{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:19:49Z","timestamp":1790957989592,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T00:00:00Z","timestamp":1646524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","doi-asserted-by":"publisher","award":["IP-2019-04-2237"],"award-info":[{"award-number":["IP-2019-04-2237"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxidative stress (OS) mediators, together with the inflammatory processes, are considered as threatening factors for bone health. The aim of this study was to investigate effects of flavonoids naringenin and chrysin on OS, inflammation, and bone degradation in retinoic acid (13cRA)-induced secondary osteoporosis (OP) in rats. We analysed changes in body and uterine weight, biochemical bone parameters (bone mineral density (BMD), bone mineral content (BMC), markers of bone turnover), bone geometry parameters, bone histology, OS parameters, biochemical and haematological parameters, and levels of inflammatory cytokines. Osteoporotic rats had reduced bone Ca and P levels, BMD, BMC, and expression of markers of bone turnover, and increased values of serum enzymes alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Malondialdehyde (MDA) production in liver, kidney, and ovary was increased, while the glutathione (GSH) content and activities of antioxidant enzymes were reduced and accompanied with the enhanced release of inflammatory mediators TNF-\u03b1, IL-1\u03b2, IL-6, and RANTES chemokine (regulated on activation normal T cell expressed and secreted) in serum. Treatment with chrysin or naringenin improved bone quality, reduced bone resorption, and bone mineral deposition, although with a lower efficacy compared with alendronate. However, flavonoids exhibited more pronounced antioxidative, anti-inflammatory and phytoestrogenic activities, indicating their great potential in attenuating bone loss and prevention of OP.<\/jats:p>","DOI":"10.3390\/ijms23052872","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:38:16Z","timestamp":1646599096000},"page":"2872","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Antioxidative and Anti-Inflammatory Activities of Chrysin and Naringenin in a Drug-Induced Bone Loss Model in Rats"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5102-3606","authenticated-orcid":false,"given":"Nada","family":"Or\u0161oli\u0107","sequence":"first","affiliation":[{"name":"Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Nemrava","sequence":"additional","affiliation":[{"name":"Polyclinic Bagatin, Grada Vukovara 269a\/10, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0475-0197","authenticated-orcid":false,"given":"\u017deljko","family":"Jele\u010d","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Specialty Hospital St. Catherine, 49210 Zabok, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3040-0673","authenticated-orcid":false,"given":"Marina","family":"Kukolj","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-755X","authenticated-orcid":false,"given":"Dyana","family":"Odeh","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Jakopovi\u0107","sequence":"additional","affiliation":[{"name":"Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5037-3919","authenticated-orcid":false,"given":"Maja","family":"Jazvin\u0161\u0107ak Jembrek","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Laboratory for Protein Dynamics, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka cesta 54, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomica","family":"Bagatin","sequence":"additional","affiliation":[{"name":"Polyclinic Bagatin, Grada Vukovara 269a\/10, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6494-0972","authenticated-orcid":false,"given":"Rajko","family":"Fure\u0161","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics, General Hospital Zabok, 49210 Zabok, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinko","family":"Bagatin","sequence":"additional","affiliation":[{"name":"Polyclinic Bagatin, Grada Vukovara 269a\/10, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.sapharm.2007.03.004","article-title":"The relationship of calcium intake and exercise to osteoporosis health beliefs in postmenopausal women","volume":"4","author":"Swaim","year":"2008","journal-title":"Res. Soc. Adm. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3109\/13697137.2015.1103615","article-title":"Drug-induced osteoporosis: From Fuller Albright to aromatase inhibitors","volume":"18","author":"Byreddy","year":"2015","journal-title":"Climacteric"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1177\/1759720X14546350","article-title":"Medication-induced osteoporosis: Screening and treatment strategies","volume":"6","author":"Panday","year":"2014","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.pmrj.2011.02.017","article-title":"Adverse effects of corticosteroids on bone metabolism: A review","volume":"3","author":"Mitra","year":"2011","journal-title":"PM R"},{"key":"ref_5","first-page":"1559","article-title":"Oxidative Stress as a Risk Factor of Osteoporotic Model Induced by Vitamin A in Rats","volume":"3","author":"Fahmy","year":"2009","journal-title":"Aust. J. Basic Appl. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.bone.2004.11.006","article-title":"Retinoid-induced bone thinning is caused by subperiosteal osteoclast activity in adult rodents","volume":"36","author":"Kneissel","year":"2005","journal-title":"Bone"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/8756-3282(90)90072-7","article-title":"Retinoic acid and 1, 25-dihydroxy vitamin D stimulate osteoclast formation by different mechanisms","volume":"11","author":"Scheven","year":"1990","journal-title":"Bone"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1007\/s00394-013-0622-7","article-title":"Role of flavonoids on oxidative stress and mineral contents in the retinoic acid-induced bone loss model of rat","volume":"53","author":"Lazarus","year":"2014","journal-title":"Eur. J. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/jsfa.7098","article-title":"Prevention of retinoic acid-induced osteoporosis in mice by isoflavone-enriched soy protein","volume":"96","author":"Yang","year":"2016","journal-title":"J. Sci. Food Agric."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s11845-015-1309-2","article-title":"Diosgenin prevents bone loss on retinoic acid-induced osteoporosis in rats","volume":"185","author":"Zhao","year":"2016","journal-title":"Ir. J. Med. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"341","DOI":"10.4103\/ijmr.IJMR_524_18","article-title":"Oxidative stress as a possible pathogenic cofactor of post-menopausal osteoporosis: Existing evidence in support of the axis oestrogen deficiency-redox imbalance-bone loss","volume":"147","author":"Bonaccorsi","year":"2018","journal-title":"Indian J. Med. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1196\/annals.1346.030","article-title":"Estrogen regulation of immune cell bone interactions","volume":"1068","author":"Weitzmann","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6445","DOI":"10.1007\/s13277-014-1843-y","article-title":"Quercetin and hyperthermia modulate cisplatin-induced DNA damage in tumor and normal tissues in vivo","volume":"35","author":"Car","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_14","first-page":"455","article-title":"Honey bee products and their polyphenolic compounds in treatment of diabetes","volume":"22","year":"2008","journal-title":"Phytopharmacol. Ther. Values IV"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1515\/pjfns-2017-0023","article-title":"The effect of quercetin on bone mineral status and markers of bone turnover in retinoic acid-induced osteoporosis","volume":"68","author":"Nemrava","year":"2018","journal-title":"Pol. J. Food Nutr. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"209","DOI":"10.11138\/ccmbm\/2017.14.1.209","article-title":"Oxidative stress in bone remodeling: Role of antioxidants","volume":"14","author":"Domazetovic","year":"2017","journal-title":"Clin. Cases Miner Bone Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.fitote.2013.12.007","article-title":"Inhibitory effect of a propolis on Di-n-Propyl Disulfide or n-Hexyl salicilate-induced skin irritation, oxidative stress and inflammatory responses in mice","volume":"93","year":"2014","journal-title":"Fitoterapia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cbi.2016.06.027","article-title":"Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid","volume":"256","author":"Kukolj","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1177\/0960327112472993","article-title":"Quercetin vs. chrysin: Effect on liver histopathology in diabetic mice","volume":"2","author":"Sirovina","year":"2013","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1007\/s10534-014-9792-x","article-title":"Effects of copper overload in P19 neurons: Impairment of glutathione redox homeostasis and crosstalk between caspase and calpain protease systems in ROS-induced apoptosis","volume":"27","author":"Jembrek","year":"2014","journal-title":"Biometals"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1515\/acph-2016-0033","article-title":"Olive leaf extract activity against Candida albicans and C. dubliniensis\u2014the in vitro viability study","volume":"66","author":"Kopjar","year":"2016","journal-title":"Acta Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1111\/jcmm.12413","article-title":"Role of inflammation and oxidative stress in post-menopausal oestrogen-dependent breast cancer","volume":"18","author":"Madeddu","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1016\/j.biotechadv.2018.03.014","article-title":"Dietary nutraceuticals as backbone for bone health","volume":"36","author":"Pandey","year":"2018","journal-title":"Biotechnol. Adv."},{"key":"ref_24","first-page":"279","article-title":"Oxidative stress and inflammation caused by n-Hexyl salicylate in mouse skin: The effectiveness of flavonoids","volume":"9","author":"Balta","year":"2017","journal-title":"Int. J. Phytomed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s13238-013-3003-3","article-title":"Chrysin promotes osteogenic differentiation via ERK\/MAPK activation","volume":"4","author":"Zeng","year":"2013","journal-title":"Protein Cell"},{"key":"ref_26","first-page":"938574","article-title":"The effects of tualang honey on bone metabolism of postmenopausal women","volume":"2012","author":"Mohamed","year":"2012","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jep.2011.09.034","article-title":"Double directional adjusting estrogenic effect of naringin from Rhizoma drynariae (Gusuibu)","volume":"138","author":"Guo","year":"2011","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.phymed.2011.01.022","article-title":"Osteogenic effects of flavonoid aglycones from an osteoprotective fraction of Drynaria fortunei--an in vitro efficacy study","volume":"18","author":"Wang","year":"2011","journal-title":"Phytomedicine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1081\/ERC-120018674","article-title":"Effects of Different Nylestriol\/Levonorgestrel Dosages on Bone Metabolism in Female Sprague\u2013Dawley Rats with Retinoic Acid-Induced Osteoporosis","volume":"29","author":"Liao","year":"2003","journal-title":"Endocr. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jds.2016.03.011","article-title":"The effect of boron on alveolar bone loss in osteoporotic rats","volume":"11","author":"Toker","year":"2016","journal-title":"J. Dent. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3389\/fimmu.2018.00657","article-title":"Immunoporosis: Immunology of Osteoporosis-Role of T Cells","volume":"9","author":"Srivastava","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"552","DOI":"10.4049\/jimmunol.166.1.552","article-title":"The chemokine RANTES is a crucial mediator of the progression from acute to chronic colitis in the rat","volume":"166","author":"Ajuebor","year":"2001","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2147\/IJGM.S152873","article-title":"The vitamin D receptor and the etiology of RANTES\/CCL-expressive fatty-degenerative osteolysis of the jawbone: An interface between osteoimmunology and bone metabolism","volume":"11","author":"Lechner","year":"2018","journal-title":"Int. J. Gen. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00223-017-0339-3","article-title":"Prebiotics, bone and mineral metabolism","volume":"102","author":"Whisner","year":"2017","journal-title":"Calcif. Tissue Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s11914-015-0292-x","article-title":"Prebiotic and probiotic regulation of bone health: Role of the intestine and its microbiome","volume":"13","author":"McCabe","year":"2015","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1196\/annals.1402.081","article-title":"Transcriptional regulation of osteoblasts","volume":"1116","author":"Franceschi","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1677\/JOE-07-0282","article-title":"Chrysin, a natural flavonoid enhances steroidogenesis and steroidogenic acute regulatory protein gene expression in mouse Leydig cells","volume":"197","author":"Jana","year":"2008","journal-title":"J. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.2147\/CIA.S115472","article-title":"A concise review of testosterone and bone health","volume":"11","author":"Mohamad","year":"2016","journal-title":"Clin. Interv. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/j.1742-7843.2004.pto_940106.x","article-title":"The citrus-derived flavonoid naringenin exerts uterotrophic effects in female mice at human relevant doses","volume":"94","author":"Breinholt","year":"2004","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1097\/MOL.0b013e32835c07fd","article-title":"Citrus flavonoids and lipid metabolism","volume":"24","author":"Assini","year":"2013","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"404","DOI":"10.3945\/an.113.005603","article-title":"Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action","volume":"5","author":"Alam","year":"2014","journal-title":"Adv. Nutr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1024\/0300-9831.73.2.101","article-title":"Non-nutritive bioactive food constituents of plants: Bioavailability of flavonoids","volume":"73","author":"Rasmussen","year":"2003","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/jn\/131.2.235","article-title":"Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice","volume":"131","author":"Erlund","year":"2001","journal-title":"J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"49","DOI":"10.4137\/ACI.S39739","article-title":"Extraction of Honey Polyphenols: Method Development and Evidence of Cis Isomerization","volume":"11","author":"Istasse","year":"2016","journal-title":"Anal. Chem. Insights"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"337","DOI":"10.12980\/APJTB.4.2014C1262","article-title":"Review of the anticancer activities of bee products","volume":"4","author":"Premratanachai","year":"2014","journal-title":"Asian Pac. J. Trop. Biomed."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1559325817711782","DOI":"10.1177\/1559325817711782","article-title":"Protective Effects of Chrysin Against Drugs and Toxic Agents","volume":"15","author":"Samarghandian","year":"2017","journal-title":"Dose-Response"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"316134","DOI":"10.1155\/2014\/316134","article-title":"Association between postmenopausal osteoporosis and experimental periodontitis","volume":"2014","author":"Luo","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1159\/000510031","article-title":"The Effect of Isotretinoin on Oocyte Maturation in Adolescent Female Rats","volume":"85","author":"Kacamak","year":"2020","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.rbmo.2013.04.010","article-title":"Decreased ovarian reserve in female Sprague\u2013Dawley rats induced by isotretinoin (retinoic acid) exposure","volume":"27","author":"Abali","year":"2013","journal-title":"Reprod. BioMed. Online"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/ki.2008.356","article-title":"Bisphosphonate Nephrotoxicity","volume":"74","author":"Perazzella","year":"2008","journal-title":"Kidney Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1177\/2040622315584114","article-title":"Atypical femoral fractures and bisphosphonate use: Current evidence and clinical implications","volume":"6","author":"Saita","year":"2015","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1002\/jbmr.1645","article-title":"Oral alendronate use and risk of cancer in postmenopausal women with osteoporosis: A nationwide study","volume":"27","author":"Chiang","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.intimp.2006.09.009","article-title":"Histidine decarboxylase-stimulating and inflammatory effects of alendronate in mice: Involvement of mevalonate pathway, TNFalpha, macrophages, and T-cells","volume":"7","author":"Deng","year":"2007","journal-title":"Int. Immunopharmacol."},{"key":"ref_54","first-page":"35","article-title":"The effects of sustained delivery of alendronate on the kidney in ovariectomized female rats","volume":"48","author":"Benghuzzi","year":"2012","journal-title":"Biomed. Sci. Instrum."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s13730-014-0132-3","article-title":"Alendronate associated focal segmental glomerulosclerosis: A case report and review of the literature","volume":"4","author":"Garimella","year":"2015","journal-title":"CEN Case Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s00198-007-0540-8","article-title":"Mechanisms of action of bisphosphonates: Similarities and differences and their potential influence on clinical efficacy","volume":"19","author":"Russell","year":"2008","journal-title":"Osteoporos. Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2872\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:32:53Z","timestamp":1760135573000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2872"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,6]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052872"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052872","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,6]]}}}