• Korean Journal of Veterinary Pathology
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• 제6권1호
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• pp.41-48
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• 2002

Oval cell is considered as facultative precursor cells for both hepatocytes and biliary cells, as well as origin of hepatocellar and cholangiocellular carcinoma (CCC) during carcinogenesis or toxic liver injury. To clarify the cellular origin or differentiation of cholagiocarcinogensis, the fate of carcinogen-induced oval cells was pathologically and phenotypically chased in Syrian golden hamster liver after Clonorchis sinensis (CS) infection which would give rise to a promoting effect. Two week treatment of hamsters with 0.005% diethylnitrosamine (DEN) followed by 2 week treatment of 1% 2-acetylaminofluorene (AAF) under choline deficient diet resulted in massive proliferation of BrdU labeleed and PCNA positive oval cells showing various distinct morphology, histochemical and immunohistochemical phenotypes for GGT, cytokeratin 19 and OV-6. Oval cells also frequently form ductular-like structures or phenotypically show hepatocyte-like characteristics. After CS infection, the oval cells showed sequential morphological changes to atypicl proliferating bile ductules and all hamsters thereafter developed well differentiated and anaplastic CCC at 16 week after CS infection. In electron microscopy, some bile ductules were constructed by intermediate oval cells and bile ductular cells surrounded by basement membrane. The results of this study strongly suggest that CCC developed in the present study were originated from hepatic stem-like oval cells, supporting the theory of stem cell origin of cancers. In addition, this hamster model would be valuable for the molecular mechanistic study during chemical-triggered cholangiocarcinogenesis.

• Journal of Preventive Medicine and Public Health
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• 제32권1호
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• pp.101-107
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• 1999

Objectives. To determine the effects of exposure to hexavalent chromium, 93 male Sprague-Dawley rats were exposed to hexavalent chromium solution. Methods. Rats were divided into 4 groups and exposed to 0.1ml of 0 mM, 0.4 mM, 2.0 mM, and 10.0 mM potassium chromate in the first experiment, and to 0.1 ml of 0 mM, 20 mM, 40 mM, and 80 mM in the second for consecutive 3 days by tracheal instillation. Three and 10 rats were the controls for the first and the second experiments, respectively. Lung tissues were then removed to measure the 8-hydroxydeoxyguanosine (8-OH-dG) level using the HPLC-ECD method, superoxide dismutase (SOD) activity using the cytochrome C method, and 8-hydroxyguanine endonuclease activity using the oligonucleotide nicking assay. Results. The results showed no significant linear relationship between chromium exposure level and 8-OH-dG level or 8-hydroxyguanine endonuclease activity. In the first experiment, 8-OH-dG level and 8-hydroxyguanine endonuclease activity increased in 0.4 mM group, and then decreased in 2.0 mM and 10.0 mM groups. The correlation coefficients between 8-OH-dG level and 8-hydroxyguanine endonuclease activity was statistically significant (P<0.01), and total SOD activity was elevated by chromium exposure in a dose-dependent manner (P<0.05). In contrast, there was no significant dose-response pattern or correlation in the secod experiment. Conclusions. Based on the fact that there was no linear relationship between chromium dose and 8-OH-dG level or activity of the repair enzyme, it seems unlikely that 8-OH-dG formation is the major mechanism of chromium carcinogenesis.

• The Korea Journal of Herbology
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• 제24권3호
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• pp.161-167
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• 2009

Objectives : Maekmoondong-tang (MMDT), a Korean herbal medicine, has been used to treat severe dry cough in patients with bronchitis and pharyngitis. MMDT has been reported to have anti-inflammatory, anti-allergic, immunomodulatory, secretory-modulating, and metabolic regulatory actions. However, there are no evidence in regard to the effects of MMDT on carcinogenesis and metastasis. Here, we investigated the effects of 70% ethanol extract of MMDT on cell viability, apoptosis, and motility in human hepatocarcinoma HepG2 cells. Methods : Cell viability was measured using the CCK-8 assay, and the apoptosis induction was evaluated by caspase-3 activity. To detect apoptotic features, the cells treated with MMDT were stained with 4'-6-diamidino-2-phenylindole (DAPI). Cell motility was examined by Boyden chamber assay and Real-time Cell Index of Migration assay. Gelatin zymography also performed to measure matrix metalloproteinase (MMP)-2/9 activity. Results : We found that MMDT significantly inhibited cell proliferation and increased caspase-3 activity in a dose-dependent manner in HepG2 cells. Apoptotic features such as chromatin condensation and apoptotic bodies were observed in MMDT-treated cells by DAPI staining. MMDT also suppressed PMA-induced cell motility and activities of MMP-2/9. Conclusions : Our results exhibited that MMDT possess the anti-carcinogenetic and anti-metastatic activities via caspase-3 activation and down-regulation of cell motility and invasion in HepG2 cells. Therefore, these findings suggest that MMDT could be potentially applied to the prevention and treatment of cancer.

• Archives of Pharmacal Research
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• 제23권6호
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• pp.605-612
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• 2000

Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in human. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the biological actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicity in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase IIgene assay, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 $\mu\textrm{m}$with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MAPK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 $\mu\textrm{m}$ to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTP.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제34권5호
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• pp.509-517
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• 2008

DNA damage accumulates in cells as a result of exposure to exogenous agents such as benzopyrene, cigarette smoke, ultraviolet light, X-ray, and endogenous chemicals including reactive oxygen species produced from normal metabolic byproducts. DNA damage can also occur during aberrant DNA processing reactions such as DNA replication, recombination, and repair. The major of DNA damage affects the primary structure of the double helix; that is, the bases are chemically modified. These modification can disrupt the molecules'regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. DNA repair genes and proteins scan the global genome to detect and remove DNA damage and damage to single nucleotides. Direct reversal of DNA damage, base excision repair, double strand break. DNA repair are known relevant DNA repair mechanisms. Four different mechanisms are distinguished within excision repair: direct reversal, base excision repair, nucleotide excision repair, and mismatch repair. Genetic variation in DNA repair genes can modulate DNA repair capacity and alter cancer risk. The instability of a cell to properly regulate its proliferation in the presence of DNA damage increase risk of gene mutation and carcinogenesis. This article aimed to review mechanism of excision repair and to understand the relationship between genetic variation of excision repair genes and head and neck cancer.

• Journal of the Korean Institute of Gas
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• 제19권3호
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• pp.1-8
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• 2015

In this study, we performed risk assessment of chloroprene by hazard evaluation and workplace investigation. The chemical is used to manufacture of shoes, tires, adhesives, and classified as IARC category 2B (possibly carcinogenic to humans) and target organ systemic toxicity. It is used about 1,300 tons per year in 27 sites. It was calculated the risk of carcinogenesis with chloroprene by Monte-carlo simulation that the averages are 2,199 and 26,404 in each case of working less than 15 minutes per day with local exhaust ventilation and over 4 hours per day without local exhaust ventilation. The risk of target organ systemic toxicity are 4.10 and 169.06 with high correlation with working time to be longer and with ventilation system. Therefore, it is recommended that the local exhaust ventilation and respirators to prevent occupational cancer and target organ systemic toxicity with chloroprene. Especially it is determined that there is a need to strengthen the workplace exposure limit (TWA 10 ppm) in Korea since it is managed with TWA less than 5 ppm ($18mg/m^3$) by the United States Occupational Safety and Health Administration (OSHA) as well as it has carcinogenicity, reproductive toxicity.

• The Korean Journal of Pharmacology
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• 제18권1호
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• pp.65-72
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• 1982

It has been known that retinoids are intrinsically of critical importance for control of premalignant epithelial cell differentiation. In the absence of retinoids, normal cellular differentiation and growth does not occur in epithelia such as those of trachea and bronchi. Furthermore, it was also reported that retinoid deficiency enhanced susceptibility to chemical carcinogenesis in the respiratory system, in the bladder, and in the colon of the experimental animal. In 1974, Bollag examined the effects of synthetic retinoids in prevention of development of cancer and demonstrated synthetic retinoids to have more favorable therapeutic index than retinoic acid for causing regression of skin papilloma in mice. Therefore, it was assumed that this anticarcinogenic effect of vitamin A derivatives could be due to modification of the metabolism of the carcinogenic polycyclic hydrocarbon, which must first be activated to exert their effect. Hill and Shih reported that vitamin A compounds and analogs had inhibitory effect on drug metabolizing enzyme from liver and lung tissue of mouse and hamster. Lucy suggested that the chemoprevention effect of vitamin A derivatives is due to reaction with molecular oxygen, and it is possible that inhibition of hydroxybenzpyrene formation is a result of this property. On the other hand, butylated hydroxytoluene which is a potent antioxidant strongly inhibited the formation of mammary tumor induced by dimethylbenranthracene. Also, it was observed that this antioxidant inhibited cancer induction in rats by N-2-fluo-renylacetamide. The purpose of this experiment was to investigate the effect of vitamin A derivatives such as retinoic acid and retinoid on drug-metabolizing enzyme and to determine whether riboflavin tetrabutylate or vitamin E could prevent of modify any changes induced by vitamin A delivatives in the rats. The results obtained were as followings. 1) Body weight was significantly reduced by retinoic acid, but not by retinoid. 2) Retinoic acid markedly increased liver weight while retincid showed no effect on liver weight. Treatment of riboflavin tetrabutylate did not affect retinoic acid-induced change in both body weight and liver weight. 3) Both retinoic acid and retinoid remarkably decreased the activity of aminopyrine demethylase. Pretreatment of riboflavin tetrabutylate, however, prevented inhibitory effect of retinoic acid on the enzyme activity. 4) No significant effect of vitamin E on aminopyrine demethylase was observed in both groups treated with retinoic acid and retinoid.

• Nutrition Research and Practice
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• 제8권3호
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• pp.257-266
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• 2014

BACKGROUND/OBJECTIVE: Licorice has been shown to possess cancer chemopreventive effects. However, glycyrrhizin, a major component in licorice, was found to interfere with steroid metabolism and cause edema and hypertension. The roasting process of licorice modifies the chemical composition and converts glycyrrhizin to glycyrrhetinic acid. The purpose of this study was to examine the anti-carcinogenic effects of the ethanol extract of roasted licorice (EERL) and to identify the active compound in EERL. MATERIALS/METHODS: Ethanol and aqueous extracts of roasted and un-roasted licorice were prepared. The active fraction was separated from the methylene chloride (MC)-soluble fraction of EERL and the structure of the purified compound was determined by nuclear magnetic resonance spectroscopy. The anti-carcinogenic effects of licorice extracts and licochalcone A was evaluated using a MTT assay, Western blot, flow cytometry, and two-stage skin carcinogenesis model. RESULTS: EERL was determined to be more potent and efficacious than the ethanol extract of un-roasted licorice in inhibiting the growth of DU145 and MLL prostate cancer cells, as well as HT-29 colon cancer cells. The aqueous extracts of un-roasted and roasted licorice showed minimal effects on cell growth. EERL potently inhibited growth of MCF-7 and MDA-MB-231 breast, B16-F10 melanoma, and A375 and A2058 skin cancer cells, whereas EERL slightly stimulated the growth of normal IEC-6 intestinal epithelial cells and CCD118SK fibroblasts. The MC-soluble fraction was more efficacious than EERL in inhibiting DU145 cell growth. Licochalcone A was isolated from the MC fraction and identified as the active compound of EERL. Both EERL and licochalcone A induced apoptosis of DU145 cells. EERL potently inhibited chemically-induced skin papilloma formation in mice. CONCLUSIONS: Non-polar compounds in EERL exert potent anti-carcinogenic effects, and that roasted rather than un-roasted licorice should be favored as a cancer preventive agent, whether being used as an additive to food or medicine preparations.

• Environmental Mutagens and Carcinogens
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• 제16권1호
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• pp.1-5
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• 1996

Fumonisin B$_1$ is hepatotoxic in all species, but liver carcinogenic and nephrotoxic in rat. Our objective was to investigate the effects of multiple iv dose of FB$_1$. Male Sprague-Dawley rats were injected intravenously (iv) with FB$_1$ at 1 mg/kg singly (T1), or daily for 2 (T2) or 3 (T3). T1 rats did not show any cytotoxicity in both liver and kidney. However, the most dramatic change occurred in this group was mitotic figures in liver, which increased 5.5-fold to that of control. Hepatotoxic effects were shown in T3, based on histopathology and serum chemistry. A few scattered single cell deaths occurred primarily in the centrilobular area of the liver in T2. Similar but more lesions in liver and a small number of degenerating cells with hypereosinophilic cytoplasm in outer stripe of medulla of kideny were found in T3 rats. Serum chemical profiles included liver enzymes increased, in which cholesterol was very sensitive. This study suggests that multiple exposure of low dose FB$_1$ cause cytotoxic in the liver earlier time point than kideny. FB$_1$$ also stimulates mitosis in liver that may be associated with carcinogenesis.

• Journal of Gastric Cancer
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• 제18권2호
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• pp.134-141
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• 2018

Purpose: Postoperative pancreatic fistula is a serious and fatal complication of gastrectomy for gastric cancer. Blunt trauma to the parenchyma of the pancreas can result from an assistant's forceps compressing and retracting the pancreas, which in turn may result in pancreatic juice leakage. However, no published studies have focused on blunt trauma to the pancreas during laparoscopic surgery. Our aim was to investigate the relationship between compression of the pancreas and pancreatic juice leakage in a swine model. Materials and Methods: Three female pigs were used in this study. The pancreas was gently compressed dorsally for 15 minutes laparoscopically with gauze grasped with forceps. Pancreatic juice leakage was visualized by fluorescence imaging after topical administration of chymotrypsin-activatable fluorophore in real time. Amylase concentrations in ascites collected at specified times was measured. In addition, pancreatic tissue was fixed with formalin, and the histology of the compressed sites was evaluated. Results: Fluorescence imaging enabled visualization of pancreatic juice leaking into ascites around the pancreas. Median concentrations of pancreatic amylase in ascites increased from 46 U/L preoperatively to 12,509 U/L 4 hours after compression. Histological examination of tissues obtained 4 hours after compression revealed necrotic pancreatic acinar cells extending from the surface to deep within the pancreas and infiltration of inflammatory cells. Conclusions: Pancreatic compression by the assistant's forceps can contribute to pancreatic juice leakage. These findings will help to improve the procedure for lymph node dissection around the pancreas during laparoscopic gastrectomy.