{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:07:30Z","timestamp":1790683650238,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T00:00:00Z","timestamp":1686009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"French National Research Agency","award":["ANR-11-LABX-0021"],"award-info":[{"award-number":["ANR-11-LABX-0021"]}]},{"name":"\u201cConseil R\u00e9gional de Bourgogne\u201d and \u201cFonds Europ\u00e9en de D\u00e9veloppement R\u00e9gional\u201d (FEDER)","award":["ANR-11-LABX-0021"],"award-info":[{"award-number":["ANR-11-LABX-0021"]}]},{"name":"Tunisian Higher Education and Scientific Research Ministry","award":["ANR-11-LABX-0021"],"award-info":[{"award-number":["ANR-11-LABX-0021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Despite the progress made in treatments, melanoma is one of the cancers for which its incidence and mortality have increased during recent decades. In the research of new therapeutic strategies, natural polyphenols such as chrysin could be good candidates owing to their capacities to modulate the different fundamental aspects of tumorigenesis and resistance mechanisms, such as oxidative stress and neoangiogenesis. In the present study, we sought to determine whether chrysin could exert antitumoral effects via the modulation of angiogenesis by acting on oxidative stress and associated DNA damage. For the first time, we show a link between chrysin-induced antiproliferative effects, the activation of the DNA damage pathway, and its ability to limit angiogenesis. More specifically, herein, we show that chrysin induces single- and double-stranded DNA breaks via the activation of the DNA damage response pathway: ATM (ataxia-telangiectasia-mutated)\/Chk2 (checkpoint kinase 2) and ATR (ataxia telangiectasia and Rad3-related)\/Chk1 (checkpoint kinase 1) pathways. Strong activation of this DNA damage response was found to be partly involved in the ability of chrysin to limit angiogenesis and may partly involve a direct interaction between the polyphenol and DNA G-quadruplex structures responsible for the replication fork collapse. Moreover, these events were associated with a marked reduction in melanoma cells\u2019 capacity to secrete proangiogenic factor VEGF-A. The disruption of these key protein actors in tumor growth by chrysin was also confirmed in a syngeneic model of B16 melanoma. This last point is of importance to further consider the use of chrysin as a new therapeutic strategy in melanoma treatment.<\/jats:p>","DOI":"10.3390\/cells12121561","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T13:42:06Z","timestamp":1686058926000},"page":"1561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Chrysin-Induced Regression of Angiogenesis via an Induction of DNA Damage Response and Oxidative Stress in In Vitro and In Vivo Models of Melanoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Aicha","family":"Sassi","sequence":"first","affiliation":[{"name":"UFR Sciences de Sant\u00e9, Universit\u00e9 de Bourgogne, 21000 Dijon, France"},{"name":"INSERM Research Center U1231\u2014Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France"},{"name":"Research Unit Bioactive Natural Products and Biotechnology UR17ES49, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Fredon","sequence":"additional","affiliation":[{"name":"UFR Sciences de Sant\u00e9, Universit\u00e9 de Bourgogne, 21000 Dijon, France"},{"name":"INSERM Research Center U1231\u2014Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexia K.","family":"Cotte","sequence":"additional","affiliation":[{"name":"UFR Sciences de Sant\u00e9, Universit\u00e9 de Bourgogne, 21000 Dijon, France"},{"name":"INSERM Research Center U1231\u2014Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Fuselier","sequence":"additional","affiliation":[{"name":"Facult\u00e9 des Sciences Exactes et Naturelles, UMR CNRS 7369 MEDyC, Universit\u00e9 de Reims Champagne Ardenne, 51687 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7867-0579","authenticated-orcid":false,"given":"Christophe","family":"Schneider","sequence":"additional","affiliation":[{"name":"Facult\u00e9 des Sciences Exactes et Naturelles, UMR CNRS 7369 MEDyC, Universit\u00e9 de Reims Champagne Ardenne, 51687 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4667-2860","authenticated-orcid":false,"given":"Laurent","family":"Martiny","sequence":"additional","affiliation":[{"name":"Facult\u00e9 des Sciences Exactes et Naturelles, UMR CNRS 7369 MEDyC, Universit\u00e9 de Reims Champagne Ardenne, 51687 Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Monchaud","sequence":"additional","affiliation":[{"name":"UFR Sciences de Sant\u00e9, Universit\u00e9 de Bourgogne, 21000 Dijon, France"},{"name":"Institut de Chimie Mol\u00e9culaire (ICMUB), CNRS UMR6302, UBFC, 21078 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Chekir-Ghedira","sequence":"additional","affiliation":[{"name":"Research Unit Bioactive Natural Products and Biotechnology UR17ES49, Faculty of Dental Medicine of Monastir, University of Monastir, Avicenne Street, Monastir 5000, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9331-5014","authenticated-orcid":false,"given":"Virginie","family":"Aires","sequence":"additional","affiliation":[{"name":"UFR Sciences de Sant\u00e9, Universit\u00e9 de Bourgogne, 21000 Dijon, France"},{"name":"INSERM Research Center U1231\u2014Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8911-8499","authenticated-orcid":false,"given":"Dominique","family":"Delmas","sequence":"additional","affiliation":[{"name":"UFR Sciences de Sant\u00e9, Universit\u00e9 de Bourgogne, 21000 Dijon, France"},{"name":"INSERM Research Center U1231\u2014Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, 21000 Dijon, France"},{"name":"Centre de Lutte Contre le Cancer Georges Fran\u00e7ois Leclerc Center, 21000 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrd2060","article-title":"Therapeutic potential of resveratrol: The in vivo evidence","volume":"5","author":"Baur","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.semcancer.2017.07.002","article-title":"Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment","volume":"46","author":"Pandey","year":"2017","journal-title":"Semin. Cancer Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ko, J.H., Sethi, G., Um, J.Y., Shanmugam, M.K., Arfuso, F., Kumar, A.P., Bishayee, A., and Ahn, K.S. (2017). The Role of Resveratrol in Cancer Therapy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122589"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1089\/ars.2017.7404","article-title":"Mitochondria-centric Review of Polyphenol Bioactivity in Cancer Models","volume":"29","author":"Stevens","year":"2017","journal-title":"Antioxid. Redox. Signal"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.toxlet.2015.01.008","article-title":"Chemopreventive and therapeutic potential of chrysin in cancer: Mechanistic perspectives","volume":"233","author":"Kasala","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2174\/1389201016666150118132457","article-title":"Common pathways in health benefit properties of RSV in cardiovascular diseases, cancers and degenerative pathologies","volume":"16","author":"Aires","year":"2015","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/mnfr.201200766","article-title":"Resveratrol metabolites inhibit human metastatic colon cancer cells progression and synergize with chemotherapeutic drugs to induce cell death","volume":"57","author":"Aires","year":"2013","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Aggarwal, V., Tuli, H.S., Varol, A., Thakral, F., Yerer, M.B., Sak, K., Varol, M., Jain, A., Khan, M.A., and Sethi, G. (2019). Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements. Biomolecules, 9.","DOI":"10.3390\/biom9110735"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1515\/hsz-2018-0327","article-title":"Oxidative stress and antioxidants in the pathophysiology of malignant melanoma","volume":"400","author":"Obrador","year":"2019","journal-title":"Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"481782","DOI":"10.1155\/2015\/481782","article-title":"Cellular Mechanisms of Oxidative Stress and Action in Melanoma","volume":"2015","author":"Venza","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R646","DOI":"10.1152\/ajpregu.00247.2017","article-title":"The differential role of reactive oxygen species in early and late stages of cancer","volume":"313","author":"Assi","year":"2017","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_13","first-page":"473","article-title":"Chrysin-induced apoptosis is mediated through p38 and Bax activation in B16-F1 and A375 melanoma cells","volume":"38","author":"Pichichero","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1002\/jcp.25861","article-title":"Chrysin induces death of prostate cancer cells by inducing ROS and ER stress","volume":"232","author":"Ryu","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.taap.2011.08.004","article-title":"Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: The role of glutathione","volume":"258","author":"Brechbuhl","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1158\/1535-7163.MCT-06-0526","article-title":"Chrysin inhibits expression of hypoxia-inducible factor-1alpha through reducing hypoxia-inducible factor-1alpha stability and inhibiting its protein synthesis","volume":"6","author":"Fu","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sioud, F., Amor, S., Toumia, I.B., Lahmar, A., Aires, V., Chekir-Ghedira, L., and Delmas, D. (2020). A New Highlight of Ephedra alata Decne Properties as Potential Adjuvant in Combination with Cisplatin to Induce Cell Death of 4T1 Breast Cancer Cells In Vitro and In Vivo. Cells, 9.","DOI":"10.3390\/cells9020362"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1002\/ijc.24264","article-title":"Effects of resveratrol analogs on cell cycle progression, cell cycle associated proteins and 5fluoro-uracil sensitivity in human derived colon cancer cells","volume":"124","author":"Colin","year":"2009","journal-title":"Int. J. Cancer."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/s41467-017-02732-5","article-title":"Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance","volume":"9","author":"Cotte","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.biochi.2008.02.019","article-title":"Ligands playing musical chairs with G-quadruplex DNA: A rapid and simple displacement assay for identifying selective G-quadruplex binders","volume":"90","author":"Monchaud","year":"2008","journal-title":"Biochimie"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17574","DOI":"10.1038\/srep17574","article-title":"Structural Insight into the interaction of Flavonoids with Human Telomeric Sequence","volume":"5","author":"Tawani","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cbi.2017.11.022","article-title":"Chrysin, a natural and biologically active flavonoid suppresses tumor growth of mouse B16F10 melanoma cells: In vitro and In vivo study","volume":"283","author":"Sassi","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1080\/21691401.2018.1452021","article-title":"Effects of nano-encapsulated curcumin-chrysin on telomerase, MMPs and TIMPs gene expression in mouse B16F10 melanoma tumour model","volume":"46","author":"Tavakoli","year":"2018","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e1533","DOI":"10.1038\/cddis.2014.486","article-title":"The role of reactive oxygen species and subsequent DNA-damage response in the emergence of resistance towards resveratrol in colon cancer models","volume":"5","author":"Colin","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"423","DOI":"10.2174\/138945006776359331","article-title":"Resveratrol as a chemopreventive agent: A promising molecule for fighting cancer","volume":"7","author":"Delmas","year":"2006","journal-title":"Curr. Drug Targets"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"920161","DOI":"10.4061\/2010\/920161","article-title":"H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy","volume":"2010","author":"Podhorecka","year":"2010","journal-title":"J. Nucleic Acids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/978-1-61779-998-3_40","article-title":"Histone H2AX phosphorylation: A marker for DNA damage","volume":"920","author":"Sharma","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lerner, L.K., and Sale, J.E. (2019). Replication of G Quadruplex DNA. Genes, 10.","DOI":"10.3390\/genes10020095"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1039\/D0CB00151A","article-title":"DNA folds threaten genetic stability and can be leveraged for chemotherapy","volume":"2","author":"Zell","year":"2021","journal-title":"RSC Chem. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5987","DOI":"10.1021\/acs.jmedchem.5b01835","article-title":"Quadruplex Nucleic Acids as Novel Therapeutic Targets","volume":"59","author":"Neidle","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nm.1947","article-title":"Histone H2AX is integral to hypoxia-driven neovascularization","volume":"15","author":"Economopoulou","year":"2009","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.fitote.2013.09.016","article-title":"Flavonoids from the leaves of Carya cathayensis Sarg. inhibit vascular endothelial growth factor-induced angiogenesis","volume":"92","author":"Tian","year":"2014","journal-title":"Fitoterapia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/mnfr.200800021","article-title":"Correlation between antiangiogenic activity and antioxidant activity of various components from propolis","volume":"53","author":"Ahn","year":"2009","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7082","DOI":"10.1021\/jf100421w","article-title":"Chrysin suppresses IL-6-induced angiogenesis via down-regulation of JAK1\/STAT3 and VEGF: An in vitro and in ovo approach","volume":"58","author":"Lin","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1055\/s-2006-931602","article-title":"Chrysin inhibits lipopolysaccharide-induced angiogenesis via down-regulation of VEGF\/VEGFR-2(KDR) and IL-6\/IL-6R pathways","volume":"72","author":"Lin","year":"2006","journal-title":"Planta Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"673002","DOI":"10.3389\/fgene.2021.673002","article-title":"Linking Oxidative Stress and DNA Damage to Changes in the Expression of Extracellular Matrix Components","volume":"12","author":"Martins","year":"2021","journal-title":"Front. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"765","DOI":"10.2741\/matsumur","article-title":"Molecular mechanisms of photocarcinogenesis","volume":"7","author":"Matsumura","year":"2002","journal-title":"Front. Biosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.semcancer.2004.06.005","article-title":"The epigenetics of cancer etiology","volume":"14","author":"Feinberg","year":"2004","journal-title":"Semin. Cancer Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.lfs.2017.02.011","article-title":"Towards therapeutic advances in melanoma management: An overview","volume":"174","author":"Singh","year":"2017","journal-title":"Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrclinonc.2017.43","article-title":"Targeted agents and immunotherapies: Optimizing outcomes in melanoma","volume":"14","author":"Luke","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.clindermatol.2012.08.016","article-title":"Chemotherapy in the management of advanced cutaneous malignant melanoma","volume":"31","author":"Luke","year":"2013","journal-title":"Clin. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1080\/15384101.2021.2020434","article-title":"Chrysin impairs genomic stability by suppressing DNA double-strand break repair in breast cancer cells","volume":"21","author":"Geng","year":"2022","journal-title":"Cell Cycle"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Nagasaka, M., Hashimoto, R., Inoue, Y., Ishiuchi, K., Matsuno, M., Itoh, Y., Tokugawa, M., Ohoka, N., Morishita, D., and Mizukami, H. (2018). Anti-Tumorigenic Activity of Chrysin from Oroxylum indicum via Non-Genotoxic p53 Activation through the ATM-Chk2 Pathway. Molecules, 23.","DOI":"10.3390\/molecules23061394"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1093\/mutage\/geaa021","article-title":"Toxicogenetic and antiproliferative effects of chrysin in urinary bladder cancer cells","volume":"35","author":"Lima","year":"2020","journal-title":"Mutagenesis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e13747","DOI":"10.1111\/and.13747","article-title":"Protective role of chrysin on doxorubicin-induced oxidative stress and DNA damage in rat testes","volume":"52","author":"Belhan","year":"2020","journal-title":"Andrologia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nrm.2017.3","article-title":"DNA G-quadruplexes in the human genome: Detection, functions and therapeutic potential","volume":"18","author":"Balasubramanian","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.2174\/0929867324666170124145557","article-title":"DNA-Damaging Anticancer Drugs\u2014A Perspective for DNA Repair-Oriented Therapy","volume":"24","author":"Blasiak","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/nm.2846","article-title":"Pathological neoangiogenesis depends on oxidative stress regulation by ATM","volume":"18","author":"Okuno","year":"2012","journal-title":"Nat. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/12\/1561\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:49:04Z","timestamp":1760125744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/12\/1561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,6]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["cells12121561"],"URL":"https:\/\/doi.org\/10.3390\/cells12121561","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,6]]}}}