{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:36:06Z","timestamp":1789187766728,"version":"build-2803163510"},"reference-count":115,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,10]],"date-time":"2018-11-10T00:00:00Z","timestamp":1541808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004054","name":"King Abdulaziz University","doi-asserted-by":"publisher","award":["G\/017\/27"],"award-info":[{"award-number":["G\/017\/27"]}],"id":[{"id":"10.13039\/501100004054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patau Syndrome (PS), characterized as a lethal disease, allows less than 15% survival over the first year of life. Most deaths owe to brain and heart disorders, more so due to septal defects because of altered gene regulations. We ascertained the cytogenetic basis of PS first, followed by molecular analysis and docking studies. Thirty-seven PS cases were referred from the Department of Pediatrics, King Abdulaziz University Hospital to the Center of Excellence in Genomic Medicine Research, Jeddah during 2008 to 2018. Cytogenetic analyses were performed by standard G-band method and trisomy13 were found in all the PS cases. Studies have suggested that genes of chromosome 13 and other chromosomes are associated with PS. We, therefore, did molecular pathway analysis, gene interaction, and ontology studies to identify their associations. Genomic analysis revealed important chr13 genes such as FOXO1, Col4A1, HMGBB1, FLT1, EFNB2, EDNRB, GAS6, TNFSF1, STARD13, TRPC4, TUBA3C, and TUBA3D, and their regulatory partners on other chromosomes associated with cardiovascular disorders, atrial and ventricular septal defects. There is strong indication of involving FOXO1 (Forkhead Box O1) gene\u2014a strong transcription factor present on chr13, interacting with many septal defects link genes. The study was extended using molecular docking to find a potential drug lead for overexpressed FOXO1 inhibition. The phenothiazine and trifluoperazine showed efficiency to inhibit overexpressed FOXO1 protein, and could be potential drugs for PS\/trisomy13 after validation.<\/jats:p>","DOI":"10.3390\/ijms19113547","type":"journal-article","created":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T02:42:41Z","timestamp":1542163361000},"page":"3547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Role of Overexpressed Transcription Factor FOXO1 in Fatal Cardiovascular Septal Defects in Patau Syndrome: Molecular and Therapeutic Strategies"],"prefix":"10.3390","volume":"19","author":[{"given":"Adel","family":"Abuzenadah","sequence":"first","affiliation":[{"name":"Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"},{"name":"King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saad","family":"Alsaedi","sequence":"additional","affiliation":[{"name":"Department of Pediatric, Faculty of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, P.O. Box 80215, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajjad","family":"Karim","sequence":"additional","affiliation":[{"name":"Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Al-Qahtani","sequence":"additional","affiliation":[{"name":"Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/S0140-6736(60)90676-0","article-title":"Multiple congenital anomaly caused by an extra autosome","volume":"1","author":"Patau","year":"1960","journal-title":"Lancet (London, England)"},{"key":"ref_2","first-page":"288","article-title":"Patau syndrome with a long survival. A case report","volume":"3","author":"Duarte","year":"2004","journal-title":"Genet. Mol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1136\/adc.71.4.343","article-title":"Natural history of trisomy 13","volume":"71","author":"Wyllie","year":"1994","journal-title":"Arch. Dis. Child."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1002\/ajmg.a.31382","article-title":"Congenital malformations among liveborn infants with trisomies 18 and 13","volume":"140","author":"Pont","year":"2006","journal-title":"Am. J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1525-1470.2010.01098.x","article-title":"Extensive comedonal and cystic acne in Patau syndrome","volume":"27","author":"Torrelo","year":"2010","journal-title":"Pediatr. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1136\/bmj.331.7526.1186","article-title":"The parents\u2019 journey: Continuing a pregnancy after a diagnosis of Patau\u2019s syndrome","volume":"331","author":"Locock","year":"2005","journal-title":"BMJ"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev.ge.18.120184.000441","article-title":"Trisomy in man","volume":"18","author":"Hassold","year":"1984","journal-title":"Annu. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1002\/ajmg.a.31835","article-title":"Variable expressivity in Patau syndrome is not all related to trisomy 13 mosaicism","volume":"143a","author":"Hsu","year":"2007","journal-title":"Am. J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/ajmg.a.31056","article-title":"Patau syndrome with a long survival (146 months): A clinical report and review of literature","volume":"140","author":"Iliopoulos","year":"2006","journal-title":"Am. J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/00019605-200104000-00014","article-title":"Long-term survival in Patau syndrome","volume":"10","author":"Tunca","year":"2001","journal-title":"Clin. Dysmorphol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1002\/ajmg.1320080207","article-title":"Long survival in trisomy-13-syndrome: 21 cases including prolonged survival in two patients 11 and 19 years old","volume":"8","author":"Redheendran","year":"1981","journal-title":"Am. J. Med. Genet."},{"key":"ref_12","first-page":"1140","article-title":"Trisomy 13 (Patau syndrome)","volume":"37","author":"Goel","year":"2000","journal-title":"Indian Pediatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1097\/MOP.0b013e328332c6ab","article-title":"Maternal age and chromosomally abnormal pregnancies: What we know and what we wish we knew","volume":"21","author":"Hassold","year":"2009","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Carey, J.C. (2005). Trisomy 18 and trisomy 13 syndromes. Manag. Genet. Syndr.","DOI":"10.1002\/0471695998.mgs047"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1002\/ajmg.a.36193","article-title":"Trisomy 13 (Patau syndrome) and congenital heart defects","volume":"164A","author":"Polli","year":"2014","journal-title":"Am. J. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s00246-010-9831-5","article-title":"Trisomy 13 in a 9-year-old girl with left ventricular noncompaction","volume":"32","author":"Yukifumi","year":"2011","journal-title":"Pediatr. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1089\/109065700316543","article-title":"Chromosome 13","volume":"4","author":"Gilbert","year":"2000","journal-title":"Genet. Test."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1161\/CIRCRESAHA.117.312052","article-title":"Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies","volume":"122","author":"Auguste","year":"2018","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8547976","DOI":"10.1155\/2018\/8547976","article-title":"Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease","volume":"2018","author":"Govindsamy","year":"2018","journal-title":"J. Nutr. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2644","DOI":"10.1101\/gad.435107","article-title":"SIRT1 controls endothelial angiogenic functions during vascular growth","volume":"21","author":"Potente","year":"2007","journal-title":"Genes Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1152\/physrev.00041.2003","article-title":"Molecular regulation of vascular smooth muscle cell differentiation in development and disease","volume":"84","author":"Owens","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.yjmcc.2014.06.006","article-title":"Deletion of FoxO1 leads to shortening of QRS by increasing Na+ channel activity through enhanced expression of both cardiac NaV1. 5 and \u03b23 subunit","volume":"74","author":"Cai","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yang, W., Ng, F.L., Chan, K., Pu, X., Poston, R.N., Ren, M., An, W., Zhang, R., Wu, J., and Yan, S. (2016). Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1\/COL4A2 Locus Affects COL4A1\/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1006127"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s00395-015-0487-4","article-title":"Soluble Flt-1 links microvascular disease with heart failure in CKD","volume":"110","author":"Kentrup","year":"2015","journal-title":"Basic Res Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/cvr\/cvw039","article-title":"The multifactorial nature of microRNAs in vascular remodelling","volume":"110","author":"Welten","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.bcp.2012.03.020","article-title":"Vascular endothelin receptor type B: Structure, function and dysregulation in vascular disease","volume":"84","author":"Mazzuca","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/1755-5922.12112","article-title":"Growth arrest-specific 6 and cardiometabolic risk factors in patients with psoriasis","volume":"33","author":"Sunbul","year":"2015","journal-title":"Cardiovasc. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hage, C., Michaelsson, E., Linde, C., Donal, E., Daubert, J.C., Gan, L.M., and Lund, L.H. (2017). Inflammatory Biomarkers Predict Heart Failure Severity and Prognosis in Patients With Heart Failure With Preserved Ejection Fraction: A Holistic Proteomic Approach. Circ. Cardiovasc. Genet., 10.","DOI":"10.1161\/CIRCGENETICS.116.001633"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1038\/onc.2010.54","article-title":"DLC2 modulates angiogenic responses in vascular endothelial cells by regulating cell attachment and migration","volume":"29","author":"Lin","year":"2010","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1093\/eurheartj\/ehv250","article-title":"A background Ca2+ entry pathway mediated by TRPC1\/TRPC4 is critical for development of pathological cardiac remodelling","volume":"36","author":"Tian","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3389\/fphys.2014.00082","article-title":"Gap junction modulation and its implications for heart function","volume":"5","author":"Kurtenbach","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"34741","DOI":"10.1074\/jbc.M314214200","article-title":"Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice","volume":"279","author":"Furuyama","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1210\/me.2015-1103","article-title":"FOXO1\/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development","volume":"29","author":"Liu","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1074\/jbc.M109.070037","article-title":"Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death","volume":"285","author":"Kobayashi","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1016\/j.celrep.2017.08.046","article-title":"mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue-Resident Peritoneal Macrophages","volume":"20","author":"Oh","year":"2017","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12747","DOI":"10.1073\/pnas.0605333103","article-title":"A FoxO-Smad synexpression group in human keratinocytes","volume":"103","author":"Gomis","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.mce.2016.06.020","article-title":"Forkhead box O member FOXO1 regulates the majority of follicle-stimulating hormone responsive genes in ovarian granulosa cells","volume":"434","author":"Herndon","year":"2016","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.2337\/db16-0001","article-title":"Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells","volume":"65","author":"Wang","year":"2016","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18975","DOI":"10.1074\/jbc.M112.427062","article-title":"Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo","volume":"288","author":"Bround","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1161\/CIRCRESAHA.110.227371","article-title":"Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes","volume":"107","author":"Hariharan","year":"2010","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1210\/me.2014-1292","article-title":"FOXO1 is required for binding of PR on IRF4, novel transcriptional regulator of endometrial stromal decidualization","volume":"29","author":"Vasquez","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"815","DOI":"10.7150\/ijbs.20052","article-title":"FOXO Signaling Pathways as Therapeutic Targets in Cancer","volume":"13","author":"Farhan","year":"2017","journal-title":"Int. J. Biol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1089\/ars.2005.7.752","article-title":"FOXO transcription factors in cell-cycle regulation and the response to oxidative stress","volume":"7","author":"Kobayashi","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1161\/CIRCRESAHA.115.303227","article-title":"FOXO1-mediated activation of Akt plays a critical role in vascular homeostasis","volume":"115","author":"Dharaneeswaran","year":"2014","journal-title":"Circ. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.cell.2016.01.004","article-title":"Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis","volume":"164","author":"Stirnimann","year":"2016","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"27907","DOI":"10.1074\/jbc.M104278200","article-title":"Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions","volume":"276","author":"Zhao","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1002\/dvdy.23759","article-title":"FoxO1 is required in endothelial but not myocardial cell lineages during cardiovascular development","volume":"241","author":"Sengupta","year":"2012","journal-title":"Dev. Dyn."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10662","DOI":"10.18632\/oncotarget.12891","article-title":"FoxO1: A novel insight into its molecular mechanisms in the regulation of skeletal muscle differentiation and fiber type specification","volume":"8","author":"Xu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/S0959-437X(00)00215-X","article-title":"Skeletal muscle formation in vertebrates","volume":"11","author":"Buckingham","year":"2001","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1038\/onc.2008.25","article-title":"The role of FoxO in the regulation of metabolism","volume":"27","author":"Gross","year":"2008","journal-title":"Oncogene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4161\/oxim.2.3.8916","article-title":"A fork in the path: Developing therapeutic inroads with FoxO proteins","volume":"2","author":"Maiese","year":"2009","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/cvr\/cvs426","article-title":"FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survival","volume":"97","author":"Puthanveetil","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12933-016-0361-1","article-title":"Forkhead box transcription factor 1: Role in the pathogenesis of diabetic cardiomyopathy","volume":"15","author":"Kandula","year":"2016","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_54","first-page":"61","article-title":"An unusual case of Trisomy 13","volume":"9","author":"Feben","year":"2015","journal-title":"S. Afr. J. Child Health"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.molmet.2014.07.006","article-title":"Foxo1 regulates Dbh expression and the activity of the sympathetic nervous system in vivo","volume":"3","author":"Kajimura","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s12265-010-9200-z","article-title":"FoxO, autophagy, and cardiac remodeling","volume":"3","author":"Ferdous","year":"2010","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"28319","DOI":"10.1074\/jbc.M109.024406","article-title":"FoxO transcription factors promote autophagy in cardiomyocytes","volume":"284","author":"Sengupta","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: Identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"327","DOI":"10.2174\/1567205013666161114115344","article-title":"Possible Molecular Interactions of Bexarotene\u2014A Retinoid Drug and Alzheimer\u2019s Abeta Peptide: A Docking Study","volume":"14","author":"Mirza","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1358\/dnp.2009.22.2.1343228","article-title":"The value of drug repositioning in the current pharmaceutical market","volume":"22","author":"Tobinick","year":"2009","journal-title":"Drug News Perspect."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/tra.12034","article-title":"Moving to the Core: Spatiotemporal Analysis of Forkhead Box O (FOXO) and Nuclear Factor-\u03baB (NF-\u03baB) Nuclear Translocation","volume":"14","author":"Zanella","year":"2013","journal-title":"Traffic"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1242\/jcs.001222","article-title":"Dynamic FoxO transcription factors","volume":"120","author":"Huang","year":"2007","journal-title":"J. Cell Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1016\/j.bbamcr.2010.11.025","article-title":"Structural basis for DNA recognition by FOXO proteins","volume":"1813","author":"Obsil","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1158\/0008-5472.CAN-08-0858","article-title":"Identification of nuclear export inhibitors with potent anticancer activity in vivo","volume":"69","author":"Mutka","year":"2009","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1535-6108(03)00303-9","article-title":"A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells","volume":"4","author":"Kau","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.2174\/138945011796150280","article-title":"FOXO1: A potential target for human diseases","volume":"12","author":"Lu","year":"2011","journal-title":"Curr. Drug Targets"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1021\/np049624z","article-title":"The psammaplysenes, specific inhibitors of FOXO1a nuclear export","volume":"68","author":"Schroeder","year":"2005","journal-title":"J. Nat. Prod."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/sj.embor.7400048","article-title":"D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a","volume":"5","author":"Rena","year":"2004","journal-title":"EMBO Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"28392","DOI":"10.1074\/jbc.M109.038984","article-title":"Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases","volume":"284","author":"Link","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S1734-1140(12)70726-0","article-title":"Chemical structure of phenothiazines and their biological activity","volume":"64","author":"Jaszczyszyn","year":"2012","journal-title":"Pharmacol. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1007\/s11427-013-4561-6","article-title":"Potential antitumor mechanisms of phenothiazine drugs","volume":"56","author":"Qi","year":"2013","journal-title":"Sci. China Life Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"27540","DOI":"10.1038\/srep27540","article-title":"Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents\u2013A drug repurposing strategy","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1002\/hep.28028","article-title":"Repurposing an old drug: A low-cost allergy medication provides new hope for hepatitis C patients","volume":"62","author":"Chen","year":"2015","journal-title":"Hepatology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ejmech.2018.03.055","article-title":"Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents","volume":"10","author":"Kang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2174\/1570180814666170602081412","article-title":"High Throughput Screening and Molecular Docking of Calmodulin with Antagonists of Trifluoperazine and Phenothiazine Chemical Class","volume":"15","author":"Abdelmonem","year":"2018","journal-title":"Lett. Drug Des. Discov."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1002\/prot.23081","article-title":"Trifluoperazine Regulation of Calmodulin Binding to Fas: A Computational Study","volume":"79","author":"Pan","year":"2011","journal-title":"Proteins"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1002\/ajmg.a.34285","article-title":"The impact of cardiac surgery in patients with trisomy 18 and trisomy 13 in Japan","volume":"155","author":"Maeda","year":"2011","journal-title":"Am. J. Med. Genet."},{"key":"ref_78","first-page":"21","article-title":"Clinical and genetic study of 20 patients with trisomy 13 (Patau\u2019s syndrome)","volume":"21","author":"Sugayama","year":"1999","journal-title":"Pediatria (S\u00e3o Paulo)"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1542\/peds.111.4.777","article-title":"Population-based analyses of mortality in trisomy 13 and trisomy 18","volume":"111","author":"Rasmussen","year":"2003","journal-title":"Pediatrics"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/BF03401945","article-title":"Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung\u2019s disease: Evidence for selective loss of Gi coupling","volume":"7","author":"Fuchs","year":"2001","journal-title":"Mol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/2484","article-title":"Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired","volume":"20","author":"Brown","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/hmg\/ddi037","article-title":"In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: Alanine tract expansion modulates DNA binding and transactivation","volume":"14","author":"Brown","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/ajmg.a.34375","article-title":"Duplication of the ZIC2 gene is not associated with holoprosencephaly","volume":"158","author":"Jobanputra","year":"2012","journal-title":"Am. J. Med. Genet."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1093\/hmg\/ddn197","article-title":"Zic2-associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation","volume":"17","author":"Warr","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1136\/jmg.2009.073049","article-title":"Mutations in ZIC2 in human holoprosencephaly: Description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals","volume":"47","author":"Solomon","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/dvg.22767","article-title":"The Zic2 gene directs the formation and function of node cilia to control cardiac situs","volume":"52","author":"Barratt","year":"2014","journal-title":"Genesis"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"38949","DOI":"10.1074\/jbc.R000029200","article-title":"The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression","volume":"275","author":"Molkentin","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.cardiores.2004.03.025","article-title":"GATA transcription factors in the developing and adult heart","volume":"63","author":"Pikkarainen","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4355","DOI":"10.1128\/MCB.19.6.4355","article-title":"Cooperative interaction between GATA-4 and GATA-6 regulates myocardial gene expression","volume":"19","author":"Charron","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"262","DOI":"10.2174\/157340311799960618","article-title":"Transcription factors in heart: Promising therapeutic targets in cardiac hypertrophy","volume":"7","author":"Kohli","year":"2011","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7781","DOI":"10.1021\/acs.jmedchem.7b00816","article-title":"Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2-5","volume":"60","author":"Valimaki","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4611","DOI":"10.1038\/s41598-018-22830-8","article-title":"Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4-NKX2-5 Interaction","volume":"8","author":"Kinnunen","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5953","DOI":"10.1242\/dev.00797","article-title":"Tbx5 specifies the left\/right ventricles and ventricular septum position during cardiogenesis","volume":"130","author":"Takeuchi","year":"2003","journal-title":"Development"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.devcel.2016.01.015","article-title":"TBX5 and NuRD Divide the Heart","volume":"36","author":"Boogerd","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/bs.ctdb.2016.08.008","article-title":"TBX5: A Key Regulator of Heart Development","volume":"122","author":"Steimle","year":"2017","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.1038\/ncomms4680","article-title":"GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development","volume":"5","author":"Stefanovic","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.devcel.2012.06.006","article-title":"Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation","volume":"23","author":"Xie","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1423-0127-21-7","article-title":"CITED2 mutation and methylation in children with congenital heart disease","volume":"21","author":"Xu","year":"2014","journal-title":"J. Biomed. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/humu.20262","article-title":"Identification and functional analysis of CITED2 mutations in patients with congenital heart defects","volume":"26","author":"Sperling","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1447-0594.2008.00504.x","article-title":"Silent information regulator, Sirtuin 1, and age-related diseases","volume":"9","author":"Zeng","year":"2009","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"110","DOI":"10.2174\/138161209787185742","article-title":"NAD(+), sirtuins, and cardiovascular disease","volume":"15","author":"Borradaile","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"12696","DOI":"10.3390\/ijms140612696","article-title":"Potential mechanisms linking atherosclerosis and increased cardiovascular risk in COPD: Focus on Sirtuins","volume":"14","author":"Corbi","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s11892-009-0034-5","article-title":"The role of FOXO in the regulation of metabolism","volume":"9","author":"Gross","year":"2009","journal-title":"Curr. Diab. Rep."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1080\/08916930701464913","article-title":"Immune regulation by Foxo transcription factors","volume":"40","author":"Peng","year":"2007","journal-title":"Autoimmunity"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2174\/1573399811666150804104858","article-title":"FoxO1 inhibitors: The future medicine for metabolic disorders?","volume":"12","author":"Pandey","year":"2016","journal-title":"Curr. Diab. Rev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5861","DOI":"10.1021\/bi001663w","article-title":"Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4)","volume":"40","author":"Weigelt","year":"2001","journal-title":"Biochemistry"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.mad.2004.09.021","article-title":"From worm to human: Bioinformatics approaches to identify FOXO target genes","volume":"126","author":"Xuan","year":"2005","journal-title":"Mech. Ageing. Dev."},{"key":"ref_108","unstructured":"Jean, M.-J., Annet, S., and Michael, S. (2016). ISCN: An International System for Human Cytogenomic Nomenclature (2016), Karger."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3892\/or.2016.4806","article-title":"Low expression of leptin and its association with breast cancer: A transcriptomic study","volume":"36","author":"Karim","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"D412","DOI":"10.1093\/nar\/gkn760","article-title":"STRING 8\u2014a global view on proteins and their functional interactions in 630 organisms","volume":"37","author":"Jensen","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"D808","DOI":"10.1093\/nar\/gks1094","article-title":"STRING v9.1: Protein-protein interaction networks, with increased coverage and integration","volume":"41","author":"Franceschini","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1021\/ci049714+","article-title":"ZINC\u2014A Free Database of Commercially Available Compounds for Virtual Screening","volume":"45","author":"Irwin","year":"2005","journal-title":"J. Chem. Inf. Model."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/1758-2946-1-15","article-title":"Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock","volume":"1","author":"Bikadi","year":"2009","journal-title":"J. Cheminform."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function","volume":"19","author":"Morris","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1287\/moor.6.1.19","article-title":"Minimization by Random Search Techniques","volume":"6","author":"Solis","year":"1981","journal-title":"Math. Oper. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3547\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:29:00Z","timestamp":1760196540000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,10]]},"references-count":115,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["ijms19113547"],"URL":"https:\/\/doi.org\/10.3390\/ijms19113547","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,10]]}}}