• Biomolecules & Therapeutics
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• v.28 no.5
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• pp.443-455
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• 2020

The thioredoxin (Trx) system plays critical roles in regulating intracellular redox levels and defending organisms against oxidative stress. Recent studies indicated that Trx reductase (TrxR) was overexpressed in various types of human cancer cells indicating that the Trx-TrxR system may be a potential target for anti-cancer drug development. This study investigated the synergistic effect of auranofin, a TrxR-specific inhibitor, on sulforaphane-mediated apoptotic cell death using Hep3B cells. The results showed that sulforaphane significantly enhanced auranofin-induced apoptosis by inhibiting TrxR activity and cell proliferation compared to either single treatment. The synergistic effect of sulforaphane and auranofin on apoptosis was evidenced by an increased annexin-V-positive cells and Sub-G1 cells. The induction of apoptosis by the combined treatment caused the loss of mitochondrial membrane potential (ΔΨm) and upregulation of Bax. In addition, the proteolytic activities of caspases (-3, -8, and -9) and the degradation of poly (ADP-ribose) polymerase, a substrate protein of activated caspase-3, were also higher in the combined treatment. Moreover, combined treatment induced excessive generation of reactive oxygen species (ROS). However, treatment with N-acetyl-L-cysteine, a ROS scavenger, reduced combined treatment-induced ROS production and apoptosis. Thereby, these results deduce that ROS played a pivotal role in apoptosis induced by auranofin and sulforaphane. Furthermore, apoptosis induced by auranofin and sulforaphane was significantly increased through inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway. Taken together, the present study demonstrated that down-regulation of TrxR activity contributed to the synergistic effect of auranofin and sulforaphane on apoptosis through ROS production and inhibition of PI3K/Akt signaling pathway.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.5 no.1
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• pp.39-50
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• 2002

Hepatitis B viral infection which affect about 10% of Korean population manifests asymptomatic carrier, chronic hepatitis and liver cirrhosis and even associates with hepatocellular carcinoma. Clinical manifestations induced by hepatitis B virus vary depending on the degree of immune response by cytotoxic T cells against viral epitope-presenting liver cells. Since hepatitis B virus presents high rate of mutaton that might change the presented epitope and eventually alter immune response, viral mutations, especially in promoters and enhancers, have an important implication in hepatic inflammation and viral replication. To identify mutations related to the hepatic inflammation, we investigated sequence variations of hepatitis B viral promotor regions in the presence or absence of symptoms in hepatitis B carriers. For this, sera from persistently hepatitis B virus-infected mother-child pairs were collected. After PCR amplifiation of all hepatitis B viral promoters (C promoter, S1 promoter, S2/S promoter, X promoter) using serum DNA from each pair, viral promotors were sequenced by automatic sequencer and then sequence data were analyzed by ClustalW. In most cases, the dominant type of maternal virus was transmitted to the child. However, in some children, some new host specific viral variants could be observed in Cp, S1p and S2/Sp. The mutations in C promoter did not seem to be vertically transmitted but arose in new host independently after the wild type had been transmitted. Enhancer I containing X promoter revealed high host specific variations as has been reported before. Two S promoters, S1p and S2/Sp, have shown some point mutations in children, but no deletion mutations were detected as in chronic hepatitis patients in whom deletion mutations are frequently found. In conclusion, the children with the vertically transmitted hepatitis B virus mostly retain the dominant type virus that had been transmitted. However, host specific variants tended to accumulate over time, possibly as clinical symptoms develop.

• Journal of the Korean Society of Food Science and Nutrition
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• v.33 no.6
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• pp.936-940
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• 2004

Doenjang (Korean soy paste) is one of the popular soybean based fermented foods in Korea. This study investigated the growth and DNA synthesis inhibitory effect of doenjang methanol extracts on AGS human gastric adenocarcinoma cells, Hep 3B human hepatocellular carcinoma cells and HT-29 human colon cancer cells. In order to determine an anticancer effect of doenjang methanol extracts, other soybean fermented foods and original materials were compared. The treatment of doenjang methanol extracts (200 $\mu\textrm{g}$/mL) to the AGS, Hep 3B and HT-29 cancer cells inhibited the growth of cancer cells by 80%, 77% and 86%, respectively. Compared to other soybean fermented foods and original materials, doenjang methanol extracts showed the highest growth inhibitory effect on different cancer cells. In addition, doenjang methanol extracts (200 $\mu\textrm{g}$/mL) significantly inhibited DNA synthesis of AGS and Hep 3B cancer cells by 76% and 59%, respectively. These results suggested that this anticancer effect of doenjang may be due to specific active compounds, which will be newly produced during soybean fermented process and not contained in soybean.

• Journal of Yeungnam Medical Science
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• v.12 no.1
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• pp.96-104
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• 1995

The transarterial embolization has been widely used to control bleeding. It has a variety of clinical utility; to reduce bleeding on the surgical field, to reduce the size of malignant tumor as a preopearative treatment, to treat arteriovenous malformation or arterial aneurysm as a curative method and to promote life quality of patient with diffuse or multiple hepatocellular carcinoma as a palliative treatment, etc. With the advance of modem technology, various embolic materials have been also developed. However, it has not been fully investigated of histopathologic changes of the embolized organs according to the embolic materials used. This study was undertaken to investigate the histopathologic changes of embolized renal artery in rabbit by various embolic materials, according to each embolic material and to time passed by after embolization. Of the 5 arteries embolized by ethylene vinyl alcohol copolymer(EVAL), one showed abscess formation in embolized kidney. The other 4 allowed to perform further pathologic study: within a week after embolization there was no any specific change in vessels, however, minimal endothelial hypertrophy was observed following 2 weeks of embolization. Of the 8 renal arteries embolized by N-buthyl-2-cyanoacrylate(Histoacryl), 4 showed total occlusion of the main renal arteries as well as renal infarction, which reflects the strong adhesiveness of Histoacryl to vascular wall. The other 4 showed fibrinoid degeneration in vascular wall within a week. However, further change was not observed thereafter. In all the 5 renal arteries embolized by polyvinyl alcohol(Ivalon), there were infiltration of inflammatory cells along the vessel walls, within one week, which represents vasculitis. They showed some fibrosis with appearance of giant cells in the vessel wall two weeks after embolization and also showed marked fibrosis of connective tissues surrounding vessels two months after embolization, respectively. The results suggest that EVAL is useful for the embolization of hypervascular lesion with limited arteriovenous fistula, Histoacryl for the curative treatment of the lesion with high blood flow or severe arteriovenous fistula, and Ivalan for palliative treatment of malignant tumor or arteriovenous malformation, respectively.

• Journal of Ginseng Research
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• v.43 no.2
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• pp.196-208
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• 2019

Background: Nonalcoholic steatohepatitis (NASH) is one of the chronic inflammatory liver diseases and a leading cause of advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The main purpose of this study was to clarify the effects of GBCK25 fermented by Saccharomyces servazzii GB-07 and pectinase, on NASH severity in mice. Methods: Six-wk-old male mice were fed either a normal diet (ND) or a Western diet (WD) for 12 wks to induce NASH. Each group was orally administered with vehicle or GBCK25 once daily at a dose of 10 mg/kg, 20 mg/kg, 100 mg/kg, 200 mg/kg, or 400 mg/kg during that time. The effects of GBCK25 on cellular damage and inflammation were determined by in vitro experiments. Results: Histopathologic analysis and hepatic/serum biochemical levels revealed that WD-fed mice showed severe steatosis and liver injury compared to ND-fed mice. Such lesions were significantly decreased in the livers of WD-fed mice with GBCK25 administration. Consistently, mRNA expression levels of NASH-related inflammatory-, fibrogenic-, and lipid metabolism-related genes were decreased in the livers of WD-fed mice administered with GBCK25 compared to WD-fed mice. Western blot analysis revealed decreased protein levels of cytochrome P450 2E1 (CYP2E1) with concomitantly reduced activation of c-Jun N-terminal kinase (JNK) in the livers of WD-fed mice administered with GBCK25. Also, decreased cellular damage and inflammation were observed in alpha mouse liver 12 (AML12) cells and RAW264.7 cells, respectively. Conclusion: Administration of GBCK25 ameliorates NASH severity through the modulation of CYP2E1 and its associated JNK-mediated cellular damage. GBCK25 could be a potentially effective prophylactic strategy to prevent metabolic diseases including NASH.

• The Korean Journal of Nuclear Medicine Technology
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• v.23 no.1
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• pp.50-53
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• 2019

Purpose Yttrium-90 (Y-90) is high-energy beta emitters ($E{\beta}$, max = 2.28 MeV) with the mean penetration depth of 2.5 mm in tissue. Radioactive microspheres containing Y-90 is widely used for the transarterial radioembolization of hepatocellular carcinoma. However, bremsstrahlung radiation from Y-90 can cause the external radiation exposure to medical staff who handle the Y-90 microspheres. In this study, shielding device for Y-90 microspheres was developed to minimize the external radiation exposure. Materials and Methods Y-90 microsphere shielding device was made from 6 mm thicknesses of tungsten including the lead glass window. Radiation shielding ability of Y-90 microsphere shielding device was evaluated using 4 GBq of $SIR-Spheres^{(R)}$ Y-90 microspheres. The bremsstrahlung radiation was measured using radiation survey meter. Results The mean radiation dose of Y-90 microspheres in acrylic shield was $261.7{\pm}2.3{\mu}Sv/h$ (n=5) at 10 cm away from the shield. With the additional tungsten shielding device, it was $23.7{\pm}1.3{\mu}Sv/h$ (n=5). Thus, the bremsstrahlung radiation dose was decreased by 90.9%. At 50 cm away from the shield, bremsstrahlung radiation was reduced by 89.2% after using tungsten shielding device. Conclusion During the preparation and radioembolization of Y-90 microsphere, medical staff are exposed to external radiation. In this study, we demonstrated that the use of tungsten shielding device devices significantly reduced the amount of bremsstrahlung radiation. Y-90 microsphere tungsten shielding device can be highly effective in reducing the bremsstrahlung radiation.

• Journal of Preventive Medicine and Public Health
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• v.55 no.3
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• pp.263-272
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• 2022

Objectives: Infections with hepatitis B, C, and D virus (HBV, HCV, and HDV) are a major public health problem and lead to serious complications such as cirrhosis and hepatocellular carcinoma. We aimed to determine the seroprevalence of hepatitis B surface antigen (HBsAg), anti-HCV, anti-HDV immunoglobulin G, alpha-fetoprotein (AFP), and dual and triple hepatitis virus infections in Mongolia. Methods: A total of 2313 participants from urban and rural regions were randomly recruited for this cross-sectional study. A questionnaire was used to identify the risk factors for hepatitis virus infections, and the seromarkers were measured using immunoassay kits. Results: Among all participants, the prevalence of HBV, HCV, and HDV was 15.6%, 36.6%, and 14.3%, respectively. The infection rates were significantly higher in females and participants with a lower education level, rural residence, older age, and a history of blood transfusion. HBV and HCV co-infection was found in 120 (5.2%) participants and HBV, HCV, and HDV triple infection was detected in 67 (2.9%) participants. The prevalence of elevated AFP was 2.7%, 5.5%, and 2.6% higher in participants who were seropositive for HBsAg (p=0.01), anti-HCV (p<0.001), and anti-HDV (p=0.022), respectively. Elevated AFP was more prevalent in participants co-infected with HBV and HCV (5.8%, p=0.023), HBV and HDV (6.0%, p<0.001), and triple-infected with HBV, HCV, and HDV (7.5%) than in uninfected individuals. Conclusions: Nearly half (49.8%) of the study population aged ≥40 years were infected with HBV, HCV, or HDV, and 22.4% had dual or triple infections.

• Journal of Life Science
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• v.32 no.2
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• pp.94-100
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• 2022

Chronic infection by hepatitis B virus (HBV) greatly increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC). The outcome of HBV infection is shaped by the complex interplay of the mode of transmission, host genetic factors, viral genotype, adaptive mutations, and environmental factors. The pregenomic RNA transcription of HBV for their replication is regulated by the core promoter activation. Core promoter mutations have been the reason for acute liver failure and are associated with HCC development. We obtained HBV genes from a patient in Myanmar who was infected with HBV and identified gene variations in the core promoter region. For measuring the relative transactivation activity of the core promoter, we prepared the core-promoter reporter construct. Among the gene variations of the core promoter, the mutations of C1731T and G1806A were associated with increase in the transactivation of the HBV core promoter. Through computer analysis for searching for a tentative transcription factor binding site, we showed that the mutations of C1713T and G1806A newly created C/EBPβ and XBP1-responsive elements of the core promoter, respectively. The ectopic expression of C/EBPβ largely increased the HBV core promoter containing the C1713T mutation and that of XBP1 activated the M95 promoter containing the G1806A mutation. Our efforts to treat and prevent HBV infections are hampered by the emergence of drug-resistant mutations and vaccine-escape mutations. Our results provide the biological properties and clinical significance of specific HBV core promoter mutations.

• Proceedings of the Korean Society of Toxicology Conference
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• 2000.11a
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• pp.45-67
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• 2000

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a mutagenic and carcinogenic heterocyclic amino found in cooked meat. The in vivo mutagenicity and hepatocarcinogenicity of MeIQx were examined in mice harboring the lacZ mutation reporter gene ($Muta^{TM}$ Mice) and bitransgenic mice over-expressing the c-myc oncogene. C57B1/$\lambda$lacZ and bitransgenic c-myc (albumin promoter)/$\lambda$lacZ mice were bred and weaned onto an AIN-76 based diet containing $0.06\%$ (w/w) MeIQx or onto control diet. After 30 weeks on diet, only male bitransgenic mice on MeIQx developed hepatocellular carcinoma ($100\%$ incidence) indicating that there was synergism between c-myc over-expression and MeIQx. By 40 weeks, hepatic tumor incidence was $100\%$ ($17\%$) and $44\%$ ($0\%$) in male c-myc/$\lambda$lacZ and C57B1/$\lambda$lacZ mice given MeIQx (or control) diet, respectively, indicating that either MeIQx or c-myc over-expression alone eventually induced hepatic tumors. At either time point, mutant frequency in the lacZ gene was at least 40-fold higher in MeIQx-treated mice than in control mice of either strain. These findings suggest that MeIQx-induced hepatocarcinogenesis is associated with MeIQx-induced mutations. Elevated mutant frequency in MeIQx-treated mice also occurred concomitant with the formation of MeIQx-guanine adducts as detected by the $^{32}P$-postlabeling assay. Irrespective of strain or diet, sequence analysis of the lacZ mutants from male mouse liver showed that the principal sequence alteration was a single guanine-base substitution. Adenine mutations, however, were detected only in animals on control diet. MeIQx-fed mice harboring the c-myc oncogene showed a l.4-2.6-fold higher mutant frequency in the lacZ gene than mice not carrying the transgene. Although there was a trend toward higher adduct levels in c-myc mice, MeIQx-DNA adduct levels were not significantly different between c-myc/$\lambda$lacZ and C57B1/$\lambda$lacZ mice after 30 weeks on diet. Thus, it appeared that factors in addition to MeIQx-DNA adduct levels, such as the enhance rate of proliferation associated with c-myc over-expression, may have accounted for a higher mutant frequency in c-myc mice. In the control diet groups, the lacZ mutant frequency was significantly higher in c-myc/$\lambda$lacZ mice than in 057B1/$\lambda$1acZ mice. The findings are consistent with the notion that c-myc over-expression is associated with an increase in mutagenesis. The mechanism for the synergistic effects of c-myc over-expression on MeIQx hepatocarcinogenicity appears to involve an enhancement of MeIQx-induced mutations.

• Journal of Life Science
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• v.32 no.3
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• pp.210-221
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• 2022

This study investigated the mechanisms underlying the anti-cancer effects of non-steroidal anti-inflammatory drugs (NSAIDs) in human cancer cells in combination with either N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, or MHY2245, a new synthetic sirtuin 1 inhibitor. The results showed both DAPT and MHY2245 as novel chemosensitizers of human colon cancer KM12 and human hepatocellular carcinoma SNU475 cells to NSAIDs involving celecoxib and 2, 5-dimethyl celecoxib. The NSAID-induced cytotoxicity of these cells was significantly increased by DAPT and MHY2245 in a cyclooxygenase-2 independent manner. In addition, DAPT and MHY2245 reduced levels of p62, Notch1 intracellular domain, and multiple cancer stemness (CS)-related markers including Notch1, CD44, CD133, octamer-binding transcription factor 4, mutated p53 and c-Myc. However, the level of activating transcription factor 4 (ATF4) was enhanced, probably indicating the down-regulation of multiple CS-related markers by DAPT or MHY2245-mediated autophagy induction. Moreover, the NSAID-mediated reduction of p62/nuclear factor erythroid-derived 2-like 2 and CS-related marker proteins and the up-regulation of C/EBP homologous protein (CHOP)/ATF4 were accelerated by DAPT and MHY2245. As such, the combination of NSAID and either DAPT or MHY2245 resulted in higher cytotoxicity than NSAID alone by accelerating the down-regulation of multiple CS-related markers and PARP activation, indicating that both inhibitors promote NSAID-mediated autophagic cell death, possibly through the CHOP/ATF4 pathway. In conclusion, either combination strategy may be useful for the effective treatment of human cancer cells expressing CS-related markers.