4--7-dihydroxyflavone and Asthma

Eotaxin/CCL-11 is a major chemoattractant that contributes to eosinophilic inflammation in asthma. Glucocorticoids inhibit inflammation, but long-time exposure may cause paradoxical adverse effects by augmenting eotaxin/CCL-11production. The aim of this study was to determine if 7,4'-dihydroxyflavone (7,4'-DHF), the eotaxin/CCL11 inhibitor isolated from Glycyrrhiza uralensis, reduces in vitro eotaxin production induced by long-time dexamethasone (Dex) exposure, and if so, to elucidate the mechanisms of this inhibition. Human lung fibroblast-1 cells were used to identify the potency of 7,4'-DHF compared with other compounds from G. uralensis, to compare 7,4'-DHF with Dex on eotaxin production following 24-h short-time culture and 72-h longer-time (LT) culture, and to determine the effects of the 7,4'-DHF on Dex LT culture augmented eotaxin production and molecule mechanisms. 7,4'-DHF was the most potent eotaxin/CCL-11 inhibitor among the ten compounds and provided continued suppression. In contrast to short-time culture, Dex LT culture increased constitutively, and IL-4/TNF-α stimulated eotaxin/CCL11 production by human lung fibroblast-1 cells. This adverse effect was abrogated by 7,4'-DHF co-culture. 7,4'-DHF significantly inhibited Dex LT culture augmentation of p-STAT6 and impaired HDAC2 expression. This study demonstrated that 7,4'-DHF has the ability to consistently suppress eotaxin production and prevent Dex-paradoxical adverse effects on eotaxin production. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Asthma; Cells, Cultured; Chemokine CCL11; Dexamethasone; Drug Interactions; Fibroblasts; Flavones; Flavonoids; Glucocorticoids; Glycyrrhiza uralensis; Histone Deacetylase 2; Humans; Interleukin-4; Lung; STAT6 Transcription Factor; Tumor Necrosis Factor-alpha

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.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Line; Disease Models, Animal; Epithelial Cells; Female; Flavonoids; Gene Expression Regulation; Glycyrrhiza uralensis; Histone Deacetylase 2; Humans; Inhibitory Concentration 50; Mice; Mice, Inbred BALB C; Mucin 5AC; Mucus; NF-kappa B; STAT6 Transcription Factor

Allergic asthma is associated with Th2-mediated inflammation. Several flavonoids were isolated from Glycyrrhiza uralensis, one of the herbs in the anti-asthma herbal medicine intervention. The aim of this investigation was to determine whether Glycyrrhiza uralensis flavonoids have inhibitory effects on memory Th2 responses in vitro and antigen-induced Th2 inflammation in vivo. The effects of three Glycyrrhiza uralensis flavonoids on effector memory Th2 cells, D10.G4.1 (D10 cells), were determined by measuring Th2 cytokine production. Isoliquiritigenin, 7, 4'-dihydroxyflavone (7, 4'-DHF) and liquiritigenin significantly suppressed IL-4 and IL-5 production in a dose-dependent manner, 7, 4'-DHF being most potent. It was also evaluated for effects on D10 cell proliferation, GATA-3 expression and IL-4 mRNA expression, which were suppressed, with no loss of cell viability. Chronic treatment with 7, 4'-DHF in a murine model of allergic asthma not only significantly reduced eosinophilic pulmonary inflammation, serum IgE levels, IL-4 and IL-13 levels, but also increased IFN-γ production in lung cell cultures in response to antigen stimulation.

Topics: Animals; Asthma; Cell Line; Chalcones; Disease Models, Animal; Female; Flavanones; Flavonoids; GATA3 Transcription Factor; Glycyrrhiza uralensis; Humans; Immunologic Memory; Interferon-gamma; Interleukin-4; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Phytotherapy; Plants, Medicinal; Th2 Cells