{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:22:58Z","timestamp":1781846578495,"version":"3.54.5"},"reference-count":37,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004043","name":"Kanazawa Medical University","doi-asserted-by":"publisher","award":["S2018\u20106"],"award-info":[{"award-number":["S2018\u20106"]}],"id":[{"id":"10.13039\/501100004043","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K16783"],"award-info":[{"award-number":["19K16783"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K07454"],"award-info":[{"award-number":["20K07454"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K17363"],"award-info":[{"award-number":["20K17363"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with no approved treatment. Zonarol, an extract from brown algae, has been proven to have anti-inflammatory and antioxidant effects. In this study, we investigated the role of zonarol in the progression of methionine- and choline-deficiency (MCD) diet-induced NAFLD in mice. After oral treatment with zonarol, a lighter body weight was observed in zonarol group (ZG) mice in comparison to control group (CG) mice. The NAFLD scores of ZG mice were lower than those of CG mice. Hepatic and serum lipid levels were also lower in ZG mice with the reduced expression of lipid metabolism-related factors. Furthermore, ZG mice showed less lipid deposition, less inflammatory cell infiltration and lower inflammatory cytokine levels in comparison to CG mice. Moreover, the numbers of 8-hydroxy-20-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic and serum thiobarbituric acid reactive substances (TBARS) were significantly lower in comparison to CG mice. The expression levels of nuclear factor erythroid 2 related factor 2 (Nrf2), as well as its upstream and downstream molecules, changed in ZG mice. Zonarol could prevent the progression of NAFLD by decreasing inflammatory responses, oxidative stress and improving lipid metabolism. Meanwhile the Nrf2 pathway may play an important role in these effects.<\/jats:p>","DOI":"10.3390\/nu13103455","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:03:42Z","timestamp":1632960222000},"page":"3455","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Zonarol Protected Liver from Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in a Mouse Model"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0108-996X","authenticated-orcid":false,"given":"Jia","family":"Han","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan"},{"name":"Department of Medical Oncology, Kanazawa Medical University, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan"},{"name":"Department of Pathology, Kanazawa Medical University Hospital, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Koyama","sequence":"additional","affiliation":[{"name":"Laboratory of Nutraceuticals and Functional Foods Science, Graduate School of Marine Science and Technology, Tokyo 108-8477, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daichi","family":"Kawai","sequence":"additional","affiliation":[{"name":"Laboratory of Nutraceuticals and Functional Foods Science, Graduate School of Marine Science and Technology, Tokyo 108-8477, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reimon","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Kanazawa Medical University, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Bioscience & Bioengineering, Hebei University of Science and Technology, Shijiazhuang 050018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiharu","family":"Motoo","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kanazawa Medical University, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Anti-Aging Food Research, School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo 192-0982, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2662-0024","authenticated-orcid":false,"given":"Sohsuke","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan"},{"name":"Department of Pathology, Kanazawa Medical University Hospital, Ishikawa 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jfma.2020.07.006","article-title":"Non-alcoholic fatty liver disease: A review with clinical and pathological correlation","volume":"120","author":"Chen","year":"2021","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/hep.24376","article-title":"Endpoints and clinical trial design for nonalcoholic steatohepatitis","volume":"54","author":"Sanyal","year":"2011","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: A multisystem disease","volume":"62","author":"Byrne","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-pathol-121808-102132","article-title":"Nonalcoholic Fatty Liver Disease: Pathology and Pathogenesis","volume":"5","author":"Tiniakos","year":"2010","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_6","first-page":"167","article-title":"Pathogenesis and Prevention of Hepatic Steatosis","volume":"11","author":"Nassir","year":"2015","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.bbagrm.2016.03.002","article-title":"Nuclear receptors and nonalcoholic fatty liver disease","volume":"1859","author":"Cave","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fcell.2019.00202","article-title":"NF\u03baB\/Orai1 facilitates endoplasmic reticulum stress by oxidative stress in the pathogenesis of non-alcoholic fatty liver disease","volume":"7","author":"Zhang","year":"2019","journal-title":"Front Cell Dev Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1002\/hep.21752","article-title":"Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes","volume":"46","author":"Barve","year":"2007","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1053\/gast.2001.23256","article-title":"Nonalcoholic steatohepatitis: Association of insulin resistance and mito-chondrial abnormalities","volume":"120","author":"Sanyal","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Meng, X., Guo, X., Zhang, J., Moriya, J., Kobayashi, J., Yamaguchi, R., and Yamada, S. (2019). Acupuncture on ST36, CV4 and KI1 suppresses the progression of methionine- and cho-line-deficient diet-induced nonalcoholic fatty liver disease in mice. Metabolites, 9.","DOI":"10.3390\/metabo9120299"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/03602532.2017.1293683","article-title":"Non-alcoholic fatty liver disease (NAFLD)\u2014Pathogenesis, classification, and effect on drug metabolizing enzymes and transporters","volume":"49","author":"Cobbina","year":"2017","journal-title":"Drug Metab. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"597134","DOI":"10.1155\/2015\/597134","article-title":"The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism","volume":"2015","author":"Chambel","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1007\/s00018-016-2223-0","article-title":"Role of Nrf2\/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism","volume":"73","author":"Loboda","year":"2016","journal-title":"Cell Mol Life Sci"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101950","DOI":"10.1016\/j.redox.2021.101950","article-title":"The diverse functionality of NQO1 and its roles in redox control","volume":"41","author":"Ross","year":"2021","journal-title":"Redox Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1007\/s12325-019-00898-6","article-title":"Pharmacological Treatment for Non-alcoholic Fatty Liver Disease","volume":"36","author":"Francque","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.3748\/wjg.v24.i30.3361","article-title":"Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis","volume":"24","author":"Leoni","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nyakudya, T.T., Tshabalala, T., Dangarembizi, R., Erlwanger, K.H., and Ndhlala, A.R. (2020). The Potential Therapeutic Value of Medicinal Plants in the Management of Metabolic Disorders. Molecules, 25.","DOI":"10.3390\/molecules25112669"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/nure.12091","article-title":"Seaweed and human health","volume":"72","author":"Brown","year":"2014","journal-title":"Nutr. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1021\/jo00953a022","article-title":"Zonarol and isozonarol, fungitoxic hydroquinones from the brown seaweed Dictyopteris zonarioides","volume":"38","author":"Fenical","year":"1973","journal-title":"J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yamada, S., Koyama, T., Noguchi, H., Ueda, Y., Kitsuyama, R., Shimizu, H., Tanimoto, A., Wang, K.-Y., Nawata, A., and Nakayama, T. (2014). Marine hydroquinone zonarol prevents inflammation and apoptosis in dextran sulfate sodium-induced mice ulcerative colitis. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0113509"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.bbrc.2015.01.059","article-title":"Zonarol, a sesquiterpene from the brown algae Dictyopteris undulata, provides neu-roprotection by activating the Nrf2\/ARE pathway","volume":"457","author":"Shimizu","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nawata, A., Noguchi, H., Mazaki, Y., Kurahashi, T., Izumi, H., Wang, K.-Y., Guo, X., Uramoto, H., Kohno, K., and Taniguchi, H. (2016). Overexpression of Peroxiredoxin 4 Affects Intestinal Function in a Dietary Mouse Model of Nonalcoholic Fatty Liver Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152549"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5118","DOI":"10.3748\/wjg.v26.i34.5118","article-title":"Acupuncture improved lipid metabolism by regulating intestinal absorption in mice","volume":"26","author":"Han","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1089\/ars.2012.4946","article-title":"Peroxiredoxin 4 Protects Against Nonalcoholic Steatohepatitis and Type 2 Diabetes in a Nongenetic Mouse Model","volume":"19","author":"Nabeshima","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_26","first-page":"1","article-title":"Triglyceride Metabolism in the Liver","volume":"8","author":"Cohen","year":"2017","journal-title":"Compr. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.2174\/13816128113199990344","article-title":"Pathophysiology of nonalcoholic steatohepatitis: Perspectives for a targeted treatment","volume":"19","author":"Marra","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_28","first-page":"123","article-title":"Nonalcoholic Lipid Accumulation and Hepatocyte Malignant Transformation","volume":"4","author":"Gu","year":"2016","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/pin.12477","article-title":"Critical in vivo roles of histamine and histamine receptor signaling in animal models of metabolic syndrome","volume":"66","author":"Yamada","year":"2016","journal-title":"Pathol. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.3109\/10715762.2015.1078461","article-title":"Endoplasmic reticulum stress and Oxidative stress in the pathogenesis of Non-alcoholic fatty liver disease","volume":"49","author":"Ashraf","year":"2015","journal-title":"Free Radic. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/pin.12634","article-title":"Peroxiredoxin 4 (PRDX4): Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease","volume":"68","author":"Yamada","year":"2018","journal-title":"Pathol. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/1476-511X-12-165","article-title":"Nrf2 deletion causes \u201cbenign\u201d simple steatosis to develop into nonalcoholic steatohepatitis in mice fed a high-fat diet","volume":"12","author":"Wang","year":"2013","journal-title":"Lipids Health Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","article-title":"The KEAP1-NRF2 System: A Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis","volume":"98","author":"Yamamoto","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2841","DOI":"10.1038\/cddis.2017.236","article-title":"Brg1-mediated Nrf2\/HO-1 pathway activation alleviates hepatic ischemia\u2013reperfusion injury","volume":"8","author":"Ge","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.tem.2010.01.001","article-title":"The Akt-SREBP nexus: Cell signaling meets lipid metabolism","volume":"21","author":"Krycer","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20157","DOI":"10.1038\/srep20157","article-title":"Involvement of resistin-like molecule \u03b2 in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice","volume":"6","author":"Okubo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4904","DOI":"10.3748\/wjg.v25.i33.4904","article-title":"Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source","volume":"25","author":"Boland","year":"2019","journal-title":"World J. Gastroenterol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/10\/3455\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:07:13Z","timestamp":1760166433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/10\/3455"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["nu13103455"],"URL":"https:\/\/doi.org\/10.3390\/nu13103455","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]}}}