GSK805 inhibits alpha-smooth muscle expression and modulates liver inflammation without impairing the well-being of mice.
GSK805
IL‐23R
animal distress
bile duct ligation (BDL)
hepatic stellate cells
primary biliary cholangitis
primary sclerosing cholangitis
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
31 Aug 2024
31 Aug 2024
Historique:
revised:
21
06
2024
received:
16
04
2024
accepted:
05
08
2024
medline:
19
8
2024
pubmed:
19
8
2024
entrez:
19
8
2024
Statut:
ppublish
Résumé
Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell-line LX-2 and in vivo using male bile duct-ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha-smooth muscle actin expression in LX-2 cells. In vivo, GSK805 significantly decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being.
Identifiants
pubmed: 39157975
doi: 10.1096/fj.202400733R
doi:
Substances chimiques
Actins
0
Nuclear Receptor Subfamily 1, Group F, Member 3
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e23889Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : ZE 712/1-2
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : ZE 712/1-3
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : BL953/10-1
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : BL953/10-2
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : VO 450/15-2
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : VO 450/15-3
Informations de copyright
© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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