• Biomolecules & Therapeutics
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• v.19 no.3
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• pp.282-287
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• 2011

Sirt1, a nicotinamide adenine dinucleotide ($NAD^+$)-dependent histone deacetylase, is known to deacetylate a number of proteins that are involved in various cellular pathways such as the stress response, apoptosis and cell growth. Modulation of the stress response by Sirtuin 1 (Sirt1) is achieved by the deacetylation of key proteins in a cellular pathway, and leads to a delay in the onset of cancer or aging. In particular, Sirt1 is known to play an important role in maintaining genomic stability, which may be strongly associated with a protective effect during tumorigenesis and during the onset of aging. In these studies, Sirt1 was generated in stably expressing cells and during the stimulation of DNA damage to examine whether it promotes survival. Sirt1 expressing cells facilitated the repair of DNA damage induced by either ionizing radiation (IR) or bleomycin (BLM) treatment. Fastened damaged DNA repair in Sirt1 expressing cells corresponded to prompt activation of Chk2 and ${\gamma}$-H2AX foci formation and promoted survival. Inhibition of Sirt1 enzymatic activity by a chemical inhibitor, nicotinamide (NIC), delayed DNA damage repair, indicating that promoted DNA damage repair by Sirt1 functions to induce survival when DNA damage occurs.

• Journal of the Korean Society of Food Science and Nutrition
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• v.31 no.5
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• pp.782-787
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• 2002

This study was done to investigate the effects of Korean mistletoe water extract and lectin on the apoptosis and preneoplastic lesion in chemically induced rat hepatocarcinogenesis. To attain the above objectives, weanling Sprague-Dawley male rats were fed modified AIN-76 diets containing 10% corn oil for 9 weeks. One week after feeding starts, rats were intraperitoneally injected twice with a dose of diethylnitrosamine (DEN, 50 mg/kg body weight (BW). Rats were provided with 0.05% phenobarbital (PB) in drinking water from one week after DEN treatment until the end of experiment. During the period of PB treatment, rats were injected with mistletoe extract (100 $\mu\textrm{g}$/kg BW) and lectin (10 $\mu\textrm{g}$/kg BW) twice a week. At the end of 9th week, rats were sacrificed and the formation of hepatic glutathione S-transferase placental form positive (GST-P$^{+}$) foci, apoptosis, DNA fragmentation and apoptosis related proteins were determined respectively. The formation of GST-P$^{+}$foci was significantly decreased by mistletoe extract or lectin treatment. Although there was no effect on apoptosis and DNA fragmentation in hepatic tissue by mistletoe extract or lectin treatment, caspase-9 and fas-L were increased. These results suggest that Korean mistletoe extract and lectin have a potential to inhibit hepatocarcinogenesis by increasing apoptosis.sis.

• Nutrition Research and Practice
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• v.2 no.2
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• pp.80-84
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• 2008

Beneficial effects of dehydroepiandrosterone (DHEA) supplement on age-associated chronic diseases such as cancer, cardiovascular disease, insulin resistance and diabetes, have been reported. However, its mechanism of action in hepatocellular carcinoma in vivo has not been investigated in detail. We have previously shown that during hepatocellular carcinogenesis, DHEA treatment decreases formation of preneoplastic glutathione S-transferase placental form-positive foci in the liver and has antioxidant effects. Here we aimed to determine the mechanism of actions of DHEA, in comparison to vitamin E, in a chemically-induced hepatocellular carcinoma model in rats. Sprague-Dawley rats were administered with control diet without a carcinogen, diets with 1.5% vitamin E, 0.5% DHEA and both of the compounds with a carcinogen for 6 weeks. The doses were previously reported to have anti-cancer effects in animals without known toxicities. With DHEA treatment, cytosolic malate dehydrogenase activities were significantly increased by ${\sim}5$ fold and glucose 6-phosphate dehydrogenase activities were decreased by ${\sim}25%$ compared to carcinogen treated group. Activities of Se-glutathione peroxidase in the cytotol was decreased siguificantly with DHEA treatment, confirming its antioxidative effect. However, liver microsomal cytochrome P-450 content and NADPH-dependent cytochrome P-450 reductase activities were not altered with DHEA treatment. Vitamin E treatment decreased cytosolic Se-glutathione peroxidase activities in accordance with our previous reports. However, vitamin E did not alter glucose 6-phosphate dehydrogenase or malate dehydrogenase activities. Our results suggest that DHEA may have decreased tumor nodule formation and reduced lipid peroxidation as previously reported, possibly by increasing the production of NADPH, a reducing equivalent for NADPH-dependent antioxidant enzymes. DHEA treatment tended to reduce glucose 6-phosphate dehydrogenase activities, which may have resulted in limited supply for de novo synthesis of DNA via inhibiting the hexose monophophaste pathway. Although both DHEA and vitamin E effectively reduced preneoplastic foci in this model, they seemed to fimction in different mechanisms. In conclusion, DHEA may be used to reduce hepatocellular carcinoma growth by targeting NADPH synthesis, cell proliferation and anti-oxidant enzyme activities during tumor growth.

• Food Science and Biotechnology
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• v.15 no.6
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• pp.980-985
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• 2006

The goal of this study was to investigate the effects of a newly developed functional food containing Bacillus polyfermenticus (BP) and other physiologically active materials on the antioxidant system and the process of colon carcinogenesis in male F344 rats. Following a one-week adaptation period, the rats were divided into 3 groups and fed either a high-fat, low-fiber diet (control and DMH groups), or a high-fat, low-fiber diet supplemented with B. polyfermenticus ($3.1{\times}10^8\;CFU/day$) and other physiologically active materials (chitosan, chicory, ${\alpha}$-tocopherol, and flavonoids) (DMH+BP group). One week after the initiation of the diets, 2 groups of rats were subjected to six weeks of treatment with 1,2-dimethylhydrazine (DMH, 180 mg/kg BW, s.c.). The dietary treatments remained consistent throughout the entire experimental period. Nine weeks after the initial DMH injection, the rats supplemented with B. polyfermenticus had significantly lower numbers of aberrant crypt foci than those in the DMH group. Injections with DMH resulted in significantly higher leukocytic DNA damage and plasma lipid peroxidation levels, as well as in a lower plasma total antioxidant potential. These effects were reversed following supplementation with B. polyfermenticus and other physiological materials. Our results indicate that a functional food containing B. polyfermenticus exerts a protective effect on the antioxidant system and on the process of colon carcinogenesis, thereby suppressing the development of preneoplastic lesions.

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.99-107
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• 1999

A series of organosulfur compounds were synthesized with the aim of developing chemopreventive compounds active against hepatotoxicity and chemical carcinogesis. 2-(Allylthio) prazine (2-AP) was effective in inhibiting cytochrome P450 2E1-mediated catalytic activities and protein expression, and in inducing microsomal epoxide hydrolase and major glutathione S-transferases. 2-AP reduced the hepatotoxicity caused by toxicant sand elevated cellular GSH content. Development of skin tumors, pulmonary adenoma and aberrant crypt foci in colon by various chemical carcinogens was inhibited by 2-AP pretreatment. Anticarcinogenic effects of 2-AP at the stage of initiation of tumors were also observed in the aflatoxin B1 ($AFB_1$)-induced three-step medium-term hepatocarcinogenesis model. Reduction of $AFB_1$-DNA adduct by 2-AP appeared to result from the decreased formation of $AFB_1$-8,9-epoxide via suppression of cytochrome P450, while induction of GST 2-AP increases the excretion of glutathione-conjugated $AFB_1$ . 2-AP was a radioprotective agent effective against the lethal dose of total body irradiation and reduced radiation-induced injury in association with the elevation of detoxifying gene expression. 2-AP produces reactive oxygen species in vivo, which is not mediated with the thiol-dependent production of oxidants and that NF-KB activation is not involved in the induction of the detoxifying enzymes. the mechanism of chemoprotection by 2-AP may involve inhibition of the P450-mediated metabolic activation of chemical carcinogens and enhancement of electrophilic detoxification through induction of phase II detoxification enzymes which would facilitate the clearance of activated metabolites through conjugation reaction.

• Journal of the Korean Society of Food Science and Nutrition
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• v.38 no.7
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• pp.839-845
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• 2009

Colorectal cancer is the third most common malignant neoplasm in the world. Much attention has been focused on reducing colon cancer risk through medical properties of natural compound that could act as anticarcinogens. In this study, we evaluated the antioxidant and antigenotoxic effects of Styela plicata (S. plicata) from in vitro experiments. S. plicata extracts showed antioxidant activity measured by TRAP assay and antigenotoxic effect in $200{\mu}M$ $H_2O_2$ induced DNA damage in human leukocytes. Especially, freeze-dried S. plicata extracted with methanol showed the highest level of TRAP (0.225 mM) and inhibition of DNA damage (66.8%). Additionally we observed the effect of S. plicata on the formation of aberrant crypt foci (ACF) induced by dimethylhydrazine (DMH) and DMH induced DNA damage (by comet assay) in male SD rats. The animals were divided into three groups and fed high-fat and low fiber diet (100 g lard+20 g cellulose/kg diet) without (normal control and DMH control) or with a 3% (w/w) of lyophilized S. plicata powder (DMH+S. plicata). One week after beginning the diets, rats were treated with DMH (30 mg/kg, s.c.) for 6 weeks except for normal control group, which was treated saline instead; dietary treatments were continued for the entire experiment. Nine weeks after DMH injection, administration of S. plicata resulted in reduction of ACF numbers, to 82.7% of the carcinogen control value ($7.67{\pm}2.04$ vs. $1.33{\pm}0.53$: p<0.01). S. plicata supplementation induced antigenotoxic effect on DMH-induced DNA damage in the blood cell (% tail intensity: $6.79{\pm}0.26$ vs. $6.13{\pm}0.22$). These data indicate that S. plicata extract has antigenotoxic and anticarcinogenic effects from in vitro experiments and S. plicata exerts a protective effect on the process of colon carcinogenesis, possibly by suppressing the DMH-induced DNA damage in blood cell and the development of preneoplastic lesions in colon.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.1983-1988
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• 2012

High temperature- and pressure-treated garlic (HTPG) has been shown to have enhanced antioxidative activity and polyphenol contents. Previously, we reported that HTPG inhibited 1,2-dimethylhydrazine-induced mucin depleted foci (premalignant lesions) and $O^6$-methylguanine DNA adduct formation in the rat colorectum. In the present study, we investigated the modifying effects of HTPG on N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG)-induced pyloric stomach and small intestinal carcinogenesis in mice. Male C57BL/6 mice were given ENNG (100 mg/l) in drinking water for the first 4 weeks, then a basal diet or diet containing 2% or 5% HTPG for 30 weeks. The incidence and multiplicity of pyloric stomach and small intestinal (duodenal and jejunal) tumors in the 2% HTPG group (but not in the 5% HTPG group) were significantly lower than those in the control group. Cell proliferation of normal-appearing duodenal mucosa was assessed by MIB-5 immunohistochemistry and shown to be significantly lower with 2% HTPG (but again not 5% HTPG) than in controls. These results in dicate that HTPG, at 2% in the diet, inhibited ENNG-induced pyloric stomach and small intestinal (especially duodenal) tumorigenesis in mice, associated with suppression of cell proliferation.