Dihydroergotamine ameliorates synaptic atrophy in Alzheimer’s disease states and its effect on cognitive function / 中国药科大学学报

@#Studies suggest that synaptic damage is closely associated with cognitive dysfunction, and lemur tyrosine kinase 1 (LMTK1) is a key kinase that affects synaptic growth. Dihydroergotamine (DHE) is an ergot alkaloid derivative with high biological activity, which could regulate cognition, memory processing and motor control.This study aims to investigate the effect of DHE on synapse atrophy and plasticity as well as cognition in Alzheimer’s disease (AD) model animals.SAMR1 mice were selected as control group (n = 12).SAMP8 mice were randomly divided into 3 groups (n = 12 for each group):AD group, DHE low-dose group and high-dose group.The DHE groups were injected DHE intraperitoneally daily for 8 weeks.Immunofluorescence experiments, Golgi staining experiment, electrophysiological experiment, Morris water maze experiment (MWM) and Western blot experiment were conducted to investigate the effect of DHE on synaptic morphology, synaptic plasticity, cognitive function as well as the phosphorylation level of LMTK1 downstream TBC1D9B in AD model mice.Subsequently, the LMTK1 silencing and overexpression cells were constructed.Immunofluorescence experiments were used to study the effect of DHE on synaptic length of nerve cell after LMTK1 silencing and overexpression.In the hippocampus of AD mice, the postsynaptic marker PSD95 was significantly increased after DHE administration, which suggested that DHE could increase the synaptic density. In Golgi staining experiment, synaptic atrophy was observed in the hippocampal of AD mice, which could be improved by high-dose DHE.Compared with normal mice, the long-term potentiation (LTP) level of AD model mice was significantly reduced (P < 0.000 1), DHE could increase LTP significantly.The MWM experiment further showed that DHE could improve cognitive function in AD mice.WB experiments showed that the level of P-LMTK1 in the hippocampus of AD mice increased significantly, and the level of downstream P-TBC1D9B decreased significantly after DHE administration.Cell immunofluorescence experiments in vitro had shown that DHE significantly improved synaptic atrophy in overexpressed C17.2 cells, while its improvement disappeared when LMTK1 was silenced. This research suggests DHE may improve synaptic atrophy and cognitive dysfunction in AD by targeting on LMTK1.

Novel MSX1 variants identified in families with nonsyndromic oligodontia / 国际口腔科学杂志·英文版

The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia, and a series of bioinformatics databases were used for variant confirmation and functional prediction. Phenotypic characterization of the members of these families was described, and an in vitro analysis was performed for functional evaluation. Five novel MSX1 heterozygous variants were identified: three missense variants [c.662A>C (p.Q221P), c.670C>T (p.R224C), and c.809C>T (p.S270L)], one nonsense variant [c.364G>T (p.G122*)], and one frameshift variant [c.277delG (p.A93Rfs*67)]. Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P, p.R224C, p.G122*, and p.A93Rfs*67 variants compared to the wild type. Three variants (p.Q221P, p.G122*, and p.A93Rfs*67) were classified as pathogenic or likely pathogenic, while p.S270L and p.R224C were of uncertain significance in the current data. Moreover, we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss. Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.

Evaluating cerebral endothelial dysfunction induced by amyloid based on the time series model / 中国药科大学学报

@#Time series model was developed to investigate the effect and contributions of related biomarkers on the cerebral endothelial dysfunction induced by beta amyloid(Aβ). HCMEC/D3 was incubated with 2. 5 μmol/L Aβ for 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 h, and biomarkers including cytosolic calcium ion, mitochondrial membrane potential(MMP), endothelial nitric oxide synthase(eNOS)and cell viability were determined. Time series model was established to assess the dynamic relationship between the related biomarkers and cell viability and the contribution of different biomarkers to cell damage. Impulse response analysis indicated that after a positive impact on cytosolic calcium ion, cell viability decreased and this impact continued to decline; after a positive impact on endothelial nitric oxide synthase and mitochondrial membrane potential, cell viability increases, which increased rapidly in the early stage, and the rate decreased in later stage. The result of variance decomposition showed that the cytosolic calcium ion played a major role in cerebral endothelial dysfunction induced by Aβ. Combined with the model study, it is concluded that the intervention on the level of cytosolic calcium ion at the early stage may be the possible way to slow the disease progression.

Effects of HBV co-infection on liver function of patientswith different types of hepatic echinococcosis / 西安交通大学学报(医学版)

Objective To clarify the effects of HBV co-infection on liver function of patients with different types of hepatic echinococcosis.Methods We recruited 409 patients diagnosed with hepatic echinococcosis at three hospitals in western regions in China from 2014 to 2015.Venous blood was withdrawn to detect to liver function indications.ELISA was performed to detect HBsAg.We analyzed liver function in patients stratified by different types of hepatic echinococcosis with or without HBV infection.Results The hepatic echinococcosis patients infected with HBV had more severe impairment in liver functions such as reduced albumin and increased transaminase.The patients with hepatic alveolar echinococcosis were more vulnerable to HBV infection compared with those with hepatic cystic echinococcosis (38.4％ vs.86.4％, P<0.05).In addition, liver injury was more severe in patients diagnosed with alveolar hepatic echinococcosis and HBV infection compared with those diagnosed with cystic hepatic echinococcosis and HBV infection (all P<0.05).Conclusion Hepatic alveolar echinococcosis patients co-infected with HBV have worse liver injury compared with those hepatic cystic with HBV. Therefore, they deserve special attention in clinical treatment.

EDA mutation screening and phenotype analysis in patients with tooth agenesis / 北京大学学报(医学版)

Objective:To screen the ectodysplasin A (EDA)gene mutation in the patients with non-syndromic tooth agenesis and ectodermal dysplasia,and to analyze the phenotype of missing teeth pattern in these two groups of patients.Methods:In the study,174 patients with tooth agenesis (143:non-syn-dromic,31:ectodermal dysplasia)and 451 health control volunteers were enrolled from the clinic,and the genome DNA was extracted from either peripheral blood or oral mucosal swab.The coding region of EDA gene was then amplified by PCR,sequenced and blasted to online NCBI database.The missing teeth were recorded for all patients,and the missing teeth from patients with EDA mutation were com-pared among the different dentition sites.Results:33 patients were identified with EDA mutation.In the non-syndromic patients,13 /143(9.09%)were identified with EDA mutation,while in patients with ec-todermal dysplasia,20 /31 (64.52%)were found with EDA mutation.Ten novel EDA mutations were identified (c.769G >C[p.G257R],c.936C >G[p.I312M],c.223G >A[p.E75K],c.1166C >T[p. P389L],c.133G >C[p.G45R],c.1109G >A[p.E370K],c.914G >T[p.S305I],c.916C >T[p. Q306X],c.602G >T[p.G201V],c.88 -89insG[p.A30GfsX69]).For each dentition site there was no statistic difference in the number of missing teeth between the left and right sides,so the number from both sides were combined later in the analysis.In the patients with EDA mutation,the non-syndromic pa-tients had fewer missing teeth (15.9 ±6.4 missing teeth for each,207 /364 in total)than the patients with ectodermal dysplasia (23.9 ±4.3,478 /560).In the non-syndromic patients with EDA mutation, the maxillay central incisors and first molars were less affected,with the same missing rate as 19.2% (5 /26).While the mandibular central incisors (with a missing rate of 76.9%,20 /26),the maxillary late-ral incisors (the missing rate:88.5%,23 /26 ),the mandibular lateral incisors (the missing rate:80.8%,21 /26),and the maxillary first premolars (the missing rate:80.8%,21 /26)were more likely to be missing.In the ectodermal dysplasia patients with EDA mutation,only maxillary central incisors (the missing rate:60%,24 /40),maxillary canines (the missing rate:70%,28 /40),mandibular ca-nines (the missing rate:67.5%,27 /40),maxillary first molars (the missing rate:65%,26 /40)and mandibular first molars (the missing rate:72.5%,29 /40)had higher possibility of persistence.Teeth at other dentition sites were more likely to be affected (the minimum missing rate:87.5%,35 /40). Conclusion:The findings would help to reveal the EDA gene and its function in ectodermal organogene-sis.

Evaluation of cardiotoxicity of doxorubicin in rat by a novel metabolic balance model / 中国药科大学学报

@#The study developed a metabolic balance model to evaluated the cardiotoxicity of doxorubicin. The rats were divided into 3 groups, control group(saline), low dose group(8 mg/kg of cumulative doxorubicin)and high dose group(15 mg/kg of cumulative doxorubicin). Doxorubicin or saline was intraperitoneally injected and blood sample was collected at day 1, 4, 7 and 10. The concentrations of nitric oxide(NO), B-type natriuretic peptide(BNP)and the activity of glutathion peroxidase(GSH-Px), xanthine oxidase(XOD)in rat plasma were determined. A metabolic balance model based on the four biomarkers was developed to evaluate the doxorubicin cardiotoxicity in rat. Doxorubicin leaded to significant changes of multiple biomarkers, resulting in metabolic balance disruption according to the metabolic balance maps and dynamic parameters of metabolic balance disruption. Moreover, the correlation study showed a good relationship between metabolic balance disruption and ejection fraction(EF). The metabolic balance model provide a novel method to integrally evaluate the doxorubicin-induced cardiotoxicity.