theLiTE™: a screening platform to identify compounds that reinforce tight junctions

Detalhes bibliográficos
Autor(a) principal: Gomes, Teresa Lopes
Data de Publicação: 2022
Outros Autores: Oliveira-Marques, Virgínia de, Hampson, Richard John, Jacinto, António, de Moraes, Luciana Vieira, Martinho, Rui Goncalo
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.1/17563
Resumo: Tight junctions (TJ) are formed by transmembrane and intracellular proteins that seal the intercellular space and control selective permeability of epithelia. Integrity of the epithelial barrier is central to tissue homeostasis and barrier dysfunction has been linked to many pathological conditions. TJ support the maintenance of cell polarity through interactions with the Par complex (Cdc42-Par-6-Par-3-aPKC) in which Par-6 is an adaptor and links the proteins of the complex together. Studies have shown that Par-6 overexpression delays the assembly of TJ proteins suggesting that Par-6 negatively regulates TJ assembly. Because restoring barrier integrity is of key therapeutic and prophylactic value, we focus on finding compounds that have epithelial barrier reinforcement properties; we developed a screening platform (theLiTE™) to identify compounds that modulate Par-6 expression in follicular epithelial cells from Par-6-GFP Drosophila melanogaster egg chambers. Hits identified were then tested whether they improve epithelial barrier function, using measurements of transepithelial electrical resistance (TEER) or dye efflux to evaluate paracellular permeability. We tested 2,400 compounds, found in total 10 hits. Here we present data on six of them: the first four hits allowed us to sequentially build confidence in theLiTE™ and two compounds that were shortlisted for further development (myricetin and quercetin). We selected quercetin due to its clinical and scientific validation as a compound that regulates TJ; food supplement formulated on the basis of this discovery is currently undergoing clinical evaluation in gastroesophageal reflux disease (GERD) sufferers.
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spelling theLiTE™: a screening platform to identify compounds that reinforce tight junctionstheLiTE (TM): uma plataforma de triagem para identificar compostos que reforçam junções apertadasPAR-6Epithelial cellsTight junctionsQuercetinMyricetinPolarity (cell)Tight junctions (TJ) are formed by transmembrane and intracellular proteins that seal the intercellular space and control selective permeability of epithelia. Integrity of the epithelial barrier is central to tissue homeostasis and barrier dysfunction has been linked to many pathological conditions. TJ support the maintenance of cell polarity through interactions with the Par complex (Cdc42-Par-6-Par-3-aPKC) in which Par-6 is an adaptor and links the proteins of the complex together. Studies have shown that Par-6 overexpression delays the assembly of TJ proteins suggesting that Par-6 negatively regulates TJ assembly. Because restoring barrier integrity is of key therapeutic and prophylactic value, we focus on finding compounds that have epithelial barrier reinforcement properties; we developed a screening platform (theLiTE™) to identify compounds that modulate Par-6 expression in follicular epithelial cells from Par-6-GFP Drosophila melanogaster egg chambers. Hits identified were then tested whether they improve epithelial barrier function, using measurements of transepithelial electrical resistance (TEER) or dye efflux to evaluate paracellular permeability. We tested 2,400 compounds, found in total 10 hits. Here we present data on six of them: the first four hits allowed us to sequentially build confidence in theLiTE™ and two compounds that were shortlisted for further development (myricetin and quercetin). We selected quercetin due to its clinical and scientific validation as a compound that regulates TJ; food supplement formulated on the basis of this discovery is currently undergoing clinical evaluation in gastroesophageal reflux disease (GERD) sufferers.Frontiers Media SASapientiaGomes, Teresa LopesOliveira-Marques, Virgínia deHampson, Richard JohnJacinto, Antóniode Moraes, Luciana VieiraMartinho, Rui Goncalo2022-02-16T15:28:38Z2022-012022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/17563eng1663-981210.3389/fphar.2021.752787info: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:RCAAP2024-11-29T10:31:52Zoai:sapientia.ualg.pt:10400.1/17563Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-11-29T10:31:52Repositório 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 theLiTE™: a screening platform to identify compounds that reinforce tight junctions
theLiTE (TM): uma plataforma de triagem para identificar compostos que reforçam junções apertadas
title theLiTE™: a screening platform to identify compounds that reinforce tight junctions
spellingShingle theLiTE™: a screening platform to identify compounds that reinforce tight junctions
Gomes, Teresa Lopes
PAR-6
Epithelial cells
Tight junctions
Quercetin
Myricetin
Polarity (cell)
title_short theLiTE™: a screening platform to identify compounds that reinforce tight junctions
title_full theLiTE™: a screening platform to identify compounds that reinforce tight junctions
title_fullStr theLiTE™: a screening platform to identify compounds that reinforce tight junctions
title_full_unstemmed theLiTE™: a screening platform to identify compounds that reinforce tight junctions
title_sort theLiTE™: a screening platform to identify compounds that reinforce tight junctions
author Gomes, Teresa Lopes
author_facet Gomes, Teresa Lopes
Oliveira-Marques, Virgínia de
Hampson, Richard John
Jacinto, António
de Moraes, Luciana Vieira
Martinho, Rui Goncalo
author_role author
author2 Oliveira-Marques, Virgínia de
Hampson, Richard John
Jacinto, António
de Moraes, Luciana Vieira
Martinho, Rui Goncalo
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Sapientia
dc.contributor.author.fl_str_mv Gomes, Teresa Lopes
Oliveira-Marques, Virgínia de
Hampson, Richard John
Jacinto, António
de Moraes, Luciana Vieira
Martinho, Rui Goncalo
dc.subject.por.fl_str_mv PAR-6
Epithelial cells
Tight junctions
Quercetin
Myricetin
Polarity (cell)
topic PAR-6
Epithelial cells
Tight junctions
Quercetin
Myricetin
Polarity (cell)
description Tight junctions (TJ) are formed by transmembrane and intracellular proteins that seal the intercellular space and control selective permeability of epithelia. Integrity of the epithelial barrier is central to tissue homeostasis and barrier dysfunction has been linked to many pathological conditions. TJ support the maintenance of cell polarity through interactions with the Par complex (Cdc42-Par-6-Par-3-aPKC) in which Par-6 is an adaptor and links the proteins of the complex together. Studies have shown that Par-6 overexpression delays the assembly of TJ proteins suggesting that Par-6 negatively regulates TJ assembly. Because restoring barrier integrity is of key therapeutic and prophylactic value, we focus on finding compounds that have epithelial barrier reinforcement properties; we developed a screening platform (theLiTE™) to identify compounds that modulate Par-6 expression in follicular epithelial cells from Par-6-GFP Drosophila melanogaster egg chambers. Hits identified were then tested whether they improve epithelial barrier function, using measurements of transepithelial electrical resistance (TEER) or dye efflux to evaluate paracellular permeability. We tested 2,400 compounds, found in total 10 hits. Here we present data on six of them: the first four hits allowed us to sequentially build confidence in theLiTE™ and two compounds that were shortlisted for further development (myricetin and quercetin). We selected quercetin due to its clinical and scientific validation as a compound that regulates TJ; food supplement formulated on the basis of this discovery is currently undergoing clinical evaluation in gastroesophageal reflux disease (GERD) sufferers.
publishDate 2022
dc.date.none.fl_str_mv 2022-02-16T15:28:38Z
2022-01
2022-01-01T00:00:00Z
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/10400.1/17563
url http://hdl.handle.net/10400.1/17563
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1663-9812
10.3389/fphar.2021.752787
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 Frontiers Media SA
publisher.none.fl_str_mv Frontiers Media SA
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
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv mluisa.alvim@gmail.com
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