Metformin promotes autophagy in Echinococcus granulosus larval stage

Autores
Loos, Julia Alexandra; Nicolao, María Celeste; Cumino, Andrea Carina
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cystic echinococcosis is a neglected parasitic disease caused by the larval stage of Echinococcus granulosus for which an effective treatment is not yet available. Since autophagy constitutes a homeostatic mechanism during stress, either inhibition or activation of its activity might be detrimental for survival of the parasite. Amongst the critical molecules that regulate autophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we have identified the autophagic machinery, the occurrence of TORC1-controlled events, and the correlation between autophagy and the activation of the unfolded protein response in E. granulosus larval stage. In addition, we have demonstrated that the parasite is susceptible to metformin (Met), a drug that indirectly activates Eg-AMPK and induces energy stress. In this work, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electron microscopy analysis revealed the presence of autophagic structures in Met-treated protoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as the transcriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantly up-regulated in Met-treated parasites. The induction of the autophagic process was concomitant with Eg-foxO over-expression and its nuclear localization, which could be correlated with the transcriptional regulation of this pathway. On the other hand, the expression of Eg-AKT and Eg-Sirts suggests a possible participation of these conserved proteins in the regulation of Eg-FoxO. Therefore, through pharmacological activation of the AMPK-FoxO signaling pathway, Met could play a role in the death of the parasite contributing to the demonstrated anti-echinococcal effects of this drug. The understanding of the regulatory mechanisms of this pathway in E. granulosus represents a solid basis for choosing appropriate targets for new chemotherapeutic agents.
Fil: Loos, Julia Alexandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Nicolao, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina
Materia
AMPK-FOXO SIGNAL PATHWAY
AUTOPHAGY
GLYCOPHAGY
METFORMIN
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/85300
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/85300
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Metformin promotes autophagy in Echinococcus granulosus larval stageLoos, Julia AlexandraNicolao, María CelesteCumino, Andrea CarinaAMPK-FOXO SIGNAL PATHWAYAUTOPHAGYGLYCOPHAGYMETFORMINhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Cystic echinococcosis is a neglected parasitic disease caused by the larval stage of Echinococcus granulosus for which an effective treatment is not yet available. Since autophagy constitutes a homeostatic mechanism during stress, either inhibition or activation of its activity might be detrimental for survival of the parasite. Amongst the critical molecules that regulate autophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we have identified the autophagic machinery, the occurrence of TORC1-controlled events, and the correlation between autophagy and the activation of the unfolded protein response in E. granulosus larval stage. In addition, we have demonstrated that the parasite is susceptible to metformin (Met), a drug that indirectly activates Eg-AMPK and induces energy stress. In this work, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electron microscopy analysis revealed the presence of autophagic structures in Met-treated protoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as the transcriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantly up-regulated in Met-treated parasites. The induction of the autophagic process was concomitant with Eg-foxO over-expression and its nuclear localization, which could be correlated with the transcriptional regulation of this pathway. On the other hand, the expression of Eg-AKT and Eg-Sirts suggests a possible participation of these conserved proteins in the regulation of Eg-FoxO. Therefore, through pharmacological activation of the AMPK-FoxO signaling pathway, Met could play a role in the death of the parasite contributing to the demonstrated anti-echinococcal effects of this drug. The understanding of the regulatory mechanisms of this pathway in E. granulosus represents a solid basis for choosing appropriate targets for new chemotherapeutic agents.Fil: Loos, Julia Alexandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata; ArgentinaFil: Nicolao, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata; ArgentinaFil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaElsevier Science2018-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/85300Loos, Julia Alexandra; Nicolao, María Celeste; Cumino, Andrea Carina; Metformin promotes autophagy in Echinococcus granulosus larval stage; Elsevier Science; Molecular and Biochemical Parasitology; 224; 9-2018; 61-700166-6851CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0166685118300835info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molbiopara.2018.07.003info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:03:48Zoai:ri.conicet.gov.ar:11336/85300instacron: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:34982025-09-29 10:03:48.525CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Metformin promotes autophagy in Echinococcus granulosus larval stage
title Metformin promotes autophagy in Echinococcus granulosus larval stage
spellingShingle Metformin promotes autophagy in Echinococcus granulosus larval stage
Loos, Julia Alexandra
AMPK-FOXO SIGNAL PATHWAY
AUTOPHAGY
GLYCOPHAGY
METFORMIN
title_short Metformin promotes autophagy in Echinococcus granulosus larval stage
title_full Metformin promotes autophagy in Echinococcus granulosus larval stage
title_fullStr Metformin promotes autophagy in Echinococcus granulosus larval stage
title_full_unstemmed Metformin promotes autophagy in Echinococcus granulosus larval stage
title_sort Metformin promotes autophagy in Echinococcus granulosus larval stage
dc.creator.none.fl_str_mv Loos, Julia Alexandra
Nicolao, María Celeste
Cumino, Andrea Carina
author Loos, Julia Alexandra
author_facet Loos, Julia Alexandra
Nicolao, María Celeste
Cumino, Andrea Carina
author_role author
author2 Nicolao, María Celeste
Cumino, Andrea Carina
author2_role author
author
dc.subject.none.fl_str_mv AMPK-FOXO SIGNAL PATHWAY
AUTOPHAGY
GLYCOPHAGY
METFORMIN
topic AMPK-FOXO SIGNAL PATHWAY
AUTOPHAGY
GLYCOPHAGY
METFORMIN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Cystic echinococcosis is a neglected parasitic disease caused by the larval stage of Echinococcus granulosus for which an effective treatment is not yet available. Since autophagy constitutes a homeostatic mechanism during stress, either inhibition or activation of its activity might be detrimental for survival of the parasite. Amongst the critical molecules that regulate autophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we have identified the autophagic machinery, the occurrence of TORC1-controlled events, and the correlation between autophagy and the activation of the unfolded protein response in E. granulosus larval stage. In addition, we have demonstrated that the parasite is susceptible to metformin (Met), a drug that indirectly activates Eg-AMPK and induces energy stress. In this work, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electron microscopy analysis revealed the presence of autophagic structures in Met-treated protoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as the transcriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantly up-regulated in Met-treated parasites. The induction of the autophagic process was concomitant with Eg-foxO over-expression and its nuclear localization, which could be correlated with the transcriptional regulation of this pathway. On the other hand, the expression of Eg-AKT and Eg-Sirts suggests a possible participation of these conserved proteins in the regulation of Eg-FoxO. Therefore, through pharmacological activation of the AMPK-FoxO signaling pathway, Met could play a role in the death of the parasite contributing to the demonstrated anti-echinococcal effects of this drug. The understanding of the regulatory mechanisms of this pathway in E. granulosus represents a solid basis for choosing appropriate targets for new chemotherapeutic agents.
Fil: Loos, Julia Alexandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Nicolao, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina
description Cystic echinococcosis is a neglected parasitic disease caused by the larval stage of Echinococcus granulosus for which an effective treatment is not yet available. Since autophagy constitutes a homeostatic mechanism during stress, either inhibition or activation of its activity might be detrimental for survival of the parasite. Amongst the critical molecules that regulate autophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we have identified the autophagic machinery, the occurrence of TORC1-controlled events, and the correlation between autophagy and the activation of the unfolded protein response in E. granulosus larval stage. In addition, we have demonstrated that the parasite is susceptible to metformin (Met), a drug that indirectly activates Eg-AMPK and induces energy stress. In this work, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electron microscopy analysis revealed the presence of autophagic structures in Met-treated protoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as the transcriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantly up-regulated in Met-treated parasites. The induction of the autophagic process was concomitant with Eg-foxO over-expression and its nuclear localization, which could be correlated with the transcriptional regulation of this pathway. On the other hand, the expression of Eg-AKT and Eg-Sirts suggests a possible participation of these conserved proteins in the regulation of Eg-FoxO. Therefore, through pharmacological activation of the AMPK-FoxO signaling pathway, Met could play a role in the death of the parasite contributing to the demonstrated anti-echinococcal effects of this drug. The understanding of the regulatory mechanisms of this pathway in E. granulosus represents a solid basis for choosing appropriate targets for new chemotherapeutic agents.
publishDate 2018
dc.date.none.fl_str_mv 2018-09
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/11336/85300
Loos, Julia Alexandra; Nicolao, María Celeste; Cumino, Andrea Carina; Metformin promotes autophagy in Echinococcus granulosus larval stage; Elsevier Science; Molecular and Biochemical Parasitology; 224; 9-2018; 61-70
0166-6851
CONICET Digital
CONICET
url http://hdl.handle.net/11336/85300
identifier_str_mv Loos, Julia Alexandra; Nicolao, María Celeste; Cumino, Andrea Carina; Metformin promotes autophagy in Echinococcus granulosus larval stage; Elsevier Science; Molecular and Biochemical Parasitology; 224; 9-2018; 61-70
0166-6851
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0166685118300835
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molbiopara.2018.07.003
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
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 13.070432

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