Albiflorin ameliorates thioacetamide-induced hepatic fibrosis: The involvement of NURR1-mediated inflammatory signaling cascades in hepatic stellate cells activation

Ecotoxicol Environ Saf. 2024 May:276:116334. doi: 10.1016/j.ecoenv.2024.116334. Epub 2024 Apr 15.

Abstract

Thioacetamide (TAA) within the liver generates hepatotoxic metabolites that can be induce hepatic fibrosis, similar to the clinical pathological features of chronic human liver disease. The potential protective effect of Albiflorin (ALB), a monoterpenoid glycoside found in Paeonia lactiflora Pall, against hepatic fibrosis was investigated. The mouse hepatic fibrosis model was induced with an intraperitoneal injection of TAA. Hepatic stellate cells (HSCs) were subjected to treatment with transforming growth factor-beta (TGF-β), while lipopolysaccharide/adenosine triphosphate (LPS/ATP) was added to stimulate mouse peritoneal macrophages (MPMs), leading to the acquisition of conditioned medium. For TAA-treated mice, ALB reduced ALT, AST, HYP levels in serum or liver. The administration of ALB reduced histopathological abnormalities, and significantly regulated the expressions of nuclear receptor-related 1 protein (NURR1) and the P2X purinoceptor 7 receptor (P2×7r) in liver. ALB could suppress HSCs epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, and pro-inflammatory factor level. ALB also remarkably up-regulated NURR1, inhibited P2×7r signaling pathway, and worked as working as C-DIM12, a NURR1 agonist. Moreover, deficiency of NURR1 in activated HSCs and Kupffer cells weakened the regulatory effect of ALB on P2×7r inhibition. NURR1-mediated inhibition of inflammatory contributed to the regulation of ALB ameliorates TAA-induced hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. Therefore, ALB plays a significant part in the mitigation of TAA-induced hepatotoxicity this highlights the potential of ALB as a protective intervention for hepatic fibrosis.

Keywords: Albiflorin; Hepatic fibrosis; NURR1; P2×7r; Thioacetamide.

MeSH terms

  • Animals
  • Bridged-Ring Compounds / pharmacology
  • Epithelial-Mesenchymal Transition / drug effects
  • Hepatic Stellate Cells* / drug effects
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Liver Cirrhosis* / chemically induced
  • Liver Cirrhosis* / drug therapy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 4, Group A, Member 2* / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2* / metabolism
  • Signal Transduction* / drug effects
  • Thioacetamide* / toxicity

Substances

  • Thioacetamide
  • albiflorin
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Bridged-Ring Compounds
  • Nr4a2 protein, mouse