Dual role of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone in inhibiting high-mobility group box 1 secretion and blocking its pro-inflammatory activity in hepatic inflammation.
A previous study reported that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) had a potential hepatoprotective effect through preventing acute liver injury in mice. This study further evaluated the preventive effects of DMC on lipopolysaccharide (LPS)-stimulated hepatic inflammation and the underlying mechanism in liver macrophage. DMC significantly suppressed LPS-stimulated secretion and nucleocytoplasmic translocation of high-mobility group box 1 (HMGB1). DMC could dose-dependently reduce the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase C alpha (PKCα), and phosphoinositide-dependent kinase 1 (PDK1). Furthermore, HMGB1 phosphorylation, the interaction between PKC and HMGB1, and the expression of HMGB1-dependent inflammation-related molecules were dose-dependently inhibited by DMC. Finally, DMC could target binding to the B box of HMGB1 by molecular modeling studies. All of these results indicated that DMC exhibited a potential protective effect against hepatitis probably via inhibiting HMGB1 secretion and blocking HMGB1 pro-inflammatory activity.
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology , 130 Meilong Road, Shanghai 200237, People's Republic of China.
Wan-Guo
WG
Yu
Hao
H
He
Jie
J
Qian
Yan-Hua
YH
Lu
D000818:Animals; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D035264:Flowers / Q000737:chemistry; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D027822:Myrtaceae / Q000737:chemistry*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D051381:Rats
C501649:2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone; D047188:Chalcones; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D024243:HMGB1 Protein; D019869:Phosphatidylinositol 3-Kinases
2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone; hepatic inflammation; high-mobility group box 1; interaction; protein kinase C alpha