TY - JOUR
T1 - The flavonoid 7,4′-dihydroxyflavone inhibits MUC5AC gene expression, production, and secretion via regulation of NF-κB, STAT6, and HDAC2
AU - Liu, Changda
AU - Weir, David
AU - Busse, Paula
AU - Yang, Nan
AU - Zhou, Zhenwen
AU - Emala, Charles
AU - Li, Xiu Min
N1 - Publisher Copyright:
Copyright © 2015 John Wiley & Sons, Ltd.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Glycyrrhiza uralensis
KW - MTT
KW - NCI-H292
KW - bronchoalveolar lavage
KW - immunoblot
KW - ovalbumin
UR - http://www.scopus.com/inward/record.url?scp=84930678284&partnerID=8YFLogxK
U2 - 10.1002/ptr.5334
DO - 10.1002/ptr.5334
M3 - Article
C2 - 25809288
AN - SCOPUS:84930678284
SN - 0951-418X
VL - 29
SP - 925
EP - 932
JO - Phytotherapy Research
JF - Phytotherapy Research
IS - 6
ER -