{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T08:53:35Z","timestamp":1762073615497,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T00:00:00Z","timestamp":1667865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre","award":["2016\/23\/B\/NZ7\/02283"],"award-info":[{"award-number":["2016\/23\/B\/NZ7\/02283"]}]},{"name":"Maj Institute of Pharmacology, Polish Academy of Sciences","award":["2016\/23\/B\/NZ7\/02283"],"award-info":[{"award-number":["2016\/23\/B\/NZ7\/02283"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The CYP2D enzymes of the cytochrome P450 superfamily play an important role in psychopharmacology, since they are engaged in the metabolism of psychotropic drugs and endogenous neuroactive substrates, which mediate brain neurotransmission and the therapeutic action of those drugs. The aim of this work was to study the effect of short- and long-term treatment with the selective antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, which possesses antidepressant properties, on CYP2D expression and activity in the liver and brain of male rats. The presented work shows time-, organ- and brain-structure-dependent effects of 5-day and 3-week treatment with CP-101,606 on CYP2D. Five-day treatment with CP-101,606 increased the activity and protein level of CYP2D in the hippocampus. That effect was maintained after the 3-week treatment and was accompanied by enhancement in the CYP2D activity\/protein level in the cortex and cerebellum. In contrast, a 3-week treatment with CP-101,606 diminished the CYP2D activity\/protein level in the hypothalamus and striatum. In the liver, CP-101,606 decreased CYP2D activity, but not the protein or mRNA level, after 5-day or 3-week treatment. When added in vitro to liver microsomes, CP-101,606 diminished the CYP2D activity during prolonged incubation. While in the brain, the observed decrease in the CYP2D activity after short- and long-term treatment with CP-101,606 seems to be a consequence of the drug effect on enzyme regulation. In the liver, the direct inhibitory effect of reactive metabolites formed from CP-101,606 on the CYP2D activity may be considered. Since CYP2Ds are engaged in the metabolism of endogenous neuroactive substances, it can be assumed that apart from antagonizing the NMDA receptor, CP-101,606 may modify its own pharmacological effect by affecting brain cytochrome P450. On the other hand, an inhibition of the activity of liver CYP2D may slow down the metabolism of co-administered substrates and lead to pharmacokinetic drug\u2013drug interactions.<\/jats:p>","DOI":"10.3390\/ijms232213746","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T02:34:52Z","timestamp":1667961292000},"page":"13746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Effect of the Selective N-methyl-D-aspartate (NMDA) Receptor GluN2B Subunit Antagonist CP-101,606 on Cytochrome P450 2D (CYP2D) Expression and Activity in the Rat Liver and Brain"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3925-3828","authenticated-orcid":false,"given":"Anna","family":"Haduch","sequence":"first","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Bromek","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata","family":"Puk\u0142o","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Jastrz\u0119bska","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7137-2990","authenticated-orcid":false,"given":"Przemys\u0142aw Jan","family":"Danek","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1226-1721","authenticated-orcid":false,"given":"W\u0142adys\u0142awa Anna","family":"Daniel","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1080\/03602532.2016.1221960","article-title":"Emerging Roles for Brain Drug-Metabolizing Cytochrome P450 Enzymes in Neuropsychiatric Conditions and Responses to Drugs","volume":"48","author":"Toselli","year":"2016","journal-title":"Drug Metab. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1080\/03602532.2018.1554674","article-title":"The Engagement of Brain Cytochrome P450 in the Metabolism of Endogenous Neuroactive Substrates: A Possible Role in Mental Disorders","volume":"50","author":"Haduch","year":"2018","journal-title":"Drug Metab. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115006","DOI":"10.1016\/j.bcp.2022.115006","article-title":"The Mechanisms of Interactions of Psychotropic Drugs with Liver and Brain Cytochrome P450 and Their Significance for Drug Effect and Drug-Drug Interactions","volume":"199","author":"Daniel","year":"2022","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1006\/bbrc.1998.9232","article-title":"Dopamine Formation from Tyramine by CYP2D6","volume":"249","author":"Hiroi","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ejphar.2009.09.062","article-title":"The Ability of Cytochrome P450 2D Isoforms to Synthesize Dopamine in the Brain: An in Vitro Study","volume":"626","author":"Bromek","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1111\/j.1471-4159.2011.07339.x","article-title":"Cytochrome P450 Mediates Dopamine Formation in the Brain in Vivo","volume":"118","author":"Bromek","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/00008571-200303000-00007","article-title":"Regeneration of Serotonin from 5-Methoxytryptamine by Polymorphic Human CYP2D6","volume":"13","author":"Yu","year":"2003","journal-title":"Pharmacogenetics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.phrs.2012.10.009","article-title":"The Catalytic Competence of Cytochrome P450 in the Synthesis of Serotonin from 5-Methoxytryptamine in the Brain: An in Vitro Study","volume":"67","author":"Haduch","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/jnc.13031","article-title":"The Cytochrome P450 2D-Mediated Formation of Serotonin from 5-Methoxytryptamine in the Brain in Vivo: A Microdialysis Study","volume":"133","author":"Haduch","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1210\/endo.142.9.8363","article-title":"Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain","volume":"142","author":"Hiroi","year":"2001","journal-title":"Endocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1210\/en.2003-1109","article-title":"Cytochrome P450 2D Catalyze Steroid 21-Hydroxylation in the Brain","volume":"145","author":"Kishimoto","year":"2004","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"337","DOI":"10.2133\/dmpk.18.337","article-title":"CYP2D in the Brain","volume":"18","author":"Funae","year":"2003","journal-title":"Drug Metab. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0006-8993(97)00428-9","article-title":"Regulation of Expression of Cytochrome P-450 2D MRNA in Rat Brain with Steroid Hormones","volume":"765","author":"Baum","year":"1997","journal-title":"Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1016\/j.neurobiolaging.2011.08.014","article-title":"The Neuroprotective Enzyme CYP2D6 Increases in the Brain with Age and Is Lower in Parkinson\u2019s Disease Patients","volume":"33","author":"Mann","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.bcp.2018.09.005","article-title":"The Activity of Brain and Liver Cytochrome P450 2D (CYP2D) Is Differently Affected by Antidepressants in the Chronic Mild Stress (CMS) Model of Depression in the Rat","volume":"156","author":"Haduch","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1530\/JOE-19-0561","article-title":"Sex Steroid Hormones Differentially Regulate CYP2D in Female Wild-Type and CYP2D6-Humanized Mice","volume":"245","author":"Konstandi","year":"2020","journal-title":"J. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"104884","DOI":"10.1016\/j.neuint.2020.104884","article-title":"The Effect of Ageing and Cerebral Serotonin Deficit on the Activity of Cytochrome P450 2D (CYP2D) in the Brain and Liver of Male Rats","volume":"141","author":"Haduch","year":"2020","journal-title":"Neurochem. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105223","DOI":"10.1016\/j.neuint.2021.105223","article-title":"Cytochrome P450 2D (CYP2D) Enzyme Dysfunction Associated with Aging and Serotonin Deficiency in the Brain and Liver of Female Dark Agouti Rats","volume":"152","author":"Haduch","year":"2022","journal-title":"Neurochem. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1124\/dmd.116.072249","article-title":"Transcriptional Regulation of CYP2D6 Expression","volume":"45","author":"Pan","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/03602532.2020.1858856","article-title":"Cytochrome P450 Expression and Regulation in the Brain","volume":"53","author":"Kuban","year":"2021","journal-title":"Drug Metab. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neuroscience.2018.03.009","article-title":"The Involvement of PPARs in the Selective Regulation of Brain CYP2D by Growth Hormone","volume":"379","author":"Zhang","year":"2018","journal-title":"Neuroscience"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/j.1365-2265.2006.02676.x","article-title":"Modulation of Growth Hormone Action by Sex Steroids","volume":"65","author":"Meinhardt","year":"2006","journal-title":"Clin. Endocrinol. (Oxf)"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1111\/bph.13206","article-title":"Sex Hormones Regulate Cerebral Drug Metabolism via Brain MiRNAs: Down-Regulation of Brain CYP2D by Androgens Reduces the Analgesic Effects of Tramadol","volume":"172","author":"Li","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1503\/jpn.120133","article-title":"Cytochrome P450-Mediated Drug Metabolism in the Brain","volume":"38","author":"Miksys","year":"2013","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_25","first-page":"342","article-title":"Cytochrome P4502D4 in the Brain: Specific Neuronal Regulation by Clozapine and Toluene","volume":"50","author":"Hedlund","year":"1996","journal-title":"Mol. Pharmacol."},{"key":"ref_26","first-page":"54","article-title":"Chronic Nicotine Treatment Induces Rat CYP2D in the Brain but Not in the Liver: An Investigation of Induction and Time Course","volume":"33","author":"Yue","year":"2008","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Danek, P.J., and Daniel, W.A. (2021). Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms. Cells, 10.","DOI":"10.3390\/cells10123472"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.pharmthera.2017.10.008","article-title":"CYP-Mediated Drug Metabolism in the Brain Impacts Drug Response","volume":"184","author":"McMillan","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0140-6736(89)90094-9","article-title":"Debrisoquine Hydroxylation Polymorphism and Personality","volume":"1","author":"Bertilsson","year":"1989","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1600-0447.1993.tb03325.x","article-title":"Relationship between Personality and Debrisoquine Hydroxylation Capacity. Suggestion of an Endogenous Neuroactive Substrate or Product of the Cytochrome P4502D6","volume":"87","author":"Llerena","year":"1993","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"833","DOI":"10.2217\/14622416.9.7.833","article-title":"Relation between CYP2D6 Phenotype and Genotype and Personality in Healthy Volunteers","volume":"9","author":"Dorado","year":"2008","journal-title":"Pharmacogenomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/bcp.12227","article-title":"CYP2D6 Variation, Behaviour and Psychopathology: Implications for Pharmacogenomics-Guided Clinical Trials","volume":"77","author":"Llerena","year":"2014","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1016\/j.neuroimage.2011.07.052","article-title":"Genetic Variation in CYP2D6 Impacts Neural Activation during Cognitive Tasks in Humans","volume":"59","author":"Stingl","year":"2012","journal-title":"Neuroimage"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41398-020-01020-z","article-title":"Effects of Genetic Variability of CYP2D6 on Neural Substrates of Sustained Attention during On-Task Activity","volume":"10","author":"Viviani","year":"2020","journal-title":"Transl. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"973","DOI":"10.3109\/00498254.2013.791410","article-title":"Potential Role of CYP2D6 in the Central Nervous System","volume":"43","author":"Cheng","year":"2013","journal-title":"Xenobiotica"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.neulet.2018.02.059","article-title":"Relationship between the Hippocampal Expression of Selected Cytochrome P450 Isoforms and the Animal Performance in the Hippocampus-Dependent Learning Task","volume":"673","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejphar.2010.10.077","article-title":"The Effect of Psychotropic Drugs on Cytochrome P450 2D (CYP2D) in Rat Brain","volume":"651","author":"Haduch","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"105209","DOI":"10.1016\/j.neuint.2021.105209","article-title":"Chronic Treatment with Asenapine Affects Cytochrome P450 2D (CYP2D) in Rat Brain and Liver. Pharmacological Aspects","volume":"151","author":"Danek","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Danek, P.J., and Daniel, W.A. (2022). The Atypical Antipsychotic Lurasidone Affects Brain, but Not Liver Cytochrome P450 2D (CYP2D) Activity. A Comparison with Other Novel Neuroleptics and Significance for Drug Treatment of Schi-Zophrenia. Cells, 20.","DOI":"10.3390\/cells11213513"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1038\/s41386-020-00797-3","article-title":"Role of the Medial Prefrontal Cortex in the Effects of Rapid Acting Antidepressants on Decision-Making Biases in Rodents","volume":"45","author":"Hales","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0028-3908(01)00191-5","article-title":"Studies on the Subtype Selectivity of CP-101,606: Evidence for Two Classes of NR2B-Selective NMDA Receptor Antagonists","volume":"42","author":"Chazot","year":"2002","journal-title":"Neuropharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1097\/JCP.0b013e31818a6cea","article-title":"An Innovative Design to Establish Proof of Concept of the Antidepressant Effects of the NR2B Subunit Selective N-Methyl-D-Aspartate Antagonist, CP-101,606, in Patients with Treatment-Refractory Major Depressive Disorder","volume":"28","author":"Preskorn","year":"2008","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s00213-017-4823-2","article-title":"Antagonism at the NR2B Subunit of NMDA Receptors Induces Increased Connectivity of the Prefrontal and Subcortical Regions Regulating Reward Behavior","volume":"235","author":"Gass","year":"2018","journal-title":"Psychopharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bromek, E., Haduch, A., Rysz, M., Jastrz\u0119bska, J., Puk\u0142o, R., W\u00f3jcikowska, O., Danek, P.J., and Daniel, W.A. (2021). The Selective NMDA Receptor GluN2B Subunit Antagonist CP-101,606 with Antidepressant Properties Modulates Cytochrome P450 Expression in the Liver. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101643"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1124\/dmd.107.016105","article-title":"Metabolism, Distribution and Excretion of a Selective N-Methyl-D-Aspartate Receptor Antagonist, Traxoprodil, in Rats and Dogs","volume":"35","author":"Prakash","year":"2007","journal-title":"Drug Metab. Dispos."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0304-4165(97)00157-8","article-title":"Tissue Distributions of CYP2D1, 2D2, 2D3 and 2D4 MRNA in Rats Detected by RT-PCR","volume":"1380","author":"Hiroi","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_47","unstructured":"Stahl, S.M. (2013). Stahl\u2019s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, Cambridge University Press."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Adell, A. (2020). Brain NMDA Receptors in Schizophrenia and Depression. Biomolecules, 10.","DOI":"10.3390\/biom10060947"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 Enzymes in Drug Metabolism: Regulation of Gene Expression, Enzyme Activities, and Impact of Genetic Variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_50","unstructured":"Paxinos, G., and Watson, C. (2007). The Rat Brain in Stereotaxic Coordinates, Academic Press. [6th ed.]."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1211\/002235702162","article-title":"Inhibition and Possible Induction of Rat CYP2D after Short- and Long-Term Treatment with Antidepressants","volume":"54","author":"Daniel","year":"2002","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1124\/dmd.30.9.970","article-title":"Catalytic Specificity of CYP2D Isoforms in Rat and Human","volume":"30","author":"Hiroi","year":"2002","journal-title":"Drug Metab. Dispos."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein Measurement with the Folin Phenol Reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.bcp.2016.04.017","article-title":"The Reverse Role of the Hypothalamic Paraventricular (PVN) and Arcuate (ARC) Nuclei in the Central Serotonergic Regulation of the Liver Cytochrome P450 Isoform CYP2C11","volume":"112","author":"Rysz","year":"2016","journal-title":"Biochem. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13746\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:12:50Z","timestamp":1760145170000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13746"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,8]]},"references-count":54,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213746"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213746","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,11,8]]}}}