• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4067-4073
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• 2012

Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferator activated receptor$receptor{\gamma}$ ($PPAR{\gamma}$) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-$A^{\mathcal{Y}}$ obesity and diabetes model mice, and tried to clarify mechanisms by which the $PPAR{\gamma}$ ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF/mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-$A^{\mathcal{Y}}$ mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer.

• Biomolecules & Therapeutics
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• v.20 no.5
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• pp.463-469
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• 2012

Atopic dermatitis is a chronic, inflammatory disease of the skin with increased transepidermal water loss. Both an abnormal inflammatory response and a defective skin barrier are known to be involved in the pathogenesis of atopic dermatitis. Protease activated receptor 2 (PAR2) belongs to a family of G-protein coupled receptors and is activated by both trypsin and a specific agonist peptide, SLIGKV-$NH_2$. PAR2 is expressed in suprabasal layers of the epidermis and regulates inflammatory responses and barrier homeostasis. In this study, we show that nordihydroguaiaretic acid (NDGA) inhibits the PAR2-mediated signal pathway and plays a role in skin barrier recovery in atopic dermatitis. Specifically, NDGA reduces the mobilization of intracellular $Ca^{2+}$ in HaCaT keratinocytes by down-regulating inflammatory mediators, such as interleukin-8, thymus and activation-regulated chemokine and intercellular cell adhesion molecule-1 in HaCaT keratinocytes. Also, NDGA decreases the protein expression of involucrin, a differentiation maker of keratinocyte, in both HaCaT keratinocytes and normal human epidermal keratinocytes. We examined NDGA-recovered skin barrier in atopic dermatitis by using an oxazolone-induced atopic dermatitis model in hairless mice. Topical application of NDGA produced an increase in transepidermal water loss recovery and a decrease in serum IgE level, without weight loss. Accordingly, we suggest that NDGA acts as a PAR2 antagonist and may be a possible therapeutic agent for atopic dermatitis.

• Journal of Life Science
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• v.27 no.10
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• pp.1130-1136
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• 2017

Traditionally, the larvae of Allomyrina dichotoma (AD), a species of the rhinoceros beetle, have been widely used for their antidiabetic, antihepatofibrotic, antineoplastic, and antiobesity effects. The United Nations' Food and Agriculture Organization has reported on the possibility of using edible insects in human dietary supplements in the future. However, despite the growing interest in insect-based bio-active products, the biological activities of these products have rarely been studied. Previously, we reported that AD larvae inhibit the in vitro differentiation of adipocytes via transcription factor downregulation. In this study, our objective was to evaluate the effects of a hot-water extract of AD larvae on allergy and inflammation. To investigate the inhibitory effect of the extract on allergic reactions, we measured the levels of ${\beta}-hexosaminidase$, tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), interleukin-4 (IL-4), and cyclooxygenase-2 (COX-2) after activation of RBL-2H3 cells using Compound 48/80. In addition, the inhibitory effect of the extract on inflammation was determined using Raw 264.7 cells after lipopolysaccharide (LPS) stimulation. The extract significantly inhibited the ${\beta}-hexosaminidase$, $TNF-{\alpha}$, IL-4, and COX-2 levels in RBL-2H3 cells. Furthermore, it effectively inhibited the inflammatory cytokine IL-6, nitric oxide, and inducible nitric oxide synthase expression in LPS-stimulated Raw 264.7 cells. These results suggest that AD larval extract can be potentially developed as an antiallergic and anti-inflammatory therapeutic agent.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.7039-7044
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• 2015

Background: Many functional molecules controlling diverse cellular function are included in low-molecular weight proteins and peptides. Materials and Methods: To identify proteins controlling function in lung adenocarcinomas (AC), we performed two-dimensional gel electrophoresis employing tricine-SDS polyacrylamide in the second dimension (tricine 2-DE). This system was able to detect proteins under 1 kDa even with post-translational modifications. To confirm the utility of detected proteins as novel tumor markers for AC, we performed immunohistochemical analysis using 170 formalin-fixed and paraffin-embedded lung AC tissues. Results: Tricine 2-DE revealed that five proteins including S100A16 were overexpressed in lung AC-derived cells compared with lung squamous cell carcinoma, small cell carcinoma, and large cell neuroendocrine carcinoma-derived cells. Immunohistochemically, S100A16 showed various subcellular localization in lung cancer tissues and a membranous staining status was correlated with the T-factor (P=0.0008), pathological stage (P=0.0015), differentiation extent (P=0.0001), lymphatic invasion (P=0.0007), vascular invasion (P=0.0001), pleural invasion (P=0.0087), and gender (P=0.039), but not with the age or smoking history. More importantly, membranous staining of S100A16 was significantly correlated with a poorer overall survival of either stage I (P=0.0088) or stage II / III (P=0.0003) lung AC patients, and multivariate analysis confirmed that membranous expression of S100A16 was an independent adverse prognostic indicator (P=0.0001). Conclusions: The present results suggest that S100A16 protein is a novel prognostic marker for lung AC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.265-271
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• 2014

Interleukin-7 (IL-7) is a potent anti-apoptotic cytokine that enhances immune effector cell functions and is essential for lymphocyte survival. While it known to induce differentiation and proliferation in some haematological malignancies, including certain types of leukaemias and lymphomas, little is known about its role in solid tumours, including breast cancer. In the current study, we investigated whether IL-7 could enhance the in vivo antitumor activity of tumor-reactive $CD8^+$ T cells with induction of IFN-${\gamma}$ in a murine breast cancer model. Human IL-7 cDNA was constructed into the eukaryotic expression plasmid pcDNA3.1, and then the recombinational pcDNA3.1-IL-7 was intratumorally injected in the TM40D BALB/C mouse graft model. Serum and intracellular IFN-${\gamma}$ levels were measured by ELISA and flow cytometry, respectively. $CD8^+$ T cell-mediated cytotoxicity was analyzed using the MTT method. Our results showed that IL-7 administration significantly inhibited tumor growth from day 15 after direct intratumoral injection of pcDNA3.1-IL-7. The anti-tumor effect correlated with a marked increase in the level of IFN-${\gamma}$ and breast cancer cells-specific CTL cytotoxicity. In vitro cytotoxicity assays showed that IL-7-treatment could augment cytolytic activity of $CD8^+$ T cells from tumor bearing mice, while anti-IFN-${\gamma}$ blocked the function of $CD8^+$ T cells, suggesting that IFN-${\gamma}$ mediated the cytolytic activity of $CD8^+$ T cells. Furthermore, in vivo neutralization of $CD8^+$ T lymphocytes by CD8 antibodies reversed the antitumor benefit of IL-7. Thus, we demonstrated that IL-7 exerts anti-tumor activity mainly through activating $CD8^+$ T cells and stimulating them to secrete IFN-${\gamma}$ in a murine breast tumor model. Based on these results, our study points to a potential novel way to treat breast cancer and may have important implications for clinical immunotherapy.

• Nutrition Research and Practice
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• v.8 no.4
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• pp.368-376
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• 2014

BACKGROUND/OBJECTIVES: The objectives of this study were to investigate the effects of lycopene on the migration, adhesion, tube formation capacity, and p38 mitogen-activated protein kinase (p38 MAPK) activity of endothelial progenitor cells (EPCs) cultivated with high glucose (HG) and as well as explore the mechanism behind the protective effects of lycopene on peripheral blood EPCs. MATERIALS/METHODS: Mononuclear cells were isolated from human peripheral blood by Ficoll density gradient centrifugation. EPCs were identified after induction of cellular differentiation. Third generation EPCs were incubated with HG (33 mmol/L) or 10, 30, and $50{\mu}g/mL$ of lycopene plus HG. MTT assay and flow cytometry were performed to assess proliferation and apoptosis of EPCs. EPC migration was assessed by MTT assay with a modified boyden chamber. Adhesion assay was performed by replating EPCs on fibronectin-coated dishes, after which adherent cells were counted. In vitro vasculogenesis activity was assayed by Madrigal network formation assay. Western blotting was performed to analyze protein expression of both phosphorylated and non-phosphorylated p38 MAPK. RESULTS: The proliferation, migration, adhesion, and in vitro vasculogenesis capacity of EPCs treated with 10, 30, and $50{\mu}g/mL$ of lycopene plus HG were all significantly higher comapred to the HG group (P < 0.05). Rates of apoptosis were also significantly lower than that of the HG group. Moreover, lycopene blocked phosphorylation of p38 MAPK in EPCs (P < 0.05). To confirm the causal relationship between MAPK inhibition and the protective effects of lycopene against HG-induced cellular injury, we treated cells with SB203580, a phosphorylation inhibitor. The inhibitor significantly inhibited HG-induced EPC injury. CONCLUSIONS: Lycopene promotes proliferation, migration, adhesion, and in vitro vasculogenesis capacity as well as reduces apoptosis of EPCs. Further, the underlying molecular mechanism of the protective effects of lycopene against HG-induced EPC injury may involve the p38 MAPK signal transduction pathway. Specifically, lycopene was shown to inhibit HG-induced EPC injury by inhibiting p38 MAPKs.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.31 no.3
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• pp.198-206
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• 2009

Purpose: The aims of this study were to assess the in vitro co-culturing pattern of isolated skin-derived precursor cells (SKPs) with a mixed demineralized bone (DMB) and fibrin glue scaffold and to evaluate in vivo osteogenesis after transplantation of autogenous SKPs with a these mixed scaffold in the animal's mandibular defects. Materials and Methods: We isolated SKPs from the ears of adult 4 miniature pigs. The isolated SKPs were co-cultured with a mixed DMB and fibrin glue scaffold in a non-osteogenic medium for 1, 2, and 4 weeks. Histological characteristics of in vitro co-cultured cells and scaffold were evaluated. $1{\times}10^7\;cells/100\;{\mu}l$ of autogenous porcine SKPs were grafted into the mandibular defects with a DMB and fibrin glue scaffold. In the control sites, only a scaffold was grafted, without SKPs. After two animals each were euthanized at 2 and 4 weeks after grafting, the in vivo osteogenesis was evaluated with histolomorphometric and osteocalcin immunohistochemical studies. Results: Homogeneously shaped skin-derived cells were isolated from porcine ear skin after 3 or 4 weeks of primary culture. In vitro osteogenic differentiation of SKPs was observed after co-culturing with a DMB and fibrin glue scaffold in a non-osteogenic medium. Von Kossa-positive bone minerals were also noted in the co-cultured medium at 4 weeks. As the culture time progressed, the number of observable cells increased. Trabecular new bone formation and osteocalcin expression were more pronounced in the SKP-grafted group compared to the control group. Conclusion: These findings suggest that autogenous SKP grafting with a DMB and fibrin glue scaffold can serve as a useful alternative to bone grafting technique.

• The Journal of Art Theory & Practice
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• no.9
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• pp.33-57
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• 2010

Focused on the performance of interactivity in the appreciation of media art, this study is associated with the continually changed art texts and a participator's physical reactions to savor the art. Digital works of art emphasizing interactivity usually decentralize and disperse the responsibility and the central role for creating and producing the art works. Proper procedure of the work is generated by actions such as clicking the mouse, controlling the joy stick or actual movement of anticipators' bodies. The art works are influenced by participators' interactivity, which makes the leading roles and the responsibility for creating art scattered and divided. These features are similar with those of the 'Rhizome' which Gilles Deleuze(1925~1995) and Felix Guattari(1930~1992) have discussed. In their argument, 'Rhizome' is an interval or being 'between', which keeps changing. 'Rhizome' is a state in which the individual and the work of art never reach the conclusion, only a phenomenon of eternally altering. Like 'Rhizome', this sort of art work has the decentralized system, opens for several directions, and activates the system which is changeable as linked items increased or decreased. These works stimulate the individual to perform and act while appreciating the art piece. In terms of processing and preceeding, interactivity is the important equipment and catalyzer. Through these procedures, the pieces can be the 'floating work of art' combined and condensed with the whole participators' reactions. The 'floating work of art' is neither the expression of an individual nor that of one particular group. Multidimensional influence of the web is the web which is constantly reorganizing and producing in its connective state. This connective state is activated by interactivity. The Rhizomatic system embodies the floating work of art process. Due to each individual perceiving art in individualistic terms, there is no dominating powers or central points. I regard this art works possessing above traits as the work of art with Rhizomatic system. The work of art with the Rhizomatic system is embodied through interactivity and because physical action activates the process of appreciation, a participator can actually experience and practice the philosophy. Ultimately the Rhizomatic speculation occurs during the interactivity of appreciating the Rhizomatic art pieces. The Rhizomatic system penetrates into the intuitive area beyond our recognition and thoughts, as we are engaged in the connective process. With the methods and manners of interactive art, we can possibly reconsider the system as a tool in which the participator is directly able to link experience and theory to the philosophies of Deleuze and Guattari.

• Journal of Ginseng Research
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• v.46 no.6
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• pp.780-789
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• 2022

Background: Incretin impairment, characterized by insufficient secretion of L-cell-derived glucagon-like peptide-1 (GLP-1), is a defining step of type 2 diabetes mellitus (T2DM). Ginsenoside compound K (CK) can stimulate GLP-1 secretion; however, the potential mechanism underlying this effect has not been established. Methods: CK (40 mg/kg) was administered orally to male db/db mice for 4 weeks. The body weight, oral glucose tolerance, GLP-1 secretion, gut microbiota sequencing, bile acid (BA) profiles, and BA synthesis markers of each subject were then analyzed. Moreover, TGR5 expression was evaluated by immunoblotting and immunofluorescence, and L-cell lineage markers involved in L-cell abundance were analyzed. Results: CK ameliorated obesity and impaired glucose tolerance in db/db mice by altering the gut microbiota, especially Ruminococcaceae family, and this changed microbe was positively correlated with secondary BA synthesis. Additionally, CK treatment resulted in the up-regulation of CYP7B1 and CYP27A1 and the down-regulation of CYP8B1, thereby shifting BA biosynthesis from the classical pathway to the alternative pathway. CK altered the BA pool by mainly increasing LCA and DCA. Furthermore, CK induced L-cell number expansion leading to enhanced GLP-1 release through TGR5 activation. These increases were supported by the upregulation of genes governing GLP-1 secretion and L-cell differentiation. Conclusions: The results indicate that CK improves glucose homeostasis by increasing L-cell numbers, which enhances GLP-1 release through a mechanism partially mediated by the gut microbiota-BA-TGR5 pathway. Therefore, that therapeutic attempts with CK might be useful for patients with T2DM.

• Clinical and Experimental Reproductive Medicine
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• v.50 no.1
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• pp.44-52
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• 2023

Objective: The DNA integrity of spermatozoa that attach to fallopian tube (FT) cells is higher than spermatozoa that do not attach. FT epithelial cells can distinguish normal and abnormal sperm chromatin. This study investigated the effects of sperm with a high-DNA fragmentation index (DFI) from men with unexplained repeated implantation failure (RIF) on the Toll-like receptor (TLR) signaling pathway in human FT cells in vitro. Methods: Ten men with a RIF history and high-DFI and 10 healthy donors with low-DFI comprised the high-DFI (>30%) and control (<30%) groups, respectively. After fresh semen preparation, sperm were co-cultured with a human FT epithelial cell line (OE-E6/E7) for 24 hours. RNA was extracted from the cell line and the human innate and adaptive immune responses were tested using an RT2 profiler polymerase chain reaction (PCR) array. Results: The PCR array data showed significantly higher TLR-1, TLR-2, TLR-3, TLR-6, interleukin 1α (IL-1α), IL-1β, IL-6, IL-12, interferon α (IFN-α), IFN-β, tumor necrosis factor α (TNF-α), CXCL8, GM-CSF, G-CSF, CD14, ELK1, IRAK1, IRAK2, IRAK4, IRF1, IRF3, LY96, MAP2K3, MAP2K4, MAP3K7, MAP4K4, MAPK8, MAPK8IP3, MYD88, NFKB1, NFKB2, REL, TIRAP, and TRAF6 expression in the high-DFI group than in the control group. These factors are all involved in the TLR-MyD88 signaling pathway. Conclusion: The MyD88-dependent pathway through TLR-1, TLR-2, and TLR-6 activation may be one of the main inflammatory pathways activated by high-DFI sperm from men with RIF. Following activation of this pathway, epithelial cells produce inflammatory cytokines, resulting in neutrophil infiltration, activation, phagocytosis, neutrophil extracellular trap formation, and apoptosis.