{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T20:54:45Z","timestamp":1780433685835,"version":"3.54.1"},"reference-count":49,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["PID2020-114871RB-I00"],"award-info":[{"award-number":["PID2020-114871RB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["20190271"],"award-info":[{"award-number":["20190271"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["PI20\/01363"],"award-info":[{"award-number":["PI20\/01363"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministry of Science and Innovation","doi-asserted-by":"publisher","award":["CB06\/06\/0027"],"award-info":[{"award-number":["CB06\/06\/0027"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Instituto de Salud Carlos III","award":["PID2020-114871RB-I00"],"award-info":[{"award-number":["PID2020-114871RB-I00"]}]},{"name":"Instituto de Salud Carlos III","award":["20190271"],"award-info":[{"award-number":["20190271"]}]},{"name":"Instituto de Salud Carlos III","award":["PI20\/01363"],"award-info":[{"award-number":["PI20\/01363"]}]},{"name":"Instituto de Salud Carlos III","award":["CB06\/06\/0027"],"award-info":[{"award-number":["CB06\/06\/0027"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Solar radiation can cause damage to the skin, leading to various adverse effects such as sunburn, reactive oxygen species production, inflammation, DNA damage, and photoaging. To study the potential of photoprotective agents, full-thickness skin models are increasingly being used as in vitro tools. One promising approach to photoprotection involves targeting the redox-sensitive transcription factor Nrf2, which is responsible for regulating various cellular defense mechanisms, including the antioxidant response, inflammatory signaling, and DNA repair. Obacunone, a natural triterpenoid, has been identified as a potent Nrf2 agonist. The present study aims to evaluate the relevance of full-thickness (FT) skin models in photoprotection studies and to explore the potential photoprotective effects of obacunone on those models and in human keratinocytes. Phenion\u00ae full-thickness skin models and keratinocytes were incubated with increasing concentrations of obacunone and irradiated with solar-simulated radiation (SSR). Various photodamage markers were evaluated, including histological integrity, oxidative stress, apoptosis, inflammation, photoaging-related dermal markers, and photocarcinogenesis markers. Increasing doses of SSR were found to modulate various biomarkers related to sun damage in the FT skin models. However, obacunone attenuated cytotoxicity, inflammation, oxidative stress, sunburn reaction, photoaging, and photocarcinogenesis in both keratinocytes and full thickness skin models exposed to SSR. These results suggest that obacunone may have potential as a photoprotective agent for preventing the harmful effects of solar radiation on the skin.<\/jats:p>","DOI":"10.3390\/ijms241411484","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:35:04Z","timestamp":1689554104000},"page":"11484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Obacunone Photoprotective Effects against Solar-Simulated Radiation\u2013Induced Molecular Modifications in Primary Keratinocytes and Full-Thickness Human Skin"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5929-5486","authenticated-orcid":false,"given":"Paula","family":"Montero","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"},{"name":"Faculty of Health Sciences, Universidad Europea de Valencia, 46185 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jos\u00e9","family":"Villarroel","sequence":"additional","affiliation":[{"name":"Department of Functional Biology and Physical Anthropology, Faculty of Biological Sciences, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7741-6600","authenticated-orcid":false,"given":"In\u00e9s","family":"Roger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"},{"name":"Faculty of Health Sciences, Universidad Europea de Valencia, 46185 Valencia, Spain"},{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anselm","family":"Morell","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, 50005 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6033-4211","authenticated-orcid":false,"given":"Javier","family":"Milara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"},{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain"},{"name":"Pharmacy Unit, University General Hospital Consortium, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Cortijo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"},{"name":"Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Health Institute Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/joa.12942","article-title":"Bioengineering the microanatomy of human skin","volume":"234","author":"Roger","year":"2019","journal-title":"J. Anat."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Marzo, N., P\u00e9rez-S\u00e1nchez, A., Ruiz-Torres, V., Mart\u00ednez-T\u00e9bar, A., Castillo, J., Herranz-L\u00f3pez, M., and Barraj\u00f3n-Catal\u00e1n, E. (2019). Antioxidant and Photoprotective Activity of Apigenin and its Potassium Salt Derivative in Human Keratinocytes and Absorption in Caco-2 Cell Monolayers. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092148"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wang, S.Q., and Lim, H.W. (2016). Principles and Practice of Photoprotection, Springer International Publishing.","DOI":"10.1007\/978-3-319-29382-0"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1562\/0031-8655(2000)071<0314:EOTPEO>2.0.CO;2","article-title":"Evaluation of the protective effect of sunscreens on in vitro reconstructed human skin exposed to UVB or UVA irradiation","volume":"71","author":"Bernerd","year":"2000","journal-title":"Photochem. Photobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3390\/ijms16010068","article-title":"Exposure to Non-Extreme Solar UV Daylight: Spectral Characterization, Effects on Skin and Photoprotection","volume":"16","author":"Marionnet","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1101\/gad.568810","article-title":"Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis","volume":"24","author":"Navid","year":"2010","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4103\/0378-6323.97351","article-title":"Solar ultraviolet radiation induces biological alterations in human skin in vitro: Relevance of a well-balanced UVA\/UVB protection","volume":"78","author":"Bernerd","year":"2012","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1039\/b9pp00164f","article-title":"Molecular modifications of dermal and epidermal biomarkers following UVA exposures on reconstructed full-thickness human skin","volume":"9","author":"Meloni","year":"2010","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S155","DOI":"10.1016\/j.jaad.2007.08.050","article-title":"An organotypic model of skin to study photodamage and photoprotection in vitro","volume":"58","author":"Bernerd","year":"2008","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"De la Vega, M.R., Krajisnik, A., Zhang, D.D., and Wondrak, G.T. (2017). Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin. Nutrients, 9.","DOI":"10.3390\/nu9121371"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1046\/j.1523-1747.2003.12355.x","article-title":"Dietary Lutein\/Zeaxanthin Decreases Ultraviolet B-Induced Epidermal Hyperproliferation and Acute Inflammation in Hairless Mice","volume":"121","author":"Astner","year":"2003","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s00403-009-1001-3","article-title":"Skin photoprotection by natural polyphenols: Anti-inflammatory, antioxidant and DNA repair mechanisms","volume":"302","author":"Nichols","year":"2009","journal-title":"Arch. Dermatol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Alberts, D., and Hess, L.M. (2014). Fundamentals of Cancer Prevention, Springer.","DOI":"10.1007\/978-3-642-38983-2"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/mc.20725","article-title":"Impact of Nrf2 on UVB-induced skin inflammation\/photoprotection and photoprotective effect of sulforaphane: Photoprotection of Nrf2 and sulforaphane","volume":"50","author":"Saw","year":"2011","journal-title":"Mol. Carcinog."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7021428","DOI":"10.1155\/2019\/7021428","article-title":"Nrf2 Overexpression for the Protective Effect of Skin-Derived Precursors against UV-Induced Damage: Evidence from a Three-Dimensional Skin Model","volume":"2019","author":"Xian","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.redox.2013.10.004","article-title":"The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV","volume":"1","author":"Tao","year":"2013","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3389\/fphar.2018.00287","article-title":"Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.bbrc.2019.03.201","article-title":"Obacunone attenuates high glucose-induced oxidative damage in NRK-52E cells by inhibiting the activity of GSK-3\u03b2","volume":"513","author":"Zhou","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bai, Y., Wang, W., Wang, L., Ma, L., Zhai, D., Wang, F., Shi, R., Liu, C., Xu, Q., and Chen, G. (2021). Obacunone Attenuates Liver Fibrosis with Enhancing Anti-Oxidant Effects of GPx-4 and Inhibition of EMT. Molecules, 26.","DOI":"10.3390\/molecules26020318"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/jcb.26248","article-title":"Obacunone causes sustained expression of MKP-1 thus inactivating p38 MAPK to suppress pro-inflammatory mediators through intracellular MIF","volume":"119","author":"Gao","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11010","DOI":"10.18632\/aging.202437","article-title":"Obacunone protects retinal pigment epithelium cells from ultra-violet radiation-induced oxidative injury","volume":"13","author":"Huang","year":"2021","journal-title":"Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/ics.12518","article-title":"Validation of a predictive method for sunscreen formula evaluation using gene expression analysis in a Chinese reconstructed full-thickness skin model","volume":"41","author":"Liu","year":"2019","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_23","first-page":"199","article-title":"Organotypic models for evaluating sunscreens","volume":"I","author":"Marionnet","year":"2016","journal-title":"Princ. Pract. Photoprotection"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1093\/carcin\/bgm065","article-title":"Conjugated linoleic acids modulate UVR-induced IL-8 and PGE2 in human skin cells: Potential of CLA isomers in nutritional photoprotection","volume":"28","author":"Storey","year":"2007","journal-title":"Carcinogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/phpp.12297","article-title":"Protective effects of Polypodium leucotomos extract against UVB-induced damage in a model of reconstructed human epidermis","volume":"33","author":"Torricelli","year":"2017","journal-title":"Photodermatol. Photoimmunol. Photomed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1034\/j.1600-0625.12.s2.10.x","article-title":"The use of reconstructed human skin to evaluate UV-induced modifications and sunscreen efficacy","volume":"12","author":"Duval","year":"2003","journal-title":"Exp. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1136\/jcp.55.11.829","article-title":"Comparison of the expression of p53, p21, Bax and the induction of apoptosis between patients with basal cell carcinoma and normal controls in response to ultraviolet irradiation","volume":"55","author":"Murphy","year":"2002","journal-title":"J. Clin. Pathol."},{"key":"ref_28","unstructured":"(2023, June 19). Acute response of human skin to solar radiation: Regulation and function of the p53 protein\u2014ScienceDirect. Available online: https:\/\/www.sciencedirect.com\/science\/article\/pii\/S1011134401002044?via%3Dihub."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.aquatox.2015.12.025","article-title":"Increased p53 and decreased p21 accompany apoptosis induced by ultraviolet radiation in the nervous system of a crustacean","volume":"173","author":"Hollmann","year":"2016","journal-title":"Aquat. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/jcp.10392","article-title":"Resistance to UV-induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53","volume":"198","author":"Chaturvedi","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1039\/c0pp00244e","article-title":"UVB-Induced p21 degradation promotes apoptosis of human keratinocytes","volume":"9","author":"Lei","year":"2010","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"86","DOI":"10.12659\/MSMBR.893608","article-title":"The Role of p21 in Apoptosis, Proliferation, Cell Cycle Arrest, and Antioxidant Activity in UVB-Irradiated Human HaCaT Keratinocytes","volume":"21","author":"Gao","year":"2015","journal-title":"Med. Sci. Monit. Basic Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1039\/b9pp00145j","article-title":"In vitro tools for photobiological testing: Molecular responses to simulated solar UV of keratinocytes growing as monolayers or as part of reconstructed skin","volume":"9","author":"Marrot","year":"2010","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1562\/0031-8655(2003)078<0043:MMITMC>2.0.CO;2","article-title":"Matrix metalloproteinase-1 is the major collagenolytic enzyme responsible for collagen damage in UV-irradiated human skin","volume":"78","author":"Brennan","year":"2003","journal-title":"Photochem. Photobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/phpp.12717","article-title":"Stratum corneum biomarkers after in vivo repeated exposure to sub-erythemal dosages of ultraviolet radiation in unprotected and sunscreen (SPF 50+) protected skin","volume":"38","author":"Keurentjes","year":"2021","journal-title":"Photodermatol. Photoimmunol. Photomed."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3389\/fphar.2018.00392","article-title":"Natural Antioxidants: Multiple Mechanisms to Protect Skin From Solar Radiation","volume":"9","author":"Dunaway","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1136\/jim-2021-001972","article-title":"Protective Effects of Sunscreen (50+) and Octatrienoic Acid 0.1% in Actinic Keratosis and UV Damages","volume":"70","author":"Pinto","year":"2022","journal-title":"J. Investig. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.freeradbiomed.2022.06.238","article-title":"NRF2 in dermatological disorders: Pharmacological activation for protection against cutaneous photodamage and photodermatosis","volume":"188","author":"Kahremany","year":"2022","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1038\/sj.jid.5701245","article-title":"Attenuation of UVB-Induced Sunburn Reaction and Oxidative DNA Damage with no Alterations in UVB-Induced Skin Carcinogenesis in Nrf2 Gene-Deficient Mice","volume":"128","author":"Kawachi","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101206","DOI":"10.1016\/j.redox.2019.101206","article-title":"Protective effects of novel derivatives of vitamin D3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and p53 defense mechanisms","volume":"24","author":"Chaiprasongsuk","year":"2019","journal-title":"Redox Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1080\/09553002.2021.1962566","article-title":"Effect of ultraviolet radiation on the Nrf2 signaling pathway in skin cells","volume":"97","year":"2021","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Marionnet, C., Pierrard, C., Golebiewski, C., and Bernerd, F. (2014). Diversity of Biological Effects Induced by Longwave UVA Rays (UVA1) in Reconstructed Skin. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105263"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Marionnet, C., Pierrard, C., Lejeune, F., Sok, J., Thomas, M., and Bernerd, F. (2010). Different Oxidative Stress Response in Keratinocytes and Fibroblasts of Reconstructed Skin Exposed to Non Extreme Daily-Ultraviolet Radiation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012059"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S1011-1344(01)00217-2","article-title":"Effects of solar radiation on cutaneous detoxification pathways","volume":"63","author":"Afaq","year":"2001","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"999","DOI":"10.3109\/09553002.2010.501842","article-title":"Solar radiation induced skin damage: Review of protective and preventive options","volume":"86","year":"2010","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/S0891-5849(00)00463-9","article-title":"Adaptive antioxidant response protects dermal fibroblasts from UVA-induced phototoxicity","volume":"30","author":"Meewes","year":"2001","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1159\/000489369","article-title":"Rapamycin Protects Skin Fibroblasts from Ultraviolet B-Induced Photoaging by Suppressing the Production of Reactive Oxygen Species","volume":"46","author":"Qin","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_48","unstructured":"OECD (2023, February 13). Test No. 442D: In Vitro Skin Sensitisation. Available online: https:\/\/www.oecd-ilibrary.org\/content\/publication\/9789264229822-en."},{"key":"ref_49","first-page":"69","article-title":"Statistics corner: A guide to appropriate use of correlation coefficient in medical research","volume":"24","author":"Mukaka","year":"2012","journal-title":"Malawi Med. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/14\/11484\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:12:25Z","timestamp":1760127145000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/14\/11484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,14]]},"references-count":49,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["ijms241411484"],"URL":"https:\/\/doi.org\/10.3390\/ijms241411484","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,14]]}}}