{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:11:54Z","timestamp":1792804314941,"version":"4.5.0"},"reference-count":109,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006379","name":"Medical University\u2014Varna (19028\/2019)","doi-asserted-by":"publisher","award":["19028\/2019"],"award-info":[{"award-number":["19028\/2019"]}],"id":[{"id":"10.13039\/501100006379","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006379","name":"Medical University\u2014Varna (19028\/2019)","doi-asserted-by":"publisher","award":["#NO-6\/30.08.2018"],"award-info":[{"award-number":["#NO-6\/30.08.2018"]}],"id":[{"id":"10.13039\/501100006379","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006379","name":"Medical University\u2014Varna (19028\/2019)","doi-asserted-by":"publisher","award":["856871\u2014TRANSTEM"],"award-info":[{"award-number":["856871\u2014TRANSTEM"]}],"id":[{"id":"10.13039\/501100006379","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bulgarian Medical Association","award":["19028\/2019"],"award-info":[{"award-number":["19028\/2019"]}]},{"name":"Bulgarian Medical Association","award":["#NO-6\/30.08.2018"],"award-info":[{"award-number":["#NO-6\/30.08.2018"]}]},{"name":"Bulgarian Medical Association","award":["856871\u2014TRANSTEM"],"award-info":[{"award-number":["856871\u2014TRANSTEM"]}]},{"name":"European Commission Horizon 2020 Framework Program","award":["19028\/2019"],"award-info":[{"award-number":["19028\/2019"]}],"id":[{"id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","asserted-by":"crossref"}]},{"name":"European Commission Horizon 2020 Framework Program","award":["#NO-6\/30.08.2018"],"award-info":[{"award-number":["#NO-6\/30.08.2018"]}],"id":[{"id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","asserted-by":"crossref"}]},{"name":"European Commission Horizon 2020 Framework Program","award":["856871\u2014TRANSTEM"],"award-info":[{"award-number":["856871\u2014TRANSTEM"]}],"id":[{"id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Apelin, a peptide initially isolated from bovine stomach extract, is an endogenous ligand for the Apelin Receptor (APLNR). Subsequently, a second peptide, ELABELA, that can bind to the receptor has been identified. The Apelin receptor and its endogenous ligands are widely distributed in mammalian organs. A growing body of evidence suggests that this system participates in various signaling cascades that can regulate cell proliferation, blood pressure, fluid homeostasis, feeding behavior, and pituitary hormone release. Additional research has been done to elucidate the system\u2019s potential role in neurogenesis, the pathophysiology of Glioblastoma multiforme, and the protective effects of apelin peptides on some neurological and psychiatric disorders-ischemic stroke, epilepsy, Parkinson\u2019s, and Alzheimer\u2019s disease. This review discusses the current knowledge on the apelinergic system\u2019s involvement in brain physiology in health and disease.<\/jats:p>","DOI":"10.3390\/genes13112172","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T03:04:20Z","timestamp":1669086260000},"page":"2172","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Distribution, Function, and Expression of the Apelinergic System in the Healthy and Diseased Mammalian Brain"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2733-3556","authenticated-orcid":false,"given":"Martin N.","family":"Ivanov","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, Medical University-Varna, 9000 Varna, Bulgaria"},{"name":"Department of Stem Cell Biology, Research Institute, Medical University-Varna, 9000 Varna, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimo S.","family":"Stoyanov","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Medical University-Varna, 9000 Varna, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stoyan P.","family":"Pavlov","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Medical University-Varna, 9000 Varna, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1536-4352","authenticated-orcid":false,"given":"Anton. B.","family":"Tonchev","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Medical University-Varna, 9000 Varna, Bulgaria"},{"name":"Department of Stem Cell Biology, Research Institute, Medical University-Varna, 9000 Varna, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1006\/bbrc.1998.9489","article-title":"Isolation and Characterization of a Novel Endogenous Peptide Ligand for the Human APJ Receptor","volume":"251","author":"Tatemoto","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1046\/j.1471-4159.2003.01587.x","article-title":"Pharmacological and Immunohistochemical Characterization of the APJ Receptor and Its Endogenous Ligand Apelin","volume":"84","author":"Medhurst","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.peptides.2011.12.005","article-title":"Central and Peripheral Apelin Receptor Distribution in the Mouse: Species Differences with Rat","volume":"33","author":"Pope","year":"2012","journal-title":"Peptides"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1159\/000054609","article-title":"Cloning, Pharmacological Characterization and Brain Distribution of the Rat Apelin Receptor","volume":"72","author":"Lenkei","year":"2000","journal-title":"Neuroendocrinology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1046\/j.1471-4159.2001.00320.x","article-title":"Physiological Role of a Novel Neuropeptide, Apelin, and Its Receptor in the Rat Brain","volume":"77","author":"Reaux","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S0167-4781(00)00072-5","article-title":"Distribution of MRNA Encoding B78\/Apj, the Rat Homologue of the Human APJ Receptor, and Its Endogenous Ligand Apelin in Brain and Peripheral Tissues","volume":"1492","author":"Selby","year":"2000","journal-title":"Biochim. Biophys. Acta Gene Struct. Expr."},{"key":"ref_7","first-page":"333","article-title":"Apelin Expression in Normal Human Tissues","volume":"16","author":"Onori","year":"2002","journal-title":"Vivo"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.3389\/fphar.2021.715095","article-title":"LIT01-196, a Metabolically Stable Apelin-17 Analog, Normalizes Blood Pressure in Hypertensive DOCA-Salt Rats via a NO Synthase-Dependent Mechanism","volume":"12","author":"Flahault","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1039\/D1MD00120E","article-title":"Metabolically Stable Apelin-Analogues, Incorporating Cyclohexylalanine and Homoarginine, as Potent Apelin Receptor Activators","volume":"12","author":"Fernandez","year":"2021","journal-title":"RSC Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5345","DOI":"10.1021\/acs.jmedchem.0c01941","article-title":"Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile","volume":"64","author":"Sainsily","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1080\/13543776.2020.1731473","article-title":"A Patent Review of Apelin Receptor (APJR) Modulators (2014\u20132019)","volume":"30","author":"Fischer","year":"2020","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0378-1119(93)90495-O","article-title":"A Human Gene That Shows Identity with the Gene Encoding the Angiotensin Receptor Is Located on Chromosome 11","volume":"136","author":"Heiber","year":"1993","journal-title":"Gene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.str.2017.04.008","article-title":"Structural Basis for Apelin Control of the Human Apelin Receptor","volume":"25","author":"Ma","year":"2017","journal-title":"Structure"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1124\/pr.110.002949","article-title":"Apelin Receptor Nomenclature, Distribution, Pharmacology, and Function; International Union of Basic and Clinical Pharmacology; LXXIV","volume":"62","author":"Pitkin","year":"2010","journal-title":"Pharmacol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"756","DOI":"10.3389\/fendo.2018.00756","article-title":"Characterization of the Apelin\/Elabela Receptors (APLNR) in Chickens, Turtles, and Zebrafish: Identification of a Novel Apelin-Specific Receptor in Teleosts","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"584314","DOI":"10.3389\/fcell.2020.584314","article-title":"Transcriptome Response and Spatial Pattern of Gene Expression in the Primate Subventricular Zone Neurogenic Niche After Cerebral Ischemia","volume":"8","author":"Chongtham","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.devcel.2007.01.012","article-title":"The G Protein-Coupled Receptor Agtrl1b Regulates Early Development of Myocardial Progenitors","volume":"12","author":"Scott","year":"2007","journal-title":"Dev. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.modgep.2006.09.006","article-title":"Zebrafish Angiotensin II Receptor-like 1a (Agtrl1a) Is Expressed in Migrating Hypoblast, Vasculature, and in Multiple Embryonic Epithelia","volume":"7","author":"Tucker","year":"2007","journal-title":"Gene Expr. Patterns"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21061","DOI":"10.1074\/jbc.M908417199","article-title":"Molecular and Functional Characteristics of APJ","volume":"275","author":"Hosoya","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1046\/j.1471-4159.2000.0740034.x","article-title":"Characterization of Apelin, the Ligand for the APJ Receptor","volume":"74","author":"Lee","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3389\/fendo.2017.00120","article-title":"Role of the Vasopressin\/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders","volume":"8","author":"Flahault","year":"2017","journal-title":"Front. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0167-4889(99)00114-7","article-title":"Apelin, the Natural Ligand of the Orphan Receptor APJ, Is Abundantly Secreted in the Colostrum","volume":"1452","author":"Habata","year":"1999","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.fob.2013.08.001","article-title":"Preferential Apelin-13 Production by the Proprotein Convertase PCSK3 Is Implicated in Obesity","volume":"3","author":"Shin","year":"2013","journal-title":"FEBS Open Bio"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S0167-4889(00)00143-9","article-title":"Molecular Properties of Apelin: Tissue Distribution and Receptor Binding","volume":"1538","author":"Kawamata","year":"2001","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ab.2013.07.006","article-title":"Pyroglutamyl Apelin-13 Identified as the Major Apelin Isoform in Human Plasma","volume":"442","author":"Zhen","year":"2013","journal-title":"Anal. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1016\/j.bbagen.2017.05.017","article-title":"Bioactivity of the Putative Apelin Proprotein Expands the Repertoire of Apelin Receptor Ligands","volume":"1861","author":"Shin","year":"2017","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1002\/cbic.201600244","article-title":"The Metalloprotease Neprilysin Degrades and Inactivates Apelin Peptides","volume":"17","author":"McKinnie","year":"2016","journal-title":"ChemBioChem"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14838","DOI":"10.1074\/jbc.M200581200","article-title":"Hydrolysis of Biological Peptides by Human Angiotensin-Converting Enzyme-Related Carboxypeptidase","volume":"277","author":"Vickers","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.ejmech.2019.01.040","article-title":"Plasma Kallikrein Cleaves and Inactivates Apelin-17: Palmitoyl- and PEG-Extended Apelin-17 Analogs as Metabolically Stable Blood Pressure-Lowering Agents","volume":"166","author":"Fischer","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/bip.22498","article-title":"Stability and Degradation Patterns of Chemically Modified Analogs of Apelin-13 in Plasma and Cerebrospinal Fluid","volume":"102","author":"Murza","year":"2014","journal-title":"Biopolym. Pept. Sci. Sect."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fnins.2017.00092","article-title":"[Pyr1]Apelin-13(1-12) Is a Biologically Active ACE2 Metabolite of the Endogenous Cardiovascular Peptide [Pyr1]Apelin-13","volume":"11","author":"Yang","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.yjmcc.2020.06.007","article-title":"Apelin-Potential Therapy for COVID-19?","volume":"145","author":"Beer","year":"2020","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2174\/1573398X18666220210145349","article-title":"Investigating COVID-19 Severity Based on Serum Apelin-17 Levels and Inflammatory Mediators","volume":"18","author":"Fekri","year":"2022","journal-title":"Curr. Respir. Med. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.devcel.2013.11.002","article-title":"ELABELA: A Hormone Essential for Heart Development Signals via the Apelin Receptor","volume":"27","author":"Chng","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1248636","DOI":"10.1126\/science.1248636","article-title":"Toddler: An Embryonic Signal That Promotes Cell Movement via Apelin Receptors","volume":"343","author":"Pauli","year":"2014","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/bies.201400103","article-title":"Identifying (Non-)Coding RNAs and Small Peptides: Challenges and Opportunities","volume":"37","author":"Pauli","year":"2015","journal-title":"BioEssays"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1093\/abbs\/gmu032","article-title":"ELABELA: A Novel Hormone in Cardiac Development Acting as a New Endogenous Ligand for the APJ Receptor","volume":"46","author":"Xie","year":"2014","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8170","DOI":"10.1038\/srep08170","article-title":"Elabela-Apelin Receptor Signaling Pathway Is Functional in Mammalian Systems","volume":"5","author":"Wang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18261","DOI":"10.1074\/jbc.M115.648238","article-title":"Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling","volume":"290","author":"Deng","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1681\/ASN.2016111210","article-title":"ELABELA and an ELABELA Fragment Protect against AKI","volume":"28","author":"Chen","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1021\/acs.jmedchem.5b01549","article-title":"Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA That Modulates Vascular and Cardiac Functions","volume":"59","author":"Murza","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1161\/CIRCULATIONAHA.116.023218","article-title":"Elabela\/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expression in Pulmonary Arterial Hypertension","volume":"135","author":"Yang","year":"2017","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/agm2.12173","article-title":"Serum Apelin-13 Levels and Total Oxidant\/Antioxidant Status of Patients with Alzheimer\u2019s Disease","volume":"4","author":"Yildiz","year":"2021","journal-title":"Aging Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1677\/jme.1.01927","article-title":"Transcriptional Regulation of the Rat Apelin Receptor Gene: Promoter Cloning and Identification of an Sp1 Site Necessary for Promoter Activity","volume":"36","author":"Lolait","year":"2006","journal-title":"J. Mol. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E1161","DOI":"10.1152\/ajpendo.00598.2009","article-title":"Apelin and APJ Regulation in Adipose Tissue and Skeletal Muscle of Type 2 Diabetic Mice and Humans","volume":"298","author":"Dray","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.regpep.2009.07.016","article-title":"Ontogeny of Apelin and Its Receptor in the Rodent Gastrointestinal Tract","volume":"158","author":"Wang","year":"2009","journal-title":"Regul. Pept."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1152\/ajpgi.90493.2008","article-title":"Involvement of a Stat3 Binding Site in Inflammation-Induced Enteric Apelin Expression","volume":"295","author":"Han","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1096\/fj.06-6315fje","article-title":"Characterization of the 5\u2032-regulatory Regions of the Rat and Human Apelin Genes and Regulation of Breast Apelin by USF","volume":"20","author":"Wang","year":"2006","journal-title":"FASEB J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1042\/BJ20130418","article-title":"Synthetic Retinoid Am80 Up-Regulates Apelin Expression by Promoting Interaction of RAR\u03b1 with KLF5 and Sp1 in Vascular Smooth Muscle Cells","volume":"456","author":"Lv","year":"2013","journal-title":"Biochem. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1096\/fj.06-7294com","article-title":"Hypoxia Inducible Factor Regulates the Cardiac Expression and Secretion of Apelin","volume":"21","author":"Ronkainen","year":"2007","journal-title":"FASEB J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1096\/fj.05-5243fje","article-title":"TNF\u03b1 Up-regulates Apelin Expression in Human and Mouse Adipose Tissue","volume":"20","author":"Daviaud","year":"2006","journal-title":"FASEB J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1007\/s10495-014-1013-0","article-title":"Apelin Is Transcriptionally Regulated by ER Stress-Induced ATF4 Expression via a P38 MAPK-Dependent Pathway","volume":"19","author":"Jeong","year":"2014","journal-title":"Apoptosis"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"114487","DOI":"10.1016\/j.jep.2021.114487","article-title":"Andrographolide, a Novel Inducer of Apelin Gene Expression","volume":"280","author":"Mehri","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.regpep.2005.08.003","article-title":"Regulation of Apelin MRNA Expression by Insulin and Glucocorticoids in Mouse 3T3-L1 Adipocytes","volume":"132","author":"Wei","year":"2005","journal-title":"Regul. Pept."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1371\/journal.pone.0063918","article-title":"Resveratrol Metabolites Modify Adipokine Expression and Secretion in 3T3-L1 Pre-Adipocytes and Mature Adipocytes","volume":"8","author":"Eseberri","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S0306-4522(02)00192-6","article-title":"Distribution of Apelin-Synthesizing Neurons in the Adult Rat Brain","volume":"113","author":"Reaux","year":"2002","journal-title":"Neuroscience"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1111\/j.1471-4159.2007.04645.x","article-title":"Apelin, an Endogenous Neuronal Peptide, Protects Hippocampal Neurons against Excitotoxic Injury","volume":"102","author":"Agrawal","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1016\/j.yexcr.2010.02.005","article-title":"Neuroprotective Effect of the Endogenous Neural Peptide Apelin in Cultured Mouse Cortical Neurons","volume":"316","author":"Zeng","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_59","first-page":"61","article-title":"Functional Expression of the Seven-Transmembrane HIV-1 Co-Receptor APJ in Neural Cells","volume":"6","author":"Choe","year":"2000","journal-title":"J. Neurovirol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Wang, Y., Lou, Y., Luo, M., Lu, Y., Li, Z., Wang, Y., and Miao, L. (2018). Elabela, a Newly Discovered APJ Ligand: Similarities and Differences with Apelin, Elsevier Inc.","DOI":"10.1016\/j.peptides.2018.09.006"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1139\/bcb-2014-0072","article-title":"The Apelin Receptor: Physiology, Pathology, Cell Signalling, and Ligand Modulation of a Peptide-Activated Class A GPCR","volume":"92","author":"Chapman","year":"2014","journal-title":"Biochem. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1161\/CIRCRESAHA.108.179333","article-title":"Hypoxia-Induced Apelin Expression Regulates Endothelial Cell Proliferation and Regenerative Angiogenesis","volume":"103","author":"Eyries","year":"2008","journal-title":"Circ. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.pnpbp.2018.10.005","article-title":"Protective Role of Apelin-13 on Amyloid \u039225\u201335-Induced Memory Deficit; Involvement of Autophagy and Apoptosis Process","volume":"89","author":"Aminyavari","year":"2019","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"101629","DOI":"10.1016\/j.redox.2020.101629","article-title":"Individual Phosphorylation Sites at the C-Terminus of the Apelin Receptor Play Different Roles in Signal Transduction","volume":"36","author":"Chen","year":"2020","journal-title":"Redox Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.bbrc.2010.03.151","article-title":"The Fate of the Internalized Apelin Receptor Is Determined by Different Isoforms of Apelin Mediating Differential Interaction with \u03b2-Arrestin","volume":"395","author":"Lee","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/S0042-6822(02)00021-1","article-title":"Cell-Cell Fusion and Internalization of the CNS-Based, HIV-1 Co-Receptor, APJ","volume":"307","author":"Zhou","year":"2003","journal-title":"Virology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1111\/j.1471-4159.2011.07383.x","article-title":"NMDA Receptor Modulation by the Neuropeptide Apelin: Implications for Excitotoxic Injury","volume":"118","author":"Cook","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"10464","DOI":"10.1073\/pnas.0403518101","article-title":"Apelin, a Potent Diuretic Neuropeptide Counteracting Vasopressin Actions through Inhibition of Vasopressin Neuron Activity and Vasopressin Release","volume":"101","author":"Chartrel","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0304-3940(96)13198-0","article-title":"Low Stringency Hybridization Study of the Dopamine D4 Receptor Revealed D4-like MRNA Distribution of the Orphan Seven-Transmembrane Receptor, APJ, in Human Brain","volume":"219","author":"Matsumoto","year":"1996","journal-title":"Neurosci. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Kasai, A., Kinjo, T., Ishihara, R., Sakai, I., Ishimaru, Y., Yoshioka, Y., Yamamuro, A., Ishige, K., Ito, Y., and Maeda, S. (2011). Apelin Deficiency Accelerates the Progression of Amyotrophic Lateral Sclerosis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023968"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.cell.2014.01.044","article-title":"Neurogenesis in the Striatum of the Adult Human Brain","volume":"156","author":"Ernst","year":"2014","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0304-3940(02)00411-1","article-title":"Apelin-Immunoreactivity in the Rat Hypothalamus and Pituitary","volume":"327","author":"Brailoiu","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.3892\/mmr.2017.6734","article-title":"Effect of the Spinal Apelin-APJ System on the Pathogenesis of Chronic Constriction Injury-Induced Neuropathic Pain in Rats","volume":"16","author":"Xiong","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1006\/viro.2000.0557","article-title":"Expression and Coreceptor Function of APJ for Primate Immunodeficiency Viruses","volume":"276","author":"Puffer","year":"2000","journal-title":"Virology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1016\/j.peptides.2011.08.006","article-title":"Up-Regulation of Apelin in Brain Tissue of Patients with Epilepsy and an Epileptic Rat Model","volume":"32","author":"Zhang","year":"2011","journal-title":"Peptides"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1016\/S0140-6736(09)60833-3","article-title":"Lancet Emergency and Comprehensive Care for Stroke Needed","volume":"373","author":"Donnan","year":"2009","journal-title":"Lancet"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.peptides.2014.09.016","article-title":"Neuroprotective Effects of Apelin-13 on Experimental Ischemic Stroke through Suppression of Inflammation","volume":"63","author":"Xin","year":"2015","journal-title":"Peptides"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s12031-012-9808-3","article-title":"Apelin-13 Protects the Brain against Ischemic Reperfusion Injury and Cerebral Edema in a Transient Model of Focal Cerebral Ischemia","volume":"48","author":"Khaksari","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.neuint.2013.09.017","article-title":"Apelin-36, a Potent Peptide, Protects against Ischemic Brain Injury by Activating the PI3K\/Akt Pathway","volume":"63","author":"Gu","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.npep.2016.08.006","article-title":"Apelin-13 Protects Neurovascular Unit against Ischemic Injuries through the Effects of Vascular Endothelial Growth Factor","volume":"60","author":"Huang","year":"2016","journal-title":"Neuropeptides"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1759091415605114","DOI":"10.1177\/1759091415605114","article-title":"Intranasal Delivery of Apelin-13 Is Neuroprotective and Promotes Angiogenesis after Ischemic Stroke in Mice","volume":"7","author":"Chen","year":"2015","journal-title":"ASN Neuro"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"106185","DOI":"10.1016\/j.eplepsyres.2019.106185","article-title":"Interneuron Dysfunction in Epilepsy: An Experimental Approach Using Immature Brain Insults to Induce Neuronal Migration Disorders","volume":"156","author":"Takano","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s12264-014-1478-4","article-title":"Dysfunction of Hippocampal Interneurons in Epilepsy","volume":"30","author":"Liu","year":"2014","journal-title":"Neurosci. Bull."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"327","DOI":"10.2147\/NDT.S238826","article-title":"MicroRNA-182 Negatively Influences the Neuroprotective Effect of Apelin against Neuronal Injury in Epilepsy","volume":"16","author":"Dong","year":"2020","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.biopha.2016.09.048","article-title":"Anticonvulsant and Neuroprotective Effects of Apelin-13 on Pentylenetetrazole-Induced Seizures in Male Rats","volume":"84","author":"Kalantaripour","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/j.biopha.2016.12.131","article-title":"Apelin-13 Protects Rat Primary Cortical Glia-Neuron Co-Culture against Pentylenetetrazole-Induced Toxicity","volume":"87","author":"Kalantaripour","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"877","DOI":"10.4252\/wjsc.v13.i7.877","article-title":"Role and Mechanism of Neural Stem Cells of the Subventricular Zone in Glioblastoma","volume":"13","author":"Zhang","year":"2021","journal-title":"World J. Stem Cells"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1093\/brain\/awx253","article-title":"Pharmacological Targeting of Apelin Impairs Glioblastoma Growth","volume":"140","author":"Jacobs","year":"2017","journal-title":"Brain"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Frisch, A., K\u00e4lin, S., Monk, R., Radke, J., Heppner, F.L., and K\u00e4lin, R.E. (2020). Apelin Controls Angiogenesis-Dependent Glioblastoma Growth. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114179"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Sun, R., and Kim, A.H. (2022). The Multifaceted Mechanisms of Malignant Glioblastoma Progression and Clinical Implications. Cancer Metastasis Rev., 1\u201328.","DOI":"10.1007\/s10555-022-10051-5"},{"key":"ref_91","first-page":"3","article-title":"Apelin, the Devil Inside Brain Tumors","volume":"12","author":"Gavard","year":"2018","journal-title":"J. Exp. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/ncb3396","article-title":"Nuclear GSK3\u03b2 Promotes Tumorigenesis by Phosphorylating KDM1A and Inducing Its Deubiquitylation by USP22","volume":"18","author":"Zhou","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Ganguly, D., Cai, C., Sims, M.M., Yang, C.H., Thomas, M., Cheng, J., Saad, A.G., and Pfeffer, L.M. (2019). APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade. Pharmaceuticals, 12.","DOI":"10.3390\/ph12010045"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Mosteiro, A., Pedrosa, L., Ferr\u00e9s, A., Diao, D., Sierra, \u00c0., and Gonz\u00e1lez, J.J. (2022). The Vascular Microenvironment in Glioblastoma: A Comprehensive Review. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061285"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1158\/0008-5472.CAN-19-0749","article-title":"Role of Apelin in Glioblastoma Vascularization and Invasion after Anti-VEGF Therapy: What Is the Impact on the Immune System?","volume":"79","author":"Amoozgar","year":"2019","journal-title":"Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1158\/0008-5472.CAN-18-0881","article-title":"Targeting APLN\/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA\/VEGFR2 Blockade in Glioblastoma","volume":"79","author":"Mastrella","year":"2019","journal-title":"Cancer Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"105562","DOI":"10.1016\/j.bioorg.2021.105562","article-title":"The Molecular Mechanism, Targets, and Novel Molecules in the Treatment of Alzheimer\u2019s Disease","volume":"119","author":"Verma","year":"2022","journal-title":"Bioorg. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Morales, V., Gonz\u00e1lez-Acedo, A., Melguizo-Rodr\u00edguez, L., Pardo-Moreno, T., Costela-Ruiz, V.J., Montiel-Troya, M., and Ramos-Rodr\u00edguez, J.J. (2021). Current Understanding of the Physiopathology, Diagnosis and Therapeutic Approach to Alzheimer\u2019s Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121910"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3389\/fphar.2019.00395","article-title":"Apelin-13 Suppresses Neuroinflammation against Cognitive Deficit in a Streptozotocin-Induced Rat Model of Alzheimer\u2019s Disease through Activation of BDNF-TrkB Signaling Pathway","volume":"10","author":"Luo","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"106546","DOI":"10.1016\/j.intimp.2020.106546","article-title":"Apelin Attenuates Streptozotocin-Induced Learning and Memory Impairment by Modulating Necroptosis Signaling Pathway","volume":"84","author":"Nasseri","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s11064-021-03448-1","article-title":"Research Progress on Mechanism of Neuroprotective Roles of Apelin-13 in Prevention and Treatment of Alzheimer\u2019s Disease","volume":"47","author":"Wan","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"959425","DOI":"10.3389\/fmolb.2022.959425","article-title":"Polymorphism in Alpha-Synuclein Oligomers and Its Implications in Toxicity under Disease Conditions","volume":"9","author":"Yoo","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1111\/jnc.14806","article-title":"Cellular Models of Alpha-Synuclein Toxicity and Aggregation","volume":"150","author":"Delenclos","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1089\/rej.2017.1951","article-title":"Protective Effect of Neuropeptide Apelin-13 on 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Dopaminergic Cells: Involvement of Its Antioxidant and Antiapoptotic Properties","volume":"21","author":"Abbasnejad","year":"2018","journal-title":"Rejuvenation Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.npep.2018.01.001","article-title":"Apelin-13 Ameliorates Cognitive Impairments in 6-Hydroxydopamine-Induced Substantia Nigra Lesion in Rats","volume":"68","author":"Haghparast","year":"2018","journal-title":"Neuropeptides"},{"key":"ref_106","first-page":"1732","article-title":"Apelin-13 Attenuates ER Stress-associated Apoptosis Induced by MPP+ in SH-SY5Y Cells","volume":"42","author":"Jiang","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.brainres.2019.03.027","article-title":"Apelin-13 Protects Dopaminergic Neurons in MPTP-Induced Parkinson\u2019s Disease Model Mice through Inhibiting Endoplasmic Reticulum Stress and Promoting Autophagy","volume":"1715","author":"Zhu","year":"2019","journal-title":"Brain Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1007\/s11064-019-02847-9","article-title":"Apelin-13 Protects PC12 Cells against Methamphetamine-Induced Oxidative Stress, Autophagy and Apoptosis","volume":"44","author":"Foroughi","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"170091","DOI":"10.1016\/j.peptides.2019.05.003","article-title":"Apelin-13 Attenuates Motor Impairments and Prevents the Changes in Synaptic Plasticity-Related Molecules in the Striatum of Parkinsonism Rats","volume":"117","author":"Haghparast","year":"2019","journal-title":"Peptides"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2172\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:22:41Z","timestamp":1760145761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,21]]},"references-count":109,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["genes13112172"],"URL":"https:\/\/doi.org\/10.3390\/genes13112172","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,21]]}}}