秀丽隐杆线虫衰老与衰老相关神经退行性疾病模型及药物筛选研究进展

秀丽隐杆线虫(C.elegans)是生命科学领域非常重要的模式生物,具有寿命短、世代周期短、易于培养与观察等特点,因而被广泛用于生命科学研究,特别是在药物筛选和药物作用机制研究等方面。衰老是一个复杂的过程,是多因素共同作用的结果。在C.elegans中的抗衰老信号通路主要有3种,包括胰岛素-胰岛素样生长因子1信号通路、饮食限制信号通路和线粒体呼吸链/ATP合成信号通路。本文主要综述了基于以上3种信号通路的衰老模型以及基于以上衰老模型的抗衰老药物研究进展。此外,通过转基因或化学诱变可获得一些与衰老相关神经退行性疾病的C.elegans模型,包括帕金森病的α-突触核蛋白转基因模型、阿尔茨海默病的β-淀粉样蛋白沉积模型和亨廷顿舞蹈病的多聚谷氨酰胺聚集的转基因模型,总结了基于以上C.elegans疾病模型筛选的有效药物。<正>随着当今社会人口老龄化的日益加重,人口老龄化已对我国社会经济的稳定和发展产生了深远影响,与此同时与衰老相关的疾病也引起了人们的广泛关注,如何安全有效地延缓衰老已成为医学界和社会关注的焦点,因而衰老机制的探索以及抗衰老药物的研究已成为当今社会研究的一大热点。在衰老与抗衰老研究中人们遴选出了各种动物衰老模型,如D-半乳糖(D-galactose,D-Gal)所致的亚急性大鼠衰老模型[1]、β淀粉样蛋白(β-amyloid     

抗衰老药物的研究进展

近年来关于衰老的研究以及根据衰老的机制寻找高效的抗衰老药物的研究已成为当前医药学研究领域中的热点问题,并已在很多方面取得了长足的进展。本文就近年来衰老及抗衰老药物的研究进展综述如下:(1)衰老的研究:衰老是机体各组织、器官功能随年龄增长而发生的退行性变化,是机体各种生化反应的综合表现,是体内外许多因素共同作用的结果。近半个多世纪以来,国际上已经提出一系列衰老学说,为揭开衰老机制及开发抗衰老药物奠定了基础。包括自由基学说、线粒体DNA损伤学说、衰老的端区学说、免疫学说(immunolog-ical theory)、内分泌学说(endocrine theory)等。(2)抗衰老药物是一类以提高生命效率(生存时间与生命活力的总和)为最终目的的药物,从多系统、多层次和多阶段来发挥其调整功能,它能在遗传学上所界定的寿限内延迟衰老或提高生命质量。抗衰老药物按理化属性可分为:①化学药物,有抗氧化剂、抗衰老激素、营养素、单胺氧化酶抑制剂、免疫调节剂、生化制剂、大脑功能促进药等。②中药,有单味中药以及复方制剂。虽然目前有很多药物研究都证明能够延缓衰老,作用安全,但抗衰老药物不可乱用,其应用既要符合综合性、早期性和长期性原则,又要从个体的实际出发,因人制宜地选用抗衰老药物。     

抗衰老药物的研究进展

目的总结近年来研究人员在抗衰老药物研究领域的发现,为后期研究提供参考。方法通过查阅近5年的相关文献,对抗衰老药物进行分类归纳。结果抗衰老药物大致可分为中药类(如当归、人参和蜂王浆等)、小分子类(如二甲双胍、白藜芦醇、原花青素和雷帕霉素)和多肽类(如大米多肽、大豆多肽和人工合成多肽),通过构建不同的生物模型(如D-半乳糖致衰老小鼠模型、p53基因敲除斑马鱼模型和秀丽隐杆线虫模型等)可证实其抗衰老作用。结论尽管抗衰老药物的作用效果得到了证实,但其分子作用机制有待进一步阐明。     

秀丽隐杆线虫在衰老分子机制研究中的应用

采用秀丽隐杆线虫研究衰老已经有近30年的历史,研究表明胰岛素/胰岛素样生长因子-1信号通路、自噬、线粒体呼吸链/ATP合成体系和进食限制能延缓线虫衰老。本文从衰老的分子机制方面入手,综述秀丽隐杆线虫在衰老分子机制研究中的应用,促进抗衰老药物的开发和评估。     

基于~1H NMR血清和肝脏代谢组学的黄芩叶抗衰老作用研究

本实验采用D-半乳糖致衰老大鼠模型结合1H NMR血清和肝脏代谢组学,探究黄芩叶醇提物的抗衰老作用以及潜在抗衰老代谢调节机制。所有动物实验均通过山西大学科学研究伦理审查委员会审查。结果表明,黄芩叶醇提物具有抗衰老作用,能够改善衰老大鼠外在表征、自主活动能力和脂质过氧化、糖基化等衰老损伤,并可通过调节血清中谷氨酸、谷氨酰胺等12种差异代谢物和D-谷氨酰胺和D-谷氨酸代谢,丙氨酸、天冬氨酸和谷氨酸代谢等11个代谢通路,调节肝脏中α-葡萄糖、β-葡萄糖等5种差异代谢物和糖酵解或糖异生、淀粉和蔗糖代谢通路,改善衰老大鼠血清和肝脏代谢异常。     

抗衰老药物开发与应用初探

我国在抗衰老药物研究方面，由于起步较晚，经费和设备限制，虽在总体上与先进国家尚有差距，但基本上已能跟上国际的发展。而我国在抗衰老药物的免疫学实验、应用细胞免疫学方法、测定首乌水提取对白细胞介素日生成的影响．以及白细胞回、巨、核糖核酸与老化关系等的研究，已经达到了国际先进水平，尤其是在中药抗衰老机理方面取得了丰硕成果。在发展祖国得天独厚的中药优势．还从一些补益中药中发现有不少抗衰老成份．并开发了数易可观的抗衰老中药制剂，使古老的中医药瑰宝重放光彩。根据衰老的自由基学说，为消除机体过多的自由基，发现…     

秀丽线虫在中药及天然药物研究中的应用

模式生物秀丽线虫（Caenorhabditis elegans）具有生命周期短暂、全身透明、易培养和观察等特点,这使其成为生命科学研究领域中的一种优秀模式生物,近年来越来越多的运用到药物筛选、模型建立及药物作用机制的研究中.本文综述了近年来秀丽线虫在中药及天然药物提取物药效及作用机制方面的研究,并展望秀丽线虫在该领域中的应用前景.     

麦冬对D半乳糖衰老模型大鼠的抗衰老作用研究

本实验采用Ｄ半乳糖衰老模型,通过测定表年对照组,模型给药组大鼠脑组织ＳＯＤ,肝组织ＧＳＨ－Ｐｘ、肝组织ＭＤ含量,研究了补益中药麦冬的抗衰老作用。结果表明与青年对照组相比,Ｄ半乳糖模型组ＳＯＤ、ＧＳＨ－Ｐｘ活性显著降低,     

基于网络药理学和体内实验的抗衰老片抗衰老作用及机制探讨

目的 基于网络药理学和体内实验探讨抗衰老片抗衰老的作用机制。方法 利用中药系统药理学数据库与分析平台（TCMSP）筛选抗衰老片中组方药材的主要化学成分及其靶点，并通过文献检索、Pubchem对抗衰老片中药材的主要成分进行补充，经SwissTargetPrediction数据库预测靶点；通过GeneCards、OMIM数据库获取衰老相关靶点；通过Venny2.1.0平台获得抗衰老片成分与衰老的共同靶点；基于STRING数据库和Cytoscape 3.8.0软件构建药物与疾病共同靶点的蛋白质相互作用网络（PPI）；基于R语言进行基因本体（GO）生物功能分析和京都基因与基因组百科全书（KEGG）通路富集分析。以秀丽隐杆线虫为实验对象，观察抗衰老片对N2野生型秀丽隐杆线虫寿命及百草枯诱导的N2野生型线虫及突变体CB1370、CF1038、MQ1333、MQ887、TJ1052寿命的影响，探究抗衰老片抗衰老的作用及潜在的作用机制。结果 筛选出抗衰老片221个活性成分和1 232个预测靶点，衰老相关靶点12 081个，抗衰老片成分和疾病的共同靶点1 020个。KEGG富集分析结果主要涉及磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）信号通路、晚期糖基化终末产物/晚期糖基化终末产物受体（AGE/RAGE）信号通路、丝裂原活化蛋白激酶（MAPK）信号通路等。线虫实验结果表明，抗衰老片可延长正常情况下及百草枯诱导下的N2野生型秀丽隐杆线虫的寿命，提高秀丽隐杆线虫对百草枯的耐性；与相应各对照组相比，抗衰老片无法延长突变体TJ1052和CF1038在氧化应激下的寿命，但突变体CB1370、MQ1333和MQ887在氧化应激下的寿命可被延长。结论 抗衰老片对秀丽隐杆线虫具有延长寿命的作用，其潜在的机制可能依赖于PI3K信号通路和叉头转录因子（FOXO）信号通路，而不依赖于胰岛素受体信号通路和线粒体相关信号通路。     

盐藻β-胡萝卜素抗衰老作用研究

目的观察盐藻β-胡萝卜素(β-C)对果蝇和大鼠的抗衰老作用,并探讨其可能机制。方法①果蝇实验:将果蝇按照不同培养基分组后进行生存实验、性活力实验和飞翔能力实验并测定头部MDA含量。②大鼠实验:老年SD♂大鼠随机分组,灌胃法给药45 d后,测定血浆MDA含量和GSH-Px、CAT活性,以及心、肝、肺、脾、脑MDA含量和SOD、GSH-Px活性。结果①果蝇实验:与对照组相比,各实验组果蝇的平均寿命、最高寿命、最短寿命、延寿率和性活力皆提高,果蝇头部MDA含量减少;②大鼠实验:与对照组相比,各实验组血浆MDA含量明显下降,GSH-Px活性明显增加,心、肝、肺、脾、脑各组织MDA含量皆降低,SOD、GSH-Px活性则皆增加。结论盐藻β-C对果蝇和老年大鼠有抗衰老作用,其可能通过增加体内抗氧化酶的活性,提高机体抗氧化能力而发挥抗衰老作用。     

Using Drosophila models of neurodegenerative diseases for drug discovery

Introduction: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increasing in prevalence as our aging population increases in size. Despite this, currently there are no disease-modifying drugs available for the treatment of these conditions. Drosophila melanogaster is a highly tractable model organism that has been successfully used to emulate various aspects of these diseases in vivo. These Drosophila models have not been fully exploited in drug discovery and design strategies. Areas covered: This review explores how Drosophila models can be used to facilitate drug discovery. Specifically, we review their uses as a physiologically-relevant medium to high-throughput screening tool for the identification of therapeutic compounds and discuss how they can aid drug discovery by highlighting disease mechanisms that may serve as druggable targets in the future. The reader will appreciate how the various attributes of Drosophila make it an unsurpassed model organism and how Drosophila models of neurodegeneration can contribute to drug discovery in a variety of ways. Expert opinion: Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions.     

快速老化小鼠SAMP10的老化特征及其研究进展

快速老化小鼠(senescence-accelerated mouse,SAM)是日本京都大学Takeda教授从AKR/J系小白鼠中通过表型选择培育出的快速老化模型。根据老化速度和病状特征,SAM鼠可以分为快速衰老的P系和抗快速老化的R系。快速老化小鼠SAMP10作为P系的一种,主要特征表现为与衰老相关的学习记忆障碍,具有β-淀粉样蛋白沉积、脑萎缩、神经DNA损伤、星形胶质细胞及小胶质细胞增生等病理变化,在行为学、神经递质以及分子水平方面均表现出一定的衰老变化,是目前较理想的研究阿尔采末病(AD)的动物模型。同龄对照组SAMR1具有正常的衰老特征,常用于SAMP10的正常对照。目前SAMP10是比较理想的用于研究学习记忆障碍的发病机制、评价抗衰老药物以及抗抑郁药的动物模型。     

菟丝子对D-半乳糖致衰老大鼠非酶糖基化及自由基的抑制作用研究

目的:探讨研究菟丝子醇提液对衰老大鼠体内非酶糖基化和自由基的抑制作用及机制.方法:大鼠随机分为青年对照组、衰老模型组和模型给药组,用D-半乳糖制造衰老模型,同时模型给药组灌服菟丝子醇提液并在不同时间杀鼠,测定糖化血红蛋白(GHb)、糖化血清蛋白(GSP),丙二醛(MDA)水平及超氧化物歧化酶(SOD)活性.结果: 菟丝子醇提液使大鼠GHb、GSP、MDA水平明显减低(P<0.05,P<0.01),SOD活性显著升高(P<0.01).结论: 菟丝子抑制非酶糖基化反应,减少自由基生成,具有一定的抗衰老作用.     

抗衰老胶囊的动物实验研究

目的研究抗衰老胶囊的药理作用。方法用复杂水迷路法测试小鼠的学习记忆状况。分别建立记忆获得障碍病理模型、记忆巩固障碍病理模型和记忆再现缺失病理模型。将抗衰老胶囊分散于鼠饲料中制成颗粒型,定量喂食,作为治疗模型。分别测定小鼠的用药后药物对外周血管与脑血管的扩张作用;和药物的抗衰老状况。结果抗衰老胶囊对记忆获得障碍有非常显著的治疗意义,治疗组与病理组（P〈0．01）,病理组与空白组（P〈0．01）的差异有非常显著意义。对记忆再现缺失有非常显著意义,治疗组与病理组（P〈0．01）,病理组与空白组（P〈0．01）,治疗组与空白组（P〈0．01）的差异有显著意义。结果表明抗衰老胶囊能扩张外周循环,脑内微循环,能减少小鼠脑部的脂褐质量。结论抗衰老胶囊能使小鼠提高学习记忆的能力,能扩张外周循环,能增加对脑部的供血量,减缓衰老程度。     

Lecithin organogel: A unique micellar system for the delivery of bioactive agents in the treatment of skin aging

Skin aging is an unavoidable aspect of human life. Premature skin aging can result from poor care, environmental pollutants, and ultraviolet radiation exposure. Wrinkles, lines, spots, uneven skin tone, and pigmentation are often indicators of skin aging. One cannot avoid aging but cosmetics and pharmaceutical approaches can minimize and delay the damage. Topical applications of biocompatible and biodegradable vehicles have been explored for delivering anti-aging compounds. Lecithin organogel (LO) is an effective vehicle for topical delivery of many bioactive agents used in aging treatment. Lecithin is cell component isolated from soya beans or eggs and purified to show excellent gelation in non-polar solvents when combined with water. LO can form a heat-stable, resistant to microbial growth, visco-elastic, optically transparent, and non-birefringent micellar system. It serves as an organic medium to enhance dermal permeation of poorly permeable drugs by effectively partitioning into the skin. Its ability to dissolve in hydrophilic as well as in lipophilic drugs makes it a dynamic vehicle, which can be explored as a carrier for anti-aging agents.     

Porcine placental peptides improve neuroblast proliferation and differentiation via enhancement of TrkB and BDNF levels in D-glatacose-induced mouse aging model

Aging affects the nervous system as well as other organs.In our study, we aimed to study the pharmacological effects and mechanism of porcine placental peptides (PPP) in aging process, and to observe the changes of neuroblast proliferation and differentiation as well as partial gene expression in hippocampus of D-galactose-induced aged mouse. Based on the analysis of experimental results, it was confirmed that PPP significantly improved neurobalst proliferation and differentiation in the mouse hippocampal DG by ki-67 and DCX immunohistochemistry. This result showed that PPP had anti-aging effects on D-galactose-induced aging mouse model. Moreover, we observed up-regulated expressions of BDNF and TrkB proteins and down-regulated expressions of Caspase 3, 8, and 9 proteins in the PPP-treated mouse hippocampus. Therefore, our results showed that PPP obviouslyimproved neuroblast proliferation and differentiation, and its anti-aging effect might berelated to down-regulation of apoptosis-related proteins, including Caspase 3, 8, and 9, via BDNF/TrkB pathway. Our findings provided valuable evidence for its applications in the health and medicine sectors.     

Lifespan-extending property of 6-shogaol from <Emphasis Type="Italic">Zingiber officinale</Emphasis> Roscoe in <Emphasis Type="Italic">Caenorhabditis elegans</Emphasis>

Aging is a key risk factor for many diseases, understanding the mechanism of which is becoming more important for drug development given the fast-growing aging population. In the course of our continued efforts to discover anti-aging natural products, the active constituent 6-shogaol was isolated from Zingiber officinale Roscoe. The chemical structure of 6-shogaol was identified by comparison of its NMR data with literature values. The lifespan-extending effect of 6-shogaol was observed in a dose-dependent manner in Caenorhabditis elegans that has been widely used as a model organism for human aging studies. Mechanism of such action was investigated using C. elegans models, suggesting that 6-shogaol is capable of increasing stress tolerances via enzyme induction. The proposed mechanism was further supported by observation of the increase in SOD and HSP expressions upon treatment with 6-shogaol in transgenic strains of C. elegans which contain GFP-based reporters. In addition, the mechanism was elaborated by confirming that the effect observed for 6-shogaol is independent from other aging-related factors that are known to affect the aging process of C. elegans.     

珍珠养颜液对小鼠抗衰老及免疫调节的研究

目的：研究珍珠养颜液对小鼠抗衰老作用及免疫功能的影响。方法：分别以D-半乳糖制备衰老小鼠模型、环磷酰胺造成免疫低下小鼠模型,以血清SOD、肝脏及脑组织中MDA水平、小鼠的学习记忆能力、胸腺及脾脏系数和碳粒廓清指数作为观察指标评价珍珠养颜液的作用。结果：珍珠养颜液能显著提高衰老小鼠血清SOD水平、降低肝脏及脑组织的MDA水平、增加衰老小鼠的胸腺系数,同时可改善衰老小鼠的学习记忆能力。同时,其可使得免疫低下小鼠的胸腺及脾脏系数增高,并能增强小鼠碳粒廓清能力。结论：珍珠养颜液可能具有抗衰老的作用,并可改善实验动物的免疫功能。     

Korean Red Ginseng Tonic Extends Lifespan in D. melanogaster

Aging is the single most important risk factor that increases susceptibility to many forms of diseases. As such, much effort has been put forward to elucidate the mechanisms behind the processes of aging and to discover novel compounds that retain antiaging activities. Korean red ginseng has been used for a variety of medical purposes in eastern countries for several thousands of years. It has been shown that Korean red ginseng affects a number of biological activities including, but not limited to, anti-inflammatory, anti-oxidative and anti-diabetic pathways. However, few studies have been performed to evaluate its anti-aging effects with an in vivo system. Here Drosophila melanogaster as an in vivo model organism demonstrates that Korean red ginseng tonic extends lifespan, increases resistance to starvation stress and prevents weight gain. This data suggest that Korean red ginseng may regulate organisms’ metabolism in favor of extending lifespan.