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Piperidylmethyloxychalcone improves immune-mediated acute liver failure via inhibiting TAK1 activity.
- Source :
-
Experimental & molecular medicine [Exp Mol Med] 2017 Nov 17; Vol. 49 (11), pp. e392. Date of Electronic Publication: 2017 Nov 17. - Publication Year :
- 2017
-
Abstract
- Mice deficient in the toll-like receptor (TLR) or the myeloid differentiation factor 88 (MyD88) are resistant to acute liver failure (ALF) with sudden death of hepatocytes. Chalcone derivatives from medicinal plants protect from hepatic damages including ALF, but their mechanisms remain to be clarified. Here, we focused on molecular basis of piperidylmethyloxychalcone (PMOC) in the treatment of TLR/MyD88-associated ALF. C57BL/6J mice were sensitized with D-galactosamine (GalN) and challenged with Escherichia coli lipopolysaccharide (LPS, TLR4 agonist) or oligodeoxynucleotide containing unmethylated CpG motif (CpG ODN, TLR9 agonist) for induction of ALF. Post treatment with PMOC sequentially ameliorated hepatic inflammation, apoptosis of hepatocytes, severe liver injury and shock-mediated death in ALF-induced mice. As a mechanism, PMOC inhibited the catalytic activity of TGF-β-activated kinase 1 (TAK1) in a competitive manner with respect to ATP, displaced fluorescent ATP probe from the complex with TAK1, and docked at the ATP-binding active site on the crystal structure of TAK1. Moreover, PMOC inhibited TAK1 auto-phosphorylation, which is an axis in the activating pathways of nuclear factor-κB (NF-κB) or activating protein 1 (AP1), in the liver with ALF in vivo or in primary liver cells stimulated with TLR agonists in vitro. PMOC consequently suppressed TAK1-inducible NF-κB or AP1 activity in the inflammatory injury, an early pathogenesis leading to ALF. The results suggested that PMOC could contribute to the treatment of TLR/MyD88-associated ALF with the ATP-binding site of TAK1 as a potential therapeutic target.
- Subjects :
- Animals
Chalcone analogs & derivatives
Chalcone chemistry
Disease Models, Animal
Gene Expression Regulation drug effects
Hepatocytes drug effects
Hepatocytes immunology
Hepatocytes metabolism
Hepatocytes pathology
Liver Failure, Acute drug therapy
Liver Failure, Acute pathology
MAP Kinase Kinase Kinases chemistry
MAP Kinase Kinase Kinases metabolism
Macrophages drug effects
Macrophages immunology
Macrophages metabolism
Macrophages pathology
Mice
Models, Molecular
Molecular Conformation
NF-kappa B metabolism
Phosphorylation
Protective Agents pharmacology
Protein Binding
Structure-Activity Relationship
Chalcone pharmacology
Immune System Diseases complications
Liver Failure, Acute etiology
Liver Failure, Acute metabolism
MAP Kinase Kinase Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2092-6413
- Volume :
- 49
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Experimental & molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 29147012
- Full Text :
- https://doi.org/10.1038/emm.2017.156