• Journal of Periodontal and Implant Science
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• v.25 no.3
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• pp.470-477
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• 1995

Flavonoids from Scutellariae Radix possessed a dual function both as an anti-inflammatory agent and an enhancer of cellular activity in gingival fibroblast. The purpose of this study was to evaluate on the toxicity of ethanolic extract from the root of Scutellariae Radix Georgi and its flavonoids, Wogonin, Baicalein, and Baicalin were isolated and purified by the following method. The crude drug was extracted with ethyl acetate and the residue was dissolved in ethyl alcohol. The ethyl alcohol soluble fraction was separated, concentrated, and then chromatographed on a silica gel column. The acute oral LD 50 in rats was determined for EtOH ex. of Scutellariae Radix and three compounds were evaluated with a single oral gavage at three graded dosage levels. The acute intravenous LD 50 was determined with a single intravenous injection via the jugular vein at three graded dosage levels. Groups of 5 male and 5 female rats, 6 week of age at the start of the study, were fed diets containing 3 graded dosage levels for 14 days. Groups of 5 male and 5 female hamster received O.5ml of the test article at once in a day for 5 days to the buccal cheek pouch for two minutes each. The acute oral LD50 for EtOH ex. of Scutellariae Radix is 1430mg/kg, and for Wogonin 1320mg/kg, for Baicalein 1250mg/kg, for Baicalin 1330mg/kg. The acute intravenous toxicity of EtOH ex. of Scutellariae Radix and its extracts was found to be 27mg/kg body weight No toxic effects were observed in rats fed up to 200mg/kg of EtOH ex. of Scutellariae Radix, Wogonin, Baicalein and Baicalin in the diet for 14 days. The acute Mucouse Membrane LD 50 in hamsters was found to be greater than 100mg/kg. These results suggested that EtOH ex. of Scutellariae Radix and its flavonoids are safe for oral care products using limited amount of extract.

• BMB Reports
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• v.40 no.6
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• pp.1039-1049
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• 2007

Overdoses of acetaminophen cause hepato-renal oxidative stress. The present study was undertaken to investigate the protective effect of a 43 kDa protein isolated from the herb Cajanus indicus, against acetaminophen-induced hepatic and renal toxicity. Male albino mice were treated with the protein for 4 days (intraperitoneally, 2 mg/kg body wt) prior or post to oral administration of acetaminophen (300 mg/kg body wt) for 2 days. Levels of different marker enzymes (namely, glutamate pyruvate transaminase and alkaline phosphatase), creatinine and blood urea nitrogen were measured in the experimental sera. Intracellular reactive oxygen species production and total antioxidant activity were also determined from acetaminophen and protein treated hepatocytes. Indices of different antioxidant enzymes (namely, superoxide dismutase, catalase, glutathione-S-transferase) as well as lipid peroxidation end-products and glutathione were determined in both liver and kidney homogenates. In addition, Cytochrome P450 activity was also measured from liver microsomes. Finally, histopathological studies were performed from liver sections of control, acetaminophen-treated and protein pre- and post-treated (along with acetaminophen) mice. Administration of acetaminophen increased all the serum markers and creatinine levels in mice sera along with the enhancement of hepatic and renal lipid peroxidation. Besides, application of acetaminophen to hepatocytes increased reactive oxygen species production and reduced the total antioxidant activity of the treated hepatocytes. It also reduced the levels of antioxidant enzymes and cellular reserves of glutathione in liver and kidney. In addition, acetaminophen enhanced the cytochrome P450 activity of liver microsomes. Treatment with the protein significantly reversed these changes to almost normal. Apart from these, histopathological changes also revealed the protective nature of the protein against acetaminophen induced necrotic damage of the liver tissues. Results suggest that the protein protects hepatic and renal tissues against oxidative damages and could be used as an effective protector against acetaminophen induced hepato-nephrotoxicity.

• Toxicological Research
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• v.32 no.4
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• pp.289-300
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• 2016

Non-genotoxic carcinogens are substances that induce tumorigenesis by non-mutagenic mechanisms and long term rodent bioassays are required to identify them. Recent studies have shown that transcription profiling can be applied to develop early identifiers for long term phenotypes. In this study, we used rat liver expression profiles from the NTP (National Toxicology Program, Research Triangle Park, USA) DrugMatrix Database to construct a gene classifier that can distinguish between non-genotoxic carcinogens and other chemicals. The model was based on short term exposure assays (3 days) and the training was limited to oxidative stressors, peroxisome proliferators and hormone modulators. Validation of the predictor was performed on independent toxicogenomic data (TG-GATEs, Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System, Osaka, Japan). To build our model we performed Random Forests together with a recursive elimination algorithm (VarSelRF). Gene set enrichment analysis was employed for functional interpretation. A total of 770 microarrays comprising 96 different compounds were analyzed and a predictor of 54 genes was built. Prediction accuracy was 0.85 in the training set, 0.87 in the test set and increased with increasing concentration in the validation set: 0.6 at low dose, 0.7 at medium doses and 0.81 at high doses. Pathway analysis revealed gene prominence of cellular respiration, energy production and lipoprotein metabolism. The biggest target of toxicogenomics is accurately predict the toxicity of unknown drugs. In this analysis, we presented a classifier that can predict non-genotoxic carcinogenicity by using short term exposure assays. In this approach, dose level is critical when evaluating chemicals at early time points.

• Molecular & Cellular Toxicology
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• v.5 no.1
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• pp.75-82
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• 2009

Saengshik is an uncooked and powdered functional food composed of various edible plants, and has been consumed widely due to its health benefits and convenient uptake. Recently, superfine ground saengshik, which contains a certain extent of nanoscale particles, has been commercialized to enhance efficacy, but its safety has not been determined. This study was conducted to evaluate the food safety of superfine saengshik (SS) through general toxicity examination after oral uptake in mice compared to conventional fine saengshik (FS). The SS particle size distribution was 0.479-26.303 f.1m in diameter, with about 68.92% of particles with a diameter < $0.955{\mu}m$. From our safety evaluation, the number of white blood cells (WBCs) and biochemical values in the serum fell into the normal range, and the weight of organs showed no significant difference between FS and SS groups. Histological observation of the liver, small intestine and large intestine did not show any abnormal or pathological findings under light microscopy. Our results suggest that oral intake of SS is not harmful to mice in terms of general toxicity.

• Molecular & Cellular Toxicology
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• v.5 no.1
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• pp.58-66
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• 2009

The 2-year rodent carcinogenicity test involves long-term, repetitive dosing of animals that is both time consuming and expensive. Alternative approaches have been attempted using specific transgenic or knockout mice or toxicogenomics to predict carcinogenicity without conducting a 2-year rodent test. In addition, toxicogenomic analysis of carcinogen-treated animals could also enhance our understanding of molecular mechanisms and aid in the diagnosis of acute toxicity induced by carcinogens. Therefore, we investigated transcription profiles after administering the carcinogens 4,4-dimethylformamide (DMF) and 4-biphenylamine (ABP). BALB/c male mice were treated once with DMF (650 mg/kg i.p.) or ABP (120 mg/kg p.o.). Standard blood biochemistry and histological changes were observed. Gene expression profiles in the livers of mice treated with either vehicle or the carcinogens were analyzed using the Affymetrix $GeneChip^{(R)}$ assay. In all, 1,474 differentially expressed genes in DMF- or ABP-treated mice were identified as being either up- or down-regulated over 1.5-fold (P< 0.01), and these genes were analyzed using hierarchical clustering and Ingenuity Pathways Analysis. Of these, 107 genes were consistently regulated in both carcinogen-treated groups. Genes associated with cancer were upregulated (Por, S100a10, Tes, Ctcf, Ddx21, Eapp, Nel, and Pa2g4) or downregulated (Cbs and Gch1). Toxicological function analysis also identified genes involved in organ toxicity, including hepatotoxicity. These data may help to identify molecular markers for acute hepatotoxicity induced by carcinogens.

• Toxicological Research
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• v.23 no.4
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• pp.301-309
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• 2007

Paecilomyces tenuipes (PT), one of the Ascomycetes family, has been used for medicinal purposes due to its broad pharmacological activities. The present study was undertaken to investigate the hepatoprotective effects of PT water extracts against $CCl_4$-induced hepatotoxicity in primary cultures of adult rat hepatocytes. When the extract of PT was directly added into the culture medium at 1, 2, and 5 mg/ml, the extracts not only reduce the $CCl_4$-induced elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, and lipid peroxide, but also protect cultured hepatocytes from $CCl_4$-induced reduction of reduced glutathione, glutathione reductase, glutathione-S-transferase, glutathione peroxidase, catalase and superoxide dismutase. In addition, the effects of PT water extracts on cytochrome P450 enzymes were relatively marginal, indicating that the hepatoprotective effects of PT extract against $CCl_4$-induced toxicity might not be due to the inhibition of $CCl_4$ activation. In conclusion, the PT extracts were effective in protecting against $CCl_4$ induced hepatotoxicity in hepatocyte cultures, at least in part, by scavenging free radicals, and by modulating enzyme systems involved in cellular oxidative stress.

• Toxicological Research
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• v.23 no.4
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• pp.363-371
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• 2007

Isaria sinelairii (IS) was orally administered at doses of 0, 0.04, 0.2, and 1 g/kg/day over a 13-week period. There were no observed clinical signs or deaths related to treatment in all the groups tested. Therefore, the approximate lethal oral dose of I. sinclairii was considered to be higher than 1 g/kg in rats. Throughout the administration periods, no significant changes in diet consumption, ophthalmologic findings, organ weight, clinical pathology (hematology, clinical chemistry, coagulation, and urinalysis) or gross pathology were detected. Minor changes were found in hematological parameters for the 0.04 g/kg/day and 0.2 g/kg/day IS treated groups (triglyceride reductions of $20.1{\sim}46.6%$ and platelet increases), but all changes were within physiological range. Microscopic examination failed to identify any treatment-related histopathologic changes in the organs of the IS-treated rats other than nuclear enlargement (cellular atypia) of the tubular regions in the medulla of the kidney in the high dose group. From these results, one can conclude that the no-observed effect level (NOAEL) of I. sinclairii is less than 0.04 g/kg/day in rats.

• Journal of Environmental Health Sciences
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• v.42 no.1
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• pp.27-33
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• 2016

Objectives: Alumina nanoparticles ($Al_2O_3$, Al-NPs) are used for various purposes, including as coating agents and paint additives. Their potential toxicity has raised concern for human health. This study focuses on exploring the toxic effects on the brain and kidneys caused by Al-NPs exposure in rats. Methods: The animals were orally administered Al-NPs at 10, 50 and 100 mg/kg body weight for 28 days following OECD TG 407. To determine the targeted toxicity of Al-NPs, histopathological examination and gene expression analysis were conducted on the rats. Results: The Al-NPs treatment induced kidney tubular dilatation. In the rat cerebrums, the expression levels of 126 genes experienced two-fold or greater increases in response to Al-NPs, including other genes encoding proteins involved in cell differentiation, transcription and signal transduction. In the rat kidneys, the expression levels of 152 genes also showed two-fold or greater increases in response to Al-NPs, including other genes encoding proteins involved in apoptosis, transcription and signal transduction. Conclusion: These results suggest that exposure to Al-NPs influences cellular signal pathways of kidney and cerebrum, and it can be a toxic indicators of nanometrials.

• BMB Reports
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• v.31 no.2
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• pp.189-195
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• 1998

Methylmercury (MeHg), which is widely distributed in the environment, is well known for both its acute and chronic poisoning effects on the human health; however, the precise biochemical mechanisms by which this compound elicits its toxicity in a cellular level are still poorly understood. To examine whether MeHg-induced liver injury involves activation of Phospholipase $A_2$ ($PLA_2$), the $PLA_2$ activity of control and MeHg-administrated livers was measured. MeHg stably enhanced a liver form of cytosolic $PLA_2$ activity, which exhibited several biochemical properties similar to those of the 100 kDa $cPLA_2$, except in its elution profile of a DEAE-5PW HPLC, and it migrated as a molecular weight of 80 kDa in Western blot analysis. This blotting analysis also indicated that the MeHg-induced enhancement of the activity could be due to the increase in the amount of the enzyme protein rather than a stable modification of the enzyme such as phosphorylation. Our data also showed the higher myeloperoxidase activity in MeHg-administrated liver than in the control, suggesting that this increase in the amounts of the 80 kDa $PLA_2$ and its activity may be resulted from infiltration of neutrophils into the liver during a hepatic injury process such as MeHg-induced inflammation. Taken together, these data suggest that MeHg-induced liver injury may be mediated by activation of the 80 kDa form of liver cytosolic $PLA_2$.

• Restorative Dentistry and Endodontics
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• v.15 no.2
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• pp.1-16
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• 1990

This study was to evaluate the cytotoxic effect in vitro and the tissue response within the rat peritoneal cavity to high copper amalgam and glass ionomer-silver cement, suggested for use as a retrograde endodontic filling material. In the cytotoxicity experiment, the radioactively ($^{51}Cr$) labeled L929 mouse fibroblasts were employed to determine the relative cytotoxicity of two experimental materials. Those materials were evaluated immediately after set and after one and seven days setting. In the tissue response experiment, two experimental materials were to evaluate mean peritoneal cellular count, differential cell count and the content of silver and copper in pooled packed cells and eluate samples taken by peritoneal lavage technique, and compared with surgical control after one day. two, four and six weeks of implantation. The results were as following: 1. High copper amalgam exhibited significant cytotoxicity immediately after set but showed no sign of toxicity after one day and seven days setting materials. 2. Glass ionomer-silver cement showed no sign of toxicity immediately after set and after one day and seven days setting. 3. High copper amalgam and glass ionomer-silver cement groups produce no significant difference in the mean peritoneal cell count when compared with the surgical control group after one day, two and four weeks of implantation. Surgical control group exhibited significantly a greater cell count when compared with the High copper amalgam group after six weeks. 4. High copper amalgam group increased significantly in the percentage macrophages after four and six weeks of implantation when compared with surgical control group. 5. The trace metal analysis involved an increased silver content in the elutes and an increased copper content in the packed cells of high copper amalgam group, and an increased silver content in the packed cells and elutes of glass ionomer-silver cement group.