Experimental and Toxicologic Pathology最新文献

According to the International Conference on Harmonization Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use (ICH S2(R1)), a positive response in any in vitro assay necessitates additional in vivo test(s) (other tissue/endpoint) in addition to the erythrocyte micronucleus test when Option 1 of the test battery is selected. When Option 2 of the test battery is selected, a bacterial gene mutation test and two in vivo tests with different tissues/endpoint are required. The in vivo alkaline comet assay is recommended as the second in vivo test because it can detect a broad spectrum of DNA damage in any tissue and can be combined with the erythrocyte micronucleus test. Considering animal welfare, a combination assay is preferable to an individual assay. Thus, we validated the protocol for the in vivo comet-micronucleus combination assay in rats with three daily administrations and determined the dose of the positive control (ethyl methanesulfonate; EMS, 200 mg/kg/day). We also collected the negative control (vehicle) and positive control (EMS) data from the comet (liver, stomach, and kidney) and micronucleus (bone marrow) combination assay using male Sprague Dawley (SD) rats. The negative control data were comparable to our historical control data obtained from stand-alone assays. The positive control data showed clear and consistent positive responses in both endpoints.

Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2 g/kg p.o. once only. After 24 h of APAP intoxication, animals were treated with three different doses of AuNPs (50 μg/kg, 100 μg/kg, 150 μg/kg) orally or silymarin at a dose of 50 mg/kg p.o., once only. Animals of all the groups were sacrificed after 24 h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies.

Background

Bulbus Fritillaria cirrhosa D. Don (BFC) has been used in China as a folk medicine for the treatment of cough and asthma for more than 2000 years. The antitussive and antiasthmatic effects of BFC have been reported before, nevertheless its toxicity and safety have not been documented. This study investigated the possible effects of BFC on spindle assembly checkpoint (SAC), mitotic fidelity and genomic stability in human NCM460 colon epithelial cells.

Methods

Cells were treated with BFC (0, 20, 40, 80 and 160 μg/ml) for 24, 48 and 72 h and harvested differently according to the biomarkers observed. Mitotic aberrations were assessed by the biomarkers of chromosome misalignment (CMA), chromosome lagging (CL) and chromatin bridge (CB). Frequencies of micronuclei (MN), nucleoplasmic bridge and nuclear bud (NB) in cytokinesis-block micronucleus assay were used as indicators of genomic instability (GIN). SAC activity was determined by anaphase to metaphase ratio (AMR) and the expression of several SAC genes, including CENP-E, Mps1, Bub1, Mad-1, BubR1 and Mad-2.

Results

Compared with the control, cells in BFC treated groups (80 and 160 μg/ml) showed: 1) increased AMR (p < 0.05), up-regulated expression of Mps1, Bub1 and Mad-1 (p < 0.05) and down-regulated expression of CENP-E, BubR1 and Mad-2 (p < 0.05); 2) increased frequencies of CMA, CL and CB (p < 0.01); 3) increased incidences of MN and NB (p < 0.01).

Conclusions

This study revealed for the first time that BFC causes mitotic aberrations and GIN in human colon epithelial cells and these effects maybe the result of SAC dysfunction.

Toxic elements such as cadmium (Cd) and lead (Pb) accumulate to the largest extent in bones. Rats at the age of 12 weeks were used to check whether tannic acid (TA) at the concentration of 0.5%, 1.0%, 1.5%. 2.0% or 2.5% would have a protective effect on the structure and properties of bones in the case of exposure to Cd and Pb (diet: 7 mg Cd/kg and 50 mg Pb/kg) for 12 weeks. The effects of administration of TA in Cd- and Pb-poisoned rats on bone mechanical and geometric properties, trabecular histomorphometry as well as the morphology of articular and growth cartilages were determined. All the rats co-exposured to Cd and Pb had enhanced heavy metals concentration in blood plasma and bone and reduced bone Ca content irrespective of the tannic acid administration. Heave metals given to adult rats did not influence the morphology and geometry of the femur, but reduced the mechanical endurance and histomorphometric parameters of trabecular bone irrespective of the treatment. A diet rich in TA improved articular cartilage and growth plate constituents in heavy metal-poisoned rats, as indicated by the measurement of the thickness of particular zones. It seems that a use of alimentary TA supplementation in adult rats can counteract, in a dose-dependent manner, only some of the destructive changes evoked by Cd and Pb excess.