Role of LRP in TGFbeta2-mediated neuronal uptake of Abeta and effects on memory

There is increasing evidence that soluble amyloid-beta peptide (Abeta) uptake into neurons is an early event in the pathogenesis of Alzheimer's disease (AD). Identification of the early events leading to neuronal dysfunction is key to developing therapeutic strategies, but relative roles of receptors and factors modulating uptake are poorly understood. Studies have shown that transforming growth factor beta (TGFbeta), particularly TGFbeta2, can influence the targeting of Abeta to cells in vitro. TGFbeta2 can target Abeta to neurons in organotypic hippocampal slice cultures (OHSC). We examine a specific mechanism for TGFbeta2-mediated targeting of Abeta to neurons. The receptor-associated protein (RAP), a low-density lipoprotein receptor-related protein (LRP) antagonist, can attenuate the cellular targeting of Abeta both in vitro and in vivo and prevent Abeta/TGFbeta2-induced memory retention deficits. Using both in vitro and in vivo methods, we identify LRP as playing a role in TGFbeta2-mediated Abeta uptake, neurodegeneration, and spatial memory impairment.     

氧化还原态失衡与冠状动脉粥样硬化性心脏病

目的探讨氧化还原态失衡与冠状动脉粥样硬化性心脏病（冠心病）的关系。方法根据冠状动脉造影结果,将123例疑似冠心病住院患者分为冠心病组（A组）41例,冠状动脉粥样硬化组（B组）45例,冠状动脉正常组（C组）37例。取所有研究对象静脉血,测血浆还原型谷胱甘肽（GSH）与氧化型谷胱甘肽（GSSG）,氧化型低密度脂蛋白（oxLDL）和丙二醛（MDA）浓度。计算GSH／GSSG氧化还原电位,与冠状动脉斑块积分及oxLDL行相关性分析。结果随冠状动脉斑块积分增高（从C组-A组）,GSH、GSH／GSSG逐次减低,分别为（321．27±56．89）μmol／L,（309．52±44．56）μmol／L,（285．71±38．23）μmol／L（P〈O．05）;10．56±1．70,9．86±1．58,8．65±1．18（P〈0．05）;GSSG、GSH／GSSG氧化还原电位逐次升高,分别为（30．42±1．53）μmol／L,（31．39±1．64）μmol／L,（33．03±1．75）μmol／L（P〈0．05）;（-142．39±1．33）mV,（-140．18±1．12）mV,（-136．17±1．01）mV（P〈0．05）;氧化应激损伤产物oxLDI、MDA亦随冠状动脉斑块积分增高而增加,分别为（417．22±126．61）μg／L,（557．24±171．83）μg／L,（691．96±203．55）μg／L（P〈0．05）;（2．39±1．24）μmol／L,（3．25±1．37）μmol／L,（4．39±1．52）μmol／L（P〈0．05）;GSH／GSSG氧化还原电位与oxLDL呈明显正相关（r=0．823,P〈0．001）。结论随着冠状动脉斑块积分增高,血浆GSH／GSSG氧化还原态向氧化方向明显偏移,这可能与动脉粥样硬化的发生发展有关。     

枯草溶菌素转换酶9与血脂代谢调节

高胆固醇血症及其引起的冠心病已成为威胁人类健康的最重要因素,血脂代谢相关研究日益受到重视.最近的研究表明,一种前蛋白转换酶家族成员--枯草溶菌素转换酶9(proproteinconvertasc kexin type 9,PCSK9)在血脂代谢调节中起着重要作用.PCSK9基因的表达和突变与低密度脂蛋白受体(low-density lipoprotein receptor,LDLR)含量密切相火,PCSK9高度表达能促进LDLR降解,从而提高血浆LDL水平;反之,PCSK9基因抑制则引起血浆LDL水平降低.因此,通过研究PCSK9的作用机制,有望开发出治疗高胆固醇血症、控制高血脂和预防冠心病的新型药物.     

Different inflammatory responses induced by three LDL‐lowering apheresis columns

Low‐density lipoprotein (LDL) apheresis is well‐established in selected patients with uncontrolled LDL levels. As such treatment affects biomarkers important in atherosclerosis and acute coronary syndromes, we systematically compared the inflammatory response induced by three LDL apheresis columns. Three patients with heterozygous familial hypercholesterolemia participated in a cross‐over study with six consecutive treatments with three different LDL apheresis columns: DL‐75 (whole blood adsorption), LA‐15 (plasma adsorption), and EC‐50W (plasma filtration). Biochemical parameters and inflammatory biomarkers, including complement activation products and 27 cytokines, chemokines, and growth factors were measured before and after treatment. Complement was activated through the alternative pathway. The final end product sC5b‐9 increased significantly (P < 0.01) and equally with all devices, whereas the anaphylatoxins C3a and C5a were lower by use of the adsorption columns. Hs‐CRP was reduced by 77% (DL‐75), 72% (LA‐15), and 43% (EC‐50W). The cytokines were consistently either increased (IL‐1ra, IP‐10, MCP‐1), decreased (IFN‐γ, TNF‐α, RANTES, PDGF, VEGF), or hardly changed (including IL‐6, IL8, MIP‐1αβ) during treatment. The changes were in general less pronounced with the adsorption columns. All columns reduced LDL significantly and to the same extent. In conclusion, three LDL‐apheresis devices with equal cholesterol‐lowering effect differed significantly with respect to the inflammatory response. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.     

Hydrangea dulcis folium preserves β-cell mass in diabetic db/db mice

The anti-diabetic efficacy of Hydrangea dulcis folium (HDF) was studied in db/db mice and their littermates (db/-). Supplementation of HDF (1% and 3%) decreased glucose level significantly by 2- and 4-fold and increased significantly insulin level by 3- and 4.5-fold compared to db/db mice (P < 0.05). Administration of HDF (1% and 3%) ameliorates hyperglycemia and improves glucose homeostasis in db/db mice in a dose-dependent manner by preventing loss of β-cell mass resulting in increase of insulin secretion. In addition, 3% HDF treatment significantly reduced the food intake, weight gain, and blood lipids in db/db mice.     

Inadequate dietary magnesium intake increases atherosclerotic plaque development in rabbits

Epidemiological studies have shown dietary magnesium (Mg) intake and serum Mg levels to be inversely correlated with the development of atherosclerosis. We hypothesized that low levels of Mg would promote atherosclerotic plaque development in rabbits. New Zealand white rabbits (4 months old, n = 22) were fed an atherogenic diet containing 0.12% (−Mg), 0.27% (control), or 0.43% (+Mg) Mg for 8 weeks. Blood samples were obtained at baseline, 2, 4, 6, and 8 weeks and were assayed for total cholesterol, high-density lipoprotein (HDL), non-HDL, triglycerides (TG), C-reactive protein, serum Mg, and erythrocyte Mg. Aortas from −Mg had significantly more plaque, with an intima thickness 42% greater than control and 36% greater than +Mg. Serum cholesterol levels rose over time, and at 8 weeks, −Mg had the highest and +Mg the lowest total and non-HDL cholesterol and TG levels, although these results did not reach significance. Over time, serum Mg levels increased, and erythrocyte Mg levels decreased. C-reactive protein significantly increased in all groups at 4 and 6 weeks but returned to baseline levels by 8 weeks. This study supports the hypothesis that inadequate intake of Mg results in an increase in atherosclerotic plaque development in rabbits.     

老年高血压及血脂与低密度脂蛋白受体基因的关系

目的：探讨老年高血压及血脂与低密度脂蛋白受体（LDLR）基因HineⅡ多态性的关系。方法：采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法测定高血压组126例，对照组150例的LDLR基因型。结果：LDLR包括CC、CT、TT三种基因型。高血压组C等位基因频率高于对照组（P〈0．01）。结论：高血压组C等位基因频率高于对照组，提示低密度脂蛋白受体基因可能与老年高血压相关。     

HMG-CoA还原酶抑制剂对肾病综合征大鼠肝脏低密度脂蛋白受体表达的影响

目的观察在大鼠肾病综合征模型中使用3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂洛伐他汀（Lovastatin）治疗对肝脏低密度脂蛋白（LDL）受体表达的影响，探讨他汀类药治疗肾病综合征高脂血症的机制。方法大鼠2次尾静脉注射阿霉素建立肾病综合征大鼠模型；采用灌胃法给予大鼠洛伐他汀治疗2周。采用Western blot和RT-PCR技术分别检测LDL受体蛋白和其mRNA在肝脏的表达，同时检测大鼠相关血生化指标。结果肾病综合征大鼠洛伐他汀治疗2周后，血清总胆固醇、LDL胆固醇和三酰甘油以及尿蛋白均显著降低（均P〈0．05），血清白蛋白显著升高（P〈0．05），血肌酐在各组间差异无显著性意义（P〉0．05）；肝脏LDL受体蛋白较肾病综合征组显著增加（P〈0．01）；肝脏LDL受体mRNA水平在各组间差异无显著性意义。结论肾病综合征大鼠经洛伐他汀治疗后，其肝脏LDL受体缺乏得到明显改善，伴随的高脂血症也得到明显改善。