{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:29:49Z","timestamp":1784374189404,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T00:00:00Z","timestamp":1588118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Leaves from Eugenia uniflora, the red Brazilian cherry, have a high content of flavonoids that possess several biological effects such as anti-inflammatory, antioxidant, and antidiabetic activities. However, their influence on carbon tetrachloride (CCl4)-induced acute liver injury in rats has not been investigated. In the current study, a bioguided fractionation assay revealed that the ethyl acetate fraction (EAF) of Eugenia uniflora is the safest and most active fraction. LC-MS analysis of the ethyl acetate fraction revealed 22 secondary metabolites, mainly myricetin and quercetin derivatives. EAF did not show toxicity up to 2000 mg\/kg, and exhibited antioxidant activities in vitro in DPPH assay with IC50 of 3.35 \u00b5g\/mL. Additionally, EAF exhibited substantial antioxidant activities in vivo by counteracting the oxidative damage of the prooxidant juglone [80 \u00b5M] in Caenorhabditis elegans model organism and increased its survival rate in a dose-dependent fashion through the DAF-16\/Foxo pathway. Furthermore, the hepatoprotective activity of EAF (200 mg\/kg against carbon tetrachloride (CCl4) intoxicated male Wistar rats was assessed. EAF significantly inhibited CCl4-induced elevation of alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TB), total cholesterol (TC), and triglycerides (TG), in the blood serum and prevented lipid peroxidation and restored superoxide dismutase (SOD) activity and glutathione (GSH) content in liver tissues. The observed hepatoprotective effects of EAF, which were supported by histopathological observations as pretreatment with EAF, effectively attenuated the CCl4-induced histopathological changes. In conclusion, EAF of Eugenia uniflora leaves has substantial hepatoprotective activities against CCl4 induced acute liver injury in rats due to its antioxidant activity.<\/jats:p>","DOI":"10.3390\/ph13050084","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T13:23:45Z","timestamp":1588166625000},"page":"84","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["RETRACTED: A Polyphenol-Rich Fraction from Eugenia uniflora Exhibits Antioxidant and Hepatoprotective Activities In Vivo"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2719-8534","authenticated-orcid":false,"given":"Mansour","family":"Sobeh","sequence":"first","affiliation":[{"name":"AgroBioSciences Research Division, Mohammed VI Polytechnic University, Lot 660\u2013Hay MoulayRachid, Ben-Guerir 43150, Morocco"},{"name":"Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa","family":"Hamza","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy Practice, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, P.O. Box 43, Cairo 11837, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9270-6267","authenticated-orcid":false,"given":"Mohamed","family":"Ashour","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4518-710X","authenticated-orcid":false,"given":"Mona","family":"Elkhatieb","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5960-3012","authenticated-orcid":false,"given":"Mohamed","family":"El Raey","sequence":"additional","affiliation":[{"name":"Department of Phytochemistry and Plant Systematics, National Research Center, Dokki, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0400-9075","authenticated-orcid":false,"given":"Ashraf","family":"Abdel-Naim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, P.O. 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[12th ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3390\/medicines2030251","article-title":"Modes of action of herbal medicines and plant secondary metabolites","volume":"2","author":"Wink","year":"2015","journal-title":"Medicines"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrd2803","article-title":"Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach?","volume":"8","author":"Trachootham","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"van Wyk, B.-E., and Wink, M. (2017). Medicinal plants of the World, Briza. [2nd ed.].","DOI":"10.1079\/9781786393258.0000"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1007\/978-94-007-2534-8_85","article-title":"Eugenia Uniflora","volume":"Volume 3","author":"Lim","year":"2012","journal-title":"Edible Medicinal and Non-Medicinal Plants"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0304-3835(00)00353-0","article-title":"EBV DNA polymerase inhibition of tannins from Eugenia uniflora","volume":"154","author":"Lee","year":"2000","journal-title":"Cancer Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1590\/S0034-89101995000600002","article-title":"Analysis of antidiarrhoeic effect of plants used in popular medicine","volume":"29","author":"Almeida","year":"1995","journal-title":"Rev. Saude Publica"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0378-8741(99)00066-5","article-title":"Improving effects of the extracts from Eugenia uniflora on hyperglycemia and hypertriglyceridemia in mice","volume":"68","author":"Arai","year":"1999","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1002\/cbdv.201600089","article-title":"Chemical profiling of the essential oils of Syzygium aqueum, Syzygium samarangense and Eugenia uniflora and their discrimination using chemometric analysis","volume":"13","author":"Sobeh","year":"2016","journal-title":"Chem. Biodiv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0378-8741(01)00247-1","article-title":"Ethnoveterinary medicine: Screening of Nigerian medicinal plants for trypanocidal properties","volume":"77","author":"Adewunmi","year":"2001","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.phymed.2009.03.009","article-title":"Antinociceptive and hypothermic evaluation of the leaf essential oil and isolated terpenoids from Eugenia uniflora L. (Brazilian Pitanga)","volume":"16","author":"Amorim","year":"2009","journal-title":"Phytomedicine"},{"key":"ref_14","unstructured":"Oliveira, M.D. (2008). Purification of a lectin from Eugenia uniflora L. seeds and its potential antibacterial activity. Lett. Appl. Microbiol., 371\u2013376."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111939","DOI":"10.1016\/j.jep.2019.111939","article-title":"Chemical profiling of secondary metabolites of Eugenia uniflora and their antioxidant, anti-inflammatory, pain killing and anti-diabetic activities: A comprehensive approach","volume":"240","author":"Sobeh","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1078\/1438-4639-00175","article-title":"2nd, Industrial solvents and liver toxicity: Risk assessment, risk factors and mechanisms","volume":"205","author":"Brautbar","year":"2002","journal-title":"Int. J. Hyg. Environ. Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.taap.2015.11.016","article-title":"Experimental models of hepatotoxicity related to acute liver failure","volume":"290","author":"Maes","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.intimp.2015.02.018","article-title":"5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside alleviated carbon tetrachloride-induced acute hepatitis in mice","volume":"25","author":"Yang","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.fct.2018.01.031","article-title":"High resolution UPLC-MS\/MS profiling of polyphenolics in the methanol extract of Syzygium samarangense leaves and its hepatoprotective activity in rats with CCl4-induced hepatic damage","volume":"113","author":"Sobeh","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jff.2017.12.055","article-title":"Phenolic compounds from Syzygium jambos (Myrtaceae) exhibit distinct antioxidant and hepatoprotective activities in vivo","volume":"41","author":"Sobeh","year":"2018","journal-title":"J. Funct. Foods"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"566","DOI":"10.3389\/fphar.2018.00566","article-title":"Syzygium aqueum: A Polyphenol-rich leaf extract exhibits antioxidant, hepatoprotective, pain-killing and anti-inflammatory activities in animal models","volume":"9","author":"Sobeh","year":"2018","journal-title":"Front Pharmacol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jep.2007.09.009","article-title":"Antioxidant and hepatoprotective activity of ethanolic and aqueous extracts of Momordica dioica Roxb. leaves","volume":"115","author":"Jain","year":"2008","journal-title":"J. Ethnopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.carbpol.2019.02.031","article-title":"Structural characterization and hepatoprotective activities of polysaccharides from the leaves of Toona sinensis (A. Juss) Roem","volume":"212","author":"Cao","year":"2019","journal-title":"Carbohydr. Polym."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12986-015-0057-7","article-title":"Antidiabetic properties of dietary flavonoids: A cellular mechanism review","volume":"12","author":"Vinayagam","year":"2015","journal-title":"Nutr. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ayuda-Dur\u00e1n, B., Gonz\u00e1lez-Manzano, S., Miranda-Vizuete, A., S\u00e1nchez-Hern\u00e1ndez, E., R Romero, M., Due\u00f1as, M., Santos-Buelga, C., and Gonz\u00e1lez-Param\u00e1s, A.M. (2019). Exploring target genes involved in the effect of quercetin on the response to oxidative stress in Caenorhabditis elegans. Antioxidants, 8.","DOI":"10.3390\/antiox8120585"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11895","DOI":"10.3390\/ijms140611895","article-title":"Myricetin-mediated lifespan extension in Caenorhabditis elegans is modulated by DAF-16","volume":"14","author":"Ackermann","year":"2013","journal-title":"IJMS"},{"key":"ref_27","unstructured":"OECD (2002). Test No. 423: Acute oral toxicity-Acute Toxic Class Method, OECD."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Falcao, T.R., de Araujo, A.A., Soares, L.A.L., de Moraes Ramos, R.T., Bezerra, I.C.F., Ferreira, M.R.A., de Souza Neto, M.A., Melo, M.C.N., de Araujo, R.F., and de Aguiar Guerra, A.C.V. (2018). Crude extract and fractions from Eugenia uniflora Linn leaves showed anti-inflammatory, antioxidant, and antibacterial activities. BMC Complement Altern. Med., 18.","DOI":"10.1186\/s12906-018-2144-6"},{"key":"ref_29","first-page":"472","article-title":"Natural Products for Prevention and Treatment of Chemical-Induced Liver Injuries","volume":"17","author":"Meng","year":"2018","journal-title":"CRFSFS"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jep.2015.06.044","article-title":"Investigations of the total flavonoids extracted from flowers of Abelmoschus manihot (L.) Medic against alpha-naphthylisothiocyanate-induced cholestatic liver injury in rats","volume":"172","author":"Yan","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0367-326X(02)00293-9","article-title":"Antioxidant activity of Paraguayan plant extracts","volume":"74","author":"Velazquez","year":"2003","journal-title":"Fitoterapia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0300-483X(89)90116-9","article-title":"Protective effect of flavonoids on drug-induced hepatotoxicity in vitro","volume":"57","author":"Davila","year":"1989","journal-title":"Toxicology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1093\/ajcn\/80.3.742","article-title":"Green tea polyphenols prevent toxin-induced hepatotoxicity in mice by down-regulating inducible nitric oxide-derived prooxidants","volume":"80","author":"Chen","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"623940","DOI":"10.1155\/2012\/623940","article-title":"Analysis of flavonoids from Eugenia uniflora leaves and its protective effect against Murine Sepsis","volume":"2012","author":"Rattmann","year":"2012","journal-title":"Evid. Based Complement Altern. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/S0090-9556(25)07515-4","article-title":"Effects of flavonoids on cytochrome P450-dependent acetaminophen metabolism in rats and human liver microsomes","volume":"22","author":"Li","year":"1994","journal-title":"Drug Metab. Dispos."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0300-483X(01)00473-5","article-title":"Carbon tetrachloride changes the activity of cytochrome P450 system in the liver of male rats: Role of antioxidants","volume":"169","author":"Sheweita","year":"2001","journal-title":"Toxicology"},{"key":"ref_37","first-page":"1","article-title":"Tannin-rich extracts from Lannea stuhlmannii and Lannea humilis (Anacardiaceae) exhibit hepatoprotective activities in vivo via enhancement of the anti-apoptotic protein Bcl-2","volume":"19","author":"Sobeh","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sobeh, M., Mahmoud, M.F., Hasan, R.A., Cheng, H., El-Shazly, A.M., and Wink, M. (2017). Senna singueana: Antioxidant, hepatoprotective, antiapoptotic properties and phytochemical profiling of a methanol bark extract. Molecules, 22.","DOI":"10.3390\/molecules22091502"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1177\/0023677215571192","article-title":"The carbon tetrachloride model in mice","volume":"49","author":"Scholten","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zakaria, Z.A., Yahya, F., Mamat, S.S., Mahmood, N.D., Mohtarrudin, N., Taher, M., Hamid, S.S., Teh, L.K., and Salleh, M.Z. (2016). Hepatoprotective action of various partitions of methanol extract of Bauhinia purpurea leaves against paracetamol-induced liver toxicity: Involvement of the antioxidant mechanisms. BMC Complement Altern. Med., 16.","DOI":"10.1186\/s12906-016-1110-4"}],"updated-by":[{"DOI":"10.3390\/ph19071038","type":"retraction","label":"Retraction","source":"publisher","updated":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T00:00:00Z","timestamp":1588118400000}}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/5\/84\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:05:04Z","timestamp":1783350304000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/5\/84"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,29]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ph13050084"],"URL":"https:\/\/doi.org\/10.3390\/ph13050084","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,29]]}}}