端粒长度调控及端粒与衰老和疾病的关系

端粒是线性染色体末端的DNA-蛋白质结构,可保护染色体末端免于降解和融合。由于大多数体细胞中存在末端复制问题和端粒酶缺乏的固有限制性,端粒DNA随着细胞每次分裂而缩短。短端粒或功能失调的端粒可诱导持续的DNA损伤反应,从而触发细胞复制性衰老。端粒长度主要通过端粒酶和端粒替代延长途经2种端粒机制维持。此外,端粒DNA还会被转录,生成含有端粒重复序列的RNA(telomeric repeat-containing RNA,TERRA),积极参与端粒维持和染色体末端保护。端粒长度是一种复杂的遗传特征,受遗传、疾病和环境因素的影响。流行病学数据显示,端粒长度与衰老、癌症、端粒生物学疾病及多种衰老相关疾病之间存在不同程度的关联。随着端粒长度检测方法的不断发展,血细胞端粒长度作为人类衰老生物标志物和衰老相关疾病的危险因素得到了广泛研究,具有作为生物标志物的潜力。     

端粒、端粒酶与衰老

古往今来,“长生不老”成为人们一直追求的梦想,曾经有多少人用各种方法来延缓衰老,但终未取得显著效果。近年来研究证实,端粒缩短导致衰老。     

端粒位置效应与人类衰老

端粒随细胞分裂进行性缩短不但防止了人类肿瘤的发展,而且与人类的衰老密切相关。另外,端粒中存在一种特殊的现象：端粒位置效应,它首先在酵母中发现,表现为靠近端粒序列附近的基因表达因端粒的位置效应而沉默。在人类细胞中也存在端粒位置效应,并且有多种因子参与此效应,它可能对细胞生长停止、肿瘤以及衰老发生时等许多随端粒缩短密切相关基因的程序性表达产生重要作用。     

端粒和端粒酶与衰老研究

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伤等,并已形成了许多学说,而端粒学说成为衰老研究的热点之一.对与衰老紧密相关的因素———端粒、端粒酶的结构及其与衰老关系的研究进展进行综述,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.     

端粒DNA与细胞的衰老,死亡

端粒ＤＮＡ与细胞的衰老、死亡白丽荣（河北衡水师专生物系,０５３０００）端粒ＤＮＡ是真核生物染色体的天然末端,它的生物学功能是保持染色体稳定。近年来研究发现,端粒ＤＮＡ决定了细胞寿命,并与细胞的自然凋亡及癌化有关。端粒（Ｔｅｌｏｍｅｒｅ）是指真核细胞线...     

端粒及端粒酶的研究进展

端粒是染色体末端独特的蛋白质-DNA结构,在保护染色体的完整性和维持细胞的复制能力方面起着重要的作用.端粒酶则是由RNA和蛋白质亚基组成的、能够延长端粒的一种特殊反转录酶.端粒长度和端粒酶活性的变化与细胞衰老和癌变密切相关.端粒结合蛋白可能通过调节端粒酶的活性来调节端粒长度,进而控制细胞的衰老、永生化和癌变.研制端粒酶的专一性抑制剂在肿瘤治疗方面有着广阔的前景.     

端粒长度及变化规律

端粒是位于染色体末段的一种特殊结构,具有维持染色体稳定的功能。不同的细胞,同一细胞的不同染色体具有不同的端粒长度;端粒长度是由基因控制的,并受到各种外界因素的影响;端粒长度随细胞的增殖与分化而缩短或者延长,细胞内在的端粒长度调控机制控制着端粒长度在一定的范围内变化。本文还分析了在端粒长度研究方面存在的问题。     

端粒(酶)的结构功能及其与衰老和癌症的关系

端粒是真核生物线性染色体末端由重复DNA序列和蛋白质结合形成的复合结构。在哺乳动物中,其特殊的环形结构与多种结合蛋白形成了端粒功能的基础。端粒酶具有逆转录酶特性和维持端粒长度的功能,其活性与恶性肿瘤的发生密切相关。衰老是大多数真核细胞分裂到一定次数后必然走上的道路,端粒的缩短是其中重要的调控因素,并在早衰症患者中表现出异常。癌细胞的恶性化过程中,端粒酶的激活是一重要步骤,此过程可受到多水平多途径的调节。癌症和衰老相互联系,端粒酶可能在两者交错的网络中体现了这一联系。     

衰老及相关疾病与细胞信号转导的关系

概述了衰老及相关病变与细胞信号转导障碍或异常的密切关系。细胞与细胞间或细胞与环境间无时无刻不在进行着信息联系 ,信号转导途径的任何一个环节出现问题 ,都可引起细胞生长失控 ,进而引起病变。因而了解细胞衰老机理和信号转导途径 ,从分子水平上认识、预防和治疗疾病有着深远的意义。     

端粒、端粒酶在动脉粥样硬化中的研究进展CSCD

端粒是真核生物线性染色体末端的DNA重复序列,维持染色体的稳定性和DNA复制的完整性。DNA复制过程中,端粒逐渐缩短达到临界值时,染色体DNA被破坏而发生复制型衰老。端粒酶是催化端粒合成的酶,但在正常体细胞中活性很低。动脉粥样硬化是一种衰老相关性疾病,为冠心病、脑梗死、外周血管病发生发展的病理基础。新近研究发现,在动脉粥样硬化患者体内存在较短的端粒,并且较短的端粒更容易导致动脉粥样硬化。本文主要综述了参与动脉粥样硬化形成过程中细胞端粒长度和端粒酶活性的变化,以及这些变化对动脉粥样硬化形成的影响,并概括了动脉粥样硬化的危险因素与端粒和端粒酶的关系。     

同型半胱氨酸与冠心病

随着社会的进步以及人类生活水平的提高,冠心痛的发病率也逐年提高,目前已经成为全球死亡率最高的疾病之一,同时医学水平的不断发展也使得人们对冠心病有了更进一步的研究.近年来同型半胱氨酸越来越受到人们的关注,众多研究表明,高同型半胱氨酸血症是冠心痛的独立危险因子,可以影响冠心病的严重程度及预后.但是迄今为止,同型半胱氨酸在冠心病发病中的确切机制尚不完全明确,认为主要与血管内皮损伤、血管平滑肌细胞增殖凋亡、破坏凝血纤溶系统、影响糖、蛋白质、脂质代谢等方面有关.针对高同型半胱氨酸血症的治疗,对于改善冠心病患者的预后有一定疗效.因此,本文就同型半胱氨酸冠心痛的关系作一综述,从而为临床更好的防治冠心痛提供相关的资料.     

血脂康胶囊对冠心病患者的抗氧化及抗炎效果研究

目的：探讨血脂康胶囊对冠心病患者的抗氧化及抗炎效果和意义。方法：选取冠心病并且有一定程度的脂代谢紊乱的患者64例,按随机对照原则随机分为A组（32例）及B组（32例）,A组给予血脂康胶囊600mg,日2次;B组予洛伐他汀40mg/d,丙氨酸转氨酶或天冬氨酸转氨酶升高超过正常值3倍以上的患者服用剂量减半,即洛伐他汀20mg/d,经治疗或者观察恢复正常后再加到40mg/d。共比8周,检测实验前后的血浆ALT,AST,CK,OX-LDL,CRP及SOD水平。结果：血脂康胶囊可以明显的降低血浆TG,CHOL,LDL水平,并且与对照组差异有显著性意义（P〈0.05）。血脂康胶囊可以明显的降低血浆OX-LD,CRP水平,与对照组差异有非常显著性意义（P〈0.01）,血脂康胶囊可以提高血浆SOD水平优于对照组（P〈0.01）,而升高ALT,AST,CK的副作用较对照组低（P〈0.05）。结论：血脂康胶囊常规剂量不仅有效调脂而安全,并且有一定的抗氧化及抗炎效果。     

氨氯地平阿托伐他汀钙片对高血压合并冠心病的临床疗效分析

目的：探讨氨氯地平阿托伐他汀钙片对高血压合并冠心病的临床疗效。方法：选取我院于2008年6月-2011年12月收治的高血压合并冠心病确诊患者58例,并在知情同意的前提下将其随机平均分组,观察组与对照组各29例,对照组使用阿托伐他汀治疗,观察组使用氨氯地平阿托伐他汀钙片治疗,疗程结束后对比两组患者的血压、心电图及不良反应等指标,分析治疗效果及安全性。结果：对照组治疗后血压及心电图改善有效率分别为72.4%及55.2%,观察组为96.6%及93.1%,观察组改善情况明显优于对照组;两组患者并发症发生率均为10.3%,无明显统计学差异。结论：氨氯地平阿托伐他汀钙片治疗高血压合并冠心病具有疗效显著、安全性高、治疗费用低等优点,值得临床广泛推广。     

Seasonality and Coronary Heart Disease Deaths in United States Firefighters

United States firefighters have a high on‐duty fatality rate, and coronary heart disease is the leading cause. Seasonality affects the incidence of cardiovascular events in the general population, but its effects on firefighters are unknown. This study statistically examined the seasonal and annual variation of all on‐duty coronary heart disease deaths among US firefighters between 1994 and 2004 using the chi‐square distribution and Poisson regression model of the monthly fatality counts. It also examined the effect of ambient temperature (apparent as well as wind chill temperature) on coronary heart disease fatalities during the study span using a time‐stratified, case‐crossover study design. When grouped by season, we observed the distribution of the 449 coronary heart disease fatalities to show a relative peak in winter (32%) and relative nadir in spring (21%). This pattern was significantly different (p=0.005) from the expected distribution under the null hypothesis of season having no effect. The pattern persisted in additional analyses, stratifying the deaths by the type of duty in which the firefighters were engaged at the time of their deaths. In the Poisson regression model of the monthly fatality counts, the overall goodness‐of‐fit between the actual and predicted case counts was excellent (χ₄²=16.63; p=0.002). Two distinct peaks were detected: one in January–February and the other in August–September. Overall temperature was not associated with increased risk of on‐duty death. After allowing for different effects of temperature in mild/hot versus cold periods, a 1°C increase was not protective in cold weather; nor did it increase the risk of death in warmer weather. The findings of this study reveal statistical evidence for excess coronary heart disease deaths among firefighters during winter; however, the temporal pattern of coronary heart disease deaths was not linked to temperature variation. The seasonal pattern was also found to be independent of duty‐related risks.     

Circadian Variation of Cardiac Performance in Coronary Heart Disease

To study the circadian variation of cardiac performance in patients with coronary heart disease, three exercise tests on a bicycle crgometer were performed during the active part of the day (10 a.m., 2 p.m. and 6 p.m.), recording ST-segment depression and pulmonary capillary wedge pressure. Ten male patients with angiographically documented coronary heart disease underwent bicycle ergometry during placebo and during nitrate therapy (placebo controlled, double-blind crossover 2 × 20 mg IS-5-MN and 1 × 120 mg ISDN sustained release). During placebo as well as during nitrate therapy there was a gradual decrease of cardiac performance during the day, documented by the increase in ST-depression and pulmonary capillary wedge pressure at equal work loads. High nitrate concns led to a significant reduction of both ST-depression and preload with a marked circadian-phase dependency of cardiovascular effects.     

Circadian Variation of Cardiac Performance in Coronary Heart Disease

To study the circadian variation of cardiac performance in patients with coronary heart disease, three exercise tests on a bicycle crgometer were performed during the active part of the day (10 a.m., 2 p.m. and 6 p.m.), recording ST-segment depression and pulmonary capillary wedge pressure. Ten male patients with angiographically documented coronary heart disease underwent bicycle ergometry during placebo and during nitrate therapy (placebo controlled, double-blind crossover 2 × 20 mg IS-5-MN and 1 × 120 mg ISDN sustained release). During placebo as well as during nitrate therapy there was a gradual decrease of cardiac performance during the day, documented by the increase in ST-depression and pulmonary capillary wedge pressure at equal work loads. High nitrate concns led to a significant reduction of both ST-depression and preload with a marked circadian-phase dependency of cardiovascular effects.     

含凝血酶敏感素1型基序的解聚素样金属蛋白酶在冠心病中作用的研究进展

含凝血酶敏感素1型基序的解聚素样金属蛋白酶(a disintegrin and metalloproteinase with thrombospondin motifs 1,ADAMTS-1)可降解细胞外基质中的多能蛋白聚糖,促进平滑肌细胞的迁移,参与动脉粥样硬化的发生,并能进一步活化粥样斑块,促进斑块破裂;还可抑制血管的新生、参与胶原代谢加速心室重构、心肌纤维化等病理过程的进展,与各种类型的冠心痛如稳定型心绞痛(stable angina,SA)、急性冠脉综合征(acute coronary syndrome,ACS)、缺血性心肌病(ischemic cardiomyopathy,ICM)均密切相关.研究表明,ADAMTS-1有助于冠脉狭窄程度评估、斑块稳定性判断、ACS的辅助诊断及治疗策略的选择,有望用于冠心病的危险分层和预后评估,并可能成为动脉粥样硬化和各种类型冠心病预防和治疗的新靶点.本文将就ADAMTS-1在冠心病中作用的研究进展进行综述.     

Age-Related Changes of Elements in the Coronary Arteries of Monkeys in Comparison with Those of Humans

To elucidate compositional changes of the coronary artery with aging, the authors investigated age-related changes of elements in the coronary arteries of rhesus and Japanese monkeys by direct chemical analysis in comparison with the coronary arteries of Japanese and Thai. Used monkeys consisted of 38 rhesus monkeys and 23 Japanese monkeys, ranging in age from newborn to 33 years. After perfusion with a fixative, the hearts were resected from the monkeys, and the anterior interventricular branches of the left coronary artery and the right coronary arteries were resected from the hearts. After ashing of the arteries, element contents were determined by inductively coupled plasma-atomic emission spectrometry. It was found that the Ca and P contents did not increase in both the left and right coronary arteries of rhesus and Japanese monkeys at old age. The average contents of Ca and P decreased by 13% and 25% in the left coronary arteries more than 20 years of age in comparison with those below 20 years of age, whereas they decreased by 4% and 15% in the right coronary arteries more than 20 years of age in comparison with those below 20 years of age. This finding indicated that atherosclerosis scarcely occurred in both the left and right coronary arteries of rhesus and Japanese monkeys at old age. In contrast with monkeys, atherosclerosis occurred frequently in the coronary arteries of Japanese and Thai at old age.     

The Important Role of Lipid Peroxidation Processes in Aging and Age Dependent Diseases

Any change in the cell membrane structure activates lipoxygenases (LOX). LOX transform polyunsaturated fatty acids (PUFAs) to lipidhydroperoxide molecules (LOOHs). When cells are severely wounded, this physiological process switches to a non-enzymatic lipid peroxidation (LPO) process producing LOO^· radicals. These oxidize nearly all-biological molecules such as lipids, sugars, and proteins. The LOO^· induced degradations proceed by transfer of the radicals from cell to cell like an infection. The chemical reactions induced by LO^· and LOO^· radicals seem to be responsible for aging and induction of age dependent diseases. Alternatively, LO^· and LOO^· radicals are generated by frying of fats and involve cholesterol-PUFA esters and thus induce atherogenesis. Plants and algae are exposed to LOO^· radicals generating radiation. In order to remove LOO^· radicals, plants and algae transform PUFAs to furan fatty acids, which are incorporated after consumption of vegetables into mammalian tissues where they act as excellent scavengers of LOO^· and LO^· radicals. Figure 6 of this article is reprinted from the paper of G. Spiteller: “Peroxyl radicals: Inductors of neurodegenerative and other inflammatory diseases. Their origin and how they transform cholesterol, phospholipids, plasmalogens, polyunsaturated fatty acids, sugars and proteins into deleterious products” published in Free Radic. Biol. Med. 41, 362–387 (2006) Elsevier, 2006 by permission from Elsevier.     

Chronotherapy in Coronary Heart Disease: Comparison of Two Nitrate Treatments

The purpose of this study was to assess the ischemic burden and the hemodynamic changes during daily activities in patients with coronary heart disease. Three exercise tests were performed during the day (10:00 a.m., 2:00 p.m., 6:00 p.m.), recording ST-segment depression, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output as well as heart rate and systemic blood pressure during placebo and nitrate therapy. With placebo as well as nitrate therapy there was a gradual increase of ischemia and preload and a decrease of cardiac output during the day. High nitrate concentrations led to a significant reduction of both preload and ST depression with a marked circadian phase dependency of cardiovascular effects.