Phytanic acid impairs mitochondrial respiration through protonophoric action

Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts. Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007 J. C. Komen, F. Distelmaier: These authors contributed equally to this work.     

<Emphasis Type="Italic">Legionella pneumophila</Emphasis> — a human pathogen that co-evolved with fresh water protozoa

The bacterial pathogen Legionella pneumophila is found ubiquitously in fresh water environments where it replicates within protozoan hosts. When inhaled by humans it can replicate within alveolar macrophages and cause a severe pneumonia, Legionnaires disease. Yet much needs to be learned regarding the mechanisms that allow Legionella to modulate host functions to its advantage and the regulatory network governing its intracellular life cycle. The establishment and publication of the complete genome sequences of three clinical L. pneumophila isolates paved the way for major breakthroughs in understanding the biology of L. pneumophila. Based on sequence analysis many new putative virulence factors have been identified foremost among them eukaryotic-like proteins that may be implicated in many different steps of the Legionella life cycle. This review summarizes what is currently known about regulation of the Legionella life cycle and gives insight in the Legionella-specific features as deduced from genome analysis. Received 1 September 2006; received after revision 10 October 2006; accepted 22 November 2006     

Developing pharmacological therapies for Alzheimer disease

Alzheimer disease (AD), while chronic and progressive with an average progression of 7 – 10 years, is both multifactorial and heterogeneous. Thus, AD offers a large window of opportunity and a large number of therapeutic targets to inhibit it. The selection of a therapeutic target, however, is one of the biggest challenges in developing a pharmacological treatment of this multifactorial disease. Inhibition of a pivotal downstream event is likely to benefit more patients than inhibition of an upstream event in AD pathogenesis. Neurofibrillary degeneration of abnormally hyperphosphorylated tau offers such a pivotal therapeutic target. Abnormal hyperphosphorylation of tau and not its aggregation into filaments appears to be the most deleterious step in neurofibrillary degeneration. Tau can be abnormally hyperphosphorylated by downregulation of protein phosphatase-2A activity or by upregulation of more than one tau kinase. Restoration of the phosphatase activity which is downregulated in AD brain or inhibition of GSK-3β and cdk5, which are required for AD-type abnormal hyperphosphorylation of tau, are among the most promising therapeutic strategies.     

粪菌移植对肺炎克雷伯菌所致小鼠肝脓肿感染的抑制作用

探讨粪菌移植(FMT)对高致病性肺炎克雷伯菌(Klebsiella pneumoniae)所致小鼠肝脓肿(KLA)感染的抑制作用及相关机制.小鼠随机分为对照(Healthy)组、肺炎克雷伯菌(Kp)组和干预(FMT)组. Kp组小鼠经口灌胃10⁶ CFU K1血清型肺炎克雷伯菌;FMT组在给菌24 h后经口灌胃给予正常小鼠粪菌悬液(300 mg/mL,0.3 mL).结果表明,与Kp组相比,FMT处理明显降低了小鼠KLA感染率;16S rRNA高通量测序分析表明,FMT显著改变了小鼠肠道菌群组成,包括增加了Alloprevotella、norank＿f＿Muribaculaceae等益生菌的丰度;同时FMT处理明显降低了小鼠血清TNF-α和胃肠内防御素分子浓度,同时增加了肠黏蛋白2(MUC2)的表达.因此,肠道菌群和免疫防御因子可能一起参与了FMT对高致病性肺炎克雷伯菌所致小鼠KLA感染的抑制作用.     

黄芪注射液治疗肺心病急性加重期73例疗效观察

目的:探讨黄芪注射液静脉注射治疗肺心病急性加重期的疗效.方法:对照组67例,采用常规的抗感染、平喘、强心及利尿等治疗;治疗组73例,在常规治疗的基础上同时加用黄芪注射液40mL溶于5%葡萄糖250mL中静脉滴注,每日一次,10d为一疗程.结果:治疗组和对照组的有效率分别为91.78%和74.63%(P<0.01);两组治疗后心输出量(CO,L/minm2)、心脏指数(CI)、左室射血分数(LVEF)、左室短轴缩短率(FS)、每搏输出量(SV)、二尖瓣快速充血期和心房收缩期血流速度(E/A)均较治疗前明显改善(P<0.05,P<0.01),但治疗组更优于对照组(P<0.05).两组动脉血气治疗后均有改善,但治疗组改善程度优于对照组(P<0.05).结论:黄芪注射液对肺心病急性加重期具有较好疗效.     

腹部消化器官病变部位与两类腹痛部位的关系

目的:探讨腹部消化器官疾病所致内脏痛及腹膜痛的部位与病变部位的关系.方法:收集1226例有腹痛表现的腹部消化器官疾病患者的临床资料,分别统计分析内脏痛部位及腹膜痛部位与内脏病变部位的关系.结果:内脏痛平面与病变内脏起源的原肠的平面呈正相关(rs=0.87,P<0.01).腹膜痛最先出现或最明显的部位与病变内脏的解剖部位一致(=0.96,P<0.01).结论:腹部消化器官疾病所致内脏痛及腹膜痛的部位均与病变部位显著相关.依据腹痛部位定位诊断,需要分清腹痛类型,分别根据内脏痛及腹膜痛部位推测病变内脏的胚胎起源及解剖部位.     

鳖鳃腺炎的组织病理学研究

用光镜和电镜技术研究鳖鳃腺炎的组织病理变化．观察表明：病变脏器普遍充血、淤血或出血,血细胞变性;肠上皮崩解脱落,微绒毛及胞器减少,AKP活性下降;肝细胞及肾近曲小管上皮细胞肿胀、颗粒变性或透明变性,局部细胞溶解,出现坏死病灶;肝糖原减少甚至消失;肾小球膨大,远曲小管和集合小管腔内充满嗜酸性物质;脾红髓扩大,多数细胞及核异形,严重者细胞破裂、解体;骨骼肌细胞肿胀、核固缩;多数病变细胞内的内质网和线粒体扩张变性．还讨论了该病的病变特征及性质等问题．     

传染性法氏囊病病毒在鸡胚细胞上的优化繁殖

研究了传染性法氏囊病病毒在鸡胚细胞上繁殖上的优化条件，结果表明，鸡胚细胞体外增殖培养后对ＩＢＤＶ的敏感性并不减弱，而且有提高。维持培养基中血清浓度的变化对病毒的繁殖影响不大。     

MPTP慢性帕金森病小鼠海马内氧化应激与细胞凋亡蛋白的表达

目的 观察 MPTP慢性帕金森病小鼠海马氧化应激指标及细胞凋亡相关蛋白的表达.方法 应用MPTP制备慢性帕金森病模型,观察行为学改变,Morris水迷宫实验,检测模型组和对照组小鼠海马内超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）及丙二醛（MDA）舍量变化,以及免疫组织化学方法、RT-PCR方法、Western blot方法检测海马Bax和Bel-2蛋白表达.结果 慢性帕金森病模型小鼠行为学特点为震颤、活动减少;水迷宫实验结果提示认知功能降低;与对照组海马比较：模型组海马SOD、GSH含量均下降,而MDA含量升高（P〈0.05）;模型组海马Bax蛋白表达增高,而Bel-2蛋白表达下降（P〈0.05）.结论 氧化应激在慢性帕全森病认知功能障碍发病机制中起重要作用,而Bax和Bcl-2蛋白参与了氧化应激诱导海马神经元凋亡的调控过程.     

外源性H2S通过调节β-位淀粉样前体蛋白裂解酶1表达对PC12细胞APP／Aβ代谢的影响

目的观察外源性硫化氢对嗜铬细胞瘤细胞β-位淀粉样前体蛋白裂解酶1（BACE1）的调节作用,进而探讨其对淀粉样前体蛋白／β-位淀粉样蛋白代谢途径的影响。方法用硫氢化钠作外源性H2s供体,实验设空白对照组、NaHs50μmol／L组、NaHS100μmol／L组和NariS200μmol／L组,按分组浓度处理PC12细胞24h后,RT-PCR和Western blot法检测细胞内BACE1 mRNA及蛋白表达,并用Western blot法继而检测APP代谢过程中关键蛋白APP、C99、C83表达变化,EusA法检测细胞培养液中AB40和AB42水平。结果NaHS在实验浓度范围内从基因与蛋白两个水平上呈剂量依赖性下调BACE1表达,并下调C99、Ap40和Ap42蛋白表达,上调C83蛋白,各NaHS组分别与对照组比较,差别均有统计学意义（P〈0．05）,而对APP蛋白表达没有影响,各组间比较差别无显著性（P〉0．05）。结论外源性H2s具有通过调节PC12细胞BACE1表达下调APP／Aβ代谢的作用。