Excitotoxicity refers to a process of neuronal death caused by excessive or prolonged activation of receptors for the excitatory amino acids, which is related to the overload of intracellular calcium ([Ca2+]i) and mitochondrial depolarization. The well accepted hypothesis that Ca2+ plays a central role in neurotoxicity, and it mediated excitotoxicity is deeply involved in both acute and chronic neurodegeneration suggests that inhibitors of Ca2+ transduction, such as NMDA antagonists, might block the pathological process at an early stage and provide more effective protections.

Objective Micronucleus test(MNT) was used to evaluate the single and combined genotoxicity of dichlorvos(DDVP),dimethoate(DM) and malathion(Mal) in HepG2 cell line,and 2?2 factorial design was adopted to elucidate the combined genotoxic effects.Methods In cytotoxicity test,HepG2 cells were exposed to the three OPPs(DDCP,DM,Mal) for 4 h respectively,and the doses at which cell viability above 80% were selected for the MNT,DDVP:3.125-25 ?g/ml,DM:25-200 ?g/ml,Mal:50400 ?g/ml,the micronucleated cell(MNC) rates and the replicative index(RI) were calculated.The combined genotoxicity of them was investigated with their doses as follows:low dose(DDVP:3.125 ?g/ml,DM:25 ?g/ml,Mal:50 ?g/ml);high dose(DDVP:12.5 ?g/ml,DM:100 ?g/ml,Mal:200 ?g/ml).Results In MNT,after treatment of HepG2 cells with DDVP,DM or Mal alone for 4 h,the MNC rates were increased in a dose-response manner(DDVP:r=0.955,P

Traditional drug development and pre-clinical tests are based on animals and involve large numbers of animals,costs and long periods. Meanwhile,inter-species differences are difficult to overcome. Human embryonic stem cells (hESCs),which can self-renew and directly differentiate to types of cells,have become a new tool for toxicity alternative testing. hESC-Based alternative testing models,such as the reproductive toxicity test system,neuro development toxicity test system and metabolic model,can be used to predict target organ toxicity and toxic mechanisms of chemicals, analyze metabolic pathways and to search for potential toxicity biomarkers, when combined with omics such techiniques as metabonomics , proteomics and genomics. Therefore, hESC-based alternative testing models have extensive application to toxicology.

AIM: To evaluate the cytotoxicity of a novel anticholinergic drug penehyclidine hydrochloride (PHC) and its four optical isomers R-1, R-2, S-1, and S-2. METHODS: Two in vitro assays, MTT assay and neutral red uptake assay, were used to evaluate the cytotoxicity following PHC and its isomers exposure to HepG2 cells at different concentrations. RESULTS: PHC and its isomers induced decreases of viability of HepG2 cells in a concentration-dependent manner. Comparison of the cytotoxicity of the five anticholinergic agents with 50% inhibitory concentration (IC50) values indicated that the order of potency was PHC>R-2>R-1>S-2>S-1 for MTT assay, and R-2>PHC≈R-1>S-2>S-1 for neutral red uptake assay. CONCLUSION: With respect to the cytotoxicity of the four isomers on HepG2 cells, the R configuration was more potent than the S configuration, and R-2 was the most potent isomer whereas S-1 was the least potent isomer among the four optical isomers.

Objective To establish the normal reference ranges of clinical pathology for Beagle dogs in the Good Laboratory Practice ( GLP ) system.Method Sixteen biochemical indexes , seventeen hematological indexs and three coagulation function indexes of 117 Beagle dogs were detected , and the mean value of each index and the normal reference ranges were calculated and compared .Results Only alkaline phosphatase ( ALP ) from the biochemical items was significantly different between males and females (P<0.01),which was higher among males than among females .Three in-dexes of hematology were significantly different between males and females (P<0.01),with red blood cell(RBC), hemo-globin(HGB)and hematocrit(HCT)lower among males than among females.The coagulation function items were not signif-icantly different between the two sexes .Conclusion Some indexes of clinical pathology were significantly different between males and females , which should be considered during statistic analysis on toxicity .Our study has established the normal reference range of clinical pathology for Beagle dogs in the GLP system , which provides reference for toxicity tests .

Metallothionein ( MT ) is a cysteine-rich and low-molecular metal binding protein. Three isoforms of MT have been found in the central nervous system, including MT-Ⅰ, Ⅱ, and Ⅲ. MT is widely involved in many critical activities in the central nervous system, such as neuronal growth, auto-defensive reaction, immune-regulation, and repair of cerebral injury. MT exerts many important biological functions like scavenging of free radicals, regulation of ion homeostasis in brain cells, detoxification of heavy metals, anti-inflammation, and anti-apoptosis. Recently, MT has been increasingly shown to have protective effects against cerebral ischemia. MT promises to be an important target for prevention and/or treatment of cerebral ischemic disease. ln this review, the expression and regulation characteristics, and the effect of cerebral ischemic stress on MT expression have been summarized, with focus on the neuro-protective effect of MT and its possible underlying mechanisms.

ASICs are H+-gated novel cation ion channels, which belong to the epithelial sodium channels (NaC/DEG) superfamily. As recent studies focus, ASICs are expected to be pharmacological targets on protecting the neuron from ischemia and damage, improving the ability of memory and study, curing epilepsy and analgesia. It is not until the most recentness that the subunits of ASICs have been cloned. Now, researchers have paid more attention to the distribution, expression, function and modulation of ASICs in the organism.

Objective To investigate the effect of glucagon-like peptide-1(GLP-1) in a dose related manner on glucose metabolism after 65% hepatectomy in rats.Methods We determined the serum glucose levels of hepatomized rats at 0,5,10,20,and 30 minutes after an intravenous glucose load(IVGTT,0.5 g/kg glucose) on the first postoperative day,and the changes of blood glucose,serum insulin and glucagon concentrations of hepatomized rats that received the volum load with normal saline or 0.3 nmol/kg GLP-1,0.45 nmol/kg GLP-1 respectively.Blood was drawn for determination of glucose(glucose oxidase),insulin,glucagon,and GLP-1(radioimmunoassay).Results The peak glucose and 30-minute glucose levels and the area under the curve(AUC 0-30) were significantly higher in the hepatomized rats compared to the control rats,which had not undergone any operation and received a same intravenous glucose load(0.5 g/kg glucose with normal saline)(P0.05).Nevertheless the peak glucose and 30-minute glucose levels and AUC 0-30 of the hepatomized rats that received with 0.45 nmol/kg GLP-1 were significantly lower compared to the rats that received the same volum load with normal saline or 0.3 nmol/kg GLP-1 respectively after liver resection.There was an increasing postoperative serum concentration of glucose,insulin,glucagon on the first day,then,the serum glucose concentration was significantly lowered after infusion of GLP-1 in rats undergoing hepatectomy(P

The purpose of risk assessment is to evaluate the permissible exposure level under specific risk factors.To extrapolate the human acceptable daily intake (ADI) and/or reference dose (RfD), the traditional method uses the no-observed-adverse-effect level ( NOAEL ) to quantify toxicity after being divided by uncertainty factor.There are many limitations with NOAEL method in safety evaluation,for it relies too much on experimental design.Benchmark dose ( BMD) approach is a more reliable method with many advantages.BMD approach and its analysis software, the advantages of BMD over NOAEL, the application and methodological perfection in risk assessment of long-team exposure toxicity are presented in this review.

Objective To evaluate the repeated dose toxicity of MNT-016 in SD rats and to provide reference for toxicity evaluation.Methods MNT-016 was administered to rats at 5, 20 and 80 mg/kg for 90 days.The toxic effects on the animals were evaluated by observing the clinical signs and measuring the body weight, hematology and blood biochemistry as well as histopathological examination.NOAEL and benchmark dose lower confidence limit(BMDL) were observed by the end point of toxicity.Results Compared with the control group, the AST, TBIL, DBIL and Crea of male rats were increased in a dose-dependent manner, while TG and CHOL decreased.The body mass(before anatomy), heart, liver, thymus, epididymis of male rats in 80 mg/kg group were significantly decreased (P<0.05), while absolute organ mass of the heart and lung was increased.The body mass (before anatomy) and thymus of female rats in 80 mg/kg group were significantly decreased (P<0.05), while absolute organ mass of lungs was increased.Vacuolation of hepatocytes was observed in groups each dose, tubule atrophy was found in the kidneys of 20 and 5 mg/kg groups, and tubule basophilia was observed in 80 mg/kg group.The incidence of the above lesions was higher in male animals than in female ones.Conclusion The NOAEL of MNT-016 is lower than 5 mg/kg in male rats and 5 mg/kg in female rats.BMDL value is 2.65 mg/kg in male animals and more accurate than NOAEL, and is 9.04 mg/kg in female animals,which is slightly larger than the corresponding NOAEL.