Chronic phosphoproteomic in temporal lobe epilepsy mouse models induced by kainic acid / 北京大学学报(医学版)

OBJECTIVE@#To investigate functions of proteins and signaling pathways involved in epileptogenesis during the chronic stage of temporal lobe epilepsy in mouse models.@*METHODS@#Kainic acid-induced temporal lobe epilepsy models were conducted, when reaching stage 4 using racine scale, the mice of experimental group were supposed to be successfully established. Pentobarbital sodium was injected to stop epileptic seizure in case of death. Twenty-eight days after the kainic acid injection, when the experimental group generally turned into chronic spontaneous seizures, mice hippocampal tissues were extracted from the control and the experimental groups respectively for phosphoproteomic. Enriched phosphorylated proteins were detected using mass spectrometry, only the proteins whose density was greater than 106 were analyzed by matching the Gene Ontology (GO) database, Kyoto Encyclopedia of Genes and Genomes (KEGG) database and STRING database to detect proteins involved in epileptogenesis in protein functions, signaling pathways and protein-protein interaction respectively. After that, literatures were reviewed about the key proteins.@*RESULTS@#(1) Total of 12 697 phosphorylation sites of enriched proteins were detected by mass spectrometry, and there were 159 sites whose phosphorylation levels were significantly different from the control (P<0.001). (2) GO database showed that 35.7% of the 159 sites were about "catalytic activity", 39.5% were about "binding" and 20.8% were about "cell communication", and the 159 proteins also participated in many biological processes, such as "primary metabolic process" "response to stimulus" "developmental process" "localization" and "phosphate-containing compound metabolic process". (3) KEGG database showed that the 159 protein sites mainly involved in 10 signaling pathways: glutamatergic synapse, Ras signaling pathway, African trypanosomiasis, Cocaine addiction, Circadian entrainment, Amyotrophic lateral sclerosis (ALS), Long-term potentiation, Endocytosis, Gap junction, Nicotine addiction. (4) STRING database showed that the protein-protein interaction network formed by the 159 proteins was focused on Grin1/Dlg3, Arhgef 2/Arhgap33/Tiam1 and Sptnb1/3/4/Add3/Ank2 protein group respectively. (5) Phosphorylation levels of Grin1, Arhgef 2, Arhgap33, Tiam1, Sptbn1/2/4 and Ank2 in experimental group were significantly higher than in the control (P<0.001).@*CONCLUSION@#Phosphoproteomic illustrated integral distribution of phosphorylated proteins at the chronic stage of temporal lobe epilepsy in the mouse model. Literatures showed that most key proteins were closely related to epileptogenesis, suggesting that some proteins or signaling pathways may play a role in epileptogenesis, such as dopamine and Kir3.1.

Design, synthesis and biological evaluation of novel 1,3 dioxolo 4,5-fisoindolone derivatives / 药学学报

A series of [1,3]dioxolo[4,5-f]isoindolone derivatives were designed, synthesized and evaluated as inhibitors of acetylcholinesterases (AChE). Furthermore, their effects on memory impairment of mice induced by scopolamine were investigated with step-through test. The results suggested that most of the target compounds exhibited potential inhibition on AChE with IC50 values at micromolar range. Compounds I1 (IC50 value of 0.086 μmol · L(-1)) and I2 (IC50 value of 0.080 μmol · L(-1)) showed the strongest AChE inhibitory activity, which are equipotent to donepezil (IC50 value of 0.094 μmol · L(-1)). Moreover, compounds I1-I4 could improve the memory impairment induced by scopolamine in mice.

Design, synthesis and biological evaluation of novel 4-substituted-3-nitrobenzamide derivatives / 药学学报

A series of novel 4-substituted-3-nitrobenzamide derivatives were designed and synthesized. The structures of the target compounds were confirmed with 1H NMR, 13C NMR, MS and element analysis. Anti-tumor activities against HCT-116, MDA-MB435 and HL-60 cell lines in vitro were evaluated by SRB assay. The results indicated most of the target compounds exhibited potent anti-tumor activity. Compound 4a showed the most potent inhibitory activities against three cancer cell lines with the GI50 values of 1.904-2.111 micromol x L(-1). Compounds 4g, 41-4n exhibited more potent inhibitory activities against MDA-MB435 and HL-60 cell lines with the GI50 values of 1.008-3.586 micromol x L(-1) and 1.993-3.778 micromol x L(-1), respectively. The structure-activity relationship of these compounds is discussed preliminarily.