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
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
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 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 .