{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:30:33Z","timestamp":1789050633424,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003193","name":"Ministerstvo \u0161kolstva, vedy, v\u00fdskumu a \u0161portu Slovenskej republiky","doi-asserted-by":"publisher","award":["VEGA 2\/0045\/11"],"award-info":[{"award-number":["VEGA 2\/0045\/11"]}],"id":[{"id":"10.13039\/501100003193","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003193","name":"Ministerstvo \u0161kolstva, vedy, v\u00fdskumu a \u0161portu Slovenskej republiky","doi-asserted-by":"publisher","award":["VEGA 2\/0136\/20"],"award-info":[{"award-number":["VEGA 2\/0136\/20"]}],"id":[{"id":"10.13039\/501100003193","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003194","name":"Agent\u00fara Ministerstva \u0160kolstva, Vedy, V\u00fdskumu a \u0160portu SR","doi-asserted-by":"publisher","award":["VEGA 2\/0115\/19"],"award-info":[{"award-number":["VEGA 2\/0115\/19"]}],"id":[{"id":"10.13039\/501100003194","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)\u2014an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO\u2014control, AIA\u2014untreated adjuvant-induced arthritis, AIA-BIL\u2014adjuvant-induced arthritis administrated UCB, CO-BIL\u2014control with administrated UCB. UCB was administered intraperitoneally 200 mg\/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund\u2019s adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.<\/jats:p>","DOI":"10.3390\/ijms22168662","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T10:54:41Z","timestamp":1628765681000},"page":"8662","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hyperbilirubinemia Maintained by Chronic Supplementation of Unconjugated Bilirubin Improves the Clinical Course of Experimental Autoimmune Arthritis"],"prefix":"10.3390","volume":"22","author":[{"given":"Tomas","family":"Sykora","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Comenius University in Bratislava, Spitalska 24, 81372 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8170-1850","authenticated-orcid":false,"given":"Pavel","family":"Babal","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Comenius University in Bratislava, Spitalska 24, 81372 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Mikus-Kuracinova","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Comenius University in Bratislava, Spitalska 24, 81372 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9287-5514","authenticated-orcid":false,"given":"Frantisek","family":"Drafi","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 84104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvester","family":"Ponist","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 84104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4873-0235","authenticated-orcid":false,"given":"Monika","family":"Dvorakova","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University in Bratislava, Spitalska 24, 81372 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0036-7286","authenticated-orcid":false,"given":"Pavol","family":"Janega","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Comenius University in Bratislava, Spitalska 24, 81372 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Bauerova","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 84104 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.1097\/01.rhu.0000166673.34461.33","article-title":"Immunologic mechanisms in the pathogenesis of rheumatoid arthritis","volume":"11","author":"Firestein","year":"2005","journal-title":"J. Clin. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S685","DOI":"10.1136\/annrheumdis-2019-216655","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update","volume":"79","author":"Smolen","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The Pathogenesis of Rheumatoid Arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature01661","article-title":"Evolving concepts of rheumatoid arthritis","volume":"423","author":"Firestein","year":"2003","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41413-018-0016-9","article-title":"Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies","volume":"6","author":"Guo","year":"2018","journal-title":"Bone Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1136\/annrheumdis-2013-204317","article-title":"Proposal for a new nomenclature of disease-modifying antirheumatic drugs","volume":"73","author":"Smolen","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1136\/ard.60.8.729","article-title":"Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis","volume":"60","author":"Cutolo","year":"2001","journal-title":"Ann. Rheum. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"i1777","DOI":"10.1136\/bmj.i1777","article-title":"Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: Abridged cochrane Systematic review and network meta-analysis","volume":"353","author":"Hazlewood","year":"2016","journal-title":"BMJ"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1084\/jem.20192048","article-title":"Interleukin-17 in rheumatoid arthritis: Trials and tribulations","volume":"217","author":"Taams","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/BOR.0000000000000496","article-title":"Recent advances in the treatment of rheumatoid arthritis","volume":"30","author":"Mahajan","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Salehi, B., Martorell, M., Arbiser, J., Sureda, A., Martins, N., Maurya, P., Sharifi-Rad, M., Kumar, P., and Sharifi-Rad, J. (2018). Antioxidants: Positive or negative actors?. Biomolecules, 8.","DOI":"10.3390\/biom8040124"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1016\/j.biocel.2013.09.014","article-title":"The molecular basis for the immunomodulatory activities of unconjugated bilirubin","volume":"45","author":"Jangi","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/MOG.0000000000000354","article-title":"Diagnosis and evaluation of hyperbilirubinemia","volume":"33","author":"Sullivan","year":"2017","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.plipres.2012.11.001","article-title":"Bilirubin and beyond: A review of lipid status in Gilbert\u2019s syndrome and its relevance to cardiovascular disease protection","volume":"52","author":"Bulmer","year":"2013","journal-title":"Prog. Lipid Res."},{"key":"ref_16","first-page":"256","article-title":"Bilirubin as a Protective Factor for Rheumatoid Arthritis: An NHANES Study of 2003\u20132006 Data","volume":"2","author":"Fischman","year":"2010","journal-title":"J. Clin. Med. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1542\/peds.113.6.1776","article-title":"Bilirubin benefits: Cellular protection by a biliverdin reductase antioxidant cycle","volume":"113","author":"Sedlak","year":"2004","journal-title":"Pediatrics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e22118","DOI":"10.1002\/jcla.22118","article-title":"Serum bilirubin and the risk of rheumatoid arthritis","volume":"31","author":"Juping","year":"2017","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1111\/j.1478-3231.2008.01716.x","article-title":"Bilirubin in clinical practice: A review","volume":"28","author":"Fevery","year":"2008","journal-title":"Liver Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.clinbiochem.2010.12.003","article-title":"Decreased small dense LDL levels in Gilbert\u2019s syndrome","volume":"44","author":"Tapan","year":"2011","journal-title":"Clin. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0021-9150(01)00601-3","article-title":"Gilbert syndrome and ischemic heart disease: A protective effect of elevated bilirubin levels","volume":"160","author":"Jirsa","year":"2002","journal-title":"Atherosclerosis"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"459","DOI":"10.33549\/physiolres.933202","article-title":"Hyperbilirubinemia decreases physiological markers in adjuvant-induced arthritis","volume":"64","author":"Bauerova","year":"2015","journal-title":"Physiol. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.4049\/jimmunol.181.3.1887","article-title":"Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis","volume":"181","author":"Liu","year":"2008","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.joca.2011.08.006","article-title":"Chondroitin sulfate effect on induced arthritis in rats","volume":"19","author":"Bauerova","year":"2011","journal-title":"Osteoarthr. Cartil."},{"key":"ref_25","first-page":"3517","article-title":"Effect of methotrexate on inflammatory cells redistribution in experimental adjuvant arthritis","volume":"32","author":"Janega","year":"2011","journal-title":"Rheumatol. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1189\/jlb.0211070","article-title":"Immunomodulatory and immunotoxic effects of bilirubin: Molecular mechanisms","volume":"90","author":"Khan","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1002\/art.1780300708","article-title":"Histopathology of arthritis induced in rats by active immunization to mycobacterial antigens or by systemic transfer of T lymphocyte lines. A light and electron microscopic study of the articular surface using cationized ferritin","volume":"30","author":"Stanescu","year":"1987","journal-title":"Arthritis Rheum."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"450","DOI":"10.4049\/jimmunol.168.1.450","article-title":"Arthritis in Rats Adjuvant-induced severity of joint disease in fibroblast growth factor-2 determines","volume":"168","author":"Yamashita","year":"2021","journal-title":"J. Immunol."},{"key":"ref_29","first-page":"73","article-title":"Heme oxygenase-1 end-products carbon monoxide and biliverdin ameliorate murine collagen induced arthritis","volume":"30","author":"Bonelli","year":"2012","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1515\/cclm.2011.662","article-title":"Relationship between bilirubin and C-reactive protein","volume":"49","author":"Hwang","year":"2011","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1097\/shk.0b013e31804d41dd","article-title":"Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia","volume":"28","author":"Kadl","year":"2007","journal-title":"Shock"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0378-3782(94)90220-8","article-title":"Increased bilirubin production, ceruloplasmin concentrations and hyperbilirubinaemia in full-term newborn infants","volume":"38","author":"Corchia","year":"1994","journal-title":"Early Hum. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1093\/toxsci\/9.2.271","article-title":"Determination of erythrocyte life span in F-344, wistar, and sprague-dawley rats using a modification of the [H]diisopropylfluorophosphate ([H]DFP) method","volume":"9","author":"Derelanko","year":"1987","journal-title":"Toxicol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cca.2006.06.012","article-title":"Bilirubin toxicity to human erythrocytes: A review","volume":"374","author":"Brito","year":"2006","journal-title":"Clin. Chim. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1542\/peds.2007-0438","article-title":"Bilirubin toxicity to human erythrocytes: A more sanguine view","volume":"120","author":"McDonagh","year":"2007","journal-title":"Pediatrics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3389\/fphar.2012.00030","article-title":"Direct antioxidant properties of bilirubin and biliverdin. Is there a role for biliverdin reductase?","volume":"3","author":"Jansen","year":"2012","journal-title":"Front. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.freeradbiomed.2010.06.001","article-title":"The biliverdin\u2013bilirubin antioxidant cycle of cellular protection: Missing a wheel?","volume":"49","author":"McDonagh","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3109\/08916934.2014.939268","article-title":"Markers of inflammation and oxidative stress studied in adjuvant-induced arthritis in the rat on systemic and local level affected by pinosylvin and methotrexate and their combination","volume":"48","author":"Bauerova","year":"2015","journal-title":"Autoimmunity"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1158\/1940-6207.CAPR-13-0125","article-title":"Anti-genotoxic potential of bilirubin in vivo: Damage to DNA in hyperbilirubinemic human and animal models","volume":"6","author":"Wallner","year":"2013","journal-title":"Cancer Prev. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0027-5107(97)00013-4","article-title":"The comet assay: What can it really tell us","volume":"375","author":"Collins","year":"1997","journal-title":"Mutat. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9886","DOI":"10.1038\/srep09886","article-title":"Bilirubin increases insulin sensitivity by regulating cholesterol metabolism, adipokines and PPAR\u03b3 levels","volume":"5","author":"Liu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.metabol.2009.04.003","article-title":"Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: An analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial","volume":"58","author":"Andersson","year":"2009","journal-title":"Metabolism"},{"key":"ref_43","first-page":"46","article-title":"Oxidative Stress in Patients with Rheumatoid Arthritis","volume":"67","year":"2015","journal-title":"Rev. Investig. Clin."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.clinbiochem.2006.10.006","article-title":"Increased DNA damage and oxidative stress in patients with rheumatoid arthritis","volume":"40","author":"Altindag","year":"2007","journal-title":"Clin. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s11010-014-2006-6","article-title":"Oxidative stress in rheumatoid arthritis patients: Relationship to diseases activity","volume":"391","author":"Veselinovic","year":"2014","journal-title":"Mol. Cell. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41584-018-0022-8","article-title":"Microvascular endothelial dysfunction in rheumatoid arthritis","volume":"14","author":"Bordy","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_47","first-page":"361","article-title":"Increased cardiovascular risk in rheumatoid arthritis: Mechanisms and implications","volume":"23","author":"England","year":"2018","journal-title":"BMJ"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1179\/135100005X83680","article-title":"ROS as signalling molecules in T cells\u2014Evidence for abnormal redox signalling in the autoimmune disease, rheumatoid arthritis","volume":"10","author":"Griffiths","year":"2005","journal-title":"Redox. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Souliotis, V.L., Vlachogiannis, N.I., Pappa, M., Argyriou, A., Ntouros, P.A., and Sfikakis, P.P. (2020). DNA Damage Response and Oxidative Stress in Systemic Autoimmunity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010055"},{"key":"ref_50","first-page":"33","article-title":"Utilization of adjuvant arthritis model for evaluation of new approaches in rheumatoid arthritis therapy focused on regulation of immune processes and oxidative stress","volume":"4","year":"2011","journal-title":"Interdiscip. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1177\/019262339902700125","article-title":"Animal models of arthritis: Relevance to human disease","volume":"27","author":"Bendele","year":"1999","journal-title":"Toxicol. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"290","DOI":"10.22270\/jddt.v10i5-s.4357","article-title":"Rheumatoid Arthritis: Etiology, treatment and animal models","volume":"10","author":"Chaudhary","year":"2020","journal-title":"J. Drug Deliv. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1289\/ehp.96104s3465","article-title":"Oxidative damage to DNA: Do we have a reliable biomarker?","volume":"104","author":"Collins","year":"1996","journal-title":"Environ. Health Perspect."},{"key":"ref_54","first-page":"136","article-title":"Serum polyphenol oxidase activity (ceruloplasmin) in conventional laboratory animals and man","volume":"24","author":"Pribyl","year":"1978","journal-title":"Folia Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1096\/fj.04-1767fje","article-title":"Establishing the background level of base oxidation in human lymphocyte DNA: Results of an interlaboratory validation study","volume":"19","author":"Gedik","year":"2005","journal-title":"FASEB J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8662\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:44:39Z","timestamp":1760165079000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8662"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,12]]},"references-count":55,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168662"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168662","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,12]]}}}