• Journal of Microbiology and Biotechnology
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• 제31권11호
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• pp.1559-1567
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• 2021

The root bark of Morus alba L. has cytotoxic activity against several types of cancer cells. However, little is known about its chemopreventive mechanisms and bioactive metabolites. In this study, we showed that M. alba L. root bark extracts (MRBE) suppressed β-catenin response transcription (CRT), which is aberrantly activated in various cancers, by promoting the degradation of β-catenin. In addition, MRBE repressed the expression of the β-catenin/T-cell factor (TCF)-dependent genes, c-myc and cyclin D1, thus inhibiting the proliferation of RPMI-8226 multiple myeloma (MM) cells. MRBE induced apoptosis in MM cells, as evidenced by the increase in the population of annexin VFITC-positive cells and caspase-3/7 activity. We identified ursolic acid in MRBE through LC/mass spectrum (MS) and observed that it also decreased intracellular β-catenin, c-myc, and cyclin D1 levels. Furthermore, it suppressed the proliferation of RPMI-8226 cells by stimulating cell cycle arrest and apoptosis. These findings suggest that MRBE and its active ingredient, ursolic acid, exert antiproliferative activity by promoting the degradation of β-catenin and may have significant chemopreventive potential against MM.

• 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.

• Biomolecules & Therapeutics
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• 제28권4호
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• pp.354-360
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• 2020

The hair cycle (anagen, catagen, and telogen) is regulated by the interaction between mesenchymal cells and epithelial cells in the hair follicles. The proliferation of dermal papilla cells (DPCs), mesenchymal-derived fibroblasts, has emerged as a target for the regulation of the hair cycle. Here, we show that vanillic acid, a phenolic acid from wheat bran, promotes the proliferation of DPCs via a PI3K/Akt/Wnt/β-catenin dependent mechanism. Vanillic acid promoted the proliferation of DPCs, accompanied by increased levels of cell-cycle proteins cyclin D1, CDK6, and Cdc2 p34. Vanillic acid also increased the levels of phospho(ser473)-Akt, phospho(ser780)-pRB, and phospho(thr37/46)-4EBP1 in a time-dependent manner. Wortmannin, an inhibitor of the PI3K/Akt pathway, attenuated the vanillic acid-mediated proliferation of DPCs. Vanillic acid-induced progression of the cell-cycle was also suppressed by wortmannin. Moreover, vanillic acid increased the levels of Wnt/β-catenin proteins, such as phospho(ser9)-glycogen synthase kinase-3β, phospho(ser552)-β-catenin, and phospho(ser675)-β-catenin. We found that vanillic acid increased the levels of cyclin D1 and Cox-2, which are target genes of β-catenin, and these changes were inhibited by wortmannin. To investigate whether vanillic acid affects the downregulation of β-catenin by dihydrotestosterone (DHT), implicated in the development of androgenetic alopecia, DPCs were stimulated with DHT in the presence and absence of vanillic acid for 24 h. Western blotting and confocal microscopy analyses showed that the decreased level of β-catenin after the incubation with DHT was reversed by vanillic acid. These results suggest that vanillic acid could stimulate anagen and alleviate hair loss by activating the PI3K/Akt and Wnt/β-catenin pathways in DPCs.

• 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 Medicine and Life Science
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• 제16권3호
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• pp.84-89
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• 2019

Docosahexaenoic acid (DHA), a principal of mackerel-derived fermented fish oil, increases the proliferation of dermal papilla cells (DPCs) via the upregulation of cell cycle-associated proteins such as cyclin D1 and cdc2 p34, and might promote hair-growth. However, the intracellular mechanisms that underlie the action of DHA in the proliferation of DPCs have not been investigated fully. In this study, we addressed the action mechanisms of DHA to trigger the activation of anagen in DPCs. DHA activated β-catenin signaling by the increased phosphorylation at serine 552 and serine 675 as well as the translocation and accumulation of activated β-catenin into the nucleus. In the other hand, DHA inhibited canonical TGF-β/Smad signaling by the decreased phosphorylation of Smad2/3. Taken together, the results indicate that DHA might stimulate anagen signaling via the activation of Wnt/β-catenin pathway, while the inactivation of canonical TGF-β signaling pathway in DPCs.

• Journal of Cancer Prevention
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• 제22권1호
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• pp.1-5
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• 2017

Pancreatic cancer is a highly aggressive malignant tumor of the digestive system and radical resection, which is available to very few patients, might be the only possibility for cure. Since therapeutic choices are limited at the advanced stage, prevention is more important for reducing incidence in high-risk individuals with family history of pancreatic cancer. Epidemiological studies have shown that a high consumption of fish oil or ${\omega}3-polyunsaturated$ fatty acids reduces the risk of pancreatic cancers. Dietary fish oil supplementation has shown to suppress pancreatic cancer development in animal models. Previous experimental studies revealed that several hallmarks of cancer involved in the pathogenesis of pancreatic cancer, such as the resistance to apoptosis, hyper-proliferation with abnormal $Wnt/{\beta}-catenin$ signaling, expression of pro-angiogenic growth factors, and invasion. Docosahexaenoic acid (DHA) is a ${\omega}3-polyunsaturated$ fatty acid and rich in cold oceanic fish oil. DHA shows anti-cancer activity by inducing oxidative stress and apoptosis, inhibiting $Wnt/{\beta}-catenin$ signaling, and decreasing extracellular matrix degradation and expression of pro-angiogenic factors in pancreatic cancer cells. This review will summarize anti-cancer mechanism of DHA in pancreatic carcinogenesis based on the recent studies.

• Korean Journal of Acupuncture
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• 제34권3호
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• pp.146-155
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• 2017

Objectives : This study was carried out to investigate the effects of Crataegi Fructus water extract(CFWE) on hair growth in an alopecia model of C57BL/6N mice and human dermal papilla cells(hDPCs). Methods : Six-week old mice were depilated and separated in 3 groups ; CON, MXD(2% Minoxidil), and CFWE. The treatments were applied twice a day for 18 days. The hair growth was determined photographically. The hair density, thickness and length were identified by Folliscope and the weights of body were measured. In dorsal skin tissue, the expression of hair growth-related protein was analyzed by Western blot. In hDPCs with/without $IFN-{\gamma}$, cell proliferation and the expression of hair growth-related genes were analyzed. Results : We observed that CFWE promoted hair growth compared to CON. CFWE improved the hair density, thickness and length compared to CON. CFWE increased the $Wnt/{\beta}$-catenin signaling in dorsal skin. In hDPCs, CFWE accelerated the cell proliferation and inhibited $IFN-{\gamma}$-induced hDPCs degeneration. CFWE increased the mRNA expression of ${\beta}$-catenin, Axin-2, BMP-4, FGF-7, FGF-10, and ALP compared to CON and $IFN-{\gamma}$ treated cells. Conclusions : These results suggest that CFWE has a hair regrowth activity via $Wnt/{\beta}$-catenin signaling and can be useful for the treatment of alopecia.

• BMB Reports
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• 제51권9호
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• pp.425-426
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• 2018

As highly conserved signaling cascades of multicellular organisms, Wnt and Hippo pathways control a wide range of cellular activities, including cell adhesion, fate determination, cell cycle, motility, polarity, and metabolism. Dysregulation of those pathways are implicated in many human diseases, including cancer. Similarly to ${\beta}-catenin$ in the Wnt pathway, the YAP transcription co-activator is a major player in Hippo. Although the intracellular dynamics of YAP are well-known to largely depend on phosphorylation by LATS and AMPK kinases, the molecular effector of YAP cytosolic translocation remains unidentified. Recently, we reported that the Dishevelled (DVL), a key scaffolding protein between canonical and non-canonical Wnt pathway, is responsible for nuclear export of phosphorylated YAP. The DVL is also required for YAP intracellular trafficking induced by E-cadherin, ${\alpha}-catenin$, or metabolic stress. Note that the p53/LATS2 and LKB1/AMPK tumor suppressor axes, commonly inactivated in human cancer, govern the reciprocal inhibition between DVL and YAP. Conversely, loss of the tumor suppressor allows co-activation of YAP and Wnt independent of epithelial polarity or contact inhibition in human cancer. These observations provide novel mechanistic insight into (1) a tight molecular connection merging the Wnt and Hippo pathways, and (2) the importance of tumor suppressor contexts with respect to controlled proliferation and epithelial polarity regulated by cell adhesion.

• 한국발생생물학회지:발생과생식
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• 제11권3호
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• pp.141-153
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• 2007

Wnt 신호 전달 과정은 다세포 생물체의 발생 과정에서 세포의 증식이나 분화를 조절하거나 성인 조직에서 항상성을 유지하는데 결정적인 역할을 한다. 따라서 Wnt 신호 전달의 조절에 이상이 생기면 암을 비롯한 다양한 질병이 유발되어진다. 최근 들어서 Wnt 신호 전달의 이상에 의해 유도될 것이라고 생각되어지는 질병의 수가 많아져서, Wnt 신호 전달의 조절에 관심을 갖는 연구자가 많아지고 있다. 많은 리뷰 논문이 출판되었지만, 대부분의 경우 Wnt 전문가들을 위한 특정 논제를 다루는 경우가 많기 때문에, 처음으로 Wnt 신호 전달을 연구하고자 하는 연구자들이 Wnt 신호 전달의 전체적인 흐름을 파악하는데 어려움을 겪는 예가 있다. 본 총설에서는 Wnt 신호 전달 과정을 전체적으로 설명함으로써 Wnt 신호 전달에서 우리가 알고 있는 사실과 앞으로 연구되어야 할 내용들을 이해하고자 한다.

• 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.