• Toxicological Research
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• v.26 no.3
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• pp.223-232
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• 2010

Artesunate, a semi-synthetic derivative of artemisinin, is used primarily as a treatment for malaria. Its effects on the central nervous system, general behavior, and cardiovascular, respiratory, and other organ systems were studied using mice, rats, guinea pigs, and dogs. Artesunate was administered orally to mice at doses of 125, 250, and 500 mg/kg and to rats and guinea pigs at 100, 200, and 400 mg/kg. In dogs, test drugs were administered orally in gelatin capsules at doses of 50, 100, and 150 mg/kg. Artesunate induced insignificant changes in general pharmacological studies, including general behavior, motor coordination, body temperature, analgesia, convulsion modulation, blood pressure, heart rate (HR), and electrocardiogram (ECG) in dogs in vivo; respiration in guinea pigs; and gut motility or direct effects on isolated guinea pig ileum, contractile responses, and renal function. On the other hand, artesunate decreased the HR and coronary flow rate (CFR) in the rat in vitro; however, the extent of the changes was small and they were not confirmed in in vivo studies in the dog. Artesunate increased hexobarbital-induced sleeping time in a dose-related manner. Artesunate induced dose-related decreases in the volume of gastric secretions and the total acidity of gastric contents, and induced increases in pH at a dose of 400 mg/kg. However, all of these changes were observed at doses much greater than clinical therapeutic doses (2.4 mg/kg in humans, when used as an anti-malarial). Thus, it can be concluded that artesunate is safe at clinical therapeutic doses.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6575-6580
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• 2014

This study aimed to evaluate the antimutagenic and anticarcinogenic activity of turmeric essential oil as well as to establish biochemical mechanisms of action. Antimutagenicity testing was accomplished using strains and known mutagens with and without microsomal activation. Anticarcinogenic activity was assessed by topical application of 7, 12 - dimethylbenz[a]anthracene (DMBA) as initiator and 1% croton oil as promoter for the induction of skin papillomas in mice. Inhibition of p450 enzymes by TEO was studied using various resorufins and aminopyrene as substrate. Turmeric essential oil (TEO) showed significant antimutagenic activity (p<0.001) against direct acting mutagens such as sodium azide ($NaN_3$), 4-nitro-O-phenylenediamine (NPD) and N-methyl-N-nitro N'nitrosoguanine (MNNG). TEO was found to have significant antimutagenic effect (>90%) against mutagen needing metabolic activation such as 2-acetamidoflourene (2-AAF). The study also revealed that TEO significantly inhibited (p<0.001) the mutagenicity induced by tobacco extract to Salmonella TA 102 strain. DMBA and croton oil induced papilloma development in mice was found to be delayed and prevented significantly by TEO application. Moreover TEO significantly (P<0.001) inhibited isoforms of cytochrome p450 (CYP1A1, CYP1A2, CYP2B1/2, CYP2A, CYP2B and CYP3A) enzymes in vitro, which are involved in the activation of carcinogens. Results indicated that TEO is antimutagenic and anticarcinogenic and inhibition of enzymes (p450) involved in the activation of carcinogen is one of its mechanisms of action.

• Environmental Mutagens and Carcinogens
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• v.15 no.2
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• pp.131-139
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• 1995

Air suspedned particulates are the most serious factor among air pollutants in Seoul and their extracts have been revealed to be pulmonary carcinogenes. Air particulates were collected at a site representative of the high traffic area of Seoul from December 1993 to May 1994. Polycyclic aromatic hydrocarbons (PAHs) and nitroarenes in organic extracts of air particulates were determined by gas chromatography and mutagenicity of particle extracts was evaluated by the pre-incubation procedure with Salmonella typhirnurium TA98 and TA 98NR. The average concentration of total suspended particulates and inhalable (less than 10 $\mu$m) particulates were 169.63 $\mu g/m^3$, 141.92 $\mu g/m^3$, respectively. The relative contribution of organic matters was highest in neutral fraction and was lowest in basic fraction. Among identified 20 PAHs, the level of PAHs with 4-benzen ring i.e., pyrene, benzo(a)anthracene and chrysene were much higher than the PAHs with higher ring numbers. The mutagenicity of air particulates was much higher in the presence of rat liver microsomai fraction (S9 mixture) than that observed in its absence, which indicates that air particulates contained both direct and indirect mutagens. Nitroarenes in this study were not almost detected but mutagenicity of their fraction was higher. These results are represent to research for the identification of nitroarenes in the forward study.

• Toxicological Research
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• v.20 no.3
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• pp.241-250
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• 2004

We previously found that bisphenol A (BPA) caused neurotoxic behavioral alteration. Since disturbance of calcium homeostasis is an implicated contributor in the neurotoxic mechanism of environmental toxicants, we investigated whether BPA alters calcium homeostasis. Unlike other neurotoxic agents which cause increase of intracellular calcium level, BPA decreased $[Ca^{2+}]_i$ dose-dependently in PC12 cells and cortical neuronal cells regardless of the calcium existence in buffer. BPA at greater concentrations than 100 $\mu\textrm{M}$ reduced cell viability significantly in both types of cells. BPA also suppressed L-glutamate (L-type channel activator, 30 mM) and trifluoperazine (calmodulin antagonist, 30 $\mu\textrm{M}$)-induced increase of $[Ca^{2+}]_i$. BPA further lowered caffeine (RYR activator, 100 $\mu\textrm{M}$)-decreased $[Ca^{2+}]_i$, but did not alter dantrolene (RYR inhibitor, 100 $\mu\textrm{M}$), heparin (IP3 inhibitor, 200 units/ml) and xestospongin C (IP3 inhibitor, 5 $\mu\textrm{M}$)-decreased $[Ca^{2+}]_i$. Cell viability was not directly related to intracellular calcium change by bisphenol A that alternation of intracellular calcium may not be a direct causal factor of BPA-induced neuronal cell death.

• Molecular & Cellular Toxicology
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• v.1 no.2
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• pp.99-105
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• 2005

Perchloroethylene (tetrachloroethylene, PCE), a dry cleaning and degreasing solvent, can enter ground-water through accidental leak or spills. PCE can be degraded to trichloroethylene (TCE), 1, 1-dichloroethylene (DCE) and vinyl chloride (VC) as potential bio-product. These compounds have been reported that they can cause clinical diseases and cytotoxicity. However, only a little genotoxic information of these compounds has been known. In this study, we investigated DNA single strand breaks of PCE, TCE, DCE and VC by single cell gel electrophoresis assay, (comet assay) which is a sensitive, reliable and rapid method for DNA single strand breaks with mouse lymphoma L5178Y cells. From these results, $37.5\;{\mu}g/ml$ of PCE, $189\;{\mu}g/ml$ of TCE and $56.4\;{\mu}g/ml$ of DCE were revealed significant DNA damages in the absence of S-9 metabolic activation system meaning direct-acting mutagen. And in the presence of S-9 metabolic activation system, $41.5\;{\mu}g/ml$ of PCE, $328.7\;{\mu}g/ml$ of TCE and $949\;{\mu}g/ml$ of DCE were induced significant DNA damage. In the case of VC, it was revealed a significant DNA damage in the presence of S-9 metabolic activation system. Therefore, we suggest that chloroethylene compounds (PCE, TCE, DCE and VC) may be induced the DNA damage in a mammalian cell.

• Toxicological Research
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• v.22 no.4
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• pp.339-348
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• 2006

Misaengtang (MST), a formula of Korean herbal medicines, has been used as a weight-controlling recipe. We have investigated two experiment of body weight regulation by MST In rats. i) The anti-obesity effect of MTS on a high fat diet-induced obesity, male Sprague-Dawley rats were fed with a high-fat diet containing 30% in the absence or presence of MST (0.3, 1 or 3%) or a reference orlistat (0.05%) for 6 weeks. ii) weight-decrease effect of MST on normal diet, same animal were fed with a normal diet in the absence or presence of MST (3%) for 6 weeks. And the body weights, daily feed and water consumptions, organ weights, fat weights serum biochemistry were measured. In both experiments, MST and orlistat did not affect the body weight gain. But orlistat significantly increased the feed and water consumptions, leading to low-feed efficiency, and orlistat markedly reduced abdominal, paratesticular and perirenal fat weights, although increased the kidney weights. In MST, low dose (0.3%) of MST decreased the perirenal fat and increased the kidney weights in rats fed HFD, and MST 3% decreased the abdominal fat weights in rats fed normal diet. In addition, Orlistat caused changes in parameters of hepatotoxicity (AST and glucose), nephrotoxicity (BUN and B/C ratio) and lipid metabolism (HDL and triglycerides). In comparison, MST decreased AST, ALP and ALT, the hepatotoxicity markers, and somewhat improved the hepatic fatty degeneration. Taken together, it is suggested that MST does not exert anti-obesity activity as well as remarkably direct effects, but MST may be potentially benefit for dietary cure and exercise-cure of obesity.

• Toxicological Research
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• v.22 no.4
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• pp.403-409
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• 2006

To localize the connection between intergeniculate nucleus and suprachisasmatic nucleus through geniculohypothalamic tract in postnatal mongolian gerbil, we injected lacZ inserted PRV-Bartha strain into suprachiasrnatic nucleus and tried to immunostain against it with Rb134 and mouse $anti-{\beta}-galactosidase$. The numbers of immunoreactive neurons in intergeniculate leaflet were $8{\pm}3.2$ in P1 Period, $10{\pm}4.1$ in P3 Period and $13{\pm}6.2$ in P7 Period, and was statistically significant (p<0.05) and had tendency to increase with time consuming. The results showed that intergeniculate leaflet had projected some axons into suprachiasrnatic nucleus through geniculohyptothalamic tract in postnatal mongolian gerbil. But we could not exclude the possibility of direct projections from dorsal and ventral geniculate nuclei into suprachisamatic nucleus completely.

• Toxicological Research
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• v.33 no.3
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• pp.211-218
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• 2017

Cytochrome P450 1B1 (CYP1B1) acts as a hydroxylase for estrogen and activates potential carcinogens. Moreover, its expression in tumor tissues is much higher than that in normal tissues. Despite this association between CYP1B1 and cancer, the detailed molecular mechanism of CYP1B1 on cancer progression in HeLa cells remains unknown. Previous reports indicated that the mRNA expression level of Herc5, an E3 ligase for ISGylation, is promoted by CYP1B1 suppression using specific small interfering RNA, and that ISGylation may be involved in ubiquitination related to ${\beta}-catenin$ degradation. With this background, we investigated the relationships among CYP1B1, Herc5, and ${\beta}-catenin$. RT-PCR and western blot analyses showed that CYP1B1 overexpression induced and CYP1B1 inhibition reduced, respectively, the expression of $Wnt/{\beta}-catenin$ signaling target genes including ${\beta}-catenin$ and cyclin D1. Moreover, HeLa cells were treated with the CYP1B1 inducer $7,12-dimethylbenz[{\alpha}]anthracene$ (DMBA) or the CYP1B1 specific inhibitor, tetramethoxystilbene (TMS) and consequently DMBA increased and TMS decreased ${\beta}-catenin$ and cyclin D1 expression, respectively. To determine the correlation between CYP1B1 expression and ISGylation, the expression of ISG15, a ubiquitin-like protein, was detected following CYP1B1 regulation, which revealed that CYP1B1 may inhibit ISGylation through suppression of ISG15 expression. In addition, the mRNA and protein expression levels of Herc5 were strongly suppressed by CYP1B1. Finally, an immunoprecipitation assay revealed a direct physical interaction between Herc5 and ${\beta}-catenin$ in HeLa cells. In conclusion, these data suggest that CYP1B1 may activate $Wnt/{\beta}-catenin$ signaling through stabilization of ${\beta}-catenin$ protein from Herc5-mediated ISGylation for proteosomal degradation.

• Toxicological Research
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• v.31 no.2
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• pp.97-104
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• 2015

The skin exposure to solar irradiation and photoreactive xenobiotics may produce abnormal skin reaction, phototoxicity. Phototoxicity is an acute light-induced response, which occurs when photoreacive chemicals are activated by solar lights and transformed into products cytotoxic against the skin cells. Multifarious symptoms of phototoxicity are identified, skin irritation, erythema, pruritis, and edema that are similar to those of the exaggerated sunburn. Diverse organic chemicals, especially drugs, are known to induce phototoxicity, which is probably from the common possession of UV-absorbing benzene or heterocyclic rings in their molecular structures. Both UVB (290~320 nm) and UVA (320~400 nm) are responsible for the manifestation of phototoxicity. Absorption of photons and absorbed energy (hv) by photoactive chemicals results in molecular changes or generates reactive oxygen species and depending on the way how endogenous molecules are affected by phototoxicants, mechanisms of phototoxcity is categorized into two modes of action: Direct when unstable species from excited state directly react with the endogenous molecules, and indirect when endogeneous molecules react with secondary photoproducts. In order to identify phototoxic potential of a chemical, various test methods have been introduced. Focus is given to animal alternative test methods, i.e., in vitro, and in chemico assays as well as in vivo. 3T3 neutral red uptake assay, erythrocyte photohemolysis test, and phototoxicity test using human 3-dimensional (3D) epidermis model are examples of in vitro assays. In chemico methods evaluate the generation of reactive oxygen species or DNA strand break activity employing plasmid for chemicals, or drugs with phototoxic potential.

• Food Science and Preservation
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• v.9 no.1
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• pp.92-96
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• 2002

The nitrite-scavenging and antimutagenic effects of various solvent extracts from different parts of the loquat. were investigated to develope as source of functional food. The nitrite-scavenging and antimutagenic effects of fractions obtained from methanol extract were most highest in ethyl acetate fraction. Ethyl acetate fraction showed better results in the nitrite scavenging activity of 80% in leaf, 81% in seedless fruit, 73% in peel and 63% in seed. The antimutagenic effect showed strong ethyl acetate fraction of 53.1%, 48.3% in leaf and seedless fruit. The antimutagenic effect increased with increasing concentration of ethyl acetate fraction against mutagenicity induced by direct mutagen of IQ in Salmonella typhimurium TA 100. Addition of 2.5 mg and 5 mg of ethyl acetate fraction showed inhibitory effect of 65.5%, 71.2% in leaf and 63.4%, 69.2% in seedless fruit, respectively.