• Molecular & Cellular Toxicology
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• v.5 no.2
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• pp.141-146
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• 2009

Toll-like receptors (TLRs) induce innate immune responses by recognizing conserved microbial structural molecules. All TLR signaling pathways culminate in the activation of nuclear factor kappa-B (NF-$\kappa$B) leading to the induction of inflammatory gene products such as cyclooxygenase-2 (COX-2). Deregulated activation of TLRs can lead to the development of severe systemic inflammation. Divalent heavy metals, cadmium and mercury, have been used for thousands of years. While cadmium and mercury are clearly toxic to most mammalian organ systems, especially the immune system, their underlying toxic mechanism(s) remain unclear. Here, we report biochemical evidence that cadmium, but not mercury, inhibits NF-$\kappa$B activation and COX-2 expression induced by TLR2 or TLR4 agonists, while cadmium does not inhibit NF-$\kappa$B activation induced by the downstream signaling component of TLRs, MyD88. Thus, the target of cadmium to inhibit NF-$\kappa$B activation may be upstream of MyD88 including TLRs themselves, or events leading to TLR activation by agonists.

• Molecular & Cellular Toxicology
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• v.5 no.2
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• pp.165-171
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• 2009

Biomarkers indicating past exposure to radiation have not yet been entirely satisfactory. In this study, we validated several genes reported as radiation response genes, as biomarkers to detect past exposure to radiation in occupationally exposed workers, especially workers in the medical field. A total of 54 radiation workers in hospital were investigated for radiation exposure dose. Their average radiation dose of recent one year was 1.09 mSv ($\pm$1.63) with a 10.63 mSv ($\pm$12.91) cumulative dose. The results of the multiple regression analysis for the various variables indicate that the Hsc70 (P=0.0292) and ORAL (P=0.0045) may be candidate biomarkers for the recent 1 year radiation exposure in radiation workers, whereas AEN (P=0.0334) and PGAMI (P=0.0003) might be for cumulative exposure.

• Molecular & Cellular Toxicology
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• v.5 no.2
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• pp.153-159
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• 2009

In this study, we assessed the acute and subacute toxicity of Angelica gigas Nakai (A. gigas Nakai) extracts, which are comprised of decursin and decursinol angelate (D/DA) in rats. For the oral acute toxicity test, Sprague-Dawley (SD) male and female rats were gavaged with two doses of D/DA (200 and 2,000 mg/kg body weight) and then observed for any toxic symptoms for 2 weeks. The LD$_{50}$ value for the rats was greater than 2,000 mg/kg body weight for both male and female rats, which indicates that there were no toxic symptoms induced by doses of up to 2,000 mg/kg body weight. For the subacute toxicity study, rats were treated with D/DA at doses of 2 and 20 mg/kg body weight once a day for 30 days. There were no significant changes in body weight and food intake observed during the subacute toxicity study. In addition, no differences were observed between the control and treated groups when urinalysis was conducted or when hematology and biochemical parameters were evaluated. Finally, histopathological examination of the organs did not reveal any lesions in the control or treated groups. Taken together, these findings indicate that D/DA is safe and non-toxic.

• Molecular & Cellular Toxicology
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• v.5 no.1
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• pp.93-98
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• 2009

Stephania delavayi Diels. has been used as an immune activator or an anti-inflammatory drug in China. We examined the immune modulation effect and 7-days repeated-dose toxicity to validate its biological safety and efficiency. Mice were repeatedly administrated with 50 mg/kg S. delavayi Diels. daily by I.P for 7 days. S. delavayi Diels. induced B cell activation but had no effect on other immune cells such as T cell, natural killer (NK) cell, and macrophage ($M{\varphi}$). S. delavayi Diels.-treated group exhibited no statistical significance from the control group in physical conditions; body weight, complete blood count (CBC), serum biochemical indexes etc. There was no difference between the control group and S. delavayi Diels.-treated group in gross findings such as histopathological alteration. In conclusion, S. delavayi Diels. is safe above the dose of immune modulation.

• Molecular & Cellular Toxicology
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• v.5 no.1
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• pp.88-92
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• 2009

The effect of Chlorella vulgaris (CV) on the urinary excretion of di-ortho PCB congeners (PCB-138, -153) was investigated. Sprague-Dawley rats (6-weeks-old, n=10 rats/group) were randomly divided into one control (0CV) or 2% CV (2CV) or 5% CV (5CV) or 10% CV (10CV) groups, respectively. Composition of normal and chlorella meal-based diet were made up of 30% casein, 15% cornstarch, 50% sucrose, 5% cellulose, 5% coconut oil, 3.5% mineral mixture, 1 % vitamin mixture. All rats had free access to water and diet for 4 weeks. A significant increase in both PCB 138 and 153 in urinary level was detected in CV fed groups, 540% and 167% for 2CV, 155% and 89% for 5CV, 114% and 144% for 10CV group, respectively, when compared with their controls. These findings suggest that CV may have potential to eliminate body burden levels of dioxin-like PCB compounds.

• Molecular & Cellular Toxicology
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• v.5 no.4
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• pp.335-345
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• 2009

A major source of paeoniflorin (PF) which was from the Paeonia lactiflora root, has been used as a herbal medicine in East Asia for its antiallergic, antiinflammatory, and immunoregulatory effects. However, only few details are known about the mechanism of apoptosis induced by this compound. The present study was undertaken to further elucidate the molecular mechanism of apoptosis and the changes of gene expression elicited by PF using DNA microarrays and computational gene-expression analysis tools in human leukemia U937 cells. A comparative global transcription analysis between treatment with PF and anisomycin (AM) that induces apoptosis in U937 cells revealed that c-Jun-$NH_2$-kinase (JNK) pathway related genes were less expressed in PF-treated cells. Elucidation of the mechanisms by which PF conducts its anti-cancer activities through comparative analysis of the gene expression is necessary to provide a solid foundation for its use as a promising agent in prevention and treatment strategies.

• Molecular & Cellular Toxicology
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• v.5 no.4
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• pp.283-290
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• 2009

Differential gene expression profiling was performed in the hepatic tissue of marine medaka fish (Oryzias javanicus) after exposure to benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), by heterologous hybridization using a medaka cDNA microarray. Thirty-eight differentially expressed candidate genes, of which 23 were induced and 15 repressed (P<0.01), were identified and found to be associated with cell cycle, development, endocrine/reproduction, immune, metabolism, nucleic acid/protein binding, signal transduction, or non-categorized. The presumptive physiological changes induced by BaP exposure were identified after considering the biological function of each gene candidate. The results obtained in this study will allow future studies to assess the molecular mechanisms of BaP toxicity and the development of a systems biology approach to the stress biology of organic chemicals.

• Molecular & Cellular Toxicology
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• v.3 no.1
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• pp.11-18
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• 2007

Mechanisms of insecticide resistance found in insects may include three general categories. Modified behavioral mechanisms can let the insects avoid the exposure to toxic compounds. The second category is physiological mechanisms such as altered penetration, rapid excretion, lower rate transportation, or increased storage of insecticides by insects. The third category relies on biochemical mechanisms including the insensitivity of target sites to insecticides and enhanced detoxification rate by several detoxifying mechanisms. Insecticides metabolism usually results in the formation of more water-soluble and therefore more readily eliminated, and generally less toxic products to the host insects rather than the parent compounds. The representative detoxifying enzymes are general esterases and monooxygenases that catalyze the toxic compounds to be more water-soluble forms and then secondary metabolism is followed by conjugation reactions including those catalyzed by glutathione S-transferases (GSTs). However, a change in the resistant species is not easily determined and the levels of mRNAs do not necessarily predict the levels of the corresponding proteins in a cell. As genomics understands the expression of most of the genes in an organism after being stressed by toxic compounds, proteomics can determine the global protein changes in a cell. In this present review, it is suggested that the environmental proteomic application may be a good approach to understand the biochemical mechanisms of insecticide resistance in insects and to predict metabolomic changes leading to physiological changes of the resistant species.

• Molecular & Cellular Toxicology
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• v.3 no.1
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• pp.31-35
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• 2007

Hesperidin, known as a flavonoid constituent of citrus, has been known to reduce the proliferation of several cancer cells. We investigated whether hesperidin-induced cell death on SNU-668, human gastric cancer cells. The cytotoxicity of hesperidin on SNU-668 cells was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay at the concentration of 1, 10, 50, and 100 ${\mu}M$. Cell viability by hesperidin was 53.18$\pm$2.85% of control value at 100 ${\mu}M$. The cell death by hesperidin showed apoptotic features, which were confirmed using a combination of 4, 6-diamidino-2-phenylindole (DAPI) staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. In the apoptosis-regulating genes, treatment of hesperidin decreased mRNA expression of B-cell CLL/lymphoma 2 (BCL2), whereas expression of BCL2-associated X protein (BAX) was increased. The mRNA expression and the activity of caspase3 (CASP3), a major apoptotic factor, was significantly increased by hesperidin treatment. These results suggest that hesperidin could induce apoptosis through CASP3 activation on SNU-668, human gastric cancer cells.

• Molecular & Cellular Toxicology
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• v.3 no.1
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• pp.68-75
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• 2007

[ $\alpha$ ]-Terpinene has been known as a repellent against the mosquito Culex pipiens pallens Coquillett based on a human forearm bioassay. $\alpha$-Terpinene showed significantly greater repellency than a commercial formulation, N, N-diethyl-m-methylbenzamide (deet). In this study, skin and eye sensitivity of $\alpha$-terpinene (2%) was examined with bioassays using white New Zealand rabbits. There were somewhat gross and histological changes observed in these treatments. Eye irritancy assays examined gross changes to cornea, iris and conjuctiva, and histological changes to smear of ocular discharge and eye tissue. Treated rabbits were divided into two cohorts, a saline washed cohort (W) or a non-washed cohort (NW). Opacity of cornea and redness, chemosis and discharge of conjuctiva were observed in both cohorts, but disappeared within 4 and 10 days in W and NW, respectively. Main components of ocular discharges were fibrin, epithelial or epitheloid cells, lymphoid cells, erythrocytes and granulocytes. These abnormal cellular components disappeared within 4 days and 10 days in W and NW, respectively. No permanent histological differences were observed between the two cohorts. However, severe irritation was determined as 57.2 of I.I.O.I value on the first day after treatment. These findings indicate a spray-type solution containing 2% $\alpha$-terpinene may serve as an alternative mosquito repellent and further studies need to reduce the eye irritation with formulation changes.