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Screening health-promoting compounds for their capacity to induce the activity of FOXO3

2022-12Journal article Open Access
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dc.contributor.authorJimenez, Lucia
dc.contributor.authorSilva, Andreia
dc.contributor.authorCalissi, Giampaolo
dc.contributor.authorGrenho, Inês
dc.contributor.authorMonteiro, Ana Rita
dc.contributor.authorMayoral-Varo, Victor
dc.contributor.authorBlanco-Aparicio, Carmen
dc.contributor.authorPastor, Joaquin
dc.contributor.authorBustos, Victor
dc.contributor.authorBracher, Franz
dc.contributor.authorMegías, Diego
dc.contributor.authorFerreira, Bibiana
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2023-03-13T11:20:20Z
dc.date.available2023-03-13T11:20:20Z
dc.date.issued2022-12
dc.description.abstractSeveral 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 beta-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).pt_PT
dc.description.sponsorshipSpanish Government RTI2018-094629-B-I00, 2 LPCC-NRS/Terry Fox grants 2016/2017, 2017/2018, German Research Foundation (DFG) BR1034/6-1pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1093/gerona/glab265pt_PT
dc.identifier.eissn1758-535X
dc.identifier.urihttp://hdl.handle.net/10400.1/19231
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.relationCentre for Biomedical Research
dc.relationCharacterizing the clinical relevance and the mechanism underlying TRIB2-mediated drug resistance to MEK inhibitiors in the context of melanoma
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAgingpt_PT
dc.subjectFOXO3pt_PT
dc.subjectHigh-content screeningpt_PT
dc.subjectLongevitypt_PT
dc.subjectNatural productspt_PT
dc.titleScreening health-promoting compounds for their capacity to induce the activity of FOXO3pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentre for Biomedical Research
oaire.awardTitleCharacterizing the clinical relevance and the mechanism underlying TRIB2-mediated drug resistance to MEK inhibitiors in the context of melanoma
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F04773%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/748585/EU
oaire.citation.endPage1493pt_PT
oaire.citation.issue8pt_PT
oaire.citation.startPage1485pt_PT
oaire.citation.titleThe Journals of Gerontology: Series Apt_PT
oaire.citation.volume77pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamH2020
person.familyNameGrenho
person.familyNameMonteiro
person.familyNameferreira
person.givenNameInês
person.givenNameAna Rita
person.givenNameBibiana
person.identifier.ciencia-id7012-6BCC-CC65
person.identifier.ciencia-id7A19-1CD0-A439
person.identifier.ciencia-idA311-E925-09C5
person.identifier.orcid0000-0003-3777-9380
person.identifier.orcid0000-0001-5694-5335
person.identifier.orcid0000-0003-4772-9395
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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