Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury

Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell deat...

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Detalles Bibliográficos
Autores: Marañón, Patricia, Wu, Hanghang, Cubero Palero, Francisco Javier, Valverde, Ángela M.
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/101884
Acceso en línea:https://hdl.handle.net/20.500.14352/101884
Access Level:acceso abierto
Palabra clave:612.017
ALK3
Acetaminophen
Acute liver failure
Bone morphogenetic proteins
DMH2
Drug induced liver injury
Ciencias Biomédicas
Inmunología
24 Ciencias de la Vida
2412 Inmunología
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oai_identifier_str oai:docta.ucm.es:20.500.14352/101884
network_acronym_str ES
network_name_str España
repository_id_str
spelling Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injuryMarañón, PatriciaWu, HanghangCubero Palero, Francisco JavierValverde, Ángela M.612.017ALK3AcetaminophenAcute liver failureBone morphogenetic proteinsDMH2Drug induced liver injuryCiencias BiomédicasInmunología24 Ciencias de la Vida2412 InmunologíaAcetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF.ElsevierUniversidad Complutense de Madrid20242024-02-1520242024-02-15journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/101884reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1018842026-06-02T12:44:21Z
dc.title.none.fl_str_mv Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
title Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
spellingShingle Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
Marañón, Patricia
612.017
ALK3
Acetaminophen
Acute liver failure
Bone morphogenetic proteins
DMH2
Drug induced liver injury
Ciencias Biomédicas
Inmunología
24 Ciencias de la Vida
2412 Inmunología
title_short Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
title_full Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
title_fullStr Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
title_full_unstemmed Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
title_sort Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury
dc.creator.none.fl_str_mv Marañón, Patricia
Wu, Hanghang
Cubero Palero, Francisco Javier
Valverde, Ángela M.
author Marañón, Patricia
author_facet Marañón, Patricia
Wu, Hanghang
Cubero Palero, Francisco Javier
Valverde, Ángela M.
author_role author
author2 Wu, Hanghang
Cubero Palero, Francisco Javier
Valverde, Ángela M.
author2_role author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 612.017
ALK3
Acetaminophen
Acute liver failure
Bone morphogenetic proteins
DMH2
Drug induced liver injury
Ciencias Biomédicas
Inmunología
24 Ciencias de la Vida
2412 Inmunología
topic 612.017
ALK3
Acetaminophen
Acute liver failure
Bone morphogenetic proteins
DMH2
Drug induced liver injury
Ciencias Biomédicas
Inmunología
24 Ciencias de la Vida
2412 Inmunología
description Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-02-15
2024
2024-02-15
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/101884
url https://hdl.handle.net/20.500.14352/101884
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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