• International Journal of Oral Biology
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• v.39 no.4
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• pp.193-199
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• 2014

Fluoride has been accepted as an important material for oral health and is widely used to prevent dental caries in dentistry. However, its safety is still questioned by some. Autophagy has been implicated in cancer cell survival and death, and may play an important role in oral cancer. This study was undertaken to examine whether sodium fluoride (NaF) modulates autophagy in SCC25 human tongue squamous cell carcinoma cells. NaF demonstrated anticancer activity via autophagic and apoptotic cell death. Autophagic vacuoles were detectable using observed to form by monodansylcadaverine (MDC) and acridine orange (AO). Analysis of NaF-treated SCC25 cells for the presence of biochemical markers revealed direct effects on the conversion of LC-3II, degradation of p62/SQSTM1, cleavage formation of ATG5 and Beclin-1, and caspase activation. NaF-induced cell death was suppressed by the autophagy inhibitor 3-methyladenine (3-MA). NaF-induced autophagy was confirmed as a pro-death signal in SCC25 cells. These results implicate NaF as a novel anticancer compound for oral cancer therapy.

• BMB Reports
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• v.39 no.6
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• pp.649-655
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• 2006

The NSAID activated gene (NAG-1), a member of the TGF-$\beta$ superfamily, is involved in tumor progression and development. The over-expression of NAG-1 in cancer cells results in growth arrest and increase in apoptosis, suggesting that NAG-1 has anti-tumorigenic activity. This conclusion is further supported by results of experiments with transgenic mice that ubiquitously express human NAG-1. These transgenic mice are resistant to the development of intestinal tumors following treatment with azoxymethane or by introduction of a mutant APC gene. In contrast, other data suggest a pro-tumorigenic role for NAG-1, for example, high expression of NAG-1 is frequently observed in tumors. NAG-1 may be like other members of the TGF-$\beta$ superfamily, acting as a tumor suppressor in the early stages, but acting pro-tumorigenic at the later stages of tumor progression. The expression of NAG-1 can be increased by treatment with drugs and chemicals documented to prevent tumor formation and development. Most notable is the increase in NAG-1 expression by the inhibitors of cyclooxygenases that prevent human colorectal cancer development. The regulation of NAG-1 is complex, but these agents act through either p53 or EGR-1 related pathways. In addition, an increase in NAG-1 is observed in inhibition of the AKT/GSK-$3{\beta}$ pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by tumor suppressor pathways and appears to modulate tumor progression.

• Korean Journal of Poultry Science
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• v.44 no.3
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• pp.211-223
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• 2017

Transforming growth factor beta ($TGF-{\beta}$) signaling pathways are involved in the regulation of proliferation, differentiation, immunity, survival, and apoptosis of many cells. The aim of this study was to investigate the differential expression of $TGF-{\beta}$-related genes, and their interactions and regulators in the spleen of two genetically disparate chicken lines (Marek's disease resistant line 6.3 and Marek's disease-susceptible line 7.2) induced with necrotic enteritis (NE) by Eimeria maxima and Clostridium perfringens infection. By using high-throughput RNA-sequencing, we investigated 76 $TGF-{\beta}$-related genes that were significantly and differentially expressed in the spleens of the chickens. Approximately 20 $TGF-{\beta}$ pathway genes were further verified by qRT-PCR, and the results were consistent with our RNA sequencing data. All 76 identified genes were analyzed through Gene Ontology and mapped onto the KEGG chicken $TGF-{\beta}$ pathway. Our results demonstrated that several key genes, including $TGF-{\beta}$1-3, bone morphogenetic proteins (BMP)1-7, inhibitor of differentiation (ID) proteins ID1-3, SMAD1-9, and Jun, showed a markedly differential expression between the two chicken lines, relative to their respective controls. We then further predicted 24 known miRNAs that targeted BMP7 mRNA from 139 known miRNAs in the two chicken lines. Among these, six miRNAs were measured by qRT-PCR. In conclusion, this study is the first to analyze most of the genes, interactions, and regulators of the $TGF-{\beta}$ pathway in the innate immune responses of NE afflicted chickens.

• Journal of Physiology & Pathology in Korean Medicine
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• v.22 no.5
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• pp.1262-1269
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• 2008

Low intensity pulsed ultrasound(LIPUS) is known to accelerate bone regeneration, but the precise cellular signaling mechanism is still unclear. The purpose if this study was to determine the effect of LIPUS on the signaling mechanism of rat chondrocyte. In the explant culture condition, there was inhibition effect of 1 $W/cm^2$ intensity LIPUS on chondrocytes proliferation but chondrocytes proliferation was increased at 0.25 $W/cm^2$ intensity. In addition, western blot analysis of MAPKs showed that LIPUS increased ERK1/2 activity from the 10 min treatment of LIPUS. Hydrogen peroxide($H_2O_2$), resulted in a time- and dose-dependent cell proliferation, which was largely attributed to apoptosis. $H_2O_2$ treatment caused marked sustained nucleus condensation in Hoechst stain. LIPUS and $H_2O_2$ activates phosphorylation of p-ERK1/2 and PD 98059($10^{-5}M$) blocked the effect of LIPUS and $H_2O_2$. Moreover, the synergistic phosphorylation of p44/42 MAPK by $H_2O_2$, LIPUS was selectively inhibited by PD 98059, ERK1/2 inhibitor. In order to determine whether the increase in cell proliferation caused by $H_2O_2$ and LIPUS could be explained by changes in the level of the prostaglandin $E_2$. Our study demonstrated that LIPUS stimulate the cell proliferation via activated phosphorylation of ERK1/2 in condrocyte. LIPUS has anabolic effects on rat cartilage in explant cultures, indicating a potential important method for the treatment of osteoarthritic cartilarge.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.625-633
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• 2017

Sphingosylphosphorylcholine (SPC) is one of the bioactive phospholipids that has many cellular functions such as cell migration, adhesion, proliferation, angiogenesis, and $Ca^{2+}$ signaling. Recent studies have reported that SPC induces invasion of breast cancer cells via matrix metalloproteinase-3 (MMP-3) secretion leading to WNT activation. Thrombospondin-1 (TSP-1) is a matricellular and calcium-binding protein that binds to a wide variety of integrin and non-integrin cell surface receptors. It regulates cell proliferation, migration, and apoptosis in inflammation, angiogenesis and neoplasia. TSP-1 promotes aggressive phenotype via epithelial mesenchymal transition (EMT). The relationship between SPC and TSP-1 is unclear. We found SPC induced EMT leading to mesenchymal morphology, decrease of E-cadherin expression and increases of N-cadherin and vimentin. SPC induced secretion of thrombospondin-1 (TSP-1) during SPC-induced EMT of various breast cancer cells. Gene silencing of TSP-1 suppressed SPC-induced EMT as well as migration and invasion of MCF10A cells. An extracellular signal-regulated kinase inhibitor, PD98059, significantly suppressed the secretion of TSP-1, expressions of N-cadherin and vimentin, and decrease of E-cadherin in MCF10A cells. ERK2 siRNA suppressed TSP-1 secretion and EMT. From online PROGgene V2, relapse free survival is low in patients having high TSP-1 expressed breast cancer. Taken together, we found that SPC induced EMT and TSP-1 secretion via ERK2 signaling pathway. These results suggests that SPC-induced TSP-1 might be a new target for suppression of metastasis of breast cancer cells.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.3
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• pp.690-696
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• 2006

Houttuynia cordata Thunb, well known as 'E-Sung-Cho' in Korea, is a traditional medicinal plant generally used in Oriental medicine therapy. In the present study, we investigated the effect of water extract of H. cordafa (WEHC) on the growth of human breast carcinoma MCF-7 cells. Exposure of MCF-7 cells to WEHC resulted in growth inhibition and apoptosis in a dose-dependent manner as measured by MTT assay and fluorescent microscope. The anti-proliferative effect of WEHC was associated with a dose-dependent up-regulation of cyclin-dependent kinase inhibitor p21 in a p53-independent fashion. We found WEHC decreased the levels of cyclooxygenase (COX)-2 and inducible nitric oxide synthease (iNOS) expression without significant changes in the expression of COX-1 , which was correlated with a decrease in prostaglandin $E_2{\;}(PGE_2)$ synthesis. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of H. cordata.

• Biomolecules & Therapeutics
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• v.16 no.4
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• pp.336-342
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• 2008

The resveratrol analogue piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene) is a polyphenol present in grapes and wine and reported to have anti-carcinogenic activities. To investigate the mechanism of anticarcinogenic activities of piceatannol, the effects on CYP 1 enzymes were determined in Escherichia coli membranes coexpressing recombinant human CYP1A1, CYP1A2 or CYP1B1 with human NADPH-P450 reductase. Piceatannol showed a strong inhibition of CYP1A1 and CYP1B1 in a concentration-dependent manner, and $IC_{50}$ of human CYP1A1 and CYP1B1 was 5.8 ${\mu}M$ and 16.6 ${\mu}M$, respectively. However, piceatannol did not inhibit CYP1A2 activity in the concentration of up to 100 ${\mu}M$. Piceatannol exhibited 3-fold selectivity for CYP1B1 over CYP1A1. The mode of inhibition of piceatannol was non-competitive for CYP1A1 and CYP1B1. The result that piceatannol did not inhibit CYP1B1-mediated $\alpha$-naphthoflavone ($\alpha$-NF) metabolism suggests piceatannol may act as a non-competitive inhibitor as well. In human prostate carcinoma PC-3 cells, piceatannol induces apoptosis and prevents Aktmediated signal pathway. Taken together, abilities of piceatannol to induce apoptotic cell death as well as CYP1 enzyme inhibition make this compound a useful tool for cancer chemoprevention.

• Proceedings of the Korean Society of Plant Biotechnology Conference
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• 2004.10a
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• pp.81-90
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• 2004

Sialic acid containing glycosphingolipids (gangliosides) have been implicated in the regulation of various biological phenomena such as atherosclerosis. Recent report suggeststhat exogenously supplied disialoganglioside (GD3) serves a dual role in vascular smooth muscle cells (VSMC) proliferation and apoptosis. However, the role of the GD3 synthase gene in VSMC responses has not yet been elucidated. To determine whether a ganglioside is able to modulate VSMC growth. the effect of overexpression of the GD3 synthase gene on DNA synthesis was examined. The results show that the overexpression of this gene has a potent inhibitory effect on DNA synthesis and ERK phosphorylation in cultured VSMC in the presence of PDGF. The suppression of the GD3 synthase gene was correlated with the down-regulation of cyclinE/CDK2. the up-regulation of the CDK inhibitor p21 and blocking of the p27 inhibition,whereas up-regulation of p53 as the result of GD3 synthase gene expression was not observed. Consistently, blockade of GD3 function with anti-GD3 antibody reversed VSMC proliferation and cell cycle proteins. The expression of the CD3 synthase gene also led to the inhibition of TNF--induced matrix metalloproteinase-9 (MMP-9) expression in VSMC as determined by zymography and immunoblot. Furthermore, GD3 synthase gene expression strongly decreased MMP-9 promoteractivlty in response to TNF-. This inhibition was characterized by the down-regulation of MMP-9,which was Iranscriptionally regulated at NF-B and activation protein-1 (AP-1) sites in the MMP-9promoter Finally, the overexpression of MMP-9 in GD3 synthase transfectant cells rescued VSMC proliferation. However MMP-2 overexpression was not affected the cell proliferation. These findings suggest that the fl13 synthase gene represents a physiological modulator of VSMC responses that may contribute to plaque instability in atherosclerosis.

• Journal of the Korean Society of Food Science and Nutrition
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• v.46 no.7
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• pp.896-902
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• 2017

In this study, we investigated citrus Kombucha (CK) produced by three different bacteria strains (Gluconacetobacter xylinus, Gluconacetobacter medellinensis, and Gluconobacter oxydans; named as CK-MOX) identified from traditional Kombucha. During fermentation, the pH level of CK-MOX was gradually reduced, and total acidity slightly increased. Antioxidant activity, measured by DPPH, ABTS, and oxygen radical absorbance capacity assays, markedly increased after fermentation. Moreover, fermented CK-MOX (Day15) exhibited anti-proliferative and anti-migratory activities against EJ human bladder carcinoma cells. Western immunoblot assays showed that treatment with CK-MOX significantly up-regulated phospho-extracellular signaling kinase (ERK) levels. To distinguish whether or not up-regulation of phospho-ERK is the cause or effect, we investigated the viability of EJ cells in the presence of U0126, a mitogen activated protein kinase/ERK kinase 1/2 inhibitor. Pre-treatment with U0126 rescued cells from CK-MOX-induced cell death, which indicates phospho-ERK may be a key regulator in the mechanism of CK-MOX-induced apoptosis of EJ bladder cancer cells. In conclusion, CK-MOX, fermented by a defined composition of bacterial starters, shows antioxidant capacity and anti-cancer activity against EJ bladder cancer cells.

• Journal of dental hygiene science
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• v.18 no.3
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• pp.188-193
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• 2018

The aim of the current study was to demonstrate the potential therapeutic efficacy of resveratrol in oral cancer patients. Lysophosphatidic acid (LPA) intensifies cancer cell invasion and metastasis, whereas resveratrol, a natural polyphenolic compound, possesses antitumor activity, suppressing cell proliferation and progression in various cancer cell lines (ovarian, gastric, oral, pancreatic, colon, and prostate cancer cells). In addition, resveratrol has been identified as an inhibitor of LPA-induced proteolytic enzyme expression and ovarian cancer invasion. Furthermore, resveratrol was shown to inhibit oral cancer cell invasion by downregulating hypoxia-inducible factor $1{\alpha}$ and vascular endothelial growth factor expression. Recently, we demonstrated that LPA is important for the expression of transcription factors TWIST and SLUG during epithelial-mesenchymal transition (EMT) in oral squamous carcinoma cells. In this study, we treated serum-starved cultures of oral squamous carcinoma cell line YD-10B with resveratrol for 24 hours prior to stimulation with LPA. To identify an optimal resveratrol concentration that does not induce apoptosis in oral squamous carcinoma cells, we determined the toxicity of resveratrol in YD-10B cells by assessing their viability using the MTT assay. Another assay was performed using Matrigel-coated cell culture inserts to detect oral cancer cell invasion activity. Immunoblotting was applied for analyzing protein expression of SLUG, TWIST1, E-cadherin, and GAPDH. We demonstrated that resveratrol efficiently inhibited LPA-induced oral cancer cell EMT and invasion by downregulating SLUG and TWIST1 expression. Therefore, resveratrol may potentially reduce oral squamous carcinoma cell invasion and metastasis in oral cancer patients, improving their survival outcomes. In summary, we identified new targets for the development of therapies against oral cancer progression and characterized the therapeutic potential of resveratrol for the treatment of oral cancer patients.