{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:11:32Z","timestamp":1789099892340,"version":"build-2803163510"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction:<\/jats:title>\n                    <jats:p>\n                      The liver is a major organ that plays a crucial role in detoxifying drugs; however, exposure to hepatotoxic drugs can lead to liver damage. Some research indicates that\n                      <jats:italic toggle=\"yes\">Zingiber officinale<\/jats:italic>\n                      , commonly known as red ginger, possesses various biological properties. The objective of this study was to examine the hepatoprotective effect of red ginger extract (RGE) against acetaminophen (APAP)-induced HepG2 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods:<\/jats:title>\n                    <jats:p>HepG2 cells were induced with APAP to simulate liver injury and subsequently treated with RGE. Levels of nitric oxide (NO) and lactate dehydrogenase (LDH) were measured using a colorimetric assay, while the levels of interleukin (IL)-6, IL-1\u03b2, and IL-10 were measured using an enzyme-linked immunosorbent assay. Gene expression of caspase-3 (Casp-3), Casp-9, and c-Jun kinase (JNK) was assessed by quantitative real-time polymerase chain reaction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>APAP-induced HepG2 cells exhibited a noticeable increase in pro-inflammatory markers. Cells treated with RGE showed lower levels of IL-1\u03b2 and IL-6, and higher levels of IL-10 compared to the positive control. RGE treatment also reduced NO and LDH levels and downregulated the expression of Casp-3, Casp-9, and JNK genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>These results indicate that RGE exerts hepatoprotective effects through increased IL-10 production, alongside the suppression of NO, IL-1\u03b2, IL-6, as well as Casp-3, Casp-9, and JNK gene expression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.4103\/aam.aam_91_24","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T12:00:10Z","timestamp":1751284810000},"page":"712-720","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":3,"title":["Hepatoprotective Activity of Red Ginger Extract on Acetaminophen-induced Liver Injury Models in HepG2 Cells"],"prefix":"10.4103","volume":"24","author":[{"given":"Wahyu","family":"Widowati","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna Sari Widya","family":"Kusuma","sequence":"additional","affiliation":[{"name":"Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didik","family":"Priyandoko","sequence":"additional","affiliation":[{"name":"Biology Study Program, Faculty of Mathematics and Sciences Education, Universitas Pendidikan Indonesia, Bandung, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wahyu","family":"Surakusumah","sequence":"additional","affiliation":[{"name":"Biology Study Program, Faculty of Mathematics and Sciences Education, Universitas Pendidikan Indonesia, Bandung, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nindia Salsabila Mia","family":"Dewi","sequence":"additional","affiliation":[{"name":"Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deni","family":"Rahmat","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universitas Pancasila, Jakarta, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dian Ratih","family":"Laksmitawati","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universitas Pancasila, Jakarta, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diah Kartika","family":"Pratami","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universitas Pancasila, Jakarta, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizal","family":"Azis","sequence":"additional","affiliation":[{"name":"Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung, Indonesia"},{"name":"Biomedical Engineering, Department of Electrical Engineering, Faculty of Engineering, Universitas Indonesia, Depok, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanar Septyawan","family":"Hadiprasetyo","sequence":"additional","affiliation":[{"name":"Biomolecular and Biomedical Research Center, Aretha Medika Utama, Bandung, Indonesia"},{"name":"Faculty of Pharmacy, Universitas Jenderal Achmad Yani, Cimahi, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Tjokropranoto","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philips","family":"Onggowidjaja","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"R1-20251015","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13105-013-0274-3","article-title":"Antioxidant and hepatoprotective potential of Pouteria campechiana on acetaminophen-induced hepatic toxicity in rats","volume":"70","author":"Aseervatham","year":"2014","journal-title":"J Physiol Biochem"},{"key":"R2-20251015","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.redox.2018.04.019","article-title":"Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions","volume":"17","author":"Yan","year":"2018","journal-title":"Redox Biol"},{"key":"R3-20251015","first-page":"131","article-title":"Acetaminophen-induced hepatotoxicity:A comprehensive update","volume":"4","author":"Yoon","year":"2016","journal-title":"J Clin Transl Hepatol"},{"key":"R4-20251015","first-page":"1385","article-title":"Liver disease-an overview","volume":"8","author":"Krishnan","year":"2019","journal-title":"World J Pharm"},{"key":"R5-20251015","first-page":"330","article-title":"Hepatoprotective effect of Crocus sativus (saffron) petals extract against acetaminophen toxicity in male Wistar rats","volume":"4","author":"Omidi","year":"2014","journal-title":"Avicenna J Phytomed"},{"key":"R6-20251015","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1159\/000374090","article-title":"Acetaminophen:Dose-dependent drug hepatotoxicity and acute liver failure in patients","volume":"33","author":"Jaeschke","year":"2015","journal-title":"Dig Dis"},{"key":"R7-20251015","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s00204-014-1432-2","article-title":"Acetaminophen hepatotoxicity:An updated review","volume":"89","author":"Lancaster","year":"2015","journal-title":"Arch Toxicol"},{"key":"R8-20251015","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S0140-6736(19)31894-X","article-title":"Acute liver failure","volume":"394","author":"Stravitz","year":"2019","journal-title":"Lancet"},{"key":"R9-20251015","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1177\/0023677215570992","article-title":"Acetaminophen-induced acute liver injury in mice","volume":"49","author":"Mossanen","year":"2015","journal-title":"Lab Anim"},{"key":"R10-20251015","first-page":"39","article-title":"Therapeutic efficacy of antihepatotoxic and antioxidant activities of Acorus calamus on acetaminophen-induced toxicity in rat","volume":"7","author":"Palani","year":"2009","journal-title":"Int J Integr Biol"},{"key":"R11-20251015","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.fct.2012.12.063","article-title":"Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products","volume":"55","author":"Jaeschke","year":"2013","journal-title":"Food Chem Toxicol"},{"key":"R12-20251015","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ajg.2018.03.002","article-title":"Oxidative stress is bane in chronic liver diseases:Clinical and experimental perspective","volume":"19","author":"Ezhilarasan","year":"2018","journal-title":"Arab J Gastroenterol"},{"key":"R13-20251015","doi-asserted-by":"crossref","first-page":"101982","DOI":"10.1016\/j.redox.2021.101982","article-title":"Decreased availability of nitric oxide and hydrogen sulfide is a hallmark of COVID-19","volume":"43","author":"Dominic","year":"2021","journal-title":"Redox Biol"},{"key":"R14-20251015","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/j.jsps.2020.08.007","article-title":"Hepatoprotective properties of red betel (Piper crocatum Ruiz and Pav) leaves extract towards H(2)O(2)-induced HepG2 cells via anti-inflammatory, antinecrotic, antioxidant potency","volume":"28","author":"Lister","year":"2020","journal-title":"Saudi Pharm J"},{"key":"R15-20251015","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3892\/etm.2011.197","article-title":"Lactate dehydrogenase production in hepatocytes is increased at an early stage of acute liver failure","volume":"2","author":"Kotoh","year":"2011","journal-title":"Exp Ther Med"},{"key":"R16-20251015","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1042\/bj2980249","article-title":"Nitric oxide synthases in mammals","volume":"298","author":"Knowles","year":"1994","journal-title":"Biochem J"},{"key":"R17-20251015","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.tips.2015.05.001","article-title":"Nitric oxide in liver diseases","volume":"36","author":"Iwakiri","year":"2015","journal-title":"Trends Pharmacol Sci"},{"key":"R18-20251015","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.2147\/JIR.S275595","article-title":"Reactive oxygen species:Drivers of physiological and pathological processes","volume":"13","author":"Checa","year":"2020","journal-title":"J Inflamm Res"},{"key":"R19-20251015","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1007\/s11033-020-05340-7","article-title":"The effect of ellagic acid on caspase-3\/bcl-2\/Nrf-2\/NF-kB\/TNF-\u03b1\/COX-2 gene expression product apoptosis pathway:A new approach for muscle damage therapy","volume":"47","author":"Aslan","year":"2020","journal-title":"Mol Biol Rep"},{"key":"R20-20251015","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1186\/s12906-015-0810-5","article-title":"Role of ellagic acid in regulation of apoptosis by modulating novel and atypical PKC in lymphoma bearing mice","volume":"15","author":"Mishra","year":"2015","journal-title":"BMC Complement Altern Med"},{"key":"R21-20251015","doi-asserted-by":"crossref","first-page":"23996","DOI":"10.18632\/oncotarget.15098","article-title":"Caspase-9:Structure, mechanisms and clinical application","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"R22-20251015","doi-asserted-by":"crossref","first-page":"35071","DOI":"10.1074\/jbc.M111.276089","article-title":"c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice","volume":"286","author":"Win","year":"2011","journal-title":"J Biol Chem"},{"key":"R23-20251015","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jhep.2018.03.016","article-title":"Pyruvate dehydrogenase complex and lactate dehydrogenase are targets for therapy of acute liver failure","volume":"69","author":"Ferriero","year":"2018","journal-title":"J Hepatol"},{"key":"R24-20251015","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1080\/14786419.2016.1160235","article-title":"Protective activity of an anthocyanin-rich extract from bilberries and blackcurrants on acute acetaminophen-induced hepatotoxicity in rats","volume":"30","author":"Cristani","year":"2016","journal-title":"Nat Prod Res"},{"key":"R25-20251015","first-page":"124","article-title":"Medicinal properties of Zingiber officinale Roscoe \u2013A review","volume":"9","author":"Kumar Gupta","year":"2014","journal-title":"IOSR J Pharm Biol Sci"},{"key":"R26-20251015","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.5897\/JMPR09.464","article-title":"Chemical composition and antioxidant properties of ginger root (Zingiber officinale)","volume":"4","author":"Shirin Adel","year":"2010","journal-title":"J Med Plants Res"},{"key":"R27-20251015","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.26538\/tjnpr\/v7i2.11","article-title":"Prospects for pharmaceutical of Zingiber officinale extracts and fractions by analysis of the chemical markers, safety profile, anti-lipoxygenase, and analgesic activity","volume":"7","author":"Rasonabe","year":"2023","journal-title":"Trop J Nat Prod Res"},{"key":"R28-20251015","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3390\/foods8060185","article-title":"Bioactive compounds and bioactivities of ginger (Zingiber officinale Roscoe)","volume":"8","author":"Mao","year":"2019","journal-title":"Foods"},{"key":"R29-20251015","doi-asserted-by":"crossref","first-page":"102579","DOI":"10.1016\/j.jksus.2023.102579","article-title":"Butterfly pea flower (Clitoria ternatea L.) extract displayed antidiabetic effect through antioxidant, anti-inflammatory, lower hepatic GSK-3\u03b2, and pancreatic glycogen on diabetes mellitus and dyslipidemia rat","volume":"35","author":"Widowati","year":"2023","journal-title":"J King Saud Univ Sci"},{"key":"R30-20251015","doi-asserted-by":"crossref","first-page":"109","DOI":"10.5614\/j.math.fund.sci.2022.54.1.6","article-title":"Piper crocatum ameliorates APAP-induced hepatotoxicity through antioxidant and anti-inflammatory mechanisms","volume":"54","author":"Lister","year":"2022","journal-title":"J Math Fundam Sci"},{"key":"R31-20251015","doi-asserted-by":"crossref","DOI":"10.1088\/1742-6596\/1374\/1\/012009","article-title":"Hepatoprotective effect of eugenol on acetaminophen-induced hepatotoxicity in HepG2 cells","volume":"1374","author":"Lister","year":"2019","journal-title":"J Phys Conf Ser"},{"key":"R32-20251015","doi-asserted-by":"crossref","first-page":"e933726","DOI":"10.12659\/MSMBR.933726","article-title":"Production of inflammatory mediators in conditioned medium of adipose tissue-derived mesenchymal stem cells (ATMSC)-treated fresh frozen plasma","volume":"28","author":"Laksmitawati","year":"2022","journal-title":"Med Sci Monit Basic Res"},{"key":"R33-20251015","doi-asserted-by":"crossref","first-page":"343","DOI":"10.4103\/2221-1691.350182","article-title":"Human Wharton's jelly mesenchymal stem cells inhibit cytokine storm in acute respiratory distress syndrome in a rat model","volume":"12","author":"Widowati","year":"2022","journal-title":"Asian Pac J Trop Biomed"},{"key":"R34-20251015","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.3748\/wjg.v24.i13.1373","article-title":"Dissecting the molecular pathophysiology of drug-induced liver injury","volume":"24","author":"Ye","year":"2018","journal-title":"World J Gastroenterol"},{"key":"R35-20251015","doi-asserted-by":"crossref","first-page":"3921","DOI":"10.1039\/D0SC05937D","article-title":"Fluorescent probe for the imaging of superoxide and peroxynitrite during drug-induced liver injury","volume":"12","author":"Wu","year":"2021","journal-title":"Chem Sci"},{"key":"R36-20251015","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3390\/foods8100456","article-title":"Comparison of phytochemicals, antioxidant and anti-inflammatory properties of sun-, oven- and freeze-dried ginger extracts","volume":"8","author":"Mustafa","year":"2019","journal-title":"Foods"},{"key":"R37-20251015","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.4103\/0973-1296.203891","article-title":"Ginger treatment ameliorates alcohol-induced myocardial damage by suppression of hyperlipidemia and cardiac biomarkers in rats","volume":"13","author":"Subbaiah","year":"2017","journal-title":"Pharmacogn Mag"},{"key":"R38-20251015","doi-asserted-by":"crossref","first-page":"353","DOI":"10.4292\/wjgpt.v7.i3.353","article-title":"Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases","volume":"7","author":"Soufli","year":"2016","journal-title":"World J Gastrointest Pharmacol Ther"},{"key":"R39-20251015","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/hep4.1631","article-title":"Liver injury in patients hospitalized with coronavirus disease 2019 correlates with hyperinflammatory response and elevated interleukin-6","volume":"5","author":"Da","year":"2021","journal-title":"Hepatol Commun"},{"key":"R40-20251015","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.3389\/fmicb.2019.01057","article-title":"The role of interleukin 6 during viral infections","volume":"10","author":"Velazquez-Salinas","year":"2019","journal-title":"Front Microbiol"},{"key":"R41-20251015","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.jhep.2016.11.017","article-title":"Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure","volume":"66","author":"Woolbright","year":"2017","journal-title":"J Hepatol"},{"key":"R42-20251015","doi-asserted-by":"crossref","first-page":"890","DOI":"10.3389\/fimmu.2017.00890","article-title":"Type I interferon supports inducible nitric oxide synthase in murine hepatoma cells and hepatocytes and during experimental acetaminophen-induced liver damage","volume":"8","author":"Bachmann","year":"2017","journal-title":"Front Immunol"},{"key":"R43-20251015","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s13765-017-0285-9","article-title":"Crosstalk between reactive oxygen species and pro-inflammatory markers in developing various chronic diseases:A review","volume":"60","author":"Ranneh","year":"2017","journal-title":"Appl Biol Chem"},{"key":"R44-20251015","doi-asserted-by":"crossref","first-page":"171","DOI":"10.9758\/cpn.2023.21.1.171","article-title":"Evaluation expression of the caspase-3 and caspase-9 apoptotic genes in schizophrenia patients","volume":"21","author":"Dirican","year":"2023","journal-title":"Clin Psychopharmacol Neurosci"},{"key":"R45-20251015","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/jsfa.11442","article-title":"Ginger and 6-gingerol prevent lipopolysaccharide-induced intestinal barrier damage and liver injury in mice","volume":"102","author":"Guo","year":"2022","journal-title":"J Sci Food Agric"},{"key":"R46-20251015","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1053\/j.gastro.2012.06.004","article-title":"A liver full of JNK:Signaling in regulation of cell function and disease pathogenesis, and clinical approaches","volume":"143","author":"Seki","year":"2012","journal-title":"Gastroenterology"}],"container-title":["Annals of African Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/aam.aam_91_24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:35:49Z","timestamp":1787067349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/aam.aam_91_24"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,30]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.4103\/aam.aam_91_24","relation":{},"ISSN":["1596-3519","0975-5764"],"issn-type":[{"value":"1596-3519","type":"print"},{"value":"0975-5764","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,30]]},"assertion":[{"value":"2024-05-29","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-29","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}