• Biomolecules & Therapeutics
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• 제31권6호
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• pp.682-691
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• 2023

Cell transformation induced by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) is a critical event in cancer initiation and progression, and understanding the underlying mechanisms is essential for the development of new therapeutic strategies. Licorice extract contains various bioactive compounds, which have been reported to have anticancer and anti-inflammatory effects. This study investigated the cancer preventive efficacy of licochalcone D (LicoD), a chalcone derivative in licorice extract, in EGF and TPA-induced transformed skin keratinocyte cells. LicoD effectively suppressed EGF-induced cell proliferation and anchorage-independent colony growth. EGF and TPA promoted the S phase of cell cycle, while LicoD treatment caused G1 phase arrest and down-regulated cyclin D1 and up-regulated p21 expression associated with the G1 phase. LicoD also induced apoptosis and increased apoptosis-related proteins such as cleaved-caspase-3, cleaved-caspase-7, and Bax (Bcl2-associated X protein). We further investigated the effect of LicoD on the AKT signaling pathway involved in various cellular processes and found decreased p-AKT, p-GSK3β, and p-NFκB expression. Treatment with MK-2206, an AKT pharmacological inhibitor, suppressed EGF-induced cell proliferation and transformed colony growth. In conclusion, this study demonstrated the potential of LicoD as a preventive agent for skin carcinogenesis.

• 생약학회지
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• 제44권4호
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• pp.384-390
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• 2013

This study was conducted to evaluate the effect of wheat bran on the promotion of hair growth. When rat vibrissa follicles were treated with n-hexane fraction of wheat bran, the hair-fiber lengths of the vibrissa follicles significantly increased. Moreover, n-hexane fraction of wheat bran was found to significantly induce the telogen-anagen transition in C57BL/6 mice. The fraction increased the proliferation of immortalized vibrissa dermal papilla cells (DPCs) in a dose dependent manner. To elucidate the molecular mechanisms in relation to proliferation of DPCs by the fraction of wheat bran, we examined the expression of cell cycle proteins and wnt/${\beta}$-catenin signaling components. Western blot analysis revealed that the proliferation of DPC by n-hexane fraction of wheat bran was accompanied by increased the level of cyclin D1, cyclin E, phospho-CDK2 and phospho-pRB. In addition, the fraction of wheat bran increased the level of phospho(ser552)-${\beta}$-catenin, phospho(ser675)-${\beta}$-catenin and phospho(ser9)-GSK$3{\beta}$. These results suggest that the hair growing potential of wheat bran mediated by proliferation of DPCs via the regulation of cell cycle proteins and Wnt/${\beta}$-catenin signaling.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.7277-7284
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• 2015

Background: The Wnt/${\beta}$-catenin signaling pathway is an important regulator of cellular functions such as proliferation, survival and cell adhesion. Wnt/${\beta}$-catenin signaling is associated with tumor initiation and progression; ${\beta}$-catenin mutations explain only 30% of aberrant signaling found in breast cancer, indicating that other components and/or regulation of the Wnt/${\beta}$-catenin pathway may be involved. Objective: We evaluated AXIN2 rs2240308 and rs151279728 polymorphisms, and expression profiles of ${\beta}$-catenin destruction complex genes in breast cancer patients. Materials and Methods: We collected peripheral blood samples from 102 breast cancer and 102 healthy subjects. The identification of the genetic variation was performed using PCR-RFLPs and DNA sequencing. RT-qPCR was used to determine expression profiles. Results: We found significant association of AXIN2 rs151279728 and rs2240308 polymorphisms with breast cancer risk. Significant increase was observed in AXIN2 level expression in breast cancer patients. Further analyses showed APC, ${\beta}$-catenin, CK1${\alpha}$, GSK3${\beta}$ and PP2A gene expression to be associated to clinic-pathological characteristics. Conclusions: The present study demonstrated, for the first time, that AXIN2 genetic defects and disturbance of ${\beta}$-catenin destruction complex expression may be found in breast cancer patients, providing additional support for roles of Wnt/${\beta}$-catenin pathway dysfunction in breast cancer tumorigenesis. However, the functional consequences of the genetic alterations remain to be determined.

• 생약학회지
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• 제45권4호
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• pp.288-293
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• 2014

The present study was conducted to evaluate the hair growth-promoting effect of Clitocybin A from mushroom Clitocybe aurantiaca with dermal papilla cells (DPCs), which play important roles in the regulation of hair cycle. Clitocybin A significantly increased the proliferation of immortalized rat vibrissa DPCs. Flow cytometry analysis revealed that Clitocybin A promoted cell-cycle progression through G0/G1 to S phase in immortalized rat vibrissa DPCs. In addition, Clitocybin A increased the level of cell cycle proteins such as cyclin D1, phospho-pRB, and phospho-CDK2. To elucidate the molecular mechanisms of Clitocybin A on the proliferation of DPCs, we examined the activation of wnt/${\beta}$-catenin signaling which is known to regulate hair follicle development, differentiation and hair growth. Clitocybin A activated wnt/${\beta}$-catenin signaling via the increase of phospho(ser552)-${\beta}$-catenin, phospho(ser675)-${\beta}$-catenin and phospho(ser9)-$GSK3{\beta}$. Furthermore, Clitocybin A markedly increased the activation of extracellular signal-regulated kinase (ERK). These results suggest that the Clitocybin A may induce hair growth by proliferation of DPCs via cell-cycle progression as well as the activation of Wnt/${\beta}$-catenin signaling and ERK pathway.

• BMB Reports
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• 제53권8호
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• pp.425-430
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• 2020

Tumor necrosis factor-inducible gene 6 protein (TSG-6) is a cytokine secreted by mesenchymal stem cells (MSCs) and regulates MSC stemness. We previously reported that TSG-6 changes primary human hepatic stellate cells (pHSCs) into stem-like cells by activating yes-associated protein-1 (YAP-1). However, the molecular mechanism behind the reprogramming action of TSG-6 in pHSCs remains unknown. Cluster of differentiation 44 (CD44) is a transmembrane protein that has multiple functions depending on the ligand it is binding, and it is involved in various signaling pathways, including the Wnt/β-catenin pathway. Given that β-catenin influences stemness and acts downstream of CD44, we hypothesized that TSG-6 interacts with the CD44 receptor and stimulates β-catenin to activate YAP-1 during TSG-6-mediated transdifferentiation of HSCs. Immunoprecipitation assays showed the interaction of TSG-6 with CD44, and immunofluorescence staining analyses revealed the colocalization of TSG-6 and CD44 at the plasma membrane of TSG-6-treated pHSCs. In addition, TSG-6 treatment upregulated the inactive form of phosphorylated glycogen synthase kinase (GSK)-3β, which is a negative regulator of β-catenin, and promoted nuclear accumulation of active/nonphosphorylated β-catenin, eventually leading to the activation of YAP-1. However, CD44 suppression in pHSCs following CD44 siRNA treatment blocked the activation of β-catenin and YAP-1, which inhibited the transition of TSG-6-treated HSCs into stem-like cells. Therefore, these findings demonstrate that TSG-6 interacts with CD44 and activates β-catenin and YAP-1 during the conversion of TSG-6-treated pHSCs into stem-like cells, suggesting that this novel pathway is an effective therapeutic target for controlling liver disease.

• 생약학회지
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• 제47권2호
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• pp.143-149
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• 2016

Grateloupia elliptica has been reported to have the proliferation effect of dermal papilla cells (DPCs), which play important roles in the regulation of hair cycle. In the present study, we examined in vitro and in vivo hair growth-promoting effect of Grateloupia elliptica. When isolated rat vibrissa follicles were treated with extract of G. elliptica, the hair-fiber lengths of the vibrissa follicles significantly increased. Furthermore, the G. elliptica extract accelerated the telogen-angen transition in C57BL/6 mice. To investigate the molecular mechanisms of the G. elliptica extract on the proliferation of DPCs, we examined the activation of $wnt/{\beta}$-catenin signaling which is known to regulate hair follicle development, differentiation and hair growth. The G. elliptica extract activated $wnt/{\beta}$-catenin signaling via the increase of ${\beta}$-catenin and phospho-$GSK3{\beta}$. In addition, the G. elliptica extract increased the level of cyclin E and CDK2, while the level of $p27^{kip1}$ was decreased. These results suggest that the the G. elliptica extract may induce hair growth by proliferation of DPCs via cell-cycle progression and the activation of $Wnt/{\beta}$-catenin signaling.

• BMB Reports
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• 제39권6호
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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.

• Experimental and Molecular Medicine
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• 제50권11호
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• pp.12.1-12.12
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• 2018

Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of ${\beta}$-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both ${\beta}$-catenin and Ras via $GSK3{\beta}$ activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both ${\beta}$-catenin and RAS as well as EGFR via targeting the $Wnt/{\beta}$-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the $Wnt/{\beta}$-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.

• Journal of Microbiology and Biotechnology
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• 제32권9호
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• pp.1168-1177
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• 2022

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79^T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3β signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.

• Journal of Veterinary Science
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• 제21권1호
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• pp.9.1-9.15
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• 2020

Regenerative therapy holds great promise in the development of cures of some untreatable diseases such as cardiovascular diseases, and pluripotent stem cells (PSCs) including induced PSCs (iPSCs) are the most important regenerative seed cells. Recently, differentiation of human PSCs into functional tissues and cells in vitro has been widely reported. However, although porcine reports are rare they are quite essential, as the pig is an important animal model for the in vitro generation of human organs. In this study, we reprogramed porcine embryonic fibroblasts into porcine iPSCs (piPSCs), and differentiated them into cluster of differentiation 31 (CD31)-positive endothelial cells (ECs) (piPSC-derived ECs, piPS-ECs) using an optimized single-layer culture method. During differentiation, we observed that a combination of GSK3β inhibitor (CHIR99021) and bone morphogenetic protein 4 (BMP4) promoted mesodermal differentiation, resulting in higher proportions of CD31-positive cells than those from separate CHIR99021 or BMP4 treatment. Importantly, the piPS-ECs showed comparable morphological and functional properties to immortalized porcine aortic ECs, which are capable of taking up low-density lipoprotein and forming network structures on Matrigel. Our study, which is the first trial on a species other than human and mouse, has provided an optimized single-layer culture method for obtaining ECs from porcine PSCs. Our approach can be beneficial when evaluating autologous EC transplantation in pig models.