端粒、端粒酶与人类衰老和肿瘤

近年来,不少学者注意到染色体端粒(telomere)的长度和端粒酶(telomerase)活性与细胞的衰老、细胞的永生化以及细胞的恶性变有着密切的关系,显示它们在细胞的增殖调控中起着重要的作用,本文仅对此作一综述.     

端粒、端粒酶与抗衰老的研究进展

端粒是染色体末端的DNA重复序列,是染色体末端的"保护帽",它能维持染色体的稳定,防止染色体相互融合.端粒酶可以合成端粒,在端粒受损时能把端粒修复延长,可以让端粒不会因细胞分裂而有所损耗,使得细胞分裂的次数增加.本文就端粒、端粒酶与衰老的关系及其在抗衰老中的应用作一综述.     

端粒、端粒酶与衰老及年龄的关系

衰老是一种多因素的复合调控过程,表现为染色体端粒长度的改变、DNA损伤、DNA的甲基化和细胞的氧化损害等,并已形成了许多学说,而端粒学说成为衰老研究的热点。本文综述了与衰老紧密相关的因素———端粒、端粒酶的结构及其与衰老和年龄关系的研究进展,阐明对端粒—端粒酶的作用将会在抗衰老方面有着十分重要的理论价值及实际意义。此外,利用端粒长度变化与年龄的相关性评估人的年龄将在法医学界显示其巨大的应用前景。     

端粒、端粒酶与肿瘤

瑞粒、端粒酶与肿瘤之间的密切关系提示攻克肿瘤的可能性,因此越来越引起人们的重视。本文就端粒、端粒酶与肿瘤的关系研究进展予以阐述。l端粒（Telomere）瑞拉是真核生物线形染色体3’末端一段重复DNA序列与结合蛋白的复合体l’］。在人类细胞中,这段重复DNA序列以（TTAGGG）n的形式存在,而在其他真核生物细胞,重复的端粒DNA单位的长度多为5到8个碱基对,亦富含鸟瞟吟（G）I’］。瑞拉结合蛋白是与端粒重复DNA序列结合的特异性蛋白。它能使端粒DNA避免被化学修饰和降解,还能参与瑞粒长度和瑞粒酶活性的调节［’］。瑞拉结…     

端粒与端粒酶:运动延缓衰老的端粒机制

背景:端粒是人体细胞染色体末端的特殊结构,与衰老有非常密切的关系;科学运动可以提高端粒酶活性,保护端粒结构,从而影响人体的身体健康;端粒变短,机体疾病发病率增加,存活率降低,因此,端粒常被认为是细胞衰老的生物学标志物,是触发衰老的“生物钟”。目的:基于端粒系统和衰老的关系,总结分析运动对端粒、端粒酶的影响,探讨运动延缓衰老的端粒理论机制,为运动抗衰老、运动健康促进提供理论依据和参考。方法:以“端粒,端粒酶,运动,衰老”为中文检索词,以“telomeres,telomerase,exercise,senescence”为英文检索词;查阅中国知网、Pub Med、Web of science数据库,初步筛选运动调控端粒延缓衰老的相关文献,在全文阅读后共纳入89篇文献进行分析。结果与结论:不同运动对端粒的影响具有差异性;运动与端粒长度存在正相关、无相关和倒U型关系,与端粒酶活性存在年龄偏移性;适宜运动可以减缓端粒缩短的速度,防止端粒过度消耗,延缓或预防与年龄相关的疾病发生,延长寿命,但其机制一直未阐明。     

端粒、端粒酶与细胞凋亡

端粒是存在于线性染色体末端的一段特殊的ＤＮＡ－ 蛋白质复合物,由于末端不能复制,正常体细胞随着细胞分裂的进行而逐渐丢失端粒序列,导致细胞老化和死亡。具有增殖潜能的正常体细胞通过被诱导可以表达端粒酶以补偿端粒序列的丢失,从而保持端粒的长度。许多正常体细胞可以检测到端粒酶活性,并可经诱导后使其水平上调,这对于防治细胞老化具有重要的意义。     

端粒、端粒酶与肝细胞肝癌

近年,有关端粒酶与恶性肿瘤相关性的研究已经成为肿瘤分子生物学领域最热门的课题之一〔1〕。在正常人体组织中除生殖细胞和部分造血干细胞显示弱端粒酶活性外,均无端粒酶活性,而恶性肿瘤细胞中端粒酶却特异性表达。1　端粒的结构与功能端粒是指真核细胞线性染色体末端的一种特殊结构,是简单重复富含G的DNA序列与特异结合蛋白的复合体。这一特殊序列在本世纪30年代,遗传学家Muller和McClm-tock就分别发现了。并且证明了该序列具有维持染色体稳定性功能,Muller〔2〕将这一结构命名为端粒。人类染色体端粒由5’→3’方向简单的重复TTAGG…     

端粒（酶）同癌症与衰老关系的研究进展

端粒是真核生物染色体的天然末端，具有稳定染色体结构，避免遗传信息在复制过程中丢失的作用。端粒酶是端粒复制成必须的一种特殊的ＤＮＡ聚合酶，在大多数的正常人体细胞中没有活性。在近年来的研究中，人们发现“衰老的端粒缩短”，而且在约８５％的肿瘤细胞中检测到了端粒酶活性。这些事实提示人们：端粒、端粒酶同癌症与衰老之间存在相关性。     

端粒、端粒酶与妇科肿瘤

端粒是染色体末端的特殊结构 ,其长度随细胞分裂而进行性缩短 ,端粒酶是一种核糖核蛋白酶 ,能够逆转录合成端粒 ,维持其长度。端粒酶活性在几乎所有恶性肿瘤中被检测到 ,并且在妇科卵巢癌、宫颈癌、子宫内膜癌及滋养细胞疾病的发生、发展过程中有重要作用 ,作为一种新的肿瘤标记物及抗癌靶点 ,日益受到重视     

Telomere und Telomerase

Zusammenfassung In letzter Zeit fanden spezielle Abschnitte des menschlichen Genoms in der Tumorforschung besondere Beachtung: die Telomere. Telomere, d.h. die Enden aller linearen eukaryotischen Chromosomen, bestehen aus repetitiven DNA-Sequenzen und aus spezifischen Proteinen. Die Funktion der Telomere besteht im Schutz der Chromosomenenden vor Degradation, Fusion und Rekombination. In den meisten somatischen Zellen verkürzen sich die Telomere mit jedem Zellzyklus. Im übertragenen Sinn kann dieser Verlust an telomeren DNA-Sequenzen als eine mitotische Uhr aufgefa?t werden, mit der eine Zelle die Anzahl der Zellteilungen z?hlt und Lebensspanne und Zellalterung dirigiert. Sind die Telomere bis zu einem kritischen Punkt verkürzt, erfolgt die Einleitung des Apoptoseprozesses. Einige wenige Zelltypen entgehen der zellul?ren Seneszenz durch die Expression des Enzyms Telomerase. Dieses Ribonukleoprotein katalysiert die De-Novo-Addition von Nukleotiden an den Telomerenden. Das Enzym ist in den meisten somatischen Zellen in vivo nicht nachweisbar, wurde aber in der Mehrzahl aller Tumorgewebe gefunden. Die Aktivierung der Telomerase scheint Tumorzellen zu unbegrenzter Proliferation und zum Erreichen der Immortalit?t zu bef?higen. Aktuelle Studien zur Telomeraseaktivit?t in Tumoren unterstreichen, da? die Progression eines Tumorzellklons u.a. ma?geblich von der Aktivierung der Telomerase abh?ngt. Deshalb k?nnten Telomeraseinhibitoren neue M?glichkeiten in der Tumortherapie er?ffnen.      

端粒与年龄

端粒在细胞正常生理功能运转过程中起重要作用, 涉及到染色体末端复制、端粒酶作用机理、肿瘤及衰老等多方面问题, 端粒的缺失将造成多种病理状况, 直接影响到细胞的生存, 随着人们对端粒酶研究的日益深入，端粒与染色体不稳定性的关系及机理的探索已引起普遍关注。     

Telomere length and telomerase activity during expansion and differentiation of human mesenchymal stem cells and chondrocytes

Chondrocyte ex vivo expansion currently performed to replace damaged articular surfaces is associated with a loss of telomeric repeats similar to decades of aging in vivo. This might affect the incidence or time of onset of age-related disorders within transplanted cells or tissues. This study examined whether more immature progenitor cells, such as mesenchymal stem cells (MSC), which can be expanded and subsequently differentiated into chondrocytes is advantageous regarding telomere-length related limitations of expansion protocols. Primary chondrocytes and bone-marrow-derived MSC were isolated from 12 donors, expanded separately to 4 x 10(6) cells, and (re-)differentiated as three-dimensional chondrogenic spheroids. Cells were collected during expansion, after three-dimensional culturing and chondrogenic differentiation, and sequential analyses of telomere length and telomerase activity were performed. Surprisingly, telomeres of expanded MSC were significantly shorter than those from expanded chondrocytes from the same donor (11.4+/-2.5 vs. 13.4+/-2.2 kb) and tended to remain shorter after differentiation in chondrogenic spheroids (11.9+/-1.8 vs. 13.0+/- kb). While telomere lengths in native chondrocytes and MSC were not related to the age of the donor, significant negative correlations with age were observed in expanded (136 bp/year), three-dimensionally reconstituted (188 bp/year), and redifferentiated (229 bp/year) chondrocytes. Low levels of telomerase activity were found in MSC and chondrocytes during expansion and after (re-)differentiation to chondrogenic spheroids. In terms of replicative potential, as determined by telomere length, ex vivo expansion followed by chondrogenic differentiation of MSC did not provide a benefit compared to the expansion of adult chondrocytes. However, accelerated telomere shortening with age during expansion and redifferentiation argues for an "age phenotype" in chondrocytes as opposed to MSC and suggests an advantage for the use of MSC especially in older individuals and protocols requiring extensive expansion     

Telomerase activation and cancer

 Normal human cells have a limited life span in culture. It is generally believed that progression of cells to malignancy requires an overriding of this natural program of cellular senescence. An understanding of the genes controlling senescence will likely be valuable in determining the underlying mechanisms of abnormal cell growth and carcinogenesis. The hypothesis that telomeres play an integral role in cell senescence and immortalization has recently received much attention. This review discusses some of the current literature pertaining to how telomeres and activation of telomerase, a ribonucleoprotein that synthesizes telomere repeats, are believed to be involved in the process of immortalization. It also discusses how a further understanding of the telomerase enzyme may lead to better diagnostic and treatment strategies for a variety of cancer types. Received: 13 August 1996 / Accepted: 9 October 1996     

Telomere length and telomerase activity: effect of ageing on human NK cells

Telomeres are repeats of TTAGGG sequences located at the end of eukaryotic chromosomes. They are essential for stabilisation and protection of chromosomal ends and for the regulation of cell replicative capacity. Due to the end-replication defect of DNA polymerase, telomeres shorten progressively with each cell division and telomere length may be an indicator of the replicative history of a cell. Compensatory mechanisms for the telomere loss have been identified. The most widely studied one is mediated by telomerase a ribonuclear protein-enzyme complex that synthesise telomeric repeats. In this study we have investigated whether NK cells, derived from a group of old healthy subjects, underwent the modifications of telomere length and telomerase activity observed in other sub-populations of lymphocytes with advancing age. We demonstrated that: (a) telomere shortening occurred and telomerase activity decreased in human NK cells with ageing; (b) the rate of telomere loss was different under and over 80 years of age; (c) similarly to telomere shortening, the modification of telomerase activity was particularly evident in octogenarians; (d) subjects with the most evident modifications of telomeres and telomerase were the oldest and those with increased NK cell numbers.     

人非小细胞肺癌细胞中端粒酶活性的检测与研究

目的 研究非小细胞肺癌细胞癌组织中端粒酶活性表达,探讨端粒酶生表达与非小细胞肺癌发生发展的关系。方法 收集经手术及病理证实的非小细胞肺癌４８例标本,１２例肺癌癌旁肺组织、７例非肿瘤病例所取正常肺组织作对照。用端粒酶检测试剂盒检测组织本端粒酶活性。结果 ７５．００％（３６／４８）非小细胞肺癌组织标本检出端粒酶活性,８．３３％（１／１２）癌旁肺组织检出端粒酶活笥,７例非肿瘤标本所取的正常肺组织均未检出     

Bone Marrow Stromal Cells (BMSCs) in Bone Engineering: Limitations and Recent Advances

Bone marrow stromal cells (BMSCs) have been isolated for the first time by Friedenstein et al. and since then have been considered the progenitor cells for the skeletal tissues. Indeed BMSCs are clonogenic, fibroblastic in shape, and can differentiate along multiple lineages such as osteoblasts, chondrocytes, adipocytes, and hematopoiesis-supportive stroma. When implanted in vivo on a three-dimensional bioceramic scaffold into immunocompromised mice, BMSCs form bone and hematopoiesis-supportive stroma. The ease of harvest from a donor bone marrow together with the ability to form bone in vivo make BMSCs ideal for clinical applications. Thus, ex vivo expanded BMSCs have been employed, first in large animal models, then in human clinical trials, to repair large bone segmental defects. Further investigation of the expanded BMSC population led to the observation that in vitro expansion appears a limiting passage: cells tend to senesce and lose their multidifferentiation potential with time in culture. To overcome these limitations, two approaches have been proposed: (1) identification of the appropriate culture conditions to prevent senescence by possibly selecting a subpopulation with stem cell characteristics, and (2) engineering of the cells by transfection with the telomerase gene to prevent cells from telomere shortening and consequent aging.     

端粒、端粒酶与细胞衰老及永生化

正常细胞体外培养时,表现为有限生长特性,经一定的细胞倍增次数后,失去了对促分裂因子刺激的反应,不可逆地失去增殖能力而停止分裂,细胞开始衰老的历程.目前认为染色体末端(端粒)的缺失会使细胞逐渐失去增殖能力,导致细胞的衰老和死亡.人端粒酶催化亚单位(hTERT)可以激活端粒酶的活性,延长染色体末端DNA,维持基因组的稳定.端粒、端粒酶、hTERT的发现为细胞衰老的研究提供了新的思路,同时也应用于永生化细胞系的建立,特别是在组织工程种子细胞生物性能研究和细胞库的建立中将发挥重要作用.     

端粒与肿瘤细胞耐药关系的研究进展

端粒是人类染色体末端结构,在维持基因组稳定性中发挥重要作用.有丝分裂导致的端粒长度的进行性缩短是细胞衰老的标志,肿瘤细胞则克服了这种现象,保留了无限增殖的能力,故端粒成为临床治疗的靶点.肿瘤细胞对化疗药物的耐受现象是临床治疗的难题.如何克服肿瘤的耐药性一直是肿瘤治疗研究的重点.该文从端粒的基本组成结构人手,对端粒与肿瘤细胞获得性耐药的关系以及端粒如何介导肿瘤细胞耐药性的产生进行综述,旨在为克服肿瘤耐药性提供新的治疗思路.