IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation

Autores
Converti, Ayelén; Bianchi, Maria Silvia; Martinez, Mario David; Montaner, Alejandro Daniel; Lux, Victoria Adela R.; Bonaventura, Maria Marta
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We have demonstrated that oligodeoxynucleotide IMT504 promotes significant improvement in the diabetic condition in diverse animal models. Based on these results, here we evaluated whether these effects observed in vivo could be due to direct effects on β-cells. We demonstrate by immunofluorescence that IMT504 enters the cell and locates in cytoplasm where it induces GSK-3β phosphorylation that inactivates this kinase. As GSK-3β tags Pdx1 for proteasomal degradation, by inactivating GSK-3β, IMT504 induces an increase in Pdx1 protein levels, demonstrated by Western blotting. Concomitantly, an increase in Ins2 and Pdx1 gene transcription was observed, with no significant increase in insulin content or secretion. Enhanced Pdx1 is promising since it is a key transcription factor for insulin synthesis and is also described as an essential factor for the maintenance β-cell phenotype and function. Dose-dependent inhibition of H2O2-induced apoptosis determined by ELISA as well as decreased expression of Bax was also observed. These results were confirmed in another β-cell line, beta-TC-6 cells, in which a cytokine mix induced apoptosis that was reversed by IMT504. In addition, an inhibitor of IMT504 entrance into cells abrogated the effect IMT504. Based on these results we conclude that the β-cell recovery observed in vivo may include direct effects of IMT504 on β-cells, by maintaining their identity/phenotype and protecting them from oxidative stress and cytokine-induced apoptosis. Thus, this work positions IMT504 as a promising option in the framework of the search of new therapies for type I diabetes treatment.
Fil: Converti, Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Bianchi, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Martinez, Mario David. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
Fil: Montaner, Alejandro Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentina
Fil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Bonaventura, Maria Marta. Universidad Nacional de San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Materia
APOPTOSIS
OLIGODEOXYNUCLEOTIDES
PROLIFERATION
TRANSCRIPTION FACTORS
Β-CELLS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/230728
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/230728
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferationConverti, AyelénBianchi, Maria SilviaMartinez, Mario DavidMontaner, Alejandro DanielLux, Victoria Adela R.Bonaventura, Maria MartaAPOPTOSISOLIGODEOXYNUCLEOTIDESPROLIFERATIONTRANSCRIPTION FACTORSΒ-CELLShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1We have demonstrated that oligodeoxynucleotide IMT504 promotes significant improvement in the diabetic condition in diverse animal models. Based on these results, here we evaluated whether these effects observed in vivo could be due to direct effects on β-cells. We demonstrate by immunofluorescence that IMT504 enters the cell and locates in cytoplasm where it induces GSK-3β phosphorylation that inactivates this kinase. As GSK-3β tags Pdx1 for proteasomal degradation, by inactivating GSK-3β, IMT504 induces an increase in Pdx1 protein levels, demonstrated by Western blotting. Concomitantly, an increase in Ins2 and Pdx1 gene transcription was observed, with no significant increase in insulin content or secretion. Enhanced Pdx1 is promising since it is a key transcription factor for insulin synthesis and is also described as an essential factor for the maintenance β-cell phenotype and function. Dose-dependent inhibition of H2O2-induced apoptosis determined by ELISA as well as decreased expression of Bax was also observed. These results were confirmed in another β-cell line, beta-TC-6 cells, in which a cytokine mix induced apoptosis that was reversed by IMT504. In addition, an inhibitor of IMT504 entrance into cells abrogated the effect IMT504. Based on these results we conclude that the β-cell recovery observed in vivo may include direct effects of IMT504 on β-cells, by maintaining their identity/phenotype and protecting them from oxidative stress and cytokine-induced apoptosis. Thus, this work positions IMT504 as a promising option in the framework of the search of new therapies for type I diabetes treatment.Fil: Converti, Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bianchi, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Martinez, Mario David. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaFil: Montaner, Alejandro Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bonaventura, Maria Marta. Universidad Nacional de San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaAmerican Physiological Society2023-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/230728Converti, Ayelén; Bianchi, Maria Silvia; Martinez, Mario David; Montaner, Alejandro Daniel; Lux, Victoria Adela R.; et al.; IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation; American Physiological Society; Physiological Reports; 11; 15; 8-2023; 1-122051-817XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.14814/phy2.15790info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-01-14T11:52:47Zoai:ri.conicet.gov.ar:11336/230728instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-01-14 11:52:47.999CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
title IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
spellingShingle IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
Converti, Ayelén
APOPTOSIS
OLIGODEOXYNUCLEOTIDES
PROLIFERATION
TRANSCRIPTION FACTORS
Β-CELLS
title_short IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
title_full IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
title_fullStr IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
title_full_unstemmed IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
title_sort IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation
dc.creator.none.fl_str_mv Converti, Ayelén
Bianchi, Maria Silvia
Martinez, Mario David
Montaner, Alejandro Daniel
Lux, Victoria Adela R.
Bonaventura, Maria Marta
author Converti, Ayelén
author_facet Converti, Ayelén
Bianchi, Maria Silvia
Martinez, Mario David
Montaner, Alejandro Daniel
Lux, Victoria Adela R.
Bonaventura, Maria Marta
author_role author
author2 Bianchi, Maria Silvia
Martinez, Mario David
Montaner, Alejandro Daniel
Lux, Victoria Adela R.
Bonaventura, Maria Marta
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv APOPTOSIS
OLIGODEOXYNUCLEOTIDES
PROLIFERATION
TRANSCRIPTION FACTORS
Β-CELLS
topic APOPTOSIS
OLIGODEOXYNUCLEOTIDES
PROLIFERATION
TRANSCRIPTION FACTORS
Β-CELLS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv We have demonstrated that oligodeoxynucleotide IMT504 promotes significant improvement in the diabetic condition in diverse animal models. Based on these results, here we evaluated whether these effects observed in vivo could be due to direct effects on β-cells. We demonstrate by immunofluorescence that IMT504 enters the cell and locates in cytoplasm where it induces GSK-3β phosphorylation that inactivates this kinase. As GSK-3β tags Pdx1 for proteasomal degradation, by inactivating GSK-3β, IMT504 induces an increase in Pdx1 protein levels, demonstrated by Western blotting. Concomitantly, an increase in Ins2 and Pdx1 gene transcription was observed, with no significant increase in insulin content or secretion. Enhanced Pdx1 is promising since it is a key transcription factor for insulin synthesis and is also described as an essential factor for the maintenance β-cell phenotype and function. Dose-dependent inhibition of H2O2-induced apoptosis determined by ELISA as well as decreased expression of Bax was also observed. These results were confirmed in another β-cell line, beta-TC-6 cells, in which a cytokine mix induced apoptosis that was reversed by IMT504. In addition, an inhibitor of IMT504 entrance into cells abrogated the effect IMT504. Based on these results we conclude that the β-cell recovery observed in vivo may include direct effects of IMT504 on β-cells, by maintaining their identity/phenotype and protecting them from oxidative stress and cytokine-induced apoptosis. Thus, this work positions IMT504 as a promising option in the framework of the search of new therapies for type I diabetes treatment.
Fil: Converti, Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Bianchi, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Martinez, Mario David. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
Fil: Montaner, Alejandro Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentina
Fil: Lux, Victoria Adela R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Bonaventura, Maria Marta. Universidad Nacional de San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
description We have demonstrated that oligodeoxynucleotide IMT504 promotes significant improvement in the diabetic condition in diverse animal models. Based on these results, here we evaluated whether these effects observed in vivo could be due to direct effects on β-cells. We demonstrate by immunofluorescence that IMT504 enters the cell and locates in cytoplasm where it induces GSK-3β phosphorylation that inactivates this kinase. As GSK-3β tags Pdx1 for proteasomal degradation, by inactivating GSK-3β, IMT504 induces an increase in Pdx1 protein levels, demonstrated by Western blotting. Concomitantly, an increase in Ins2 and Pdx1 gene transcription was observed, with no significant increase in insulin content or secretion. Enhanced Pdx1 is promising since it is a key transcription factor for insulin synthesis and is also described as an essential factor for the maintenance β-cell phenotype and function. Dose-dependent inhibition of H2O2-induced apoptosis determined by ELISA as well as decreased expression of Bax was also observed. These results were confirmed in another β-cell line, beta-TC-6 cells, in which a cytokine mix induced apoptosis that was reversed by IMT504. In addition, an inhibitor of IMT504 entrance into cells abrogated the effect IMT504. Based on these results we conclude that the β-cell recovery observed in vivo may include direct effects of IMT504 on β-cells, by maintaining their identity/phenotype and protecting them from oxidative stress and cytokine-induced apoptosis. Thus, this work positions IMT504 as a promising option in the framework of the search of new therapies for type I diabetes treatment.
publishDate 2023
dc.date.none.fl_str_mv 2023-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/230728
Converti, Ayelén; Bianchi, Maria Silvia; Martinez, Mario David; Montaner, Alejandro Daniel; Lux, Victoria Adela R.; et al.; IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation; American Physiological Society; Physiological Reports; 11; 15; 8-2023; 1-12
2051-817X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/230728
identifier_str_mv Converti, Ayelén; Bianchi, Maria Silvia; Martinez, Mario David; Montaner, Alejandro Daniel; Lux, Victoria Adela R.; et al.; IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation; American Physiological Society; Physiological Reports; 11; 15; 8-2023; 1-12
2051-817X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.14814/phy2.15790
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/vnd.openxmlformats-officedocument.wordprocessingml.document
application/pdf
dc.publisher.none.fl_str_mv American Physiological Society
publisher.none.fl_str_mv American Physiological Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.113929

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