{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:08:44Z","timestamp":1776913724222,"version":"3.51.2"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2011,6,16]],"date-time":"2011-06-16T00:00:00Z","timestamp":1308182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Esculetin (ESC) is a coumarin that is present in several plants such as Fraxinus rhynchophylla and Artemisia capillaris. Our previous study found that FR ethanol extract (FREtOH) significantly ameliorated rats\u2019 liver function. This study was intended to investigate the protective mechanism of ESC in hepatic apoptosis in rats induced by carbon tetrachloride. Rat hepatic apoptosis was induced by oral administration of CCl4. All rats were administered orally with CCl4 (20%, 0.5 mL\/rat) twice a week for 8 weeks. Rats in the ESC groups were treated daily with ESC, and silymarin group were treated daily with silymarin. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) as well as the activities of the anti-oxidative enzymes glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase in the liver were measured. In addition, expression of liver apoptosis proteins and anti-apoptotic proteins were detected. ESC (100, 500 mg\/kg) significantly reduced the elevated activities of serum ALT and AST caused by CCl4 and significantly increased the activities of catalase, GPx and SOD. Furthermore, ESC (100, 500 mg\/kg) significantly decreased the levels of the proapoptotic proteins (t-Bid, Bak and Bad) and significantly increased the levels of the anti-apoptotic proteins (Bcl-2 and Bcl-xL). ESC inhibited the release of cytochrome c from mitochondria. In addition, the levels of activated caspase-9 and activated caspase-3 were significantly decreased in rats treated with ESC than those in rats treated with CCl4 alone. ESC significantly reduced CCl4-induced hepatic apoptosis in rats.<\/jats:p>","DOI":"10.3390\/ijms12064053","type":"journal-article","created":{"date-parts":[[2011,6,17]],"date-time":"2011-06-17T13:56:03Z","timestamp":1308318963000},"page":"4053-4067","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Esculetin Ameliorates Carbon Tetrachloride-Mediated Hepatic Apoptosis in Rats"],"prefix":"10.3390","volume":"12","author":[{"given":"Yun-Chen","family":"Tien","sequence":"first","affiliation":[{"name":"School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, 91 Hsueh-Shih road, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung-Chun","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih road, Taichung, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan-Sung","family":"Chiu","sequence":"additional","affiliation":[{"name":"School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, 91 Hsueh-Shih road, Taichung 404, Taiwan"},{"name":"Hsin Sheng College of Medical Care and Management, Taoyuan, 325, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tai-Hung","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy, China Medical University, 91 Hsueh-Shih road, Taichung, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih-Yang","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Basic Medical Science, China Medical University, 91, Hsueh-Shih road, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Te","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, 91 Hsueh-Shih road, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Huang","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, 91 Hsueh-Shih road, Taichung 404, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2011,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1093\/carcin\/bgl234","article-title":"Urinary 8-oxodeoxyguanosine, aflatoxin B1 exposure and hepatitis B virus infection and hepatocellular carcinoma in Taiwan","volume":"28","author":"Wu","year":"2007","journal-title":"Carcinogenesis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"G90","DOI":"10.1046\/j.1440-1746.2000.02273.x","article-title":"Asian perspectives on viral hepatitis: Hepatitis C virus infection","volume":"15","author":"McCaughan","year":"2000","journal-title":"J. Gastroenterol. Hepatol"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.2174\/1381612043382710","article-title":"Natural and synthetic coumarin derivatives with anti-inflammatory\/antioxidant activities","volume":"10","author":"Fylaktakidou","year":"2004","journal-title":"Curr. Pharm. Des"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1111\/j.1745-7254.2008.00878.x","article-title":"Protective effect of esculetin against oxidative stress-induced cell damage via scavenging reactive oxygen species","volume":"29","author":"Kim","year":"2008","journal-title":"Acta Pharmacol. Sin"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1007\/BF02980270","article-title":"Anti-oxidative and photo-protective effects of coumarins isolated from Fraxinus chinensis","volume":"30","author":"Lee","year":"2007","journal-title":"Arch. Pharm. Res"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1159\/000021978","article-title":"Effects of the antioxidant (6,7-dihydroxycoumarin) esculetin on the glutathione system and lipid peroxidation in mice","volume":"44","author":"Benedi","year":"1998","journal-title":"Gerontology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0031-6989(88)80847-6","article-title":"Anti-inflammatory and peripheral analgesic activity of esculetinin vivo","volume":"20","author":"Tubaro","year":"1988","journal-title":"Pharmacol Res Commun"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0014-2999(93)90090-5","article-title":"Antiproliferative effect of esculetin on vascular smooth muscle cells: Possible roles of signal transduction pathways","volume":"237","author":"Huang","year":"1993","journal-title":"Eur. J. Pharmacol"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s002040000148","article-title":"Inhibitory effect of esculetin on oxidative damage induced by t-butyl hydroperoxide in rat liver","volume":"74","author":"Lin","year":"2000","journal-title":"Arch. Toxicol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0009-3084(00)00151-1","article-title":"Thermotropic and lyotropic properties of long chain alkyl glycopyranosides. Part II. Disaccharide headgroups","volume":"106","author":"Brandenburg","year":"2000","journal-title":"Chem. Phys. Lipids"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1042\/bj2060203","article-title":"The phospholipids of the hepatic endoplasmic reticulum. Structural change in liver injury","volume":"206","author":"James","year":"1982","journal-title":"Biochem. J"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1056\/NEJMra035021","article-title":"Management of cirrhosis and ascites","volume":"350","author":"Gines","year":"2004","journal-title":"N. Engl. J. Med"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1136\/bmj.327.7407.143","article-title":"Cirrhosis: New research provides a basis for rational and targeted treatments","volume":"327","author":"Iredale","year":"2003","journal-title":"Br. Med. J. Int. Ed"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1254\/jphs.08189FP","article-title":"Protective effect of a mixture of Aloe vera and Silybum marianum against carbon tetrachloride-induced acute hepatotoxicity and liver fibrosis","volume":"109","author":"Kim","year":"2009","journal-title":"J. Pharmacol. Sci"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1248\/bpb.30.1898","article-title":"Protective mechanism of glycyrrhizin on acute liver injury induced by carbon tetrachloride in mice","volume":"30","author":"Lee","year":"2007","journal-title":"Biol. Pharm. Bull"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0022-3565(25)21727-X","article-title":"Glucuronidation and biliary excretion of acetaminophen in rats","volume":"228","author":"Hjelle","year":"1984","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1002\/jcp.10111","article-title":"Mitochondria, the killer organelles and their weapons","volume":"192","author":"Ravagnan","year":"2002","journal-title":"J. Cell Physiol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15782","DOI":"10.1073\/pnas.2636393100","article-title":"Endonuclease G is required for early embryogenesis and normal apoptosis in mice","volume":"100","author":"Zhang","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/S0014-5793(03)01464-9","article-title":"Mitochondrial effectors in caspase-independent cell death","volume":"557","author":"Lorenzo","year":"2004","journal-title":"FEBS Lett"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0005-2728(98)00110-8","article-title":"Mitochondria as regulators of apoptosis: Doubt no more","volume":"1366","author":"Susin","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0092-8674(00)80434-1","article-title":"Cytochrome c and dATP-dependent formation of Apaf-1\/caspase-9 complex initiates an apoptotic protease cascade","volume":"91","author":"Li","year":"1997","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S0167-4838(98)00083-1","article-title":"Biosynthesis of 2-aceto-2-hydroxy acids: Acetolactate synthases and acetohydroxyacid synthases","volume":"1385","author":"Chipman","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1254\/jphs.FP0051053","article-title":"Glycoprotein isolated from Ulmus davidiana NAKAI protects against carbon tetrachloride-induced liver injury in the mouse","volume":"101","author":"Ko","year":"2006","journal-title":"J. Pharmacol. Sci"},{"key":"ref_24","first-page":"1577","article-title":"Deficient liver regeneration after carbon tetrachloride injury in mice lacking type 1 but not type 2 tumor necrosis factor receptor","volume":"152","author":"Yamada","year":"1998","journal-title":"Am. J. Pathol"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/hep.1840010511","article-title":"Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis","volume":"1","author":"Knodell","year":"1981","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.freeradbiomed.2005.05.003","article-title":"Antioxidant strategies in the treatment of stroke","volume":"39","author":"Margaill","year":"2005","journal-title":"Free Radic. Biol. Med"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1254\/jphs.FP0071392","article-title":"Protective effect of baicalin against carbon tetrachloride-induced acute hepatic injury in mice","volume":"106","author":"Park","year":"2008","journal-title":"J. Pharmacol. Sci"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1254\/jphs.93.501","article-title":"Metformin protects against carbon tetrachloride hepatotoxicity in mice","volume":"93","author":"Poon","year":"2003","journal-title":"J. Pharmacol. Sci"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1007\/BF02253360","article-title":"Actions of melatonin in the reduction of oxidative stress. A review","volume":"7","author":"Reiter","year":"2000","journal-title":"J. Biomed. Sci"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1016\/0006-2952(95)00083-C","article-title":"Effect of eugenol on drug-metabolizing enzymes of carbon tetrachloride-intoxicated rat liver","volume":"49","author":"Kumaravelu","year":"1995","journal-title":"Biochem. Pharmacol"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0300-483X(02)00443-2","article-title":"Mercuric chloride induces apoptosis via a mitochondrial-dependent pathway in human leukemia cells","volume":"184","author":"Araragi","year":"2003","journal-title":"Toxicology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S0925-4439(00)00098-3","article-title":"Evaluation of oxidative stress during apoptosis and necrosis caused by carbon tetrachloride in rat liver","volume":"1535","author":"Sun","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1042\/bss0660017","article-title":"Nitric oxide, cytochrome c and mitochondria","volume":"66","author":"Brown","year":"1999","journal-title":"Biochem. Soc. Symp"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1211\/jpp.58.5.0011","article-title":"Water-soluble extract of Salvia miltiorrhiza ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats","volume":"58","author":"Lee","year":"2006","journal-title":"J. Pharm. Pharmacol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-1097(03)00100-9","article-title":"Role of oxidative stress and mitochondrial changes in cyanobacteria-induced apoptosis and hepatotoxicity","volume":"220","author":"Ding","year":"2003","journal-title":"FEMS Microbiol. Lett"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0076-6879(84)05016-3","article-title":"Catalase in vitro","volume":"105","author":"Aebi","year":"1984","journal-title":"Meth. Enzymol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6960","DOI":"10.1016\/S0021-9258(19)44679-6","article-title":"The generation of superoxide radical during the autoxidation of hemoglobin","volume":"247","author":"Misra","year":"1972","journal-title":"J. Biol. Chem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/S0076-6879(84)05015-1","article-title":"Assays of glutathione peroxidase","volume":"105","author":"Flohe","year":"1984","journal-title":"Meth. Enzymol"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/12\/6\/4053\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:56:26Z","timestamp":1760219786000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/12\/6\/4053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,6,16]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2011,6]]}},"alternative-id":["ijms12064053"],"URL":"https:\/\/doi.org\/10.3390\/ijms12064053","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,6,16]]}}}