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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice

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Autor(es):
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Yanguas, Sara Crespo [1] ; da Silva, Tereza C. [2] ; Pereira, Isabel V. A. [2] ; Willebrords, Joost [1] ; Maes, Michael [1] ; Nogueira, Marina Sayuri [3] ; de Castro, Inar Alves [3] ; Leclercq, Isabelle [4] ; Romualdo, Guilherme R. [5] ; Barbisan, Luis F. [5] ; Leybaert, Luc [6] ; Cogliati, Bruno [2] ; Vinken, Mathieu [1]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Vrije Univ Brussel, Dept Vitro Toxicol & Dermatocosmetol, B-1090 Brussels - Belgium
[2] Univ Sao Paulo, Sch Vet Med & Anim Sci, Dept Pathol, BR-05508270 Sao Paulo - Brazil
[3] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Food & Expt Nutr, BR-05508000 Sao Paulo - Brazil
[4] Catholic Univ Louvain, Inst Rech Expt & Clin, Lab Hepatogastroenterol, B-1200 Brussels - Belgium
[5] UNESP Sao Paulo State Univ, Botucatu Med Sch, Dept Pathol, BR-18600000 Botucatu, SP - Brazil
[6] Univ Ghent, Dept Basic Med Sci, Physiol Grp, B-9000 Ghent - Belgium
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 19, n. 3 MAR 2018.
Citações Web of Science: 5
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. (AU)

Processo FAPESP: 13/50420-6 - Canais de conexina e panexina como alvos terapêuticos e biomarcadores nas doenças hepáticas aguda e crônica
Beneficiário:Mathieu Frederick Alexander Vinken
Linha de fomento: Auxílio à Pesquisa - Programa SPEC
Processo FAPESP: 14/23887-3 - Canais de conexina e panexina como alvos terapêuticos e biomarcadores nas doenças hepáticas aguda e crônica
Beneficiário:Tereza Cristina da Silva
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 14/23890-4 - Canais de conexina e panexina como alvos terapêuticos e biomarcadores nas doenças hepáticas aguda e crônica
Beneficiário:Isabel Veloso Alves Pereira
Linha de fomento: Bolsas no Brasil - Pós-Doutorado