姜黄素对阿尔茨海默病小鼠海马InR和IGF1R表达的影响

目的观察姜黄素对阿尔茨海默病(Alzheimer's disease,AD)模型APP/PS1双转基因小鼠胰岛素受体(insulin receptor,InR)和胰岛素样生长因子1受体(insulin-like growth factor 1 receptor,IGF1R)表达的影响。方法将3月龄的APP/PS1双转基因小鼠随机分为模型组、阳性罗格列酮对照组(每日10 mg/kg)、姜黄素大(每日400 mg/kg)、中(每日200 mg/kg)、小剂量组(100 mg/kg),正常组为相同背景非转基因小鼠。灌胃3个月后,应用免疫组织化学和Western blot方法进行检测。结果 InR和IGF1R免疫组化染色,模型组小鼠大脑海马CA1区较正常对照组InR阳性细胞明显增加(P<0.01),姜黄素干预组有所恢复;而模型组小鼠大脑海马CA1区较正常对照组IGF1R阳性细胞明显减少(P<0.01),姜黄素干预组有所恢复。Western blot检测海马InR和IGF1R的蛋白表达结果与免疫组织化学检测结果一致。结论姜黄素可以使APP/PS1双转基因小鼠海马增加的InR和减少的IGF1R得以恢复,改善APP/PS1双转基因小鼠胰岛素信号转导。

Preliminary examination of early neuroconnectivity features in the R6/1 mouse model of Huntington's disease by ultra-high field diffusion MRI

During the last decades,advances in the understanding of genetic,cellular,and microstructural alterations associated to Huntington's disease(HD)have improved the understanding of this progressive and fatal illness.However,events related to early neuropathological events,neuroinflammation,deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown.Ultra-high field diffusion MRI(UHFD-MRI)techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD.In addition,it is possible to evaluate if early imaging microstructural parameters might be linked to histological biomarkers.Moreover,qualitative studies analyzing histological complexity in brain areas susceptible to neurodegeneration could provide information on inflammatory events,compensatory increase of neuroconnectivity and mechanisms of brain repair and regeneration.The application of ultra-high field diffusion-MRI technology in animal models,particularly the R6/1 mice(a common preclinical mammalian model of HD),provide the opportunity to analyze alterations in a physiologically intact model of the disease.Although some disparities in volumetric changes across different brain structures between preclinical and clinical models has been documented,further application of different diffusion MRI techniques used in combination like diffusion tensor imaging,and neurite orientation dispersion and density imaging have proved effective in characterizing early parameters associated to alteration in water diffusion exchange within intracellular and extracellular compartments in brain white and grey matter.Thus,the combination of diffusion MRI imaging techniques and more complex neuropathological analysis could accelerate the discovery of new imaging biomarkers and the early diagnosis and neuromonitoring of patients affected with HD.

中期阿尔茨海默病小鼠模型海马组织Mst1r基因甲基化初探

目的探讨Mst1r基因在中期病程阿尔茨海默病模型(presenilins条件性双基因敲除小鼠,d KO mice)中海马组织的甲基化状态。方法选取12月龄雌性d KO mice及同系野生型小鼠各3只,采用二代测序技术(简化表观亚硫氢酸盐测序技术,RRBS)检测其海马组织基因组DNA以获得甲基化异常基因。结果RRBS测序成果显示中期AD d KO mice海马组织中Mst1r基因呈超甲基化状态(P<0.05)。结论超甲基化的Mst1r基因可能在中期AD d KO mice的病理过程中发挥着一定作用。

Further Pharmacological Studies Using the Compound （1 z）-2-（Hyd roxym et hyl）-Dodec-1 -E ne-1,3-D iol

The compound （1 z）-2-（hydroxymethyl）-dodec-1-ene-1,3-diol was previously isolated from the integument of the red palm weevil Rhynhophorus ferruginous and found to antagonize calcium chloride induced dysrrhythmia in mice. Further calcium-dependent pharmacological actions performed in this study revealed that it has the ability to inhibit platelets aggregation induced in guinea pigs with either ADP or archegonia acids, and the compound also decreased the arterial pressure in rats in a dose-dependent manner and exerted potential ant consultant activity in mice against pentylene tetrazole-induced seizures. However, no complete protection was observed. Analgesic studies in mice using the hot plate （58 ℃） revealed its potential analgesic activities. Its effective dose 50 （ED50） was 85.7 ± 6.3 mg/kg （N= 5）. The compound seamed to produce all of the above actions via a calcium antagonistic action.

普伐他汀和辛伐他汀对载脂蛋白E缺陷小鼠主动脉粥样硬化形成及主动脉壁血管细胞粘附分子-1表达的影响

为观察普伐他汀和辛伐他汀对载脂蛋白E缺陷小鼠主动脉粥样斑块形成的影响及主动脉壁血管细胞粘附分子 1表达的影响 ,将载脂蛋白E缺陷小鼠分为普伐他汀组 (每天 10mg/kg)、辛伐他汀组 (每天 5mg/kg)和阳性对照组 (等量生理盐水 ) ,从主动脉血管根部连续切片 ,常规HE染色 ,计算机图像扫描 ,分析主动脉粥样硬化斑块的面积和斑块占管腔面积等 ;采用免疫组织化学及Western杂交方法测定主动脉壁血管细胞粘附分子 1表达。结果发现 ,除降胆固醇作用外 ,普伐他汀和辛伐他汀皆延缓斑块形成 ,与对照载脂蛋白E缺陷小鼠比 ,用药组小鼠的主动脉粥样斑块明显缩小 ;普伐他汀和辛伐他汀还明显抑制载脂蛋白E缺陷小鼠主动脉壁血管细胞粘附分子 1的表达 ;其中 2药对 14和 2 4周龄小鼠主动脉壁血管细胞粘附分子 1表达的抑制作用强于 34周龄小鼠。结果提示 ,普伐他汀和辛伐他汀可延缓或缩小载脂蛋白E缺陷小鼠主动脉粥样斑块的形成 ,抑制或下调主动脉壁血管细胞粘附分子 1表达 ,其效果与降胆固醇作用不成比例 。

海南红树林淡紫拟青霉胞外多糖抗HSV-1作用研究

目的探讨红树林淡紫拟青霉胞外多糖体内抗单纯疱疹病毒-1(HSV-1)作用。方法选取昆明种小鼠75只,随机分为正常对照组,病毒对照组,低、中、高剂量组,每组15只。正常对照组给予DMEM 0.5 ml腹腔注射,其余4组给予HSV-10.5 ml腹腔注射。次日低、中、高剂量组小鼠分别经腹腔注射淡紫拟青霉胞外多糖6、8、10 g/(kg·d);正常对照组和病毒对照组腹腔注射生理盐水0.5 ml,连续注射7 d。观察并比较各组小鼠肝脏病理变化;5组小鼠脑组织匀浆上清液接种于Vero细胞,观察其细胞病变情况;提取同一部位脑组织病毒基因组DNA,检测病毒DNA相对含量及血清干扰素-γ(IFN-γ)、白介素-12(IL-12)和肿瘤坏死因子-α(TNF-α)含量。结果与正常对照组比较,病毒对照组和低剂量组小鼠肝脏汇管区大量炎性细胞浸润,部分肝细胞肿胀;中剂量和高剂量组炎性细胞浸润明显减少。与病毒对照组相比,中、高剂量组脑组织HSV-1病毒DNA相对含量减低(P<0.01),低剂量组病毒DNA相对含量与病毒对照组比较差异无统计学意义(P>0.05)。与正常对照组比较,其余4组小鼠血清IFN-γ、IL-12、TNF-α水平均显著升高(P<0.01);高剂量组IFN-γ水平高于病毒对照组和低、中剂量组(P<0.01);中、高剂量组IL-12水平高于病毒对照组和低剂量组(P<0.01)。与病毒对照组比较,低、中、高剂量组TNF-α水平均显著降低,且中、高剂量组低于低剂量组(P<0.01)。结论红树林淡紫拟青霉胞外多糖具有一定抗HSV-1作用,可能是通过抑制病毒复制、刺激IFN-γ和IL-12分泌,抑制TNF-α产生完成的。

The adjustment of γ-aminobutyric acid_A tonic subunits in Huntington＇s disease：from transcription to translation to synaptic levels into the neostriatum

γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of GABAA receptors,including tonic subunits.The studies about of GABAA tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.

快速老化系小鼠与昆明系小鼠AD相关指标的比较

目的:观察6月龄的快速老化系SAM-P/8、SAM-R/1小鼠与昆明系小鼠的AD相关指标的变化。方法:取健康(20±5)g6月龄SAM-P/8小鼠、SAM-R/1小鼠和昆明系小鼠各14只,雌雄各半,随机分成:SAM-P/8小鼠(AD疾病模型小鼠)、SAM-R/1小鼠对照组和昆明系小鼠对照组,观察上述3组小鼠行为学、神经生化、超微结构、基因表达情况。结果:6月龄SAM-P/8小鼠1-4d学习成绩、第5d记忆成绩低于6月龄SMA-R小鼠和昆明系小鼠(P<0.05),真性胆碱酯酶活性则高于6月龄SMA-R/1小鼠和昆明系小鼠(P<0.05);SAM-P/8小鼠海马神经元超微结构显示明显纤维化,而SAM-R/1小鼠和昆明系小鼠无明显纤维化;SAM-P/8小鼠脑神经细胞的凋亡相关基因表达有明显上调达2倍以上,而SAM-R/1小鼠和昆明系小鼠则未见这些基因有明显上调。SAM-R/1小鼠和昆明系小鼠比较,除基因表达略有差异之外,其它指标无明显差异。结论:6月龄SAM-P/8小鼠在很多方面已经具备了AD自然发病模型典型特征。而用于正常对照的6月龄SAM-R/1与昆明系小鼠的行为学、TchE活性、超微结构则无显著差异;凋亡相关基因表达差异不明显,而部分基因表达则有一定差异。