（6.24-6.30/2012）
恒峰g22国际集团:陶国新 

　　重要内容：幼分子DNA适体推进神经髓鞘的再生和建复
；食品纤维扭转胃肠路菌群推进胃肠健全
；肌营养不良疾病LGMD2D的自体细胞移植
；干细胞和癌细胞中端粒酶的调节
；源于人胚胎干细胞的胰腺祖细胞发育成有职能的胰岛医治老鼠的糖尿
；褫夺葡萄糖激活代谢和信号的放大回路导致细胞殒命。

　　焦点动态：幼分子DNA适体推进神经髓鞘的再生和建复。

1.  幼分子DNA适体推进神经髓鞘的再生和建复

【动态】多发性硬化病是一种中枢神经系统炎症，会部门粉碎包裹神经轴突的绝缘的髓鞘，使人体越来越虚弱。全世界有20多万多发性硬化病人，而不足预防病情进展和诱导建复的医治伎俩使该病很是辣手？寡琢品ㄖ辉谠し栏捶⒎矫嬗杏邢蕹尚。以前所做的人血清样本的筛查显示天然IgM抗体结合少突细胞，在脑脊髓炎泰勒病毒慢性习染的易感老鼠模型和部门脱髓鞘作用的溶血卵磷脂模型中推进细胞信号传导并对中枢神经系统再髓鞘化。这个有趣的了局批注可能特异结合少突细胞或髓鞘组分的分子可能会推进多发性硬化病的医治性髓鞘再生。鉴于IgM抗体太大太复杂，有必要寻找更幼的可能在体内推进髓鞘再生的髓鞘特异性分子。美国科学家最近的钻研显示筛选出的特异结合老鼠髓鞘的一种40个核苷的单链DNA适体拥有这种个性。该DNA适体在体表能与髓鞘的多个组分结合，腹腔注射的该适体可能散布到中枢神经组织并推进泰勒病毒习染的老鼠受损的模型中枢神经系统髓鞘再生。相对于单克隆抗体，DNA适体更幼，更不变，没有免疫原性，有望成为新的医治多发性硬化的伎俩。

【点评】 该钻研发现的幼分子DNA可能代替IgM抗体在老鼠模型中推进神经髓鞘的再生和建复，有可能成为医治人类多发性硬化病的选项，但是还必要在其他的动物模型上确认其能否成为人体临床尝试的候选物。

【参考论文】   
PLoS ONE, 2012; 7 (6): e39595 DOI: 10.1371/journal.pone.0039595
Remyelination Induced by a DNA Aptamer in a Mouse Model of Multiple Sclerosis
Branislav Nastasijevic, Brent R. Wright, John Smestad, et al.
Multiple sclerosis (MS) is a debilitating inflammatory disease of the central nervous system (CNS) characterized by local destruction of the insulating myelin surrounding neuronal axons. With more than 200 million MS patients worldwide, the absence of treatments that prevent progression or induce repair poses a major challenge. Anti-inflammatory therapies have met with limited success only in preventing relapses. Previous screening of human serum samples revealed natural IgM antibodies that bind oligodendrocytes and promote both cell signaling and remyelination of CNS lesions in an MS model involving chronic infection of susceptible mice by Theiler’s encephalomyelitis virus and in the lysolecithin model of focal demyelination. This intriguing result raises the possibility that molecules with binding specificity for oligodendrocytes or myelin components may promote therapeutic remyelination in MS. Because of the size and complexity of IgM antibodies, it is of interest to identify smaller myelin-specific molecules with the ability to promote remyelination in vivo. Here we show that a 40-nucleotide single-stranded DNA aptamer selected for affinity to murine myelin shows this property. This aptamer binds multiple myelin components in vitro. Peritoneal injection of this aptamer results in distribution to CNS tissues and promotes remyelination of CNS lesions in mice infected by Theiler’s virus. Interestingly, the selected DNA aptamer contains guanosine-rich sequences predicted to induce folding involving guanosine quartet structures. Relative to monoclonal antibodies, DNA aptamers are small, stable, and non-immunogenic, suggesting new possibilities for MS treatment.

 2. 食品纤维扭转胃肠路菌群推进胃肠健全

【动态】美国科学家的最新钻研批注食品纤维可能推进胃肠路分歧类型有益菌群的滋生，而这些有益菌群据信不止可能推进胃肠路的健全，还可能影响我们对多种疾病的敏感性，好比2型糖尿病、肥胖、炎症性肠病、结肠癌以及免疫性疾病像类风湿性关节炎。这些有益菌群在肠路发酵纤维，造作短链脂肪酸和其他代谢产品，对宿主产生诸多健全方面的益处。若是可能相识哪种食品纤维可能最好的滋养这些推进健全的菌群，就可能纠正饮食和肠路菌群的不平衡，支持和推进胃肠路健全。该钻研批注食品纤维除了推进胃肠蠕动，对人体还有更多益处。他们进行了有慰藉剂对照的双盲试验，每天给与受试人员分歧种类的补充纤维（聚葡萄糖或可溶性谷物纤维），在第16-21天，查抄其大便样品中菌群的“指纹图谱”。两种纤维都在门种属水平上影响菌群的数量。补充可溶性谷物纤维的人，其肠路益生菌乳酸杆菌的数量增长。补充聚葡萄糖或可溶性谷物纤维的人都能增长肠路有益菌群。因而，聚葡萄糖或可溶性谷物纤维有潜力作为益生元使用推进肠路益生菌的滋生。

【点评】 该钻研批注食品纤维不仅仅是援手人体推进胃肠蠕动和食品消化，并且是人体很重要的营养物质，间接通过滋养肠路益生菌推进人体健全。

【参考论文】   
Journal of Nutrition, 2012; 142 (7): 1259 DOI: 10.3945/jn.112.158766
454 Pyrosequencing Reveals a Shift in Fecal Microbiota of Healthy Adult Men Consuming Polydextrose or Soluble Corn Fiber
S. Hooda, B. M. V. Boler, M. C. R. Serao, et al.
The relative contribution of novel fibers such as polydextrose and soluble corn fiber (SCF) to the human gut microbiome and its association with host physiology has not been well studied. This study was conducted to test the impact of polydextrose and SCF on the composition of the human gut microbiota using 454 pyrosequencing and to identify associations among fecal microbiota and fermentative end-products. Healthy adult men (n = 20) with a mean dietary fiber (DF) intake of 14 g/d were enrolled in a randomized, double-blind, placebo-controlled crossover study. Participants consumed 3 treatment snack bars/d during each 21-d period that contained no supplemental fiber (NFC), polydextrose (PDX; 21 g/d), or SCF (21 g/d) for 21 d. There were no washout periods. Fecal samples were collected on d 16–21 of each period; DNA was extracted, followed by amplification of the V4-V6 region of the 16S rRNA gene using barcoded primers. PDX and SCF significantly affected the relative abundance of bacteria at the class, genus, and species level. The consumption of PDX and SCF led to greater fecal Clostridiaceae and Veillonellaceae and lower Eubacteriaceae compared with a NFC. The abundance of Faecalibacterium,Phascolarctobacterium, and Dialister was greater (P < 0.05) in response to PDX and SCF intake, whereas Lactobacillus was greater (P < 0.05) only after SCF intake.Faecalibacterium prausnitzii, well known for its antiinflammatory properties, was greater (P < 0.05) after fiber consumption. Principal component analysis clearly indicated a distinct clustering of individuals consuming supplemental fibers. Our data demonstrate a beneficial shift in the gut microbiome of adults consuming PDX and SCF, with potential application as prebiotics.

 3.  肌营养不良疾病LGMD2D的自体细胞移植

【动态】一项欧洲和日本科学家参加的最新钻研显示源于一种罕见的肌营养不良症患者的干细胞被成功移植入有同样症状的老鼠模型中。  Mesoangioblast（一种与血管有关的干细胞）干/祖细胞是源于表白碱性磷酸酶的肌肉中发现的周皮细胞亚群，已显示出在肌营养不良症的分歧动物模型中改善症状的作用，并在患有杜兴肌营养不良患儿中进行临床测试
；加杏泄丶∮涣技膊GMD2D的发病原因是编码α-肌糖 的基因发生突变，周皮细胞削减，不能产生足够自体细胞医治的Mesoangioblast。因而，该钻研从LGMD2D患者的成纤维细胞和成肌细胞重编程成iPSC，并成立一套法式从iPSC 转化成Mesoangioblast样细胞，通过在体表基因建改并扩增该源于iPSC的Mesoangioblast细胞，而后将其移植到没有α-肌糖的免疫缺点老鼠，它们产生了表白α-肌糖的肌纤维。而将源于老鼠iPSC的Mesoangioblast细胞移植到没有α-肌糖的免疫缺点老鼠改善了症状，复原了缺失的祖细胞。

【点评】 该钻研了局意味着移植基因建改后的源于LGMD2D患者iPSC的Mesoangioblast样细胞可能对该种以及其他种类的肌营养不良的医治有效。

【参考论文】   
Sci Transl Med, 27 June 2012 DOI: 10.1126/scitranslmed.3003541
Transplantation of Genetically Corrected Human iPSC-Derived Progenitors in Mice with Limb-Girdle Muscular Dystrophy
Francesco Saverio Tedesco, Mattia F. M. Gerli, Laura Perani, et al.  
Mesoangioblasts are stem/progenitor cells derived from a subset of pericytes found in muscle that express alkaline phosphatase. They have been shown to ameliorate the disease phenotypes of different animal models of muscular dystrophy and are now undergoing clinical testing in children affected by Duchenne’s muscular dystrophy. Here, we show that patients with a related disease, limb-girdle muscular dystrophy 2D (LGMD2D), which is caused by mutations in the gene encoding α-sarcoglycan, have reduced numbers of this pericyte subset and thus produce too few mesoangioblasts for use in autologous cell therapy. Hence, we reprogrammed fibroblasts and myoblasts from LGMD2D patients to generate human induced pluripotent stem cells (iPSCs) and developed a protocol for the derivation of mesoangioblast-like cells from these iPSCs. The iPSC-derived mesoangioblasts were expanded and genetically corrected in vitro with a lentiviral vector carrying the gene encoding human α-sarcoglycan and a promoter that would ensure expression only in striated muscle. When these genetically corrected human iPSC-derived mesoangioblasts were transplanted into α-sarcoglycan–null immunodeficient mice, they generated muscle fibers that expressed α-sarcoglycan. Finally, transplantation of mouse iPSC-derived mesoangioblasts into α-sarcoglycan–null immunodeficient mice resulted in functional amelioration of the dystrophic phenotype and restoration of the depleted progenitors. These findings suggest that transplantation of genetically corrected mesoangioblast-like cells generated from iPSCs from LGMD2D patients may be useful for treating this type of muscular dystrophy and perhaps other forms of muscular dystrophy as well.

 4. 干细胞和癌细胞中端粒酶的调节

【动态】德国科学家最近发现了Wnt/β-联蛋白信号蹊径与端粒酶亚基 Tert表白之间的分子联系。端粒酶的活性节造着端粒长度，在干细胞，衰老和癌症中起关键作用。β-联蛋白缺点的老鼠胚胎干细胞端粒较短，相反地，表白有活性的β-联蛋白的胚胎干细胞其端粒比力长。钻研批注β-联蛋白通过与多能性转录网络的主题组分Klf4相互作用调节Tert表白，在老鼠肠癌模型和人体癌细胞中β-联蛋白结合到Tert推进子，直接调节端粒酶基因。调节谬误或β-联蛋白突变会导致肿瘤发生。

【点评】 该钻研关于β-联蛋白调节Tert表白进而调节端粒酶活性和端粒长度的发现对于干细胞的钻研以及抗癌钻研可能产生重要影响。

【参考论文】   
Science, 2012; 336 (6088): 1549 DOI: 10.1126/science.1218370
Wnt/ -Catenin Signaling Regulates Telomerase in Stem Cells and Cancer Cells
K. Hoffmeyer, A. Raggioli, S. Rudloff, et al.  
Telomerase activity controls telomere length and plays a pivotal role in stem cells, aging, and cancer. Here, we report a molecular link between Wnt/β-catenin signaling and the expression of the telomerase subunit Tert. β-Catenin–deficient mouse embryonic stem (ES) cells have short telomeres; conversely, ES cell expressing an activated form of β-catenin (β-catΔEx3/+) have long telomeres. We show that β-catenin regulates Tert expression through the interaction with Klf4, a core component of the pluripotency transcriptional network. β-Catenin binds to the Tert promoter in a mouse intestinal tumor model and in human carcinoma cells. We uncover a previously unknown link between the stem cell and oncogenic potential whereby β-catenin regulates Tert expression, and thereby telomere length, which could be critical in human regenerative therapy and cancer.

 5. 源于人胚胎干细胞的胰腺祖细胞发育成有职能的胰岛医治老鼠的糖尿病

【动态】加拿大科学家最近报路了一套规划，能够使贸易化的人体胚胎干细胞体表分化成富集的PDX1+胰腺祖细胞群，进而在体内进一步发育成熟为胰腺排泄细胞。未成熟的胰腺前体细胞被移植到链脲霉素诱导的糖尿病免疫缺点老鼠，而最初通过表源性胰岛素节造高血糖症状，随着移植细胞产生的胰岛素随功夫的增长，糖尿病老鼠逐步能够脱离表源性胰岛素，人C-肽的排泄最终能够通过饮食和葡萄糖耐受调节。在免疫缺点的大白鼠中也观察到了类似的胰腺祖细胞的分化，体内源于人体胚胎干细胞的排泄细胞的成熟过程中出现的基因和蛋白表白显著类似于人体胚胎发育中的胰腺。

【点评】 该钻研发现的了局支持利用分化的人体胚胎干细胞医治糖尿病的可能性，但是由于此类的动物试验都是利用不大倾轧细胞移植的免疫缺点动物模型进行的，显著分歧于正常的性命，因而其试验了局也只是提供某种可能性的参考，并不具备现实意思。

【参考论文】   
Diabetes, June 27, 2012 DOI:10.2337/db11-1711
Maturation of Human Embryonic Stem Cell–Derived Pancreatic Progenitors into Functional Islets Capable of Treating Pre-existing Diabetes in Mice
Alireza Rezania, Jennifer E. Bruin, Michael J. Riedel, et al.
Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.

 6. 褫夺葡萄糖激活代谢和信号的放大回路导致细胞殒命

【动态】癌细胞变异的代谢让细胞生计依赖于代谢底物的存在。美国科学家通过钻研依赖葡萄糖生计的细胞殒命的信号机造说明迅速褫夺葡萄糖供给导致超正常生理水平的磷酸化酪氨酸信号，甚至是在表白结构上活跃的酪氨酸激酶的细胞里。通过客观的基于质谱的磷酸化蛋白谱，该钻研发现褫夺葡萄糖激活启动了与部门衔接有关的怪异的磷酸化酪氨酸署名，激活了涉及NADPH和线粒体出产活性氧，氧化抑造酪氨酸蛋白磷酸化酶，以及增长酪氨酸激酶信号的正反馈回路，最终导致活性氧介导的细胞殒命。

【点评】 该钻研说了然癌细胞维持动态平衡过程中代谢和信号在系统水平上的互换。褫夺葡萄糖诱生涯性氧，抑造磷酸化酶，激活酪氨酸激酶转而产生更多活性氧，正反馈的回路不休放大活性氧水平直至细胞进行活性氧介导的细胞殒命。

【参考论文】   
Molecular Systems Biology, 2012; 8 DOI: 10.1038/msb.2012.20
Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death
Nicholas A Graham, Martik Tahmasian, Bitika Kohli, et al.    
The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis.