{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T22:26:33Z","timestamp":1782512793352,"version":"3.54.5"},"reference-count":59,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T00:00:00Z","timestamp":1611273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre (NCN), Poland","award":["2012\/07\/B\/NZ4\/01770"],"award-info":[{"award-number":["2012\/07\/B\/NZ4\/01770"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Two immortalized brain microvascular endothelial cell lines (hCMEC\/D3 and RBE4, of human and rat origin, respectively) were applied as an in vitro model of cellular elements of the blood\u2013brain barrier in a nanotoxicological study. We evaluated the impact of CdSe\/ZnS core-shell-type quantum dot nanoparticles on cellular homeostasis, using gold nanoparticles as a largely bioorthogonal control. While the investigated nanoparticles had surprisingly negligible acute cytotoxicity in the evaluated models, a multi-faceted study of barrier-related phenotypes and cell condition revealed a complex pattern of homeostasis disruption. Interestingly, some features of the paracellular barrier phenotype (transendothelial electrical resistance, tight junction protein gene expression) were improved by exposure to nanoparticles in a potential hormetic mechanism. However, mitochondrial potential and antioxidant defences largely collapsed under these conditions, paralleled by a strong pro-apoptotic shift in a significant proportion of cells (evidenced by apoptotic protein gene expression, chromosomal DNA fragmentation, and membrane phosphatidylserine exposure). Taken together, our results suggest a reactive oxygen species-mediated cellular mechanism of blood\u2013brain barrier damage by quantum dots, which may be toxicologically significant in the face of increasing human exposure to this type of nanoparticles, both intended (in medical applications) and more often unintended (from consumer goods-derived environmental pollution).<\/jats:p>","DOI":"10.3390\/ijms22031068","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T11:13:53Z","timestamp":1611314033000},"page":"1068","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["CdSe\/ZnS Core-Shell-Type Quantum Dot Nanoparticles Disrupt the Cellular Homeostasis in Cellular Blood\u2013Brain Barrier Models"],"prefix":"10.3390","volume":"22","author":[{"given":"Katarzyna Dominika","family":"Kania","sequence":"first","affiliation":[{"name":"Laboratory of Transcriptional Regulation, Institute for Medical Biology, PAS, Lodowa 106 Street, 93-232 Lodz, Poland"},{"name":"Laboratory of Virology, Institute for Medical Biology, PAS, Lodowa 106 Street, 93-232 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1286-8360","authenticated-orcid":false,"given":"Waldemar","family":"Wagner","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Immunology, Institute for Medical Biology, PAS, Lodowa 106 Street, 93-232 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8063-801X","authenticated-orcid":false,"given":"\u0141ukasz","family":"Pu\u0142aski","sequence":"additional","affiliation":[{"name":"Laboratory of Transcriptional Regulation, Institute for Medical Biology, PAS, Lodowa 106 Street, 93-232 Lodz, Poland"},{"name":"Department of Molecular Biophysics, Faculty of Biology and Environmental Sciences, University of Lodz, Banacha 12\/16, 90-237 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/ana.23648","article-title":"The blood-brain barrier in health and disease","volume":"72","author":"Daneman","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.neuron.2008.01.003","article-title":"The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders","volume":"57","author":"Zlokovic","year":"2008","journal-title":"Neuron"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a020412","DOI":"10.1101\/cshperspect.a020412","article-title":"The Blood\u2013Brain Barrier","volume":"7","author":"Daneman","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1021\/acschemneuro.9b00470","article-title":"Nanotechnology-Based Diagnostics and Therapy for Pathogen-Related Infections in the CNS","volume":"11","author":"Selvan","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.2174\/1568026614666140329230311","article-title":"Recent Advances in Delivery through the Blood-Brain Barrier","volume":"14","author":"Larsen","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Logothetidis, S. (2012). Nanostructured Materials and Their Applications, Springer.","DOI":"10.1007\/978-3-642-22227-6"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1080\/15376516.2019.1566425","article-title":"Review of emerging concepts in nanotoxicology: Opportunities and challenges for safer nanomaterial design","volume":"29","author":"Singh","year":"2019","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3424","DOI":"10.1039\/C9NA00334G","article-title":"Quantum dot cellular uptake and toxicity in the developing brain: Implications for use as imaging probes","volume":"1","author":"Zhang","year":"2019","journal-title":"Nanoscale Adv."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Orlando, A., Colombo, M., Prosperi, D., Corsi, F., Panariti, A., Rivolta, I., Masserini, M., and Cazzaniga, E. (2016). Evaluation of gold nanoparticles biocompatibility: A multiparametric study on cultured endothelial cells and macrophages. J. Nanoparticle Res., 18.","DOI":"10.1007\/s11051-016-3359-4"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4200","DOI":"10.2174\/0929867321666140716100449","article-title":"Interactions between Nanosized Materials and the Brain","volume":"21","author":"Mattsson","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.2217\/nnm-2018-0139","article-title":"Nanoparticle crossing of blood\u2013brain barrier: A road to new therapeutic approaches to central nervous system diseases","volume":"13","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.4103\/1673-5374.170324","article-title":"Targeting brain microvascular endothelial cells: A therapeutic approach to neuroprotection against stroke","volume":"10","author":"Yu","year":"2015","journal-title":"Neural Regen. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.2147\/IJN.S231479","article-title":"Overcoming the Blood\u2013Brain Barrier: Successes and Challenges in Developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours","volume":"15","author":"Ferraris","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_14","first-page":"281","article-title":"Nanoparticles and neurotoxicity: Dual response of glutamatergic receptors","volume":"245","author":"Engin","year":"2019","journal-title":"Sleep Deprivation Cogn."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s12951-018-0412-8","article-title":"Redox nanoparticles: Synthesis, properties and perspectives of use for treatment of neuro-degenerative diseases","volume":"16","author":"Bartosz","year":"2018","journal-title":"J. Nanobiotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.etap.2016.09.009","article-title":"Influence of silver and titanium dioxide nanoparticles on in vitro blood-brain barrier permeability","volume":"47","author":"Chen","year":"2016","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"105598","DOI":"10.1016\/j.envint.2020.105598","article-title":"Study of the neurotoxicity of indoor airborne nanoparticles based on a 3D human blood-brain barrier chip","volume":"143","author":"Liu","year":"2020","journal-title":"Environ. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1096\/fj.04-3458fje","article-title":"Blood-brain barrier-specific properties of a human adult brain endothelial cell line","volume":"19","author":"Weksler","year":"2005","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2045-8118-10-16","article-title":"The hCMEC\/D3 cell line as a model of the human blood brain barrier","volume":"10","author":"Weksler","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2011.08.044","article-title":"Beta amyloid effects on expression of multidrug efflux transporters in brain endothelial cells","volume":"1418","author":"Kania","year":"2011","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9260748","DOI":"10.1155\/2020\/9260748","article-title":"Nitroxide Radical-Containing Redox Nanoparticles Protect Neuroblastoma SH-SY5Y Cells against 6-Hydroxydopamine Toxicity","volume":"2020","author":"Pichla","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e1419","DOI":"10.1002\/wnan.1419","article-title":"Intracellular imaging of quantum dots, gold, and iron oxide nanoparticles with associated endocytic pathways","volume":"9","author":"Chen","year":"2016","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1021\/acs.molpharmaceut.0c01074","article-title":"Uptake and Transport of Ultrafine Nanoparticles (Quantum Dots) in the Nasal Mucosa","volume":"18","author":"Bejgum","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.actbio.2016.09.008","article-title":"RETRACTED: Functional quantum dot-siRNA nanoplexes to regulate chondrogenic differentiation of mesenchymal stem cells","volume":"46","author":"Wu","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wang, Z., Zhao, Q., Cui, M., Pang, S., Wang, J., Liu, Y., and Xie, L. (2017). Probing Temperature- and pH-Dependent Binding between Quantum Dots and Bovine Serum Albumin by Fluorescence Correlation Spectroscopy. Nanomaterials, 7.","DOI":"10.3390\/nano7050093"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Liao, C., Jin, Y., Li, Y., and Tjong, S.C. (2020). Interactions of Zinc Oxide Nanostructures with Mammalian Cells: Cytotoxicity and Photocatalytic Toxicity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176305"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1021\/es204430f","article-title":"Degradation Products from Consumer Nanocomposites: A Case Study on Quantum Dot Lighting","volume":"46","author":"Liu","year":"2012","journal-title":"Environ. Sci. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1007\/s00253-017-8140-9","article-title":"Cadmium-containing quantum dots: Properties, applications, and toxicity","volume":"101","author":"Mo","year":"2017","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12951-017-0312-3","article-title":"Quantifying engineered nanomaterial toxicity: Comparison of common cytotoxicity and gene expression measurements","volume":"15","author":"Atha","year":"2017","journal-title":"J. Nanobiotechnol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"905","DOI":"10.2174\/1389557516666160211121247","article-title":"Cadmium-containing Quantum Dots: Current Perspectives on Their Application as Nanomedicine and Toxicity Concerns","volume":"16","author":"Wang","year":"2016","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s12551-020-00653-0","article-title":"Revisiting the cytotoxicity of quantum dots: An in-depth overview","volume":"12","author":"Nikazar","year":"2020","journal-title":"Biophys. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.tox.2011.01.015","article-title":"An in vitro study of vascular endothelial toxicity of CdTe quantum dots","volume":"282","author":"Yan","year":"2011","journal-title":"Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13435","DOI":"10.3390\/ijerph121013435","article-title":"Threshold Dose of Three Types of Quantum Dots (QDs) Induces Oxidative Stress Triggers DNA Damage and Apoptosis in Mouse Fibroblast L929 Cells","volume":"12","author":"Zhang","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.tox.2013.02.010","article-title":"Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells","volume":"306","author":"Nguyen","year":"2013","journal-title":"Toxicology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00232-016-9920-3","article-title":"Size Effects on the Interaction of QDs with the Mitochondrial Membrane In Vitro","volume":"249","author":"Lai","year":"2016","journal-title":"J. Membr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117104","DOI":"10.1016\/j.saa.2019.05.009","article-title":"Molecular mechanism of CAT and SOD activity change under MPA-CdTe quantum dots induced oxidative stress in the mouse primary hepatocytes","volume":"220","author":"Hao","year":"2019","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1177\/0960327119843578","article-title":"Dose- and duration-dependent cytotoxicity and genotoxicity in human hepato carcinoma cells due to CdTe QDs exposure","volume":"38","author":"Katubi","year":"2019","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"104827","DOI":"10.1016\/j.tiv.2020.104827","article-title":"CdTe and CdTe@ZnS quantum dots induce IL-1\u00df-mediated inflammation and pyroptosis in microglia","volume":"65","author":"Liang","year":"2020","journal-title":"Toxicol. Vitr."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Larner, S.F., Wang, J., Goodman, J., Altman, M.B.O., Xin, M., and Wang, K.K.W. (2017). In Vitro Neurotoxicity Resulting from Exposure of Cultured Neural Cells to Several Types of Nanoparticles. J. Cell Death, 10.","DOI":"10.1177\/1179670717694523"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3543","DOI":"10.1166\/jnn.2011.3803","article-title":"Cytotoxicity Tests of Water Soluble ZnS and CdS Quantum Dots","volume":"11","author":"Li","year":"2011","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Panzarini, E., Mariano, S., Carata, E., Mura, F., Rossi, M., and Dini, L. (2018). Intracellular Transport of Silver and Gold Nanoparticles and Biological Responses: An Update. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051305"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"104753","DOI":"10.1016\/j.phrs.2020.104753","article-title":"Gold Nanoparticles in Glioma Theranostics","volume":"156","author":"Norouzi","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"898034","DOI":"10.1155\/2013\/898034","article-title":"Cadmium and Its Neurotoxic Effects","volume":"2013","author":"Wang","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.neuro.2019.07.007","article-title":"The role of zinc, copper, manganese and iron in neurodegenerative diseases","volume":"74","author":"Mezzaroba","year":"2019","journal-title":"NeuroToxicology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.bbrc.2017.11.074","article-title":"Acute and chronic cadmium telluride quantum dots-exposed human bronchial epithelial cells: The effects of particle sizes on their cytotoxicity and carcinogenicity","volume":"495","author":"Zheng","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41551-019-0465-5","article-title":"A ionic particles inable the oral delivery of proteins by enhancing intes-tinal permeability","volume":"4","author":"Lamson","year":"2020","journal-title":"Nat. Biomed. Eng."},{"key":"ref_47","first-page":"202","article-title":"Nonlinear Effects of Nanoparticles: Biological Variability from Hormetic Doses, Small Particle Sizes, and Dynamic Adaptive Interactions","volume":"12","author":"Bell","year":"2013","journal-title":"Dose Response"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.freeradbiomed.2012.07.003","article-title":"Activation of AMP-activated protein kinase alleviates High-glucose-induced dysfunction of brain microvascular endothelial cell tight-junction dynamics","volume":"53","author":"Liu","year":"2012","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.yexmp.2014.09.006","article-title":"Activation of AMPK attenuates lipopolysaccharide-impaired integrity and function of blood\u2013brain barrier in human brain microvascular endothelial cells","volume":"97","author":"Zhao","year":"2014","journal-title":"Exp. Mol. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e3102","DOI":"10.1038\/cddis.2017.491","article-title":"Adiponectin controls the apoptosis and the expression of tight junction proteins in brain endothelial cells through AdipoR1 under beta amyloid toxicity","volume":"8","author":"Song","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/jcp.1041590114","article-title":"Regulation of gamma-glutamyl transpeptidase and alkaline phosphatase activities in immortalized rat brain microvessel endothelial cells","volume":"159","author":"Roux","year":"1994","journal-title":"J. Cell. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.brainres.2009.07.039","article-title":"Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC\/D3, restricts apical-to-basolateral permeability to rhodamine 123","volume":"1292","author":"Tai","year":"2009","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s13402-014-0205-5","article-title":"Relationship between therapeutic efficacy of doxorubicin-transferrin conjugate and expression of P-glycoprotein in chronic erythromyeloblastoid leukemia cells sensitive and resistant to doxorubicin","volume":"37","author":"Szwed","year":"2014","journal-title":"Cell. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.biochi.2014.10.005","article-title":"Changes in the activity of antioxidant barrier after treatment of K562 and CCRF-CEM cell lines with doxorubicin\u2013transferrin conjugate","volume":"107","author":"Szwed","year":"2014","journal-title":"Biochimie"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.biocel.2015.10.020","article-title":"Assessment of pro-apoptotic activity of doxorubicin\u2013transferrin conjugate in cells derived from human solid tumors","volume":"70","author":"Szwed","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/0014-4827(88)90265-0","article-title":"A simple technique for quantitation of low levels of DNA damage in individual cells","volume":"175","author":"Singh","year":"1988","journal-title":"Exp. Cell Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S1383-5718(02)00251-6","article-title":"A cross-platform public domain PC image-analysis program for the comet assay","volume":"534","author":"Lankoff","year":"2003","journal-title":"Mutat. Res. Toxicol. Environ. Mutagen."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.cellbi.2007.03.024","article-title":"Analysis of aclarubicin-induced cell death in human fibroblasts","volume":"31","author":"Kania","year":"2007","journal-title":"Cell Biol. Int."},{"key":"ref_59","first-page":"555","article-title":"The lactate receptor (HCAR1\/GPR81) contributes to doxorubicin chemo-resistance via ABCB1 transporter up-regulation in human cervical cancer HeLa cells","volume":"68","author":"Wagner","year":"2017","journal-title":"J. Physiol. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1068\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:13:53Z","timestamp":1760159633000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,22]]},"references-count":59,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22031068"],"URL":"https:\/\/doi.org\/10.3390\/ijms22031068","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,22]]}}}