Tilianin Inhibits MUC5AC Expression Mediated Via Down-Regulation of EGFR-MEK-ERK-Sp1 Signaling Pathway in NCI-H292 Human Airway Cells

Song, Won-Yong; Song, Yong; Ryu, Hyung Won; Oh, Sei‐Ryang; Jiang, Hong; Yoon, Do‐Young

doi:10.4014/jmb.1610.10012

Cited by 15 publications

(8 citation statements)

References 36 publications

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“…In this study, the expression levels of Muc5ac, p-ERK, and SP1 were significantly increased in the lung tissues of COPD mice. The result was associated with previous reports [ 34 , 35 ]. However, treatment with GFDHP significantly downregulated the expression levels of those proteins, indicating that GFDHP reduced mucus overproduction by inhibiting the ERK-SP1-Muc5ac pathway.…”

Section: Discussionsupporting

confidence: 93%

Guifu Dihuang Pills Ameliorated Mucus Hypersecretion by Suppressing Muc5ac Expression and Inactivating the ERK-SP1 Pathway in Lipopolysaccharide/Cigarette Smoke-Induced Mice

Zhang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Mucus hypersecretion is a hallmark of chronic obstructive pulmonary disease (COPD) and is associated with increasing sputum production and declining pulmonary function. Therefore, reducing mucus secretion can be a new therapeutic opportunity for preventing COPD. The Guifu Dihuang pill (GFDHP) is a classical Chinese medicine and has been used as an immunoregulator for treatment of kidney yang deficiency syndrome, including hypothyroidism, adrenocortical hypofunction, chronic bronchitis, and COPD, for more than 2000 years. However, the protective effects and mechanisms of GFDHP against mucus hypersecretion in COPD remain obscure. The aim of the present study was to explore the inhibitory effects of GFDHP on lipopolysaccharide/cigarette smoke- (LPS/CS-) induced Mucin5ac (Muc5ac) overproduction and airway goblet cell hyperplasia in mice. The mice were randomly assigned into 6 groups: control, model, GFDHP-L, GFDHP-M, GFDHP-H, and dexamethasone. The mice were given LPS twice through intranasal inhalation and then exposed to CS daily for 6 weeks. Three doses of GFDHP were orally administered daily during the last 3 weeks of the experiment. Pulmonary function was examined with an EMKA pulmonary system, and pulmonary hyperpermeability and lung damage were evaluated with an in vivo imaging system. Inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were detected with a cell count analyzer and though ELISA analysis, respectively. Lung pathological changes and airway goblet cell hyperplasia were analyzed with hematoxylin and eosin and Alcian blue periodic acid Schiff staining. The protein expression levels of Muc5ac and extracellular signal-regulated kinase (ERK)-specificity protein1 (SP1) signaling pathway were measured with Western blot and immunohistochemistry. The results demonstrated that GFDHP improved pulmonary function and suppressed mouse pulmonary hyperpermeability and edema. GFDHP suppressed inflammatory cell infiltration and cytokine release in BALF, thereby elevating pulmonary function. It ameliorated lung pathological changes and airway goblet cell hyperplasia, and suppressed expression levels of Muc5ac mRNA and protein and phospho-ERK and SP1 levels in the lung tissues of the COPD mice. In conclusion, GFDHP inhibited mucus hypersecretion induced by LPS/CS by suppressing the activation of the ERK-SP1 pathway.

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Section: Discussionsupporting

confidence: 93%

Guifu Dihuang Pills Ameliorated Mucus Hypersecretion by Suppressing Muc5ac Expression and Inactivating the ERK-SP1 Pathway in Lipopolysaccharide/Cigarette Smoke-Induced Mice

Zhang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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“…In our study, as part of an ongoing search for potential anti-COPD agents, TN was used as a representative standardized compound of AR. In particular, it was previously reported that tilianin inhibited MUC5AC expression mediated via modulating the EGFR-MEK-ERK-Sp1 signaling pathway in human-airway epithelial cells [43], and effectively regulated inflammatory cytokines such as TNF-α, IL-1β, IL-18, and MCP-1 [44]. However, the mechanisms by which GG, AR, and their mixture inhibit neutrophilic lung inflammation has not been fully elucidated; in our study, we employed a murine COPD model for such purpose.…”

Section: Discussionmentioning

confidence: 99%

Herbal Combinational Medication of Glycyrrhiza glabra, Agastache rugosa Containing Glycyrrhizic Acid, Tilianin Inhibits Neutrophilic Lung Inflammation by Affecting CXCL2, Interleukin-17/STAT3 Signal Pathways in a Murine Model of COPD

et al. 2020

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Chronic obstructive pulmonary disease (COPD) is caused by exposure to toxic particles, such as coal fly ash (CFA), diesel-exhaust particle (DEP), and cigarette smoke (CS), leading to chronic bronchitis, mucus production, and a subsequent lung dysfunction. This study, using a mouse model of COPD, aimed to evaluate the effect of herbal combinational medication of Glycyrrhiza glabra (GG), Agastache rugosa (AR) containing glycyrrhizic acid (GA), and tilianin (TN) as active ingredients. GA, a major active component of GG, possesses a range of pharmacological and biological activities including anti-inflammatory, anti-allergic, anti-oxidative. TN is a major flavonoid that is present in AR. It has been reported to have anti-inflammatory effects of potential utility as an anti-COPD agent. The COPD in the mice model was induced by a challenge with CFA and DEP. BALB/c mice received CFA and DEP alternately three times for 2 weeks to induce COPD. The herbal mixture of GG, AR, and TN significantly decreased the number of neutrophils in the lungs and bronchoalveolar lavage (BAL) fluid. It also significantly reduced the production of C-X-C motif chemokine ligand 2 (CXCL-2), IL-17A, CXCL-1, TNF-α, symmetric dimethylarginine (SDMA) in BALF and CXCL-2, IL-17A, CXCL-1, MUC5AC, transient receptor potential vanilloid-1 (TRPV1), IL-6, COX-2, NOS-II, and TNF-α mRNA expression in the lung tissue. Notably, a combination of GG and AR was more effective at regulating such therapeutic targets than GG or AR alone. The histolopathological lung injury was alleviated by treatment with the herbal mixture and their active ingredients (especially TN). In this study, the herbal combinational mixture more effectively inhibited neutrophilic airway inflammation by regulating the expression of inflammatory cytokines and CXCL-2 by blocking the IL-17/STAT3 pathway. Therefore, a herbal mixture of GG and AR may be a potential therapeutic agent to treat COPD.

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“…Therefore, suppression of the production of MUC5AC may be a therapeutic method for secretory chronic airway inflammatory diseases (4). In our previous studies, mucosal airway hypersecretion was investigated in A549 lung adenocarcinoma cells, human NCI-H292 airway epithelial cells and normal human bronchial epithelial (NHBE) cells (33-35). In the present study, A549 alveolar only basal epithelial cells were used to investigate mucosal airway hypersecretion, owing to their high stability, medium culture conditions and low cost.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the human mucin 5AC promoter and its regulation by the histone acetyltransferase P300

Shu

et al. 2019

Int J Mol Med

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Histone acetylation is important in the modification of gene transcription in asthma and is regulated by histone acetyltransferases (HATs). P300 (P300 HAT) is an enzyme that is able to acetylate a wide variety of proteins. The modification of core histones can further regulate gene transcription, cell proliferation and other cell processes. Airway mucus hypersecretion is one of the most serious pathophysiological symptoms of chronic airway inflammatory diseases, and the human mucin 5AC (MUC5AC) gene has been reported to be a major component of respiratory secretions related to asthma and chronic obstructive pulmonary disease. In the present study, the 5′ sequence of the human MUC5AC gene with a 1,348-bp DNA sequence was amplified from human A549 cells genomic DNA by polymerase chain reaction (PCR), and the product of the PCR was sequenced. By promoter deletion analysis, five promoter segments with different lengths were amplified by PCR. The products were identified by DNA sequencing and the six promoter segments were inserted into pGL3-enhancer vectors. The core promoter area was identified with a series of 5′ deletion promoter plasmids using luciferase reporter assays. MUC5AC promoter activity, and the mRNA and protein expression levels of MUC5AC were observed in P300 wild-type, P300 mutant, P300 small interfering RNA and P300 control groups. The results showed that the core promoter area of MUC5AC was located within the −935/+48 region and that P300 reduced the expression of MUC5AC in A549 cells.

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Tilianin Inhibits MUC5AC Expression Mediated Via Down-Regulation of EGFR-MEK-ERK-Sp1 Signaling Pathway in NCI-H292 Human Airway Cells

Cited by 15 publications

References 36 publications

Guifu Dihuang Pills Ameliorated Mucus Hypersecretion by Suppressing Muc5ac Expression and Inactivating the ERK-SP1 Pathway in Lipopolysaccharide/Cigarette Smoke-Induced Mice

Guifu Dihuang Pills Ameliorated Mucus Hypersecretion by Suppressing Muc5ac Expression and Inactivating the ERK-SP1 Pathway in Lipopolysaccharide/Cigarette Smoke-Induced Mice

Herbal Combinational Medication of Glycyrrhiza glabra, Agastache rugosa Containing Glycyrrhizic Acid, Tilianin Inhibits Neutrophilic Lung Inflammation by Affecting CXCL2, Interleukin-17/STAT3 Signal Pathways in a Murine Model of COPD

Characterization of the human mucin 5AC promoter and its regulation by the histone acetyltransferase P300

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