Search

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive biliary inflammation and fibrosis, leading to liver cirrhosis and cholangiocarcinoma. GPBAR1 (TGR5) is a G protein-coupled receptor for secondary bile acids. In this study, we have examined the therapeutic potential of BAR501, a selective GPBAR1 agonist in a PSC model., Methods: Single-cell analysis of healthy human liver samples and gene expression analysis of PSC liver samples were conducted. In vitro studies on a human cholangiocyte cell line (NHC), U937 and human hepatic stellate cells (hSteCs) were performed. Additionally, Abcb4 -/- mice were treated with BAR501 for 12-24 weeks., Results: Single-cell analysis demonstrated that GPBAR1 is expressed by macrophages, NK cells, sinusoidal cells and to a lesser extent by cholangiocytes. Total liver expression of GPBAR1 increases in PSC patients compared to that in healthy controls and positively correlates with markers for monocytes and NK cells and cytokeratin 19. In vitro treatment of NHCs with BAR501 reversed the acquisition of a pro-inflammatory phenotype and the downregulation of GPBAR1 expression promoted by LPS in an NF-κB-dependent manner. Treating Abcb4 -/- mice reduced bile duct inflammation and liver fibrosis and prevented the downregulation of GPBAR1 expression. Treating mice with BAR501 also modulated the bile acid pool composition and reduced the dysbiosis-associated gut permeability, and intestinal and systemic inflammation. Ex vivo experiments using conditioned media from BAR501-treated cholangiocytes mitigated the activation of macrophages., Conclusions: Our study provides evidence for the therapeutic potential of selective GPBAR1 agonists in intestinal inflammation-associated cholestasis, warranting the evaluation of BAR501 in PSC patients., (© 2025 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: Anticoagulant rodenticides (ARs) are a very effective tool to control rodent pest populations. Nevertheless, AR resistance has been documented worldwide. ARs block the cycle of vitamin K, leading to the death of the animal by internal bleeding: mutations in Vkorc1 gene can cause resistance. The spreading of AR-resistant rodents could lead to an increase of their populations, the associated diffusion of zoonotic pathogens, and to the amplified exposure of non-target animals to ARs, thus it is important to study its diffusion widely. This study aimed to report firstly the presence of Vkorc1 mutations in synanthropic rodents from the Emilia-Romagna region, Italy, and evaluate their role in resistance by means of molecular docking analysis., Results: A total of 67 animals were analyzed: 24 Rattus norvegicus, 35 Rattus rattus and eight Mus musculus. Single nucleotide polymorphisms (SNPs) associated with AR resistance, in homozygosis or heterozygosis, were detected in 6/8 mice, on codons 128 and 139, and 13/24 R. norvegicus, on codons 61 and 139, and in 10/35 R. rattus, on codon 59. Furthermore, several newly described missense mutations were detected in all the tested species: the molecular docking analysis suggests a role of some of these (e.g., I123S and F87L) in resistance to brodifacoum, both in rats and in mice., Conclusion: The discovery of AR resistance SNPs in the 43.28% of tested rodents sounds as an alarm bell that requires the introduction of an integrated control approach, where ARs are not used routinely, but under specific monitoring evaluation. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)