ABSTRACT
There are some shortcomings of animal experiments applied in chemical toxicity testing, such as long period, large cost, species differences and dose differences, which limit the use of animal experiments' results in predicting human toxicity.Accordingly, we established a toxicity testing alternative screening system in line with the toxicity endpoints which required in chemical safety evaluation and risk assessment (genotoxicity, carcinogenicity, reproductive toxicity, acute toxicity and general toxicity) based on 3R principles (replacement, reduction, refinement) for animal experiments.This system covers most of the endpoints of toxicity assessment, and molecular biology technology was also applied to integrate the toxicity test, as well as some operation was optimized in order to shorten the experimental period, reduce experimental costs, improve animal welfare.Furthermore, the results from the screening system have higher clinical relevance because it is based on the toxicity mechanisms.
ABSTRACT
In view of the characteristics of the computerized system,the key points in the quality assurance (QA) of the computerized system was discussed and summarized combined with the requirements of the GLP laboratory in Europe and America.The validation of computerized system,the control during the use of computerized system,period maintenance and safety protection of computerized system,archives of electronic data was discussed,expecting to provide reference for the management of computerized system in Chinese GLP laboratory which is generally not high currently.The experiences were obtained as follow:Through repeated inspection and review,the problem was found and set as the risk point;a targeted QA inspection plan was made focusing on the risk-based inspection and the QA inspection plan was timely adjusted according to the problems,which ensures the pertinence and validity of the QA inspection.
ABSTRACT
The safety and risk assessment of pediatric pharmaceuticals has become a hot spot on drug development and man?agement in recent years. The shortage and unreasonable use of pediatric medicines and lack of preclinical juvenile safety evaluation of marketed pharmaceuticals have caused safety problems,a serious threat to the health and safety of pediatric population. Therefore,gov?ernments have formulated relevant regulative and administrative regulations and policies. In preclinical research ,due to the similarity of the young animals and children in the development process,a series of juvenile animal studies were carried out and the respective guidelines were gradually improved in Europe and the US. Therefore,the toxic effects of pharmaceuticals on children can be effective?ly predicted. In this paper,a detailed analysis and explanation is provided on the difficulties confronted with on R& D of pediatric pharmaceuticals,physiological differences between children and adults,and particularly,the importance and focus of preclinical safe?ty evaluation of pediatric pharmaceuticals,in order to offer a reference for the safety evaluation of pediatric drugs in China.
ABSTRACT
Microbiome is a novel research field related to human health,agriculture,bio-energy and the environment. Gut microbiome has received much attention from researchers recently. Studies have shown that gut flora is related to some diseases,such as digestive disease(inflammatory bowel disease),metabolic disease(type 2 diabetes), cardie-cerebral vascular disease(Parkinson disease). Traditional Chinese materia medica(TCMM) has long been used as a tonic and taken in a large amount. Gut flora has an effect on pharmacology and toxicology of TCMM after entering the gastroin?testinal tract. This article is intended to review recent researches on microbiome,common detection techniques and the relationship with hepatotoxicity induced by Polygonum multiflorum Thunb.,scutel?laria baicalensis that directly affects the intestinal tract,nephrotoxicity induced by Rhizoma Alismatis and pneumonia induced by Xiao-Chaihu-Tang.
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There is emerging evidence from clinical studies that the existence of liver cancer stem cells(CSCs)or tumor initiating cells is responsible for the high recurrence rates of tumor,generation of metastasis,and resistance to therapeutic regimens after therapy. Here,the characteristics of liver CSCs,clinical manifestation,molecular signaling Wnt/β-catenin,signal transducers and activators of transcription 3,NANOG,annexin A3/c-Jun N-terminal kinase,and chapter four-transmembrane 4 L six family member 5/CD44 in liver CSC self-renewal were briefly reviewed. In addition,potential targets for drug therapy were analyzed,providing some reference for drug discovery that selectively target liver CSC self-renewal signals.
ABSTRACT
Objective To research the toxicity of ethanol extracts from Poylgonum multiflorum Thunb(PMT)induced by en?dotoxin of Gram-negative bacteria lipopolysaccharide(LPS)in rat liver,and then investigate the hepatotoxicity mechanisms of PMT on immune inflammatory signal pathway Toll-Like receptor 4(TLR4)-interferon regulated factor3(IRF-3). Methods SD rats were randomly assigned into normal control,LPS(4 mg/kg),acetaminophen APAP(625 mg/kg),PMT 6 g/kg(PMT-L),PMT 12 g/kg (PMT-H),LPS+APAP and LPS+PMT-L/-H groups. The 4 groups later were injected LPS 4 mg/kg by caudal vein,after 2 h,the corre?sponding drugs were administered once a day for 7 consecutive days,respectively. The changes of weight of rats were observed every day. The tissue morphology of liver tissue of rats on 2 h,14 h,5 d,8 d after administration were detected by hematoxylin-eosin stain? ing respectively. Real time quantitative PCR(RT-qPCR)method and Western blotting were used to detect the expression of TLR4, TRIF and IRF3 in the TLR4 signaling pathway in liver cells. Results Two hours after the rat tail vein injection of LPS,the liver tiny granulomas of rats could be observed in LPS-induced groups,and then,the liver injury of rats in LPS group was gradually recovered. Eight Days after LPS induction,the liver tissue structure of rats in LPS group was clear and complete,but in LPS+APAP group and LPS+PMT 6 or 12 g/kg groups,the focal necrosis of hepatocytes,with inflammatory cell infiltration could be observed. The results of RT-qPCR and Western blotting showed that in oral administration of PMT groups,the expression of TLR4,TRIF and IRF-3 mRNA and protein in the liver cells had no significant change compared with the normal control group. But in 4 groups induced with LPS,the expression of TLR4, TRIF and IRF-3 mRNA and protein in the liver cells were significantly higher than that of the normal control group and LPS group(P<0.05). Conclusion PMT can cause liver damage induced by LPS,the hepatotoxicity is related to the positive regulation of TLR4/IRF-3 signaling pathways,which is not related to the dosage of PMT. The results show that activating TLR4/IRF3 signaling pathway is one of the mechanisms of liver injury of PMT in rats induced by LPS.
ABSTRACT
As an integral part of translational medicine,translational toxicology is intended to apply the results of toxicological studies to the prevention of diseases and the harmful effects on organisms. As far as drug safety evaluation is concerned,translational work is focused on developing more sensitive and specific translational safety biomarkers. Previous research focused on indicators of the liver and kidney,cardiovascular damage in the early stage,and detection of early-stage cancer. MicroRNA is hot sphere of research and considered a potential biomarker. Translational toxicology requires multi-discipli-nary and multi-agency communication and cooperation. The approach adopted by the Predictive Safety Testing Consortium is relatively perfect and is worth learnikng from.
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Objective To explore the effect of resveratrol ( Rev) as an antioxidant on oxidative damage to HepaRG cells induced by troglitazone ( Tro).Methods Cells were divided into five groups: control ( RPMI 1640 only with 0.1%DMSO), Tro(50 μmol/L), Tro(50 μmol/L) +Rev(15 μmol/L), Tro(50 μmol/L) +Rev(7.5 μmol/L) and Tro (50 μmol/L)+Rev(3.75 μmol/L) groups.MTT assay was performed to detect the viability of Rev-treated, Tro-treated and Rev with 50 μmol/L Tro-treated HepaRG cells.After 48 hours, the level of reactive oxygen species (ROS) and lipid oxidation ( malondialdehyde , MDA ) , degree of apoptosis , total antioxidant capacity , activity of hydrogenperoxidase (catalase, CAT), glutathione peroxidase (GSH-px) and superoxide dismutase(SOD)of these groups were identified. Results Tro could obviously cause HepaRG cells to produce oxidative stress .Compared with control group ,ROS and lipid peroxidation ( MDA) levels and the rate of apoptosis and necrosis in Tro-treated group were significantly increased ( P<0.05),total antioxidant capacity greatly reduced (P<0.05),and the activity of CAT,GSH-px and SOD was decreased (P<0.05).After adding various concentrations of Rev interaction , ROS and MDA production volume decreased (P < 0.05), and the apoptosis and necrosis rate correspondingly declined (P<0.05).Total antioxidant capacity of the cells and the activity of the three antioxidant enzymes were increased (P<0.05), and there was a dose-dependent relationship. Conclusion Tro can cause HepaRG cells to produce significant oxidative stress while Rev can significantly improve the oxidative damage of Tro to HepaRG cells .