• Molecules and Cells
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• 제45권12호
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• pp.935-949
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• 2022

Liver cancer has a high prevalence, with majority of the cases presenting as hepatocellular carcinoma (HCC). The prognosis of metastatic HCC has hardly improved over the past decade, highlighting the necessity for liver cancer research. Studies have reported the ability of the KiSS1 gene to inhibit the growth or metastasis of liver cancer, but contradictory research results are also emerging. We, therefore, sought to investigate the effects of KiSS1 on growth and migration in human HCC cells. HepG2 human HCC cells were infected with lentivirus particles containing KiSS1. The overexpression of KiSS1 resulted in an increased proliferation rate of HCC cells. Quantitative polymerase chain reaction and immunoblotting revealed increased Akt activity, and downregulation of the G1/S phase cell cycle inhibitors. A significant increase in tumor spheroid formation with upregulation of β-catenin and CD133 was also observed. KiSS1 overexpression promoted the migratory, invasive ability, and metastatic capacity of the hepatocarcinoma cell line, and these effects were associated with changes in the expressions of epithelial mesenchymal transition (EMT)- related genes such as E-cadherin, N-cadherin, and slug. KiSS1 overexpression also resulted in dramatically increased tumor growth in the xenograft mouse model, and upregulation of proliferating cell nuclear antigen (PCNA) and Ki-67 in the HCC tumors. Furthermore, KiSS1 increased the angiogenic capacity by upregulation of the vascular endothelial growth factor A (VEGF-A) and CD31. Based on these observations, we infer that KiSS1 not only induces HCC proliferation, but also increases the metastatic potential by increasing the migratory ability and angiogenic capacity.

• Asian Pacific Journal of Cancer Prevention
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• 제15권7호
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• pp.3219-3226
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• 2014

Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. ${\beta}$-catenin, caspase-3/8, Bcl-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells.

• Journal of Ginseng Research
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• 제40권4호
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• pp.423-430
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• 2016

Background: The induction of cellular defensive genes such as phase II detoxifying and antioxidant enzymes is a highly effective strategy for protection against carcinogenesis as well as slowing cancer development. Transcription factor Nrf2 (nuclear factor E2-related factor 2) is responsible for activation of phase II enzymes induced by natural chemopreventive compounds. Methods: Red ginseng oil (RGO) was extracted using a supercritical $CO_2$ extraction system and chemical profile of RGO was investigated by GC/MS. Effects of RGO on regulation of the Nrf2/antioxidant response element (ARE) pathway were determined by ARE-luciferase assay, western blotting, and confocal microscopy. Results: The predominant components of RGO were 9,12-octadecadienoic acid (31.48%), bicyclo[10.1.0] tridec-1-ene (22.54%), and 22,23-dihydrostigmasterol (16.90%). RGO treatment significantly increased nuclear translocation of Nrf2 as well as ARE reporter gene activity, leading to upregulation of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Phosphorylation of the upstream kinases such as apoptosis signal-regulating kinase (ASK)1, mitogen-activated protein kinase (MAPK) kinase (MKK)4/7, c-Jun N-terminal kinase (JNK), and p38 MAPK were enhanced by treatment with RGO. In addition, RGO-mediated Nrf2 expression and nuclear translocation was attenuated by JNK inhibitor SP600125 and p38 MAPK inhibitor SB202190. Conclusion: RGO could be used as a potential chemopreventive agent, possibly by induction of Nrf2/ARE-mediated phase II enzymes via ASK1-MKK4/7-JNK and p38 MAPK signaling pathways.

• Nuclear Engineering and Technology
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• 제45권2호
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• pp.151-164
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• 2013

A key input for the assessment of Human Error Probabilities (HEPs) with Human Reliability Analysis (HRA) methods is the evaluation of the factors influencing the human performance (often referred to as Performance Shaping Factors, PSFs). In general, the definition of these factors and the supporting guidance are such that their evaluation involves significant subjectivity. This affects the repeatability of HRA results as well as the collection of HRA data for model construction and verification. In this context, the present paper considers the TAsk COMplexity (TACOM) measure, developed by one of the authors to quantify the complexity of procedure-guided tasks (by the operating crew of nuclear power plants in emergency situations), and evaluates its use to represent (objectively and quantitatively) task complexity issues relevant to HRA methods. In particular, TACOM scores are calculated for five Human Failure Events (HFEs) for which empirical evidence on the HEPs (albeit with large uncertainty) and influencing factors are available - from the International HRA Empirical Study. The empirical evaluation has shown promising results. The TACOM score increases as the empirical HEP of the selected HFEs increases. Except for one case, TACOM scores are well distinguished if related to different difficulty categories (e.g., "easy" vs. "somewhat difficult"), while values corresponding to tasks within the same category are very close. Despite some important limitations related to the small number of HFEs investigated and the large uncertainty in their HEPs, this paper presents one of few attempts to empirically study the effect of a performance shaping factor on the human error probability. This type of study is important to enhance the empirical basis of HRA methods, to make sure that 1) the definitions of the PSFs cover the influences important for HRA (i.e., influencing the error probability), and 2) the quantitative relationships among PSFs and error probability are adequately represented.

• 대한화장품학회지
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• 제42권3호
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• pp.269-278
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• 2016

천연자원으로부터 항노화 화장품 신소재를 탐색하던 중, 국내 자생버섯의 일종인 붉은싸리버섯 자실체 추출물이 항산화 활성과 인체 호중구 엘라스타제 저해활성이 우수함을 확인하고 일련의 연구를 수행하였다. 붉은싸리버섯 추출물의 DPPH 라디칼 소거활성은 붉은싸리버섯 추출물 $500{\mu}g/mL$ 처리시 $117.0{\mu}g/mL$ (ascorbic acid 환산값)의 매우 우수한 소거활성을 나타냈다. Peroxy 라디칼 소거활성을 oxygen radical absorbance capacity (ORAC) assay 를 통하여 측정한 결과 붉은싸리버섯 추출물 1, 10, $20{\mu}g/mL$ 처리 시, 각각 0.8, 5.2, 7.8 $ORAC_{Roo}$ (trolox equivalents, $1{\mu}M$)로 농도 의존적으로 높은 소거활성을 나타냈다. 뿐만아니라 cellular antioxidant capacity를 DCF fluorescence intensity (% of control)로 조사한 결과에서도 붉은싸리버섯 추출물 $20{\mu}g/mL$ 처리시 약 30% 이상 높은 항산화 활성을 나타냈다. Human neutrophil elastase 저해활성은 농도 의존적으로 저해활성을 나타냈으며 특히 에탄올 추출분획에서 $ED_{50}$ 값은 $42.9{\mu}g/mL$이었다. 붉은싸리버섯 추출물은 Bacillus subtilis (B. subtilis), Escherichia coli (E. coli), Candida albicans (C. albicans), Aspergillus oryzae (A. oryzae) 균주 모두에서 항균활성은 나타나지 않았다. 또한 염증성 cytokine인 interleukin-10 및 interferon-${\gamma}$ (IFN-${\gamma}$)의 생산 또는 분비 조절에는 영향을 미치지 않았다. 이상의 결과로 붉은싸리버섯 추출물은 항산화활성과 elastase 저해활성을 우수하여 피부에 자극이 없는 항노화 화장품 조성물로 유용하게 사용될 수 있음을 확인하였다.

• Nutrition Research and Practice
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• 제4권2호
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• pp.93-98
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• 2010

Our previous study demonstrated that methanolic extract of Chrysanthemum zawadskii Herbich var. latilobum Kitamura (Compositae) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) and glutathione S-transferase (GST). In this study we further fractionated methanolic extract of Chrysanthemum zawadskii and investigated the detoxifying enzyme-inducing potential of each fraction. The fraction (CZ-6) shown the highest QR-inducing activity was found to contain (+)-(3S,4S,5R,8S)-(E)-8-acetoxy-4-hydroxy-3-isovaleroyloxy-2-(hexa-2,4-diynyliden)-1,6-dioxaspiro [4,5] decane and increased QR enzyme activity in a dose-dependent manner. Furthermore, CZ-6 fraction caused a dose-dependent enhancement of luciferase activity in HepG2-C8 cells generated by stably transfecting antioxidant response element-luciferase gene construct, suggesting that it induces antioxidant/detoxifying enzymes through antioxidant response element (ARE)-mediated transcriptional activation of the relevant genes. Although CZ-6 fraction failed to induce hepatic QR in mice over the control, it restored QR activity suppressed by $CCl_4$ treatment to the control level. Hepatic injury induced by $CCl_4$ was also slightly protected by pretreatment with CZ-6. In conclusion, although CZ-6 fractionated from methanolic extract of Chrysanthemum zawadskii did not cause a significant QR induction in mice organs such as liver, kidney, and stomach, it showed protective effect from liver damage caused by $CCl_4$.

• Food Science and Biotechnology
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• 제18권5호
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• pp.1204-1211
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• 2009

Hericium erinaceus is an edible mushroom used as a medicinal food in Asian countries. In this study, the chemopreventive effects of H. erinaceus mycelia hot water extract (HEW) were evaluated. HEW remarkably induced the luciferase activity of the antioxidant response element (ARE), located in the promoter region of phase 2 and antioxidant genes and regulated by nuclear factor E2-related factor 2 (Nrf2). The up-regulation of ARE activity by HEW corresponded with the induction of Nrf2 and the antioxidant enzyme, hemeoxygenase-1. The inhibition of cyclooxygenase-2 (COX-2) activity is a promising effective approach in cancer chemoprevention, and HEW prominently suppressed COX-2 protein expression in HepG2 cells. Furthermore, HEW showed anti-inflammatory activity by modulating inflammatory mediators such as nitric oxide (NO), inducible NO synthase, tumor necrosis factor-${\alpha}$, interleukin-$1{\beta}$, and the transcription factor, nuclear factor-${\kappa}B$, in lipopolysaccharide-stimulated RAW 264.7 cells. These results suggest that H. erinaceus possessed anti-tumor and anti-inflammatory effects via the modulation of Nrf2/ARE and inflammatory signaling pathways, and may therefore have potential use as a natural chemopreventive agent.

• KSBB Journal
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• 제18권1호
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• pp.55-61
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• 2003

항균 및 항암성 물질을 탐색하기 위하여 도꼬마리 열수 추출액을 ether 및 ethylacetate를 이용하여 중성, 산성, 염기성조건에서 추출한 후, 각각의 추출물을 세균 16균주 및 곰팡이와 효모 2균주를 대상으로 항균활성을 조사하였다. Ether 중성 추출물(XE-N)은 항균효과가 가장 우수하였으며, 특히 그람 양성세균(7균주), 그람 음성세균(7균주)을 비롯하여 진균중 Cryptococcus neoformans에도 뚜렷한 항균효과를 나타내었다. XE-N 및 XEA-N을 대상으로 FDA method에 의한 항균효과를 검토한 결과, p. aeruginosa를 제외한 3균주에 대해 30 ng/mL에서도 저해효과를 나타내었다 XE-N으로부터 XE-N-S1, XE-N-S3을, Ether 산성 추출물(XE-A)로부터 XE-N-S3 을, ethylacetate 중성 추출물(XEA-N)로부터 XEA-N-S2를 항균, 항암성 물질로 정제하였으나, XE-N-S1을 제외한 다른 물질들은 빠른 시간 내에 모두 분해되었다 도꼬마리 추출물 및 정제된 생리활성물질에 대한 항암효과를 검토한 결과, HeLa 자궁암 세포에 대해서는 XE-N-S1이 가장 우수하였다. HepG2간암세포에 대한 항암효과는 XE-N-S, XE-N-S3가 우수하였고, HT29 대장암세포에 대한 항암효과는 XE-N, XE-N-S1이 우수하였다. Saos2 골육종 암세포, NCI H522 폐선 암세포, NCI H1703 폐 편평세포 암세포와 Clone M3 흑색종 암세포에 대한 항암효과는 XE-N-S1이 가장 우수하였다. LN CAP 전립선 암세포에 대한 항암효과는 XE-N-S3가 가장 우수한 효과를 나타내었다. 또한 HSF 인간 정상 피부 섬유아세포에 대한 각종 추출물 및 정제물의 세포독성을 기존의 항암제인 etoposide와 cisplatin과 비교·검토한 결과, XE-A, XEA-A 및 XEA-B가 가장 독성이 낮았으며, XE-B도 etoposide에 비해 독성이 낮았다. 한편 XE-N-S1, XE-N-S3은 etoposide보다 높은 독성을 나타내었으며, XE-A-S3은 etoposide보다는 독성이 높았으나, cisplatin보다는 낮았다.

• BMB Reports
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• 제39권3호
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• pp.304-310
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• 2006

Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of Phase II detoxifying enzymes and antioxidant enzymes in response to many cancer chemopreventive compounds. In this study, we investigated the role of receptor associated coactivator (RAC3) or steroid receptor coactivator-3 (SRC3) and other nuclear co-regulators including CBP/p300 (CREB-binding protein), CARM1 (Coactivator-associated arginine methyltransferase), PRMT1 (Protein arginine methyl-transferase 1), and p/CAF (p300/CBP-associated factor) in the transcriptional activation of a chimeric Gal4-Nrf2-Luciferase system containing the transactivation domain (TAD) of Nrf2 in HepG2 cells. The results indicated that RAC3 up-regulated the transactivation activity of Gal4-Nrf2-(1-370) in a dose-dependent manner. The enhancement of transactivation domain activity of Gal4-Nrf2-(1-370) by RAC3 was dampened in the presence of dominant negative mutants of RAC3. Next we studied the effects of other nuclear co-regulators including CBP/p300, CARM1, PRMT1 and p/CAF, and the results showed that they had different level of positive effects on this transactivation domain activity of Gal4-Nrf2-(1-370). But importantly, synergistic effects of these co-regulators in the presence of RAC3/SRC3 on the transactivation activity of Gal4-Nrf2-(1-370) were observed. In summary, our present study showed for the first time that the 160 RAC3/SRC3 is involved in the functional transactivation of TAD of Nrf2 and that the other nuclear co-regulators such as CBP/p300, CARM1, PRMT1 and p/CAF can also transcriptionally activate this TAD of Nrf2 and that they could further enhance the transactivation activity mediated by RAC3/SRC3.

• 한국식생활문화학회지
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• 제35권5호
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• pp.467-477
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• 2020

Doenjang is a major fermented soy-based food in Korea. Recent investigations have shown that fermented soybean foods have immunity-enhancing, anti-cancer, anti-obesity and anti-diabetic effects. Several studies also have reported that genistein and daidzein, which are easily absorbed in the body are produced in larger quantities in aged doenjang. The purpose of this study was to evaluate the variations in the anti-cancer effects of commercialized doenjang as it ages. Four groups were formed for this study according to aging periods of doenjang, namely short (under 5 years, S group), mid (under 10 years, M group), long (under 15 years, L group) and very long (over 15 years, E group). The anti-cancer effects of doenjang were determined by cell cytotoxicity assays in A549, YAC-1, and HepG2 cancer cell lines. Also, NK cell activity and splenocyte proliferation were assayed for cancer immunotherapy. The quantities of phenolic compounds in doenjang at different ages were also measured. The results showed that the anti-cancer effects increased in the S and M groups for all three cancer cell lines. Interestingly, similar to this result, splenocyte proliferation and NK activity were also the highest in the S and M groups. In contrast, the E group showed significantly reduced splenocyte proliferation. The quantity of phenolic compounds was similar to that of the anti-cancer results. Collectively, these results suggest that the fermentation period of doenjang plays a very important role in determining its anti-cancer effects.