title: The Flavonoid 7,4'-Dihydroxyflavone Inhibits MUC5AC Gene Expression, Production, and Secretion via Regulation of NF-κB, STAT6, and HDAC2.
abstract: Mucus overproduction is a significant component of the pathophysiology of obstructive lung diseases. Currently, there are only a few medications available that inhibit mucus production. Previous studies showed that glycyrrhizin, a triterpenoid in Glycyrrhiza uralensis inhibits mucin 5AC (MUC5AC) mRNA and protein expression. Other potential mucus production inhibitory compounds contained within in G. uralensis have not been fully investigated. The aim of the present study was to determine if the G. uralensis flavonoid 7,4'-dihydroxyflavone (7,4'-DHF) inhibits MUC5AC gene expression, mucus production, and secretion, and if so, to elucidate the mechanism of this inhibition. 7,4'-Dihydroxyflavone significantly decreased phorbol 12-myristate 13-acetate-stimulated NCI-H292 human airway epithelial cell MUC5AC gene expression and mucus production, at a 28-fold lower concentration than glycyrrhizin (The half maximal inhibitory concentration IC50 value of 1.4 μM vs 38 μM, respectively); 7,4'-DHF also inhibited MUC5AC mucus secretion. Inhibition was associated with the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signal transducer and activator of transcription 6 (STAT6) activation, and enhanced histone deacetylase 2 (HDAC2) expression. In a murine model of asthma, 7,4'-DHF-treated mice exhibited a marked reduction in MUC5AC secretion in the bronchoalveolar lavage fluid compared with control mice. These findings, together with previous findings linking NF-κB, STAT6, and HDAC2 modulation to the control of MUC5AC expression, demonstrate that 7,4'-DHF is a newly identified component of G. uralensis that regulates MUC5AC expression and secretion via regulation of NF-κB, STAT6, and HDAC2.
authors: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Changda
authors: C
authors: Liu
authors: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: David
authors: D
authors: Weir
authors: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Paula
authors: P
authors: Busse
authors: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Nan
authors: N
authors: Yang
authors: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China.
authors: Zhenwen
authors: Z
authors: Zhou
authors: Department of Anesthesiology, Columbia University, New York, NY, USA.
authors: Charles
authors: C
authors: Emala
authors: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Xiu-Min
authors: XM
authors: Li
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation; D029882:Glycyrrhiza uralensis / Q000737:chemistry; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC / Q000378:metabolism*; D009093:Mucus / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism*
chemical_list: D005419:Flavonoids; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D016328:NF-kappa B; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C085172:4',7-dihydroxyflavone; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: Glycyrrhiza uralensis; MTT; NCI-H292; bronchoalveolar lavage; immunoblot; ovalbumin