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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

TAT-Gap19 and Carbenoxolone Alleviate Liver Fibrosis in Mice

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Author(s):
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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]
Total Authors: 13
Affiliation:
[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
Total Affiliations: 6
Document type: Journal article
Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 19, n. 3 MAR 2018.
Web of Science Citations: 5
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. (AU)

FAPESP's process: 13/50420-6 - Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease
Grantee:Mathieu Frederick Alexander Vinken
Support type: Research Projects - SPEC Program
FAPESP's process: 14/23887-3 - Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease
Grantee:Tereza Cristina da Silva
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 14/23890-4 - Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver diseases
Grantee:Isabel Veloso Alves Pereira
Support type: Scholarships in Brazil - Post-Doctorate