• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8067-8073
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• 2016

Background: Long non-coding RNAs (lncRNAs) are emerging as key players in gene expression that govern cell developmental processes, and thus contributing to diseases, especially cancers. Many studies have suggested that aberrant expression of lncRNAs is responsible for drug resistance, a substantial obstacle for cancer therapy. Drug resistance not only results from individual variations in patients, but also from genetic and epigenetic differences in tumors. It is reported that drug resistance is tightly modulated by lncRNAs which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, and drug metabolism. In this review, we summarize recent advances in research on lncRNAs associated with drug resistance and underlying molecular or cellular mechanisms, which may contribute helpful approaches for the development of new therapeutic strategies to overcome treatment failure.

• Proceedings of the Korean Society of Toxicology Conference
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• 2003.10b
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• pp.179-179
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• 2003

2,3,7,8-Tetrachlorodibenzo-$\rho$-dioxin (TCDD) displays high toxicity in animals and has been implicated in human carcinogenesis. Although the mechanisms of TCDD-induced carcinogenesis are poorly understood, it considered to be non-genotoxic and tumor promoter. In this study, we investigated the tumor promotion effect of TCDD on the two-stage skin chemical carcinogenesis using hairless mouse (SKH1).(omitted)

• Genomics & Informatics
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• v.19 no.1
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• pp.10.1-10.7
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• 2021

Although many models have been proposed to accurately predict the response of drugs in cell lines recent years, understanding the genome related to drug response is also the key for completing oncology precision medicine. In this paper, based on the cancer cell line gene expression and the drug response data, we established a reliable and accurate drug response prediction model and found predictor genes for some drugs of interest. To this end, we first performed pre-selection of genes based on the Pearson correlation coefficient and then used ElasticNet regression model for drug response prediction and fine gene selection. To find more reliable set of predictor genes, we performed regression twice for each drug, one with IC₅₀ and the other with area under the curve (AUC) (or activity area). For the 12 drugs we tested, the predictive performance in terms of Pearson correlation coefficient exceeded 0.6 and the highest one was 17-AAG for which Pearson correlation coefficient was 0.811 for IC₅₀ and 0.81 for AUC. We identify common predictor genes for IC₅₀ and AUC, with which the performance was similar to those with genes separately found for IC₅₀ and AUC, but with much smaller number of predictor genes. By using only common predictor genes, the highest performance was AZD6244 (0.8016 for IC₅₀, 0.7945 for AUC) with 321 predictor genes.

• Genomics & Informatics
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• v.9 no.4
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• pp.173-180
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• 2011

Recent trends in generating multiple, large-scale datasets provide new challenges to manipulating the relationship of different types of components, such as gene expression and drug response data. Integrative analysis of compound response and gene expression datasets generates an opportunity to capture the possible mechanism of compounds by using signature genes on diverse types of cancer cell lines. Here, we integrated datasets of compound response and gene expression profiles on NCI60 cell lines and constructed a network, revealing the relationship for 801 compounds and 341 gene probes. As examples, obtusol, which shows an exclusive sensitivity on a small number of colon cell lines, is related to a set of gene probes that have unique overexpression in colon cell lines. We also found that the SLC7A11 gene, a direct target of miR-26b, might be a key element in understanding the action of many diverse classes of anticancer compounds. We demonstrated that this network might be useful for studying the mechanisms of varied compound response on diverse cancer cell lines.

• Environmental Mutagens and Carcinogens
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• v.19 no.2
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• pp.89-94
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• 1999

Cell proliferation and c-Jun expression pattern in liver exposed by nongenotoxic carcinogens phenobarbital (PB) and clofibrate, and genotoxic carcinogen 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) were investigated to see whether differential effects of genotoxic and non-genotoxic carcinogens on the development of neoplastic foci may be related to differential effect on cell proliferation. Male F344 rats were initially given a single intraperitioneal injection of diethylnitrosamine (200 mg/kg body weight), and 2 weeks later, animals were fed diets containing 0.03% IQ or 0.5% CE or 0.05% PB or basal diet as a control for 6 weeks. All rats were subjected to the two-thirds partial hepatectomy (PH) at week 3. Sequential sacrifice of rats was performed until 8 weeks. Cell proliferation was examined by immunohistochemical staining of bromodeoxyuridine and c-Jun expression was determined by northern blotting. The increase of cell proliferation rate after PH was significant in the rats fed 0.05% IQ and continued until 8 weeks, while the increase was not significant in the rats fed phenobarbital and clofibrate compared to that in the rats fed control diet. mRNA level of c-Jun in the liver treated with IQ was about 7 fold higher than that of control and peak at 5 hours after rH. In the liver treated with CE, mRNA level of c-Jun was 3-4 fold higher than that of control and the highest level of mRNA of c-Jun was seen at 24 hours after PH. These results show that differential effects of genotoxic and non-genotoxic carcinogens on the development of neoplastic foci may be related to differential effect on cell proliferation pattern.

• BMB Reports
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• v.40 no.6
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• pp.1021-1027
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• 2007

We demonstrated the genetic polymorphism of aldehyde oxidase (AO) in Donryu strain rats: the ultrarapid metabolizer (UM) with nucleotide mutation of (377G, 2604C) coding for amino acid substitution of (110Gly, 852Val), extensive metabolizer (EM) with (377G/A, 2604C/T) coding for (110Gly/Ser, 852Val/Ala), and poor metabolizer (PM) with (377A, 2604T) coding for (110Ser, 852Ala), respectively. The results suggested that 377G > A and/or 2604C > T should be responsible for the genetic polymorphism. In this study, we constructed an E. coli expression system of four types of AO cDNA including Mut-1 with (377G, 2604T) and Mut-2 with (377A, 2604C) as well as naturally existing nucleotide sequences of UM and PM in order to clarify which one is responsible for the polymorphism. Mut-1 and Mut-2 showed almost the same high and low activity as that of the UM and PM groups, respectively. Thus, the expression study of mutant AO cDNA directly revealed that the nucleotide substitution of 377G > A, but not that of 2604C > T, will play a critical role in the genetic polymorphism of AO in Donryu strain rats. The reason amino acid substitution will cause genetic polymorphism in AO activity was discussed.

• Food Science and Biotechnology
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• v.16 no.2
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• pp.205-211
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• 2007

This study was designed to investigate the suppressive effect of chlorophyll a on nitric oxide (NO) production and intracellular oxidative stress. In addition, chlorophyll a regulation of nuclear factor (NF) ${\kappa}B$ activation and inducible NO synthase (iNOS) expression were explored as potential mechanisms of NO suppression in a lipopolysaccharide (LPS)-stimulated macrophage cell line. RAW 264.7 murine macrophages were preincubated with various concentrations ($0-10\;{\mu}g/ mL$) of chlorophyll a and stimulated with LPS to induce oxidative stress and inflammatory response. Treatment with chlorophyll a reduced the accumulation of thiobarbituric acid-reactive substances (TBARS), enhancing glutathione level and the activities of antioxidative enzymes including superoxide dismutase, catalase, glutathione peroxidase (GSH-px), and glutathione reductase in LPS-stimulated macrophages compared to LPS-only treated cells. NO production was significantly suppressed in a dose-dependent manner (p<0.05) with an $IC_{50}$ of $12.8\;{\mu}g/mL$. Treatment with chlorophyll a suppressed the levels of iNOS protein and its mRNA expression. The specific DNA binding activities of NFkB on nuclear extracts from chlorophyll a treated cells were significantly suppressed in a dose-dependent manner with an $IC_{50}$ of $10.7\;{\mu}g/mL$. Chlorophyll a ameliorates NO production and iNOS expression through the down-regulation of NFkB activity, which may be mediated by attenuated oxidative stress in RAW 264.7 macrophages.

• YAKHAK HOEJI
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• v.49 no.3
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• pp.217-224
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• 2005

Human Immunodeficiency Virus type 1 (HIV-l) based lentivirus vector has demonstrated great potential as gene therapy vectors mediating efficient gene delivery and long-term transgene expression in both dividing and nondividing cells. However, for clinical studies it must be confirmed that vector preparations are safe and not contaminated by replication competent lentivirus (RCL) related to the parental pathogenic virus, HIV-l. In this study, we would like to establish the method for titration and RCL detection of lentivirus vector. The titration was determined by vector expression containing the green fluorescent protein, GFP in transduced cells. The titer was $1{\times}10^7$ Transducing Unit/ml in the GFP expression assay and $8.9{\times}10^7$ molecules/ml in the real-time PCR. Also, for the detection of RCL, we have used a combination method of PCR and p24 antigen detection. First, PBS/psi and VSV-G region in the genomic DNA of transduced cells was detected by PCR assay. Second, transfer and expression of the HIV-1 gag gene was detected by p24 ELISA. In an attempt to amplify any RCL, the transduced cells were cultured for 3 weeks (amplification phase) and the supernatant of amplified transduced cell was used for the second transduction to determine whether a true RCL was present (indicator phase). Analysis of cells and supernatant at day 6 in indicator phase were negative for PBS/psi, VSV-G, and p24 antigen. These results suggest that they are not mobilized and therefore there are no RCL in amplification phase. Thus, real-time PCR is a reliable and sensitive method for titration and RCL detection of lentivirus vector.

• Journal of Ginseng Research
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• v.45 no.6
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• pp.683-694
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• 2021

Background: Ginsenoside Rg1 (Rg1) has been well documented to be effective against various cardiovascular disease. The aim of this study is to evaluate the effect of Rg1 on mechanical stress-induced cardiac injury and its possible mechanism with a focus on the calcium sensing receptor (CaSR) signaling pathway. Methods: Mechanical stress was implemented on rats through abdominal aortic constriction (AAC) procedure and on cardiomyocytes and cardiac fibroblasts by mechanical stretching with Bioflex Collagen I plates. The effects of Rg1 on cell hypertrophy, fibrosis, cardiac function, [Ca²⁺]_i, and the expression of CaSR and calcineurin (CaN) were assayed both on rat and cellular level. Results: Rg1 alleviated cardiac hypertrophy and fibrosis, and improved cardiac decompensation induced by AAC in rat myocardial tissue and cultured cardiomyocytes and cardiac fibroblasts. Importantly, Rg1 treatment inhibited CaSR expression and increase of [Ca²⁺]_i, which similar to the CaSR inhibitor NPS2143. In addition, Rg1 treatment inhibited CaN and TGF-b1 pathways activation. Mechanistic analysis showed that the CaSR agonist GdCl₃ could not further increase the [Ca²⁺]_i and CaN pathway related protein expression induced by mechanical stretching in cultured cardiomyocytes. CsA, an inhibitor of CaN, inhibited cardiac hypertrophy, cardiac fibrosis, [Ca²⁺]_i and CaN signaling but had no effect on CaSR expression. Conclusion: The activation of CaN pathway and the increase of [Ca²⁺]_i mediated by CaSR are involved in cardiac hypertrophy and fibrosis, that may be the target of cardioprotection of Rg1 against myocardial injury.

• Journal of Ginseng Research
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• v.46 no.6
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• pp.819-829
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• 2022

Background: Anxiolytic properties of Korean Red Ginseng (KRG) have been previously reported. However, the exact mechanism(s) of action remains to be elucidated. The present study investigated the effect of KRG on immobilization-induced anxiety-like behaviors in mice and explored the involvement of the serotonin and GABA systems and BDNF in the anxiolytic action. Methods: Mice were orally administered with KRG (200 mg/kg/day) for 4 weeks and immobilized once daily for 2 h. p-Chlorophenylalanine (p-CPA) was intraperitoneally injected on day 22-28, and flumazenil or bicuculline was injected on day 25-28. After behavioral evaluations, brains were dissected for biochemical analyses. Results: KRG improved immobilization-induced anxiety-like behaviors in mice, as assessed by the elevated plus maze (EPM) and marble burying tests (MBT). The anxiolytic effect of KRG was comparable to that of fluoxetine, a reference drug clinically used for anxiety disorders. A serotonin synthesis inhibitor, p-CPA, blocked the effect of KRG in the EPM and MBT, indicating the requirement of serotonin synthesis for anxiolytic action. In addition, the anxiolytic effect of KRG was inhibited by bicuculline (a GABA_A antagonist) in MBT, implying the involvement of GABA transmission. Western blotting analyses revealed that KRG upregulated the expression of tryptophan hydroxylase and GABA_A receptor in the brain, which was blocked by p-CPA. Enhanced BDNF expression by KRG in the hippocampus was also indicated to mediate the anxiolytic action of KRG in immobilized mice. Conclusion: KRG exhibited the anxiolytic effect in immobilized mice by multiple mechanisms of action, involving enhanced serotonin and GABA transmissions and BDNF expression.