{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:23:47Z","timestamp":1787131427078,"version":"build-2736575974"},"reference-count":50,"publisher":"American Chemical Society (ACS)","issue":"2","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100003042","name":"Else Kr?ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2019_T06"],"award-info":[{"award-number":["2019_T06"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nonalcoholic fatty liver disease (NAFLD) is an epidemic chronic liver disease and may progress over nonalcoholic steatohepatitis (NASH) to liver cirrhosis and hepatocellular carcinoma. The multiple metabolic, environmental, and genetic factors that are involved in NAFLD\/NASH pathogenesis and progression suggest a need for multimechanistic interventions. We have developed and preliminarily characterized a concept of dual farnesoid X receptor (FXR) and soluble epoxide hydrolase (sEH) modulation as a promising polypharmacological strategy to counteract NASH. Here we report the profiling of FXR activation, sEH inhibition, and simultaneous FXR\/sEH modulation as an interventional treatment in pre-established NASH in mice with diet-induced obesity (DIO). We found that full FXR activation was required to obtain antisteatosis effects but also worsened ballooning degeneration and fibrosis. In contrast, sEH inhibition and dual FXR\/sEH modulation, despite a lack of antisteatosis activity, had anti-inflammatory effects and efficiently counteracted hepatic fibrosis. These results demonstrate great therapeutic potential of sEH inhibition to counteract hepatic fibrosis and validate the designed polypharmacology concept of dual FXR\/sEH modulation as a potentially superior avenue for the effective treatment of the multifactorial condition NASH.<\/jats:p>","DOI":"10.1021\/acsptsci.1c00041","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T18:52:46Z","timestamp":1617043966000},"page":"966-979","source":"Crossref","is-referenced-by-count":15,"title":["Differential Therapeutic Effects of FXR Activation,\nsEH Inhibition, and Dual FXR\/sEH Modulation in NASH in Diet-Induced\nObese Mice"],"prefix":"10.1021","volume":"4","author":[{"given":"Moritz","family":"Helmsta\u0308dter","sequence":"first","affiliation":[{"name":"Goethe University Frankfurt , , Max-von-Laue-Strasse 9 , ,","place":["Frankfurt, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurema","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt , , Max-von-Laue-Strasse 9 , ,","place":["Frankfurt, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt , , Max-von-Laue-Strasse 9 , ,","place":["Frankfurt, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilia","family":"Weizel","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt , , Max-von-Laue-Strasse 9 , ,","place":["Frankfurt, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1961-1859","authenticated-orcid":true,"given":"Ewgenij","family":"Proschak","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt , , Max-von-Laue-Strasse 9 , ,","place":["Frankfurt, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5359-8128","authenticated-orcid":true,"given":"Daniel","family":"Merk","sequence":"additional","affiliation":[{"name":"Goethe University Frankfurt , , Max-von-Laue-Strasse 9 , ,","place":["Frankfurt, Germany, 60438"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"issue":"8","key":"2026081904091560500_cit1","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The Multiple-Hit\nPathogenesis of\nNon-Alcoholic Fatty Liver Disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metab.,\nClin. Exp."},{"issue":"8","key":"2026081904091560500_cit2","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1053\/j.gastro.2016.02.066","article-title":"Pathogenesis of Nonalcoholic Steatohepatitis","volume":"150","author":"MacHado","year":"2016","journal-title":"Gastroenterology"},{"issue":"21","key":"2026081904091560500_cit3","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1056\/NEJMra1503519","article-title":"Cause, Pathogenesis,\nand Treatment of Nonalcoholic Steatohepatitis","volume":"377","author":"Diehl","year":"2017","journal-title":"N. Engl. J. Med."},{"issue":"2","key":"2026081904091560500_cit4","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1002\/hep.31518","article-title":"Multiple\nParallel Hits Hypothesis\nin Nonalcoholic Fatty Liver Disease: Revisited After a Decade","volume":"73","author":"Tilg","year":"2021","journal-title":"Hepatology"},{"issue":"11","key":"2026081904091560500_cit5","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1111\/hepr.13425","article-title":"Phase 3 Drug Pipelines in the Treatment\nof Non-Alcoholic Steatohepatitis","volume":"49","author":"Sumida","year":"2019","journal-title":"Hepatol. Res."},{"issue":"14","key":"2026081904091560500_cit6","doi-asserted-by":"publisher","first-page":"4939","DOI":"10.3390\/ijms21144939","article-title":"Common Drug Pipelines\nfor the Treatment of Diabetic Nephropathy and Hepatopathy: Can We\nKill Two Birds with One Stone?","volume":"21","author":"Sumida","year":"2020","journal-title":"Int. J. Mol.\nSci."},{"issue":"1","key":"2026081904091560500_cit7","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/1751-2980.12830","article-title":"Development\nof New Drugs for the Treatment of Nonalcoholic\nSteatohepatitis","volume":"21","author":"Tang","year":"2020","journal-title":"J. Dig. Dis."},{"issue":"9972","key":"2026081904091560500_cit8","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/S0140-6736(14)61933-4","article-title":"Farnesoid X Nuclear Receptor Ligand\nObeticholic Acid for Non-Cirrhotic, Non-Alcoholic Steatohepatitis\n(FLINT): A Multicentre, Randomised, Placebo-Controlled Trial","volume":"385","author":"Neuschwander-Tetri","year":"2015","journal-title":"Lancet"},{"issue":"5","key":"2026081904091560500_cit9","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1053\/j.gastro.2016.01.038","article-title":"Elafibranor, an Agonist\nof the Peroxisome Proliferator-Activated Receptor-\u03b1 and -\u03b4,\nInduces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis\nWorsening","volume":"150","author":"Ratziu","year":"2016","journal-title":"Gastroenterology"},{"issue":"8","key":"2026081904091560500_cit10","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/d41573-020-00126-9","article-title":"FDA Rejects\nNASH Drug","volume":"19","author":"Mullard","year":"2020","journal-title":"Nat. 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Hepatol."},{"issue":"2","key":"2026081904091560500_cit13","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/13543784.2020.1718106","article-title":"Targeting CCR2\/5 in the Treatment\nof Nonalcoholic Steatohepatitis (NASH) and Fibrosis: Opportunities\nand Challenges","volume":"29","author":"Lefere","year":"2020","journal-title":"Expert Opin. Invest. Drugs"},{"issue":"12","key":"2026081904091560500_cit14","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1016\/j.cgh.2014.04.038","article-title":"The Fatty Acid-Bile\nAcid Conjugate Aramchol Reduces Liver Fat Content in Patients with\nNonalcoholic Fatty Liver Disease","volume":"12","author":"Safadi","year":"2014","journal-title":"Clin. Gastroenterol.\nHepatol."},{"issue":"3","key":"2026081904091560500_cit15","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1053\/j.gastro.2013.05.042","article-title":"Efficacy and Safety of the Farnesoid x Receptor Agonist\nObeticholic Acid in Patients with Type 2 Diabetes and Nonalcoholic\nFatty Liver Disease","volume":"145","author":"Mudaliar","year":"2013","journal-title":"Gastroenterology"},{"issue":"6","key":"2026081904091560500_cit16","doi-asserted-by":"publisher","first-page":"e39165","DOI":"10.1371\/journal.pone.0039165","article-title":"Inhibition of Soluble\nEpoxide Hydrolase Attenuates High-Fat-Diet-Induced\nHepatic Steatosis by Reduced Systemic Inflammatory Status in Mice","volume":"7","author":"Liu","year":"2012","journal-title":"PLoS One"},{"issue":"2","key":"2026081904091560500_cit17","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.taap.2015.03.022","article-title":"Inhibition\nof Soluble\nEpoxide Hydrolase Attenuates Hepatic Fibrosis and Endoplasmic Reticulum\nStress Induced by Carbon Tetrachloride in Mice","volume":"286","author":"Harris","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"issue":"2","key":"2026081904091560500_cit18","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1073\/pnas.1422590112","article-title":"Inhibition\nof Soluble Epoxide Hydrolase\nModulates Inflammation and Autophagy in Obese Adipose Tissue and Liver:\nRole for Omega-3 Epoxides","volume":"112","author":"Lo\u0301pez-Vicario","year":"2015","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"33","key":"2026081904091560500_cit19","doi-asserted-by":"publisher","first-page":"13528","DOI":"10.1073\/pnas.1311565110","article-title":"Epoxyeicosanoids Promote Organ and Tissue Regeneration","volume":"110","author":"Panigrahy","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Chem."},{"issue":"2","key":"2026081904091560500_cit23","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1021\/acs.jmedchem.8b00760","article-title":"Polypharmacology\nby Design: A Medicinal\nChemist\u2019s Perspective on Multitargeting Compounds","volume":"62","author":"Proschak","year":"2019","journal-title":"J. Med. Chem."},{"key":"2026081904091560500_cit24","doi-asserted-by":"crossref","DOI":"10.1080\/13543784.2020.1839888","article-title":"The Nonalcoholic\nSteatohepatitis (NASH) Drug Development\nGraveyard: Established Hurdles and Planning for Future Success","volume-title":"Expert Opinion on Investigational Drugs","author":"Drenth","year":"2020"},{"key":"2026081904091560500_cit25","doi-asserted-by":"crossref","DOI":"10.1080\/17425255.2021.1867105","article-title":"Multi-Factorial Pharmacokinetic Interactions: Unraveling Complexities\nin Precision Drug Therapy","volume-title":"Expert Opinion\non Drug Metabolism and Toxicology","author":"Bechtold","year":"2021"},{"issue":"18","key":"2026081904091560500_cit26","doi-asserted-by":"publisher","first-page":"7703","DOI":"10.1021\/acs.jmedchem.7b00398","article-title":"A Dual Modulator\nof Farnesoid X Receptor and Soluble Epoxide Hydrolase to Counter Nonalcoholic\nSteatohepatitis","volume":"60","author":"Schmidt","year":"2017","journal-title":"J. Med. Chem."},{"key":"2026081904091560500_cit27","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.bcp.2019.05.023","article-title":"A Dual Farnesoid X Receptor\/Soluble\nEpoxide Hydrolase Modulator Treats Non-Alcoholic Steatohepatitis in\nMice","volume":"166","author":"Hye\nKhan","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"2026081904091560500_cit28","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s12876-020-01356-2","article-title":"Human Translatability\nof the GAN Diet-Induced Obese Mouse Model of Non-Alcoholic Steatohepatitis","volume":"20","author":"Hansen","year":"2020","journal-title":"BMC Gastroenterol."},{"key":"2026081904091560500_cit29","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1038\/s41598-020-58059-7","article-title":"Multi-Omics Characterization\nof a Diet-Induced Obese Model of Non-Alcoholic Steatohepatitis","volume":"10","author":"\u00c6gidius","year":"2020","journal-title":"Sci. Rep."},{"key":"2026081904091560500_cit30","doi-asserted-by":"publisher","first-page":"9046","DOI":"10.1038\/s41598-019-45178-z","article-title":"Combined Obeticholic\nAcid and Elafibranor Treatment Promotes Additive Liver Histological\nImprovements in a Diet-Induced Ob\/Ob Mouse Model of Biopsy-Confirmed\nNASH","volume":"9","author":"Roth","year":"2019","journal-title":"Sci. Rep."},{"issue":"2","key":"2026081904091560500_cit31","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3748\/wjg.v24.i2.179","article-title":"Metabolic\nand Hepatic Effects of Liraglutide, Obeticholic Acid and Elafibranor\nin Diet-Induced Obese Mouse Models of Biopsy-Confirmed Nonalcoholic\nSteatohepatitis","volume":"24","author":"T\u00f8lb\u00f8l","year":"2018","journal-title":"World J. Gastroenterol."},{"issue":"11","key":"2026081904091560500_cit32","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.1016\/j.molmet.2017.09.001","article-title":"Superior\nReductions in Hepatic Steatosis and Fibrosis with Co-Administration\nof a Glucagon-like Peptide-1 Receptor Agonist and Obeticholic Acid\nin Mice","volume":"6","author":"Jouihan","year":"2017","journal-title":"Mol. Metab."},{"issue":"3","key":"2026081904091560500_cit33","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.jceh.2015.02.005","article-title":"Remogliflozin Etabonate\nImproves Fatty Liver Disease in Diet-Induced Obese Male Mice","volume":"5","author":"Nakano","year":"2015","journal-title":"J. Clin. Exp. Hepatol."},{"issue":"2","key":"2026081904091560500_cit34","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3748\/wjg.v24.i2.179","article-title":"Metabolic\nand Hepatic Effects of Liraglutide, Obeticholic Acid and Elafibranor\nin Diet-Induced Obese Mouse Models of Biopsy-Confirmed Nonalcoholic\nSteatohepatitis","volume":"24","author":"T\u00f8lb\u00f8l","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"2026081904091560500_cit35","doi-asserted-by":"publisher","first-page":"14782","DOI":"10.1038\/srep14782","article-title":"NSAIDs Ibuprofen, Indometacin, and\nDiclofenac Do Not Interact with Farnesoid X Receptor","volume":"5","author":"Schmidt","year":"2015","journal-title":"Sci. Rep."},{"issue":"1","key":"2026081904091560500_cit36","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1002\/cmdc.201900576","article-title":"Dual Farnesoid X Receptor\/Soluble\nEpoxide Hydrolase Modulators Derived from Zafirlukast","volume":"15","author":"Schierle","year":"2020","journal-title":"ChemMedChem"},{"issue":"1","key":"2026081904091560500_cit37","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1021\/acs.jmedchem.5b01239","article-title":"N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available\nDual Soluble Epoxide Hydrolase\/Peroxisome Proliferator-Activated Receptor\n\u03b3 Modulators","volume":"59","author":"Blo\u0308cher","year":"2016","journal-title":"J. Med. Chem."},{"issue":"4","key":"2026081904091560500_cit38","doi-asserted-by":"publisher","first-page":"2112","DOI":"10.1021\/acs.jmedchem.8b01848","article-title":"Tuning Nuclear Receptor Selectivity\nof Wy14,643 towards Selective Retinoid X Receptor Modulation","volume":"62","author":"Pollinger","year":"2019","journal-title":"J. Med. Chem."},{"issue":"13","key":"2026081904091560500_cit39","doi-asserted-by":"publisher","first-page":"6727","DOI":"10.1021\/acs.jmedchem.9b02150","article-title":"L-Thyroxin and the Nonclassical Thyroid\nHormone TETRAC Are Potent Activators of PPAR\u03b3","volume":"63","author":"Gellrich","year":"2020","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026081904091560500_cit40","doi-asserted-by":"publisher","first-page":"2915","DOI":"10.1038\/s41467-019-10853-2","article-title":"Molecular Tuning of Farnesoid X Receptor\nPartial Agonism","volume":"10","author":"Merk","year":"2019","journal-title":"Nat. Commun."},{"issue":"10","key":"2026081904091560500_cit41","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1055\/s-2006-946680","article-title":"Carnosic Acid and Carnosol, Phenolic\nDiterpene Compounds of the Labiate Herbs Rosemary and Sage, Are Activators\nof the Human Peroxisome Proliferator-Activated Receptor Gamma","volume":"72","author":"Rau","year":"2006","journal-title":"Planta Med."},{"issue":"5","key":"2026081904091560500_cit42","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1016\/j.bmcl.2017.01.066","article-title":"DrugBank Screening\nRevealed Alitretinoin and Bexarotene as Liver X Receptor Modulators","volume":"27","author":"Heitel","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"16","key":"2026081904091560500_cit43","doi-asserted-by":"publisher","first-page":"7199","DOI":"10.1021\/acs.jmedchem.7b00903","article-title":"Non-Acidic Farnesoid X Receptor Modulators","volume":"60","author":"Flesch","year":"2017","journal-title":"J. Med. Chem."},{"issue":"12","key":"2026081904091560500_cit44","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1016\/j.bcp.2012.02.027","article-title":"Investigation of Imatinib\nand Other Approved Drugs\nas Starting Points for Antidiabetic Drug Discovery with FXR Modulating\nActivity","volume":"83","author":"Steri","year":"2012","journal-title":"Biochem. Pharmacol."},{"issue":"31","key":"2026081904091560500_cit45","doi-asserted-by":"publisher","first-page":"28857","DOI":"10.1074\/jbc.M011610200","article-title":"Human Bile Salt Export Pump Promoter Is Transactivated\nby the Farnesoid X Receptor\/Bile Acid Receptor","volume":"276","author":"Ananthanarayanan","year":"2001","journal-title":"J. Biol. Chem."},{"issue":"7","key":"2026081904091560500_cit46","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1016\/j.bbalip.2007.04.007","article-title":"Functional\nCharacterization of Vitamin\nD Responding Regions in the Human 5-Lipoxygenase Gene","volume":"1771","author":"Seuter","year":"2007","journal-title":"Biochim. Biophys. Acta, Mol. Cell Biol. Lipids"},{"issue":"19","key":"2026081904091560500_cit47","doi-asserted-by":"publisher","first-page":"8035","DOI":"10.1021\/jm500937v","article-title":"Extending\nthe Structure-Activity Relationship of Anthranilic Acid Derivatives\nas Farnesoid X Receptor Modulators: Development of a Highly Potent\nPartial Farnesoid X Receptor Agonist","volume":"57","author":"Merk","year":"2014","journal-title":"J. Med.\nChem."},{"issue":"1","key":"2026081904091560500_cit48","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.ab.2005.03.041","article-title":"Fluorescent Substrates for Soluble\nEpoxide Hydrolase and Application to Inhibition Studies","volume":"343","author":"Jones","year":"2005","journal-title":"Anal. Biochem."},{"key":"2026081904091560500_cit49","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.ab.2006.04.045","article-title":"Development\nof a High-Throughput Screen for Soluble Epoxide Hydrolase Inhibition","volume":"355","author":"Wolf","year":"2006","journal-title":"Anal. Biochem."},{"key":"2026081904091560500_cit500","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and\nvalidation of a histological scoring system for nonalcoholic fatty\nliver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"}],"container-title":["ACS Pharmacology &amp; Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsptsci.1c00041","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/4\/2\/966\/16837362\/pt1c00041.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/4\/2\/966\/16837362\/pt1c00041.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:23:43Z","timestamp":1787127823000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article\/4\/2\/966\/1587165\/Differential-Therapeutic-Effects-of-FXR-Activation"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,3,29]]},"published-print":{"date-parts":[[2021,4,9]]}},"URL":"https:\/\/doi.org\/10.1021\/acsptsci.1c00041","relation":{},"ISSN":["2575-9108"],"issn-type":[{"value":"2575-9108","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]}}}