• The Korea Journal of Herbology
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• v.33 no.4
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• pp.9-18
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• 2018

Objectives : This study aimed to investigate the anti-ulcer effect of an standardized herbal extracts mixture of Inulae Flos and Paeoniae Radix (HT074) on acidified ethanol induced gastric injury and its potential mechanisms. Methods : Antioxidant activities of HT074 and its constituents were measured by DPPH (2,2-Diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging capacity. After the oral administration of HT074 at doses of 100, 300 mg/kg twice per day for 14 days, Gastric lesions were induced by oral administration of acidified ethanol in Sprague Dawley rats. Oxidative stress markers, such as super oxide dismutase (SOD) activity, concentrations of catalase (CAT) and glutathione (GSH) were measured in gastric mucosal tissues. Additionally, the expression of human mucin gene, Mucin 5AC (MUC5AC) mRNA in gastric mucosal tissues was measured. Results : HT074 showed dose dependent radical scavenging activities against DPPH and ABTS radicals. Oral administration of HT074 300 mg/kg for 14 consecutive days significantly decreased gastric lesions and histological damages induced by HCl/EtOH in rats. HT074 treatment significantly increased the activity of SOD (300 mg/kg) and concentration of GSH (100 and 300 mg/kg), however catalase concentration was not significantly increased. MUC5AC mRNA expression was significantly increased by HT074 100, 300 mg/kg treatment. Conclusions : HT074 protects the gastric mucosa from oxidative stress caused by acidified ethanol by increasing the activity of SOD, concentration of GSH and mucin biosynthesis. These findings suggest that HT074 could be an effective candidate for prevention and treatment of gastritis and gastric ulcer.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6447-6453
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• 2012

Background: The mucin components of the gastric gel layer function as a protective and lubricating factor against luminal acid and proteolytic enzymes. Alteration of mucin expression in gastric preneoplastic and neoplastic lesions has suggested potential roles in neoplastic processes. This study aimed to assess the clinicopathological and prognostic significance of MUC-2, MUC-4 and MUC-5AC in Japanese gastric cancer. Methods: Expression of MUC-2, -4 and -5AC was evaluated on tissue microarrays of gastric carcinomas and adjacent non-cancerous mucosa specimens by immunohistochemistry and compared with clinicopathological parameters and survival time of the patients. Results: The three mucins were found to be expressed to a lesser extent in gastric carcinomas in comparison with non-cancerous mucosa (p<0.05). MUC-2 expression was negatively correlated with tumor size, depth of invasion, and TNM staging of gastric cancer (p<0.05), while that of MUC-5AC was negatively associated with the depth of invasion, venous invasion, lymph node metastasis and TNM staging (p<0.05), but positively with MUC-4 and MUC-2 expression (p<0.05). There was higher MUC-2 expression in intestinal- than diffuse-type carcinomas (p<0.05). Kaplan-Meier analysis indicated no relationship between expression of the three mucins and the cumulative survival rate of patients, even stratified according to the depth of invasion (p>0.05). Conclusion: Down-regulated expression of MUC-2, -4 and -5AC may be involved in pathogenesis, invasion, metastasis or differentiation of gastric carcinoma. Their altered expression might therefore be employed as an indicator of pathobiological behavior.

• YAKHAK HOEJI
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• v.58 no.1
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• pp.1-6
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• 2014

We examined whether silibinin and resveratrol affect airway mucin production, degradation of $I{\kappa}B$ and translocation of NF-${\kappa}B$ p65 induced by TNF-${\alpha}$ in NCI-H292 cells. Cells were pretreated with each agent for 30 min and then stimulated with TNF-${\alpha}$ for 24 h or the indicated periods. The two compounds suppressed TNF-${\alpha}$-induced airway mucin production, degradation of $I{\kappa}B$ and translocation of NF-${\kappa}B$ p65. This result suggests that silibinin and resveratrol can regulate the production of mucin induced by TNF-${\alpha}$ through the inactivation of NF-${\kappa}B$ pathway in airway epithelial cells.

• Journal of Ginseng Research
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• v.46 no.3
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• pp.496-504
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• 2022

Background: Cigarette smoke (CS) is considered a principal cause of chronic obstructive pulmonary disease (COPD) and is associated with mucus hypersecretion and airway inflammation. Ginsenoside compound K (CK), a product of ginsenoside metabolism, has various biological activities. Studies on the effects of CK for the treatment of COPD and mucus hypersecretion, including the underlying signaling mechanism, have not yet been conducted. Methods: To study the protective effects and molecular mechanism of CK, phorbol 12-myristate 13-acetate (PMA)-induced human airway epithelial (NCI-H292) cells were used as a cellular model of airway inflammation. An experimental mouse COPD model was also established via CS inhalation and intranasal administration of lipopolysaccharide. Mucin 5AC (MUC5AC), monocyte chemoattractant protein-1, tumor necrosis factor-α (TNF-α), and interleukin-6 secretion, as well as elastase activity and reactive oxygen species production, were determined through enzyme-linked immunosorbent assay. Inflammatory cell influx and mucus secretion in mouse lung tissues were estimated using hematoxylin and eosin and periodic acid-schiff staining, respectively. PKCδ and its downstream signaling molecules were analyzed via western blotting. Results: CK prevented the secretion of MUC5AC and TNF-α in PMA-stimulated NCI-H292 cells and exhibited a protective effect in COPD mice via the suppression of inflammatory mediators and mucus secretion. These effects were accompanied by an inactivation of PKCδ and related signaling in vitro and in vivo. Conclusion: CK suppressed pulmonary inflammation and mucus secretion in COPD mouse model through PKC regulation, highlighting the compound's potential as a useful adjuvant in the prevention and treatment of COPD.

• BMB Reports
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• v.50 no.10
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• pp.516-521
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• 2017

$CLB_{2.0}$, a constituent of PM, induces secretion of multiple cytokines and chemokines that regulate airway inflammation. Specifically, IL-6 upregulates $CLB_{2.0}$-induced MUC5AC and MUC1 expression. Interestingly, of the tight junction proteins examined, claudin-1 expression was inhibited by $CLB_{2.0}$. While the overexpression of claudin-1 decreased $CLB_{2.0}$-induced MUC5AC expression, it increased the expression of the anti-inflammatory mucin, MUC1. $CLB_{2.0}$-induced IL-6 secretion was mediated by ROS. The ROS scavenger N-acetyl-cysteine inhibited $CLB_{2.0}$-induced IL-6 secretion, thereby decreasing the $CLB_{2.0}$-induced MUC5AC expression, whereas $CLB_{2.0}$-induced MUC1 expression increased. $CLB_{2.0}$ activated the ERK1/2 MAPK via a ROS-dependent pathway. ERK1/2 downregulated the claudin-1 and MUC1 expressions, whereas it dramatically increased $CLB_{2.0}$-induced MUC5AC expression. These findings suggest that $CLB_{2.0}$-induced ERK1/2 activation acts as a switch for regulating inflammatory conditions though a ROS-dependent pathway. Our data also suggest that secreted IL-6 regulates $CLB_{2.0}$-induced MUC5AC and MUC1 expression via ROS-mediated downregulation of claudin-1 expression to maintain mucus homeostasis in the airway.

• Tuberculosis and Respiratory Diseases
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• v.58 no.6
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• pp.590-599
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• 2005

Object : Cigarette smoking is a major cause of mucus hypersecretion, which is a pathophysiological feature of many inflammatory airway diseases. Mucins, which are an important part of the airway mucus, are synthesized from the Muc gene in airway epithelial cells. However, the signaling pathways for cigarette smoke-induced mucin synthesis are unknown. The aim of this study was to determine the signal pathway for smoking induced Muc5ac gene expression. Methods : A549 cells were cultured and transiently transfected with the Muc5ac promoter fragment. These cells were stimulated with 5% cigarette smoke extract (CSE) alone or with CSE after a pretreatment with various signal transduction pathway inhibitors (AG1478, PD98059 and SB203580). The Muc5ac promoter activity was examined using the luciferase reporter system, and the level of phosphorylated EGFR, ERK1/2, p38 MAPK and JNK were all examined using Western blot analysis. Muc5ac mRNA expression was also examined using reverse transcriptase polymerase chain reactions (RT-PCR). Results : 1. The peak level of luciferase activity of the Muc5ac promoter was observed at 5% concentration and after 3 hours of incubation with the CSE. The level of EGFR phosphorylation and the luciferase activity of the transfected cells caused by the CSE were significantly suppressed by AG1478 or PD98059 (P<0.01). 2. CSE phosphorylated ERK1/2 or p38 MAPK but not JNK. The Muc5ac mRNA expression level was increased by the CSE but that was suppressed by PD98059 or AG1478. 3. The CSE-induced phosphorylation of ERK1/2 was blocked by PD98059 and that of p38 MAPK was blocked by either PD98059 or SB203580. Either PD98059 or SB203580 suppressed the luciferase activity of the transfected cells (P<0.0001). Conclusion : The Muc5ac mRNA expression level was increased by the CSE. The increased CSE-induced transcriptional activity was mediated via EGF receptor activation, which led to ERK1/2 and p38 MAPK phosphorylation.

• Biomolecules & Therapeutics
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• v.24 no.5
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• pp.469-474
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• 2016

Liriopogons (Liriope and Opiopogon) species are used as a main medicinal ingredient in several Asian countries. The Liriopes Radix (tuber, root of Liriope platyphylla) has to be a promising candidate due to their source of phytochemicals. Steroidal saponins and their glycosides, phenolic compounds, secondary metabolites are considered of active constituents in Liriopes Radix. Spicatoside A, a steroidal saponin, could be more efficacious drug candidate in future. In this review, we summarized the available knowledge on phytochemical and pharmacological activities for spicatoside A. It significantly suppressed the level of NF-${\kappa}B$, NO, iNOS, Cox-2, IL-$1{\beta}$, IL-6 and MAPKs in LPS-stimulated inflammation. The production of MUC5AC mucin was increased. MMP-13 expression was down-regulated in IL-$1{\beta}$-treated cells and reduced glycosaminoglycan release from IL-$1{\alpha}$-treated cells. The neurite outgrowth activity, PI3K, Akt, ERK1/2, TrkA and CREB phosphorylation and neurotropic factors such as NGF and BDNF were upregulated with increased latency time. It also showed cell growth inhibitory activity on various carcinoma cells. From this, spicatoside A exerts anti-inflammation, anti-asthma, anti-osteoclastogenesis, neurite outgrowth, memory consolidation and anticancer activities. Further studies are needed on spicatoside A in order to understand mechanisms of action to treat various human diseases.

• The Korea Journal of Herbology
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• v.34 no.5
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• pp.21-28
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• 2019

Objectives : In present study, we investigated a therapeutic effect and optimum dose of Socheongryong-Tang (SCT) on LPS-induced lung inflammation rats model. Methods : Male Sprague-Dawley rats ($260{\pm}10g$) were divided into 12 groups : Group 1 included the normal rats, and Group 2-12 were administrated LPS by intranasal injection to induce experimental lung inflammation. After 1 day of LPS administration, Group 3-9 were treated with SCT ${\times}1/4$, ${\times}1/2$, ${\times}1$, ${\times}3$, ${\times}6$, ${\times}12$ or ${\times}18$, respectively. Group 10-12 (positive control) were treated with dexamethasone 1 mg/kg or acetylcystein 1.5 mg/kg or diclofenac sodium 0.4 mg/kg, respectively. After sacrifice, bronchoalveolar lavage fluid (BALF) was isolated. The levels of IL-$1{\beta}$, TNF-${\alpha}$, mucin glycoprotein 5AC (MUG5AC) were measured in BALF using enzyme-linked immunosorbent assay (ELISA). Results : LPS injected rats exhibited outstanding lung inflammation manifestations, including increased amount of total cells and neutrophil, and upregulated inflammatory cytokines level in BALF. However, the administration of SCT ${\times}1/4$, ${\times}1/2$ and ${\times}1$ decreased total cells and neutrophil, and suppressed the production of inflammatory cytokines, including $IL-1{\beta}$ and TNF-${\alpha}$, and MUG5AC in BALF. Notably, inhibitory effect of SCT ${\times}1/2$ and ${\times}1$ on the level of TNF-${\alpha}$ was markedly better than that of positive controls, dexamethasone and acetylcystein. Conclusions : Taken together, these results suggest that SCT ${\times}1/2$ and ${\times}1$ has therapeutic effects on LPS-induced lung inflammation rats model.

• BMB Reports
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• v.51 no.2
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• pp.59-64
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• 2018

The airway epithelium is the first place, where a defense mechanism is initiated against environmental stimuli. Mucociliary transport (MCT), which is the defense mechanism of the airway and the role of airway epithelium as mechanical barriers are essential in innate immunity. To maintain normal physiologic function, normal oxygenation is critical for the production of energy for optimal cellular functions. Several pathologic conditions are associated with a decrease in oxygen tension in airway epithelium and chronic sinusitis is one of the airway diseases, which is associated with the hypoxic condition, a potent inflammatory stimulant. We have observed the overexpression of the hypoxia-inducible factor 1 (HIF-1), an essential factor for oxygen homeostasis, in the epithelium of sinus mucosa in sinusitis patients. In a series of previous reports, we have found hypoxia-induced mucus hyperproduction, especially by MUC5AC hyperproduction, disruption of epithelial barrier function by the production of VEGF, and down-regulation of junctional proteins such as ZO-1 and E-cadherin. Furthermore, hypoxia-induced inflammation by HMGB1 translocation into the cytoplasm results in the release of IL-8 through a ROS-dependent mechanism in upper airway epithelium. In this mini-review, we briefly introduce and summarize current progress in the pathogenesis of sinusitis related to hypoxia. The investigation of hypoxia-related pathophysiology in airway epithelium will suggest new insights on airway inflammatory diseases, such as rhinosinusitis for clinical application and drug development.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.2765-2769
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• 2013

Background: A close association between patterns identified by magnifying narrow-band imaging (M-NBI) and histological type has been described. M-NBI patterns were also recently reported to be related to the mucin phenotype; however, detials remain unclear. Materials and Methods: We investigated the cellular differentiation of gastric cancer lesions, along with their mucosal distribution observed by M-NBI. Ninety-seven depressed-type early gastric cancer lesions (74 differentiated and 23 undifferentiated adenocarcinomas) were visualized by M-NBI. Findings were divided into 4 patterns based on abnormal microvascular architecture: a chain loop pattern (CLP), a fine network pattern (FNP), a corkscrew pattern (CSP), and an unclassified pattern. Mucin phenotypes were judged as gastric (G-type), intestinal (I-type), mixed gastric and intestinal (M-type), and null (N-type) based on 4 markers (MAC5AC, MUC6, MUC2, and CD10). The relationship of each pattern of microvascular architecture with organoid differentiation indicated by cancer cell differentiation and its distribution in each histological type of early gastric cancer was investigated. Results: All CLP and FNP lesions were differentiated. The cancer cell distribution showed organoid differentiation in 84.2% (16/19) and 61.1% (22/36) of the two types of lesions, respectively, and there was a significant difference from the unclassified pattern with organoid differentiation (p<0.001). Almost all (94.7%; 18/19) CSP lesions were undifferentiated, and organoid differentiation was observed in 72.2% (13/18). There was a significant difference from the unclassified pattern with organoid differentiation (p<0.05). Conclusions: Cellular differentiation and distribution are associated with microvascular architecture observed by M-NBI.