{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:17:37Z","timestamp":1773274657010,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004462","name":"Consiglio Nazionale delle Ricerche (CNR, Italy)","doi-asserted-by":"publisher","award":["DSB.AD007.247"],"award-info":[{"award-number":["DSB.AD007.247"]}],"id":[{"id":"10.13039\/501100004462","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004462","name":"Consiglio Nazionale delle Ricerche (CNR, Italy)","doi-asserted-by":"publisher","award":["GAE: P0002653 [CUP B55F21003380007]"],"award-info":[{"award-number":["GAE: P0002653 [CUP B55F21003380007]"]}],"id":[{"id":"10.13039\/501100004462","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lo.Li. Pharma srl (Rome, Italy)","award":["DSB.AD007.247"],"award-info":[{"award-number":["DSB.AD007.247"]}]},{"name":"Lo.Li. Pharma srl (Rome, Italy)","award":["GAE: P0002653 [CUP B55F21003380007]"],"award-info":[{"award-number":["GAE: P0002653 [CUP B55F21003380007]"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL\/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes\u2019 size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.<\/jats:p>","DOI":"10.3390\/ijms242115872","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T07:24:04Z","timestamp":1698823444000},"page":"15872","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Lithium Treatment Induces Cardiac Dysfunction in Mice"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4462-0645","authenticated-orcid":false,"given":"Serena","family":"L\u2019Abbate","sequence":"first","affiliation":[{"name":"Health Science Interdisciplinary Center, Scuola Superiore Sant\u2019Anna, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppina","family":"Nicolini","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianpiero","family":"Forte","sequence":"additional","affiliation":[{"name":"R&D Department, Lo.Li Pharma, 00156 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Lepore","sequence":"additional","affiliation":[{"name":"R&D Department, Lo.Li Pharma, 00156 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Unfer","sequence":"additional","affiliation":[{"name":"A.G.Un.Co. Obstetrics and Gynaecology Center, 00155 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8064-8311","authenticated-orcid":false,"given":"Claudia","family":"Kusmic","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1002\/zaac.201700394","article-title":"200 years of Lithium and 100 years of organolithium chemistry","volume":"644","author":"Wietelmann","year":"2018","journal-title":"Z. Anorg. Allg. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.ecoenv.2008.02.026","article-title":"Toxicity of lithium to humans and the environment\u2014A literature review","volume":"70","author":"Aral","year":"2008","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s10653-010-9343-5","article-title":"The occurrence of lithium in the environment of the Jordan Valley and its transfer into the food chain","volume":"33","author":"Ammari","year":"2011","journal-title":"Environ. Geochem. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.plaphy.2016.05.034","article-title":"Lithium toxicity in plants: Reasons, mechanisms and remediation possibilities\u2014A review","volume":"107","author":"Shahzad","year":"2016","journal-title":"Plant Physiol. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100252","DOI":"10.1016\/j.ese.2023.100252","article-title":"Reimagining safe lithium applications in the living environment and its impacts on human, animal, and plant system","volume":"15","author":"Shakoor","year":"2023","journal-title":"Environ. Sci. Ecotechnol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3389\/fpsyt.2020.00377","article-title":"Lithium treatment over the lifespan in bipolar disorders","volume":"11","author":"Volkmann","year":"2020","journal-title":"Front. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40345-019-0151-2","article-title":"International Group for Studies of Lithium (IGSLi). Clinical use of lithium salts: Guide for users and prescribers","volume":"7","author":"Tondo","year":"2019","journal-title":"Int. J. Bipolar Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3233\/JAD-150437","article-title":"Lithium as a treatment for Alzheimer\u2019s Disease: A systematic review and meta-analysis","volume":"48","author":"Matsunaga","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1055\/a-1157-9433","article-title":"Drug-drug interactions between lithium and cardiovascular as well as anti-inflammatory drugs","volume":"53","author":"Treiber","year":"2020","journal-title":"Pharmacopsychiatry"},{"key":"ref_10","first-page":"76","article-title":"Optimizing lithium treatment","volume":"1","author":"Dunner","year":"2000","journal-title":"J. Clin. Psychiatry."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"\u00d6hlund, L., Ott, M., Oja, S., Bergqvist, M., Lundqvist, R., Sandlund, M., Salander Renberg, E., and Werneke, U. (2018). Reasons for lithium discontinuation in men and women with bipolar disorder: A retrospective cohort study. BMC Psychiatry, 18, Erratum in BMC Psychiatry 2018, 18, 322.","DOI":"10.1186\/s12888-018-1622-1"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s40345-016-0068-y","article-title":"Lithium side effects and toxicity: Prevalence and management strategies","volume":"4","author":"Gitlin","year":"2016","journal-title":"Int. J. Bipolar Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s11920-015-0603-z","article-title":"Management of adverse effects of mood stabilizers","volume":"17","author":"Murru","year":"2015","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ferensztajn-Rochowiak, E., and Rybakowski, J.K. (2023). Long-term lithium therapy: Side effects and interactions. Pharmaceuticals, 16.","DOI":"10.3390\/ph16010074"},{"key":"ref_15","first-page":"e40949","article-title":"Lithium-induced bradycardia and cardiomyopathy in a patient with bipolar disorder and paranoid schizophrenia","volume":"15","author":"Khalid","year":"2023","journal-title":"Cureus"},{"key":"ref_16","first-page":"69","article-title":"Lithium Toxicity","volume":"8","author":"Corriveau","year":"2013","journal-title":"Can. J. Gen. Intern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1002\/clc.22822","article-title":"Lithium-induced electrocardiographic changes: A complete review","volume":"40","author":"Mehta","year":"2017","journal-title":"Clin. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e241555","DOI":"10.1136\/bcr-2021-241555","article-title":"Lithium-induced ECG modifications: Navigating from acute coronary syndrome to Brugada syndrome","volume":"14","author":"Diserens","year":"2021","journal-title":"BMJ Case Rep."},{"key":"ref_19","first-page":"e16778","article-title":"Lithium-induced sinoatrial node dysfunction","volume":"13","author":"Sarangi","year":"2021","journal-title":"Cureus"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"H1453","DOI":"10.1152\/ajpheart.00554.2015","article-title":"Drug-induced mitochondrial dysfunction and cardiotoxicity","volume":"309","author":"Varga","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1080\/15563650.2016.1185110","article-title":"Lithium poisoning in the intensive care unit: Predictive factors of severity and indications for extracorporeal toxin removal to improve outcome","volume":"54","author":"Vodovar","year":"2016","journal-title":"Clin. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Truedson, P., Ott, M., Lindmark, K., Str\u00f6m, M., Maripuu, M., Lundqvist, R., and Werneke, U. (2022). Effects of toxic lithium levels on ECG-findings from the LiSIE retrospective cohort study. J. Clin. Med., 11.","DOI":"10.3390\/jcm11195941"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.biopha.2017.09.027","article-title":"Lithium induced oxidative damage and inflammation in the rat\u2019s heart: Protective effect of grape seed and skin extract","volume":"95","author":"Mezni","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Salimi, A., Gholamifar, E., Naserzadeh, P., Hosseini, M.J., and Pourahmad, J. (2017). Toxicity of lithium on isolated heart mitochondria and cardiomyocyte: A justification for its cardiotoxic adverse effect. J. Biochem. Mol. Toxicol., 31.","DOI":"10.1002\/jbt.21836"},{"key":"ref_25","first-page":"1684","article-title":"Lithium carbonate induced histopathological changes in the heart of albino rats","volume":"4","author":"Shah","year":"2015","journal-title":"World J. Pharm. Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.biopha.2016.12.004","article-title":"Lithium induced, oxidative stress and related damages in testes and heart in male rats: The protective effects of Malva sylvestris extract","volume":"86","author":"Rjeibi","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1177\/0960327119897759","article-title":"The molecular mechanisms of lithium-induced cardiotoxicity in male rats and its amelioration by N-acetyl cysteine","volume":"39","author":"Ibrahim","year":"2020","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1248\/bpb.34.272","article-title":"Lithium induced toxicity in rats: Blood serum chemistry, antioxidative enzymes in red blood cells and histopathological studies","volume":"34","author":"Ahmad","year":"2011","journal-title":"Biol. Pharm. Bull."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.biopha.2016.10.026","article-title":"Malva sylvestris extract protects upon lithium carbonate-induced kidney damages in male rat","volume":"84","author":"Rjeibi","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1080\/13880209.2016.1255976","article-title":"Phytochemical, antioxidant and protective effect of cactus cladodes extract against lithium-induced liver injury in rats","volume":"55","author":"Dalel","year":"2017","journal-title":"Pharm. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.jelectrocard.2012.10.014","article-title":"QT and Tpeak-Tend intervals in shift workers","volume":"46","author":"Mozos","year":"2013","journal-title":"J Electrocardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/S0140-6736(00)02035-3","article-title":"QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients","volume":"355","author":"Reilly","year":"2000","journal-title":"Lancet"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jelectrocard.2004.10.004","article-title":"Lithium concentration correlates with QTc in patients with psychosis","volume":"38","author":"Mamiya","year":"2005","journal-title":"J. Electrocardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1097\/JCP.0000000000001164","article-title":"Clinical risk factors for therapeutic Lithium-associated electrocardiographic changes in patients with bipolar disorder","volume":"40","author":"Chen","year":"2021","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, C.-H., Chen, Y.-C., Lu, Y.-Y., Lin, Y.-K., Higa, S., Chen, S.-A., and Chen, Y.-J. (2022). Gender difference in Lithium-induced sodium current dysregulation and ventricular arrhythmogenesis in right ventricular outflow tract cardiomyocytes. Biomedicines, 10.","DOI":"10.3390\/biomedicines10112727"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.ijcard.2015.04.080","article-title":"Ablation of androgenreceptor gene triggers right ventricular outflow tract ventricular tachycardia","volume":"189","author":"Tsai","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1016\/S0735-1097(21)03597-X","article-title":"Long-term lithium carbonate use and hypertrophic cardiomyopathy. Is there a possible link?","volume":"77","author":"Vavrenyuk","year":"2021","journal-title":"JACC"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12355","DOI":"10.1073\/pnas.1934654100","article-title":"Phosphoinositide 3-kinase(p110\u03b1) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy","volume":"100","author":"McMullen","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lee, T.M., Lin, S.Z., and Chang, N.C. (2017). Effect of lithium on ventricular remodelling in infarcted rats via the Akt\/mTOR signalling pathways. Biosci. Rep., 37.","DOI":"10.1042\/BSR20160257"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hu, B., Song, J.T., Ji, X.F., Liu, Z.Q., Cong, M.L., and Liu, D.X. (2017). Sodium Ferulate protects against angiotensin II-Induced cardiac hypertrophy in mice by regulating the MAPK\/ERK and JNK pathways. Biomed. Res. Int., 2017.","DOI":"10.1155\/2017\/3754942"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.yjmcc.2018.12.010","article-title":"Heat-shock protein 90 modulates cardiac ventricular hypertrophy via activation of MAPK pathway","volume":"127","author":"Tamura","year":"2019","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"473","DOI":"10.5603\/CJ.a2020.0061","article-title":"Role of extracellular signal-regulated kinase 1\/2 signaling underlying cardiac hypertrophy","volume":"28","author":"Yan","year":"2021","journal-title":"Cardiol. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.lfs.2017.04.016","article-title":"Caffeic acid phenethyl ester attenuates pathological cardiac hypertrophy by regulation of MEK\/ERK signalling pathway in vivo and vitro","volume":"181","author":"Ren","year":"2017","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s11010-017-3253-0","article-title":"Apocynin prevents isoproterenol-induced cardiac hypertrophy in rat","volume":"445","author":"Saleem","year":"2018","journal-title":"Mol. Cell Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"636","DOI":"10.3892\/mmr.2021.12275","article-title":"Interactions between the ERK1\/2 signaling pathway and PCAF play a key role in PE-induced cardiomyocyte hypertrophy","volume":"24","author":"Mao","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1161\/01.RES.0000124977.59827.80","article-title":"Phosphorylation of eukaryotic translation initiation factor 2Bepsilon by glycogen synthase kinase-3beta regulates beta-adrenergic cardiac myocyte hypertrophy","volume":"94","author":"Hardt","year":"2004","journal-title":"Circ. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s11748-009-0505-2","article-title":"Effect of inhibition of glycogen synthase kinase-3 on cardiac hypertrophy during acute pressure overload","volume":"58","author":"Tateishi","year":"2010","journal-title":"Gen. Thorac. Cardiovasc. Surg."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1073\/pnas.93.16.8455","article-title":"A molecular mechanism for the effect of lithium on development","volume":"93","author":"Klein","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/S0960-9822(02)70790-2","article-title":"Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells","volume":"6","author":"Stambolic","year":"1996","journal-title":"Curr. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1042\/BST0371133","article-title":"Validating GSK3 as an in vivo target of lithium action","volume":"37","author":"Klein","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3389\/fnmol.2012.00014","article-title":"Inhibition of GSK3 by lithium, from single molecules to signaling networks","volume":"5","author":"Freland","year":"2012","journal-title":"Front. Mol. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s00232-017-9998-2","article-title":"Towards a unified understanding of lithium action in basic biology and its significance for applied biology","volume":"250","author":"Jakobsson","year":"2017","journal-title":"J. Membr. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s10557-013-6467-8","article-title":"The consequences of long-term glycogen synthase kinase-3 inhibition on normal and insulin resistant rat hearts","volume":"27","author":"Flepisi","year":"2013","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pharmthera.2014.11.016","article-title":"Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases","volume":"148","author":"Beurel","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1113\/EP088061","article-title":"Low-dose lithium feeding increases the SERCA2a-to-phospholamban ratio, improving SERCA function in murine left ventricles","volume":"105","author":"Hamstra","year":"2020","journal-title":"Exp. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12302-020-00333-6","article-title":"The toxicity of lithium to human cardiomyocytes","volume":"32","author":"Shen","year":"2020","journal-title":"Environ. Sci. Eur."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and humans","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_58","first-page":"H747","article-title":"Measurement of heart rate and Q-T interval in the conscious mouse","volume":"274","author":"Mitchell","year":"1998","journal-title":"Am. J. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15872\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:15:38Z","timestamp":1760130938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15872"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,1]]},"references-count":58,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115872"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115872","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,1]]}}}