{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:16:15Z","timestamp":1787498175824,"version":"build-2736575974"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK117570"],"award-info":[{"award-number":["DK117570"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK108735-01"],"award-info":[{"award-number":["DK108735-01"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acetaminophen is the most common cause of acute drug-induced liver injury in the United States. However, research into the mechanisms of acetaminophen toxicity and the development of novel therapeutics is hampered by the lack of robust, reproducible, and cost-effective model systems. Herein, we characterize a novel\n                    <jats:italic>Drosophila<\/jats:italic>\n                    -based model of acetaminophen toxicity. We demonstrate that acetaminophen treatment of\n                    <jats:italic>Drosophila<\/jats:italic>\n                    results in similar pathophysiologic alterations as those observed in mammalian systems, including a robust production of reactive oxygen species, depletion of glutathione, and dose-dependent mortality. Moreover, these effects are concentrated in the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    fat body, an organ analogous to the mammalian liver. Utilizing this system, we interrogated the influence of environmental factors on acetaminophen toxicity which has proven difficult in vertebrate models due to cost and inter-individual variability. We find that both increasing age and microbial depletion sensitize\n                    <jats:italic>Drosophila<\/jats:italic>\n                    to acetaminophen toxicity. These environmental influences both alter oxidative stress response pathways in metazoans. Indeed, genetic and pharmacologic manipulations of the antioxidant response modify acetaminophen toxicity in our model. Taken together, these data demonstrate the feasibility of\n                    <jats:italic>Drosophila<\/jats:italic>\n                    for the study of acetaminophen toxicity, bringing with it an ease of genetic and microbiome manipulation, high-throughput screening, and availability of transgenic animals.\n                  <\/jats:p>","DOI":"10.1038\/s41598-022-21156-w","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T08:02:26Z","timestamp":1668153746000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Oxidative stress mediates end-organ damage in a novel model of acetaminophen-toxicity in Drosophila"],"prefix":"10.1038","volume":"12","author":[{"given":"Bejan J.","family":"Saeedi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hunter-Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken H.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"issue":"2","key":"21156_CR1","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.cld.2018.01.007","volume":"22","author":"C Bunchorntavakul","year":"2018","unstructured":"Bunchorntavakul, C. & Reddy, K. R. Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and acute liver failure. Clin. Liver Dis. 22(2), 325\u2013346 (2018).","journal-title":"Clin. Liver Dis."},{"issue":"2","key":"21156_CR2","first-page":"131","volume":"4","author":"E Yoon","year":"2016","unstructured":"Yoon, E. et al. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. J. Clin. Transl. Hepatol. 4(2), 131\u2013142 (2016).","journal-title":"J. Clin. Transl. Hepatol."},{"issue":"2","key":"21156_CR3","doi-asserted-by":"publisher","first-page":"93","DOI":"10.2165\/00003088-198207020-00001","volume":"7","author":"JA Forrest","year":"1982","unstructured":"Forrest, J. A., Clements, J. A. & Prescott, L. F. Clinical pharmacokinetics of paracetamol. Clin. Pharmacokinet 7(2), 93\u2013107 (1982).","journal-title":"Clin. Pharmacokinet"},{"issue":"3","key":"21156_CR4","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1067\/mcp.2000.104736","volume":"67","author":"PT Manyike","year":"2000","unstructured":"Manyike, P. T. et al. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin. Pharmacol. Ther. 67(3), 275\u2013282 (2000).","journal-title":"Clin. Pharmacol. Ther."},{"issue":"3","key":"21156_CR5","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1021\/jm00177a019","volume":"23","author":"MW Gemborys","year":"1980","unstructured":"Gemborys, M. W., Mudge, G. H. & Gribble, G. W. Mechanism of decomposition of N-hydroxyacetaminophen, a postulated toxic metabolite of acetaminophen. J. Med. Chem. 23(3), 304\u2013308 (1980).","journal-title":"J. Med. Chem."},{"issue":"4","key":"21156_CR6","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1055\/s-2008-1040482","volume":"10","author":"SD Nelson","year":"1990","unstructured":"Nelson, S. D. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 10(4), 267\u2013278 (1990).","journal-title":"Semin Liver Dis"},{"issue":"4","key":"21156_CR7","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1586\/17474124.2016.1127756","volume":"10","author":"JG Stine","year":"2016","unstructured":"Stine, J. G. & Lewis, J. H. Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert Rev. Gastroenterol. Hepatol. 10(4), 517\u2013536 (2016).","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"issue":"3","key":"21156_CR8","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1111\/j.1365-2125.1974.tb00249.x","volume":"1","author":"BG Gazzard","year":"1974","unstructured":"Gazzard, B. G. et al. Charcoal haemoperfusion for paracetamol overdose. Br. J. Clin. Pharmacol. 1(3), 271\u2013275 (1974).","journal-title":"Br. J. Clin. Pharmacol."},{"issue":"3","key":"21156_CR9","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1136\/emj.7.3.148","volume":"7","author":"TJ Underhill","year":"1990","unstructured":"Underhill, T. J., Greene, M. K. & Dove, A. F. A comparison of the efficacy of gastric lavage, ipecacuanha and activated charcoal in the emergency management of paracetamol overdose. Arch. Emerg. Med. 7(3), 148\u2013154 (1990).","journal-title":"Arch. Emerg. Med."},{"issue":"10","key":"21156_CR10","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1080\/15563650.2017.1334915","volume":"55","author":"AL Chiew","year":"2017","unstructured":"Chiew, A. L. et al. Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin. Toxicol. (Phila.) 55(10), 1055\u20131065 (2017).","journal-title":"Clin. Toxicol. (Phila.)"},{"issue":"3","key":"21156_CR11","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1001\/archinte.1981.00340030112020","volume":"141","author":"BH Rumack","year":"1981","unstructured":"Rumack, B. H. et al. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch. Intern. Med. 141(3), 380\u2013385 (1981).","journal-title":"Arch. Intern. Med."},{"key":"21156_CR12","first-page":"CD003328","volume":"2","author":"AL Chiew","year":"2018","unstructured":"Chiew, A. L. et al. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst. Rev. 2, CD003328 (2018).","journal-title":"Cochrane Database Syst. Rev."},{"issue":"4","key":"21156_CR13","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1080\/15563650.2021.1996591","volume":"60","author":"SL Link","year":"2022","unstructured":"Link, S. L. et al. Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series. Clin. Toxicol. (Phila.) 60(4), 472\u2013477 (2022).","journal-title":"Clin. Toxicol. (Phila.)"},{"issue":"9","key":"21156_CR14","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1007\/s11095-013-1007-6","volume":"30","author":"MR McGill","year":"2013","unstructured":"McGill, M. R. & Jaeschke, H. Metabolism and disposition of acetaminophen: Recent advances in relation to hepatotoxicity and diagnosis. Pharm. Res. 30(9), 2174\u20132187 (2013).","journal-title":"Pharm. Res."},{"issue":"6","key":"21156_CR15","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1111\/j.1365-2125.1986.tb02953.x","volume":"22","author":"JA Critchley","year":"1986","unstructured":"Critchley, J. A. et al. Inter-subject and ethnic differences in paracetamol metabolism. Br. J. Clin. Pharmacol. 22(6), 649\u2013657 (1986).","journal-title":"Br. J. Clin. Pharmacol."},{"issue":"1","key":"21156_CR16","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3109\/03602532.2010.527984","volume":"43","author":"L Zhao","year":"2011","unstructured":"Zhao, L. & Pickering, G. Paracetamol metabolism and related genetic differences. Drug Metab. Rev. 43(1), 41\u201352 (2011).","journal-title":"Drug Metab. Rev."},{"issue":"4","key":"21156_CR17","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1053\/jhep.2002.32148","volume":"35","author":"LE Schmidt","year":"2002","unstructured":"Schmidt, L. E., Dalhoff, K. & Poulsen, H. E. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology 35(4), 876\u2013882 (2002).","journal-title":"Hepatology"},{"issue":"6","key":"21156_CR18","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1046\/j.1365-2710.2002.00444.x","volume":"27","author":"W Abebe","year":"2002","unstructured":"Abebe, W. Herbal medication: potential for adverse interactions with analgesic drugs. J. Clin. Pharm. Ther. 27(6), 391\u2013401 (2002).","journal-title":"J. Clin. Pharm. Ther."},{"issue":"10","key":"21156_CR19","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1124\/dmd.115.065698","volume":"43","author":"CD Klaassen","year":"2015","unstructured":"Klaassen, C. D. & Cui, J. Y. Review: Mechanisms of how the intestinal microbiota alters the effects of drugs and bile acids. Drug Metab. Dispos. 43(10), 1505\u20131521 (2015).","journal-title":"Drug Metab. Dispos."},{"issue":"1 Suppl","key":"21156_CR20","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1177\/0023677215570992","volume":"49","author":"JC Mossanen","year":"2015","unstructured":"Mossanen, J. C. & Tacke, F. Acetaminophen-induced acute liver injury in mice. Lab Anim 49(1 Suppl), 30\u201336 (2015).","journal-title":"Lab Anim"},{"issue":"4","key":"21156_CR21","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.cmet.2007.09.002","volume":"6","author":"KD Baker","year":"2007","unstructured":"Baker, K. D. & Thummel, C. S. Diabetic larvae and obese flies-emerging studies of metabolism in Drosophila. Cell Metab. 6(4), 257\u2013266 (2007).","journal-title":"Cell Metab."},{"issue":"112","key":"21156_CR22","doi-asserted-by":"publisher","first-page":"re3","DOI":"10.1126\/scisignal.3112re3","volume":"3","author":"GP Sykiotis","year":"2010","unstructured":"Sykiotis, G. P. & Bohmann, D. Stress-activated cap\u2019n\u2019collar transcription factors in aging and human disease. Sci. Signal 3(112), re3 (2010).","journal-title":"Sci. Signal"},{"issue":"8","key":"21156_CR23","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.celrep.2015.07.042","volume":"12","author":"RM Jones","year":"2015","unstructured":"Jones, R. M. et al. Lactobacilli Modulate Epithelial Cytoprotection through the Nrf2 Pathway. Cell Rep. 12(8), 1217\u20131225 (2015).","journal-title":"Cell Rep."},{"issue":"8","key":"21156_CR24","doi-asserted-by":"publisher","first-page":"4611","DOI":"10.1073\/pnas.081082098","volume":"98","author":"K Chan","year":"2001","unstructured":"Chan, K., Han, X. D. & Kan, Y. W. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc. Natl. Acad. Sci. USA 98(8), 4611\u20134616 (2001).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"5","key":"21156_CR25","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.cmet.2020.03.006","volume":"31","author":"BJ Saeedi","year":"2020","unstructured":"Saeedi, B. J. et al. Gut-resident lactobacilli activate hepatic nrf2 and protect against oxidative liver injury. Cell Metab. 31(5), 956\u2013968 (2020).","journal-title":"Cell Metab."},{"issue":"1","key":"21156_CR26","doi-asserted-by":"publisher","first-page":"4731","DOI":"10.1038\/s41467-018-07192-z","volume":"9","author":"M Pende","year":"2018","unstructured":"Pende, M. et al. High-resolution ultramicroscopy of the developing and adult nervous system in optically cleared Drosophila melanogaster. Nat. Commun. 9(1), 4731 (2018).","journal-title":"Nat. Commun."},{"issue":"4","key":"21156_CR27","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1016\/j.ajpath.2012.12.010","volume":"182","author":"P Scheiermann","year":"2013","unstructured":"Scheiermann, P. et al. Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury. Am. J. Pathol. 182(4), 1107\u20131113 (2013).","journal-title":"Am. J. Pathol."},{"issue":"3","key":"21156_CR28","first-page":"153","volume":"2","author":"H Jaeschke","year":"2014","unstructured":"Jaeschke, H., Xie, Y. & McGill, M. R. Acetaminophen-induced liver injury: from animal models to humans. J. Clin. Transl. Hepatol. 2(3), 153\u2013161 (2014).","journal-title":"J. Clin. Transl. Hepatol."},{"key":"21156_CR29","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/978-1-4939-9424-3_20","volume":"1982","author":"BJ Saeedi","year":"2019","unstructured":"Saeedi, B. J., Chandrasekharan, B. & Neish, A. S. Hydro-Cy3-mediated detection of reactive oxygen species in vitro and in vivo. Methods Mol. Biol. 1982, 329\u2013337 (2019).","journal-title":"Methods Mol. Biol."},{"issue":"1","key":"21156_CR30","first-page":"211","volume":"187","author":"JR Mitchell","year":"1973","unstructured":"Mitchell, J. R. et al. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther. 187(1), 211\u2013217 (1973).","journal-title":"J. Pharmacol. Exp. Ther."},{"issue":"20","key":"21156_CR31","doi-asserted-by":"publisher","first-page":"12063","DOI":"10.1074\/jbc.271.20.12063","volume":"271","author":"SS Lee","year":"1996","unstructured":"Lee, S. S. et al. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. Chem. 271(20), 12063\u201312067 (1996).","journal-title":"J. Biol. Chem."},{"key":"21156_CR32","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1186\/1471-2105-12-357","volume":"12","author":"Y Hu","year":"2011","unstructured":"Hu, Y. et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinf. 12, 357 (2011).","journal-title":"BMC Bioinf."},{"issue":"11","key":"21156_CR33","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1080\/17425255.2020.1817896","volume":"16","author":"JY Akakpo","year":"2020","unstructured":"Akakpo, J. Y., Ramachandran, A. & Jaeschke, H. Novel strategies for the treatment of acetaminophen hepatotoxicity. Expert Opin. Drug Metab. Toxicol. 16(11), 1039\u20131050 (2020).","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"21156_CR34","doi-asserted-by":"publisher","first-page":"660","DOI":"10.3389\/fphys.2019.00660","volume":"10","author":"Z Ge","year":"2019","unstructured":"Ge, Z. et al. Tempol protects against acetaminophen induced acute hepatotoxicity by inhibiting oxidative stress and apoptosis. Front. Physiol. 10, 660 (2019).","journal-title":"Front. Physiol."},{"issue":"7","key":"21156_CR35","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s40266-018-0559-x","volume":"35","author":"P Mian","year":"2018","unstructured":"Mian, P. et al. Paracetamol in older people: Towards evidence-based dosing?. Drugs Aging 35(7), 603\u2013624 (2018).","journal-title":"Drugs Aging"},{"issue":"3","key":"21156_CR36","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1111\/liv.12689","volume":"35","author":"LA Possamai","year":"2015","unstructured":"Possamai, L. A. et al. The role of intestinal microbiota in murine models of acetaminophen-induced hepatotoxicity. Liver Int. 35(3), 764\u2013773 (2015).","journal-title":"Liver Int."},{"issue":"12","key":"21156_CR37","doi-asserted-by":"publisher","first-page":"3009","DOI":"10.1093\/emboj\/cdf306","volume":"21","author":"T Igaki","year":"2002","unstructured":"Igaki, T. et al. Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 21(12), 3009\u20133018 (2002).","journal-title":"EMBO J."},{"issue":"1","key":"21156_CR38","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.devcel.2007.12.002","volume":"14","author":"GP Sykiotis","year":"2008","unstructured":"Sykiotis, G. P. & Bohmann, D. Keap1\/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev. Cell 14(1), 76\u201385 (2008).","journal-title":"Dev. Cell"},{"issue":"7977","key":"21156_CR39","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/S0140-6736(76)92842-7","volume":"2","author":"LF Prescott","year":"1976","unstructured":"Prescott, L. F. et al. Cysteamine, methionine, and penicillamine in the treatment of paracetamol poisoning. Lancet 2(7977), 109\u2013113 (1976).","journal-title":"Lancet"},{"issue":"3","key":"21156_CR40","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1242\/dmm.023762","volume":"9","author":"B Ugur","year":"2016","unstructured":"Ugur, B., Chen, K. & Bellen, H. J. Drosophila tools and assays for the study of human diseases. Dis. Model Mech. 9(3), 235\u2013244 (2016).","journal-title":"Dis. Model Mech."},{"issue":"2","key":"21156_CR41","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1124\/pr.110.003293","volume":"63","author":"UB Pandey","year":"2011","unstructured":"Pandey, U. B. & Nichols, C. D. Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol. Rev. 63(2), 411\u2013436 (2011).","journal-title":"Pharmacol. Rev."},{"issue":"1\u20132","key":"21156_CR42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/gene.10150","volume":"34","author":"JB Duffy","year":"2002","unstructured":"Duffy, J. B. GAL4 system in Drosophila: A fly geneticist\u2019s Swiss army knife. Genesis 34(1\u20132), 1\u201315 (2002).","journal-title":"Genesis"},{"issue":"2","key":"21156_CR43","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/S0009-8981(98)00089-8","volume":"275","author":"DP Jones","year":"1998","unstructured":"Jones, D. P. et al. Glutathione measurement in human plasma. Evaluation of sample collection, storage and derivatization conditions for analysis of dansyl derivatives by HPLC. Clin. Chim. Acta 275(2), 175\u2013184 (1998).","journal-title":"Clin. Chim. Acta"},{"issue":"8","key":"21156_CR44","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.1093\/jn\/132.8.2303","volume":"132","author":"LT Miller","year":"2002","unstructured":"Miller, L. T. et al. Oxidation of the glutathione\/glutathione disulfide redox state is induced by cysteine deficiency in human colon carcinoma HT29 cells. J. Nutr. 132(8), 2303\u20132306 (2002).","journal-title":"J. Nutr."},{"issue":"4","key":"21156_CR45","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/S0891-5849(99)00275-0","volume":"28","author":"DP Jones","year":"2000","unstructured":"Jones, D. P. et al. Redox state of glutathione in human plasma. Free Radic. Biol. Med. 28(4), 625\u2013635 (2000).","journal-title":"Free Radic. Biol. Med."},{"issue":"11\u201312","key":"21156_CR46","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1016\/S0891-5849(99)00145-8","volume":"27","author":"WG Kirlin","year":"1999","unstructured":"Kirlin, W. G. et al. Glutathione redox potential in response to differentiation and enzyme inducers. Free Radic. Biol. Med. 27(11\u201312), 1208\u20131218 (1999).","journal-title":"Free Radic. Biol. Med."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21156-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21156-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21156-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T12:15:37Z","timestamp":1668428137000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21156-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["21156"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-21156-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,11]]},"assertion":[{"value":"4 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19309"}}