| Xerocomic acid was largely separated from Chroogomphus rutilus,and the safety evaluation,the pharmacokinetics and the antitumor mechanisms of xerocomic acid were further studied.By pre-experiments to determine the dosage of the LD0 and the LD100 of xerocomic acid,calculated the formal groups in the experiment.If LD100 can not be measured in pre-experiments,Line maximum dosage(MLD)experiments will be performed.During pre-experiments period of the MLD(14d),there were no abnormal changes about weight,coat color,secretion,faeces,breathing and activity in xerocomic acidand control groups,and no effect on growth and major organs are in mice.Conclusion: xerocomic acid don't show any poisonous and can be considered medication safety.To establish a method for determining xerocomic acid in plasma and tissues of rats,and to study its pharmacokinetic characteristics and tissue distribution characteristics after intragastric administration and intravenous injection.The concentration of xerocomic acid in plasma and tissues of rats were analyzed by HPLC using an Agilent ZORBAX Eclipse XDB-C18 column(4.6mm×250mm,0.5?m)with the mobile phase of methanol-water(75:25),the temperature of column was 25?,flow rate was set at 1.0mL·min-1,and the UV detector was set at 243 nm.The endogenous ingredients in plasma and liver tissue showed no interference to the determination.The curves of average concentration-time for determining xerocomic acid after intragastric administration was fit to one compartment model.The primary pharmacokinetic pharameters were: Tmax(0.76±0.21)h,Cmax(8.76±0.81)?g·ml-1,t1/2(0.18±0.28)h,AUC0-inf(102.95±1.76)?g·ml-1·h-1.The curves of average concentration-time for determining xerocomic acid after intravenous injection was fit to two compartment model.The primary pharmacokinetic pharameters were: t1/2(0.33±0.71)h,AUC0-inf(34.14±2.38)?g·ml-1·h-1.The established HPLC method is proved to meet the requirements of biological sample analyses,and is rapid,sensitive and accurate.In addition,it is the first time to study the pharmacoineic characters and tissue distribution of xerocomic acid in rats,which provides the basis for drug discovery,pharmacological effects and mechanism research of xerocomic acid.Xerocomic acid was used to analyze the differential expression,gene ontology and pathway with a lot of data by Affymetrix gene chip on HepG2 in this part.The significant analysis of microarrays was done with fold-charge and p-value.Xerocomicacid was analyzed with fold-charge greater than 2 and p-value less than 0.05 as a standard.There were 1002 up-regulated expression genes and 1230 down-regulated expression in 2232 significant changed genes.607 significant expressed genesattended in Biological Process,which mainly involved the regulation of genetic transcription,cell signal transduction process andparticipate in the process of the synthesis of chromatin and some material metabolism.648 significant expressed genesattended in Cellular Component,obvious changes in gene ontology analysis mainly concentrated in the cytosol,centriole,cell membrane,golgi apparatus,cytoplasm,nuclear small,chromosome,extracellular region,etc,which may be associated with regulating chromatin transcriptional and cell membrane permeability and transport by controlling the permeability of cell membrane to regulate the matter and energy exchange,the stability of the damaged cells to promote the apoptosis.602 ignificant expressed genesattended in Molecular Function mainly concentrated in the regulation of protein expression and degradation protein,DNA,RNA and metal ions on the binding activity,which involved in regulation of protein phosphorylation and signal transduction process,mainly toregulate the activity of a variety of protein kinases in the transmembrane signal transduction pathway.Comprehensive analysis of the results: xerocomic acid played a major role in the process of mitosis,which participated in regulating of chromatin conformation changes,transcription,expression and transport function of cell membrane and metabolism.In Pathway analysis,xerocomic acid participate in the four tumor related signaling pathway,respectively TGF-beta signaling pathway,TNF signaling pathway,p53 signaling pathway,Estrogen signaling pathway,which were considered by influencing these four signaling pathways to achieve control the process cells,promote cell apoptosis,inhibition of cell proliferation and differentiation and other functions.And xerocomic acid may regulate the change of chromatin conformation in mitosis,transcription,different genes or specific gene expression by influencing the four signaling pathways or interaction between these four signaling pathways,which can inhibite tumor cell cycle and proliferation.Xerocomic acid may be associated with regulating chromatin transcriptional and cell membrane permeability and transport by controlling the permeability of cell membrane to regulate the matter and energy exchange,the stability of the damaged cells to promote the apoptosis... |
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