• Journal of Life Science
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• v.28 no.2
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• pp.265-273
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• 2018

Estrogen (E2) is involved in the development and progression of breast cancer and is mediated by estrogen receptor (ER). ER plays important roles in cellular proliferation, migration, invasion and causing drug resistance through diverse cross-talks with epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathways in breast cancer cells. Breast cancer is caused mainly by break-down of homeostasis of endocrine signaling pathways especially by the uncontrolled expression and increased activities of E2/IGF-1/EGF, ER/G-protein estrogen receptor (GPER)/IGF-1R/EGFR and their intracellular signaling mediators. These changes influence the complex cross-talk between E2 and growth factors' signaling, eventually resulting in the progression of cancer and resistance against endocrine regulators. Thus, elucidation of the molecular mechanisms in stepwise of the cross-talk between E2 and growth factors will contribute to the customized treatment according to the diverse types of breast cancer. In particular, as strategies for the treatment of breast cancer with diverse genotypes and phenotypes, there can be use of aromatase inhibitors and blockers of E2 action for the ER+ hormone-dependent breast cancer cells and use of IGF-1R/EGFR activity blockers for suppression of cancer cell proliferation from the cross-talk between E2 and growth factors. Furthermore, changes in the expression of the ECM molecules regulated by the cross-talk between ER and EGFR/IGF-1R can be used for the targeted therapeutics against the migration of breast cancer cells. Therefore, it is required for the cross-talk among the signaling pathways of ER, GPER, IGF-1R and EGFR concerning cancer progression to be elucidated in more detail at the molecular level.

• Development and Reproduction
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• v.12 no.3
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• pp.267-274
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• 2008

Differentiation of blastocyst is critical step for implantation and is under the control of regulation factors originated from embryo or reproductive tracts. The sequential communication with those factors is suspected as critical events for differentiation. It has been suggested that intracellular signaling pathways activated by calcium is essential in differentiation of blastocyst. Previously, it was known that concanavalin A (Con A) increase the levels of free calcium in blastocyst stage. However, Con A can not accelerate the hatching, although heparin-binding epidermal growth factor-like growth factor (HB-EGF), a modulator of calcium level, accelerate the hatching of blastocyst. In this study, it was investigated whether Con A or prostaglandin $E_2$ ($PGE_2$) can modulate the differentiation of blastocyst. Con A accelerated the expansion of blastocyst in both 1 hr pulse treatment group and continuous treatment group. However, Con A significantly suppressed the hatching in both groups. The inhibition was significantly strong in continuous treatment group compared with 1 hr pulse treatment group. On the other hand, $PGE_2$ induced the increase the free calcium level, but did not accelerate the expansion. In addition $10{\mu}m\;PGE_2$ inhibited hatching. However, $PGE_2$ could accelerate hatching in Con A pretreated blastocyst. $PGE_2$ also caused the increase of free calcium level in Con A pretreated blastocyst. From these results, it is suggested that changes of the free calcium level induce a different calcium-mediated signaling pathways. In addition, sequential stimulation by signal molecules may triggers the cellular mechanisms for the differentiation of blastocyst.

• Toxicological Research
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• v.24 no.1
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• pp.1-9
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• 2008

Ptdlns(4,5)$P_2$ is a key cellular phosphoinositide that localizes in separate and distinctive pools in subcellular membrane and vesicular compartments. In membranes, Ptdlns(4,5)$P_2$ acts as a precursor to second messengers and is itself a main signaling and targeting molecule. Specific subcellular localization of type I PIP kinases directed by interacting with specific targeting module differentiates Ptdlns(4,5)$P_2$ production in a spatial and temporal manner. Several lines of evidences support the idea that Ptdlns(4,5)$P_2$ is generated in very specific pools in a spatial and temporal manner or by feeding Ptdlns(4,5)$P_2$ directly to effectors. In this concept, the interaction of PIPKI isoforms with a specific targeting module to allow precise subcellular targeting modulates highly specific Ptdlns(4,5)$P_2$ synthesis and channeling overall effectors. For instance, localization of PIPKI${\gamma}$661 to focal adhesions by an interaction with talin results in spatial and temporal production of Ptdlns(4,5)$P_2$, which regulates EGF-stimulated directional cell migration. In addition, Type $I{\gamma}$ PIPK is targeted to E-cadherin in cell adherence junction and plays a role in controlling dynamics of cell adherence junction and endocytosis of E-cadherin. Characterizing how PIP kinase isoforms are regulated by interactions with their targeting modules, as well as the mechanisms by which their product, Ptdlns(4,5)$P_2$, exerts its effects on cellular signaling processes, is crucial to understand the harmonized control of numerous cellular signaling pathways. Thus, in this review the roles of the Ptdlns(4)P(5) kinases and Ptdlns(4,5)$P_2$ were described and critically reviewed in terms of regulation of the E-cadherin trafficking, cell migration, and formation of cell adherence junction which is indispensable and is tightly controlled in epithelial-to-mesenchymal transition process.

• Food Science of Animal Resources
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• v.40 no.4
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• pp.659-667
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• 2020

Muscle stem cells isolated from domestic animals, including cows and pigs, were recently spotlighted as candidates for the production of alternative protein resources, so-called cultured meat or lab-grown meat. In the present study, we aimed to optimize the in vitro culture conditions for the long-term expansion of pig muscle stem cells via the screening of various signaling molecules. Pig muscle stem cells were collected from the biceps femoris muscles of 3-d-old crossbred pigs (Landrace×Yorkshire×Duroc, LYD) and cultured in minimum essential medium-based growth media. However, the pig muscle stem cells gradually lost their proliferation ability and featured morphologies during the long-term culture over two weeks. To find suitable in vitro culture conditions for an extended period, skeletal muscle growth medium-2, including epidermal growth factor (EGF), dexamethasone, and a p38 inhibitor (SB203580), was used to support the stemness of the pig muscle stem cells. Interestingly, pig muscle stem cells were stably maintained in a long-term culture without loss of the expression of myogenic marker genes as determined by PCR analysis. Immunostaining analysis showed that the stem cells were capable of myogenic differentiation after multiple passaging. Therefore, we found that basal culture conditions containing EGF, dexamethasone, and a p38 inhibitor were suitable for maintaining pig muscle stem cells during expanded culture in vitro. This culture method may be applied for the production of cultured meat and further basic research on muscle development in the pig.

• The Journal of Korean Medicine Ophthalmology and Otolaryngology and Dermatology
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• v.32 no.3
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• pp.58-76
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• 2019

Objectives : This study was designed to examine the effects of Daecheonglyong-tang(DCL) on atopic dermatitis induced by DNCB in mice Methods : The Nc/Nga mice were divided into 5 groups, and four groups excluding the normal group were applied by 2,4-dinitrochlorobenzene(DNCB), to cause AD and were orally administered with distilled water(negative control), dexamethasone(positive control), and DCL 200 or 400mg/kg once a day for 4 weeks respectively. The visual changes on skin, changes in skin tissue thickness and eosinophil infiltration were observed. IgE, Histamine, Cytokines, immune cells and the amount of gene expression of filaggrin, VEGF, $TGF-{\beta}1$, EGF were measured. Results : Dermatitis score showed a gross improvement on all DCL groups, similar to or better than positive control. All DCL groups showed no significant change in the basophils, while neutrophils and eosinophils decreased. In only DCL 400 mg/kg groups, white blood cells and mononuclear cells were decreased and lymphocytes were increased. In particular, neutrophils had similar or better effects than the positive control. In all DCL groups, IgE, Histamine, $IL-1{\beta}$, IL-4, IL-5, IL-6 and $TNF-{\alpha}$ were decreased and IL-2 was increased. In only DCL 400 mg/kg groups, IL-10 decreased and $IFN-{\gamma}$ increased. In particular, $IL-1{\beta}$ and $IFN-{\gamma}$ showed a similar rate of increase and decrease comparing positive control in DCL 400 mg/kg. $TGF-{\beta}$1 was increased in all DCL groups, filaggrin and VEGF were increased in only DCL 400 mg/kg groups. EGF did not make any changes. Epidermis, dermis thickness and eosinophil infiltration were also decreased in all DCL groups. Conclusions : By increasing Th1 cytokine and decreasing Th2 cytokine, DCL extracts appear to be effective in controlling immune response imbalances, anti-inflammatory and skin regeneration and are likely to be available as a treatment for AD.

• Journal of Life Science
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• v.30 no.8
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• pp.680-687
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• 2020

Several studies have proved Hovenia dulcis extracts to be an effective antidote for alcoholism, and they are frequently used in the clinical treatment of alcoholic liver disease. The purpose of this study was to investigate the anti-oxidant and anti-senescent activities of 80% methanol fractions of H. dulcis Thunberg in human dermal fibroblast (HDF) cells. The ethanol ethyl acetate fraction showed the highest inhibition of 2,2-diphenyl-1-picryhydrazyl radical scavenging (RC₅₀=3.6±0.8 ㎍/ml) as well as the highest total phenol content (417.2antiholic liver disease. Extracts from e & Tech., Sungkyunkwan University, progressed in the HDF cells, SM22 expression (p<0.001) and β-galactosidase staining intensity increased (p<0.001). An increase in SM22 expression is associated with slower aging which suggests that its expression is high in early aging. HDF treatment using the ethyl acetate fraction significantly increased production of EGF (p<0.01) and PDGF-BB (p<0.01) while SHH expression was reduced (p<0.05). These results suggest that an 80% ethyl acetate fraction of H. dulcis can suppress early aging and demonstrate the potential application of the fraction as a natural anti-senescence agent.

• Molecules and Cells
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• v.37 no.6
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• pp.487-496
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• 2014

Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout ($AGT^{+/-}$) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of $AGT^{+/-}$ EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in $AGT^{+/-}$ EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-$1{\alpha}$and $-2{\alpha}$ were downregulated in $AGT^{+/-}$ early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-$1{\alpha}$ were suppressed in $AGT^{+/-}$ EPCs. In $AGT^{+/-}$ mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.37 no.2
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• pp.97-108
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• 2011

Cancer stem cells have stem cell-like features, such as the ability for self-renewal and differentiation but show unlimited growth because they have the lost normal regulation of cell growth. Cancer stem cells and normal stem cells have similar features. They show high motility, diversity of progeny, robust proliferative potential, association with blood vessels, immature expression profiles, nestin expression, epidermal growth factor (EGF)-receptor expression, phosphatase and tensin homolog (PTEN) expression, hedgehog pathway activity, telomerase activity, and Wnt pathway activity. On the other hand, with cancer cells, some of these signaling pathways are abnormally modified. In 1875, Cohnheim suggested the concept of cancer stem cells. Recently, evidence for the existence of cancer stem cells was identified. In 1994, the cancer stem cells' specific cell surface marker for leukemia was identified. Since then, other specific cell surface markers for cancer stem cells in solid tumors (e.g. breast and colon cancer) have been identified. In oral cancer, studies on cancer stem cells have been performed mainly with squamous cell carcinomas. Oral cancer specific cell surface markers, which are genes strongly expressed in oral cancer and cancer stem cell specific side populations, have been identified. Cancer stem cells are resistant to radiotherapy and chemotherapy. Therefore, to eliminate malignant tumors efficiently and reduce the recurrence rate, therapy targeting cancer stem cells needs to be performed. Currently, studies targeting the cancer stem cells' specific signaling pathways, telomerase and tumor vasculatures are being done.

• The Journal of Korean Medicine Ophthalmology and Otolaryngology and Dermatology
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• v.33 no.2
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• pp.83-99
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• 2020

Objectives : Atopic dermatitis is a chronic inflammatory skin disease with frequent relapses. This study was to investigate the effects of Gammakdaejo-tang(GMD) in DNCB induced atopic dermatitis mice. Methods : The study was divided into five comparion groups. 2,4-dinitrochlorobenzene(DNCB) solution was applied to Nc/Nga mice to induce atopic dermatitis, followed by normal group, negative control group with distilled water, positive control group with Dexamethasione and GMD 200mg/kg or 400mg/kg. The control group was orally administered 200㎕ once daily for 4 weeks. Visual skin condition, Immunoglobulin E, Histamine, Cytokine, Immune cells, Tissue biomarkers were observed. Results : As a result of the dermatitis score evaluation, it was confirmed that the GMD-administered group improved symptoms compared to the negative control group. As a result of measuring IgE, the GMD-administered group significantly decreased compared to the negative control group. As a result of measuring Histamine, GMD group except 200mg/kg of GMD significantly decreased compared to negative control group. As a result of measuring cytokine, GMD 200mg/kg significantly reduced IL-1β, IL-6 and TNF-α compared to the negative control. 400mg/kg significantly reduced IL-1β, IL-4, IL-5, IL-6, IL-10, TNF-α and significantly increased IL-2, IFNγ. As a result of confirming the immune cells, all experimental groups showed no difference in basophil, GMD group significantly reduced monocyte and eosinophil compared to negative control group, and GMD 400mg/kg group significantly reduced white blood cell and neutrophil. And significantly increased lymphocytes. As a result of measuring the gene expression level, all GMD group significantly increased TGF-β1 compared with the negative control group, and filaggrin, VEGF and EGF were significantly increased in GMD 400mg/kg group. Epidermis, dermis thickness, and eosinophil infiltration were found to be decreased in all GMD groups compared with the negative control group. Conclusions : GMD is effective in atopic dermatitis by reducing imbalance of immune response of T cells (Th1 / Th2) and reducing skin tissue damage and inflammatory response.

• Korean Journal of Animal Reproduction
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• v.26 no.1
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• pp.61-68
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• 2002

The present study was examined effects of aesculetin and $O_2$concentrations on in vitro development of Hanwoo (Korean Native Cattle) embryos derived from in-vitro matured and fertilized (IVM-lVF) oocytes. The oocytes were cultured for the first 40~44 h after in vitro fertilization, then embryos of 2 to 8 cell stages were cultured under the different culture conditions for another 6 days. In experiment 1, the higher rates of morulae and blastocysts were produced in 5% $O_2$, than in 20% $O_2$(P＜0.05). There was significantly (P＜0.05) higher in embryos cultured with 1 $\mu\textrm{g}$/$m\ell$ than with 0, 5 and 10 $\mu\textrm{g}$/$m\ell$ of aesculetin. In experiment 2, the proportions of embryo developed with blastocysts and morulae plus blastocysts in 5% $O_2$, again was significantly (P＜0.05) higher in 20% $O_2$, during the culture with aesculetin and/or taurine. In the 5 and 20% $O_2$atmosphere, the inclusion of 1 $\mu\textrm{g}$/$m\ell$ aesculetin or 2.5mM taurine increased significantly (P＜0.05) the percentages of blastocysts and morulae plus blastocysts. In experiment 3, in medium with aesculetin plus PDGF and taurine plus EGF than other treatment groups, significantly (P＜0.05) higher developmental rates were obtained. Number of blastomere in balstocyst stage were also higher in medium with that than without aesculetin. However, there were no significant differences in all culture conditions. In experiment 4, the proportions of embryo developed to the morulae and blastocyst stages were significantly (P＜0.05) higher rates in medium with natural and commercial aesculetin than in control medium. No significant differences, however, were observed in between natural (71%) and commercial (70.0%) aesculetin. Number of blastomere in blastocyst stage were also higher in medium with natural and commercial aesculetin than in control medium. However, there was no effect on the number of blastomeres by these treatment. These data indicate that preimplatation embryos are very sensitive to condition that can cause oxygen concentration and show that efficiency role of aesculetin for improving bovine embryo development in vitro.