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

A method of detecting lead was developed using square wave anodic stripping voltammetry (SWASV) with DNA-carbon nanotube paste electrode (CNTPE). The results indicated a sensitive oxidation peak current of lead on the DNA-CNTPE. The curves were obtained within a concentration range of 50 ngL-1-20 mgL-1 with preconcentration time of 100, 200, and 400 sec at the concentration of mgL-1, microgL-1, and ngL-1, respectively. The observed relative standard deviation was 0.101% (n = 12) in the lead concentration of 30.0 microgL-1 under optimum conditions. The low detection limit (S/N) was pegged at 8 ngL-1 (2.6 x10-8 M). Results showed that the developed method can be used in real-time assay in vivo without requiring any pretreatment and pharmaceutical samples, and food samples, as well as other materials requiring water source contamination analyses.
Electrodes ; Limit of Detection ; Nanotubes ; Plants* ; Water

Ginseng is a well-known traditional medicine used in Asian countries for several thousand years, and it is currently applied to medicine, cosmetics, and nutritional supplements due to its many healing and energy-giving properties. It is well demonstrated that ginsenosides, the main ingredient of ginseng, produce a variety of pharmacological and therapeutic effects on central nerve system (CNS) disorders, cardiovascular disease, endocrine secretions, aging, and immune function. Korean red ginseng extract is a dietary supplement containing ginsenoside Rb1 and ginsenoside Rg1 extracted from Panax ginseng. While the pharmacokinetics and bioavailability of the extract have been well established, its toxicological properties remain obscure. Thus, four-week oral toxicity studies in rats were conducted to investigate whether Korean red ginseng extract could have a potential toxicity to humans. The test article was administered once daily by oral gavage to four groups of male and female Sprague-Dawley (SD) rats at dose levels of 0, 500, 1,000, and 2,000 mg/kg/day for four weeks. Neither deaths nor clinical symptoms were observed in any group during the experiment. Furthermore, no abnormalities in body weight, food consumption, ophthalmology, urinalysis, hematology, serum biochemistry, gross findings, organ weights, or histopathology were revealed related to the administration of the test article in either sex of any dosed group. Therefore, a target organ was not determined in this study, and the no observed adverse effect level (NOAEL) of Korean red ginseng extract was established to be 2,000 mg/kg/day.
Aging ; Animals ; Asian Continental Ancestry Group ; Biochemistry ; Biological Availability ; Body Weight ; Cardiovascular Diseases ; Dietary Supplements ; Female ; Ginsenosides ; Hematology ; Humans ; Male ; Medicine, Traditional ; No-Observed-Adverse-Effect Level ; Ophthalmology ; Organ Size ; Panax* ; Pharmacokinetics ; Rats ; Rats, Sprague-Dawley* ; Urinalysis

Acanthopanax koreanum Nakai, a well known traditional herb grown in Jeju Island, South of Korea, has been used as a tonic and sedative agent, as well as in the treatment of diabetes and immune diseases. Mutagenicity of two lignans, syringaresinol and tortoside A isolated from A. koreanum, was assessed using Salmonella/microsome (Ames) test. Tester strains used were Salmonella typhimurium TA98, TA100, TA1535, and Escherichia coli WP2uvrA. The mutagenic activity was determined both in the absence or presence of S9 mixture. As a result, tortoside A did not cause any increase in the number of his+ revertants in S. typhimurium and E. coli WP2uvrA strains in the presence or absence of S9 mix, compared to the controls. Similarly, low concentrations of syringaresinol (750 and 1,500 microg/plate) did not show any mutagenic properties in all bacterial strains, in the presence or absence of S9 mixture. However, in the high concentration of syringaresinol (3,000 microg/plate), the number of revertants were increased in TA1535 strains, in the absence of S9 metabolic activation. Therefore, in vivo experiments such as comet assay are needed to further determine the genotoxic/carciogenic potential of syringaresinol isolated from A. koreanum.
Eleutherococcus* ; Biotransformation ; Comet Assay ; Escherichia coli ; Immune System Diseases ; Korea ; Lignans* ; Salmonella typhimurium

The silkworm extract powder contain 1-deoxynojirimycin (DNJ), a potent alpha-glycosidase inhibitor, has therapeutic potency against diabetes mellitus. Therefore, natural products containing DNJ from mulberry leaves and silkworm are consumed as health functional food. The present study was performed to evaluate the safety of the silkworm extract powder, a health food which containing the DNJ. The repeated toxicity studies and gentic toxicity studies of the silkworm extract powder were performed to obtain the data for new functional food approval in MFDS. The safety was evaluated by a single-dose oral toxicity study and a 90 day repeated-dose oral toxicity study in Sprague-Dawley rats. The silkworm extract powder was also evaluated for its mutagenic potential in a battery of genetic toxicity test: in vitro bacterial reverse mutation assay, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay. The results of the genetic toxicology assays were negative in all of the assays. The approximate lethal dose in single oral dose toxicity study was considered to be higher than 5000 mg/kg in rats. In the 90 day study, the dose levels were wet at 0, 500, 1000, 2000 mg/kg/day, and 10 animals/sex/dose were treated with oral gavage. The parameters that were monitored were clinical signs, body weights, food and water consumptions, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weights, and histopathological examination. No adverse effects were observed after the 90 day administration of the silkworm extract powder. The No-Observed-Adverse-Effect-Level (NOAEL) of silkworm extract powder in the 90 day study was 2000 mg/kg/day in both sexes, and no target organ was identified.
1-Deoxynojirimycin ; Animals ; Biochemistry ; Biological Agents ; Body Weight ; Bombyx* ; Bone Marrow ; Chromosome Aberrations ; Diabetes Mellitus ; Functional Food ; Food, Organic ; Hematology ; Mice ; Micronucleus Tests ; Morus ; Mutagenicity Tests ; Organ Size ; Rats ; Rats, Sprague-Dawley ; Toxicology ; Urinalysis ; Drinking

alpha-Curcumene is one of the physiologically active components of Curcuma zedoaria, which is believed to perform anti-tumor activities, the mechanisms of which are poorly understood. In the present study, we investigated the mechanism of the apoptotic effect of alpha-curcumene on the growth of human overian cancer, SiHa cells. Upon treatment with alpha-curcumene, cell viability of SiHa cells was inhibited > 73% for 48 h incubation. alpha-Curcumene treatment showed a characteristic nucleosomal DNA fragmentation pattern and the percentage of sub-diploid cells was increased in a concentration-dependent manner, hallmark features of apoptosis. Mitochondrial cytochrome c activation and an in vitro caspase-3 activity assay demonstrated that the activation of caspases accompanies the apoptotic effect of alpha-curcumene, which mediates cell death. These results suggest that the apoptotic effect of alpha-curcumene on SiHa cells may converge caspase-3 activation through the release of mitochondrial cytochrome c.
Apoptosis ; Caspase 3 ; Caspases ; Cell Death ; Cell Survival ; Curcuma* ; Cytochromes c ; DNA Fragmentation ; Humans ; Ovarian Neoplasms*

Erythritol is a sugar alcohol that is widely used as a natural sugar substitute. Thus, the safety of its usage is very important. In the present study, short-term genotoxicity assays were conducted to evaluate the potential genotoxic effects of erythritol. According to the OECD test guidelines, the maximum test dose was 5,000 microg/plate in bacterial reverse mutation tests, 5,000 microg/ml in cell-based assays, and 5,000 mg/kg for in vivo testing. An Ames test did not reveal any positive results. No clastogenicity was observed in a chromosomal aberration test with CHL cells or an in vitro micronucleus test with L5178Y tk +/- cells. Erythritol induced a marginal increase of DNA damage at two high doses by 24 hr of exposure in a comet assay using L5178Y tk +/- cells. Additionally, in vivo micronucleus tests clearly demonstrated that oral administration of erythritol did not induce micronuclei formation of the bone marrow cells of male ICR mice. Taken together, our results indicate that erythritol is not mutagenic to bacterial cells and does not cause chromosomal damage in mammalian cells either in vitro or in vivo.
Administration, Oral ; Animals ; Bone Marrow Cells ; Chromosome Aberrations ; Comet Assay ; DNA Damage ; Erythritol* ; Humans ; Male ; Mice ; Mice, Inbred ICR ; Micronucleus Tests ; Sweetening Agents

The purpose of this study was to investigate the current status of metal pollution in the sediment from rivers, lakes, and streams in active gold mining districts in Ghana. Two hundred and fifty surface sediment samples from 99 locations were collected and analyzed for concentrations of As, Hg, Cr, Co, Cu, Fe, Zn, Pb, Cd, Ni, and Mn using inductively coupled plasma-mass spectroscopy (ICP-MS). Metal concentrations were then used to assess the human health risks to resident children and adults in central tendency exposure (CTE) and reasonable maximum exposure (RME) scenarios. The concentrations of Pb, Cd, and As were almost twice the threshold values established by the Hong Kong Interim Sediment Quality Guidelines (ISQG). Hg, Cu, and Cr concentrations in sediment were 14, 20, and 26 times higher than the Canadian Freshwater Sediment Guidelines for these elements. Also, the concentrations of Pb, Cu, Cr, and Hg were 3, 11, 12, and 16 times more than the Australian and New Zealand Environment and Conservation Council (ANZECC) sediment guideline values. The results of the human health risk assessment indicate that for ingestion of sediment under the central tendency exposure (CTE) scenario, the cancer risks for child and adult residents from exposure to As were 4.18 x 10(-6) and 1.84 x 10(-7), respectively. This suggests that up to 4 children out of one million equally exposed children would contract cancer if exposed continuously to As over 70 years (the assumed lifetime). The hazard index for child residents following exposure to Cr(VI) in the RME scenario was 4.2. This is greater than the United States Environmental Protection Agency (USEPA) threshold of 1, indicating that adverse health effects to children from exposure to Cr(VI) are possible. This study demonstrates the urgent need to control industrial emissions and the severe heavy metal pollution in gold mining environments.
Adult ; Child ; Chromium ; Contracts ; Eating ; Fresh Water ; Ghana ; Hong Kong ; Humans ; Lakes ; Metals ; Mining ; New Zealand ; Risk Assessment ; Rivers ; Spectrum Analysis ; United States Environmental Protection Agency

Development of a therapy providing protection from, or reversing gentamicin-sulfate (GS)-induced oxidative stress and nephrotoxicity would be of great clinical significance. The present study was designed to investigate the protective effects of Houttuynia cordata Thunb. (HC) against gentamicin sulfate-induced renal damage in rats. Twenty-eight Sprague-Dawley rats were divided into 4 equal groups as follows: group 1, control; group 2, GS 100 mg/kg/d, intraperitoneal (i.p.) injection; group 3, GS 100 mg/kg/d, i.p. + HC 500 mg/kg/d, oral; and group 4, GS 100 mg/kg/d i.p. + HC 1000 mg/kg/d, oral administration). Treatments were administered once daily for 12 d. After 12 d, biochemical and histopathological analyses were conducted to evaluate oxidative stress and renal nephrotoxicity. Serum levels of creatinine, malondialdehyde (MDA), and blood urea nitrogen (BUN), together with renal levels of MDA, glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were quantified to evaluate antioxidant activity. Animals treated with GS alone showed a significant increase in serum levels of creatinine, BUN, and MDA, with decreased renal levels of GSH, SOD, and CAT. Treatment of rats with HC showed significant improvement in renal function, presumably as a result of decreased biochemical indices and oxidative stress parameters associated with GS-induced nephrotoxicity. Histopathological examination of the rat kidneys confirmed these observations. Therefore, the novel natural antioxidant HC may protect against GS-induced nephrotoxicity and oxidative stress in rats.
Animals ; Blood Urea Nitrogen ; Catalase ; Cats ; Creatinine ; Drug Combinations ; Gentamicins ; Glutathione ; Glycerides ; Houttuynia ; Kidney ; Malondialdehyde ; Monoterpenes ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase

Studies on milk transfer of drugs in non-human primates (NHPs) are among the crucial components in the assessment of peri- and postnatal toxicity because of the similarity between NHPs and humans. To evaluate the milk transfer of valproic acid (VPA) in NHPs, the toxicokinetics of VPA, an antiepileptic drug, were studied in pregnant cynomolgus monkeys. VPA was administered once daily to pregnant cynomolgus monkeys at doses of 0, 30, 90, and 270 mg/kg by oral gavage from Day 100 of gestation (GD 100) to Day 31 of lactation (LD 31). Concentrations of VPA and its metabolite, 4-ene-VPA, in the maternal plasma on GD 100, GD 140, and LD 30, and concentrations of VPA and 4-ene-VPA in the offspring plasma and milk on LDs 30 and 31, respectively, were quantified using liquid chromatography tandem mass spectrometry (LC/MS/MS). After administration of a single oral dose of VPA to pregnant monkeys on GD 100, the concentrations of VPA and 4-ene-VPA were generally quantifiable in the plasma of all treatment groups up to 24 hr after administration, which showed that VPA was absorbed and that the monkeys were systemically exposed to VPA and 4-ene-VPA. After administration of multiple doses of VPA to the monkeys, VPA was detected in the pup's plasma and in milk taken on LD 30 and LD 31, respectively, which showed that VPA was transferred via milk, and the pup was exposed to VPA. Further, the concentration of VPA in the milk increased with an increase in the dose. Extremely low concentrations of 4-ene VPA were detected in the milk and in the pup plasma. In conclusion, pregnant monkeys were exposed to VPA and 4-ene-VPA after oral administration of VPA at doses of 30, 90, and 270 mg/kg/day from GD 100 to LD 31. VPA was transferred via milk, and the VPA exposure to the pup increased with an increase in the dose of VPA. The metabolite, 4-ene VPA, was present in extremely low concentrations (< 0.5 microg/ml) in the milk and in the pup plasma. In this study, we established methods to confirm milk transfer in NHPs, such as mating and diagnosis of pregnancy by examining gestational sac with ultrasonography, collection of milk and pup plasma and determination of toxicokinetics, using cynomolgus monkeys.
Administration, Oral ; Chromatography, Liquid ; Fatty Acids, Monounsaturated ; Female ; Gestational Sac ; Haplorhini ; Humans ; Lactation ; Macaca fascicularis ; Milk ; Plasma ; Pregnancy ; Primates ; Tandem Mass Spectrometry ; Valproic Acid