• Biomolecules & Therapeutics
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• v.31 no.6
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• pp.648-654
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• 2023

Oxidative stress-induced melanocyte apoptosis is linked to the immune system and plays a critical role in the pathogenesis of vitiligo. Aquaporin-3 (AQP3), which is downregulated in vitiligo keratinocytes, regulates intracellular H₂O₂ accumulation. However, the role of AQP3 in oxidative stress is uncertain in vitiligo. This study investigated the effect of downregulated AQP3 on oxidative stress in vitiligo using lesional and non-lesional skin specimen sets from vitiligo patients and primary cultured adult normal human epidermal keratinocytes, with or without downregulation and overexpression of AQP3 in the presence or absence of H₂O₂ treatment. The levels of nuclear factor E2-related factor 2 (NRF2) and/or its main target, NAD(P)H quinone dehydrogenase 1 (NQO-1), were lower in the lesional keratinocytes and cultured keratinocytes with AQP3 knockdown, but were increased in keratinocytes upon AQP3 overexpression. Ratios of NRF2 nuclear translocation and NQO-1 expression levels were further reduced in AQP3-knockdown keratinocytes following H₂O₂ treatment. The conditioned media from AQP3-knockdown keratinocytes treated with H₂O₂ contained higher concentrations of reactive oxygen species (ROS). Moreover, the number of viable melanocytes was reduced when the conditioned media were added to the culture media. Overall, AQP3 downregulation in the keratinocytes of patients with vitiligo can induce oxidative stress in neighboring melanocytes, leading to melanocyte death.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2349-2354
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• 2013

NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T gene polymorphisms have been reported to influence the risk for digestive tract cancer (DTC) in many studies; however, the results remain controversial and ambiguous. We therefore carried out a meta-analysis of published case-control studies to derive a more precise estimation of any associations. Electronic searches were conducted on links between this variant and DTC in several databases through April 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of associations in fixed or random effect models. Heterogeneity and publication bias were also assessed. A total of 21 case-control studies were identified, including 6,198 cases and 7,583 controls. Overall, there was a statistically significant association between the NQO1 C609T polymorphism and DTC risk (TT vs. CC: OR=1.224, 95%CI=1.055-1.421; TT/CT vs. CC: OR=1.195, 95%CI=1.073-1.330; TT vs. CT/CC: OR=1.183, 95%CI=1.029-1.359; T vs. C: OR=1.180, 95%CI=1.080-1.290). When stratified for tumor location, the results based on all studies showed the variant allele 609T might have a significantly increased risk of upper digest tract cancer (UGIC), but not colorectal cancer. In the subgroup analysis by ethnicity, we observed a significantly risk for DTC in Caucasians. For esophageal and gastric cancer, a significantly risk was found in both populations, and for colorectal, a weak risk was observed in Caucasians, but not Asians. This meta-analysis suggested that the NQO1 C609T polymorphism may increase the risk of DTC, especially in the upper gastric tract.

• Radiation Oncology Journal
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• v.31 no.2
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• pp.57-65
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• 2013

Beta-lapachone (${\beta}$-Lap; 3,4-dihydro-2, 2-dimethyl-2H-naphthol[1, 2-b]pyran-5,6-dione) is a novel anti-cancer drug under phase I/II clinical trials. ${\beta}$-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human cancer cells in vitro and in vivo. The mechanisms underlying the ${\beta}$-Lap toxicity against cancer cells has been controversial. The most recent view is that ${\beta}$-Lap, which is a quinone compound, undergoes two-electron reduction to hydroquinone form utilizing NAD(P)H or NADH as electron source. This two-electron reduction of ${\beta}$-Lap is mediated by NAD(P)H:quinone oxidoreductase (NQO1), which is known to mediate the reduction of many quinone compounds. The hydroquinone forms of ${\beta}$-Lap then spontaneously oxidizes back to the original oxidized ${\beta}$-Lap, creating futile cycling between the oxidized and reduced forms of ${\beta}$-Lap. It is proposed that the futile recycling between oxidized and reduced forms of ${\beta}$-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced ${\beta}$-Lap is converted first to one-electron reduced ${\beta}$-Lap, i.e., semiquinone ${\beta}$-Lap $(SQ)^{{\cdot}-}$ causing production of reactive oxygen species (ROS), which then causes apoptotic cell death. The second mechanism is that severe depletion of NAD(P)H and NADH as a result of futile cycling between the quinone and hydroquinone forms of ${\beta}$-Lap causes severe disturbance in cellular metabolism leading to apoptosis and necrosis. The relative importance of the aforementioned two mechanisms, i.e., generation of ROS or depletion of NAD(P)H/NADH, may vary depending on cell type and environment. Importantly, the NQO1 level in cancer cells has been found to be higher than that in normal cells indicating that ${\beta}$-Lap may be preferentially toxic to cancer cells relative to non-cancer cells. The cellular level of NQO1 has been found to be significantly increased by divergent physical and chemical stresses including ionizing radiation. Recent reports clearly demonstrated that ${\beta}$-Lap and ionizing radiation kill cancer cells in a synergistic manner. Indications are that irradiation of cancer cells causes long-lasting elevation of NQO1, thereby sensitizing the cells to ${\beta}$-Lap. In addition, ${\beta}$-Lap has been shown to inhibit the repair of sublethal radiation damage. Treating experimental tumors growing in the legs of mice with irradiation and intraperitoneal injection of ${\beta}$-Lap suppressed the growth of the tumors in a manner more than additive. Collectively, ${\beta}$-Lap is a potentially useful anti-cancer drug, particularly in combination with radiotherapy.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.11 no.1
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• pp.171-186
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• 1989

This study was undertaken to investigate the effects of indomethacin on 4-nitroquinoline 1-oxide (4NQO) induced palatal carcinoma of albino rats. Sixty albino rats about 100 gms of body weight, 6 weeks old-were used classifying as 1) six albino rats of normal group received no treatment, 2) six albino rats of control group treated with propane 1, 2-diol 3 times a week, 3) twenty four albino rats of experimental group I treated with 0.5% 4NQO in propane 1, 2-diol 3 times a week, 4) twenty four albino rats of experimental group II treated with 0.5% of 4NQO in propane 1, 2-diol 3 times a week and administrated 20${\mu}g/ml$ indomethacin in drinking water ad lib. The animals of normal and control groups were sacrificed 7th, 11th, 15th, 19th, 23rd and 27th week, while those of experimental group I and II were sacrificed 7th, 9th, 11th, 13th, 15th, 17th, 19th, 21st, 23rd, 25th, 27th and 29th week after the experiment. The palatal mucosa was excised and examined grossly, light-microscopically and electron-microscopically. Following results were obtained. 1. In control group, there was no specific difference from normal tissue histopathologically. 2. In group I, hyperkeratosis mild acantosis and dyskeratosis in in 7th week, dysplasia in 11th week and severe acantosis in 19th week were observed, but squamous cell carcinoma not observed until 29th week on light-microscope. 3. In group II, hyperkeratosis, mild acantosis in 9th week, dyskeratosis and dysplasia in 21st week, severe acantosis in 27th week and squamous cell carcinoma in 29th week were observed on light-microscope. 4. In group I, widening of intercellular space in 7th week, increasing of desmosome, giant desmosome and tonofilament in cytoplasm in 9th week, severe widening of intercellular space, increasing of mitochondria and vascular degeneration in 11th week, irregular pattern of cell feature and nucleus and prominent nucleoli in 19th week, and continuity of basal lamina in 29th week were observed on electron-microscope. 5. In group II, mild widening of intercellular space in 9th week, increasing of mitochondria, vascular degeneration and tonofilament in cytoplasm in 13th week, increasing of desmosome and giant desmosome in 15th week, irregular pattern of cell surface and nucleus and prominent nucleoli, and in 21st week continuity of basal lamina were observed on electron-microscope which phenomenon occurred little later than group I. After 21st week, however, severe widening of intercellular space, vascular degeneration and continuity of basal lamina were observed as in group I.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.11 no.1
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• pp.187-202
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• 1989

This study was undertaken to investigate the effect of indomethacin on prostaglandins in 4-Nitroquinoline-N-Oxide (4-NQO) induced palatal carcinoma of albino rats. 128 Sprague-Dawley strain albino rats-about 100g in body weight-were used in this study, divided into as belows; 1. Normal group (16-albino rats) with no treatment, 2. Control group (16-albino rats) treated with prophylene application onto palatal mucosa 3 times a week. 3. Experimental group I (48-albino rats) treated with 0.5% 4-NQO in prophylene application onto palatal mucosa 3 times a week. 4. Experimental group II (48-albino rats) treated with 0.5% 4-NQO in prophylene application with administered $20{\mu}g/ml$ of indomethacin in drinking water ad. lib. Four animals were sacrificed 7th, 13th, 19th, and 25th week respectively in normal and control group, and 7th, 9th, 11th, 13th, 15th, 17th, 19th, 21st, 23rd, 25th, 27th and 29th week respectively in experimental group I and II at each time. The palatal and lingual tissues were excised and kept frozen at $-70^{\circ}C$. Densitometer scan and Beta-counting counter were used for the thin layer chromatography of the arachidonic acid metabolites. The obtained results were as belows; 1. In normal and control group, there was little change of the arachidonic acid metabolites during experiment period, and the tissue homogenates included prostaglandin $D_2$, 6-keto-prostaglandin $F_{1{\alpha}}$, prostaglandin $E_2$, thromboxane $B_2$, prostaglandin $F_{2{\alpha}}$ in that order of relative abundances. 2. In experimental group I, prostaglandin $D_2$, and prostaglandin $E_2$ were increased, while 6-keto-prostaglandin $F_{1{\alpha}}$ and thromboxane $B_2$ were decreased in relative abundances of arachidonic acid metabolites. And there was little change in prostaglandin $F_{1{\alpha}}$ 3. In experimental group II, prostaglandin $D_2$, and prostaglandin $E_2$ were increased, while 6-keto-prostaglandin $F_{1{\alpha}}$ and thromboxane $B_2$ were decreased in relative abundances of arachidonic acid metabolites. And there was little change in prostaglandin $F_{2{\alpha}}$ also. 4. In the range of increase in prostaglandin $D_2$, and prostaglandin $E_2$, and that of decrease in 6-keto-prostaglandin $F_{1{\alpha}}$ and thromboxane $B_2$, in relative abundances, there was wider in experimental group I than in group II. 5. In the range of increase in prostaglandin $D_2$, and prostaglandin $E_2$, and that of decrease in 6-keto-prostaglandin $F_{1{\alpha}}$ and thromboxane $B_2$, in relative abundances, there was wider in palatal mucosa than in lingual mucosa in experimental group I and II.

• Food Science and Preservation
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• v.15 no.2
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• pp.274-279
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• 2008

This study investigated the antimutagenic and anticancer effects of soybean sauce (kanjang) supplemented with deep sea water and Sea Tangle. The Ames test indicated that kanjang had no mutagenicity but it significantly inhibited mutations induced by N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) and 4-nitroquinoline-1-oxide (4NQO). Kanjang (200 ug/plate) with supplementary deep sea water and Sea Tangle had approximately 90.9% and 62.0% inhibitory effect, respectively, against mutagenesis of TA100 induced by MNNG and 4NQO. There was 61.7% inhibition of mutagenesis induced by 4NQO against the TA98 strain. Kanjang inhibited growth of cell lines of human cervical adenocarcinoma (HeLa), human hepatocellular carcinoma (Hep3B), human gastric carcinoma (AGS), human lung carcinoma (A549), and human breast adenocarcinoma (MCF-7) in a concentration-dependent manner. Treatment with kanjang supplemented with 1.0 mg/mL deep sea water had cytotoxicities of 69.4% 70.5% 55.6% 82.1 % and 73.2% against HeLa, Hep3B, AGS, A549 and MCF-7 cells respectively. In contrast kanjang supplemented with 1 mg/mL deep sea water had only $10{\sim}40%$ cytotoxicity on normal human embryonal kidney cells (293). Kanjang supplemented with deep sea water significantly inhibited tumor growth in mice injected sarcoma-180 cells. In particular, kanjang supplemented with deep sea water (25 mg/kg) inhibited tumor cell activity by 40.9%.

• Food Science and Preservation
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• v.8 no.1
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• pp.109-117
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• 2001

Cordyceps militaris is a parasitic fungus that has been used as a Chinese medicine for the treatment of fatigue, debility, kidney disease, tuberculosis, asthma and cardiac insufficiency etc. This study was carried out to determine the antioxidative and antimutagenic effects of Cordyceps militaris using DPPH free radical donating method and Ames test, respectively. They were extracted with ethanol and then further fractionated to n-hexane, chloroform, ethyl acetate, butanol and water, stepwise. Among five fractions, the EtOAc and BuOH fractions showed the highest electron donating activities, about 2-fold higher than other fractions. In Ames test, most of the extracts had strong antimutagenic effects against the mutagenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine(MNNG), 4-nitroquinoline-1-oxide(4NQO), benzo($\alpha$)pyrene(B($\alpha$)P) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indol (Trp-P-1). The EtOH extracts of C. militaris (200 $\mu\textrm{g}$/plate) showed 62.8%, 74.4% and 67.2% inhibitory effects on the mutagenesis induced by 4NQO, B($\alpha$)P and Trp-P-1, respectively, against TA98 strain, whereas 78.1%, 78.6%, 78.6% and 82.7% inhibition were observed on the mutagenesis induced by MNNG, 4NQO, B($\alpha$)P and Trp-P-1, respectively, against TA100 strain. Especially, the BuOH fraction showed the highest antimutagenic effects against mutation induced by MNNG.

• Journal of the Korean Society of Food Science and Nutrition
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• v.21 no.2
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• pp.143-148
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• 1992

The antimutagenic effects of green-yellow vegetables toward aflatoxin B$_1$(AFB$_1$) and 4-nitroquinoline-1-ox-ide (4-NQO) using the Ames assay system with Salmonella typhimurium TA98 and TA100 were studied. Forty six to fifty percent of the methanol extracts of the vegetable samples inhibited the mutagenicity induced by AFB$_1$in TA98 and TA100. Perilla leaf, lettuce, broccoli, crown daisy, water dropwort, small water dropwort, red pepper, red pepper leaves, amaranth, spinach and radish root were significantly reduced the mutagenicity of AFB$_1$(p< 0.01). Whereas 25 out of 27 samples (93%) exhibited antimutagenicity toward a direct mutagen of 4-NQO (p< 0.01. 0.05). The samples which showed the strong antimutagenicity (>60%) were cabbage, kale, lettuce, broccoli, mustard leaf, green red pepper, green sweet pepper, spinach, amaranth, soybean sprout and immature pumpkin. The juices from the several samples also showed antimu-tagenic activity toward AFB$_1$. Cabbage, perilla leaf, small water dropwort and spinach reduced TAT100 revertants dose dependently in the range of 50-500$m\ell$/plate, however, cucumber and carrot showed little effect.

• Korean Journal of Medicinal Crop Science
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• v.10 no.2
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• pp.132-138
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• 2002

This study was performed to determine the antimutagenic and cytotoxic effect of ,Kalopanacis cortex endothelium. Methanol extract was used on Salmonella typhimurium TA98, TA100 and three cancer cell lines. In the Ames test, methanol extract of Kalopanacis cortex endothelium alone did not exhibit any mutagenicity but showed substantial inhibitory effects against mutation induced by 4-nitroquinoline-l-oxide(4NQO), N'-methyl- N'-nitro-N-nitrosoguanidine(MNNG) and benzo(a)pyrene(B(a)P). The methanol extract of Kalopanacis cortex endothelium showed approximately 79.29% and 75.38% inhibitory effect on the mutagenesis induced by 4NQO and B(a)P, respectively, against TA98 strain. Whereas 79.49%, 89.3% and 68.85% inhibitions were observed on the mutagenesis induced by 4NQO, MNNG and B(a)P against TA100 strain. Methanol extracts from Kalopanacis cortex endothelium showed high antimutagenic effects against 4NQO, MNNG and B(a)P. The anticancer effects of methanol extract from Kalopanacis cortex endothelium against human lung carcinoma(A549), human breast adenocarcinoma (MCF-7) and human hepatocellular carcinoma(Hep3B) were investigated. The treatment of 0.5mg/ml Kalopanacis cortex endothelium methanol extracts had the highest cytotoxicity against A549(81.54%), followed by MCF-7(81.92%) and Hep3B (78.57%). In contrast 0.5mg/ml treatment of methanol extracts from Kalopanacis cortex endothelium had only $4{\sim}25%$ cytotoxicity on normal human liver cell(293).

• Korean Journal of Food Science and Technology
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• v.32 no.6
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• pp.1371-1378
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• 2000

This study was performed to determine the antimutagenic and cytotoxic effect of Agaricus blazei Murill methanol extract on Salmonella typhimurium TA98, TA100 and human cancer cell lines using Ames test and cytotoxicity assay, respectively. In Ames test, methanol extract from A. blazei Murill did not exhibit any mutagenicity and most of the samples showed high antimutagenic effects against mutation induced by N-methyl-N'-nitro-N-nitrosoguanidine(MNNG), 4-nitroquinoline-1-oxide(4NQO), 3-amino-1,4-dimethyl-5H-pyrido [4,3-b] indol(Trp-P-1) and $benzo({\alpha})pyrene(B({\alpha})P)$. The methanol extracts of A. blazei Murill$(200\;{\mu}g/plate)$ showed approximately 92.4%, 81.9% and 83.4% inhibitory effect on the mutagenesis induced by 4NQO, Trp-P-1 and $B({\alpha})P$ against TA98 strain, whereas 87.3%, 94.7%. 92.3% and 89.9% inhibitions were observed on the mutagenesis induced by MNNG, 4NQO, Trp-P-1 and $B({\alpha})P$ against TA100 strain. The solvent fractions of methanol extracts from A. blazei Murill except water fraction showed high antimutagenic effects of $70{\sim}90%$ against mutation induced by MNNG, 4NQO. Trp-P-1 and $B({\alpha})P$. In anticancer effects of A. blazei Murill extract and fraction against cancer cell lines including human breast adenocarcinoma(MCF7), human lung carcinoma(A549), human fibrosarcoma(HT1080), human hepatocellular carcinoma(Hep3B), human epitheloid carcinoma(HeLa), human gastric carcinoma(KATO III) and human chronic myelogenous leukemia(K562) were investigated. The treatment of 1 mg/mL A. blazei Murill extracts had the highest cytotoxicity with 91.9% against HeLa, followed by KATO III(88.7%), A549(86.5%) and Hpe3B(84.3%). Whereas 1 mg/mL treatment of A. blazei Murill extracts had only $10{\sim}40%$ cytotoxicity on human normal liver cell (WRL68).