智力包括了逻辑推理能力、理解能力、自我意识能力、学习能力、计划能力、创造能力和解决问题等能力。智力发育存在性别差异，女性智力的成熟时间往往早于男性。然而，关于智力发育性别差异的关键基因及其分子网络机制尚不清楚。迄今为止，全基因组关联分析(Genome-Wide Association Studies, GWAS)发现了507个与智力显著相关的基因。本论文首先分析了BrainSpan人脑RNA-seq数据集中大脑在各个发育阶段的转录测序数据，发现在胚胎晚期，507个智力基因在大脑中的平均表达水平男性高于女性，而在青春期则相反。接着进一步构建了大脑中表达水平具有性别差异的智力基因的互作网络，包括胚胎晚期中男性高表达的智力基因互作网络HELP-M (intelligence genes with higher expression levels in prenatal males)、青春期女性高表达的智力基因互作网络HELP-F (intelligence genes with higher expression levels in pubertal females)。结果表明，这两个网络的关键基因均是Ep300和Ctnnb1。其中Ep300在HELP-M和HELP-F中调控了53个基因的转录，Ctnnb1在HELP-M和HELP-F中调控了45个基因转录，Ctnnb1在HELP-M以及Ep300在HELP-F中分别发挥更重要的作用。对不同发育时间的大鼠进行测序验证，发现在青春期雌性大鼠前额叶皮层中HELP-F的智力基因和关键基因Ep300、Ctnnb1表达水平显著高于雄性大鼠，并且参与了神经发育等相关生物过程。以上结果揭示了在神经发育过程中表达水平具有性别差异的智力基因网络及其关键基因。
Objective To investigate the mechanisms of excitotoxic effects of glutamate on human neuroblastoma SH-SY5Y cells. Methods SH-SY5Y cell viability was measured by MTT assay. Other damaged profile was detected by lactate...
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Objective To investigate the mechanisms of excitotoxic effects of glutamate on human neuroblastoma SH-SY5Y cells. Methods SH-SY5Y cell viability was measured by MTT assay. Other damaged profile was detected by lactate dehydrogenase （LDH） release and by 4＇, 6-diamidino-2-phenylindole （DAPI） staining. The cytosolic calcium concentration was tested by calcium influx assay. The glutamate-induced oxidative stress was analyzed by cytosolic glutathione assay, superoxide dismutase （SOD） assay and extracellular malondialdehyde （MDA） assay. Results Glutamate treatment caused damage in SH- SY5Y cells, including the decrease of cell viability, the increase of LDH release and the alterations of morphological structures. Furthermore, the concentration of cytoplasmic calcium in SH-SY5Y cells was not changed within 20 min following glutamate treatment, while cytosolic calcium concentration significantly increased within 24 h after glutamate treatment, which could not be inhibited by MK801, an antagonist of NMDA receptors, or by LY341495, an antagonist of metabotropic glutamate receptors. On the other hand, oxidative damage was observed in SH-SY5Y cells treated with glutamate, including decreases in glutathione content and SOD activity, and elevation of MDA level, all of which could be alleviated by an antioxidant Tanshinone IIA （Tan IIA, a major active ingredient from a Chinese plant Salvia Miltiorrhiza Bge）. Conclusion Glutamate exerts toxicity in human neuroblastoma SH-SY5Y cells possibly through oxidative damage, not through calcium homeostasis destruction mediated by NMDA receptors.
Objective This report aims to describe the oxidative damage profile in brain ofpresenilinl andpresenilin2 conditional double knockout mice （dKO） at both early and late age stages, and to discuss the correlation betw...
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Objective This report aims to describe the oxidative damage profile in brain ofpresenilinl andpresenilin2 conditional double knockout mice （dKO） at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice. Methods The protein level of Aβ42 in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately. Results Significant decrease of Aβ42 was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation （assessed by MDA） was increased only in dKO cortex at 3 months and protein oxidation （assessed by carbonyl groups） was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 1 2 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months. Conclusion Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Aβ42. Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.
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