TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice

Detalhes bibliográficos
Autor(a) principal: Yanguas, Sara Crespo
Data de Publicação: 2018
Outros Autores: da Silva, Tereza C., Pereira, Isabel V. A., Willebrords, Joost, Maes, Michaël, Nogueira, Marina Sayuri, de Castro, Inar Alves, Leclercq, Isabelle, Romualdo, Guilherme R. [UNESP], Barbisan, Luís F. [UNESP], Leybaert, Luc, Cogliati, Bruno, Vinken, Mathieu
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.3390/ijms19030817
http://hdl.handle.net/11449/176027
Resumo: Although a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building stone of hemichannels and gap junctions. While gap junctions support intercellular communication, and hence the maintenance of liver homeostasis, hemichannels provide a circuit for extracellular communication and are typically opened by pathological stimuli, such as oxidative stress and inflammation. The present study was set up to investigate the effects of inhibition of connexin43-based hemichannels and gap junctions on liver fibrosis in mice. Liver fibrosis was induced by administration of thioacetamide to Balb/c mice for eight weeks. Thereafter, mice were treated for two weeks with TAT-Gap19, a specific connexin43 hemichannel inhibitor, or carbenoxolone, a general hemichannel and gap junction inhibitor. Subsequently, histopathological analysis was performed and markers of hepatic damage and functionality, oxidative stress, hepatic stellate cell activation and inflammation were evaluated. Connexin43 hemichannel specificity of TAT-Gap19 was confirmed in vitro by fluorescence recovery after photobleaching analysis and the measurement of extracellular release of adenosine-5′-triphosphate. Upon administration to animals, both TAT-Gap19 and carbenoxolone lowered the degree of liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins, respectively. These results support a role of connexin-based signaling in the resolution of liver fibrosis, and simultaneously demonstrate the therapeutic potential of TAT-Gap19 and carbenoxolone in the treatment of this type of chronic liver disease.
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spelling TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in miceConnexin43Gap junctionHemichannelHepatic stellate cellsInflammationLiver fibrosisAlthough a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building stone of hemichannels and gap junctions. While gap junctions support intercellular communication, and hence the maintenance of liver homeostasis, hemichannels provide a circuit for extracellular communication and are typically opened by pathological stimuli, such as oxidative stress and inflammation. The present study was set up to investigate the effects of inhibition of connexin43-based hemichannels and gap junctions on liver fibrosis in mice. Liver fibrosis was induced by administration of thioacetamide to Balb/c mice for eight weeks. Thereafter, mice were treated for two weeks with TAT-Gap19, a specific connexin43 hemichannel inhibitor, or carbenoxolone, a general hemichannel and gap junction inhibitor. Subsequently, histopathological analysis was performed and markers of hepatic damage and functionality, oxidative stress, hepatic stellate cell activation and inflammation were evaluated. Connexin43 hemichannel specificity of TAT-Gap19 was confirmed in vitro by fluorescence recovery after photobleaching analysis and the measurement of extracellular release of adenosine-5′-triphosphate. Upon administration to animals, both TAT-Gap19 and carbenoxolone lowered the degree of liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins, respectively. These results support a role of connexin-based signaling in the resolution of liver fibrosis, and simultaneously demonstrate the therapeutic potential of TAT-Gap19 and carbenoxolone in the treatment of this type of chronic liver disease.European Research CouncilDepartment of In Vitro Toxicology and Dermato-Cosmetology Vrije Universiteit BrusselDepartment of Pathology School of Veterinary Medicine and Animal Science University of São PauloDepartment of Food and Experimental Nutrition Faculty of Pharmaceutical Sciences University of São PauloLaboratory of Hepatogastroenterology Institut de Recherche Expérimentale et clinique Université Catholique de LouvainDepartment of Pathology Botucatu Medical School UNESP-São Paulo State UniversityDepartment of Basic Medical Sciences Physiology Group Ghent UniversityDepartment of Pathology Botucatu Medical School UNESP-São Paulo State UniversityEuropean Research Council: 335476Vrije Universiteit BrusselUniversidade de São Paulo (USP)Université Catholique de LouvainUniversidade Estadual Paulista (Unesp)Ghent UniversityYanguas, Sara Crespoda Silva, Tereza C.Pereira, Isabel V. A.Willebrords, JoostMaes, MichaëlNogueira, Marina Sayuride Castro, Inar AlvesLeclercq, IsabelleRomualdo, Guilherme R. [UNESP]Barbisan, Luís F. [UNESP]Leybaert, LucCogliati, BrunoVinken, Mathieu2018-12-11T17:18:37Z2018-12-11T17:18:37Z2018-03-12info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://dx.doi.org/10.3390/ijms19030817International Journal of Molecular Sciences, v. 19, n. 3, 2018.1422-00671661-6596http://hdl.handle.net/11449/17602710.3390/ijms190308172-s2.0-850441573172-s2.0-85044157317.pdfScopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengInternational Journal of Molecular Sciences1,260info:eu-repo/semantics/openAccess2024-09-03T13:18:43Zoai:repositorio.unesp.br:11449/176027Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestrepositoriounesp@unesp.bropendoar:29462024-09-03T13:18:43Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
title TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
spellingShingle TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
Yanguas, Sara Crespo
Connexin43
Gap junction
Hemichannel
Hepatic stellate cells
Inflammation
Liver fibrosis
title_short TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
title_full TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
title_fullStr TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
title_full_unstemmed TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
title_sort TAT-Gap19 and Carbenoxolone alleviate liver fibrosis in mice
author Yanguas, Sara Crespo
author_facet Yanguas, Sara Crespo
da Silva, Tereza C.
Pereira, Isabel V. A.
Willebrords, Joost
Maes, Michaël
Nogueira, Marina Sayuri
de Castro, Inar Alves
Leclercq, Isabelle
Romualdo, Guilherme R. [UNESP]
Barbisan, Luís F. [UNESP]
Leybaert, Luc
Cogliati, Bruno
Vinken, Mathieu
author_role author
author2 da Silva, Tereza C.
Pereira, Isabel V. A.
Willebrords, Joost
Maes, Michaël
Nogueira, Marina Sayuri
de Castro, Inar Alves
Leclercq, Isabelle
Romualdo, Guilherme R. [UNESP]
Barbisan, Luís F. [UNESP]
Leybaert, Luc
Cogliati, Bruno
Vinken, Mathieu
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Vrije Universiteit Brussel
Universidade de São Paulo (USP)
Université Catholique de Louvain
Universidade Estadual Paulista (Unesp)
Ghent University
dc.contributor.author.fl_str_mv Yanguas, Sara Crespo
da Silva, Tereza C.
Pereira, Isabel V. A.
Willebrords, Joost
Maes, Michaël
Nogueira, Marina Sayuri
de Castro, Inar Alves
Leclercq, Isabelle
Romualdo, Guilherme R. [UNESP]
Barbisan, Luís F. [UNESP]
Leybaert, Luc
Cogliati, Bruno
Vinken, Mathieu
dc.subject.por.fl_str_mv Connexin43
Gap junction
Hemichannel
Hepatic stellate cells
Inflammation
Liver fibrosis
topic Connexin43
Gap junction
Hemichannel
Hepatic stellate cells
Inflammation
Liver fibrosis
description Although a plethora of signaling pathways are known to drive the activation of hepatic stellate cells in liver fibrosis, the involvement of connexin-based communication in this process remains elusive. Connexin43 expression is enhanced in activated hepatic stellate cells and constitutes the molecular building stone of hemichannels and gap junctions. While gap junctions support intercellular communication, and hence the maintenance of liver homeostasis, hemichannels provide a circuit for extracellular communication and are typically opened by pathological stimuli, such as oxidative stress and inflammation. The present study was set up to investigate the effects of inhibition of connexin43-based hemichannels and gap junctions on liver fibrosis in mice. Liver fibrosis was induced by administration of thioacetamide to Balb/c mice for eight weeks. Thereafter, mice were treated for two weeks with TAT-Gap19, a specific connexin43 hemichannel inhibitor, or carbenoxolone, a general hemichannel and gap junction inhibitor. Subsequently, histopathological analysis was performed and markers of hepatic damage and functionality, oxidative stress, hepatic stellate cell activation and inflammation were evaluated. Connexin43 hemichannel specificity of TAT-Gap19 was confirmed in vitro by fluorescence recovery after photobleaching analysis and the measurement of extracellular release of adenosine-5′-triphosphate. Upon administration to animals, both TAT-Gap19 and carbenoxolone lowered the degree of liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins, respectively. These results support a role of connexin-based signaling in the resolution of liver fibrosis, and simultaneously demonstrate the therapeutic potential of TAT-Gap19 and carbenoxolone in the treatment of this type of chronic liver disease.
publishDate 2018
dc.date.none.fl_str_mv 2018-12-11T17:18:37Z
2018-12-11T17:18:37Z
2018-03-12
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://dx.doi.org/10.3390/ijms19030817
International Journal of Molecular Sciences, v. 19, n. 3, 2018.
1422-0067
1661-6596
http://hdl.handle.net/11449/176027
10.3390/ijms19030817
2-s2.0-85044157317
2-s2.0-85044157317.pdf
url http://dx.doi.org/10.3390/ijms19030817
http://hdl.handle.net/11449/176027
identifier_str_mv International Journal of Molecular Sciences, v. 19, n. 3, 2018.
1422-0067
1661-6596
10.3390/ijms19030817
2-s2.0-85044157317
2-s2.0-85044157317.pdf
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv International Journal of Molecular Sciences
1,260
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.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
repository.mail.fl_str_mv repositoriounesp@unesp.br
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