{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:06:13Z","timestamp":1788296773877,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CSH-2017-C-029"],"award-info":[{"award-number":["CSH-2017-C-029"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The aim is to investigate the effect of lotus (Nelumbo nucifera Gaertn.) seedpod extract (LSE) on acetaminophen (APAP)-induced hepatotoxicity. LSE is rich in polyphenols and has potent antioxidant capacity. APAP is a commonly used analgesic, while APAP overdose is the main reason for drug toxicity in the liver. Until now, there has been no in vitro test of LSE in drug-induced hepatotoxicity responses. LSEs were used to evaluate the effect on APAP-induced cytotoxicity, ROS level, apoptotic rate, and molecule mechanisms. The co-treatment of APAP and LSEs elevated the survival rate and decreased intracellular ROS levels on HepG2 cells. LSEs treatment could significantly reduce APAP-induced HepG2 apoptosis assessed by DAPI and Annexin V\/PI. The further molecule mechanisms indicated that LSEs decreased Fas\/FasL binding and reduced Bax and tBid to restore mitochondrial structure and subsequently suppress downstream apoptosis cascade activation. These declines in COX-2, NF-\u03baB, and iNOS levels were observed in co-treatment APAP and LSEs, which indicated that LSEs could ameliorate APAP-induced inflammation. LSE protected APAP-induced apoptosis by preventing extrinsic, intrinsic, and JNK-mediated pathways. In addition, the restoration of mitochondria and inflammatory suppression in LSEs treatments indicated that LSEs could decrease oxidative stress induced by toxic APAP. Therefore, LSE could be a novel therapeutic option for an antidote against overdose of APAP.<\/jats:p>","DOI":"10.3390\/molecules27134030","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T22:43:00Z","timestamp":1656024180000},"page":"4030","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Hepatoprotective Activity of Nelumbo nucifera Gaertn. Seedpod Extract Attenuated Acetaminophen-Induced Hepatotoxicity"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0021-5709","authenticated-orcid":false,"given":"Hui-Hsuan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung City 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5232-8428","authenticated-orcid":false,"given":"Jen-Ying","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiao-Yun","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Chun","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan"},{"name":"Department of Radiation Oncology, School of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, Taichung City 40201, Taiwan"},{"name":"Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (1996). Cancer Pain Relief: With a Guide to Opioid Availability, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/bcpt.12527","article-title":"Acetaminophen for Chronic Pain: A Systematic Review on Efficacy","volume":"118","author":"Ennis","year":"2016","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13049-017-0468-8","article-title":"Long-term mortality of acetaminophen poisoning: A nationwide population-based cohort study with 10-year follow-up in Taiwan","volume":"26","author":"Huang","year":"2018","journal-title":"Scand. J. Trauma Resusc. Emerg. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1111\/bcp.13656","article-title":"Long-term adverse effects of paracetamol\u2014A review","volume":"84","author":"McCrae","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1124\/dmd.31.12.1499","article-title":"Acetaminophen-induced hepatotoxicity","volume":"31","author":"James","year":"2003","journal-title":"Drug Metab. Dispos."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.tox.2017.03.008","article-title":"Long-term acetaminophen treatment induced liver fibrosis in mice and the involvement of Egr-1","volume":"382","author":"Bai","year":"2017","journal-title":"Toxicology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"789124","DOI":"10.1155\/2015\/789124","article-title":"Phytochemical Profile and Biological Activity of Nelumbo nucifera","volume":"2015","author":"Paudel","year":"2015","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/1541-4337.12333","article-title":"Lotus Flavonoids and Phenolic Acids: Health Promotion and Safe Consumption Dosages","volume":"17","author":"Limwachiranon","year":"2018","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.foodchem.2012.10.111","article-title":"Oligomeric procyanidins of lotus seedpod inhibits the formation of advanced glycation end-products by scavenging reactive carbonyls","volume":"138","author":"Wu","year":"2013","journal-title":"Food Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.foodchem.2010.02.020","article-title":"Inhibition effect of procyanidins from lotus seedpod on mouse B16 melanoma invivo and in vitro","volume":"122","author":"Duan","year":"2010","journal-title":"Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1007\/s10068-012-0234-7","article-title":"Antioxidative effect of lotus seed and seedpod extracts","volume":"21","author":"Kim","year":"2012","journal-title":"Food Sci. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110912","DOI":"10.1016\/j.foodres.2021.110912","article-title":"Comparative study of the inhibitory effects of lotus seedpod oligomeric procyanidins on dietary AGE released from glycated casein during digestion","volume":"152","author":"Wu","year":"2022","journal-title":"Food Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15368378.2021.1963762","article-title":"Medicinal plants in mitigating electromagnetic radiation-induced neuronal damage: A concise review","volume":"41","author":"Raghu","year":"2022","journal-title":"Electromagn. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6731360","DOI":"10.1155\/2022\/6731360","article-title":"(E)-9-Octadecenoic Acid Ethyl Ester Derived from Lotus Seedpod Ameliorates Inflammatory Responses by Regulating MAPKs and NF-\u03baB Signalling Pathways in LPS-Induced RAW264.7 Macrophages","volume":"2022","author":"Xie","year":"2022","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.exger.2015.11.020","article-title":"Ameliorative effect of lotus seedpod proanthocyanidins on cognitive impairment and brain aging induced by D-galactose","volume":"74","author":"Gong","year":"2016","journal-title":"Exp. Gerontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1142\/S0192415X19500083","article-title":"In Vitro and In Vivo Protective Effects of Flavonoid-Enriched Lotus Seedpod Extract on Lipopolysaccharide-Induced Hepatic Inflammation","volume":"47","author":"Tseng","year":"2019","journal-title":"Am. J. Chin. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liu, Y.-T., Lai, Y.-H., Lin, H.-H., and Chen, J.-H. (2019). Lotus Seedpod Extracts Reduced Lipid Accumulation and Lipotoxicity in Hepatocytes. Nutrients, 11.","DOI":"10.3390\/nu11122895"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1586\/17512433.2014.904744","article-title":"A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States","volume":"7","author":"Blieden","year":"2014","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5654","DOI":"10.1074\/jbc.274.9.5654","article-title":"Mitochondrial depolarization accompanies cytochrome c release during apoptosis in PC6 cells","volume":"274","author":"Heiskanen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.freeradbiomed.2005.10.056","article-title":"JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species","volume":"40","author":"Shen","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.1038\/onc.2008.301","article-title":"JNK signaling in apoptosis","volume":"27","author":"Dhanasekaran","year":"2008","journal-title":"Oncogene"},{"key":"ref_22","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":"ref_23","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1093\/toxsci\/kfw158","article-title":"Editor\u2019s Highlight: Metformin Protects Against Acetaminophen Hepatotoxicity by Attenuation of Mitochondrial Oxidant Stress and Dysfunction","volume":"154","author":"Du","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1042\/bj20021121","article-title":"Complex I-mediated reactive oxygen species generation: Modulation by cytochrome c and NAD(P)+ oxidation-reduction state","volume":"368","author":"Kushnareva","year":"2002","journal-title":"Biochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e171","DOI":"10.1111\/liv.12514","article-title":"Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease","volume":"34","author":"Michaut","year":"2014","journal-title":"Liver Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2696432","DOI":"10.1155\/2020\/2696432","article-title":"Green tea polyphenols protect against acetaminophen-induced liver injury by regulating the drug metabolizing enzymes and transporters","volume":"2020","author":"Lv","year":"2020","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1006\/taap.2002.9407","article-title":"Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: Mitochondrial dysfunction versus glutathione depletion","volume":"181","author":"Knight","year":"2002","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.fct.2018.06.025","article-title":"The role of apoptosis in acetaminophen hepatotoxicity","volume":"118","author":"Jaeschke","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0168-8278(02)00209-X","article-title":"Death receptor-mediated apoptosis and the liver","volume":"37","author":"Yoon","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s12551-017-0308-0","article-title":"Mitochondrial outer membrane permeabilization: A focus on the role of mitochondrial membrane structural organization","volume":"9","author":"Suhaili","year":"2017","journal-title":"Biophys. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/jcb.24709","article-title":"Apoptosis regulation at the mitochondrial outer membrane","volume":"115","author":"Gillies","year":"2014","journal-title":"J. Cell. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.redox.2016.10.001","article-title":"Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential","volume":"10","author":"Du","year":"2016","journal-title":"Redox. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17940","DOI":"10.1074\/jbc.273.28.17940","article-title":"Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry","volume":"273","author":"Qiu","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3109\/03602532.2011.602688","article-title":"Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity","volume":"44","author":"Jaeschke","year":"2012","journal-title":"Drug Metab. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"62040","DOI":"10.1039\/C5RA07838E","article-title":"Pathways involved in acetaminophen hepatotoxicity with specific targets for inhibition\/downregulation","volume":"5","author":"Karthivashan","year":"2015","journal-title":"RSC Adv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13565","DOI":"10.1074\/jbc.M708916200","article-title":"Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury","volume":"283","author":"Hanawa","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"453","DOI":"10.3389\/fphar.2018.00453","article-title":"Mitochondrial-Lysosomal Axis in Acetaminophen Hepatotoxicity","volume":"9","author":"Moles","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3727\/105221617X15084371374138","article-title":"Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives","volume":"18","author":"Ramachandran","year":"2018","journal-title":"Gene Expr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.tice.2014.06.008","article-title":"Inhibition of NF-kappaB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL\/6 mice","volume":"46","author":"Rodrigues","year":"2014","journal-title":"Tissue Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1161\/CIRCULATIONAHA.107.689810","article-title":"Cardioprotection afforded by inducible nitric oxide synthase gene therapy is mediated by cyclooxygenase-2 via a nuclear factor-kappaB dependent pathway","volume":"116","author":"Li","year":"2007","journal-title":"Circulation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/toxsci\/62.2.212","article-title":"Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: Role of mitochondrial oxidant stress","volume":"62","author":"Knight","year":"2001","journal-title":"Toxicol. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1053\/jhep.2002.30956","article-title":"Protection against acetaminophen-induced liver injury and lethality by interleukin 10: Role of inducible nitric oxide synthase","volume":"35","author":"Bourdi","year":"2002","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.lfs.2016.06.001","article-title":"Dihydromyricetin ameliorates oleic acid-induced lipid accumulation in L02 and HepG2 cells by inhibiting lipogenesis and oxidative stress","volume":"157","author":"Xie","year":"2016","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"A.3B.1","DOI":"10.1002\/0471142735.ima03bs21","article-title":"Trypan blue exclusion test of cell viability","volume":"21","author":"Strober","year":"1997","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00606-009-0184-6","article-title":"Cytotaxonomy of diploid and polyploid Aristolochia (Aristolochiaceae) species based on the distribution of CMA\/DAPI bands and 5S and 45S rDNA sites","volume":"280","author":"Berjano","year":"2009","journal-title":"Plant Syst. Evol."},{"key":"ref_46","first-page":"e2597","article-title":"Modified annexin V\/propidium iodide apoptosis assay for accurate assessment of cell death","volume":"50","author":"Rieger","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0022-1759(92)90008-H","article-title":"A microplate assay for the detection of oxidative products using 2\u2032,7\u2032-dichlorofluorescin-diacetate","volume":"156","author":"Rosenkranz","year":"1992","journal-title":"J. Immunol. Methods"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1002\/pmic.200800344","article-title":"A critical comparison between two classical and a kit-based method for mitochondria isolation","volume":"9","author":"Hartwig","year":"2009","journal-title":"Proteomics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e13518","DOI":"10.1111\/jfbc.13518","article-title":"Aqueous extract from Pepino (Solanum muricatum Ait.) leaves ameliorated insulin resistance, hyperlipidemia, and hyperglycemia in mice with metabolic syndrome","volume":"44","author":"Hsu","year":"2020","journal-title":"J. Food Biochem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4030\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:38:13Z","timestamp":1760139493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,23]]},"references-count":49,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27134030"],"URL":"https:\/\/doi.org\/10.3390\/molecules27134030","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,23]]}}}