{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T21:10:32Z","timestamp":1773695432032,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T00:00:00Z","timestamp":1532044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Chronic alcohol intake leads to alcoholic fatty liver. The pathogenesis of alcoholic fatty liver is related to abnormal lipid accumulation, oxidative stress, endotoxins, and cytokines. Solanum muricatum Ait. (Pepino) is a plant food commonly cultivated in the Penghu island, Taiwan. Previous studies indicated that the aqueous extract of pepino was able to attenuate diabetic progression via its antioxidative and anti-inflammatory effects. However, the mechanisms of the antioxidative and anti-inflammatory effects of pepino leaf in preventing alcoholic fatty liver remain unknown. In this study, Lieber\u2013DeCarli ethanol-containing liquid diet was used to induce alcoholic hepatic injury in C57BL\/6 mice. The hepatoprotective effects and the related mechanisms of aqueous extract of pepino leaf (AEPL) were examined. Our results showed that 2% AEPL treatments protected the liver from ethanol-induced injury through reducing serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and triglyceride (TG) (all p &lt; 0.05). AEPL had the effects in improving the ethanol-induced lipid accumulation in mice under histological examination. Molecular data indicated that the anti-lipid accumulation effect of AEPL might be mediated via inducing hepatic levels of phospho-adenosine monophosphate-activated kinase (p-AMPK) and peroxisome proliferator-activated receptor (PPAR)-\u03b1, and reducing the expressions of hepatic lipogenic enzymes, including sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) (all p &lt; 0.05). AEPL also decreased hepatic levels of thiobarbituric acid relative substances (TBARS), tumor necrosis factor (TNF)-\u03b1, and interleukin (IL)-6, as well as the expression of nuclear factor kappa B (NF-\u03baB) (all p &lt; 0.05). Moreover, AEPL significantly elevated the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), and glutathione (GSH) content compared to the ethanol-fed group (all p &lt; 0.05). Our present study suggests that AEPL could protect the liver against ethanol-induced oxidative injury and lipid accumulation.<\/jats:p>","DOI":"10.3390\/nu10070931","type":"journal-article","created":{"date-parts":[[2018,7,23]],"date-time":"2018-07-23T03:24:27Z","timestamp":1532316267000},"page":"931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Aqueous Extract of Pepino (Solanum muriactum Ait) Leaves Ameliorate Lipid Accumulation and Oxidative Stress in Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"10","author":[{"given":"Jen-Ying","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City 40201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Hsuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City 40201, Taiwan"},{"name":"Department of Clinical Laboratory, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Road, Taichung City 40201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Chin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City 40201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing-Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City 40201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5756-5959","authenticated-orcid":false,"given":"Jing-Hsien","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Road, Taichung City 40201, Taiwan"},{"name":"Department of Clinical Laboratory, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Road, Taichung City 40201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic liver disease: Pathogenesis and new therapeutic targets","volume":"141","author":"Gao","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14672","DOI":"10.3748\/wjg.v20.i40.14672","article-title":"Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver","volume":"20","author":"Liu","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.cmet.2011.03.009","article-title":"AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice","volume":"13","author":"Li","year":"2011","journal-title":"Cell Metab."},{"key":"ref_4","first-page":"393","article-title":"Peroxisome proliferator-activated receptor alpha target genes","volume":"61","author":"Rakhshandehroo","year":"2010","journal-title":"PPAR Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/WOX.0b013e3182439613","article-title":"Oxidative stress and antioxidant defense","volume":"5","author":"Birben","year":"2012","journal-title":"World Allergy Organ J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e554","DOI":"10.1038\/cddis.2013.78","article-title":"Regulation of cytochrome P450 2e1 expression by ethanol: Role of oxidative stress-mediated pkc\/jnk\/sp1 pathway","volume":"4","author":"Jin","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.freeradbiomed.2007.11.004","article-title":"CYP2E1 and oxidative liver injury by alcohol","volume":"44","author":"Lu","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"894","DOI":"10.3109\/10715762.2013.819428","article-title":"Role of oxidative stress in the pathogenesis of alcohol-induced liver disease","volume":"47","author":"Sid","year":"2013","journal-title":"Free Radic. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3748\/wjg.v22.i1.37","article-title":"Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes","volume":"22","author":"Han","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7463571","DOI":"10.1155\/2017\/7463571","article-title":"Protective effects of lemon juice on alcohol-induced liver injury in mice","volume":"2017","author":"Zhou","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.4049\/jimmunol.173.6.3589","article-title":"Cutting edge: Direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kB","volume":"173","author":"Park","year":"2004","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.jff.2017.03.059","article-title":"Ganoderma lucidum repress injury of ethanol-induced steatohepatitis via anti-inflammation, anti-oxidation and reducing hepatic lipid in C57BL\/6J mice","volume":"33","author":"Chung","year":"2017","journal-title":"J. Funct. Foods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.fct.2013.10.011","article-title":"Hepatoprotective effect of mulberry water extracts on ethanol-induced liver injury via anti-inflammation and inhibition of lipogenesis in C57BL\/6J mice","volume":"62","author":"Tang","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4820414","DOI":"10.1155\/2017\/4820414","article-title":"Baicalin ameliorates liver injury induced by chronic plus binge ethanol feeding by modulating oxidative stress and inflammation via CYP2E1 and NRF2 in mice","volume":"2017","author":"He","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_16","first-page":"403","article-title":"Extract of solanum muricatum (Pepino\/CSG) inhibits tumor growth by inducing apoptosis","volume":"19","author":"Ren","year":"1999","journal-title":"Anticancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1002\/jsfa.4345","article-title":"Protective effects of an aqueous extract from pepino (solanum muricatum Ait.) in diabetic mice","volume":"91","author":"Hsu","year":"2011","journal-title":"J. Sci. Food Agric."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1039\/C5FO01358E","article-title":"Pepino polyphenolic extract improved oxidative, inflammatory and glycative stress in the sciatic nerves of diabetic mice","volume":"7","author":"Ma","year":"2016","journal-title":"Food Funct."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/0006-2944(76)90049-1","article-title":"A simple fluorometric assay for lipoperoxide in blood plasma","volume":"15","author":"Yagi","year":"1976","journal-title":"Biochem. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0003-2697(86)90061-8","article-title":"Evaluation of the micromethod for determination of glutathione using enzymatic cycling and ellman\u2019s reagent","volume":"153","author":"Eyer","year":"1986","journal-title":"Anal. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/jn\/117.4.732","article-title":"The effect of progressive selenium deficiency on anti-glutathione peroxidase antibody reactive protein in rat liver","volume":"117","author":"Knight","year":"1987","journal-title":"J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/clinchem\/34.3.497","article-title":"A simple method for clinical assay of superoxide dismutase","volume":"34","author":"Sun","year":"1988","journal-title":"Clin. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1432-1033.1974.tb03751.x","article-title":"Heterogeneity of erythrocyte catalase ii. Isolation and characterization of normal and variant erythrocyte catalase and their subunits","volume":"48","author":"Aebi","year":"1974","journal-title":"Eur. J. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0891-5849(98)00315-3","article-title":"Antioxidant activity applying an improved ABTS radical cation decolorization assay","volume":"26","author":"Re","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1177\/33.8.4020099","article-title":"Application of Nile red, a fluorescent hydrophobic probe, for the detection of neutral lipid deposits in tissue sections: Comparison with oil red O","volume":"33","author":"Fowler","year":"1985","journal-title":"J. Histochem. Cytochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1096\/fasebj.3.11.2570725","article-title":"Role of reversible phosphorylation of acetyl-COA carboxylase in long-chain fatty acid synthesis","volume":"3","author":"Kim","year":"1989","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.alcohol.2012.08.004","article-title":"Rodent models of alcoholic liver disease: Of mice and men","volume":"46","author":"Schrum","year":"2012","journal-title":"Alcohol"},{"key":"ref_28","first-page":"90","article-title":"Hypothesis: Energy wastage in alcoholism and drug abuse: Possible role of hepatic microsomal enzymes","volume":"29","author":"Pirola","year":"1976","journal-title":"AJCN"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.drugalcdep.2008.03.022","article-title":"Supplementing the liquid alcohol diet with chow enhances alcohol intake in C57 BL\/6 mice","volume":"97","author":"Anji","year":"2008","journal-title":"Drug Alcohol Depend."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.jhep.2006.05.009","article-title":"Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model","volume":"45","author":"Ji","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver","volume":"109","author":"Horton","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zeng, T., Zhang, C.L., Song, F.Y., Zhao, X.L., and Xie, K.Q. (2014). CMZ Reversed Chronic Ethanol-Induced Disturbance of PPAR-\u03b1 Possibly by Suppressing Oxidative Stress and PGC-1\u03b1 Acetylation, and Activating the MAPK and GSK3\u03b2 Pathway. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098658"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.alcohol.2004.07.005","article-title":"Molecular mechanisms of alcoholic fatty liver: Role of peroxisome proliferator-activated receptor alpha","volume":"34","author":"Crabb","year":"2004","journal-title":"Alcohol"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27997","DOI":"10.1074\/jbc.M302140200","article-title":"Peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1) agonist treatment reverses PPAR\u03b1 dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice","volume":"278","author":"Fischer","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/MOL.0b013e3283606845","article-title":"Alcohol and plasma triglycerides","volume":"24","author":"Klop","year":"2013","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1161\/01.CIR.102.19.2347","article-title":"Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins a-i and a-ii","volume":"102","author":"Foster","year":"2000","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/aps.2014.46","article-title":"Impact of chronic low to moderate alcohol consumption on blood lipid and heart energy profile in acetaldehyde dehydrogenase 2-deficient mice","volume":"35","author":"Fan","year":"2014","journal-title":"Acta. Pharmacol. Sin."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"853175","DOI":"10.1155\/2012\/853175","article-title":"Oxidative stress and inflammation: Essential partners in alcoholic liver disease","volume":"2012","author":"Ambade","year":"2012","journal-title":"Int. J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.jhep.2008.10.028","article-title":"Evidence that chronic alcohol exposure promotes intestinal oxidative stress, intestinal hyperpermeability and endotoxemia prior to development of alcoholic steatohepatitis in rats","volume":"50","author":"Keshavarzian","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1053\/he.2000.5634","article-title":"Kupffer cell activation by lipopolysaccharide in rats: Role for lipopolysaccharide binding protein and toll-like receptor 4","volume":"31","author":"Su","year":"2000","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"495156","DOI":"10.1155\/2013\/495156","article-title":"The effect of inflammatory cytokines in alcoholic liver disease","volume":"2013","author":"Kawaratani","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.tice.2014.06.008","article-title":"Inhibition of NF-kB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL\/6 mice","volume":"46","author":"Rodrigues","year":"2014","journal-title":"Tissue Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/emmm.201000085","article-title":"Regulation of liver regeneration by growth factors and cytokines","volume":"2","author":"Bohm","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1002\/hep.20137","article-title":"TNF \u03b1-induced ras activation due to ethanol promotes hepatocyte proliferation independently of liver injury in the mouse","volume":"39","author":"Isayama","year":"2004","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1002\/hep.23909","article-title":"Interleukin-6 is an important mediator for mitochondrial DNA repair after alcoholic liver injury in mice","volume":"52","author":"Zhang","year":"2010","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"162750","DOI":"10.1155\/2013\/162750","article-title":"Chemistry and biological activities of flavonoids: An overview","volume":"2013","author":"Kumar","year":"2013","journal-title":"Sci. World J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.freeradbiomed.2011.10.483","article-title":"The anthocyanin cyanidin-3-O-\u03b2-glucoside, a flavonoid, increases hepatic glutathione synthesis and protects hepatocytes against reactive oxygen species during hyperglycemia: Involvement of a cAMP-PKA-dependent signaling pathway","volume":"52","author":"Zhu","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.bbrc.2004.02.099","article-title":"The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelial cells","volume":"316","author":"Ludwig","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"28","DOI":"10.4103\/2008-7802.173051","article-title":"The effect of green tea extract supplementation on liver enzymes in patients with nonalcoholic fatty liver disease","volume":"7","author":"Pezeshki","year":"2016","journal-title":"Int. J. Prev. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/7\/931\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:13:22Z","timestamp":1760195602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/7\/931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,20]]},"references-count":49,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["nu10070931"],"URL":"https:\/\/doi.org\/10.3390\/nu10070931","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,20]]}}}