• Journal of Life Science
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• v.29 no.3
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• pp.318-324
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• 2019

Squamous cell carcinoma is the primary tumor type in head and neck cancers, the fifth most common malignant neoplasm world-wide. Survivin, a member of the inhibitor of apoptosis family, is highly expressed in head and neck carcinoma patients and correlated with more aggressive forms. In this study, we investigated whether YM155, a specific survivin inhibitor, could induce apoptosis in head and neck AMC-HN4 cells. YM155 was found to markedly induce apoptosis and cleavage of PARP, a marker of apoptosis. Furthermore, YM155 promoted apoptosis in other cancer cells, such as glioma (U251MG) and renal carcinoma (Caki) cells. In contrast, YM155 had no effect on apoptosis in normal mesangial cells. YM155 significantly induced caspase activation, and pan caspase inhibitor z-VAD-fmk markedly blocked apoptosis, PARP cleavage, and caspase-3 cleavage. Therefore, YM155 was seen to instigate caspase-dependent apoptosis in head and neck AMC-HN4 cells, inducing downregulation of survivin as well as other apoptotic proteins such as c-FLIP and Mcl-1. In addition, the induction of apoptosis and PARP cleavage by YM155 treatment was effectively inhibited in survivin-, c-FLIP- and Mcl-1-over-expressing head and neck AMC-HN4 cells. In conclusion, YM155 is a potent candidate for inducing cell death in head and neck AMC-HN4 cells.

• Korean Journal of Food Science and Technology
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• v.50 no.6
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• pp.688-696
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• 2018

This study aimed to investigate the effects of red ginseng-derived saponin fraction (SF) on lipid accumulation, reactive oxygen species (ROS) production, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling during adipocyte differentiation. SF effectively inhibited lipid accumulation, with the downregulation of adipogenic factors such as peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) and CCAAT/enhancer-binding protein alpha ($C/EBP{\alpha}$). A high dose of SF decreased the protein levels of $PPAR{\gamma}$ and $C/EBP{\alpha}$ by over 90% compared to the control. SF-mediated downregulation of adipogenic factors was due to the regulation of early adipogenic factors including $C/EBP{\beta}$ and $Kr{\ddot{u}}ppel$-like Factor 2 (KLF2). In addition, SF ($200{\mu}g/mg$) decreased intracellular ROS generation by 40% during adipocyte differentiation. However, the SF significantly upregulated Nrf2 and its target proteins, hemoxygenase-1 (HO-1) and NADPH dehydrogenase quinone 1 (NQO1). Furthermore, SF ($200{\mu}g/mg$) promoted the nuclear translocation of Nrf2. The SF-mediated reduction of lipid accumulation was associated with the regulation of the Nrf2/Keap1 pathway.

• Journal of Ginseng Research
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• v.47 no.4
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• pp.515-523
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• 2023

Background: 20(S)-protopanaxadiol (PPD), one of the main components of ginseng, has anti-inflammatory, anti-estrogenic, and anti-tumor activities. It is known that activated hepatic stellate cells (HSCs) are the primary producers of extracellular matrix (ECM) in the liver, and the Wnt/β-catenin pathway participates in the activation of HSCs. We aimed to explore whether PPD inhibits liver fibrosis is associated with the Wnt/β-catenin pathway inactivation. Methods: The anti-fibrotic roles of PPD were examined both in vitro and in vivo. We also examined the levels of Wnt inhibitory factor 1 (WIF1), DNA methyltransferase 1 (DNMT1) and WIF1 methylation. Results: PPD obviously ameliorated liver fibrosis in carbon tetrachloride (CCl₄)-treated mice and reduced collagen deposition. PPD also suppressed the activation and proliferation of primary HSCs. Notably, PPD inhibited the Wnt/β-catenin pathway, reduced TCF activity, and increased P-β-catenin and GSK-3β levels. Interestingly, WIF1 was found to mediate the inactivation of the Wnt/β-catenin pathway in PPD-treated HSCs. WIF1 silencing suppressed the inhibitory effects of PPD on HSC activation and also restored α-SMA and type I collagen levels. The downregulation of WIF1 expression was associated with the methylation of its promoter. PPD induced WIF1 demethylation and restored WIF1 expression. Further experiments confirmed that DNMT1 overexpression blocked the effects of PPD on WIF1 expression and demethylation and enhanced HSC activation. Conclusion: PPD up-regulates WIF1 levels and impairs Wnt/β-catenin pathway activation via the downregulation of DNMT1-mediated WIF1 methylation, leading to HSC inactivation. Therefore, PPD may be a promising therapeutic drug for patients with liver fibrosis.

• Journal of Veterinary Science
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• v.24 no.6
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• pp.83.1-83.12
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• 2023

Background: Ellipticine (Ellip.) was recently reported to have beneficial effects on the differentiation of adipose-derived stem cells into mature chondrocyte-like cells. On the other hand, no practical results have been derived from the transplantation of bone marrow stem cells (BMSCs) in a rabbit osteoarthritis (OA) model. Objectives: This study examined whether autologous BMSCs incubated with ellipticine (Ellip.+BMSCs) could regenerate articular cartilage in rabbit OA, a model similar to degenerative arthritis in human beings. Methods: A portion of rabbit articular cartilage was surgically removed, and Ellip.+BMSCs were transplanted into the lesion area. After two and four weeks of treatment, the serum levels of proinflammatory cytokines, i.e., tumor necrosis factor α (TNF-α) and prostaglandin E2 (PGE2), were analyzed, while macroscopic and micro-computed tomography (CT) evaluations were conducted to determine the intensity of cartilage degeneration. Furthermore, immuno-blotting was performed to evaluate the mitogen-activated protein kinases, PI3K/Akt, and nuclear factor-κB (NF-κB) signaling in rabbit OA models. Histological staining was used to confirm the change in the pattern of collagen and proteoglycan in the articular cartilage matrix. Results: The transplantation of Ellip.+BMSCs elicited a chondroprotective effect by reducing the inflammatory factors (TNF-α, PGE2) in a time-dependent manner. Macroscopic observations, micro-CT, and histological staining revealed articular cartilage regeneration with the downregulation of matrix-metallo proteinases (MMPs), preventing articular cartilage degradation. Furthermore, histological observations confirmed a significant boost in the production of chondrocytes, collagen, and proteoglycan compared to the control group. Western blotting data revealed the downregulation of the p38, PI3K-Akt, and NF-κB inflammatory pathways to attenuate inflammation. Conclusions: The transplantation of Ellip.+BMSCs normalized the OA condition by boosting the recovery of degenerated articular cartilage and inhibiting the catabolic signaling pathway.

• IMMUNE NETWORK
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• v.23 no.4
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• pp.35.1-35.16
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• 2023

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8⁺ T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8⁺ T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8⁺ T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8⁺ T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8⁺ T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8⁺ T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.368-378
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• 2024

Cordycepin, a valuable bioactive component isolated from Cordyceps militaris, has been reported to possess anti-cancer potential and the property to enhance the effects of chemotherapeutic agents in various types of cancers. However, the ability of cordycepin to chemosensitize cholangiocarcinoma (CCA) cells to gemcitabine has not yet been evaluated. The current study was performed to evaluate the above, and the mechanisms associated with it. The study analyzed the effects of cordycepin in combination with gemcitabine on the cancer stem-like properties of the CCA SNU478 cell line, including its anti-apoptotic, migratory, and antioxidant effects. In addition, the combination of cordycepin and gemcitabine was evaluated in the CCA xenograft model. The cordycepin treatment significantly decreased SNU478 cell viability and, in combination with gemcitabine, additively reduced cell viability. The cordycepin and gemcitabine co-treatment significantly increased the Annexin V+ population and downregulated B-cell lymphoma 2 (Bcl-2) expression, suggesting that the decreased cell viability in the cordycepin+gemcitabine group may result from an increase in apoptotic death. In addition, the cordycepin and gemcitabine co-treatment significantly reduced the migratory ability of SNU478 cells in the wound healing and trans-well migration assays. It was observed that the cordycepin and gemcitabine cotreatment reduced the CD44^highCD133^high population in SNU478 cells and the expression level of sex determining region Y-box 2 (Sox-2), indicating the downregulation of the cancer stem-like population. Cordycepin also enhanced oxidative damage mediated by gemcitabine in MitoSOX staining associated with the upregulated Kelch like ECH Associated Protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) expression ratio. In the SNU478 xenograft model, co-administration of cordycepin and gemcitabine additively delayed tumor growth. These results indicate that cordycepin potentiates the chemotherapeutic property of gemcitabine against CCA, which results from the downregulation of its cancer-stem-like properties. Hence, the combination therapy of cordycepin and gemcitabine may be a promising therapeutic strategy in the treatment of CCA.

• International Journal of Oncology
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• v.56 no.1
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• pp.368-378
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• 2020

Meridianin C is a marine natural product with anticancer activity. Several meridianin C derivatives (compounds 7a-j) were recently synthesized, and their inhibitory effects on pro-viral integration site for Moloney murine leukemia virus (PIM) kinases, as well as their antiproliferative effects on human leukemia cells, were reported. However, the anti-leukemic effects and mechanisms of action of meridianin C and its derivatives remain largely unknown. The aim of the present study was to investigate the effects of meridianin C and its derivatives on MV4-11 human acute myeloid leukemia cell growth. The parent compound meridianin C did not markedly affect the viability and survival of MV4-11 cells. By contrast, MV4-11 cell viability and survival were reduced by meridianin C derivatives, with compound 7a achieving the most prominent reduction. Compound 7a notably inhibited the expression and activity of PIM kinases, as evidenced by reduced B-cell lymphoma-2 (Bcl-2)-associated death promoter phosphorylation at Ser112. However, meridianin C also suppressed PIM kinase expression and activity, and the pan-PIM kinase inhibitor AZD1208 only slightly suppressed the survival of MV4-11 cells. Thus, the anti-survival effect of compound 7a on MV4-11 cells was unrelated to PIM kinase inhibition. Moreover, compound 7a induced apoptosis, caspase-9 and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage, but did not affect death receptor (DR)-4 or DR-5 expression in MV4-11 cells. Compound 7a also induced the generation of cleaved Bcl-2, and the downregulation of myeloid cell leukemia (Mcl)-1 and X-linked inhibitor of apoptosis (XIAP) in MV4-11 cells. Furthermore, compound 7a increased eukaryotic initiation factor (eIF)-2α phosphorylation and decreased S6 phosphorylation, whereas GRP-78 expression was unaffected. Importantly, treatment with a pan-caspase inhibitor (z-VAD-fmk) significantly attenuated compound 7a-induced apoptosis, caspase-9 and -3 activation, PARP cleavage, generation of cleaved Bcl-2 and downregulation of Mcl-1 and XIAP in MV4-11 cells. Collectively, these findings demonstrated the strong anti-survival and pro-apoptotic effects of compound 7a on MV4-11 cells through regulation of caspase-9 and -3, Bcl-2, Mcl-1, XIAP, eIF-2α and S6 molecules.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.3865-3871
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• 2014

It is becoming progressively more understandable that different phytochemicals isolated from edible plants interfere with specific stages of carcinogenesis. Cancer cells have evolved hallmark mechanisms to escape from death. Concordant with this approach, there is a disruption of spatiotemproal behaviour of signaling cascades in cancer cells, which can escape from apoptosis because of downregulation of tumor suppressor genes and over-expression of oncogenes. Genomic instability, intra-tumor heterogeneity, cellular plasticity and metastasizing potential of cancer cells all are related to molecular alterations. Data obtained through in vitro studies has convincingly revealed that curcumin, EGCG, resveratrol and quercetin are promising anticancer agents. Their efficacy has been tested in tumor xenografted mice and considerable experimental findings have stimulated researchers to further improve the bioavailability of these nutraceuticals. We partition this review into different sections with emphasis on how bioavailability of curcumin, EGCG, resveratrol and quercetin has improved using different nanotechnology approaches.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6803-6812
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• 2015

Caveolin-1 is a 22-kD trans-membrane protein enriched in particular plasma membrane invaginations known as caveolae. Cav-1 expression is often dysregulated in human breast cancers, being commonly upregulated in cancer cells and downregulated in stromal cells. As an intracellular scaffolding protein, Cav-1, is involved in several vital biological regulations including endocytosis, transcytosis, vesicular transport, and signaling pathways. Several pathways are modulated by Cav-1 including estrogen receptor, EGFR, Her2/neu, $TGF{\beta}$, and mTOR and represent as major drivers in mammary carcinogenesis. Expression and role of Cav-1 in breast carcinogenesis is highly variable depending on the stage of tumor development as well as context of the cell. However, recent data have shown that downregulation of Cav-1 expression in stromal breast tumors is associated with frequent relapse, resistance to therapy, and poor outcome. Modification of Cav-1 expression for translational cancer therapy is particularly challenging since numerous signaling pathways might be affected. This review focuses on present understanding of Cav-1 in breast carcinogenesis and its potential role as a new biomarker for predicting therapeutic response and prognosis as well as new target for therapeutic manipulation.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3631-3634
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• 2013

MicroRNAs (MiRNAs) play important roles in coordinating a variety of cellular processes and abnormal expression has been linked to the occurrence of several cancers. The miRNA miR-451 is downregulated in colorectal carcinoma (CRC) cells, suggested by several research groups including our own. In this study, synthetic miR-451 mimics were transfected into the SW620 human CRC cell line using Lipofectamine 2000 and expression of miR-451 was analyzed by real time PCR, while expression of CAB39, LKB1, AMPK, AKT, PI3K and Bcl2 was analyzed by Western blot, and cell growth was detected by MTT assay. In comparison to the controls, a significant increase in the expression of miR-451 was associated with significantly decreased expression of CAB39, LKB1, AMPK, AKT, PI3K and Bcl2. The capacity of cell proliferation was significantly decreased by miR-451 expression, which also inhibited cell growth. Our study confirmed that miR-451 has a repressive role in CRC cells by inhibiting cell growth through down-regulating the P13K/AKT pathway.