世界生命科學前沿動態(tài)周報（四）

（04.12--04.18 / 2010）
美寶國際集團:陶國新 

　　 本周動態(tài)主要有以下內(nèi)容：西方抗衰老的研究；心臟干細胞療法尚未成功；殼聚糖可以修復(fù)受損的神經(jīng)細胞膜；高速DNA測序技術(shù)揭示轉(zhuǎn)移腫瘤的特定來源；綠茶中活性物質(zhì)EGCG可解除和預(yù)防與老年癡呆癥等疾病有關(guān)的異常蛋白沉積；瘦女孩長大后患乳癌風險更大。其中前兩條討論了目前西方在衰老和干細胞治療方面所處境地。
1. 延長健康生命的途徑
【摘要】
　　最新一期科學雜志上的一篇文章討論了目前的可以延長健康壽命的途徑，主要是兩條：一是節(jié)制飲食，一是通過突變或化學抑制降低營養(yǎng)傳感通路的活性。二者可能通過相似的進化過程中的保留機制來延緩衰老。

【點評】
　　點評：目前西方抗衰老的研究還在延緩衰老的分子機制上做文章，并沒有意識到人體再生在這里面的主導(dǎo)作用。

【原文摘錄】
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. 心臟干細胞療法尚未成功
【摘要】
　　 作為目前生命科學的研究熱點，干細胞療法修復(fù)器官的研究領(lǐng)域中約有1/3是有關(guān)心臟病干細胞療法的。一篇發(fā)表在最新一期Science Translational Medicine的文章總結(jié)說，長期的心臟病干細胞療法臨床試驗結(jié)果令人失望。部分原因是干細胞治療的臨床前試驗沒能成功優(yōu)化干細胞的運送數(shù)量，最佳運送時間，運送類型和運送技術(shù)，也沒能解釋心衰時形態(tài)變化的原因。 在用心肌細胞進行的細胞治療中，所用細胞沒能實現(xiàn)準確定位并與主體組織融合。文章總結(jié)分析了目前直接運送干細胞或干細胞衍化來的心肌細胞到心臟的細胞療法的研究態(tài)勢和面臨的各種挑戰(zhàn)。

【點評】
　　點評：本文是主流生命科學界自己所做的總結(jié)分析，說明他們的干細胞療法至少是心臟病的干細胞治療的臨床試驗是失敗的，面臨的困難很大，挑戰(zhàn)很多，成功的希望不大。簡而言之，不知道機體如何調(diào)控自身干細胞修復(fù)器官，就很難去人工復(fù)制這一過程。

【原文摘錄】
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. 殼聚糖可以修復(fù)受損的神經(jīng)細胞膜
【摘要】
　　Borgens研究組發(fā)現(xiàn)，殼聚糖可以修復(fù)受損的神經(jīng)細胞膜。最初測試了甘露糖，結(jié)果發(fā)現(xiàn)它不能修復(fù)脊髓神經(jīng)細胞膜，于是決定測試殼聚糖，結(jié)果發(fā)現(xiàn)殼聚糖修復(fù)了受損的細胞膜。不止如此，進一步的測試發(fā)現(xiàn)殼聚糖可能既修復(fù)了神經(jīng)細胞膜，又修復(fù)了線粒體膜。 而且殼聚糖有能力修復(fù)受損的脊髓，從而讓它能夠把動物身體的信號傳遞給大腦。Borgens對于這項殼聚糖有能力定位并修復(fù)受損脊髓組織的發(fā)現(xiàn)極為興奮，而且他對于殼聚糖的納米顆?？赡苡嗅槍π缘刂苯酉蚴軗p區(qū)域供給神經(jīng)保護藥物的“雙重收益”的前景更加充滿熱情。
來源：《實驗生物學雜志》

【點評】
　　點評：殼聚糖是自然界唯一帶正電荷的多糖，這一特征很可能與它能夠定位在受損神經(jīng)細胞膜上有關(guān)。 自然產(chǎn)物殼聚糖有能力定位并修復(fù)受損脊髓組織的發(fā)現(xiàn)以及因其定位能力而來的可能有針對性地直接向受損區(qū)域供給神經(jīng)保護藥物的“雙重收益”的前景對于藥物治療神經(jīng)損傷是個福音。

【原文摘錄】
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測序技術(shù)揭示轉(zhuǎn)移腫瘤的特定來源
【摘要】
　　 目前DNA測序技術(shù)高速發(fā)展，因此有可能對整個一個基因組進行篩選，以尋找與腫瘤進展相關(guān)的基因變化。華盛頓大學的研究人員利用最新的測序技術(shù)對一位乳腺癌患者的四個DNA樣本的完整序列進行了序列分析，從中發(fā)現(xiàn)轉(zhuǎn)移腫瘤特定選擇來自原發(fā)性腫瘤中業(yè)已存在突變的一個亞群細胞，并且還會形成少量新突變。 此次測序工作揭示了幾乎所有潛在的致癌染色體易位及導(dǎo)致該癌癥發(fā)展的基因缺失和突變。

【點評】
　　點評：該項研究的最大意義不在于對闡明癌癥發(fā)生機制多大貢獻，而是實踐了最新的高速DNA測序技術(shù)，對于診斷上的意義可能更大，有助于癌癥預(yù)防。

【原文摘錄】
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. 綠茶中活性物質(zhì)EGCG可解除和預(yù)防與老年癡呆癥等疾病有關(guān)的異常蛋白沉積
【摘要】
　　 一項最新研究成果顯示，綠茶中活性物質(zhì)EGCG可解除與老年癡呆癥等疾病有關(guān)的蛋白質(zhì)異常沉積帶來的毒性。β淀粉樣蛋白是由蛋白質(zhì)的錯誤折疊導(dǎo)致的，β淀粉樣蛋白異常沉積是老年癡呆癥和帕金森氏癥等疾病的重要病因。德國馬克斯•德爾布呂克分子醫(yī)學中心研究人員在試管和細胞培養(yǎng)基實驗中發(fā)現(xiàn)，植入這種有毒蛋白沉積會導(dǎo)致神經(jīng)細胞新陳代謝水平下降，細胞膜也會變得不穩(wěn)定。而一旦有綠茶活性物質(zhì)EGCG介入，這些細胞受損的現(xiàn)象會消失。EGCG解毒作用的機理是其首先與纖維狀β淀粉樣蛋白結(jié)合，將后者轉(zhuǎn)變成對神經(jīng)細胞無害、之后又會被細胞分解的球狀蛋白聚集體。它還能夠與還沒有折疊的蛋白質(zhì)結(jié)合，阻止其錯誤折疊，從而阻止與老年癡呆癥、帕金森氏癥和亨廷頓舞蹈病有關(guān)的蛋白沉積的形成。

【點評】
　　點評：綠茶的保健功能又多了一項，有可能預(yù)防和緩解與異常蛋白沉積有關(guān)的老年癡呆癥、帕金森氏癥和亨廷頓舞蹈病等疾病。關(guān)鍵是看EGCG能否通過血腦屏障。

【原文摘錄】
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. 瘦女孩長大后患乳癌風險更大
【摘要】 新浪健康 2010-4-16 13:51:23
　　瑞典斯德哥爾摩卡羅林斯卡醫(yī)學院的研究發(fā)現(xiàn)，消瘦的女孩日后更有可能患上乳癌。與小時候較胖的女孩相比，7歲時身材較瘦的女孩長大后患乳癌的風險更大?？茖W家還發(fā)現(xiàn)，小時候稍胖的女孩患難以攻克的腫瘤的概率較小。研究為把童年時舊照片作為評估女性乳癌風險的方法鋪平了道路。小時候較胖的女性絕經(jīng)期患乳癌的風險較小。之前的研究顯示，肥胖的女性更易患乳癌，而且她們死于乳癌的風險高達50%。 科學家不確定瘦女孩易患乳癌的原因是什么。他們表示，新發(fā)現(xiàn)可能對判斷女性乳癌風險具有重要意義。

【點評】
　　點評：這個與以前認識不同的發(fā)現(xiàn)其實是有其合理性的，癌癥的預(yù)防與身體免疫系統(tǒng)關(guān)系密切，而越來越多的研究表明人體脂肪組織與免疫系統(tǒng)可能有很大關(guān)系，在形成自身成熟免疫體系的少兒期，身體脂肪相對充足一些可能有利于更好的成就自身免疫系統(tǒng)。

【原文摘錄】
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.