• Molecular & Cellular Toxicology
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• 제3권2호
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• pp.127-131
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• 2007

Chronic treatment with olanzapine (OLZ), an atypical antipsychotic drug, is associated with the adverse effects of weight gain, hyperglycemia and/or hypertriglyceridemia. Green tea or epigallocatechin gallate (EGCG), one of the most abundant green tea polyphenols, significantly reduces or prevents an increase in glucose levels, lipid markers and/or body weight. We hypothesized that combined treatment with OLZ and green tea extract (GTE) or EGCG may prevent body weight gain and increase of the lipid markers. ICR male mice weighing an average of 30.51 g (n=32) at the beginning of the experiment were used. OLZ, OLZ+GTE and OLZ+EGCG were administered for 27 d in the drinking water, and then the levels of fasting glucose, nitric oxide (NO), and a typical lipid marker triglyceride (TG) were determined in plasma. The body weight and food intake were also compared. The chronic treatment of OLZ increased the average body weight compared with that of controls. In the presence of GTE or EGCG, the OLZ-induced increase in body weight was significantly prevented. Furthermore, in the OLZ group, the plasma levels of glucose, NO and TG were significantly increased, whereas GTE or EGCG prevented these increases. These results implicate that OLZ may induce systematic inflammatory reaction, and suggest that GTE or EGCG can protect against OLZinduced weight gain, hyperglycemia and hypertriglyceridemia.

• Molecular & Cellular Toxicology
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• 제4권4호
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• pp.338-347
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• 2008

Yeast RAD2, a yeast homolog of human XPG gene, is an essential element of nucleotide excision repair (NER), and its deletion confers UV sensitivity and NER deficiency. 6-Azauracil (6AU) sensitivity of certain rad2 mutants revealed that RAD2 has transcription elongation function. However, the fundamental mechanism by which the rad2 mutations confer 6AU sensitivity was not clearly elucidated yet. Using an insertional mutagenesis, PUF4 gene encoding a yeast pumilio protein was identified as a deletion suppressor of rad2${\Delta}$ 6AU sensitivity. Microarray analysis followed by confirmatory RT-qPCR disclosed that RAD2 and PUF4 regulated expression of HPT1 and URA3. Overexpression of HPT1 and URA3 rescued the 6AU sensitivity of rad2${\Delta}$ and puf4${\Delta}$ mutants. These results indicate that 6AU sensitivity of rad2 mutants is in part ascribed to impaired expression regulation of genes in the nucleotide metabolism. Based on the results, the possible connection between impaired transcription elongation function of RAD2/XPG and Cockayne syndrome via PUF4 is discussed.

• Molecular & Cellular Toxicology
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• 제4권4호
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• pp.360-365
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• 2008

In the last several years, studies on the association of oxidative stress damage with exposure in the work place have been conducted. Xenobiotics create an imbalance of the homeostasis between oxidant molecules and antioxidant defense. By monitoring oxidative stress biomarkers, information was obtained on damages induced by oxidative stress and the toxicity of xenobiotics. In the present study, a Job Exposure Matrix (JEM) was constructed using the data from the Working Environment Measurement (WEM) of painters in the shipyard industry from the past 3 years to assess the exposure status. Additionally, by measuring the concentration of urinary malondialdehyde (MDA), the effect of lipid peroxidation was examined. The subjects consisted of 68 workers who were exposed to mixed organic solvents in the painting process and 25 non-exposure controls. The exposure indices of the exposure groups were significantly different (sprayer: 0.83, touchup: 0.54, assistant: 0.13, P<0.05). The urinary MDA concentration of the exposure group was 48.60${\pm}$ 39.23 ${\mu}mol$/mol creatinine, which was significantly higher than 18.03${\pm}$16.33 ${\mu}mol$/mol creatinine of the control group (P<0.05). From the multiple regression analysis of urinary MDA, the regression coefficient for exposure grade was statistically significant. In future studies, evaluation of the antioxidant levels of subjects should be performed simultaneously with quantitative exposure measurements.

• Molecular & Cellular Toxicology
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• 제4권4호
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• pp.307-310
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• 2008

AAD16034 is an alginate lyase from Pseudoalteromonas sp. IAM14594. A very close homologue with known 3D structure exists (marine bacterium Pseudoalteromonas sp. strain no. 272). A three-dimensional structure of AAD16034 was generated based on this template (PDB code: 1J1T) by comparative modeling. The modeled enzyme exhibited a jelly-roll like structure very similar to its template structure. Both enzymes possess the characteristic alginate sequence YFKhG+Y-Q. Since AAD16034 displays enzymatic activity for poly-M alginate, docking of a tri-mannuronate into the modeled structure was performed. Two separate and adjacent binding sites were found. The ligand was accommodated inside each binding site. By considering both binding sites, a plausible binding pose for the poly-M alginate polymer could be deduced. From the modeled docking pose (i.e., the most important factor that attracts alginate polymer into this lyase) the most likely interaction was electrostatic. In accordance with a previous report, the hydroxyl group of Y345 was positioned close to the ${\alpha}$-hydrogen of ${\beta}$-mannuronate, which was suitable to initiate a ${\beta}$-elimination reaction. K347 was also very near to the carboxylatemoiety of the ligand, which might stabilize the dianion intermediate during the ${\beta}$-elimination reaction. This implies that the characteristic alginate sequence is absolutely crucial for the catalysis. These results may be exploited in the design of novel enzymes with desired properties.

• Molecular & Cellular Toxicology
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• 제4권4호
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• pp.331-337
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• 2008

This study was conducted to quantitatively evaluate the recovery effects of herbal medicines on acetaminophen-induced hepatotoxicity. In the present study, the recovery effects of 251 herbal medicines on THLE-2 cells that had been damaged by acetaminophen were evaluated using an MTS assay. THLE-2 cells were cultured in 96-well plates and then pretreated with or without 60 ${\mu}M$ acetaminophen (${IC}_{50}$ value: 35.84) for 1 hr. Next, different herbal medicines were added to the wells, after which the cells were reincubated at $37^{\circ}C$ for 24 hr. After first round of screening, the candidate herbal medicines were selected based on a recovery rate of greater than 40% and their efficacy were then determined by dose response kinetic analysis. Among these extracts, 8 herbal medicines (Terminalia chebula, Pueraria lobata, Acronychia laurifolia, Lopatherum gracile, Oroxylum indicum, Cynanchum atratum, Senecio scandens, and Sophora flavescens) had a strong recovery effect on acetaminophen-induced damage in THLE-2 cells. Dose response non-linear regression analysis demonstrated that Senecio scandens showed the best recovery rate (98%), and that its ${EC}_{50}$ was 19.54 ng/mL. Additional studies of these herbal medicines should be conducted to determine if they possess novel therapeutic agents for the prevention or treatment of liver disorders.

• Molecular & Cellular Toxicology
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• 제4권4호
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• pp.355-359
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• 2008

This study aimed to determine the relationship between the C825T polymorphism in the G-protein ${\beta}$3-subunit (GNB3) gene and the response to citalopram in a Korean population with major depressive disorder (MDD). Citalopram was administered for 8 weeks to the 84 MDD patients who completed this study. All subjects were examined using the Structured Clinical Interview for DSM-IV, and the severity of depression was assessed using the 21-item Hamilton Depression Rating (HAMD-21) scale. A main effect of an interaction of genotype with time on the decrease in the HAMD-21 score during the 8-week study period was not found. ANOVA revealed no significant effects of the GNB3 C825T polymorphism on the decrease in the HAMD-21 score at each time period. Although the C825T polymorphism of the GNB3 gene may affect the pathogenesis of MDD, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to citalopram in Korean patients with MDD.

• Molecular & Cellular Toxicology
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• 제2권1호
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• pp.67-73
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• 2006

In previous studies, it has been discovered that cancer cells not only overexpress regulatory subunit I (Rl)/protein kinase type I (PKA-I) but also secrete outside the cell an extracellular form of PKA (ECPKA) and that the ECPKA secretion detected in patients' serum is obviously greater than that found in non-cancer patients or healthy subjects. We now found that ECPKA elicits the formation of serum autoantibodies that can serve as a cancer diagnostic and prognostic marker. To measure the presence of anti-ECPKA autoantibody in the human sera, basic methodology for ECPKA assay was established an enzyme-linked immunosorbent assay (ELISA). We obtained serum samples from 199 patients with different types of cancer, and also obtained 31 serum samples to compare with ECPKA concentrations from non-cancer patients and 119 normal volunteers. Compared with normal or non-cancer patient sera, we found that the frequency of anti-ECPKA autoantibody was significantly higher in cancer patients (88%) than in those without cancer (17%). Furthermore the presence of anti-ECPKA autoantibodies in the serum of cancer patients was highly correlated with the site of metastasis. The immunoassay developed for anti-ECPKA antibodies is highly sensitive and specific. Therefore, this discovery of an autoantibody-based cancer diagnostic may have serious clinical application and may become an important advance over current technology.

• Molecular & Cellular Toxicology
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• 제2권1호
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• pp.35-47
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• 2006

2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD) are well known as the most toxic environmental compound in these days. Many researches are reported that dioxin produces multiple toxic effects, such as endocrine toxicity, reproductive toxicity, immunotoxicity and cancer. In this study, we carried to discover novel evidence for previously unknown gene expression patterns in human exposed to dioxin by using radioactive cDNA microarray. 548 workers who were divided into experimental and control groups according to their urinary Naphthol levels were enrolled in our study. Blood mRNA in human was isolated, and the gene expression profiles were analyzed by cDNA microarray. Gene expression analysis identified 52 genes which exhibited a significant change. In our study, most notably, genes involved in cell cycle, cell proliferation, signal transduction and apoptosis in human exposed to dioxin, such as CCND3, TSHR, and EFRN5, were up-regulated. In the current study, we observed gene expression of people that are exposed to dioxin using radioactive cDNA microarray. Through these results, we suggest when objects are exposed to toxic compounds, such as dioxin, the radioactive cDNA microarray may be using in sensitively detecting of cancerous change.

• Molecular & Cellular Toxicology
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• 제2권1호
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• pp.21-28
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• 2006

Gadolinium chloride ($GdCl_{3}$) was known to block Kupffer cells and generally its toxicity study based on blocking these cells. Therefore, $GdCl_{3}$ frequently used to study toxic mechanisms of hepatotoxicants inducing injury through Kupffer cells. We also tried to investigate the effect of $GdCl_{3}\;on\;CCl_{4}$ toxicity, typical hepatotoxicants. Administration of $GdCl_{3}$ to mice significantly suppressed AST (asparatate amino transferase), ALT (alanine amino transferase) levels which were increased by $CCl_{4}$ treatment. However, $GdCl_{3}$ didn't inhibit the phagocytotic activity of Kupffer cells. Malondialdehyde (MDA) is a good indicator of the degree of lipid peroxidation. In this study, MDA increased by $GdCl_{3}$ administration not by $CCl_{4}$. To understand the toxicity of $GdCl_{3}$, we analyzed global gene expression profile of mice liver after acute $GdCl_{3}$ injection. Four hundred fifty two genes were differentially expressed with more than 2-fold in at least one time point among 3 hr, 6 hr, and 24 hr. Several genes involved in fibrogenesis regulation. Several types of pro-collagens (Col1a2, Col5a2, Col6a3, and Col13a1) and tissue inhibitor of metal-loproteinase1 (TIMP1) were up regulated during all the time points. Genes related to growth factors, chemokines, and oxidative stress, which were known to control fibrogenesis, were significantly changed. In addition, $GdCl_{3}$ induced abnormal regulation between lipid synthesis and degradation related genes. These data will provide the information about influence of $GdCl_{3}$ to hepatotoxicity.

• Molecular & Cellular Toxicology
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• 제1권3호
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• pp.172-178
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• 2005

[ $21{\alpha}$ ]- and ${\beta}$-Methylmelianodiol were isolated as the inhibitor of IL-5 bioactivity from Poncirus tripoliata. To develope as an anti-septic drug, the genotoxicity of $21{\alpha}\;-and\;{\beta}-methylmelianodiol$ was subjected to high throughput toxicity screening (HTTS) because they revealed strong IL-5 inhibitory activity and limitation of quantity. Mouse lymphoma thymidine kinase ($tk^{+/-}$) gene assay (MOLY), single cell gel electrophoresis (Comet) assay in mammalian cells and Ames reverse mutation assay in bacterial system were used as simplified, inexpensive, short-term in vitro screening tests in our laboratory. These compounds are not mutagenic in S. typhimurium TA98 and TA100 strains both in the presence and absence of metabolic activation. Before performing the comet assay, $IC_{20}$ of $21{\alpha}-methylmelianodiol$ was determined the concentration of $25.51\;{\mu}g/mL\;and\;21.99\;{\mu}g/mL$ with and without S-9, respectively. Also $21{\beta}-methylmelianodiol$ was determined the concentration of $24.15\;{\mu}g/mL\;and\;\;22.46\;{\mu}g/mL$ with and without S-9, respectively. In the comet assay, DNA damage was not observed both $21{\alpha}-methylmelianodiol\;and\;21{\beta}-methylmelianodiol$ in mouse lymphoma cell line. Also, the mutant frequencies in the treated cultures were similar to the vehicle controls, and none of $21{\alpha}\;-and\;{\beta}-methylmelianodiol$ with and without S-9 doses induced a mutant frequency over. twice the background. It is suggests that $21{\alpha}\;-and\;{\beta}-methylmelianodiol$ are non-mutagenic in MOLY assay. The results of this battery of assays indicate that $21{\alpha}\;-and\;{\beta}-methylmelianodiol$ have no genotoxic potential in bacterial or mammalian cell systems. Therefore, we suggest that $21{\alpha}\;-and\;{\beta}-methylmelianodiol$, as the optimal candidates with both no genotoxic potential and IL-5 inhibitory effects must be chosen.