The process of drug discovery and development requires substantial resources and time. The drug industry has tried to reduce costs by conducting appropriate animal studies together with molecular biological and genetic analyses. Basic science research has been limited to in vitro studies of cellular processes and ex vivo tissue examination using suitable animal models of disease. However, in the past two decades new technologies have been developed that permit the imaging of live animals using radiotracer emission, X-rays, magnetic resonance signals, fluorescence, and bioluminescence. The main objective of this review is to provide an overview of small animal molecular imaging, with a focus on nuclear imaging (single photon emission computed tomography and positron emission tomography). These technologies permit visualization of toxicodynamics as well as toxicity to specific organs by directly monitoring drug accumulation and assessing physiological and/or molecular alterations. Nuclear imaging technology has great potential for improving the efficiency of the drug development process.
Animals ; Drug Discovery ; Drug Industry ; Electrons ; Fluorescence ; Magnetic Resonance Spectroscopy ; Models, Animal ; Molecular Imaging ; Tomography, Emission-Computed

This study was carried out to examine the action mechanism of Chamaecyparis obtusa oil (CO) on hair growth in C57BL/6 mice. For alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (gamma-GT) activities in the skin tissue, at week 4, the 3% minoxidil (MXD) and 3% CO treatment groups showed an ALP activity that was significantly higher by 85% (p < 0.001) and 48% (p < 0.05) and an gamma-GT activity that was significantly higher by 294% (p < 0.01) and 254% (p < 0.05) respectively, as compared to the saline (SA) treatment group. For insulin-like growth factor-1 (IGF-1) mRNA expression in the skin tissue, at week 4, the MXD and CO groups showed a significantly higher expression by 204% (p < 0.05) and 426% (p < 0.01) respectively, as compared to the SA group. At week 4, vascular endothelial growth factor (VEGF) expression in the MXD and CO groups showed a significantly higher expression by 74% and 96% (p < 0.05) respectively, however, epidermal growth factor (EGF) expression in the MXD and CO groups showed a significantly lower expression by 66% and 61% (p < 0.05) respectively, as compared to the SA group. Stem cell factor (SCF) expression in the MXD and CO groups was observed by immunohistochemistry as significant in a part of the bulge around the hair follicle and in a part of the basal layer of the epidermis. Taking all the results together, on the basis of effects on ALP and gamma-GT activity, and the expression of IGF-1, VEGF and SCF, which are related to the promotion of hair growth, it can be concluded that CO induced a proliferation and division of hair follicle cells and maintained the anagen phase. Because EGF expression was decreased significantly, CO could delay the transition to the catagen phase.
Alkaline Phosphatase ; Animals ; Chamaecyparis* ; Epidermal Growth Factor ; Epidermis ; gamma-Glutamyltransferase ; Hair Follicle ; Hair* ; Immunohistochemistry ; Insulin-Like Growth Factor I ; Mice ; Minoxidil ; RNA, Messenger ; Skin ; Stem Cell Factor ; Vascular Endothelial Growth Factor A

Extracellular accumulation of amyloid beta protein (Abeta) plays a central role in Alzheimer's disease (AD). Some metals, such as copper, lead, and aluminum can affect the Abeta accumulation in the brain. However, the effect of mercury on Abeta accumulation in the brain is not clear. Thus, this study was proposed to estimate whether mercury concentration affects Abeta accumulation in PC12 cells. We treated 10, 100, and 1000 nM HgCl2 (Hg) or CH3HgCl2 (MeHg) for 48 hr in PC12 cells. After treatment, Abeta40 in culture medium increased in a dose- and time-dependent manner. Hg and MeHg increased amyloid precursor protein (APP), which is related to Abeta production. Neprilysin (NEP) levels in PC12 cells were decreased by Hg and MeHg treatment. These results suggested that Hg induced Abeta accumulation through APP overproduction and reduction of NEP.
Aluminum ; Alzheimer Disease ; Amyloid beta-Peptides ; Amyloid Precursor Protein Secretases ; Amyloid* ; Animals ; Brain ; Copper ; Mercuric Chloride ; Metals ; Neprilysin ; PC12 Cells*

Phytoestrogens exist in edible compounds commonly found in fruits or plants. For long times, phytoestrogens have been used for therapeutic treatments against human diseases, and they can be promising ingredients for future pharmacological industries. Kaempferol is a yellow compound found in grapes, broccoli and yellow fruits, which is one of flavonoid as phytoestrogens. Kaempferol has been suggested to have an antioxidant and anti-inflammatory effect. In past decades, many studies have been performed to examine anti-toxicological role(s) of kaempferol against human cancers. It has been shown that kaempferol may be involved in the regulations of cell cycle, metastasis, angiogenesis and apoptosis in various cancer cell types. Among them, there have been a few of the studies to examine a relationship between kaempferol and apoptosis. Thus, in this review, we highlight the effect(s) of kaempferol on the regulation of apoptosis in diverse cancer cell models. This could be a forecast in regard to use of kaempferol as promising treatment against human diseases.
Apoptosis* ; Brassica ; Cell Cycle ; Fruit ; Humans ; Neoplasm Metastasis ; Phytoestrogens* ; Receptors, Estrogen ; Social Control, Formal ; Vitis

Embryonic stem (ES) cells have potential for use in evaluation of developmental toxicity because they are generated in large numbers and differentiate into three germ layers following formation of embryoid bodies (EBs). In earlier study, embryonic stem cell test (EST) was established for assessment of the embryotoxic potential of compounds. Using EBs indicating the onset of differentiation of mouse ES cells, many toxicologists have refined the developmental toxicity of a variety of compounds. However, due to some limitation of the EST method resulting from species-specific differences between humans and mouse, it is an incomplete approach. In this regard, we examined the effects of several developmental toxic chemicals on formation of EBs using human ES cells. Although human ES cells are fastidious in culture and differentiation, we concluded that the relevancy of our experimental method is more accurate than that of EST using mouse ES cells. These types of studies could extend our understanding of how human ES cells could be used for monitoring developmental toxicity and its relevance in relation to its differentiation progress. In addition, this concept will be used as a model system for screening for developmental toxicity of various chemicals. This article might update new information about the usage of embryonic stem cells in the context of their possible ability in the toxicological fields.
Animals ; Embryoid Bodies ; Embryonic Stem Cells* ; Germ Layers ; Humans* ; Mass Screening ; Mice

Hypertension is a serious health problem due to high frequency and concomitant other diseases including cardiovascular and renal dysfunction. Olmesartan cilexetil is a new antihypertensive drug associated with angiotensin II receptor antagonist. This study was conducted to evaluate the mutagenicity of olmesartan cilexetil by bacterial reverse mutation test using Salmonella typhimurium (TA100, TA1535, TA98, and TA1537) and Escherichia coli (WP2 uvrA). At the concentrations of 0, 62, 185, 556, 1667, and 5000 microg/plate, olmesartan cilexetil was negative in both Salmonella typhimurium and Escherichia coli regardless of presence or absence of metabolic activation system (S9 mix). These results demonstrate that olmesartan cilexetil does not induce bacterial reverse mutation.
Biotransformation ; Escherichia coli ; Hypertension ; Imidazoles ; Receptors, Angiotensin ; Salmonella typhimurium ; Tetrazoles

The trace toxic metal copper was assayed using mercury immobilized on a carbon nanotube electrode (MCW), with a graphite counter and a reference electrode. In this study, a macro-scale convection motor was interfaced with a MCW three-electrode system, in which a handmade MCW was optimized using cyclic-and square-wave stripping voltammetry. An analytical electrolyte for tap water was used instead of an expensive acid or base ionic solution. Under these conditions, optimum parameters were 0.09 V amplitude, 40 Hz frequency, 0.01 V incremental potential, and a 60-s accumulation time. A diagnostic working curve was obtained from 50.0 to 350 microg/L. At a constant Cu(II) concentration of 10.0 microg/L, the statistical relative standard deviation was 1.78% (RSD, n = 15), the analytical accumulation time was only 60 s, and the analytical detection limit approached 4.6 microg/L (signal/noise = 3). The results were applied to non-treated drinking water. The content of the analyzed copper using 9.0 and 4.0 microg/L standards were 8.68 microg/L and 3.96 microg/L; statistical values R2 = 0.9987 and R2 = 0.9534, respectively. This method is applicable to biological diagnostics or food surveys.
Convection ; Copper ; Diagnosis ; Drinking Water* ; Drinking* ; Electrodes ; Graphite ; Limit of Detection ; Metals* ; Nanotubes, Carbon ; Organothiophosphorus Compounds ; Reference Standards ; Drinking Water

A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of epsilon-acetamidocaproic acid (AACA), the primary metabolite of zinc acexamate (ZAC), in rat plasma by using normetanephrine as an internal standard. Sample preparation involved protein precipitation using methanol. Separation was achieved on a Gemini-NX C18 column (150 mm x 2.0 mm, i.d., 3 microm particle size) using a mixture of 0.1% formic acid-water : acetonitrile (80 : 20, v/v) as the mobile phase at a flow rate of 200 microl/min. Quantification was performed on a triple quadrupole mass spectrometer employing electrospray ionization and operating in multiple reaction monitoring (MRM) and positive ion mode. The total chromatographic run time was 4.0 min, and the calibration curves of AACA were linear over the concentration range of 20~5000 ng/ml in rat plasma. The coefficient of variation and relative error at four QC levels were ranged from 1.0% to 5.8% and from -8.4% to 6.6%, respectively. The present method was successfully applied for estimating the pharmacokinetic parameters of AACA following intravenous or oral administration of ZAC to rats.
6-Aminocaproic Acid ; Acetonitriles ; Administration, Oral ; Animals ; Calibration ; Mass Spectrometry* ; Methanol ; Normetanephrine ; Pharmacokinetics ; Plasma* ; Rats* ; Zinc

The anti-inflammatory effects of glycosaminoglycan (GAG) derived from Isaria sinclairii (IS) and of IS extracts were investigated in a complete Freund's adjuvant (CFA)-treated chronic arthritis rat model. Groups of rats were treated orally with 30 mg/kg one of the following: [1] saline control, extracts of [2] water-IS, [3] methanol-IS, [4] butanol-IS, [5] ethyl acetate-IS, or [6] Indomethacin(R) as the positive control for a period of two weeks. The anti-paw edema effects of the individual extracts were in the following order: water-IS ex. > methanol ex. > butanol ex. > ethyl acetate ex. The water/methanol extract from I. sinclairii remarkably inhibited UV-mediated upregulation of NF-kappaB activity in transfected HaCaT cells. GAG as a water-soluble alcohol precipitated fraction also produced a noticeable anti-edema effect. This GAG also inhibited the pro-inflammatory cytokine levels of prostaglandin E2-stimulated lipopolysaccharide in LAW 264.7 cells, cytokine TNF-alpha production in splenocytes, and atherogenesis cytokine levels of vascular endothelial growth factor (VEGF) production in HUVEC cells in a dose-dependent manner. In the histological analysis, the LV dorsal root ganglion, including the articular cartilage, and linked to the paw-treated IS GAG, was repaired against CFA-induced cartilage destruction. Combined treatment with Indomethacin(R) (5 mg/kg) and IS GAG (10 mg/kg) also more effectively inhibited CFA-induced paw edema at 3 hr, 24 hr, and 48 hr to levels comparable to the anti-inflammatory drug, indomethacin. Thus, the IS GAG described here holds great promise as an anti-inflammatory drug in the future.
Acetates ; Animals ; Arthritis* ; Atherosclerosis ; Cartilage ; Cartilage, Articular ; Edema ; Freund's Adjuvant ; Ganglia, Spinal ; Human Umbilical Vein Endothelial Cells ; Indomethacin ; Inflammation ; Jurisprudence ; Methanol ; NF-kappa B ; Rats* ; Tumor Necrosis Factor-alpha ; Up-Regulation ; Vascular Endothelial Growth Factor A

The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione-S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of N-methylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage.
Animals ; Body Weight ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme System ; Dimethylformamide* ; Formamides ; Glutathione Peroxidase ; Lipid Peroxides ; Liver ; Olea ; Plant Oils ; Rats* ; Solvents ; Toluene* ; Veins ; Olive Oil