{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:43:15Z","timestamp":1787794995124,"version":"build-2784847793"},"reference-count":57,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T00:00:00Z","timestamp":1581638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UNIVERSITY OF THE BASQUE COUNTRY-UPV\/EHU","award":["GIU 17\/018"],"award-info":[{"award-number":["GIU 17\/018"]}]},{"DOI":"10.13039\/501100003086","name":"BASQUE GOVERNMENT","doi-asserted-by":"publisher","award":["POS_2013_1_191 and IT773-13"],"award-info":[{"award-number":["POS_2013_1_191 and IT773-13"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012440","name":"BIOEF","doi-asserted-by":"publisher","award":["BIO18\/IC\/003"],"award-info":[{"award-number":["BIO18\/IC\/003"]}],"id":[{"id":"10.13039\/501100012440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the process of neonatal encephalopathy, oxidative stress and neuroinflammation have a prominent role after perinatal asphyxia. With the exception of therapeutic hypothermia, no therapeutic interventions are available in the clinical setting to target either the oxidative stress or inflammation, despite the high prevalence of neurological sequelae of this devastating condition. The endocannabinoid system (ECS), recently recognized as a widespread neuromodulatory system, plays an important role in the development of the central nervous system (CNS). This study aims to evaluate the potential effect of the cannabinoid (CB) agonist WIN 55,212-2 (WIN) on reactive oxygen species (ROS) and early inflammatory cytokine production after hypoxia\u2013ischemia (HI) in fetal lambs. Hypoxic\u2013ischemic animals were subjected to 60 min of HI by partial occlusion of the umbilical cord. A group of lambs received a single dose of 0.01 \u03bcg\/kg WIN, whereas non-asphyctic animals served as controls. WIN reduced the widespread and notorious increase in inflammatory markers tumor necrosis factor (TNF)-\u03b1 and interleukin (IL)-1\u03b2 and IL-6 induced by HI, a modulatory effect not observed for oxidative stress. Our study suggests that treatment with a low dose of WIN can alter the profile of pro-inflammatory cytokines 3 h after HI.<\/jats:p>","DOI":"10.3390\/ijms21041283","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T04:06:01Z","timestamp":1582085161000},"page":"1283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Cannabinoid-mediated Modulation of Oxidative Stress and Early Inflammatory Response after Hypoxia\u2013Ischemia"],"prefix":"10.3390","volume":"21","author":[{"given":"Daniel","family":"Alonso-Alconada","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV\/EHU), 48940 Leioa, Vizcaya, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Jos\u00e9","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Biocruces Bizkaia Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Go\u00f1i-de-Cerio","sequence":"additional","affiliation":[{"name":"GAIKER Centro Tecnol\u00f3gico, Parque Tecnol\u00f3gico, ed. 202, 48230 Zamudio, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Hilario","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV\/EHU), 48940 Leioa, Vizcaya, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country (UPV\/EHU), 48940 Leioa, Vizcaya, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1016\/S0140-6736(16)31593-8","article-title":"Global, regional, and national causes of under-5 mortality in 2000-15: An updated systematic analysis with implications for the Sustainable Development Goals","volume":"388","author":"Liu","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3389\/fncel.2017.00078","article-title":"Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges","volume":"11","author":"Millar","year":"2017","journal-title":"Front. Cell Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1093\/jnen\/nlx046","article-title":"Insights Into the Neuroinflammatory Responses After Neonatal Hypoxia-Ischemia","volume":"76","author":"Jaworska","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3389\/fped.2018.00369","article-title":"Oxidative Stress as a Primary Risk Factor for Brain Damage in Preterm Newborns","volume":"6","author":"Panfoli","year":"2018","journal-title":"Front. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1177\/1933719111432868","article-title":"Apoptotic cell death correlates with ROS overproduction and early cytokine expression after hypoxia-ischemia in fetal lambs","volume":"19","author":"Hilario","year":"2012","journal-title":"Reprod. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/nrneurol.2015.13","article-title":"The role of inflammation in perinatal brain injury","volume":"11","author":"Hagberg","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhou, J., Noori, H., Burkovskiy, I., Lafreniere, J.D., Kelly, M.E.M., and Lehmann, C. (2019). Modulation of the Endocannabinoid System Following Central Nervous System Injury. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020388"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1124\/pr.54.2.161","article-title":"International Union of Pharmacology. XXVII. Classification of cannabinoid receptors","volume":"54","author":"Howlett","year":"2002","journal-title":"Pharmacol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.brainres.2010.09.050","article-title":"The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic-ischemic injury in fetal lambs","volume":"1362","author":"Alvarez","year":"2010","journal-title":"Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s11064-011-0594-z","article-title":"The cannabinoid WIN 55212-2 mitigates apoptosis and mitochondrial dysfunction after hypoxia ischemia","volume":"37","author":"Alvarez","year":"2012","journal-title":"Neurochem. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1742-4658.2008.06765.x","article-title":"Post-ischemic brain damage: The endocannabinoid system in the mechanisms of neuronal death","volume":"276","author":"Mannaioni","year":"2009","journal-title":"FEBS J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.neulet.2014.03.077","article-title":"The cannabinoid CB2 receptor agonist GW405833 does not ameliorate brain damage induced by hypoxia-ischemia in rats","volume":"569","author":"Smith","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.2174\/138161208785740054","article-title":"Role of cannabinoids and endocannabinoids in cerebral ischemia","volume":"14","author":"Hillard","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2174\/157015907780866884","article-title":"The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration","volume":"5","author":"Ashton","year":"2007","journal-title":"Curr. Neuropharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"F541","DOI":"10.1136\/archdischild-2014-306284","article-title":"New horizons for newborn brain protection: Enhancing endogenous neuroprotection","volume":"100","author":"Hassell","year":"2015","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.3389\/fphar.2019.01221","article-title":"Comparative efficacy and safety of neuroprotective therapies for neonates with hypoxic ischemic encephalopathy: A network meta-analysis","volume":"10","author":"Lee","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhao, M., Zhu, P., Fujino, M., Zhuang, J., Guo, H., Sheikh, I., Zhao, L., and Li, X.K. (2016). Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122078"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.freeradbiomed.2019.06.011","article-title":"Brain oxidative damage in murine models of neonatal hypoxia\/ischemia and reoxygenation","volume":"142","author":"Gressens","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1124\/jpet.104.079509","article-title":"Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury","volume":"313","author":"Kim","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.brainres.2012.02.058","article-title":"Cannabinoids prevent lipopolysaccharide-induced neurodegeneration in the rat substantia nigra in vivo through inhibition of microglial activation and NADPH oxidase","volume":"1451","author":"Chung","year":"2012","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1203\/PDR.0b013e318156e8aa","article-title":"Resuscitation of hypoxic newborn piglets with oxygen induces a dose-dependent increase in markers of oxidation","volume":"62","author":"Solberg","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.freeradbiomed.2009.11.022","article-title":"Cannabinoid-2 receptor limits inflammation, oxidative\/nitrosative stress, and cell death in nephropathy","volume":"48","author":"Mukhopadhyay","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00395-010-0090-7","article-title":"CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function","volume":"105","author":"Tiyerili","year":"2010","journal-title":"Basic Res. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1124\/mol.54.3.459","article-title":"Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity","volume":"54","author":"Shen","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1046\/j.0022-3042.2001.00716.x","article-title":"Neuroprotective properties of cannabinoids against oxidative stress: Role of the cannabinoid receptor CB1","volume":"80","author":"Marsicano","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tauber, S., Paulsen, K., Wolf, S., Synwoldt, P., Pahl, A., Schneider-Stock, R., and Ullrich, O. (2012). Regulation of MMP-9 by a WIN-binding site in the monocyte-macrophage system independent from cannabinoid receptors. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048272"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/pr.2016.149","article-title":"Short-term effects of cannabidiol after global hypoxia-ischemia in newborn piglets","volume":"80","author":"Garberg","year":"2016","journal-title":"Pediatr. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.neuropharm.2012.05.034","article-title":"Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function","volume":"63","author":"Pazos","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.neures.2006.01.002","article-title":"Contribution of reduced and oxidized glutathione to signals detected by magnetic resonance spectroscopy as indicators of local brain redox state","volume":"55","author":"Satoh","year":"2006","journal-title":"Neurosci. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3574","DOI":"10.2174\/138161208786848739","article-title":"Inflammatory cytokines in acute ischemic stroke","volume":"14","author":"Tuttolomondo","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1067\/S0022-3476(03)00531-6","article-title":"Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic-ischemic encephalopathy","volume":"143","author":"Silveira","year":"2003","journal-title":"J. Pediatr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.braindev.2005.06.006","article-title":"IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy","volume":"28","author":"Aly","year":"2006","journal-title":"Brain Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1093\/tropej\/fmp098","article-title":"Increased umbilical cord plasma interleukin-1 beta levels was correlated with adverse outcomes of neonatal hypoxic-ischemic encephalopathy","volume":"56","author":"Liu","year":"2010","journal-title":"J. Trop. Pediatr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.bbi.2012.09.001","article-title":"Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and\/or hypoxic-ischemic injuries","volume":"26","author":"Girard","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.ijdevneu.2013.10.003","article-title":"Inflammatory response and oxidative stress in developing rat brain and its consequences on motor behavior following maternal administration of LPS and perinatal anoxia","volume":"31","author":"Stigger","year":"2013","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_36","first-page":"905","article-title":"The role of TNF-alpha, IL-6, IL-10, and GDNF in neuronal apoptosis in neonatal rat with hypoxic-ischemic encephalopathy","volume":"18","author":"Li","year":"2014","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/sj.cdd.4401189","article-title":"Tumor necrosis factor signaling","volume":"10","author":"Wajant","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3109\/00207454.2012.744755","article-title":"Changes of inflammatory cytokines and neurotrophins emphasized their roles in hypoxic-ischemic brain damage","volume":"123","author":"Wang","year":"2013","journal-title":"Int. J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"PL125","DOI":"10.1016\/S0024-3205(98)00324-5","article-title":"Effects of cannabinoid receptor ligands on LPS-induced pulmonary inflammation in mice","volume":"63","author":"Berdyshev","year":"1998","journal-title":"Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0014-2999(01)01142-6","article-title":"Modulation of cytokine responses in Corynebacterium parvum-primed endotoxemic mice by centrally administered cannabinoid ligands","volume":"425","author":"Smith","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1203\/01.pdr.0000228839.00122.6c","article-title":"Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats","volume":"60","author":"Nunez","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1161\/01.STR.26.6.1093","article-title":"Cerebral hypoxia-ischemia stimulates cytokine gene expression in perinatal rats","volume":"26","author":"Szaflarski","year":"1995","journal-title":"Stroke"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1203\/00006450-199610000-00015","article-title":"Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats","volume":"40","author":"Hagberg","year":"1996","journal-title":"Pediatr. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1007\/s00210-017-1417-9","article-title":"Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 ameliorate neuroinflammatory responses in chronic cerebral hypoperfusion model by blocking NF-kappaB pathways","volume":"390","author":"Su","year":"2017","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.nbd.2009.01.014","article-title":"Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis","volume":"34","author":"Marchalant","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"510","DOI":"10.3109\/00207454.2011.582237","article-title":"Cannabinoid treatment renders neurons less vulnerable than oligodendrocytes in Experimental Autoimmune Encephalomyelitis","volume":"121","author":"Hasseldam","year":"2011","journal-title":"Int. J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1161\/STROKEAHA.110.599357","article-title":"The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia","volume":"41","author":"Pradillo","year":"2010","journal-title":"Stroke"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/sj.jcbfm.9600447","article-title":"Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia\/reperfusion model","volume":"27","author":"Zhang","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2174\/187152410790780145","article-title":"The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies","volume":"10","author":"Rivers","year":"2010","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/j.neuropharm.2012.01.030","article-title":"Cannabinoids ameliorate disease progression in a model of multiple sclerosis in mice, acting preferentially through CB1 receptor-mediated anti-inflammatory effects","volume":"62","author":"Cabranes","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0304-3940(97)00915-4","article-title":"Dimethylsulfoxide (DMSO) treatment reduces infarction volume after permanent focal cerebral ischemia in rats","volume":"239","author":"Shimizu","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref_52","first-page":"501","article-title":"Dimethyl sulfoxide provides neuroprotection in a traumatic brain injury model","volume":"26","author":"Hou","year":"2008","journal-title":"Restor. Neurol. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2008.11.006","article-title":"Dimethyl sulfoxide (DMSO) produces widespread apoptosis in the developing central nervous system","volume":"34","author":"Hanslick","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s12640-018-9944-9","article-title":"Neuroprotective Action of the CB1\/2 Receptor Agonist, WIN 55,212-2, against DMSO but Not Phenobarbital-Induced Neurotoxicity in Immature Rats","volume":"35","author":"Huizenga","year":"2019","journal-title":"Neurotox. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/j.1651-2227.2005.tb02009.x","article-title":"Cerebral blood flow and morphological changes after hypoxic-ischaemic injury in preterm lambs","volume":"94","author":"Hilario","year":"2005","journal-title":"Acta Paediatr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s13311-012-0108-y","article-title":"The instrumented fetal sheep as a model of cerebral white matter injury in the premature infant","volume":"9","author":"Back","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref_57","first-page":"111","article-title":"Early cerebral hemodynamic, metabolic, and histological changes in hypoxic-ischemic fetal lambs during postnatal life","volume":"5","author":"Mielgo","year":"2011","journal-title":"Front. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1283\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:57:43Z","timestamp":1760173063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1283"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,14]]},"references-count":57,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijms21041283"],"URL":"https:\/\/doi.org\/10.3390\/ijms21041283","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,14]]}}}