{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:37:49Z","timestamp":1792798669665,"version":"4.5.0"},"reference-count":69,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2017,9,12]],"date-time":"2017-09-12T00:00:00Z","timestamp":1505174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian National Grant MIUR","award":["Art.13 D.LGS 297\/99-Progetto Nutrizione e Salute"],"award-info":[{"award-number":["Art.13 D.LGS 297\/99-Progetto Nutrizione e Salute"]}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"publisher","award":["2017 Post-doctoral fellowship"],"award-info":[{"award-number":["2017 Post-doctoral fellowship"]}],"id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["U01AA020821"],"award-info":[{"award-number":["U01AA020821"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl\/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH.<\/jats:p>","DOI":"10.3390\/nu9091006","type":"journal-article","created":{"date-parts":[[2017,9,12]],"date-time":"2017-09-12T10:40:04Z","timestamp":1505212804000},"page":"1006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-alcoholic Steatohepatitis"],"prefix":"10.3390","volume":"9","author":[{"given":"Veronica","family":"Marin","sequence":"first","affiliation":[{"name":"Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Gazzin","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Gambaro","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9294-2107","authenticated-orcid":false,"given":"Matteo","family":"Dal Ben","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Calligaris","sequence":"additional","affiliation":[{"name":"Universit\u00e0 di Udine, Dipartimento di Scienze AgroAlimentari, Ambientali e Animali, Via Sondrio 2\/A, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Anese","sequence":"additional","affiliation":[{"name":"Universit\u00e0 di Udine, Dipartimento di Scienze AgroAlimentari, Ambientali e Animali, Via Sondrio 2\/A, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Raseni","sequence":"additional","affiliation":[{"name":"IRCCS Burlo Garofolo Paediatric Hospital, Clinical Chemistry Laboratory, 34100 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Avellini","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliero-Universitaria \u201cSanta Maria della Misericordia\u201d, Dipartimento di Laboratorio, Istituto di Anatomia Patologica, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Giraudi","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Rosso","sequence":"additional","affiliation":[{"name":"Fondazione Italiana Fegato ONLUS-Centro Studi Fegato, Area Science Park Basovizza Bldg, Q SS 14 Km 163,5, Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1002\/hep.28785","article-title":"The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatolory"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/sj.ijo.0803711","article-title":"Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis","volume":"32","author":"Manco","year":"2008","journal-title":"Int. J. Obes."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s12072-009-9160-z","article-title":"Fatty liver disease in children: Eat now pay later","volume":"4","author":"Fitzpatrick","year":"2010","journal-title":"Hepatol. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1177\/1756283X16638830","article-title":"Lifestyle changes for the treatment of nonalcoholic fatty liver disease: A review of observational studies and intervention trials","volume":"9","author":"Godos","year":"2016","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1111\/liv.13435","article-title":"The Mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: Evidence and plausible mechanisms","volume":"37","author":"Salomone","year":"2017","journal-title":"Liver Int."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bae, J.C., Suh, S., Park, S.E., Rhee, E.J., Park, C.Y., Oh, K.W., Park, S.W., Kim, S.W., Hur, K.Y., and Kim, J.H. (2012). Regular exercise is associated with a reduction in the risk of NAFLD and decreased liver enzymes in individuals with NAFLD independent of obesity in Korean adults. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046819"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S1499-3872(13)60021-1","article-title":"Therapeutic approaches to non-alcoholic fatty liver disease: Past achievements and future challenges","volume":"12","author":"Xiao","year":"2013","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1001\/2012.jama.11614","article-title":"Dietary composition during weight-loss maintenance","volume":"308","author":"Bistrian","year":"2012","journal-title":"JAMA J. Am. Med. Assoc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/jvim.12002","article-title":"Milk thistle and its derivative compounds: A review of opportunities for treatment of liver disease","volume":"27","author":"Hackett","year":"2013","journal-title":"J. Vet. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1002\/ptr.3207","article-title":"Milk thistle in liver diseases: Past, present, future","volume":"24","author":"Abenavoli","year":"2010","journal-title":"Phytother. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1572-0241.1998.00139.x","article-title":"Milk thistle (Silybum marianum) for the therapy of liver disease","volume":"93","author":"Flora","year":"1998","journal-title":"Am. J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.2165\/00003495-200161140-00003","article-title":"The use of silymarin in the treatment of liver diseases","volume":"61","author":"Saller","year":"2001","journal-title":"Drugs"},{"key":"ref_13","first-page":"491","article-title":"Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine","volume":"124","author":"Pradhan","year":"2006","journal-title":"Indian J. Med. Res."},{"key":"ref_14","first-page":"169","article-title":"Silymarin and skin cancer prevention: Anti-inflammatory, antioxidant and immunomodulatory effects","volume":"26","author":"Katiyar","year":"2005","journal-title":"Int. J. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1177\/1534735407301727","article-title":"Clinical applications of Silybum marianum in oncology","volume":"6","author":"Greenlee","year":"2007","journal-title":"Integr. Cancer Ther."},{"key":"ref_16","first-page":"4457","article-title":"Anticancer potential of silymarin: From bench to bed side","volume":"26","author":"Agarwal","year":"2006","journal-title":"Anticancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s10555-010-9237-0","article-title":"Antimetastatic efficacy of silibinin: Molecular mechanisms and therapeutic potential against cancer","volume":"29","author":"Deep","year":"2010","journal-title":"Cancer Metastasis Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/jcp.20852","article-title":"Silibinin polarizes Th1\/Th2 immune responses through the inhibition of immunostimulatory function of dendritic cells","volume":"210","author":"Lee","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1055\/s-2006-957391","article-title":"Silymarin inhibits the development of diet-induced hypercholesterolemia in rats","volume":"64","author":"Krecman","year":"1998","journal-title":"Planta Med."},{"key":"ref_20","first-page":"1","article-title":"Silymarin as a potential hypocholesterolaemic drug","volume":"47","author":"Krecman","year":"1998","journal-title":"Physiol. Res. Acad. Sci. Bohemoslov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.3748\/wjg.v17.i18.2288","article-title":"Silybin and the liver: From basic research to clinical practice","volume":"17","author":"Loguercio","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2165\/00044011-200222010-00007","article-title":"Pharmacology of Silymarin","volume":"22","author":"Fraschini","year":"2002","journal-title":"Clin. Drug Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4119","DOI":"10.1002\/jps.21704","article-title":"Solid state mechanochemical activation of Silybum marianum dry extract with betacyclodextrins: Characterization and bioavailability of the coground systems","volume":"98","author":"Voinovich","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.dld.2011.11.010","article-title":"Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis","volume":"44","author":"Salamone","year":"2012","journal-title":"Dig. Liver Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/j.freeradbiomed.2012.02.008","article-title":"Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial","volume":"52","author":"Loguercio","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109","DOI":"10.4254\/wjh.v5.i3.109","article-title":"Silymarin in non alcoholic fatty liver disease","volume":"5","author":"Cacciapuoti","year":"2013","journal-title":"World J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.2174\/0929867322666150729114235","article-title":"The pros and the cons for the use of Silybin-rich oral formulations in treatment of liver damage (NAFLD in particular)","volume":"22","author":"Rosso","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s10620-016-4126-1","article-title":"Lifestyle Interventions Including Nutrition, Exercise, and Supplements for Nonalcoholic Fatty Liver Disease in Children","volume":"61","author":"Africa","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Marin, V., Rosso, N., Dal Ben, M., Raseni, A., Boschelle, M., Degrassi, C., Nemeckova, I., Nachtigal, P., Avellini, C., and Tiribelli, C. (2016). An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158817"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chavez-Tapia, N.C., Rosso, N., and Tiribelli, C. (2012). Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease. BMC Gastroenterol., 12.","DOI":"10.1186\/1471-230X-12-20"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1177\/1534735407301825","article-title":"Milk thistle nomenclature: Why it matters in cancer research and pharmacokinetic studies","volume":"6","author":"Kroll","year":"2007","journal-title":"Integr. Cancer Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1089\/109793301753407948","article-title":"Nile Red binding to HepG2 cells: An improved assay for in vitro studies of hepatosteatosis","volume":"14","author":"McMillian","year":"2001","journal-title":"In Vitro Mol. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1083\/jcb.100.3.965","article-title":"Nile red: A selective fluorescent stain for intracellular lipid droplets","volume":"100","author":"Greenspan","year":"1985","journal-title":"J. Cell Biol."},{"key":"ref_34","first-page":"891","article-title":"Relationship of body weight and volume of liver. A morphometrical and stereological study","volume":"28","author":"Altunkaynak","year":"2007","journal-title":"Saudi Med. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"150","DOI":"10.3164\/jcbn.2008022","article-title":"A Mouse Model of Metabolic Syndrome; Increase in Visceral Adipose Tissue Precedes the Development of Fatty Liver and Insulin Resistance in High-Fat Diet-Fed Male KK\/Ta Mice","volume":"42","author":"Akagiri","year":"2008","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Nonalcoholic Steatohepatitis Clinical Research Network Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: Distinct clinicopathologic meanings","volume":"53","author":"Brunt","year":"2011","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1177\/33.8.2410480","article-title":"A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections","volume":"33","author":"Rojkind","year":"1985","journal-title":"J. Histochem. Cytochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0891-5849(91)90192-6","article-title":"Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes","volume":"11","author":"Esterbauer","year":"1991","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1007\/s004250050524","article-title":"Improving the thiobarbituric acid-reactive-substances assay for estimating lipid peroxidation in plant tissues containing anthocyanin and other interfering compounds","volume":"207","author":"Hodges","year":"1999","journal-title":"Planta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.3892\/ol.2012.931","article-title":"Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients","volume":"4","author":"Zitka","year":"2012","journal-title":"Oncol. Lett."},{"key":"ref_42","unstructured":"Held, P. (2006). Fluorimetric Quantitation of Protein using the Reactive Compound Fluorescamine. Nat. Methods Appl. Notes."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0016-5085(03)00907-7","article-title":"Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis","volume":"125","author":"Feldstein","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_45","unstructured":"(2017, July 03). European Health Interview Survey Almost 1 Adult in 6 in the EU is Considered Obese. Available online: http:\/\/ec.europa.eu\/eurostat\/documents\/2995521\/7700898\/3-20102016-BP-EN.pdf\/c26b037b-d5f3-4c05-89c1-00bf0b98d646."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1053\/j.gastro.2007.03.059","article-title":"Obesity, inflammation, and insulin resistance","volume":"132","author":"Shoelson","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1542\/peds.2006-1212","article-title":"Prevalence of fatty liver in children and adolescents","volume":"118","author":"Schwimmer","year":"2006","journal-title":"Pediatrics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00431-013-2157-6","article-title":"Pediatric non-alcoholic fatty liver disease: An increasing public health issue","volume":"173","author":"Berardis","year":"2014","journal-title":"Eur. J. Pediatr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"25168","DOI":"10.3390\/ijms161025168","article-title":"Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease","volume":"16","author":"Valenzuela","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.jhep.2012.11.031","article-title":"Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver disease","volume":"58","author":"Centis","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_52","first-page":"70","article-title":"An updated systematic review of the pharmacology of silymarin","volume":"14","author":"Saller","year":"2007","journal-title":"Forsch. Komplementarmed."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.lfs.2015.10.025","article-title":"Men and mice: Relating their ages","volume":"152","author":"Dutta","year":"2016","journal-title":"Life Sci."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Xiao, P., Yang, Z., Sun, J., Tian, J., Chang, Z., Li, X., Zhang, B., Ye, Y., Ji, H., and Yu, E. (2017). Silymarin inhibits adipogenesis in the adipocytes in grass carp Ctenopharyngodon idellus in vitro and in vivo. Fish Physiol. Biochem., 1\u201314.","DOI":"10.1007\/s10695-017-0387-7"},{"key":"ref_55","unstructured":"de Groot, L.J., Chrousos, G., and Dungan, K. (2000). The Role of Lipids and Lipoproteins in Atherosclerosis. Endotext, MDText.com, Inc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1172\/JCI116375","article-title":"Dietary fat increases high density lipoprotein (HDL) levels both by increasing the transport rates and decreasing the fractional catabolic rates of HDL cholesterol ester and apolipoprotein (Apo) A-I. Presentation of a new animal model and mechanistic studies in human Apo A-I transgenic and control mice","volume":"91","author":"Hayek","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/j.jhep.2006.02.011","article-title":"Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2","volume":"44","author":"Haukeland","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1055\/s-2001-17554","article-title":"Cytokine receptors and signaling in hepatic stellate cells","volume":"21","author":"Pinzani","year":"2001","journal-title":"Semin. Liver Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"29","DOI":"10.5507\/bp.2005.002","article-title":"Silybin and silymarin\u2014New effects and applications","volume":"149","author":"Kren","year":"2005","journal-title":"Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czechoslov."},{"key":"ref_60","first-page":"105","article-title":"Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin","volume":"27","author":"Valenzuela","year":"1994","journal-title":"Biol. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.etp.2010.04.009","article-title":"Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis","volume":"63","author":"Aghazadeh","year":"2011","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1096\/fj.08-111005","article-title":"Life and death by death receptors","volume":"23","author":"Guicciardi","year":"2009","journal-title":"FASEB J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.jhep.2009.02.023","article-title":"Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells","volume":"50","author":"Trappoliere","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_64","first-page":"477","article-title":"Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis","volume":"159","author":"Salamone","year":"2012","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease","volume":"149","author":"Angulo","year":"2015","journal-title":"Gastroenterol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1007\/s11892-013-0448-y","article-title":"Nonalcoholic fatty liver disease and type 2 diabetes in obese children","volume":"14","author":"Hecht","year":"2014","journal-title":"Curr. Diab. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/cncr.24723","article-title":"A randomized controlled, double-blind pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL)","volume":"116","author":"Ladas","year":"2010","journal-title":"Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"575","DOI":"10.5455\/medscience.2013.02.8057","article-title":"Investigating the Efficacy and Safety of Silymarin in Management of Hyperbilirubinemia in Neonatal Jaundice","volume":"2","author":"Kassem","year":"2013","journal-title":"Med. Sci."},{"key":"ref_69","unstructured":"(2017, August 22). Home\u2014ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/home."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/9\/9\/1006\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:44:44Z","timestamp":1760208284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/9\/9\/1006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,12]]},"references-count":69,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2017,9]]}},"alternative-id":["nu9091006"],"URL":"https:\/\/doi.org\/10.3390\/nu9091006","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,12]]}}}