Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo

Autores
Loos, Julia Alexandra; Negro, Perla; Salerno, Graciela Lidia; Cumino, Andrea Carina
Año de publicación
2022
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Cystic echinococcosis is a progressive and chronic disease caused by the larval stage of the species complex Echinococcus granulosus sensu latu. New treatment options are needed especially for advanced disease. Since in these cestodes glycogen is the main energy storage molecule and glucose the major fermentative substrate, our approach was to target the metabolic pathways of the parasite involved in energy production, focusing on the AMPK/TOR pathway. Here, the aim was to assess the in vivo efficacy of metformin as an indirect AMPK agonist, in an advanced disease model (1year post-infection in mice), employing the highest dose of assayed drug (250 mg kg−1 day−1). Metformin-treated mice exhibited a reduction of cellular integrity of the germinal layer of cysts, registering a drug concentration of 1.7 mM (which inhibits mitochondrial respiratory chain complex I), a reduction in intracystic glucose with an increase in lactate concentration, consistent with the rise in the glycogen breakdown and in the LDH activity. Interestingly, the fraction of reducing soluble sugars decreased by 3 times in the cystic fluid and germinal cells after of drug-treatment. However, non-reducing soluble sugars, such as sucrose and trehalose, were consumed in the cystic fluid but showed a significant increase at the intracellular level in presence of the drug. It is surprising that trehalose and sucrose biosynthesis was upregulated during starvation induced by metformin. That is, a futile cycle of non-reducing sugars synthesis and glycogen catabolism during starvation. Function of these disaccharides as stress protectants during starvation provides some resolution to this paradox, as it also occurs in others invertebrates and plants. In the same line evidence, fasting and starvation induce hepatic gluconeogenesis in mammalians. Thus, in this parasite metformin affects glucose-starvation-induced AMPK activation and restructures carbohydrate metabolism prior induction of cell death.
Fil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Negro, Perla. Universidad Nacional de Rosario. Facultad de Ciencias Veterinarias; Argentina
Fil: Salerno, Graciela Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXX Reunión Anual de la Sociedad Argentina de Inmunología & 3er Congreso Franco Argentino de Inmunología y Reunión Anual 2022 de la Sociedad Argentina de Fisiología
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
Materia
ECHINOCOCCUS SP
INTERMEDIARY CARBON METABOLISM
METFORMIN
IN VIVO TREATMENT
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:11336/234238
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivoLoos, Julia AlexandraNegro, PerlaSalerno, Graciela LidiaCumino, Andrea CarinaECHINOCOCCUS SPINTERMEDIARY CARBON METABOLISMMETFORMININ VIVO TREATMENThttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Cystic echinococcosis is a progressive and chronic disease caused by the larval stage of the species complex Echinococcus granulosus sensu latu. New treatment options are needed especially for advanced disease. Since in these cestodes glycogen is the main energy storage molecule and glucose the major fermentative substrate, our approach was to target the metabolic pathways of the parasite involved in energy production, focusing on the AMPK/TOR pathway. Here, the aim was to assess the in vivo efficacy of metformin as an indirect AMPK agonist, in an advanced disease model (1year post-infection in mice), employing the highest dose of assayed drug (250 mg kg−1 day−1). Metformin-treated mice exhibited a reduction of cellular integrity of the germinal layer of cysts, registering a drug concentration of 1.7 mM (which inhibits mitochondrial respiratory chain complex I), a reduction in intracystic glucose with an increase in lactate concentration, consistent with the rise in the glycogen breakdown and in the LDH activity. Interestingly, the fraction of reducing soluble sugars decreased by 3 times in the cystic fluid and germinal cells after of drug-treatment. However, non-reducing soluble sugars, such as sucrose and trehalose, were consumed in the cystic fluid but showed a significant increase at the intracellular level in presence of the drug. It is surprising that trehalose and sucrose biosynthesis was upregulated during starvation induced by metformin. That is, a futile cycle of non-reducing sugars synthesis and glycogen catabolism during starvation. Function of these disaccharides as stress protectants during starvation provides some resolution to this paradox, as it also occurs in others invertebrates and plants. In the same line evidence, fasting and starvation induce hepatic gluconeogenesis in mammalians. Thus, in this parasite metformin affects glucose-starvation-induced AMPK activation and restructures carbohydrate metabolism prior induction of cell death.Fil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; ArgentinaFil: Negro, Perla. Universidad Nacional de Rosario. Facultad de Ciencias Veterinarias; ArgentinaFil: Salerno, Graciela Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; ArgentinaFil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; ArgentinaLXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXX Reunión Anual de la Sociedad Argentina de Inmunología & 3er Congreso Franco Argentino de Inmunología y Reunión Anual 2022 de la Sociedad Argentina de FisiologíaMar del PlataArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaSociedad Argentina de FisiologíaFundación Revista Medicina2022info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/234238Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo; LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXX Reunión Anual de la Sociedad Argentina de Inmunología & 3er Congreso Franco Argentino de Inmunología y Reunión Anual 2022 de la Sociedad Argentina de Fisiología; Mar del Plata; Argentina; 2022; 1-31669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.medicinabuenosaires.com/revistas/vol82-22/s5/1s5.pdfNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:02:48Zoai:ri.conicet.gov.ar:11336/234238instacron: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:34982025-10-22 12:02:48.991CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
title Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
spellingShingle Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
Loos, Julia Alexandra
ECHINOCOCCUS SP
INTERMEDIARY CARBON METABOLISM
METFORMIN
IN VIVO TREATMENT
title_short Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
title_full Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
title_fullStr Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
title_full_unstemmed Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
title_sort Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo
dc.creator.none.fl_str_mv Loos, Julia Alexandra
Negro, Perla
Salerno, Graciela Lidia
Cumino, Andrea Carina
author Loos, Julia Alexandra
author_facet Loos, Julia Alexandra
Negro, Perla
Salerno, Graciela Lidia
Cumino, Andrea Carina
author_role author
author2 Negro, Perla
Salerno, Graciela Lidia
Cumino, Andrea Carina
author2_role author
author
author
dc.subject.none.fl_str_mv ECHINOCOCCUS SP
INTERMEDIARY CARBON METABOLISM
METFORMIN
IN VIVO TREATMENT
topic ECHINOCOCCUS SP
INTERMEDIARY CARBON METABOLISM
METFORMIN
IN VIVO TREATMENT
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Cystic echinococcosis is a progressive and chronic disease caused by the larval stage of the species complex Echinococcus granulosus sensu latu. New treatment options are needed especially for advanced disease. Since in these cestodes glycogen is the main energy storage molecule and glucose the major fermentative substrate, our approach was to target the metabolic pathways of the parasite involved in energy production, focusing on the AMPK/TOR pathway. Here, the aim was to assess the in vivo efficacy of metformin as an indirect AMPK agonist, in an advanced disease model (1year post-infection in mice), employing the highest dose of assayed drug (250 mg kg−1 day−1). Metformin-treated mice exhibited a reduction of cellular integrity of the germinal layer of cysts, registering a drug concentration of 1.7 mM (which inhibits mitochondrial respiratory chain complex I), a reduction in intracystic glucose with an increase in lactate concentration, consistent with the rise in the glycogen breakdown and in the LDH activity. Interestingly, the fraction of reducing soluble sugars decreased by 3 times in the cystic fluid and germinal cells after of drug-treatment. However, non-reducing soluble sugars, such as sucrose and trehalose, were consumed in the cystic fluid but showed a significant increase at the intracellular level in presence of the drug. It is surprising that trehalose and sucrose biosynthesis was upregulated during starvation induced by metformin. That is, a futile cycle of non-reducing sugars synthesis and glycogen catabolism during starvation. Function of these disaccharides as stress protectants during starvation provides some resolution to this paradox, as it also occurs in others invertebrates and plants. In the same line evidence, fasting and starvation induce hepatic gluconeogenesis in mammalians. Thus, in this parasite metformin affects glucose-starvation-induced AMPK activation and restructures carbohydrate metabolism prior induction of cell death.
Fil: Loos, Julia Alexandra. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
Fil: Negro, Perla. Universidad Nacional de Rosario. Facultad de Ciencias Veterinarias; Argentina
Fil: Salerno, Graciela Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Biodiversidad y Biotecnología; Argentina
Fil: Cumino, Andrea Carina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Mar del Plata. Instituto de Investigaciones En Produccion, Sanidad y Ambiente.; Argentina
LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXX Reunión Anual de la Sociedad Argentina de Inmunología & 3er Congreso Franco Argentino de Inmunología y Reunión Anual 2022 de la Sociedad Argentina de Fisiología
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Inmunología
Sociedad Argentina de Fisiología
description Cystic echinococcosis is a progressive and chronic disease caused by the larval stage of the species complex Echinococcus granulosus sensu latu. New treatment options are needed especially for advanced disease. Since in these cestodes glycogen is the main energy storage molecule and glucose the major fermentative substrate, our approach was to target the metabolic pathways of the parasite involved in energy production, focusing on the AMPK/TOR pathway. Here, the aim was to assess the in vivo efficacy of metformin as an indirect AMPK agonist, in an advanced disease model (1year post-infection in mice), employing the highest dose of assayed drug (250 mg kg−1 day−1). Metformin-treated mice exhibited a reduction of cellular integrity of the germinal layer of cysts, registering a drug concentration of 1.7 mM (which inhibits mitochondrial respiratory chain complex I), a reduction in intracystic glucose with an increase in lactate concentration, consistent with the rise in the glycogen breakdown and in the LDH activity. Interestingly, the fraction of reducing soluble sugars decreased by 3 times in the cystic fluid and germinal cells after of drug-treatment. However, non-reducing soluble sugars, such as sucrose and trehalose, were consumed in the cystic fluid but showed a significant increase at the intracellular level in presence of the drug. It is surprising that trehalose and sucrose biosynthesis was upregulated during starvation induced by metformin. That is, a futile cycle of non-reducing sugars synthesis and glycogen catabolism during starvation. Function of these disaccharides as stress protectants during starvation provides some resolution to this paradox, as it also occurs in others invertebrates and plants. In the same line evidence, fasting and starvation induce hepatic gluconeogenesis in mammalians. Thus, in this parasite metformin affects glucose-starvation-induced AMPK activation and restructures carbohydrate metabolism prior induction of cell death.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
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http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/234238
Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo; LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXX Reunión Anual de la Sociedad Argentina de Inmunología & 3er Congreso Franco Argentino de Inmunología y Reunión Anual 2022 de la Sociedad Argentina de Fisiología; Mar del Plata; Argentina; 2022; 1-3
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/234238
identifier_str_mv Advanced experimental cystic echinococcosis: reprogramming of the intermediary carbon metabolism in the parasite under metformin treatment in vivo; LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXX Reunión Anual de la Sociedad Argentina de Inmunología & 3er Congreso Franco Argentino de Inmunología y Reunión Anual 2022 de la Sociedad Argentina de Fisiología; Mar del Plata; Argentina; 2022; 1-3
1669-9106
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://www.medicinabuenosaires.com/revistas/vol82-22/s5/1s5.pdf
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dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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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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