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

Detalhes bibliográficos
Autor(a) principal: Jimenez, Lucia
Data de Publicação: 2022
Outros Autores: Silva, Andreia, Calissi, Giampaolo, Grenho, Inês, Monteiro, Ana Rita, Mayoral-Varo, Victor, Blanco-Aparicio, Carmen, Pastor, Joaquin, Bustos, Victor, Bracher, Franz, Megías, Diego, Ferreira, Bibiana, Link, Wolfgang
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.1/19231
Resumo: 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 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).
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spelling Screening health-promoting compounds for their capacity to induce the activity of FOXO3AgingFOXO3High-content screeningLongevityNatural productsSeveral 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).Spanish Government RTI2018-094629-B-I00, 2 LPCC-NRS/Terry Fox grants 2016/2017, 2017/2018, German Research Foundation (DFG) BR1034/6-1Oxford University PressSapientiaJimenez, LuciaSilva, AndreiaCalissi, GiampaoloGrenho, InêsMonteiro, Ana RitaMayoral-Varo, VictorBlanco-Aparicio, CarmenPastor, JoaquinBustos, VictorBracher, FranzMegías, DiegoFerreira, BibianaLink, Wolfgang2023-03-13T11:20:20Z2022-122022-12-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/19231eng10.1093/gerona/glab2651758-535Xinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-24T10:31:39Zoai:sapientia.ualg.pt:10400.1/19231Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:08:51.802963Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Screening health-promoting compounds for their capacity to induce the activity of FOXO3
title Screening health-promoting compounds for their capacity to induce the activity of FOXO3
spellingShingle Screening health-promoting compounds for their capacity to induce the activity of FOXO3
Jimenez, Lucia
Aging
FOXO3
High-content screening
Longevity
Natural products
title_short Screening health-promoting compounds for their capacity to induce the activity of FOXO3
title_full Screening health-promoting compounds for their capacity to induce the activity of FOXO3
title_fullStr Screening health-promoting compounds for their capacity to induce the activity of FOXO3
title_full_unstemmed Screening health-promoting compounds for their capacity to induce the activity of FOXO3
title_sort Screening health-promoting compounds for their capacity to induce the activity of FOXO3
author Jimenez, Lucia
author_facet Jimenez, Lucia
Silva, Andreia
Calissi, Giampaolo
Grenho, Inês
Monteiro, Ana Rita
Mayoral-Varo, Victor
Blanco-Aparicio, Carmen
Pastor, Joaquin
Bustos, Victor
Bracher, Franz
Megías, Diego
Ferreira, Bibiana
Link, Wolfgang
author_role author
author2 Silva, Andreia
Calissi, Giampaolo
Grenho, Inês
Monteiro, Ana Rita
Mayoral-Varo, Victor
Blanco-Aparicio, Carmen
Pastor, Joaquin
Bustos, Victor
Bracher, Franz
Megías, Diego
Ferreira, Bibiana
Link, Wolfgang
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Sapientia
dc.contributor.author.fl_str_mv Jimenez, Lucia
Silva, Andreia
Calissi, Giampaolo
Grenho, Inês
Monteiro, Ana Rita
Mayoral-Varo, Victor
Blanco-Aparicio, Carmen
Pastor, Joaquin
Bustos, Victor
Bracher, Franz
Megías, Diego
Ferreira, Bibiana
Link, Wolfgang
dc.subject.por.fl_str_mv Aging
FOXO3
High-content screening
Longevity
Natural products
topic Aging
FOXO3
High-content screening
Longevity
Natural products
description 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 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).
publishDate 2022
dc.date.none.fl_str_mv 2022-12
2022-12-01T00:00:00Z
2023-03-13T11:20:20Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.1/19231
url http://hdl.handle.net/10400.1/19231
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 10.1093/gerona/glab265
1758-535X
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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