{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:29:49Z","timestamp":1780637389824,"version":"3.54.1"},"reference-count":57,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T00:00:00Z","timestamp":1583193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>MicroRNAs (miRs) regulate complex processes, including angiogenesis, by targeting multiple mRNAs. miR-24-3p-3p directly represses eNOS, GATA2, and PAK4 in endothelial cells (ECs), thus inhibiting angiogenesis during development and in the infarcted heart. miR-24-3p is widely expressed in cardiovascular cells, suggesting that it could additionally regulate angiogenesis by acting on vascular mural cells. Here, we have investigated: (1) new miR-24-3p targets; (2) the expression and the function of miR-24-3p in human vascular ECs; (3) the impact of miR-24-3p inhibition in the angiogenesis reparative response to limb ischemia in mice. Using bioinformatics target prediction platforms and 3\u2032-UTR luciferase assays, we newly identified Notch1 and its Delta-like ligand 1 (Dll1) to be directly targeted by miR-24-3p. miR-24-3p was expressed in human ECs and pericytes cultured under normal conditions. Exposure to hypoxia increased miR-24-3p in ECs but not in pericytes. Transfection with a miR-24-3p precursor (pre-miR-24-3p) increased miR-24-3p expression in ECs, reducing the cell survival, proliferation, and angiogenic capacity. Opposite effects were caused by miR-24-3p inhibition. The anti-angiogenic action of miR-24-3p overexpression could be prevented by simultaneous adenovirus (Ad)-mediated delivery of constitutively active Notch intracellular domain (NICD) into cultured ECs. We next demonstrated that reduced Notch signalling contributes to the anti-angiogenic effect of miR-24-3p in vitro. In a mouse unilateral limb ischemia model, local miR-24-3p inhibition (by adenovirus-mediated miR-24-3p decoy delivery) restored endothelial Notch signalling and increased capillary density. However, the new vessels appeared disorganised and twisted, worsening post-ischemic blood perfusion recovery. To better understand the underpinning mechanisms, we widened the search for miR-24-3p target genes, identifying several contributors to vascular morphogenesis, such as several members of the Wingless (Wnt) signalling pathway, \u03b2-catenin signalling components, and VE-cadherin, which synergise to regulate angiogenesis, pericytes recruitment to neoformed capillaries, maturation, and stabilization of newly formed vessels. Among those, we next focussed on \u03b2-catenin to demonstrate that miR-24-3p inhibition reduces \u03b2-catenin expression in hypoxic ECs, which is accompanied by reduced adhesion of pericytes to ECs. In summary, miR-24-3p differentially targets several angiogenesis modulators and contributes to autonomous and non-autonomous EC crosstalk. In ischemic limbs, miR-24-3p inhibition increases the production of dysfunctional microvessels, impairing perfusion. Caution should be observed in therapeutic targeting of miR-24-3p.<\/jats:p>","DOI":"10.3390\/ijms21051733","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T13:06:23Z","timestamp":1583240783000},"page":"1733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["MicroRNA-24-3p Targets Notch and Other Vascular Morphogens to Regulate Post-ischemic Microvascular Responses in Limb Muscles"],"prefix":"10.3390","volume":"21","author":[{"given":"Micol","family":"Marchetti","sequence":"first","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6689-7381","authenticated-orcid":false,"given":"Marco","family":"Meloni","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Anwar","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2145-2925","authenticated-orcid":false,"given":"Ayman","family":"Al-Haj-Zen","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela","family":"Sala-Newby","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadie","family":"Slater","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerrie","family":"Ford","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Caporali","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"},{"name":"BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Emanueli","sequence":"additional","affiliation":[{"name":"Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK"},{"name":"National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: Genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"ref_2","first-page":"1","article-title":"Experimental identification of microRNA targets","volume":"451","author":"Lund","year":"2010","journal-title":"Gene"},{"key":"ref_3","first-page":"1426","article-title":"HypoxamiRs: Regulators of cardiac hypoxia and energy metabolism","volume":"12","author":"Leptidis","year":"2008","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1111\/j.1582-4934.2008.00398.x","article-title":"Hypoxia response and microRNAs: No longer two separate worlds","volume":"12","author":"Ivan","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1681\/ASN.2013121329","article-title":"MicroRNA-24 antagonism prevents renal ischemia reperfusion injury","volume":"25","author":"Lorenzen","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1161\/CIRCULATIONAHA.111.039008","article-title":"MicroRNA-24 regulates vascularity after myocardial infarction","volume":"124","author":"Fiedler","year":"2011","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/mt.2013.89","article-title":"Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodeling and function in mice with myocardial infarction","volume":"21","author":"Meloni","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8287","DOI":"10.1073\/pnas.1105254108","article-title":"Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23\u223c27\u223c24 clusters","volume":"108","author":"Zhoua","year":"2011","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1084\/jem.20101547","article-title":"miR-24 inhibits apoptosis and represses Bim in mouse cardiomyocytes","volume":"208","author":"Qian","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5214","DOI":"10.1038\/ncomms6214","article-title":"miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development","volume":"5","author":"Maegdefessel","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1002\/jcb.21523","article-title":"Vasculogenesis, Angiogenesis, and Arteriogenesis: Mechanisms of Blood Vessel Formation and Remodeling","volume":"102","author":"Semenza","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.12703\/P7-26","article-title":"Angiogenesis versus arteriogenesis: Neuropilin 1 modulation of VEGF signaling","volume":"7","author":"Kofler","year":"2015","journal-title":"F1000Prime Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13741","DOI":"10.1074\/jbc.M110.181842","article-title":"Vascular smooth muscle Notch signals regulate endothelial cell sensitivity to angiogenic stimulation","volume":"286","author":"Yang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1242\/dev.104422","article-title":"Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis","volume":"141","author":"Korn","year":"2014","journal-title":"Development"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrm3176","article-title":"Molecular control of endothelial cell behaviour during blood vessel morphogenesis","volume":"12","author":"Herbert","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1161\/CIRCRESAHA.111.263319","article-title":"Extrinsic Notch Ligand Delta-Like 1 Regulates Tip Cell Selection and Vascular Branching Morphogenesis","volume":"110","author":"Napp","year":"2012","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/nature05571","article-title":"Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis","volume":"445","author":"Phng","year":"2007","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1182\/blood-2007-09-112748","article-title":"Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos","volume":"112","author":"Trinidade","year":"2008","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1083\/jcb.200302047","article-title":"VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia","volume":"161","author":"Gerhardt","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_20","first-page":"9462","article-title":"VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells","volume":"9","author":"Shushy","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/mt.2009.70","article-title":"Trial Investigators. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: Results of the NORTHERN trial","volume":"17","author":"Stewart","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0008-6363(00)00281-9","article-title":"Molecular mechanisms of blood vessel growth","volume":"49","author":"Conway","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/37138","article-title":"Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling","volume":"390","author":"Slusarski","year":"1997","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.devcel.2008.12.009","article-title":"Nrarp Coordinates Endothelial Notch and Wnt Signaling to Control Vessel Density in Angiogenesis","volume":"1","author":"Phng","year":"2009","journal-title":"Dev. Cell."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2011.08.039","article-title":"Basic and Therapeutic Aspects of Angiogenesis","volume":"6","author":"Potente","year":"2011","journal-title":"Cell"},{"key":"ref_26","first-page":"131","article-title":"The Role of Wnt Signalling in Angiogenesis","volume":"38","author":"Olsen","year":"2017","journal-title":"Clin. Biochem Rev."},{"key":"ref_27","first-page":"1","article-title":"Wnt\/\u03b2-catenin coupled with HIF-1\u03b1\/VEGF signaling pathways involved in galangin neurovascular unit protection from focal cerebral ischemia","volume":"5","author":"Wu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1026522216059","article-title":"Cadherins as modulators of angiogenesis and the structural integrity of blood vessels","volume":"19","author":"Blaschuk","year":"2000","journal-title":"Cancer Metastasis Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e354","DOI":"10.1038\/mtna.2016.62","article-title":"The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b","volume":"5","author":"Li","year":"2016","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1038\/ncb3227","article-title":"Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity","volume":"17","author":"Kourtidis","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_31","first-page":"9","article-title":"Wnt\/beta-catenin signaling: Components, mechanisms, and diseases Dev","volume":"17","author":"MacDonald","year":"2009","journal-title":"Cell."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1242\/dev.111.4.1029","article-title":"The segment polari-ty gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pat-tern formation","volume":"111","author":"Peifer","year":"1991","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1101\/gr.139758.112","article-title":"Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation","volume":"23","author":"Hausser","year":"2013","journal-title":"Genome Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1476-4598-13-28","article-title":"Integrated analysis of microRNA and mRNA expression and association with HIF binding reveals the complexity of microRNA expression regulation under hypoxia","volume":"13","author":"Camps","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.canlet.2018.10.025","article-title":"HIF-1\u03b1-induced miR-23a\u223c27a\u223c24 cluster promotes colorectal cancer progression via reprogramming metabolism","volume":"440\u2013441","author":"Jin","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1083\/jcb.200904114","article-title":"Convergence of Notch and beta-catenin signaling induces arterial fate in vascular progenitors","volume":"189","author":"Yamamizu","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1242\/dev.01724","article-title":"Notch modulates Wnt signalling by associating with Armadillo\/beta-catenin and regulating its transcriptional activity","volume":"132","author":"Hayward","year":"2005","journal-title":"Development"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1038\/ncb2313","article-title":"Notch Post-Translationally Regulates \u03b2-Catenin Protein in Stem and Progenitor Cells","volume":"13","author":"Kwon","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative CT method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/978-3-030-02601-1_9","article-title":"Pericytes Derived from Human Pluripotent Stem Cells","volume":"1109","author":"Jamieson","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e12549","DOI":"10.1111\/micc.12549","article-title":"Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia","volume":"26","author":"Boardman","year":"2019","journal-title":"Microcirculation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1161\/CIRCRESAHA.108.177386","article-title":"The neurotrophin receptor p75NTR triggers endothelial cell apoptosis and inhibits angiogenesis: Implications for diabetes-induced impairment of reparative neovascularization","volume":"103","author":"Caporali","year":"2008","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.bbamcr.2015.11.020","article-title":"The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGF\u03b2\/BMP and hypoxia pathways","volume":"1863","author":"Borggrefea","year":"2016","journal-title":"Biochim. Biophys Acta."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.devcel.2017.02.021","article-title":"MicroRNAs Establish Uniform Traits during the Architecture of Vertebrate Embryos","volume":"27","author":"Kasper","year":"2017","journal-title":"Dev. Cell."},{"key":"ref_45","first-page":"3179","article-title":"Effects of microRNA-21 and microRNA-24 inhibitors on neuronal apoptosis in ischemic stroke","volume":"8","author":"Wansheng","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.celrep.2014.07.028","article-title":"Nontranscriptional role of Hif-1\u03b1 in activation of \u03b3-secretase and notch signaling in breast cancer","volume":"21","author":"Villa","year":"2014","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.bbamcr.2008.10.002","article-title":"Beta-catenin modulates the level and transcriptional activity of Notch1\/NICD through its direct interaction","volume":"1793","author":"Jin","year":"2009","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.devcel.2009.01.015","article-title":"Angiogenesis: A team effort coordinated by Notch","volume":"16","author":"Phng","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1101\/gad.14.11.1343","article-title":"Notch signaling is essential for vascular morphogenesis in mice","volume":"14","author":"Krebs","year":"2000","journal-title":"Genes Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/jcb.23390","article-title":"Interaction of Wnt\/beta-catenin and notch signaling in the early stage of cardiac differentiation of P19CL6 cells","volume":"113","author":"Li","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.devcel.2005.09.010","article-title":"Hypoxia requires notch signaling to maintain the undifferentiated cell state","volume":"9","author":"Gustafsson","year":"2005","journal-title":"Dev. Cell."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/2040-2384-2-3","article-title":"Notch regulates the angiogenic response via induction of VEGFR-1","volume":"2","author":"Funahashi","year":"2010","journal-title":"J. Angiogenes. Res."},{"key":"ref_53","unstructured":"Darden, J., Payne, L.B., Zhao, H., and Chappell, J.C. Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Avnit-Sagi, T., Kantorovich, L., Kredo-Russo, S., Hornstein, E., and Walker, M.D. (2009). The Promoter of the pri-miR-375 Gene Directs Expression Selectively to the Endocrine Pancreas. PLoS One, 4.","DOI":"10.1371\/journal.pone.0005033"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nature10908","article-title":"Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF\u2013VEGFR2 signalling","volume":"484","author":"Benedito","year":"2012","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1161\/CIRCRESAHA.111.251546","article-title":"Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132","volume":"30","author":"Katare","year":"2011","journal-title":"Circ. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1177\/1358863X08091485","article-title":"Critical limb ischemia: Medical and surgical management","volume":"13","author":"Slovut","year":"2008","journal-title":"Vasc. Med."}],"updated-by":[{"DOI":"10.3390\/ijms27115014","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T00:00:00Z","timestamp":1583193600000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1733\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T10:16:39Z","timestamp":1780395399000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1733"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,3]]},"references-count":57,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21051733"],"URL":"https:\/\/doi.org\/10.3390\/ijms21051733","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,3]]}}}