{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T04:40:59Z","timestamp":1792557659752,"version":"4.5.0"},"reference-count":307,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007343","name":"Universit\u00e0 degli Studi di Brescia","doi-asserted-by":"publisher","award":["ex-60%"],"award-info":[{"award-number":["ex-60%"]}],"id":[{"id":"10.13039\/501100007343","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>For years the thymus gland (TG) and the pineal gland (PG) have been subject of increasingly in-depth studies, but only recently a link that can associate the activities of the two organs has been identified. Considering, on the one hand, the well-known immune activity of thymus and, on the other, the increasingly emerging immunological roles of circadian oscillators and the rhythmically secreted main pineal product, melatonin, many studies aimed to analyse the possible existence of an interaction between these two systems. Moreover, data confirmed that the immune system is functionally associated with the nervous and endocrine systems determining an integrated dynamic network. In addition, recent researches showed a similar, characteristic involution process both in TG and PG. Since the second half of the 20th century, evidence led to the definition of an effectively interacting thymus-pineal axis (TG-PG axis), but much has to be done. In this sense, the aim of this review is to summarize what is actually known about this topic, focusing on the impact of the TG-PG axis on human life and ageing. We would like to give more emphasis to the implications of this dynamical interaction in a possible therapeutic strategy for human health. Moreover, we focused on all the products of TG and PG in order to collect what is known about the role of peptides other than melatonin. The results available today are often unclear and not linear. These peptides have not been well studied and defined over the years. In this review we hope to awake the interest of the scientific community in them and in their future pharmacological applications.<\/jats:p>","DOI":"10.3390\/ijms21228806","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T01:28:48Z","timestamp":1606094928000},"page":"8806","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Thymus-Pineal Gland Axis: Revisiting Its Role in Human Life and Ageing"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7515-5846","authenticated-orcid":false,"given":"Rita","family":"Rezzani","sequence":"first","affiliation":[{"name":"Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy"},{"name":"Interdipartimental University Center of Research \u201cAdaption and Regeneration of Tissues and Organs-(ARTO)\u201d, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Franco","sequence":"additional","affiliation":[{"name":"Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Hardeland","sequence":"additional","affiliation":[{"name":"Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of G\u00f6ttingen, Lower Saxony, D-37073 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi Fabrizio","family":"Rodella","sequence":"additional","affiliation":[{"name":"Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy"},{"name":"Interdipartimental University Center of Research \u201cAdaption and Regeneration of Tissues and Organs-(ARTO)\u201d, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"ref_1","unstructured":"Bjertness, E. (2008). Light, circadian and circannual rhythms. Solar Radiation and Human Health, The Norwegian Academy of Science and Letters."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.31031\/GGS.2017.01.000506","article-title":"Age-Related Changes in the Melatonin and Thymulin Biorhythms as Risk Factors for Human Neurodegenerative Diseases","volume":"1","author":"Labunets","year":"2017","journal-title":"Gerontol. Geriatr. Stud."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.advms.2020.07.001","article-title":"Circadian disruption, melatonin rhythm perturbations and their contributions to chaotic physiology","volume":"65","author":"Reiter","year":"2020","journal-title":"Adv. Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3466","DOI":"10.1016\/j.jmb.2020.01.009","article-title":"Molecular Regulation of Circadian Chromatin","volume":"432","author":"Zhu","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev.ph.55.030193.000313","article-title":"Temporal organization: Reflections of a Darwinian clock-watcher","volume":"55","author":"Pittendrigh","year":"1993","journal-title":"Annu. Rev. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1562\/0031-8655(2000)071<0758:DACVIS>2.0.CO;2","article-title":"Daily and circadian variation in survival from ultraviolet radiation in Chlamydomonas Reinhardtii","volume":"71","author":"Nikaido","year":"2000","journal-title":"Photochem. Photobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3864","DOI":"10.4161\/cc.9.19.13205","article-title":"Circadian clocks and cell division. What\u2019s the pacemaker?","volume":"9","author":"Johnson","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0165-7992(95)90065-9","article-title":"Melatonin protects human blood lymphocytes from radiation-induced chromosome damage","volume":"346","author":"Reiter","year":"1995","journal-title":"Mutat. Res. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.ijrobp.2004.02.006","article-title":"Melatonin as a radioprotective agent: A review","volume":"59","author":"Reiter","year":"2004","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12576-016-0450-7","article-title":"The mammalian circadian clock and its entrainment by stress and exercise","volume":"67","author":"Tahara","year":"2017","journal-title":"J. Physiol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.yhbeh.2019.02.018","article-title":"The physiological significance of the circadian dynamics of the HPA axis: Interplay between circadian rhythms, allostasis and stress resilience","volume":"110","author":"Rao","year":"2019","journal-title":"Horm. Behav."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104832","DOI":"10.1016\/j.nbd.2020.104832","article-title":"The wrinkling of time: Aging, inflammation, oxidative stress, and the circadian clock in neurodegeneration","volume":"139","author":"Lananna","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.32794\/mr11250012","article-title":"Melatonin and chromatin","volume":"2","author":"Hardeland","year":"2019","journal-title":"Melatonin Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3233\/NIB-190159","article-title":"Noncoding RNAs: Bridging regulation of circadian rhythms and inflammation","volume":"7","author":"Hardeland","year":"2019","journal-title":"Adv. Neuroimmune Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature09253","article-title":"Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes","volume":"466","author":"Marcheva","year":"2010","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1600-079X.2011.00934.x","article-title":"Melatonin, the circadian multioscillator system and health: The need for detailed analyses of peripheral melatonin signaling","volume":"52","author":"Hardeland","year":"2012","journal-title":"J. Pineal Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1615\/CritRevOncog.v13.i4.30","article-title":"Light at night, chronodisruption, melatonin suppression, and cancer risk: A review","volume":"13","author":"Reiter","year":"2007","journal-title":"Crit. Rev. Oncog."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s00114-007-0335-y","article-title":"Chronodisruption and cancer","volume":"95","author":"Erren","year":"2008","journal-title":"Naturwissenschaften"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1002\/iub.2287","article-title":"Melatonin: An atypical hormone with major functions in the regulation of angiogenesis","volume":"72","author":"Reiter","year":"2020","journal-title":"IUBMB Life"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.2174\/1381612820666140130201131","article-title":"Chronobiology of the neuroimmunoendocrine system and aging","volume":"20","author":"Mate","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/brbi.1995.1009","article-title":"Altered thyrotropic and somatotropic responses to environmental challenges in congenitally athymic mice","volume":"9","author":"Goya","year":"1995","journal-title":"Brain Behav. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.3109\/07420528.2012.719969","article-title":"When the circadian clock becomes a ticking time bomb","volume":"29","author":"Reiter","year":"2012","journal-title":"Chronobiol. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11972","DOI":"10.18632\/oncotarget.7863","article-title":"Morphofunctional and signaling molecules overlap of the pineal gland and thymus: Role and significance in aging","volume":"7","author":"Paltsev","year":"2016","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s10517-011-1400-2","article-title":"Functional unity of the thymus and pineal gland and study of the mechanisms of aging","volume":"151","author":"Polyakova","year":"2011","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1556\/030.63.2016.2.1","article-title":"The Immunoendocrine Thymus as a Pacemaker of Lifespan","volume":"63","author":"Csaba","year":"2016","journal-title":"Acta Microbiol. Immunol. Hung."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.exger.2007.05.001","article-title":"No Immune Risk Profile among individuals who reach 100 years of age: Findings from the Swedish NONA immune longitudinal study","volume":"42","author":"Strindhall","year":"2007","journal-title":"Exp. Gerontol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1089\/ars.2010.3228","article-title":"Aging and immune function: Molecular mechanisms to interventions","volume":"14","author":"Ponnappan","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"167","DOI":"10.2174\/1568026023394335","article-title":"Melatonin-immune system relationships","volume":"2","author":"Guerrero","year":"2002","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1196\/annals.1356.008","article-title":"The pineal aging and death program: Life prolongation in pre-aging pinealectomized mice","volume":"1057","author":"Pierpaoli","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/014850102317267427","article-title":"Effects of gonadal hormones on thymus gland after bilateral ovariectomy and orchidectomy in rats","volume":"48","author":"Oner","year":"2002","journal-title":"Arch. Androl."},{"key":"ref_31","first-page":"543","article-title":"Influence of peptides from pineal gland on thymus function at aging","volume":"23","author":"Linkova","year":"2010","journal-title":"Adv. Gerontol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0022-5193(05)80118-3","article-title":"The role of a thymus-pineal axis in an immune mechanism of aging","volume":"145","author":"Cardarelli","year":"1990","journal-title":"J. Theor. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.anndiagpath.2003.11.006","article-title":"Histologic and molecular assessment of human thymus","volume":"8","author":"Hale","year":"2004","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev.immunol.26.021607.090408","article-title":"Thymus organogenesis","volume":"26","author":"Rodewald","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s11357-013-9564-5","article-title":"Thymus and aging: Morphological, radiological, and functional overview","volume":"36","author":"Rezzani","year":"2014","journal-title":"Age"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.coi.2013.06.002","article-title":"Thymic rejuvenation and aging","volume":"25","author":"Ventevogel","year":"2013","journal-title":"Curr. Opin. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/cei.12851","article-title":"Immune senescence: Significance of the stromal microenvironment","volume":"187","author":"Masters","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1080\/00207454.2019.1692838","article-title":"Revisiting the pineal gland: A review of calcification, masses, precocious puberty, and melatonin functions","volume":"130","author":"Patel","year":"2020","journal-title":"Int. J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1038\/nri3534","article-title":"Thymus involution and regeneration: Two sides of the same coin?","volume":"13","author":"Boehm","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.immuni.2011.12.016","article-title":"Intravital imaging of thymopoiesis reveals dynamic lympho-epithelial interactions","volume":"36","author":"Hess","year":"2012","journal-title":"Immunity"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1084\/jem.181.4.1445","article-title":"Early human T cell development: Analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment","volume":"181","author":"Haynes","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1182\/blood-2006-02-004531","article-title":"Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells","volume":"108","author":"Gray","year":"2006","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/j.1365-3083.1985.tb01916.x","article-title":"The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study","volume":"22","author":"Steinmann","year":"1985","journal-title":"Scand. J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8447","DOI":"10.1073\/pnas.0601040103","article-title":"Thymic output in aged mice","volume":"103","author":"Hale","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4784","DOI":"10.4049\/jimmunol.1403158","article-title":"Young, proliferative thymic epithelial cells engraft and function in aging thymuses","volume":"194","author":"Kim","year":"2015","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1210\/endo.142.3.8032","article-title":"Androgen receptors in thymic epithelium modulate thymus size and thymocyte development","volume":"142","author":"Olsen","year":"2001","journal-title":"Endocrinology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/j.1600-0897.1996.tb00176.x","article-title":"Estrogen blocks early T cell development in the thymus","volume":"36","author":"Rijhsinghani","year":"1996","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1210\/endo.136.11.7588221","article-title":"Mechanism of androgen-induced thymolysis in rats","volume":"136","author":"Kumar","year":"1995","journal-title":"Endocrinology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"12021","DOI":"10.1073\/pnas.96.21.12021","article-title":"Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility","volume":"96","author":"Tibbetts","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1113\/jphysiol.1904.sp001032","article-title":"On the relationship of the thymus to the sexual organs: I. The influence of castration on the thymus","volume":"31","author":"Henderson","year":"1904","journal-title":"J. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.smim.2005.05.006","article-title":"Reevaluating current models of thymic involution","volume":"17","author":"Min","year":"2005","journal-title":"Semin. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"245","DOI":"10.4049\/jimmunol.173.1.245","article-title":"Reduction in the developmental potential of intrathymic T cell progenitors with age","volume":"173","author":"Min","year":"2004","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.4049\/jimmunol.164.4.2180","article-title":"Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy","volume":"164","author":"Sempowski","year":"2000","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1002\/eji.200839149","article-title":"Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis","volume":"39","author":"Esashi","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/S1567-5769(01)00038-8","article-title":"Gonadotropin-releasing hormone: Potential role in autoimmunity","volume":"1","author":"Jacobson","year":"2001","journal-title":"Int. Immunopharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1159\/000054306","article-title":"Cyclical expression of GnRH and GnRH receptor mRNA in lymphoid organs","volume":"67","author":"Jacobson","year":"1998","journal-title":"Neuroendocrinology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/0091-3057(95)02165-5","article-title":"Differential effects of gonadectomy on the thymocyte phenotypic profile in male and female rats","volume":"54","author":"Kosec","year":"1996","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/0047-6374(89)90030-4","article-title":"Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy","volume":"47","author":"Utsuyama","year":"1989","journal-title":"Mech. Ageing. Dev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1210\/edrv.18.2.0296","article-title":"The somatogenic hormones and insulin-like growth factor-1: Stimulators of lymphopoiesis and immune function","volume":"18","author":"Clark","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1159\/000026365","article-title":"The immune-endocrine loop during aging: Role of growth hormone and insulin-like growth factor-I","volume":"6","author":"Burgess","year":"1999","journal-title":"Neuroimmunomodulation"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.pneurobio.2015.02.001","article-title":"Melatonin and brain inflammaging","volume":"127\u2013128","author":"Hardeland","year":"2015","journal-title":"Prog. Neurobiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.tem.2016.09.005","article-title":"Inflammaging and \u2018garb-aging\u2019","volume":"28","author":"Franceschi","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1679\/aohc.45.139","article-title":"Histophysiology of thymic epithelial reticular cells","volume":"45","author":"Savino","year":"1982","journal-title":"Arch. Histol. Jpn."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-079X.1993.tb00478.x","article-title":"The immunoneuroendocrine role of melatonin","volume":"14","author":"Maestroni","year":"1993","journal-title":"J. Pineal. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1556\/AMicr.60.2013.2.1","article-title":"The pineal regulation of the immune system: 40 years since the discovery","volume":"60","author":"Csaba","year":"2013","journal-title":"Acta Microbiol. Immunol. Hung."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1034\/j.1600-079X.2003.02111.x","article-title":"Melatonin\u2014A hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin","volume":"34","author":"Tan","year":"2003","journal-title":"J. Pineal Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00018-007-6435-1","article-title":"Melatonin biosynthesis in the thymus of humans and rats","volume":"64","author":"Naranjo","year":"2007","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1007\/s00018-014-1579-2","article-title":"Extrapineal melatonin: Sources, regulation, and potential functions","volume":"71","author":"Escames","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1023\/A:1020107915919","article-title":"Gastrointestinal melatonin: Localization, function, and clinical relevance","volume":"47","author":"Bubenik","year":"2002","journal-title":"Dig. Dis. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Reiter, R.J., Tan, D.-X., Rosales-Corral, S., Galano, A., Zhou, X.J., and Xu, B. (2018). Mitochondria: Central organelles for melatonin\u2019s antioxidant and anti-aging actions. Molecules, 23.","DOI":"10.3390\/molecules23020509"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1743-7075-2-22","article-title":"Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug","volume":"2","author":"Hardeland","year":"2005","journal-title":"Nutr. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1155\/MBD.1994.233","article-title":"Interactions between zinc and thymulin","volume":"1","author":"Dardenne","year":"1994","journal-title":"Met. Based Drugs"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000022082","article-title":"Homeostasis, thymic hormones and aging","volume":"45","author":"Goya","year":"1999","journal-title":"Gerontology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/BF02985220","article-title":"Thymulin, a zinc-dependent hormone","volume":"6","author":"Bach","year":"1989","journal-title":"Med. Oncol. Tumor Pharm."},{"key":"ref_75","first-page":"109","article-title":"Feedback regulation of the secretion of a thymic hormone (thymulin) by human thymic epithelial cells in culture","volume":"8","author":"Cohen","year":"1986","journal-title":"Thymus"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4690","DOI":"10.2174\/1381612820666140130211157","article-title":"Physiology and therapeutic potential of the thymic peptide thymulin","volume":"20","author":"Reggiani","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_77","first-page":"421","article-title":"Involution of the mammalian thymus, one of the leading regulators of aging","volume":"11","author":"Bodey","year":"1997","journal-title":"In Vivo"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/0167-5699(95)80144-8","article-title":"Immune-neuroendocrine interactions","volume":"16","author":"Savino","year":"1995","journal-title":"Immunol. Today"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1152\/ajpendo.00085.2007","article-title":"Thymulin gene therapy prevents the reduction in circulating gonadotropins induced by thymulin deficiency in mice","volume":"293","author":"Goya","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3922","DOI":"10.1210\/en.2012-1183","article-title":"Neonatal thymulin gene therapy prevents ovarian dysgenesis and attenuates reproductive derangements in nude female mice","volume":"153","author":"Reggiani","year":"2012","journal-title":"Endocrinology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1365-2826.1992.tb00171.x","article-title":"Interactions between the hypothalamo-pituitary adrenal axis and the thymus in the rat: A role for corticotrophin in the control of thymulin release","volume":"4","author":"Buckingham","year":"1992","journal-title":"J. Neuroendocrinol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1196\/annals.1366.006","article-title":"Role of thymulin or its analogue as a new analgesic molecule","volume":"1088","author":"Dardenne","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_83","first-page":"412","article-title":"Neuroendocrine control of thymus physiology","volume":"21","author":"Savino","year":"2000","journal-title":"Endocr. Rev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.exger.2007.10.013","article-title":"Clinical, immunological, anti-inflammatory and antioxidant roles of zinc","volume":"43","author":"Prasad","year":"2008","journal-title":"Exp. Gerontol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.intimp.2015.01.021","article-title":"Modulation of inflammatory response in mice with severe autoimmune disease by thymic peptide thymulin and an inhibitor of NF-kappaB signalling","volume":"25","author":"Lunin","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1111\/j.1348-0421.2004.tb03471.x","article-title":"Serum thymic factor prevents LPS-induced pancreatic cell damage in mice via up-regulation of Bcl-2 expression in pancreas","volume":"48","author":"Saitoh","year":"2004","journal-title":"Microbiol. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jconrel.2014.02.010","article-title":"DNA nanoparticle-mediated thymulin gene therapy prevents airway remodeling in experimental allergic asthma","volume":"180","author":"Martini","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1134\/S0012496609050263","article-title":"Involvement of NF-kappaB transcription factor in the antiinflammatory activity of thymic peptides","volume":"428","author":"Novoselova","year":"2009","journal-title":"Dokl. Biol. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.molimm.2009.09.034","article-title":"Thymulin and zinc (Zn2+)-mediated inhibition of endotoxin-induced production of proinflammatory cytokines and NF-kappaB nuclear translocation and activation in the alveolar epithelium: Unraveling the molecular immunomodulatory, anti-inflammatory effect of thymulin\/Zn2+ in vitro","volume":"47","author":"Haddad","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"724838","DOI":"10.1155\/2014\/724838","article-title":"Anti-inflammatory effects of IKK inhibitor XII, thymulin, and fat-soluble antioxidants in LPS-treated mice","volume":"2014","author":"Novoselova","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1073\/pnas.56.3.1010","article-title":"Preparation, assay, and partial purification of a thymic lymphocytopoietic factor (thymosin)","volume":"56","author":"Goldstein","year":"1966","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1415.045","article-title":"History of the discovery of the thymosins","volume":"1112","author":"Goldstein","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.msard.2018.09.035","article-title":"Thymosins in multiple sclerosis and its experimental models: Moving from basic to clinical application","volume":"27","author":"Severa","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/14712598.2018.1474196","article-title":"Thymosin fraction 5 re-evaluated after 35 years by high-resolution mass spectrometry","volume":"18","author":"Hannappel","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"6645","DOI":"10.1021\/acs.biochem.8b01075","article-title":"Binding affinity and function of the extremely disordered protein complex containing human linker histone H1.0 and its chaperone ProT\u03b1","volume":"57","author":"Feng","year":"2018","journal-title":"Biochemistry"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3425","DOI":"10.1016\/j.yexcr.2006.07.021","article-title":"Zyxin is upregulated in the nucleus by thymosin \u03b24 in SiHa cells","volume":"312","author":"Moon","year":"2006","journal-title":"Exp. Cell Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1196\/annals.1415.031","article-title":"Subcellular distribution of thymosin \u03b24","volume":"1112","author":"Zoubek","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1080\/14712598.2018.1490409","article-title":"Thymosin \u03b24-mediated protective effects in the heart","volume":"18","author":"Hinkel","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1080\/14712598.2018.1456527","article-title":"Potential mechanism of thymosin-\u03b11-membrane interactions leading to pleiotropy: Experimental evidence and hypotheses","volume":"18","author":"Mandaliti","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1196\/annals.1415.018","article-title":"\u03b2-Thymosins","volume":"1112","author":"Hannappel","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1007\/s00268-004-7817-2","article-title":"Roles of thymosins in cancers and other organ systems","volume":"29","author":"Chen","year":"2005","journal-title":"World J. Surg."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0014-5793(94)00439-0","article-title":"Prothymosin alpha binds to histone H1 in vitro","volume":"345","author":"Papamarcaki","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1517\/14712598.2015.1044895","article-title":"Thymosin \u03b11: Burying secrets in the thymus","volume":"15","author":"Moretti","year":"2015","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1073\/pnas.87.9.3269","article-title":"Cellular levels of thymosin immunoreactive peptides are linked to proliferative events: Evidence for a nuclear site of action","volume":"87","author":"Conteas","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.2010.05465.x","article-title":"Thymosin \u03b11: The regulator of regulators?","volume":"1194","author":"Pierluigi","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.2012.06716.x","article-title":"Jack of all trades: Thymosin \u03b11 and its pleiotropy","volume":"1269","author":"Romani","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S0165-5728(97)00189-6","article-title":"A role of the thymus and thymosin-alpha1 in brain NGF levels and NGF receptor expression","volume":"82","author":"Turrini","year":"1998","journal-title":"J. Neuroimmunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/WNR.0000000000001370","article-title":"Immunopotentiator thymosin alpha-1 attenuates inflammatory pain by modulating the Wnt3a\/\u03b2-catenin pathway in spinal cord","volume":"31","author":"Huang","year":"2020","journal-title":"Neuroreport"},{"key":"ref_109","first-page":"698","article-title":"Thymosin alpha1. SciClone Pharmaceuticals","volume":"3","author":"Billich","year":"2002","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_110","first-page":"133","article-title":"Thymosin alpha 1\u2013A peptide immune modulator with a broad range of clinical applications","volume":"3","author":"Tuthill","year":"2013","journal-title":"Clin. Exp. Pharmacol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/bs.vh.2016.04.003","article-title":"Immune Modulation with Thymosin Alpha 1 Treatment","volume":"102","author":"King","year":"2016","journal-title":"Vitam. Horm."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3389\/fonc.2019.00873","article-title":"A Reappraisal of Thymosin Alpha1 in Cancer Therapy","volume":"9","author":"Costantini","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Liu, F., Wang, H., Wang, T., Zhang, Y., and Zhu, X. (2016). The efficacy of thymosin alpha1 as immunomodulatory treatment for sepsis: A systematic review of randomized controlled trials. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-1823-5"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1182\/blood-2006-02-004762","article-title":"Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance","volume":"108","author":"Romani","year":"2006","journal-title":"Blood"},{"key":"ref_115","first-page":"55","article-title":"Thymosin beta in macrophage","volume":"11","author":"Rath","year":"2007","journal-title":"J. Endocrinol. Reprod."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S1357-2725(00)00087-X","article-title":"beta-Thymosins, small acidic peptides with multiple functions","volume":"33","author":"Huff","year":"2001","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s00418-016-1529-1","article-title":"Thymosin beta4 overexpression regulates neuron production and spatial distribution in the developing avian optic tectum","volume":"147","author":"Lever","year":"2017","journal-title":"Histochem. Cell Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1196\/annals.1415.046","article-title":"Identification and quantification of thymosin beta4 in human saliva and tears","volume":"1112","author":"Badamchian","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1517\/14712598.2012.634793","article-title":"Thymosin beta4: A multi-functional regenerative peptide. Basic properties and clinical applications","volume":"12","author":"Goldstein","year":"2012","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/14712598.2018.1459558","article-title":"Thymosin \u03b24 and the vasculature: Multiple roles in development, repair and protection against disease","volume":"18","author":"Smart","year":"2018","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1517\/14728222.2010.499127","article-title":"Thymus hormones as prospective anti-inflammatory agents","volume":"14","author":"Lunin","year":"2010","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_122","first-page":"1","article-title":"Precursors of thymic peptides as stress sensors [published online ahead of print]","volume":"2020","author":"Lunin","year":"2020","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/247011a0","article-title":"Isolation of bovine thymin: A polypeptide hormone of the thymus","volume":"247","author":"Goldstein","year":"1974","journal-title":"Nature"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"6283","DOI":"10.1073\/pnas.91.14.6283","article-title":"Three distinct human thymopoietins are derived from alternatively spliced mRNAs","volume":"91","author":"Harris","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1159\/000203673","article-title":"Ubiquitous expression of a cloned murine thymopoietin cDNA","volume":"97","author":"Theodor","year":"1997","journal-title":"Acta Haematol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1006\/geno.1995.1131","article-title":"Structure and mapping of the human thymopoietin (TMPO) gene and relationship of human TMPO beta to rat lamin-associated polypeptide 2","volume":"28","author":"Harris","year":"1995","journal-title":"Genomics"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1242\/jcs.112.15.2485","article-title":"LAP2 binding protein 1 (L2BP1\/BAF) is a candidate mediator of LAP2-chromatin interaction","volume":"112","author":"Furukawa","year":"1999","journal-title":"J. Cell Sci."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.cell.2018.10.054","article-title":"LAP2 proteins chaperone GLI1 movement between the lamina and chromatin to regulate transcription","volume":"176","author":"Mirza","year":"2019","journal-title":"Cell"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1101\/gr.6.5.361","article-title":"The characterization and localization of the mouse thymopoietin\/lamina-associated polypeptide 2 gene and its alternatively spliced products","volume":"6","author":"Berger","year":"1996","journal-title":"Genome Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/j.1749-6632.1975.tb29076.x","article-title":"Antigenic and functional evidence for the in vitro inductive activity of thymopoietin (thymin) on thymocyte precursors","volume":"249","author":"Basch","year":"1975","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.451537","article-title":"A synthetic pentapeptide with biological activity characteristic of the thymic hormone thymopoietin","volume":"204","author":"Goldstein","year":"1979","journal-title":"Science"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1021\/jp909017j","article-title":"Direct binding of thymopentin to surface class II major histocompatibility complex in living cells","volume":"114","author":"Liu","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1530\/acta.0.1150455","article-title":"Thymopoietin and thymopentin enhance the levels of ACTH, beta-endorphin and beta-lipotropin from rat pituitary cells in vitro","volume":"115","author":"Malaise","year":"1987","journal-title":"Eur. J. Endocrinol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1530\/acta.0.1270237","article-title":"Acute beta-interferon or thymopentin administration increases plasma growth hormone and cortisol levels in children","volume":"127","author":"Angioni","year":"1992","journal-title":"Eur. J. Endocrinol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/199653a0","article-title":"Evidenc for a humoral thymus factor responsible for the maturation of immunological faculty","volume":"199","author":"Osoba","year":"1963","journal-title":"Nature"},{"key":"ref_136","first-page":"261","article-title":"Immunopotentiating and immunotherapeutic effects of thymic hormones and factors with special emphasis on thymic humoral factor THF-gamma2","volume":"19","author":"Keisari","year":"1999","journal-title":"Crit. Rev. Immunol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/j.1365-2249.1992.tb03000.x","article-title":"Effect of synthetic thymic humoral factor (THF-gamma 2) on T cell activities in immunodeficient ageing mice","volume":"87","author":"Goso","year":"1992","journal-title":"Clin. Exp. Immunol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1002\/ijc.2910450633","article-title":"A synthetic thymic hormone, THF-\u03b32, repairs immunodeficiency of mice cured of plasmacytoma by melphalan","volume":"45","author":"Ophir","year":"1990","journal-title":"Int. J. Cancer"},{"key":"ref_139","first-page":"269","article-title":"Immunomodulation of T cell deficiency in humans by thymic humoral factor: From crude extract to synthetic thymic humoral factor-\u03b32","volume":"9","author":"Handzel","year":"1990","journal-title":"J. Biol. Response Mod."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/0923-2494(93)80123-G","article-title":"Effects of thymus humoral factor gamma-2 (THF gamma 2) on lymphohaematopoietic progenitor cells: An in vitro study","volume":"144","author":"Calenda","year":"1993","journal-title":"Res. Immunol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0192-0561(99)00084-3","article-title":"Review of thymic hormones in cancer diagnosis and treatment","volume":"22","author":"Bodey","year":"2000","journal-title":"Int. J. Immunopharmacol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1098\/rstb.2003.1303","article-title":"Evolution of photosensory pineal organs in new light: The fate of neuroendocrine photoreceptors","volume":"358","author":"Meissl","year":"2003","journal-title":"Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13024-019-0330-8","article-title":"Pineal gland dysfunction in Alzheimer\u2019s disease: Relationship with the immune-pineal axis, sleep disturbance, and neurogenesis","volume":"14","author":"Song","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_144","first-page":"111","article-title":"Morphometric parameters of the human pineal gland in relation to age, body weight and height","volume":"61","author":"Golan","year":"2002","journal-title":"Folia Morphol"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0304-3940(93)90850-K","article-title":"The preoptic nucleus: The probable location of the circadian pacemaker of the hagfish","volume":"164","author":"Kadota","year":"1993","journal-title":"Eptatretus Burgeri. Neurosci. Lett."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.mod.2017.09.002","article-title":"The evolution of asymmetric photosensitive structures in metazoans and the Nodal connection","volume":"147","author":"Boutet","year":"2017","journal-title":"Mech. Dev."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/BF01451040","article-title":"The pineal gland and geographical distribution of animals","volume":"19","author":"Ralph","year":"1975","journal-title":"Int. J. Biometeorol."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Tan, D.X., Xu, B., Zhou, X., and Reiter, R.J. (2018). Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland. Molecules, 23.","DOI":"10.3390\/molecules23020301"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1600-079X.1995.tb00156.x","article-title":"Day-night changes in melatonin levels in different organs of the cricket (Gryllus bimaculatus)","volume":"18","author":"Itoh","year":"1995","journal-title":"J. Pineal Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/j.1467-789X.2010.00756.x","article-title":"Significance and application of melatonin in the regulation of brown adipose tissue metabolism: Relation to human obesity","volume":"12","author":"Tan","year":"2011","journal-title":"Obes. Rev."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1111\/jsr.12125","article-title":"Pineal gland volume in primary insomnia and healthy controls: A magnetic resonance imaging study","volume":"23","author":"Bumb","year":"2014","journal-title":"J. Sleep Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1007\/BF01946705","article-title":"The pineal gland is very large and active in newborn antarctic seals","volume":"42","author":"Bryden","year":"1986","journal-title":"Experientia"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"575","DOI":"10.3174\/ajnr.A4153","article-title":"Physiologic pineal region, choroid plexus, and dural calcifications in the first decade of life","volume":"36","author":"Whitehead","year":"2015","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_154","first-page":"60","article-title":"Age-dependent morphology of human pineal gland: Supravital study","volume":"20","author":"Ivanov","year":"2007","journal-title":"Adv. Gerontol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"13","DOI":"10.5334\/jbr-btr.892","article-title":"Assessment of Pineal Gland Volume and Calcification in Healthy Subjects: Is it Related to Aging?","volume":"100","author":"Turamanlar","year":"2016","journal-title":"J. Belg. Soc. Radiol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1146\/annurev.ph.35.030173.001513","article-title":"Comparative physiology: Pineal gland","volume":"35","author":"Reiter","year":"1973","journal-title":"Annu. Rev. Physiol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00441-002-0580-5","article-title":"The anatomy and innervation of the mammalian pineal gland","volume":"309","author":"Baeres","year":"2002","journal-title":"Cell Tissue Res."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/B978-0-12-416021-7.00005-5","article-title":"The pineal gland from development to function","volume":"106","author":"Cau","year":"2013","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/joa.12771","article-title":"The origins of the circumventricular organs","volume":"232","author":"Kiecker","year":"2018","journal-title":"J. Anat."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Iba\u00f1ez Rodriguez, M.P., Noctor, S.C., and Mu\u00f1oz, E.M. (2016). Cellular basis of pineal gland development: Emerging role of microglia as phenotype regulator. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167063"},{"key":"ref_161","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_162","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1016\/S0021-9258(18)61591-1","article-title":"Molecular cloning and nucleotide sequence of cDNA encoding hydroxyindole O-methyltransferase of bovine pineal glands","volume":"262","author":"Ishida","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-8993(78)90234-2","article-title":"Immunohistochemical demonstration of S-100 protein and GFA protein in interstitial cells of rat pineal gland","volume":"140","author":"Ingild","year":"1978","journal-title":"Brain Res."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.pneurobio.2011.01.005","article-title":"GFAP in health and disease","volume":"93","author":"Middeldorp","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1679\/aohc.57.47","article-title":"Immunohistochemical studies on sympathetic and non-sympathetic nerve fibers and neuronal cell bodies in the pineal gland of cotton rats, Sigmodon hispidus","volume":"57","author":"Matsushima","year":"1994","journal-title":"Arch. Histol. Cytol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/(SICI)1097-0029(19990815\/01)46:4\/5<239::AID-JEMT2>3.0.CO;2-2","article-title":"Neuropeptide Y in the mammalian pineal gland","volume":"46","author":"Mikkelsen","year":"1999","journal-title":"Microsc. Res. Tech."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1034\/j.1600-079X.2001.310312.x","article-title":"Presence of oxytocinergic neuronal-like cells in the bovine pineal gland: An immunocytochemical and in situ hybridization study","volume":"31","author":"Badiu","year":"2001","journal-title":"J. Pineal Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1126\/science.1067262","article-title":"Phototransduction by retinal ganglion cells that set the circadian clock","volume":"295","author":"Berson","year":"2002","journal-title":"Science"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1007\/BF01923947","article-title":"The melatonin rhythm: Both a clock and a calendar","volume":"49","author":"Reiter","year":"1993","journal-title":"Experientia"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1007\/s00018-008-8001-x","article-title":"Melatonin, hormone of darkness and more: Occurrence, control mechanisms, actions and bioactive metabolites","volume":"65","author":"Hardeland","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/bem.10053","article-title":"Calcite microcrystals in the pineal gland of the human brain: First physical and chemical studies","volume":"23","author":"Baconnier","year":"2002","journal-title":"Bioelectromagnetics"},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Hardeland, R. (2019). Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051223"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.pneurobio.2010.12.004","article-title":"Melatonin\u2014A pleiotropic, orchestrating regulator molecule","volume":"93","author":"Hardeland","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1699-0463.1958.tb01060.x","article-title":"A microradiographic and X-ray crystallographic study of calcium in the pineal body and in intracranial tumours","volume":"44","author":"Angervall","year":"2009","journal-title":"Acta Pathol. Microbiol. Scand."},{"key":"ref_175","first-page":"226","article-title":"The morphological and functional characteristics of the pineal gland","volume":"92","author":"Gheban","year":"2019","journal-title":"Med. Pharm. Rep."},{"key":"ref_176","first-page":"17","article-title":"Varying Appearances of Calcification in Human Pineal Gland: A Light Microscopic Study","volume":"50","author":"Koshy","year":"2001","journal-title":"J. Anat. Soc. India"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.neurobiolaging.2006.10.003","article-title":"Pineal calcification in Alzheimer\u2019s disease: An in vivo study using computed tomography","volume":"29","author":"Mahlberg","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"95","DOI":"10.3109\/00207459408987233","article-title":"Pineal calcification and its relationship to the fatigue of multiple sclerosis","volume":"74","author":"Sandyk","year":"1994","journal-title":"Int. J. Neurosci."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3109\/00207459308994259","article-title":"The relationship of thought disorder to third ventricle width and calcification of the pineal gland in chronic schizophrenia","volume":"68","author":"Sandyk","year":"1993","journal-title":"Int. J. Neurosci."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/srep00984","article-title":"Growth patterns for acervuli in human pineal gland","volume":"2","author":"Kim","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/BF02431274","article-title":"The aged rat pineal gland as revealed in sem and tem","volume":"5","author":"Allen","year":"1982","journal-title":"Age"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0197-0186(95)80002-3","article-title":"The role of the neurohormone melatonin as a buffer against macromolecular oxidative damage","volume":"27","author":"Reiter","year":"1995","journal-title":"Neurochem. Int."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S1040-8428(03)00021-0","article-title":"The role of pineal gland in breast cancer development","volume":"46","author":"Anisimov","year":"2003","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0024-3205(77)90298-3","article-title":"Pineal antigonadotrophic substances: Polypeptides and indoles","volume":"21","author":"Reiter","year":"1977","journal-title":"Life Sci."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1874360900901010001","article-title":"Melatonin beyond its classical functions","volume":"1","author":"Hardeland","year":"2008","journal-title":"Open Physiol. J."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"168","DOI":"10.2174\/157015910792246164","article-title":"Melatonin metabolism in the central nervous system","volume":"8","author":"Hardeland","year":"2010","journal-title":"Curr. Neuropharmacol."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0306-4530(83)90041-0","article-title":"Is 5-methoxytryptamine a pineal hormone?","volume":"8","year":"1983","journal-title":"Psychoneuroendocrinology"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1046\/j.1471-4159.1998.71031108.x","article-title":"Modulation of neurosteroid synthesis\/accumulation by L-ascorbic acid in rat brain tissue: Inhibition by selected serotonin antagonists","volume":"71","author":"Roscetti","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"289","DOI":"10.2174\/187152407783220823","article-title":"Actions of melatonin, its structural and functional analogs in the central nervous system and the significance of metabolism","volume":"7","author":"Hardeland","year":"2007","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref_190","first-page":"113","article-title":"The influence of different 5-methoxyindoles on the process of protein\/peptide secretion characterized by the formation of granular vesicles in the mouse pineal gland. An in vitro study","volume":"230","year":"1983","journal-title":"Cell Tissue Res."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-079X.1987.tb00835.x","article-title":"Both hydroxy- and methoxyindoles modify basal temperature in the rat","volume":"4","author":"Morton","year":"1987","journal-title":"J. Pineal Res."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1586\/17446651.2013.811866","article-title":"Physiological and pharmacological properties of 5-methoxytryptophol","volume":"8","author":"Ouzir","year":"2013","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/jcb.25005","article-title":"A new role for 5-methoxytryptophol on bone cells function in vitro","volume":"116","author":"Ramis","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/BF01243372","article-title":"Acyltryptophols reversibly inhibit muscle contractions caused by the actions of acetylcholine and raised potassium ion concentrations","volume":"56","author":"Fernando","year":"1983","journal-title":"J. Neural Transm."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1006\/gcen.1996.0018","article-title":"Secretion of the methoxyindoles melatonin, 5-methoxytryptophol, 5-methoxyindoleacetic acid, and 5-methoxytryptamine from trout pineal organs in superfusion culture: Effects of light intensity","volume":"101","author":"Meissl","year":"1996","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0006-2952(81)90278-1","article-title":"Identification and quantification of 1,2,3,4-tetrahydro-beta-carboline, 2-methyl-1,2,3,4-tetrahydro-beta-carboline, and 6-methoxy-1,2,3,4-tetrahydro-beta-carboline as in vivo constituents of rat brain and adrenal gland","volume":"30","author":"Barker","year":"1981","journal-title":"Biochem. Pharmacol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0014-4835(83)90096-9","article-title":"6-Methoxy-tetrahydro-beta-carboline in the retinae of rabbits and pigs","volume":"36","author":"Leino","year":"1983","journal-title":"Exp. Eye Res."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1071\/BI9830379","article-title":"Effects of 6-methoxy-1,2,3,4-tetrahydro-beta-carboline and yohimbine on hypothalamic monoamine status and pituitary hormone release in the rat","volume":"36","author":"Smythe","year":"1983","journal-title":"Aust. J. Biol. Sci."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/S0091-3057(99)00265-8","article-title":"Differential effects of beta-carbolines and antidepressants on rat exploratory activity in the elevated zero-maze","volume":"65","author":"Kask","year":"2000","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/j.1600-079X.1999.tb00589.x","article-title":"Pharmacological aspects of N-acetyl-5-methoxytryptamine (melatonin) and 6-methoxy-1,2,3,4-tetrahydro-\u03b2-carboline (pinoline) as antioxidants: Reduction of oxidative damage in brain region homogenates","volume":"26","author":"Pless","year":"1999","journal-title":"J. Pineal Res."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1444-0938.2004.tb03170.x","article-title":"Effects of vitamin E and pinoline on retinal lipid peroxidation","volume":"87","author":"Tam","year":"2004","journal-title":"Clin. Exp. Optom."},{"key":"ref_202","unstructured":"Relkin, R. (1983). Pineal peptides and reproduction. The Pineal Gland, Elsevier."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1016\/S0024-3205(99)00335-5","article-title":"A cytotoxic, apoptotic, low-molecular weight factor from pineal gland","volume":"65","author":"Catrina","year":"1999","journal-title":"Life Sci."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0079-6123(08)64084-4","article-title":"Involvement of pineal indoles and polypeptides with the neuroendocrine axis","volume":"39","author":"Reiter","year":"1973","journal-title":"Prog. Brain Res."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1159\/000122694","article-title":"Stimulation of rat prolactin secretion in vivo by arginine vasotocin: Influence of age of solution, nighttime administration, and dose","volume":"24","author":"Vaughan","year":"1977","journal-title":"Neuroendocrinology"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s004410051228","article-title":"Arginine vasotocin mRNA revealed by in situ hybridization in bovine pineal gland cells","volume":"295","author":"Badiu","year":"1999","journal-title":"Cell Tissue Res."},{"key":"ref_207","first-page":"353","article-title":"Die akute antidiuretische Aktivit\u00e4t der Epiphysis cerebri von Wistar-Ratten","volume":"55","author":"Meyer","year":"1970","journal-title":"Endokrinologie"},{"key":"ref_208","doi-asserted-by":"crossref","unstructured":"Khavinson, V., Diomede, F., Mironova, E., Linkova, N., Trofimova, S., Trubiani, O., Caputi, S., and Sinjari, B. (2020). AEDG Peptide (Epitalon) Stimulates Gene Expression and Protein Synthesis during Neurogenesis: Possible Epigenetic Mechanism. Molecules, 25.","DOI":"10.3390\/molecules25030609"},{"key":"ref_209","first-page":"157","article-title":"Pineal peptides","volume":"13","author":"Benson","year":"1978","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_210","first-page":"137","article-title":"The pineal gland as a source of releasing hormones","volume":"17","author":"Damian","year":"1979","journal-title":"Endocrinologie"},{"key":"ref_211","first-page":"109","article-title":"Decrease of testosterone, cholesterol and ascorbic acid in the rat testis after administration of pineal polypeptides","volume":"17","author":"Damian","year":"1979","journal-title":"Endocrinologie"},{"key":"ref_212","first-page":"79","article-title":"Purification and characterization of the antigonadotropic pineal substance","volume":"18","author":"Damian","year":"1980","journal-title":"Endocrinologie"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/0014-5793(87)80689-0","article-title":"Modified forms of vasopressin and oxytocin in a bovine pineal preparation","volume":"216","author":"Noteborn","year":"1987","journal-title":"FEBS Lett."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1600-079X.1994.tb00082.x","article-title":"The presence of nerve fibers immunoreactive for vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), and preproVIP (111\u2013122) in the mouse pineal gland","volume":"16","author":"Mikkelsen","year":"1994","journal-title":"J. Pineal Res."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s10517-017-3922-8","article-title":"Identification of Peptide AEDG in the Polypeptide Complex of the Pineal Gland","volume":"164","author":"Khavinson","year":"2017","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s12015-019-09938-8","article-title":"Peptide Regulation of Cell Differentiation","volume":"16","author":"Khavinson","year":"2020","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.arr.2018.07.010","article-title":"The role of melatonin, a multitasking molecule, in retarding the processes of ageing","volume":"47","author":"Majidinia","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0047-6374(89)90075-4","article-title":"Effect of low molecular-weight factors of thymus and pineal gland on life span and spontaneous tumour development in female of different age","volume":"49","author":"Anisimov","year":"1989","journal-title":"Mech. Ageing Dev."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.exger.2004.10.004","article-title":"Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas","volume":"40","author":"Goncharova","year":"2005","journal-title":"Exp. Gerontol."},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s10522-009-9249-8","article-title":"Peptide bioregulation of aging: Results and prospects","volume":"11","author":"Anisimov","year":"2010","journal-title":"Biogerontology"},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/neup.12020","article-title":"Neural stem cell-based treatment for neurodegenerative diseases","volume":"33","author":"Kim","year":"2013","journal-title":"Neuropathology"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"879","DOI":"10.3233\/JAD-160406","article-title":"Stem Cell Therapy for Alzheimer\u2019s Disease: A Review of Recent Clinical Trials","volume":"54","author":"Kang","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2058738419828613","article-title":"Effect of short peptides on neuronal differentiation of stem cells","volume":"33","author":"Caputi","year":"2019","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/0165-5728(90)90059-V","article-title":"The involvement of pineal gland and melatonin in immunity and aging. I. Thymus-mediated, immunoreconstituting and antiviral activity of thyrotropin-releasing hormone","volume":"27","author":"Pierpaoli","year":"1990","journal-title":"J. Neuroimmunol."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3109\/00207459108999767","article-title":"The involvement of pineal gland and melatonin in immunity and aging: II. Thyrotropin-releasing hormone and melatonin forestall involution and promote reconstitution of the thymus in anterior hypothalamic area (AHA)-lesioned mice","volume":"62","author":"Lesnikov","year":"1992","journal-title":"Int. J. Neurosci."},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1073\/pnas.91.2.787","article-title":"Pineal control of aging: Effect of melatonin and pineal grafting on aging mice","volume":"91","author":"Pierpaoli","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/BF00501909","article-title":"An immunocytochemical study of thyrotropin releasing hormone in the porcine, ovine and rodent pineal gland","volume":"91","author":"Lew","year":"1989","journal-title":"Histochemistry"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/0006-291X(86)91159-9","article-title":"Type-II thyroxine 5\u2032-deiodinase is present in the rat pineal gland","volume":"137","author":"Tanaka","year":"1986","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1210\/endo-107-6-1791","article-title":"Evidence for a thyrotropin-releasing hormone inhibitor in the pineal gland","volume":"107","author":"Vriend","year":"1980","journal-title":"Endocrinology"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1111\/bph.14083","article-title":"Immune-pineal axis-acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes","volume":"175","author":"Markus","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1007\/s12094-018-1934-0","article-title":"Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization","volume":"21","author":"Farhood","year":"2019","journal-title":"Clin. Transl. Oncol."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1210\/er.2018-00084","article-title":"Melatonin as a Hormone: New Physiological and Clinical Insights","volume":"39","author":"Amaral","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/0163-7258(95)02020-9","article-title":"Chronobiotics\u2014Drugs that shift rhythms","volume":"69","author":"Dawson","year":"1996","journal-title":"Pharmacol. Ther."},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1600-079X.2005.00220.x","article-title":"Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: Role of the pineal gland","volume":"39","author":"Guerrero","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.exger.2009.02.002","article-title":"Age-related changes in melatonin synthesis in rat extrapineal tissues","volume":"44","author":"Naranjo","year":"2009","journal-title":"Exp. Gerontol."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1600-079X.2009.00683.x","article-title":"Evidence of immune system melatonin production by two pineal melatonin deficient mice, C57BL\/6 and Swiss strains","volume":"47","author":"Cerrillo","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1007\/BF01953049","article-title":"Melatonin biosynthesis in the mammalian pineal gland","volume":"45","author":"Sugden","year":"1989","journal-title":"Experientia"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1210\/edrv-12-2-151","article-title":"Pineal melatonin: Cell biology of its synthesis and of its physiological interactions","volume":"12","author":"Reiter","year":"1991","journal-title":"Endocr. Rev."},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1210\/endo.143.1.8585","article-title":"Melatonin enters the cerebrospinal fluid through the pineal recess","volume":"143","author":"Tricoire","year":"2002","journal-title":"Endocrinology"},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1007\/s00429-014-0719-7","article-title":"Delivery of pineal melatonin to the brain and SCN: Role of canaliculi, cerebrospinal fluid, tanycytes and Virchow-Robin perivascular spaces","volume":"219","author":"Reiter","year":"2014","journal-title":"Brain Struct. Funct."},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.mehy.2015.11.018","article-title":"CSF generation by pineal gland results in a robust melatonin circadian rhythm in the third ventricle as an unique light\/dark signal","volume":"86","author":"Tan","year":"2016","journal-title":"Med. Hypotheses"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1055\/s-2007-1014427","article-title":"The influence of intravenous L-tryptophan on plasma melatonin and sleep in men","volume":"24","author":"Hajak","year":"1991","journal-title":"Pharmacopsychiatry"},{"key":"ref_243","unstructured":"Hardeland, R. (2017). A short overview of duodenal signaling by melatonin. Mini-Reviews in Recent Melatonin Research, Cuvillier."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.intimp.2014.06.038","article-title":"MT1 receptor expression and AA-NAT activity in lymphatic tissue following melatonin administration in male golden hamster","volume":"22","author":"Haldar","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1007\/s00018-003-3207-4","article-title":"Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system","volume":"60","author":"Naji","year":"2003","journal-title":"Cell Mol. Life Sci."},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1600-079X.2008.00604.x","article-title":"Decreased MT1 and MT2 melatonin receptor expression in extrapineal tissues of the rat during physiological aging","volume":"46","author":"Lardone","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.molmet.2019.07.007","article-title":"Temporal expression patterns of the melatoninergic system in the human thymus of children","volume":"28","author":"Rubio","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/imm.13180","article-title":"Expression of melatonin receptors and CD4 in the ovine thymus, lymph node, spleen and liver during early pregnancy","volume":"160","author":"Bai","year":"2020","journal-title":"Immunology"},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/jpi.12336","article-title":"On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: Comparisons across species","volume":"61","author":"Tan","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1096\/fasebj.11.6.9194527","article-title":"Expression of the Mel1a-melatonin receptor mRNA in T and B subsets of lymphocytes from rat thymus and spleen","volume":"11","author":"Pozo","year":"1997","journal-title":"FASEB J."},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1385\/ENDO:27:2:189","article-title":"A review of the multiple actions of melatonin on the immune system","volume":"27","author":"Guerrero","year":"2005","journal-title":"Endocrine"},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1677\/joe.0.0910477","article-title":"Increase in the level of retinal melatonin and persistence of its diurnal rhythm in rats after pinealectomy","volume":"91","author":"Yu","year":"1981","journal-title":"J. Endocrinol."},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1677\/joe.0.1050263","article-title":"Plasma and tissue concentrations of melatonin after midnight light exposure and pinealectomy in the pigeon","volume":"105","author":"Vakkuri","year":"1985","journal-title":"J. Endocrinol."},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0304-4165(99)00125-7","article-title":"Identification of highly elevated levels of melatonin in bone marrow: Its origin and significance","volume":"1472","author":"Tan","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1111\/j.1742-4658.2006.05322.x","article-title":"Melatonin: Nature\u2019s most versatile biological signal?","volume":"273","author":"Srinivasan","year":"2006","journal-title":"FEBS J."},{"key":"ref_256","first-page":"11","article-title":"Medical implications of melatonin: Receptor-mediated and receptor-independent actions","volume":"52","author":"Reiter","year":"2007","journal-title":"Adv. Med. Sci."},{"key":"ref_257","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/biof.23","article-title":"Melatonin: Signaling mechanisms of a pleiotropic agent","volume":"35","author":"Hardeland","year":"2009","journal-title":"BioFactors"},{"key":"ref_258","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2174\/1871524918666180531083944","article-title":"Recent findings in melatonin research and their relevance to the CNS","volume":"18","author":"Hardeland","year":"2018","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref_259","doi-asserted-by":"crossref","first-page":"7997","DOI":"10.1073\/pnas.1705768114","article-title":"Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release","volume":"114","author":"Suofu","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_260","first-page":"4446","article-title":"Melatonin promotes osteoblast differentiation of bone marrow mesenchymal stem cells in aged rats","volume":"21","author":"Chu","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_261","first-page":"1","article-title":"Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function","volume":"63","author":"Florido","year":"2017","journal-title":"J. Pineal Res."},{"key":"ref_262","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.18632\/aging.101602","article-title":"Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress","volume":"10","author":"Fang","year":"2018","journal-title":"Aging"},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/978-1-4615-0135-0_63","article-title":"Mitochondrial regulation by melatonin and its metabolites","volume":"527","author":"Escames","year":"2003","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_264","doi-asserted-by":"crossref","first-page":"221","DOI":"10.2174\/156802611794863517","article-title":"Melatonin-mitochondria interplay in health and disease","volume":"11","author":"Escames","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"3883","DOI":"10.1007\/s00018-017-2615-9","article-title":"Melatonin and the electron transport chain","volume":"74","author":"Hardeland","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_266","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s13105-017-0548-2","article-title":"Contribution of inducible and neuronal nitric oxide synthases to mitochondrial damage and melatonin rescue in LPS-treated mice","volume":"73","author":"Ortiz","year":"2017","journal-title":"J. Physiol. Biochem."},{"key":"ref_267","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.mce.2012.04.009","article-title":"Role of melatonin in the regulation of autophagy and mitophagy: A review","volume":"361","author":"Boga","year":"2012","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_268","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/jpi.12264","article-title":"Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis","volume":"59","author":"Reiter","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_269","doi-asserted-by":"crossref","unstructured":"Tan, D.-X., Manchester, L.C., Qin, L., and Reiter, R.J. (2016). Melatonin: A mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122124"},{"key":"ref_270","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.3389\/fphar.2018.01086","article-title":"Promising Antineoplastic Actions of Melatonin","volume":"9","author":"Favero","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_271","doi-asserted-by":"crossref","first-page":"e12534","DOI":"10.1111\/jpi.12534","article-title":"Therapeutic potential of melatonin related to its role as an autophagy regulator: A review","volume":"66","author":"Boga","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_272","first-page":"57","article-title":"Melatonin: A potent, endogenous hydroxyl radical scavenger","volume":"1","author":"Tan","year":"1993","journal-title":"Endocr. J."},{"key":"ref_273","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0149-7634(05)80016-8","article-title":"The significance of the metabolism of the neurohormone melatonin: Antioxidative protection and formation of bioactive substances","volume":"17","author":"Hardeland","year":"1993","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_274","doi-asserted-by":"crossref","first-page":"181","DOI":"10.2174\/1568026023394443","article-title":"Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger","volume":"2","author":"Tan","year":"2002","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_275","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/jpi.12360","article-title":"Melatonin as an antioxidant: Under promises but over delivers","volume":"61","author":"Reiter","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_276","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1007\/s00018-017-2609-7","article-title":"Melatonin as a mitochondria-targeted antioxidant: One of evolution\u2019s best ideas","volume":"74","author":"Reiter","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_277","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1055\/a-0656-6643","article-title":"Pleiotropic Effects of Melatonin","volume":"69","author":"Mahmood","year":"2019","journal-title":"Drug Res."},{"key":"ref_278","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1385\/ENDO:27:2:119","article-title":"Antioxidative protection by melatonin: Multiplicity of mechanisms from radical detoxification to radical avoidance","volume":"27","author":"Hardeland","year":"2005","journal-title":"Endocrine"},{"key":"ref_279","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.bcp.2005.09.030","article-title":"Characterization of the melatoninergic MT3 binding site on the NRH:quinone oxidoreductase 2 enzyme","volume":"71","author":"Mailliet","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_280","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0024-3205(93)90670-X","article-title":"Binding of 3H-melatonin to calmodulin","volume":"53","year":"1993","journal-title":"Life Sci."},{"key":"ref_281","first-page":"14","article-title":"Mitochondrial actions of melatonin\u2014An endeavor to identify their adaptive and cytoprotective mechanisms","volume":"65","author":"Hardeland","year":"2009","journal-title":"Abh. Sachs. Akad. Wiss. Math. Nat. Kl."},{"key":"ref_282","doi-asserted-by":"crossref","first-page":"28531","DOI":"10.1016\/S0021-9258(19)61934-4","article-title":"Pineal gland hormone melatonin binds and activates an orphan of the nuclear receptor superfamily","volume":"269","author":"Wiesenberg","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_283","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1002\/bies.201600204","article-title":"ROR\u03b1 is not a receptor for melatonin","volume":"38","author":"Slominski","year":"2016","journal-title":"Bioessays"},{"key":"ref_284","doi-asserted-by":"crossref","first-page":"77","DOI":"10.32794\/mr11250005","article-title":"Melatonin and retinoid orphan receptors: Demand for new interpretations after their exclusion as nuclear melatonin receptors","volume":"1","author":"Hardeland","year":"2018","journal-title":"Melatonin Res."},{"key":"ref_285","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1042\/bst0300365","article-title":"14\u20133-3 Proteins and photoneuroendocrine transduction: Role in controlling the daily rhythm in melatonin","volume":"30","author":"Klein","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"ref_286","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1600-079X.2007.00551.x","article-title":"Melatonin and ischemia-reperfusion injury of the brain","volume":"45","author":"Cervantes","year":"2008","journal-title":"J. Pineal Res."},{"key":"ref_287","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.jss.2014.11.018","article-title":"Melatonin attenuates intestinal ischemia\u2012reperfusion-induced lung injury in rats by upregulating N-myc downstream-regulated gene 2","volume":"194","author":"Yang","year":"2015","journal-title":"J. Surg. Res."},{"key":"ref_288","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1159\/000491474","article-title":"Melatonin attenuates myocardial ischemia\/reperfusion injury by inhibiting autophagy via an AMPK\/mTOR signaling pathway","volume":"47","author":"Chen","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_289","doi-asserted-by":"crossref","first-page":"117036","DOI":"10.1016\/j.lfs.2019.117036","article-title":"Melatonin ameliorates cerebral ischemia\/reperfusion injury through SIRT3 activation","volume":"239","author":"Liu","year":"2019","journal-title":"Life Sci."},{"key":"ref_290","doi-asserted-by":"crossref","first-page":"4372","DOI":"10.2174\/138161211798999357","article-title":"Melatonin, a promising supplement in inflammatory bowel disease: A comprehensive review of evidences","volume":"17","author":"Mozaffari","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_291","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.lfs.2016.11.031","article-title":"Melatonin\u2019s role as a co-adjuvant treatment in colonic diseases: A review","volume":"170","author":"Tan","year":"2017","journal-title":"Life Sci."},{"key":"ref_292","doi-asserted-by":"crossref","unstructured":"Reiter, R.J., Rosales-Corral, S.A., Tan, D.X., Acuna-Castroviejo, D., Qin, L., Yang, S.F., and Xu, K. (2017). Melatonin, a full service anti-cancer agent: Inhibition of initiation, progression and metastasis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040843"},{"key":"ref_293","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s12551-017-0256-8","article-title":"The melatonin immunomodulatory actions in radiotherapy","volume":"9","author":"Najafi","year":"2017","journal-title":"Biophys. Rev."},{"key":"ref_294","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/jpi.12416","article-title":"Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways","volume":"63","author":"Majidinia","year":"2017","journal-title":"J. Pineal Res."},{"key":"ref_295","doi-asserted-by":"crossref","first-page":"e12539","DOI":"10.1111\/jpi.12539","article-title":"Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA","volume":"66","author":"Reiter","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_296","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1269\/jrr.06070","article-title":"A radiobiological review on melatonin: A novel radioprotector","volume":"48","author":"Shirazi","year":"2007","journal-title":"J. Radiat Res."},{"key":"ref_297","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1177\/039463201002300127","article-title":"Circadian variations of cortisol, melatonin and lymphocyte subpopulations in geriatric age","volume":"23","author":"Mazzoccoli","year":"2010","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_298","first-page":"387","article-title":"A timetable of 24-hour patterns for human lymphocyte subpopulations","volume":"25","author":"Mazzoccoli","year":"2011","journal-title":"J. Biol. Regul. Homeost. Agents"},{"key":"ref_299","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s002130050408","article-title":"No evidence for a physiological coupling between melatonin and glucocorticoids","volume":"133","author":"Hajak","year":"1997","journal-title":"Psychopharmacology"},{"key":"ref_300","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1600-079X.1988.tb00657.x","article-title":"Influence of dexamethasone on nocturnal melatonin production in healthy adult subjects","volume":"5","author":"Demisch","year":"1988","journal-title":"J. Pineal Res."},{"key":"ref_301","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0165-5728(86)90047-0","article-title":"Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone","volume":"13","author":"Maestroni","year":"1986","journal-title":"J. Neuroimmunol."},{"key":"ref_302","first-page":"11","article-title":"35-Year Experience of Investigation of Senescence Peptide Regulation","volume":"7","author":"Khavinson","year":"2009","journal-title":"Uspekhi Gerontol."},{"key":"ref_303","first-page":"14","article-title":"Senescence Tendencies of Inhabitants of Russia and Ukraine","volume":"7","author":"Pirozhkov","year":"2000","journal-title":"Uspekhi Gerontol."},{"key":"ref_304","doi-asserted-by":"crossref","first-page":"4864","DOI":"10.1073\/pnas.89.11.4864","article-title":"Constitutive synthesis of tumor necrosis factor in the thymus","volume":"89","author":"Giroir","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_305","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1159\/000110635","article-title":"The immune-pineal axis: A shuttle between endocrine and paracrine melatonin sources","volume":"14","author":"Markus","year":"2007","journal-title":"Neuroimmunomodulation"},{"key":"ref_306","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1600-079X.2007.00487.x","article-title":"Pineal melatonin and the innate immune response: The TNF- increase after caesarean section suppresses nocturnal melatonin production","volume":"43","author":"Pontes","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_307","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/j.1600-079X.2005.00265.x","article-title":"Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: Regulation of pro-\/antiinflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects","volume":"39","author":"Lardone","year":"2005","journal-title":"J. Pineal Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8806\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:35:13Z","timestamp":1760178913000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,20]]},"references-count":307,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21228806"],"URL":"https:\/\/doi.org\/10.3390\/ijms21228806","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,20]]}}}