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Abstract
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.
Keywords
connexin43, hemichannel, gap junction, hepatic stellate cells, inflammation, liver fibrosis, HEPATIC STELLATE CELLS, GAP-JUNCTIONS, INTERCELLULAR COMMUNICATION, KUPFFER CELLS, CONNEXIN, CHANNELS, INJURY, RAT, MACROPHAGES, CIRRHOSIS

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MLA
Crespo Yanguas, Sara et al. “TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice.” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 19.3 (2018): n. pag. Print.
APA
Crespo Yanguas, S., da Silva, T., Pereira, I., Willebrords, J., Maes, M., Sayuri Nogueira, M., Alves de Castro, I., et al. (2018). TAT-Gap19 and carbenoxolone alleviate liver fibrosis in mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 19(3).
Chicago author-date
Crespo Yanguas, Sara, Tereza da Silva, Isabel Pereira, Joost Willebrords, Michaël Maes, Marina Sayuri Nogueira, Inar Alves de Castro, et al. 2018. “TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice.” International Journal of Molecular Sciences 19 (3).
Chicago author-date (all authors)
Crespo Yanguas, Sara, Tereza da Silva, Isabel Pereira, Joost Willebrords, Michaël Maes, Marina Sayuri Nogueira, Inar Alves de Castro, Isabelle Leclercq, Guilherme Romualdo, Luís Barbisan, Luc Leybaert, Bruno Cogliati, and Mathieu Vinken. 2018. “TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice.” International Journal of Molecular Sciences 19 (3).
Vancouver
1.
Crespo Yanguas S, da Silva T, Pereira I, Willebrords J, Maes M, Sayuri Nogueira M, et al. TAT-Gap19 and carbenoxolone alleviate liver fibrosis in mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 2018;19(3).
IEEE
[1]
S. Crespo Yanguas et al., “TAT-Gap19 and carbenoxolone alleviate liver fibrosis in mice,” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 19, no. 3, 2018.
@article{8607698,
  abstract     = {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.},
  articleno    = {817},
  author       = {Crespo Yanguas, Sara and da Silva, Tereza and Pereira, Isabel and Willebrords, Joost and Maes, Michaël and Sayuri Nogueira, Marina and Alves de Castro, Inar and Leclercq, Isabelle and Romualdo, Guilherme and Barbisan, Luís and Leybaert, Luc and Cogliati, Bruno and Vinken, Mathieu},
  issn         = {1422-0067},
  journal      = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
  keywords     = {connexin43,hemichannel,gap junction,hepatic stellate cells,inflammation,liver fibrosis,HEPATIC STELLATE CELLS,GAP-JUNCTIONS,INTERCELLULAR COMMUNICATION,KUPFFER CELLS,CONNEXIN,CHANNELS,INJURY,RAT,MACROPHAGES,CIRRHOSIS},
  language     = {eng},
  number       = {3},
  pages        = {17},
  title        = {TAT-Gap19 and carbenoxolone alleviate liver fibrosis in mice},
  url          = {http://dx.doi.org/10.3390/ijms19030817},
  volume       = {19},
  year         = {2018},
}

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