{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:46:11Z","timestamp":1792107971451,"version":"4.4.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T00:00:00Z","timestamp":1668643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82074114 81973562"],"award-info":[{"award-number":["82074114 81973562"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012172","name":"Double First Class University Plan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012172","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012154","name":"Graduate Research and Innovation Projects of Jiangsu Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012154","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:italic>Tripterygium wilfordii<\/jats:italic>multiglycoside (GTW), extracted and purified from the peeled roots of<jats:italic>T. wilfordii<\/jats:italic>Hook.f. (TwHF), is a well-known traditional Chinese medicine and applied to various autoimmune diseases clinically. However, it has been reported to cause severe liver injury. At present, the mechanism underlying GTW-induced hepatotoxicity remain poorly defined. Here, we evaluated the effects of GTW on mouse liver and elucidated the associated mechanisms<jats:italic>via<\/jats:italic>label-free proteomics combined with bioinformatics analysis. Male C57BL\/6J mice were randomly divided into normal group, a low-dose GTW (70\u00a0mg\/kg) group and a high-dose GTW (140\u00a0mg\/kg) group. After 1-week administration, GTW dose-dependently induced hepatotoxicity. Further analysis showed that GTW could act on the intestinal immune network for IgA production pathway, which plays an important role in maintaining intestinal homeostasis and influences the crosstalk between gut and liver. Western blots confirmed that GTW could decrease pIgR protein expression in the liver and ileum, and, as a result, the secretion of IgA into gut lumen was reduced. Further validation showed that intestinal barrier integrity was impaired in GTW-treated mice, promoting bacteria transferring to the liver and triggering proinflammatory response. Our study demonstrated that gut-liver axis may play a vital part in the progression of GTW-induced hepatotoxicity, which provides guidance for basic research and clinical application of GTW.<\/jats:p>","DOI":"10.3389\/fphar.2022.1032741","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T05:10:12Z","timestamp":1668661812000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Proteomics analysis reveals novel insights into the mechanism of hepatotoxicity induced by Tripterygium wilfordii multiglycoside in mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Yingying","family":"Miao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxia","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Chai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinwei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhou","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.jhep.2019.10.003","article-title":"The gut-liver axis in liver disease: Pathophysiological basis for therapy","volume":"72","author":"Albillos","year":"2020","journal-title":"J. Hepatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"E1018","DOI":"10.3390\/ijms18051018","article-title":"Drug-induced liver injury: Cascade of events leading to cell death, apoptosis or necrosis","volume":"18","author":"Andrea Iorga","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/1471-2105-4-2","article-title":"An automated method for finding molecular complexes in large protein interaction networks","volume":"4","author":"Bader","year":"2003","journal-title":"BMC Bioinforma."},{"key":"B4","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1080\/14789450.2018.1443007","article-title":"The future role of proteomics in the understanding of acute kidney injury","volume":"15","author":"Bennett","year":"2018","journal-title":"Expert Rev. Proteomics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO : A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformatics"},{"key":"B6","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1002\/hep.1840090518","article-title":"The liver and IgA: Immunological, cell biological and clinical implications","volume":"9","author":"Brown","year":"1989","journal-title":"Hepatology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"W317","DOI":"10.1093\/nar\/gkab447","article-title":"KOBAS-i: Intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis","volume":"49","author":"Bu","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"303","DOI":"10.4103\/0976-500X.119726","article-title":"How to calculate sample size in animal studies?","volume":"4","author":"Charan","year":"2013","journal-title":"J. Pharmacol. Pharmacother."},{"key":"B9","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/s12276-018-0126-x","article-title":"Mechanisms regulating intestinal barrier integrity and its pathological implications","volume":"50","author":"Chelakkot","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2686","DOI":"10.1016\/j.ajpath.2017.08.015","article-title":"Acrolein disrupts tight junction proteins and causes endoplasmic reticulum stress-mediated epithelial cell death leading to intestinal barrier dysfunction and permeability","volume":"187","author":"Chen","year":"2017","journal-title":"Am. J. Pathol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.lfs.2018.08.017","article-title":"Gut inflammation exacerbates hepatic injury in the high-fat diet induced NAFLD mouse: Attention to the gut-vascular barrier dysfunction","volume":"209","author":"Cheng","year":"2018","journal-title":"Life Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1155\/1998\/303549","article-title":"Canadian association of gastroenterology Practice guidelines: Evaluation of dysphagia","volume":"12","author":"Cockeram","year":"1998","journal-title":"Can. J. Gastroenterol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"115090","DOI":"10.1016\/j.jep.2022.115090","article-title":"Metabolomics reveals the role of PPAR\u03b1 in Tripterygium Wilfordii-induced liver injury","volume":"289","author":"Dai","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"699","DOI":"10.3389\/fphar.2018.00699","article-title":"Proteomics analysis of monocyte-derived hepatocyte-like cells identifies integrin beta 3 as a specific biomarker for drug-induced liver injury by Diclofenac","volume":"9","author":"Dragoi","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/S1875-5364(21)60078-X","article-title":"Tripterygium wilfordii multiglycoside-induced hepatotoxicity via inflammation and apoptosis in zebrafish","volume":"19","author":"Duan","year":"2021","journal-title":"Chin. J. Nat. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1016\/j.fitote.2011.08.019","article-title":"Inhibition of mitochondrial respiratory chain is involved in triptolide-induced liver injury","volume":"82","author":"Fu","year":"2011","journal-title":"Fitoterapia"},{"key":"B17","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.livres.2020.03.002","article-title":"Intestinal barrier function and metabolic\/liver diseases","volume":"4","author":"Ghosh","year":"2020","journal-title":"Liver Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e21102","DOI":"10.1097\/MD.0000000000021102","article-title":"Rapid induction of clinical remission in sapho syndrome using high-dose Tripterygium glycosides: A case report","volume":"99","author":"Gong","year":"2020","journal-title":"Med. Baltim."},{"key":"B19","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1111\/imr.12189","article-title":"Intestinal IgA production and its role in host-microbe interaction","volume":"260","author":"Gutzeit","year":"2014","journal-title":"Immunol. Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"B21","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1007\/s00535-017-1400-8","article-title":"Immunoglobulin A and liver diseases","volume":"53","author":"Inamine","year":"2018","journal-title":"J. Gastroenterol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fphar.2016.00087","article-title":"Sex-related differences of lipid metabolism induced by triptolide: The possible role of the LXR\u03b1\/SREBP-1 signaling pathway","volume":"7","author":"Jiang","year":"2016","journal-title":"Front. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"8796","DOI":"10.1073\/pnas.88.19.8796","article-title":"The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: A local defense function for IgA","volume":"88","author":"Kaetzel","year":"1991","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B24","doi-asserted-by":"publisher","first-page":"461","DOI":"10.3389\/fimmu.2014.00461","article-title":"Toll-like receptor signaling pathways","volume":"5","author":"Kawasaki","year":"2014","journal-title":"Front. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2645465","DOI":"10.1155\/2018\/2645465","article-title":"Tight junction in the intestinal epithelium: Its association with diseases and regulation by phytochemicals","volume":"2018","author":"Lee","year":"2018","journal-title":"J. Immunol. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"11","DOI":"10.5217\/ir.2015.13.1.11","article-title":"Intestinal permeability regulation by tight junction: Implication on inflammatory bowel diseases","volume":"13","author":"Lee","year":"2015","journal-title":"Intest. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e100685","DOI":"10.1371\/journal.pone.0100685","article-title":"Activation of Nrf2 protects against triptolide-induced hepatotoxicity","volume":"9","author":"Li","year":"2014","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1700001","DOI":"10.1002\/pmic.201700001","article-title":"Quantitative proteomics and targeted fatty acids analysis reveal the damage of triptolide in liver and kidney","volume":"17","author":"Li","year":"2017","journal-title":"Proteomics"},{"key":"B29","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jep.2014.06.006","article-title":"Triptolide: Progress on research in pharmacodynamics and toxicology","volume":"155","author":"Li","year":"","journal-title":"J. Ethnopharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1186\/s12906-018-2305-7","article-title":"Efficacy and safety of Tripterygium wilfordii hook F for chronic urticaria: A systematic review and meta-analysis","volume":"18","author":"Liu","year":"2018","journal-title":"BMC Complement. Altern. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.jpba.2015.08.043","article-title":"Simultaneous determination of triptolide, tripterifordin, celastrol and nine sesquiterpene alkaloids in Tripterygium preparations using high-performance liquid chromatography-triple quadrupole mass spectrometry","volume":"117","author":"Luo","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B32","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/mi.2011.41","article-title":"Secretory IgA\u2019s complex roles in immunity and mucosal homeostasis in the gut","volume":"4","author":"Mantis","year":"2013","journal-title":"Mucosal Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/mi.2011.41","article-title":"Secretory IgA\u2019s complex roles in immunity and mucosal homeostasis in the gut","volume":"4","author":"Mantis","year":"2011","journal-title":"Mucosal Immunol."},{"key":"B34","first-page":"3648","article-title":"Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease","volume":"8","author":"Mao","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.fitote.2010.11.024","article-title":"Tripterygium wilfordii hook F. Versus sulfasalazine in the treatment of rheumatoid arthritis: A well-designed clinical trial of a botanical demonstrating effectiveness","volume":"82","author":"Marks","year":"2011","journal-title":"Fitoterapia"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3468","DOI":"10.19540\/j.cnki.cjcmm.20190301.002","article-title":"Study on difference of liver toxicity and its molecular mechanisms caused by Tripterygium wilfordii multiglycoside and equivalent amount of triptolid in rats","volume":"44","author":"Miao","year":"2019","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"B37","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1093\/bioinformatics\/btt019","article-title":"Systems biology CluePedia Cytoscape plugin : Pathway insights using integrated experimental and in silico data","volume":"29","author":"Mlecnik","year":"2013","journal-title":"Bioinformatics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1080\/00498254.2021.1900626","article-title":"FXR activation prevents liver injury induced by Tripterygium wilfordii preparations","volume":"51","author":"Peng","year":"2021","journal-title":"Xenobiotica."},{"key":"B39","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1111\/pin.12206","article-title":"Label-free visualization of acetaminophen-induced liver injury by high-speed stimulated Raman scattering spectral microscopy and multivariate image analysis","volume":"64","author":"Satoh","year":"2014","journal-title":"Pathol. Int."},{"key":"B40","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1097\/MOG.0b013e32835ff948","article-title":"Linking intestinal homeostasis and liver disease","volume":"29","author":"Schnabl","year":"2013","journal-title":"Curr. Opin. Gastroenterol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"376","DOI":"10.4049\/jimmunol.175.1.376","article-title":"Regulation of the polymeric ig receptor by signaling through TLRs 3 and 4: Linking innate and adaptive immune responses","volume":"175","author":"Schneeman","year":"2005","journal-title":"J. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1113\/jphysiol.2011.219691","article-title":"Role of innate immunity and the microbiota in liver fibrosis: Crosstalk between the liver and gut","volume":"590","author":"Seki","year":"2012","journal-title":"J. Physiol."},{"key":"B43","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.4049\/jimmunol.163.10.5367","article-title":"Generation of polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA","volume":"163","author":"Shimada","year":"1999","journal-title":"J. Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.4254\/wjh.v7.i19.2189","article-title":"Herbal medicine-related hepatotoxicity","volume":"7","author":"Stournaras","year":"2015","journal-title":"World J. Hepatol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/nrmicro2384","article-title":"The role of secretory antibodies in infection immunity","volume":"8","author":"Strugnell","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B47","first-page":"2160","article-title":"A phase I study of ethyl acetate extract of the Chinese antirheumatic herb Tripterygium wilfordii Hook F in rheumatoid arthritis","volume":"28","author":"Tao","year":"2001","journal-title":"J. Rheumatol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/s41575-018-0011-z","article-title":"The gut-liver axis and the intersection with the microbiome","volume":"15","author":"Tripathi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.3390\/v10050237","article-title":"The role of the polymeric immunoglobulin receptor and secretory immunoglobulins during mucosal infection and immunity","volume":"10","author":"Turula","year":"2018","journal-title":"Viruses"},{"key":"B50","doi-asserted-by":"publisher","first-page":"595","DOI":"10.12122\/j.issn.1673-4254.2020.04.23","article-title":"Gut microbiota-an important contributor to liver diseases","volume":"40","author":"Wang","year":"2020","journal-title":"Nan Fang. Yi Ke Da Xue Xue Bao"},{"key":"B51","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.fct.2013.04.039","article-title":"Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats","volume":"58","author":"Wang","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.jim.2014.12.015","article-title":"Methods to determine intestinal permeability and bacterial translocation during liver disease","volume":"421","author":"Wang","year":"2015","journal-title":"J. Immunol. Methods"},{"key":"B53","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41423-020-00592-6","article-title":"Gut microbiome, liver immunology, and liver diseases","volume":"18","author":"Wang","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.fitote.2014.01.006","article-title":"Th17\/Treg imbalance in triptolide-induced liver injury","volume":"93","author":"Wang","year":"2014","journal-title":"Fitoterapia"},{"key":"B55","doi-asserted-by":"publisher","first-page":"c223","DOI":"10.1159\/000208990","article-title":"Tripterygium wilfordii hook F treatment for idiopathic refractory nephrotic syndrome in adults : A meta-analysis","volume":"111","author":"Xu","year":"2009","journal-title":"Nephron. Clin. Pract."},{"key":"B56","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.tox.2019.01.005","article-title":"A new perspective of triptolide-associated hepatotoxicity: Liver hypersensitivity upon LPS stimulation","volume":"414","author":"Yuan","year":"2019","journal-title":"Toxicology"},{"key":"B57","doi-asserted-by":"publisher","first-page":"402","DOI":"10.3389\/fphar.2016.00402","article-title":"Safety profiles of Tripterygium wilfordii hook F: A systematic review and meta-analysis","volume":"7","author":"Zhang","year":"2016","journal-title":"Front. Pharmacol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"154185","DOI":"10.1016\/j.phymed.2022.154185","article-title":"Yi-Xin-Shu capsule ameliorates cardiac hypertrophy by regulating RB\/HDAC1\/GATA4 signaling pathway based on proteomic and mass spectrometry image analysis","volume":"103","author":"Zhang","year":"2022","journal-title":"Phytomedicine."},{"key":"B59","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.jep.2012.02.015","article-title":"Toxicogenomic analysis of the gene expression changes in rat liver after a 28-day oral Tripterygium wilfordii multiglycoside exposure","volume":"141","author":"Zhang","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"356","DOI":"10.3389\/fphar.2018.00356","article-title":"The effectiveness and safety of Tripterygium wilfordii hook. F extracts in rheumatoid arthritis: A systematic review and meta-analysis","volume":"9","author":"Zhou","year":"2018","journal-title":"Front. Pharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1032741\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,12]],"date-time":"2023-03-12T17:13:52Z","timestamp":1678641232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1032741\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,17]]},"references-count":60,"alternative-id":["10.3389\/fphar.2022.1032741"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.1032741","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,17]]},"article-number":"1032741"}}