{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T23:36:11Z","timestamp":1778628971715,"version":"3.51.4"},"reference-count":67,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biotechnology and Biological Sciences Research Council East of Scotland BioScience Doctoral Training Partnership PhD Studentship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The pineal gland is integral to the circadian timing system due to its role in nightly melatonin production. Retinoic acid (RA) is a potent regulator of gene transcription and has previously been found to exhibit diurnal changes in synthesis and signalling in the rat pineal gland. This study investigated the potential for the interaction of these two systems. PCR was used to study gene expression in mouse and human pineal glands, ex-vivo organotypic cultured rat pineal gland and cell lines. The mouse and human pineal glands were both found to express the necessary components required for RA signalling. RA influences the circadian clock in the brain, therefore the short-term effect of RA on clock gene expression was determined in ex vivo rat pineal glands but was not found to rapidly regulate Per1, Per2, Bmal1, or Cry1. The interaction between RA and melatonin was also investigated and, unexpectedly, melatonin was found to suppress the induction of gene transcription by RA. This study demonstrates that pineal expression of the RA signalling system is conserved across mammalian species. There is no short-term regulation of the circadian clock but an inhibitory effect of melatonin on RA transcriptional activity was demonstrated, suggesting that there may be functional cross-talk between these systems.<\/jats:p>","DOI":"10.3390\/cells12020286","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T02:28:44Z","timestamp":1673490524000},"page":"286","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Retinoic Acid Signalling in the Pineal Gland Is Conserved across Mammalian Species and Its Transcriptional Activity Is Inhibited by Melatonin"],"prefix":"10.3390","volume":"12","author":[{"given":"Anna","family":"Ashton","sequence":"first","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Clark","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Fedo","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Sementilli","sequence":"additional","affiliation":[{"name":"Department of Physiopathology, Universidade Metropolitana de Santos and Centro, Universitario Lus\u00edada, Santos 11050-071, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yara D.","family":"Fragoso","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK"},{"name":"Department of Post Graduate Studies, Universidade Metropolitana de Santos, Santos 11045-002, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5956-3997","authenticated-orcid":false,"given":"Peter","family":"McCaffery","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1074\/jbc.R600036200","article-title":"Arylalkylamine N-acetyltransferase: \u201cThe timezyme\u201d","volume":"282","author":"Klein","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_2","first-page":"307","article-title":"The melatonin rhythm-generating enzyme: Molecular regulation of serotonin N-acetyltransferase in the pineal gland","volume":"52","author":"Klein","year":"1997","journal-title":"Recent Prog. Horm. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1126\/science.270.5242.1681","article-title":"Pineal serotonin N-acetyltransferase: Expression cloning and molecular analysis","volume":"270","author":"Coon","year":"1995","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8083","DOI":"10.1073\/pnas.141118798","article-title":"Role of a pineal cAMP-operated arylalkylamine N-acetyltransferase\/14-3-3-binding switch in melatonin synthesis","volume":"98","author":"Ganguly","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1210\/en.2006-0043","article-title":"Characterization of human melatonin synthesis using autoptic pineal tissue","volume":"147","author":"Ackermann","year":"2006","journal-title":"Endocrinology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/378783a0","article-title":"Diurnal variation in mRNA encoding serotonin N-acetyltransferase in pineal gland","volume":"378","author":"Borjigin","year":"1995","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1600-079X.1989.tb00667.x","article-title":"Melatonin content of the pineal gland in different mouse strains","volume":"7","author":"Goto","year":"1989","journal-title":"J. Pineal Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1126\/science.3941912","article-title":"Genetic control of melatonin synthesis in the pineal gland of the mouse","volume":"231","author":"Ebihara","year":"1986","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0169-328X(98)00273-3","article-title":"Natural melatonin \u201cknockdown\u201d in C57BL\/6J mice: Rare mechanism truncates serotonin N-acetyltransferase","volume":"63","author":"Roseboom","year":"1998","journal-title":"Mol. Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6412","DOI":"10.1073\/pnas.0914399107","article-title":"Genetic variation of melatonin productivity in laboratory mice under domestication","volume":"107","author":"Kasahara","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0304-3940(99)00324-9","article-title":"Daily variation and light responsiveness of mammalian clock gene, Clock and BMAL1, transcripts in the pineal body and different areas of brain in rats","volume":"267","author":"Namihira","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0304-3940(00)01129-0","article-title":"Circadian expression of Period 1, Period 2, and arylalkylamine N-acetyltransferase mRNA in the rat pineal gland under different light conditions","volume":"286","author":"Fukuhara","year":"2000","journal-title":"Neurosci. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0168-0102(01)00255-3","article-title":"Circadian and photic regulation of cryptochrome mRNAs in the rat pineal gland","volume":"41","author":"Nakamura","year":"2001","journal-title":"Neurosci. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1146\/annurev-physiol-021909-135821","article-title":"The mammalian circadian timing system: Organization and coordination of central and peripheral clocks","volume":"72","author":"Dibner","year":"2010","journal-title":"Annu. Rev. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/j.1471-4159.2004.03008.x","article-title":"Pineal circadian clocks gate arylalkylamine N-acetyltransferase gene expression in the mouse pineal gland","volume":"93","author":"Fukuhara","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.molbrainres.2003.10.019","article-title":"Daily rhythm and regulation of clock gene expression in the rat pineal gland","volume":"120","author":"Simonneaux","year":"2004","journal-title":"Mol. Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1111\/j.0953-816X.2004.03444.x","article-title":"Clock gene mRNA and protein rhythms in the pineal gland of mice","volume":"19","author":"Karolczak","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_18","first-page":"1","article-title":"The in vitro maintenance of clock genes expression within the rat pineal gland under standard and norepinephrine-synchronized stimulation","volume":"81\u201382","year":"2014","journal-title":"Neurosci. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1111\/j.1460-9568.2009.06742.x","article-title":"Endogenous rhythmicity of Bmal1 and Rev-erb\u03b1 in the hamster pineal gland is not driven by norepinephrine","volume":"29","author":"Wongchitrat","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1159\/000327430","article-title":"A noradrenergic sensitive endogenous clock is present in the rat pineal gland","volume":"94","author":"Wongchitrat","year":"2011","journal-title":"Neuroendocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"dev167502","DOI":"10.1242\/dev.167502","article-title":"Retinoic acid signaling pathways","volume":"146","author":"Ghyselinck","year":"2019","journal-title":"Development"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1111\/jnc.12620","article-title":"The rhythm of retinoids in the brain","volume":"129","author":"Ransom","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.tins.2012.08.005","article-title":"A vitamin for the brain","volume":"35","author":"Shearer","year":"2012","journal-title":"Trends Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1002\/hipo.22037","article-title":"Patterning of retinoic acid signaling and cell proliferation in the hippocampus","volume":"22","author":"Goodman","year":"2012","journal-title":"Hippocampus"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8219","DOI":"10.1007\/s12035-018-0964-5","article-title":"Rhythmic Diurnal Synthesis and Signaling of Retinoic Acid in the Rat Pineal Gland and its Action to Rapidly Down-regulate ERK Phosphorylation","volume":"55","author":"Ashton","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.bbrc.2006.10.031","article-title":"Bidirectional CLOCK\/BMAL1-dependent circadian gene regulation by retinoic acid in vitro","volume":"351","author":"Shirai","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/S0092-8674(01)00401-9","article-title":"Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: A humoral mechanism to reset a peripheral clock","volume":"105","author":"McNamara","year":"2001","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jnutbio.2010.11.017","article-title":"All-trans retinoic acid modifies the expression of clock and disease marker genes","volume":"23","author":"Sherman","year":"2012","journal-title":"J. Nutr. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nakahata, Y., Akashi, M., Trcka, D., Yasuda, A., and Takumi, T. (2006). The in vitro real-time oscillation monitoring system identifies potential entrainment factors for circadian clocks. BMC Mol. Biol., 7.","DOI":"10.1186\/1471-2199-7-5"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.jnutbio.2012.05.006","article-title":"Retinoic acid receptors move in time with the clock in the hippocampus. Effect of a vitamin-A-deficient diet","volume":"24","author":"Golini","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1002\/hipo.22007","article-title":"Daily patterns of clock and cognition-related factors are modified in the hippocampus of vitamin A-deficient rats","volume":"22","author":"Golini","year":"2012","journal-title":"Hippocampus"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.nutres.2014.02.002","article-title":"Circadian rhythms of locomotor activity and hippocampal clock genes expression are dampened in vitamin A-deficient rats","volume":"34","author":"Delgado","year":"2014","journal-title":"Nutr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1002\/hipo.20571","article-title":"Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A-deficient rats","volume":"19","author":"Golini","year":"2009","journal-title":"Hippocampus"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7606","DOI":"10.1074\/jbc.M808394200","article-title":"Night\/Day Changes in Pineal Expression of >600 Genes: Central Role of Adrenergic\/cAMP signaling","volume":"284","author":"Bailey","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1177\/074873098129000228","article-title":"Daily Variations in Pineal Melatonin Concentrations in Inbred and Outbred Mice","volume":"13","author":"Malan","year":"1998","journal-title":"J. Biol. Rhythms."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1538\/expanim.58.123","article-title":"Unique inbred strain MSM\/Ms established from the Japanese wild mouse","volume":"58","author":"Moriwaki","year":"2009","journal-title":"Exp. Anim."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/343177a0","article-title":"Identification of a retinoic acid responsive element in the retinoic acid receptor \u03b2 gene","volume":"343","author":"Tiollais","year":"1990","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0304-3835(01)00548-1","article-title":"Chemoprevention of NMU-induced rat mammary carcinoma with the combination of melatonin and 9-cis-retinoic acid","volume":"168","author":"Teplitzky","year":"2001","journal-title":"Cancer Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1023\/A:1014912919470","article-title":"Tumor prevention by 9-cis-retinoic acid in the N-nitroso-N-methylurea model of mammary carcinogenesis is potentiated by the pineal hormone melatonin","volume":"72","author":"Nowfar","year":"2002","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/978-1-4615-0067-4_46","article-title":"Melatonin enhances retinoic acid induction of cone arrestin gene expression in retinoblastoma cells","volume":"533","author":"Li","year":"2003","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/j.1600-079X.2004.00198.x","article-title":"Differential regulation of estrogen receptor alpha, glucocorticoid receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins","volume":"38","author":"Kiefer","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1210\/mend.14.9.0518","article-title":"Cytochrome P450RAI(CYP26) promoter: A distinct composite retinoic acid response element underlies the complex regulation of retinoic acid metabolism","volume":"14","author":"Loudig","year":"2000","journal-title":"Mol. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1126\/science.279.5355.1358","article-title":"Melatonin production: Proteasomal proteolysis in serotonin N-acetyltransferase regulation","volume":"279","author":"Gastel","year":"1998","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1073\/pnas.0406871102","article-title":"Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205","volume":"102","author":"Ganguly","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1600-079X.2011.00880.x","article-title":"Dynamics in enzymatic protein complexes offer a novel principle for the regulation of melatonin synthesis in the human pineal gland","volume":"51","author":"Maronde","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16015","DOI":"10.1073\/pnas.0804801105","article-title":"Retinoic acid regulates RAR\u03b1-mediated control of translation in dendritic RNA granules during homeostatic synaptic plasticity","volume":"105","author":"Maghsoodi","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"32544","DOI":"10.1074\/jbc.M301523200","article-title":"Activation of protein kinase C by all-trans-retinoic acid","volume":"278","author":"Kambhampati","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1210\/me.2007-0062","article-title":"Rapid, nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor","volume":"21","author":"Alvarez","year":"2007","journal-title":"Mol. Endocrinol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1210\/en.2003-0838","article-title":"Photoperiodic Regulation of Hypothalamic Retinoid Signaling: Association of Retinoid X Receptor \u03b3 with Body Weight","volume":"145","author":"Ross","year":"2004","journal-title":"Endocrinology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1210\/en.2011-1792","article-title":"Photoperiod regulates vitamin A and Wnt\/\u03b2-catenin signaling in F344 rats","volume":"153","author":"Helfer","year":"2012","journal-title":"Endocrinology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1046\/j.1460-9568.2000.00990.x","article-title":"Transcription factor dynamics and neuroendocrine signalling in the mouse pineal gland: A comparative analysis of melatonin-deficient C57BL mice and melatonin-proficient C3H mice","volume":"12","author":"Lewy","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/j.1600-079X.1996.tb00249.x","article-title":"HPLC validation of a circadian melatonin rhythm in the pineal gland of inbred mice","volume":"20","author":"Conti","year":"1996","journal-title":"J. Pineal Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1023\/A:1006442017658","article-title":"Pathways through which a regimen of melatonin and retinoic acid induces apoptosis in MCF-7 human breast cancer cells","volume":"61","author":"Kiefer","year":"2000","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1111\/j.1600-079X.2008.00620.x","article-title":"The G\u03b1i and G\u03b1q proteins mediate the effects of melatonin on steroid\/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation","volume":"45","author":"Lai","year":"2008","journal-title":"J. Pineal Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1023\/A:1013301408464","article-title":"Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells","volume":"71","author":"Kiefer","year":"2002","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/nar\/23.3.327","article-title":"Transcriptional activation of the nuclear receptor RZR\u03b1 by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand","volume":"23","author":"Wiesenberg","year":"1995","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0303-7207(01)00449-X","article-title":"; Hill SM Transcriptional repression of ROR\u03b1 activity in human breast cancer cells by melatonin","volume":"176","author":"Dai","year":"2001","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/j.1600-079X.2011.00909.x","article-title":"Melatonin synthesized by T lymphocytes as a ligand of the retinoic acid-related orphan receptor","volume":"51","author":"Lardone","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"19732","DOI":"10.1074\/jbc.271.33.19732","article-title":"Identification of Natural Monomeric Response Elements of the Nuclear Receptor RZR\/ROR","volume":"271","author":"Schrader","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"20156","DOI":"10.1074\/jbc.270.34.20156","article-title":"Functional interactions between retinoic acid receptor-related orphan nuclear receptor (ROR\u03b1) and the retinoic acid receptors in the regulation of the \u03b3F-crystallin promoter","volume":"270","author":"Tini","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1210\/endo.132.4.8384988","article-title":"Induction of retinoic acid receptor-\u03b2 by retinoic acid is cell specific","volume":"132","author":"Davis","year":"1993","journal-title":"Endocrinology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"32200","DOI":"10.1074\/jbc.273.48.32200","article-title":"Promoter architecture, cofactors, and orphan receptors contribute to cell-specific activation of the retinoic acid receptor \u03b22 promoter","volume":"273","author":"Folkers","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1194\/jlr.R100015-JLR200","article-title":"Gene expression regulation by retinoic acid","volume":"43","author":"Balmer","year":"2002","journal-title":"J. Lipid Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1586\/ern.09.86","article-title":"All-trans-retinoic acid as a novel therapeutic strategy for Alzheimer\u2019s Disease","volume":"9","author":"Lee","year":"2009","journal-title":"Expert Rev. Neurother."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1600-079X.2011.00937.x","article-title":"Alzheimer\u2019s disease: Pathological mechanisms and the beneficial role of melatonin","volume":"52","author":"Boga","year":"2012","journal-title":"J. Pineal Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1159\/000081966","article-title":"Analysis of adrenergic regulation of melatonin synthesis in Siberian hamster pineal emphasizes the role of HIOMT","volume":"13","author":"Ceinos","year":"2004","journal-title":"NeuroSignals"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0092-8674(04)00127-8","article-title":"Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs","volume":"116","author":"Cawley","year":"2004","journal-title":"Cell"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/286\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:03:12Z","timestamp":1760119392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/286"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":67,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12020286"],"URL":"https:\/\/doi.org\/10.3390\/cells12020286","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,11]]}}}