• Biomolecules & Therapeutics
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• 제24권6호
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• pp.623-629
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• 2016

(1S,2S,3E,7E,11E)-3,7,11,15-cembratetraen-17,2-olide (LS-1), a marine cembrenolide diterpene, has anticancer activity against colon cancer cells such as HT-29, SNU-C5/5-FU (fluorouracil-resistant SNU-C5) and SNU-C5. However, the action mechanism of LS-1 on SNU-C5 human colon cancer cells has not been fully elucidated. In this study, we investigated whether the anticancer effect of LS-1could result from apoptosis via the modulation of $Wnt/{\beta}$-catenin and the TGF-${\beta}$ pathways. When treated with the LS-1, we could observe the apoptotic characteristics such as apoptotic bodies and the increase of sub-G1 hypodiploid cell population, increase of Bax level, decrease of Bcl-2 expression, cleavage of procaspase-3 and cleavage of poly (ADP-ribose) polymerase in SNU-C5 cells. Furthermore, the apoptosis induction of SNU-C5 cells upon LS-1 treatment was also accompanied by the down-regulation of $Wnt/{\beta}$-catenin signaling pathway via the decrease of GSK-$3{\beta}$ phosphorylation followed by the decrease of ${\beta}$-catenin level. In addition, the LS-1 induced the activation of TGF-${\beta}$ signaling pathway with the decrease of carcinoembryonic antigen which leads to decrease of c-Myc, an oncoprotein. These data suggest that the LS-1 could induce the apoptosis via the down-regulation of $Wnt/{\beta}$-catenin pathway and the activation of TGF-${\beta}$ pathway in SNU-C5 human colon cancer cells. The results support that the LS-1 might have potential for the treatment of human colon cancer.

• Natural Product Sciences
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• 제29권1호
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• pp.31-37
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• 2023

In this study, we investigated the efficacy of Celtis choseniana Nakai (C. choseniana) as complementary herbal medicine to ameliorate androgenic alopecia (AGA). The effects of C. choseniana on AGA were evaluated using testosterone propionate-induced AGA mouse model and dihydrotestosterone-treated human hair follicle dermal papilla cells. In vivo, C. choseniana treatment deactivated androgen signaling by reducing the concentration of serum dihydrotestosterone level and expressions of 5α-reductase 2 and androgen receptor. Next, C. choseniana treatment increased the hair regrowth rate. Histological studies demonstrated that C. choseniana induced the anagen phase in testosterone propionate-induced AGA mouse model. Cellular proliferation was promoted by C. choseniana treatment via increasing the expression of proliferation factors, such as proliferating cell nuclear antigen and cyclin D1. Furthermore, C. choseniana treatment increased the expression of proteins related to the Wnt/β-catenin signaling pathway. In addition, dickkopf-1, a Wnt inhibitor, was downregulated with C. choseniana treatment. Likewise, C. choseniana treatment promoted cellular proliferation in vitro. This study demonstrated the inhibitory effect of C. choseniana on androgen-induced AGA. Moreover, C. choseniana induced activation of Wnt/β-catenin signaling, resulting in prolonged anagen and cellular proliferation. Therefore, we suggest that C. choseniana can be used as a therapeutic agent to alleviate AGA.

• Molecules and Cells
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• 제46권7호
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• pp.441-450
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• 2023

β-Catenin (Ctnnb1) has been shown to play critical roles in the development and maintenance of epithelial cells, including the retinal pigment epithelium (RPE). Ctnnb1 is not only a component of intercellular junctions in the epithelium, it also functions as a transcriptional regulator in the Wnt signaling pathway. To identify which of its functional modalities is critically involved in mouse RPE development and maintenance, we varied Ctnnb1 gene content and activity in mouse RPE lineage cells and tested their impacts on mouse eye development. We found that a Ctnnb1 double mutant (Ctnnb1^dm), which exhibits impaired transcriptional activity, could not replace Ctnnb1 in the RPE, whereas Ctnnb1^Y654E, which has reduced affinity for the junctions, could do so. Expression of the constitutively active Ctnnb1^∆ex3 mutant also suppressed the development of RPE, instead facilitating a ciliary cell fate. However, the post-mitotic or mature RPE was insensitive to the loss, inactivation, or constitutive activation of Ctnnb1. Collectively, our results suggest that Ctnnb1 should be maintained within an optimal range to specify RPE through transcriptional regulation of Wnt target genes in the optic neuroepithelium.

• Experimental and Molecular Medicine
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• 제50권12호
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• pp.3.1-3.14
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• 2018

Type 1 diabetes mellitus (T1DM) is a pathological condition associated with osteopenia. $WNT/{\beta}$-catenin signaling is implicated in this process. Trabecular and cortical bone respond differently to $WNT/{\beta}$-catenin signaling in healthy mice. We investigated whether this signaling has different effects on trabecular and cortical bone in T1DM. We first established a streptozotocin-induced T1DM mouse model and then constitutively activated ${\beta}$-catenin in osteoblasts in the setting of T1DM (T1-CA). The extent of bone loss was greater in trabecular bone than that in cortical bone in T1DM mice, and this difference was consistent with the reduction in the expression of ${\beta}$-catenin signaling in the two bone compartments. Further experiments demonstrated that in T1DM mice, trabecular bone showed lower levels of insulin-like growth factor-1 receptor (IGF-1R) than the levels in cortical bone, leading to lower $WNT/{\beta}$-catenin signaling activity through the inhibition of the IGF-1R/Akt/glycogen synthase kinase $3{\beta}$ ($GSK3{\beta}$) pathway. After ${\beta}$-catenin was activated in T1-CA mice, the bone mass and bone strength increased to substantially greater extents in trabecular bone than those in cortical bone. In addition, the cortical bone of the T1-CA mice displayed an unexpected increase in bone porosity, with increased bone resorption. The downregulated expression of WNT16 might be responsible for these cortical bone changes. In conclusion, we found that although the activation of $WNT/{\beta}$-catenin signaling increased the trabecular bone mass and bone strength in T1DM mice, it also increased the cortical bone porosity, impairing the bone strength. These findings should be considered in the future treatment of T1DM-related osteopenia.

• 한국발생생물학회지:발생과생식
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• 제7권2호
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• pp.69-80
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• 2003

대량의 발생 유전학적 연구가 가능한 척추동물로서 최근 제브라피쉬가 새로운 동물모델로 급부상하고 있다 다양한 형태의 돌연변이들로부터 새로운 유전자들이 발굴되어지고 있으며, 인간 유전체의 기능 분석 수단으로 활용되어지고 있다. 신경계의 형성과 분화에 이상이 있는 hendless와 mind bomb이라는 두 가지 돌연변이주에서 positional cloning에 의한 원인 유전자의 발굴과 기능 분석의 예로써 현재 제브라피쉬의 연구 현황을 살펴보고자 한다. headless의 원인 유전자로 Tcf-3가 밝혀졌으며, 초기 발생단계에서 Wnt 신호전달이 두뇌의 형태형성과 영역 결정에서 핵심적 역할을 하고 있다는 사실이 밝혀졌다. mind bomb에서의 비정상적인 신경세포의 운명 결정은 lateral inhibition과 Notch 신호전달의 결함에 의한 것이고, 그 원인 유전자는 Notch ligand인 Delta에 결합하는 새로운 ubiquitin E3 ligase로 밝혀졌다. 이러한 돌연변이를 통한 연구는 현재 인간 질환모델의 개발이라는 방향으로 확대되고 있다.

• 공업화학
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• 제32권6호
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• pp.647-652
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• 2021

본 연구에서는 에탄올과 노말헥산을 이용하여 당목향 뿌리 추출물을 제조하고, 인체 모유두세포의 세포증식 및 모발성장 관련 신호전달에 미치는 영향을 평가하였다. 당목향 뿌리 추출물의 세포증식 효과는 MTT assay를 실시하였으며, ERK, Akt, Wnt/𝛽-catenin 신호 경로, 5𝛼-reductase의 발현을 western blot 분석을 통해 측정하였다. 당목향 뿌리 추출물은 인체 모유두세포의 증식을 유의하게 증가시켰고, 세포증식에 관여하는 ERK와 Akt의 인산화를 촉진하였으며, 당목향 뿌리 추출물에 의해 증가된 ERK, Akt 인산화 촉진과 세포증식은 MEK/ERK 억제제 PD98059와 PI3K/Akt 억제제 LY294002에 의해 유의하게 감소되었다. 또한 당목향 뿌리 추출물은 GSK-3𝛽 (Ser9)의 인산화를 통한 𝛽-catenin(Ser552, 675)의 인산화를 촉진함으로써 핵 내의 𝛽-catenin 축적을 유도하였고, 5𝛼-reductase type I, II의 활성을 억제하였다. 종합적으로 당목향 뿌리 추출물은 모유두세포의 ERK, Akt 경로의 활성화를 통해 세포의 증식을 유도하며, 𝛽-catenin 신호 경로 활성화 및 5𝛼-reductase 활성 억제를 통해 탈모 예방 및 모발 성장 효과를 나타냄으로써 헤어케어제품의 소재로 응용가능성이 있음을 시사한다.

• 생약학회지
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• 제52권4호
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• pp.234-241
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• 2021

Dermal papilla cells (DPCs) are present throughout the hair cycle and play an essential role in hair cycle and hair growth. In this study, we investigated the effect of Carex dispalata on the activation of anagen pathway in DPCs. C. dispalata extract increased the proliferation of DPCs and induced changes in the levels of cell cycle-related proteins. To elucidate the mechanism by which C. dispalata extract stimulates the anagen pathway related to the proliferation of DPCs, we evaluated the effect of C. dispalata extract on the activation of Akt signaling. The increase in the level of phospho-Akt by C. dispalata extract was inhibited by PI3K inhibitor (wortmannin). Wortmannin reduced the effects of C. dispalata extract on the levels of cell cycle-related proteins and proliferation of DPCs. C. dispalata extract increased the levels of Wnt/β-catenin proteins. Wnt/β-catenin inhibitor (XAV939) inhibited changes in cell cycle, cell cycle-related proteins, Wnt/β-catenin proteins, and proliferation induced by C. dispalata extract. C. dispalata extract increased the level of autophagy protein (LC3I/II), and this change was inhibited by XAV939. These results suggest that C. dispalata extract can activate PI3K/Akt, Wnt/β-catenin, and autophagy pathways in DPCs to induce cell proliferation, and thereby promote hair growth phase.

• Journal of Microbiology and Biotechnology
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• 제31권7호
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• pp.933-941
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• 2021

Ginsenoside Rg4 is a rare ginsenoside that is naturally found in ginseng, and exhibits a wide range of biological activities including antioxidant and anti-inflammatory properties in several cell types. The purpose of this study was to use an in vivo model of hair follicle (HF)-mimic based on a human dermal papilla (DP) spheroid system prepared by three-dimensional (3D) culture and to investigate the effect of Rg4 on the hair-inductive properties of DP cells. Treatment of the DP spheroids with Rg4 (20 to 50 ㎍/ml) significantly increased the viability and size of the DP spheres in a dose-dependent manner. Rg4 also increased the mRNA and protein expression of DP signature genes that are related to hair growth including ALP, BMP2, and VCAN in the DP spheres. Analysis of the signaling molecules and luciferase reporter assays further revealed that Rg4 induces the activation of phosphoinositide 3-kinase (PI3K)/AKT and the inhibitory phosphorylation of GSK3β, which activates the WNT/β-catenin signaling pathway. These results correlated with not only the increased nuclear translocation of β-catenin following the treatment of the DP spheres with Rg4 but also the significant elevation of mRNA expression of the downstream target genes of the WNT/β-catenin pathway including WNT5A, β-catenin, and LEF1. In conclusion, these results demonstrated that ginsenoside Rg4 promotes the hair-inductive properties of DP cells by activating the AKT/GSK3β/β-catenin signaling pathway in DP spheres, suggesting that Rg4 could be a potential natural therapy for hair growth.

• BMB Reports
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• 제52권7호
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• pp.451-456
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• 2019

NDRG1 has been reported to exert pivotal roles in tumor progression and metastasis via Wnt/${\beta}$-catenin signaling pathway. However, little is known about the role of NDRG3 in hepatocarcinogenesis despite its classification in the same subfamily of NDRG1. The present study was aimed to characterize the expression pattern and understand the biological roles of NDRG3 in hepatocarcinogenesis, as a means to exploit its therapeutic potential. It was observed that NDRG3 was up-regulated in HCC tissues and higher NDRG3 expression was associated with significantly shorter overall survival. Furthermore, a lower level of NDRG3 exhibited marked positive correlation with metastasis-free survival. In vitro and in vivo experiments revealed that knock-down of NDRG3 inhibits HCC metastasis and angiogenesis. We further demonstrated that activation of WNT/${\beta}$-catenin signaling and enhanced CSC-like properties were responsible for NDRG3-mediated promoting effect on HCC. In conclusion, the principal findings demonstrated that high NDRG3 expression facilitates HCC metastasis via regulating the turnover of ${\beta}$-catenin, as well as provides a potential therapeutic target for future therapeutic interventions.

• 대한본초학회지
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• 제39권1호
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• pp.23-29
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• 2024

Objectives : Polyporus umbellatus is a medicinal mushroom that has been used for over thousands years in Chinese medicine as a powerful diuretic to relieve fluid retention and edema. Dermal papilla is located at the bottom of the hair follicle and connected to the blood vessels where it gets the nutrients and oxygen to nurture hair follicle. This study examined the mechanism through which the ethanol extract of Polyporus umbellatus (EPU) promoted the proliferation of human dermal papilla cells (HHDPCs). Methods : To estimate the proliferative effects of EPU on HHDPCs, cell viability was estimated by thiazolyl blue tetrazolium bromide (MTT) assay. Western blotting was used to investgate the activation of ERK, phosphoinositide 3-kinase (PI3K)/Akt, β-catenin, GSK-3β and heme oxygenase-1 (HO-1). Cells were treated with inhibitors of ERK and Akt prior to EPU treatment. Results : EPU promoted the proliferation of HHDPCs and the phosphorylation of ERK and Akt in dose dependent manner. However, the proliferative effect of EPU on HHDPCs was inhibited by pre-treatment of ERK inhibitor (PD98059) and Akt inhibitor (LY294002). Furthermore, EPU respectively stimulated the protein expression of β-catenin and phosphorylated GSK-3β. EPU significantly increased the protein expression levels of proliferation and cytoprotection related genes such as Bcl-2, SIRT-1, and HO-1 in cells. Conclusion : This results suggest that EPU promoted the proliferation of HHDPCs via activating PI3K/Akt and Wnt/β-catenin signaling pathway in HHDPCs.