann Hepatol"},{"key":"5268_CR3","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.jhep.2008.10.010","volume":"50","author":"JG Fan","year":"2009","unstructured":"Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol. 2009;50:204\u2013210.","journal-title":"J Hepatol"},{"key":"5268_CR4","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/nrgastro.2013.149","volume":"10","author":"A Wree","year":"2013","unstructured":"Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol. 2013;10:627\u2013636.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"5268_CR5","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","volume":"114","author":"CP Day","year":"1998","unstructured":"Day CP, James OF. Steatohepatitis: a tale of two \u201chits\u201d? Gastroenterology. 1998;114:842\u2013845.","journal-title":"Gastroenterology"},{"key":"5268_CR6","doi-asserted-by":"publisher","first-page":"20704","DOI":"10.3390\/ijms141020704","volume":"14","author":"A Takaki","year":"2013","unstructured":"Takaki A, Kawai D, Yamamoto K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH). Int J Mol Sci. 2013;14:20704\u201320728.","journal-title":"Int J Mol Sci"},{"key":"5268_CR7","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1002\/ptr.3207","volume":"24","author":"L Abenavoli","year":"2010","unstructured":"Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24:1423\u20131432.","journal-title":"Phytother Res"},{"key":"5268_CR8","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.etp.2010.04.009","volume":"63","author":"S Aghazadeh","year":"2011","unstructured":"Aghazadeh S, Amini R, Yazdanparast R, Ghaffari SH. Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis. Exp Toxicol Pathol. 2011;63:569\u2013574.","journal-title":"Exp Toxicol Pathol"},{"key":"5268_CR9","doi-asserted-by":"publisher","first-page":"109","DOI":"10.4254\/wjh.v5.i3.109","volume":"5","author":"F Cacciapuoti","year":"2013","unstructured":"Cacciapuoti F, Scognamiglio A, Palumbo R, Forte R, Cacciapuoti F. Silymarin in non alcoholic fatty liver disease. World J Hepatol. 2013;5:109\u2013113.","journal-title":"World J Hepatol"},{"key":"5268_CR10","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.jhep.2012.09.034","volume":"58","author":"Z Marino","year":"2013","unstructured":"Marino Z, Crespo G, D\u2019Amato M, et al. Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period. J Hepatol. 2013;58:415\u2013420.","journal-title":"J Hepatol"},{"key":"5268_CR11","doi-asserted-by":"publisher","first-page":"e6099","DOI":"10.5812\/hepatmon.6099","volume":"12","author":"AA Hajiaghamohammadi","year":"2012","unstructured":"Hajiaghamohammadi AA, Ziaee A, Oveisi S, Masroor H. Effects of metformin, pioglitazone, and silymarin treatment on Nonalcoholic Fatty liver disease: a randomized controlled pilot study. Hepat Mon. 2012;12:e6099.","journal-title":"Hepat Mon"},{"key":"5268_CR12","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1590\/1414-431X20122551","volume":"46","author":"J Yao","year":"2013","unstructured":"Yao J, Zhi M, Gao X, Hu P, Li C, Yang X. Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with Nonalcoholic fatty liver. Braz J Med Biol Res. 2013;46:270\u2013277.","journal-title":"Braz J Med Biol Res"},{"key":"5268_CR13","first-page":"9","volume":"5","author":"H Solhi","year":"2014","unstructured":"Solhi H, Ghahremani R, Kazemifar AM, Hoseini Yazdi Z. Silymarin in treatment of Nonalcoholic steatohepatitis: A randomized clinical trial. Caspian J Intern Med. 2014;5:9\u201312.","journal-title":"Caspian J Intern Med"},{"key":"5268_CR14","doi-asserted-by":"publisher","first-page":"1940","DOI":"10.1016\/j.cgh.2017.04.016","volume":"15","author":"C Wah Kheong","year":"2017","unstructured":"Wah Kheong C, Nik Mustapha NR, Mahadeva S. A randomized trial of silymarin for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2017;15:1940\u20131949. e1948.","journal-title":"Clin Gastroenterol Hepatol"},{"key":"5268_CR15","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.dld.2004.11.009","volume":"37","author":"G Carpino","year":"2005","unstructured":"Carpino G, Morini S, Ginanni Corradini S, et al. Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation. Dig Liver Dis. 2005;37:349\u2013356.","journal-title":"Dig Liver Dis"},{"key":"5268_CR16","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/j.jhep.2015.11.002","volume":"64","author":"A Eguchi","year":"2016","unstructured":"Eguchi A, De Mollerat Du, Jeu X, Johnson CD, Nektaria A, Feldstein AE. Liver Bid suppression for treatment of fibrosis associated with NonalcoholicNonalcoholic steatohepatitis. J Hepatol. 2016;64:699\u2013707.","journal-title":"J Hepatol"},{"key":"5268_CR17","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1055\/s-0030-1267540","volume":"30","author":"ME Guicciardi","year":"2010","unstructured":"Guicciardi ME, Gores GJ. Apoptosis as a mechanism for liver disease progression. Semin Liver Dis. 2010;30:402\u2013410.","journal-title":"Semin Liver Dis"},{"key":"5268_CR18","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1309\/4UBB-BF78-F55V-50KA","volume":"114","author":"BF Banner","year":"2000","unstructured":"Banner BF, Savas L, Zivny J, Tortorelli K, Bonkovsky HL. Ubiquitin as a marker of cell injury in nonalcoholic steatohepatitis. Am J Clin Pathol. 2000;114:860\u2013866.","journal-title":"Am J Clin Pathol"},{"key":"5268_CR19","doi-asserted-by":"publisher","first-page":"506","DOI":"10.5152\/tjg.2015.150199","volume":"26","author":"S Kayacetin","year":"2015","unstructured":"Kayacetin S, Basaranoglu M. Mallory-Denk bodies: correlation with steatosis, severity, zonal distribution, and identification with ubiquitin. Turk J Gastroenterol. 2015;26:506\u2013510.","journal-title":"Turk J Gastroenterol"},{"key":"5268_CR20","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1016\/j.jhep.2012.05.019","volume":"57","author":"MA Abdelmegeed","year":"2012","unstructured":"Abdelmegeed MA, Banerjee A, Yoo SH, Jang S, Gonzalez FJ, Song BJ. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced Nonalcoholic steatohepatitis. J Hepatol. 2012;57:860\u2013866.","journal-title":"J Hepatol"},{"key":"5268_CR21","first-page":"426","volume":"4","author":"U Teufel","year":"2015","unstructured":"Teufel U, Peccerella T, Engelmann G, et al. Detection of carcinogenic etheno-DNA adducts in children and adolescents with Nonalcoholic steatohepatitis (NASH). Hepatobiliary Surg Nutr. 2015;4:426\u2013435.","journal-title":"Hepatobiliary Surg Nutr"},{"key":"5268_CR22","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1093\/toxsci\/kfu184","volume":"142","author":"LY Lee","year":"2014","unstructured":"Lee LY, Kohler UA, Zhang L, et al. Activation of the Nrf2-ARE pathway in hepatocytes protects against steatosis in nutritionally induced Nonalcoholic steatohepatitis in mice. Toxicol Sci. 2014;142:361\u2013374.","journal-title":"Toxicol Sci"},{"issue":"9","key":"5268_CR23","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.3390\/nu9091006","volume":"9","author":"Veronica Marin","year":"2017","unstructured":"Marin V, Gazzin S, Gambaro SE, et al. Effects of oral administration of silymarin in a juvenile murine model of Nonalcoholic steatohepatitis. Nutrients 2017;9.","journal-title":"Nutrients"},{"key":"5268_CR24","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1194\/jlr.M800042-JLR200","volume":"49","author":"ME Rinella","year":"2008","unstructured":"Rinella ME, Elias MS, Smolak RR, Fu T, Borensztajn J, Green RM. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res. 2008;49:1068\u20131076.","journal-title":"J Lipid Res"},{"key":"5268_CR25","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1590\/S0004-28032011000100015","volume":"48","author":"E Marcolin","year":"2011","unstructured":"Marcolin E, Forgiarini LF, Tieppo J, Dias AS, Freitas LA, Marroni NP. Methionine- and choline-deficient diet induces hepatic changes characteristic of Nonalcoholic steatohepatitis. Arq Gastroenterol. 2011;48:72\u201379.","journal-title":"Arq Gastroenterol"},{"key":"5268_CR26","first-page":"171","volume":"24","author":"N Phung","year":"2009","unstructured":"Phung N, Pera N, Farrell G, Leclercq I, Hou JY, George J. Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. Int J Mol Med. 2009;24:171\u2013180.","journal-title":"Int J Mol Med"},{"key":"5268_CR27","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1159\/000282097","volume":"28","author":"JM Schattenberg","year":"2010","unstructured":"Schattenberg JM, Galle PR. Animal models of Nonalcoholic steatohepatitis: of mice and man. Dig Dis. 2010;28:247\u2013254.","journal-title":"Dig Dis"},{"key":"5268_CR28","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.addr.2017.05.007","volume":"121","author":"T Higashi","year":"2017","unstructured":"Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017;121:27\u201342.","journal-title":"Adv Drug Deliv Rev"},{"key":"5268_CR29","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.yexmp.2014.10.001","volume":"97","author":"H Liu","year":"2014","unstructured":"Liu H, Gong M, French BA, Li J, Tillman B, French SW. Mallory-Denk Body (MDB) formation modulates Ufmylation expression epigenetically in alcoholic hepatitis (AH) and Nonalcoholic steatohepatitis (NASH). Exp Mol Pathol. 2014;97:477\u2013483.","journal-title":"Exp Mol Pathol"},{"key":"5268_CR30","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1007\/s10695-017-0387-7","volume":"43","author":"P Xiao","year":"2017","unstructured":"Xiao P, Yang Z, Sun J, et al. Silymarin inhibits adipogenesis in the adipocytes in grass carp Ctenopharyngodon idellus in vitro and in vivo. Fish Physiol Biochem. 2017;43:1487\u20131500.","journal-title":"Fish Physiol Biochem"},{"key":"5268_CR31","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1016\/j.bbadis.2014.02.012","volume":"1842","author":"P Jha","year":"2014","unstructured":"Jha P, Knopf A, Koefeler H, et al. Role of adipose tissue in methionine-choline-deficient model of Nonalcoholic steatohepatitis (NASH). Biochim Biophys Acta. 2014;1842:959\u2013970.","journal-title":"Biochim Biophys Acta"},{"key":"5268_CR32","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.clinre.2011.04.015","volume":"35","author":"J Aubert","year":"2011","unstructured":"Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol. 2011;35:630\u2013637.","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"5268_CR33","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1002\/hep.510270121","volume":"27","author":"MD Weltman","year":"1998","unstructured":"Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology. 1998;27:128\u2013133.","journal-title":"Hepatology"},{"key":"5268_CR34","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1053\/jhep.2001.0330311","volume":"33","author":"J Maher","year":"2001","unstructured":"Maher J. The CYP2E1 knockout delivers another punch: first ASH, now NASH. Alcoholic steatohepatitis Nonalcoholic steatohepatitis. Hepatology. 2001;33:311\u2013312.","journal-title":"Hepatology"},{"key":"5268_CR35","doi-asserted-by":"publisher","first-page":"409","DOI":"10.3109\/15376516.2012.673090","volume":"22","author":"SK Das","year":"2012","unstructured":"Das SK, Mukherjee S. Biochemical and immunological basis of silymarin effect, a milk thistle (Silybum marianum) against ethanol-induced oxidative damage. Toxicol Mech Methods. 2012;22:409\u2013413.","journal-title":"Toxicol Mech Methods"},{"key":"5268_CR36","doi-asserted-by":"publisher","first-page":"264","DOI":"10.4062\/biomolther.2013.020","volume":"21","author":"W Zhang","year":"2013","unstructured":"Zhang W, Hong R, Tian T. Silymarin\u2019s protective effects and possible mechanisms on alcoholic fatty liver for rats. Biomol Ther (Seoul). 2013;21:264\u2013269.","journal-title":"Biomol Ther (Seoul)"},{"key":"5268_CR37","doi-asserted-by":"publisher","first-page":"6016","DOI":"10.3748\/wjg.v22.i26.6016","volume":"22","author":"G Vecchione","year":"2016","unstructured":"Vecchione G, Grasselli E, Voci A, et al. Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells. World J Gastroenterol. 2016;22:6016\u20136026.","journal-title":"World J Gastroenterol"},{"key":"5268_CR38","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1016\/j.jhep.2014.07.006","volume":"61","author":"X Zhang","year":"2014","unstructured":"Zhang X, Shen J, Man K, et al. CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of Nonalcoholic steatohepatitis. J Hepatol. 2014;61:1365\u20131375.","journal-title":"J Hepatol"},{"key":"5268_CR39","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1053\/j.gastro.2014.06.043","volume":"147","author":"F Marra","year":"2014","unstructured":"Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147:577\u2013594. e571.","journal-title":"Gastroenterology"}],"container-title":["Digestive Diseases and Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10620-018-5268-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10620-018-5268-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10620-018-5268-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T09:50:52Z","timestamp":1567763452000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10620-018-5268-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,6]]},"references-count":39,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2018,12]]}},"alternative-id":["5268"],"URL":"https:\/\/doi.org\/10.1007\/s10620-018-5268-0","relation":{},"ISSN":["0163-2116","1573-2568"],"issn-type":[{"value":"0163-2116","type":"print"},{"value":"1573-2568","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,6]]},"assertion":[{"value":"27 February 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 September 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"There is no conflict of interest to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}