{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:57:39Z","timestamp":1790719059850,"version":"4.1.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T00:00:00Z","timestamp":1631318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/BIM\/04773\/2013"],"award-info":[{"award-number":["UID\/BIM\/04773\/2013"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019184","name":"Centre for Biomedical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019184","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["RTI2018-094629-B-I00"],"award-info":[{"award-number":["RTI2018-094629-B-I00"]}]},{"name":"Spanish Ministry of Science, Innovation and Universities","award":["FCT-SFRH\/BPD\/100434\/2014"],"award-info":[{"award-number":["FCT-SFRH\/BPD\/100434\/2014"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BR1034\/6-1"],"award-info":[{"award-number":["BR1034\/6-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived \u03b2-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)\/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).<\/jats:p>","DOI":"10.1093\/gerona\/glab265","type":"journal-article","created":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T15:47:03Z","timestamp":1631375223000},"page":"1485-1493","source":"Crossref","is-referenced-by-count":14,"title":["Screening Health-Promoting Compounds for Their Capacity to Induce the Activity of FOXO3"],"prefix":"10.1093","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9576-1766","authenticated-orcid":false,"given":"Lucia","family":"Jimenez","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d (CSIC-UAM) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreia","family":"Silva","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas , Faro , Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Campus de Gambelas , Faro , Portugal"},{"name":"Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas , Faro , Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7997-0728","authenticated-orcid":false,"given":"Giampaolo","family":"Calissi","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d (CSIC-UAM) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Grenho","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas , Faro , Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Campus de Gambelas , Faro , Portugal"},{"name":"Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas , Faro , Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas , Faro , Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Campus de Gambelas , Faro , Portugal"},{"name":"Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas , Faro , Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Mayoral-Varo","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d (CSIC-UAM) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Blanco-Aparicio","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaquin","family":"Pastor","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2251-8295","authenticated-orcid":false,"given":"Victor","family":"Bustos","sequence":"additional","affiliation":[{"name":"Refoxy Pharmaceuticals GmbH , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Bracher","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University , Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Meg\u00edas","sequence":"additional","affiliation":[{"name":"Spanish National Cancer Research Centre (CNIO) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibiana I","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas , Faro , Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Campus de Gambelas , Faro , Portugal"},{"name":"Algarve Biomedical Center (ABC), University of Algarve, Campus de Gambelas , Faro , Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3340-5165","authenticated-orcid":false,"given":"Wolfgang","family":"Link","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d (CSIC-UAM) , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,11]]},"reference":[{"issue":"17","key":"2022081214093773000_CIT0001","doi-asserted-by":"crossref","first-page":"R741","DOI":"10.1016\/j.cub.2012.07.024","article-title":"Ageing as a risk factor for disease","volume":"22","author":"Niccoli","year":"2012","journal-title":"Curr Biol"},{"issue":"6","key":"2022081214093773000_CIT0002","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"issue":"7764","key":"2022081214093773000_CIT0003","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41586-019-1365-2","article-title":"From discoveries in ageing research to therapeutics for healthy ageing","volume":"571","author":"Campisi","year":"2019","journal-title":"Nature"},{"issue":"2","key":"2022081214093773000_CIT0004","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nrm3507","article-title":"FOXOs: signalling integrators for homeostasis maintenance","volume":"14","author":"Eijkelenboom","year":"2013","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"2022081214093773000_CIT0005","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/acel.12427","article-title":"Long live FOXO: unraveling the role of FOXO proteins in aging and longevity","volume":"15","author":"Martins","year":"2016","journal-title":"Aging Cell"},{"issue":"2","key":"2022081214093773000_CIT0006","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1534\/genetics.115.177998","article-title":"Longevity genes revealed by integrative analysis of isoform-specific daf-16\/FoxO mutants of Caenorhabditis elegans","volume":"201","author":"Chen","year":"2015","journal-title":"Genetics"},{"issue":"37","key":"2022081214093773000_CIT0007","doi-asserted-by":"crossref","first-page":"13987","DOI":"10.1073\/pnas.0801030105","article-title":"FOXO3A genotype is strongly associated with human longevity","volume":"105","author":"Willcox","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"2022081214093773000_CIT0008","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1159\/000375235","article-title":"FOXO3: a major gene for human longevity\u2014a mini-review","volume":"61","author":"Morris","year":"2015","journal-title":"Gerontology"},{"issue":"24","key":"2022081214093773000_CIT0009","doi-asserted-by":"crossref","first-page":"4897","DOI":"10.1093\/hmg\/ddp459","article-title":"Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations","volume":"18","author":"Li","year":"2009","journal-title":"Hum Mol Genet"},{"key":"2022081214093773000_CIT0010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4939-8900-3_1","article-title":"Introduction to FOXO biology","volume":"1890","author":"Link","year":"2019","journal-title":"Methods Mol Biol"},{"issue":"12","key":"2022081214093773000_CIT0011","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1002\/ijc.30840","article-title":"FOXO transcription factors at the interface of metabolism and cancer","volume":"141","author":"Link","year":"2017","journal-title":"Int J Cancer"},{"key":"2022081214093773000_CIT0012","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/bs.ctdb.2017.10.006","article-title":"Regulation of FOXO factors in mammalian cells","volume":"127","author":"Brown","year":"2018","journal-title":"Curr Top Dev Biol"},{"issue":"1","key":"2022081214093773000_CIT0013","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41573-020-0088-2","article-title":"Therapeutic strategies targeting FOXO transcription factors","volume":"20","author":"Calissi","year":"2021","journal-title":"Nat Rev Drug Discov"},{"issue":"11","key":"2022081214093773000_CIT0014","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1111\/bph.13631","article-title":"Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine: pharmacological mechanisms and implications for drug discovery","volume":"174","author":"Shen","year":"2017","journal-title":"Br J Pharmacol"},{"issue":"7","key":"2022081214093773000_CIT0015","doi-asserted-by":"crossref","first-page":"351","DOI":"10.3390\/md18070351","article-title":"Astaxanthin as a putative geroprotector: molecular basis and focus on brain aging","volume":"18","author":"Sorrenti","year":"2020","journal-title":"Mar Drugs"},{"issue":"24","key":"2022081214093773000_CIT0016","doi-asserted-by":"crossref","DOI":"10.3390\/molecules25245962","article-title":"How to separate kinase inhibition from undesired monoamine oxidase A inhibition\u2014the development of the DYRK1A inhibitor AnnH75 from the alkaloid harmine","volume":"25","author":"Wurzlbauer","year":"2020","journal-title":"Molecules"},{"issue":"14","key":"2022081214093773000_CIT0017","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1002\/cbic.200800255","article-title":"Chemical genetic analysis of FOXO nuclear-cytoplasmic shuttling by using image-based cell screening","volume":"9","author":"Zanella","year":"2008","journal-title":"Chembiochem"},{"key":"2022081214093773000_CIT0018","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1471-2121-10-14","article-title":"Using multiplexed regulation of luciferase activity and GFP translocation to screen for FOXO modulators","volume":"10","author":"Zanella","year":"2009","journal-title":"BMC Cell Biol"},{"issue":"3","key":"2022081214093773000_CIT0019","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1089\/adt.2007.058","article-title":"An HTS approach to screen for antagonists of the nuclear export machinery using high content cell-based assays","volume":"5","author":"Zanella","year":"2007","journal-title":"Assay Drug Dev Technol"},{"issue":"1","key":"2022081214093773000_CIT0020","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1177\/1087057113501389","article-title":"High-content screening of natural products reveals novel nuclear export inhibitors","volume":"19","author":"Cautain","year":"2014","journal-title":"J Biomol Screen"},{"issue":"20","key":"2022081214093773000_CIT0021","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1038\/onc.2010.58","article-title":"Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells","volume":"29","author":"Zanella","year":"2010","journal-title":"Oncogene"},{"issue":"2","key":"2022081214093773000_CIT0022","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1042\/bj3490629","article-title":"Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues","volume":"349","author":"Furuyama","year":"2000","journal-title":"Biochem J."},{"issue":"16","key":"2022081214093773000_CIT0023","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1038\/onc.2008.21","article-title":"The FoxO code","volume":"27","author":"Calnan","year":"2008","journal-title":"Oncogene"},{"issue":"4","key":"2022081214093773000_CIT0024","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1523\/JNEUROSCI.16-04-01324.1996","article-title":"Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine","volume":"16","author":"Bindokas","year":"1996","journal-title":"J Neurosci"},{"issue":"3","key":"2022081214093773000_CIT0025","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.fct.2009.12.019","article-title":"Beta-carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO)","volume":"48","author":"Herraiz","year":"2010","journal-title":"Food Chem Toxicol"},{"issue":"21","key":"2022081214093773000_CIT0026","doi-asserted-by":"crossref","first-page":"6324","DOI":"10.1111\/j.1742-4658.2009.07346.x","article-title":"Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation","volume":"276","author":"G\u00f6ckler","year":"2009","journal-title":"FEBS J"},{"issue":"11","key":"2022081214093773000_CIT0027","doi-asserted-by":"crossref","first-page":"4042","DOI":"10.1523\/JNEUROSCI.18-11-04042.1998","article-title":"Prevention of PC12 cell death by N-Acetylcysteine requires activation of the Ras pathway","volume":"18","author":"Van Irene","year":"1998","journal-title":"J Neurosci"},{"issue":"1","key":"2022081214093773000_CIT0028","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1750-2187-5-10","article-title":"Inhibition of PI3K\/AKT and MAPK\/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer","volume":"5","author":"Roy","year":"2010","journal-title":"J Mol Signal"},{"issue":"12","key":"2022081214093773000_CIT0029","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.3390\/cancers12123689","article-title":"Harmine and piperlongumine revert TRIB2-mediated drug resistance","volume":"12","author":"Machado","year":"2020","journal-title":"Cancers (Basel)"},{"issue":"Pt 3","key":"2022081214093773000_CIT0030","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1042\/bj3550597","article-title":"The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site","volume":"355","author":"Woods","year":"2001","journal-title":"Biochem J"},{"issue":"6","key":"2022081214093773000_CIT0031","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrd2060","article-title":"Therapeutic potential of resveratrol: the in vivo evidence","volume":"5","author":"Baur","year":"2006","journal-title":"Nat Rev Drug Discov"},{"issue":"6","key":"2022081214093773000_CIT0032","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1016\/j.bbadis.2014.10.005","article-title":"The molecular targets of resveratrol","volume":"1852","author":"Kulkarni","year":"2015","journal-title":"Biochim Biophys Acta"},{"issue":"21","key":"2022081214093773000_CIT0033","doi-asserted-by":"crossref","first-page":"20589","DOI":"10.1074\/jbc.M412357200","article-title":"Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes","volume":"280","author":"Frescas","year":"2005","journal-title":"J Biol Chem"}],"container-title":["The Journals of Gerontology: Series A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/advance-article-pdf\/doi\/10.1093\/gerona\/glab265\/41761009\/glab265.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article-pdf\/77\/8\/1485\/45403377\/glab265.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article-pdf\/77\/8\/1485\/45403377\/glab265.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T14:13:32Z","timestamp":1660313612000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article\/77\/8\/1485\/6368778"}},"subtitle":[],"editor":[{"given":"David G","family":"Le Couteur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,9,11]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,9,11]]},"published-print":{"date-parts":[[2022,8,12]]}},"URL":"https:\/\/doi.org\/10.1093\/gerona\/glab265","relation":{},"ISSN":["1079-5006","1758-535X"],"issn-type":[{"value":"1079-5006","type":"print"},{"value":"1758-535X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,8,1]]},"published":{"date-parts":[[2021,9,11]]}}}