世界生命科学前沿动态周报（四）

（04.12--04.18 / 2010）
美宝国际集团:陶国新 

　　 本周动态主要有以下内容：西方抗衰老的研究；心脏干细胞疗法尚未成功；壳聚糖可以修复受损的神经细胞膜；高速DNA测序技术揭示转移肿瘤的特定来源；绿茶中活性物质EGCG可解除和预防与老年痴呆症等疾病有关的异常蛋白沉积；瘦女孩长大后患乳癌风险更大。其中前两条讨论了目前西方在衰老和干细胞治疗方面所处境地。
1. 延长健康生命的途径
【摘要】
　　最新一期科学杂志上的一篇文章讨论了目前的可以延长健康寿命的途径，主要是两条：一是节制饮食，一是通过突变或化学抑制降低营养传感通路的活性。二者可能通过相似的进化过程中的保留机制来延缓衰老。

【点评】
　　点评：目前西方抗衰老的研究还在延缓衰老的分子机制上做文章，并没有意识到人体再生在这里面的主导作用。

【原文摘录】
Science 16 April 2010: Vol. 328. no. 5976, pp. 321 - 326
Review
Extending Healthy Life Span—From Yeast to Humans
Luigi Fontana,1,2,* Linda Partridge,3,* Valter D. Longo4,*
When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.

2. 心脏干细胞疗法尚未成功
【摘要】
　　 作为目前生命科学的研究热点，干细胞疗法修复器官的研究领域中约有1/3是有关心脏病干细胞疗法的。一篇发表在最新一期Science Translational Medicine的文章总结说，长期的心脏病干细胞疗法临床试验结果令人失望。部分原因是干细胞治疗的临床前试验没能成功优化干细胞的运送数量，最佳运送时间，运送类型和运送技术，也没能解释心衰时形态变化的原因。 在用心肌细胞进行的细胞治疗中，所用细胞没能实现准确定位并与主体组织融合。文章总结分析了目前直接运送干细胞或干细胞衍化来的心肌细胞到心脏的细胞疗法的研究态势和面临的各种挑战。

【点评】
　　点评：本文是主流生命科学界自己所做的总结分析，说明他们的干细胞疗法至少是心脏病的干细胞治疗的临床试验是失败的，面临的困难很大，挑战很多，成功的希望不大。简而言之，不知道机体如何调控自身干细胞修复器官，就很难去人工复制这一过程。

【原文摘录】
Sci Transl Med 14 April 2010: Vol. 2,Issue 27,p. 27ps17 DOI: 10.1126/scitranslmed.3000558
Challenges in Using Stem Cells for Cardiac Repair
Christine L. Mummery1,*, Richard P. Davis1 and Jose E. Krieger2
Of the many diseases discussed in the context of stem cell therapy, those concerning the heart account for almost one-third of the publications in the field. However, the long-term clinical outcomes have been disappointing, in part because of preclinical studies failing to optimize the timing, number, type, and method of cell delivery and to account for shape changes that the heart undergoes during failure. In situations in which cardiomyocytes have been used in cell therapy, their alignment and integration with host tissue have not been realized. Here we review the present status of direct delivery of stem cells or their derivative cardiomyocytes to the heart and the particular challenges each cell type brings, and consider where we should go from here.

3. 壳聚糖可以修复受损的神经细胞膜
【摘要】
　　Borgens研究组发现，壳聚糖可以修复受损的神经细胞膜。最初测试了甘露糖，结果发现它不能修复脊髓神经细胞膜，于是决定测试壳聚糖，结果发现壳聚糖修复了受损的细胞膜。不止如此，进一步的测试发现壳聚糖可能既修复了神经细胞膜，又修复了线粒体膜。 而且壳聚糖有能力修复受损的脊髓，从而让它能够把动物身体的信号传递给大脑。Borgens对于这项壳聚糖有能力定位并修复受损脊髓组织的发现极为兴奋，而且他对于壳聚糖的纳米颗粒可能有针对性地直接向受损区域供给神经保护药物的“双重收益”的前景更加充满热情。
来源：《实验生物学杂志》

【点评】
　　点评：壳聚糖是自然界唯一带正电荷的多糖，这一特征很可能与它能够定位在受损神经细胞膜上有关。 自然产物壳聚糖有能力定位并修复受损脊髓组织的发现以及因其定位能力而来的可能有针对性地直接向受损区域供给神经保护药物的“双重收益”的前景对于药物治疗神经损伤是个福音。

【原文摘录】
Journal of Experimental Biology 213, 1513-1520 (2010）doi: 10.1242/jeb.035162
Chitosan produces potent neuroprotection and physiological recovery following traumatic spinal cord injury
Youngnam Cho1,*, Riyi Shi1,2 and Richard B. Borgens1,2
Chitosan, a non-toxic biodegradable polycationic polymer with low immunogenicity, has been extensively investigated in various biomedical applications. In this work, chitosan has been demonstrated to seal compromised nerve cell membranes thus serving as a potent neuroprotector following acute spinal cord trauma. Topical application of chitosan after complete transection or compression of the guinea pig spinal cord facilitated sealing of neuronal membranes in ex vivo tests, and restored the conduction of nerve impulses through the length of spinal cords in vivo, using somatosensory evoked potential recordings. Moreover, chitosan preferentially targeted damaged tissues, served as a suppressor of reactive oxygen species (free radical) generation, and the resultant lipid peroxidation of membranes, as shown in ex vivo spinal cord samples. These findings suggest a novel medical approach to reduce the catastrophic loss of behavior after acute spinal cord and brain injury.

4. 高速DNA测序技术揭示转移肿瘤的特定来源
【摘要】
　　 目前DNA测序技术高速发展，因此有可能对整个一个基因组进行筛选，以寻找与肿瘤进展相关的基因变化。华盛顿大学的研究人员利用最新的测序技术对一位乳腺癌患者的四个DNA样本的完整序列进行了序列分析，从中发现转移肿瘤特定选择来自原发性肿瘤中业已存在突变的一个亚群细胞，并且还会形成少量新突变。 此次测序工作揭示了几乎所有潜在的致癌染色体易位及导致该癌症发展的基因缺失和突变。

【点评】
　　点评：该项研究的最大意义不在于对阐明癌症发生机制多大贡献，而是实践了最新的高速DNA测序技术，对于诊断上的意义可能更大，有助于癌症预防。

【原文摘录】
Nature 464, 999-1005 (15 April 2010) doi:10.1038/nature08989
Genome remodelling in a basal-like breast cancer metastasis and xenograf
Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.

5. 绿茶中活性物质EGCG可解除和预防与老年痴呆症等疾病有关的异常蛋白沉积
【摘要】
　　 一项最新研究成果显示，绿茶中活性物质EGCG可解除与老年痴呆症等疾病有关的蛋白质异常沉积带来的毒性。β淀粉样蛋白是由蛋白质的错误折叠导致的，β淀粉样蛋白异常沉积是老年痴呆症和帕金森氏症等疾病的重要病因。德国马克斯•德尔布吕克分子医学中心研究人员在试管和细胞培养基实验中发现，植入这种有毒蛋白沉积会导致神经细胞新陈代谢水平下降，细胞膜也会变得不稳定。而一旦有绿茶活性物质EGCG介入，这些细胞受损的现象会消失。EGCG解毒作用的机理是其首先与纤维状β淀粉样蛋白结合，将后者转变成对神经细胞无害、之后又会被细胞分解的球状蛋白聚集体。它还能够与还没有折叠的蛋白质结合，阻止其错误折叠，从而阻止与老年痴呆症、帕金森氏症和亨廷顿舞蹈病有关的蛋白沉积的形成。

【点评】
　　点评：绿茶的保健功能又多了一项，有可能预防和缓解与异常蛋白沉积有关的老年痴呆症、帕金森氏症和亨廷顿舞蹈病等疾病。关键是看EGCG能否通过血脑屏障。

【原文摘录】
PNAS April 12, 2010, doi: 10.1073/pnas.0910723107
EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity
Jan Bieschke1, Jenny Russ, Ralf P. Friedrich, Dagmar E. Ehrnhoefer2, Heike Wobst, Katja Neugebauer, and Erich E. Wanker1
Protein misfolding and formation of β-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer’s and Parkinson’s disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits α-synuclein and amyloid-β fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.

6. 瘦女孩长大后患乳癌风险更大
【摘要】 新浪健康 2010-4-16 13:51:23
　　瑞典斯德哥尔摩卡罗林斯卡医学院的研究发现，消瘦的女孩日后更有可能患上乳癌。与小时候较胖的女孩相比，7岁时身材较瘦的女孩长大后患乳癌的风险更大。科学家还发现，小时候稍胖的女孩患难以攻克的肿瘤的概率较小。研究为把童年时旧照片作为评估女性乳癌风险的方法铺平了道路。小时候较胖的女性绝经期患乳癌的风险较小。之前的研究显示，肥胖的女性更易患乳癌，而且她们死于乳癌的风险高达50%。 科学家不确定瘦女孩易患乳癌的原因是什么。他们表示，新发现可能对判断女性乳癌风险具有重要意义。

【点评】
　　点评：这个与以前认识不同的发现其实是有其合理性的，癌症的预防与身体免疫系统关系密切，而越来越多的研究表明人体脂肪组织与免疫系统可能有很大关系，在形成自身成熟免疫体系的少儿期，身体脂肪相对充足一些可能有利于更好的成就自身免疫系统。

【原文摘录】
Breast Cancer Research 2010, 12:R23 | doi:10.1186/bcr2564
Effects of childhood body size on breast cancer tumour characteristics
Jingmei Li , Keith Humphreys , Louise Eriksson , Kamila Czene , Jianjun Liu and Per Hall
Introduction
Although a role of childhood body size in postmenopausal breast cancer risk has been established, less is known about its influence on tumour characteristics.
Methods
We studied the relationships between childhood body size and tumour characteristics in a Swedish population-based case-control study consisting of 2,818 breast cancer cases and 3,111 controls. Our classification of childhood body size was derived from a nine-level somatotype. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from fitting unconditional logistic regression models. Association between somatotype at age 7 and tumour characteristics were evaluated in a case-only analysis where P-values for heterogeneity were obtained by performing one degree of freedom trend tests.
Results
A large somatotype at age 7 was found to be associated with decreased postmenopausal breast cancer risk. Although strongly associated with other risk factors such as age of menarche, adult body mass index and mammographic density, somatotype at age 7 remained a significant protective factor (odds ratio (OR) comparing large to lean somatotype at age 7 = 0.73, 95% confidence interval (CI) = 0.58-0.91, P trend = 0.004) after adjustment. The significant protective effect was observed within all subgroups defined by estrogen receptor (ER) and progesterone receptor (PR) status, with a stronger effect for ER-negative (0.40, 95% CI = 0.21-0.75, P trend = 0.002), than for ER-positive (0.80, 95% CI = 0.62-1.05, P trend = 0.062), tumours (P heterogeneity = 0.046). Somatotype at age 7 was not associated with tumour size, histology, grade or the presence or absence of metastatic nodes.
Conclusions
Greater body size at age 7 is associated with a decreased risk of postmenopausal breast cancer, and the associated protective effect is stronger for the ER-negative breast cancer subtype than for the ER-positive subtype.