热量限制对延缓衰老的作用

热量限制(caloric restriction,CR)在很多物种中能够改善健康和延缓衰老,近年来的许多研究发现,热量限制可以减少多种与年龄相关性疾病的发生,但至今热量限制延缓衰老的机制尚未十分清楚.最近有研究表明,热量限制延缓衰老的机制可能与营养调控、生殖滞育等过程有密切的关系,SIRT1、PGC-1α、AMPK、T...     

哺乳动物雷帕霉素靶蛋白与运动、高脂肪/高盐饮食和衰老的关系

背景：衰老是一个不可逆的过程，其特征与基因、饮食和环境有关。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTor)作为生长发育的中心调节剂对衰老、运动及不良饮食导致的负面影响具有调节作用，这些作用与mTor及其复合物的活性相互关联。然而各因素间的相互联系仍不十分清楚，如mTor、运动对衰老的影响。目的：拟通过研究运动、高脂/高盐饮食和mTor在衰老中的关系，从而对衰老的防治机制有更加全面的认识。方法：(1)文献资料法，通过在CNKI及Web of Science核心合集数据库中进行检索，围绕“mTor基因(mammalian target of rapamycin/mTor)、运动(exercise)、高脂肪/高盐饮食(high-fat diet/high-salt diet)及衰老(aging)”等关键词进行关键词的组合搜索，对相关文献进行检索、查阅和筛选，为文章提供理论支撑。(2)对比分析法，通过对所得到的有效文献进行仔细阅读，比较各文献间的差异，为文章论点提供理论基础。(3)通过对比分析文献间的异同点，明确各指标的定义及关系，从而理清文章思...     

营养因子影响成年神经再生和认知功能

成年神经再生是海马脑区中的干细胞增殖并分化为新神经元和其他常驻脑细胞的复杂过程。该过程受到许多内在和外在因素的影响,包括饮食等。神经再生在神经可塑性、脑内稳态和中枢系统的维持中起关键作用,并且是保护受损脑细胞的认知功能和修复的关键因素。衰老、神经炎性反应、氧化应激和脑损伤等内在因素以及高脂高糖饮食、乙醇和阿片类成瘾等生活方式类外在因素对成年神经再生有不良影响。相反地,许多膳食成分如白藜芦醇、蓝莓多酚、不饱和脂肪(PUFA)以及热量限制、体育锻炼已经显示出具有诱导神经再生的能力。尽管营养物质和饮食因素影响成年神经元再生的机制尚未揭晓,但营养方法为刺激成年神经再生、抵御神经退行性疾病和认知能力下降提供了前景。在这篇评论中,我们总结了营养因子在成年神经再生的修饰和衰老过程中对认知功能保护的一些佐证。     

热量限制及其对阿尔茨海默病等退行性疾病的可能作用

热量限制(CR)是指一种有计划的减少由食物提供的热量,热量限制摄取的营养供给标准。CR对延缓衰老、维持机体年轻的生理状况、延缓或预防一些与衰老相关疾病的发生或发展等有利作用日益引起人们的关注。目前对于CR导致机体延缓衰老的机制形成了很多相关的理论及假说。阿尔茨海默病(AD)是一种以进行性认知障碍和记忆力减退为主要特征的中枢神经退行性疾病。随着社会老龄化的加剧,老年人脑健康问题,尤其是AD日益成为威胁人类健康的主要疾病之一。不少研究表明CR具有提高认知及记忆能力、延缓退行性疾病的发生及发展、延缓衰老等有利作用。本文主要从基因的表达及转录方面和凋亡及氧化应激两方面来概括其相关的作用机制。深入研究CR在AD等神经退行性疾病中的作用机制,对于该疾病的预防及治疗方面具有重要的意义。     

糖原合酶激酶3β参与饮食限制促进Tg2576小鼠神经发生的作用及机制

<正>在AD病人脑内增加神经发生可有效改善认知功能,饮食限制(DR)能够增加成年哺乳动物脑内的神经发生,而机制不明。为明确饮食限制促进3×Tg-AD小鼠海马DG区神经发生并改善认知功能障碍,进一步阐明GSK-3β激活在饮食限制促进神经发生中起重要作用,为AD的防治提供新的策略,我们合成了降低小鼠GSK-3β表达的shRNA,并将其连接入慢病毒转     

睡眠间歇低氧大鼠心室重塑与心肌细胞凋亡和Rho激酶表达的关系

目的 观察睡眠中间歇低氧状态下大鼠心室重塑、血液动力学异常与心肌细胞凋亡和Rho激酶表达的关系,探讨间歇低氧与心室重塑和心力衰竭之间关系的分子机制.方法 24只雄性Wistar大鼠分3组,每组8只.给予适度限制饮食量的普通饮食和每天正常运动量游泳1h,分为常氧(A组)、间歇低氧(B组)、间歇低氧+法舒地尔(C组),60...     

衰老的免疫学机制

免疫反应是机体的稳态(homeostasis)调节机制中的重要一环,伴随衰老出现的机体免疫功能减退,使机体的稳态调节机制发生障碍,抗病能力减弱,感染、自身免疫性疾病和肿瘤的发病率均增加。因此认识衰老时免疫功能的改变,对阐明衰老的机制,防止早衰和延长寿命是非常重要的。     

~(137)Cs γ-射线诱导小鼠胚胎成纤维细胞衰老模型的建立

<正>随着老龄人口的增加,各种老年疾病随之而来,如何延缓衰老已经成为世界各国学者研究的热点。研究衰老机制,建立衰老模型尤为必要。有学者根据衰老的自由基理论,利用一定剂量的γ射线照射建立衰老模型[1-5],但检测的衰老相关指标较少。为此采用137Csγ射线照射小鼠胚胎成纤维细胞(mouse embryo fibroblast,MEF),探讨衰老模型的建立。     

建立早衰动物模型及几种药物抗衰老作用的研究

近年来人们对衰老与抗衰老进行了广泛的研究,并取得一定的进展。但是,由于动物模型问题,使抗衰老,尤其是抗衰老药物的研究受到一定的限制。用于衰老、抗衰老研究的理想动物模型应具有如下特征:(1)衰老过程与人类的自然衰老过程类似;(2)寿命短,老年期出现早。而现有的实验动物均不能满足以上要求。为此,通过一些实验手段,促使动物提     

间充质干细胞在衰老相关疾病应用中的研究进展

衰老相关疾病严重影响老年人的身体健康，间充质干细胞(MSCs)在衰老相关疾病中的作用和机制研究受到越来越多的关注，国内外研究者也开展了多项相关的临床试验研究。本文对MSCs及其来源外泌体(exosome)在衰老相关的典型疾病如骨质疏松、帕金森病、2型糖尿病、动脉粥样硬化、慢性阻塞性肺病和肿瘤中的作用机制和临床试验进行综述，希望为MSCs在衰老相关疾病中的研究提供一定的理论依据和参考。     

CSE／H2 S在心血管系统的作用及机制

硫化氢（ H2 S）是一种内源性气体信号分子,在机体各系统中均发挥着重要作用。体内H2 S的主要由多种酶催化生成,其在心血管系统主要由胱硫醚-γ-裂解酶（ cystathionine-r-lyase, CSE）催化产生。近年来研究显示CSE／H2 S通路与多种心血管疾病的发生发展关系密切。文章以CSE／H2 S通路在心血管系统的作用为切入点,阐述H2 S在心血管系统的保护作用及其分子调控机制。     

Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide

Both nitric oxide (NO) and hydrogen sulfide (H(2)S) are two important gaseous mediators regulating heart function. The present study examined the interaction between these two biological gases and its role in the heart. We found that l-arginine, a substrate of NO synthase, decreased the amplitudes of myocyte contraction and electrically induced calcium transients. Sodium hydrogen sulfide (an H(2)S donor), which alone had minor effect, reversed the negative inotropic effects of l-arginine. The effect of l-arginine + sodium hydrogen sulfide was abolished by three thiols (l-cysteine, N-acetyl-cysteine, and glutathione), suggesting that the effect of H(2)S + NO is thiol sensitive. The stimulatory effect on heart contractility was also induced by GYY4137, a slow-releasing H(2)S donor, when used together with sodium nitroprusside, an NO-releasing donor. More importantly, enzymatic generation of H(2)S from recombinant cystathionine-γ-lyase protein also interacted with endogenous NO generated from l-arginine to stimulate heart contraction. In summary, our data suggest that endogenous NO may interact with H(2)S to produce a new biological mediator that produces positive inotropic effect. The crosstalk between H(2)S and NO also suggests an intriguing potential for the endogenous formation of a thiol-sensitive molecule, which may be of physiological significance in the heart.     

Hypoxia-induced arterial chemoreceptor stimulation and hydrogen sulfide: too much or too little?

This brief review presents and discusses some of the important issues surrounding the theory which asserts that endogenous hydrogen sulfide (H(2)S) is the mediator of, or at least an important contributor to, hypoxia-induced arterial chemorereceptor stimulation. The view presented here is that before H(2)S can seriously be considered as a candidate for transducing the O(2)-signal in the carotid bodies (CB), fundamental contradictions need to be resolved. One of these major contradictions is certainly the discrepancy between the levels of H(2)S endogenously present in the CB during hypoxia compared to the levels required to stimulate the arterial chemoreceptors in vitro. Very small amounts of H(2)S are thought to be produced endogenously during a given level of hypoxia, yet the partial pressure of tissue H(2)S which is needed to produce an effect commensurate with that of hypoxia is thousands to millions of times higher. This review discusses this and other contradictions in light of what is known about H(2)S concentration and production in various tissues, the lessons we have learnt from the response to exogenous sulfide and the ability of the blood and the mitochondria to oxidize very large amounts of sulfide. These considerations suggest that the increased production of H(2)S in hypoxia and exogenous sulfide cannot produce the same effect on the carotid bodies and breathing. While the effects of the endogenous H(2)S on breathing remains to be established, the effects exogenous sulfide can be accounted for by its long established toxicity on cytochrome C oxidase.     

Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells

Hydrogen sulfide (H(2)S) is synthesized intracellularly by the enzymes cystathionine-γ-lyase and cystathionine-β-synthase (CBS), and is proposed to be a gasotransmitter with effects in modulating inflammation and cellular proliferation. We determined a role of H(2)S in airway smooth muscle (ASM) function. ASM were removed from resection or transplant donor lungs and were placed in culture. Proliferation of ASM was induced by FCS and the proinflammatory cytokine, IL-1β. Proliferation of ASM and IL-8 release were measured by bromodeoxyuridine incorporation and ELISA, respectively. Exposure of ASM to H(2)S "donors" inhibited this proliferation and IL-8 release. Methemoglobin, a scavenger of endogenous H(2)S, increased DNA synthesis induced by FCS and IL-1β. In addition, methemoglobin increased IL-8 release induced by FCS, but not by IL-1β, indicating a role for endogenous H(2)S in these systems. Inhibition of CBS, but not cystathionine-γ-lyase, reversed the inhibitory effect of H(2)S on proliferation and IL-8 release, indicating that this is dependent on CBS. CBS mRNA and protein expression were inhibited by H(2)S donors, and were increased by methemoglobin, indicating that CBS is the main enzyme responsible for endogenous H(2)S production. Finally, we found that exogenous H(2)S inhibited the phosphorylation of extracellular signal-regulated kinase-1/2 and p38, which could represent a mechanism by which H(2)S inhibited cellular proliferation and IL-8 release. In summary, H(2)S production provides a novel mechanism for regulation of ASM proliferation and IL-8 release. Therefore, regulation of H(2)S may represent a novel approach to controlling ASM proliferation and cytokine release that is found in patients with asthma.     

Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats

Hydrogen sulfide (H2S) is a naturally occurring gas that may act as an endogenous signaling molecule. In the brain, H2S is mainly produced by cystathionine beta-synthase (CBS) and its cellular effects have been attributed to interactions with N-methyl-D-aspartate (NMDA) receptors and cyclic adenosine 3',5'-monophosphate (cAMP). In contrast, direct vasodilator actions of H2S are most probably mediated by opening smooth muscle ATP-sensitive K+ (K(ATP)) channels. In the hypothalamus, K(ATP) channel-dependent mechanisms are involved in CNS-mediated regulation of blood pressure. In this report, we investigated the hypothesis that H2S may act via K(ATP) channels in the hypothalamus to regulate blood pressure. Mean arterial blood pressure (MAP) and heart rate were monitored in freely moving rats via a pressure transducer placed in the femoral artery. Drugs were infused via a cannula placed in the posterior hypothalamus. Infusion of 200 microM sodium hydrogen sulfide (NaHS), an H2S donor, into the hypothalamus of freely moving rats reduced MAP and heart rate. Infusion of 300 nM to 3 microM gliclazide dose-dependently blocked the effect of 200 microM NaHS. Infusion of the CBS activator, s-adenosyl-L-methionine (0.1 mM and 1 mM), likewise decreased MAP. Infusion of the CBS inhibitors aminooxyacetic acid (10 mM) and hydroxylamine (20 mM) increased MAP but did not block the effects of infusion of 200 microM NaHS. These data indicate that actions of H2S in the hypothalamus decrease blood pressure and heart rate in freely moving rats. This effect appears to be mediated by a K(ATP) channel-dependent mechanism and mimicked by endogenous H2S.     

Cytoprotective actions of hydrogen sulfide in ischaemia-reperfusion injury

Hydrogen sulfide (H(2)S) has been known as a highly toxic gas for several centuries. There have been considerable advances made in the H(2)S field regarding its physiological role; however, there is much more work that needs to be done. The biosynthesis of H(2)S has been attributed to three endogenous enzymes: cystathionine β-synthase (CBS), cystathionine γ-lyase (CGL or CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes require further investigation to more fully elucidate the cellular expression profile, regulation and precise role of these critical enzymes in the production of H(2)S. In recent years, H(2)S has been demonstrated to have cytoprotective effects in multiple organ systems. In particular, it has been demonstrated that the administration of H(2)S either prior to ischaemia or at reperfusion significantly ameliorates myocardial and hepatic ischaemia-reperfusion injury. Therefore, this review focuses on the cardioprotective and hepatoprotective role of H(2)S. In addition, the review provides a summary of several known molecular targets of H(2)S protection.     

A source of hydrogen sulfide and a mechanism of its release in the brain

Hydrogen sulfide (H2S) is recognized as a neuromodulator as well as neuroprotectant in the brain. H2S can be produced from cysteine by enzymes such as cystathionine beta-synthase. However, a mechanism for releasing H2S under physiologic conditions has not been identified. Here we show that H2S is released from bound sulfur, an intracellular store of sulfur, in neurons and astrocytes of mice and rats in the presence of physiologic concentrations of endogenous reducing substances glutathione and cysteine. The highest pH to release H2S from another sulfur store, acid-labile sulfur, which is localized mainly in mitochondria, is 5.4. Because mitochondria are not in the acidic condition, acid-labile sulfur may not be a physiologic source of H2S. Free H2S is immediately absorbed and stored as bound sulfur. Our novel method, using silver particles to measure free H2S, shows that free H2S is maintained at a low level in basal conditions. Alkalinization of the cytoplasm is required for effective release of H2S from bound sulfur, and this condition is achieved in astrocytes by the high concentrations of extracellular K+ that are normally present when nearby neurons are excited. These data present a new perspective on the regulation of H2S in the brain.     

L-精氨酸对大鼠高肺血流所致肺血管结构重建及内源性硫化氢的影响

探讨L 精氨酸 (L Arg)对高肺血流量所致大鼠肺血管结构重建和内源性硫化氢的影响及其机制。 2 1只SD大鼠随机分为对照组 (n =7) ,分流组 (n =7) ,分流 +L 精氨酸组 (n =7)。对后两组大鼠行腹主动脉、下腔静脉分流术。对分流 +L 精氨酸组大鼠每天灌胃L Arg 1g kg。 1 1周后观察肺动脉平均压 (mPAP)和右心室肥厚的改变。并且在光学显微镜和电子显微镜下观测肺血管结构的变化。测定血浆硫化氢含量和肺组织硫化氢产出率。结果表明 ,分流组大鼠mPAP、右心室 /体重 (RV BW)及右心室 /左心室 +室间隔 [RV (LV +S) ]比值明显高于对照组 (P <0 0 1 ) ,光镜下肺小血管肌化程度明显增强 ,电镜下 ,肺中、小肌型动脉内皮细胞增生、肥厚 ,平滑肌细胞由收缩表型向合成表型转化。分流组大鼠的血浆H2 S含量及肺组织CSE活性 (肺组织H2 S产出率 )明显低于对照组 (P <0 0 1 ) ,肺动脉平均压与血浆H2 S浓度呈负相关。同时L Arg缓解了肺动脉结构重建的形成 ,同时提高了内源性硫化氢水平 ,这可能是L Arg缓解高肺血流量所致肺动脉高压形成的机制之一。     

Hydrogen sulfide in the mammalian cardiovascular system

For more than a century, hydrogen sulfide (H(2)S) has been regarded as a toxic gas. This review surveys the growing recognition of the role of H(2)S as an endogenous signaling molecule in mammals, with emphasis on its physiological and pathological pathways in the cardiovascular system. In biological fluids, H(2)S gas is a weak acid that exists as about 15% H(2)S, 85% HS(-), and a trace of S(2-). Here, we use "H(2)S" to refer to this mixture. H(2)S has been found to influence heart contractile functions and may serve as a cardioprotectant for treating ischemic heart diseases and heart failure. Alterations of the endogenous H(2)S level have been found in animal models with various pathological conditions such as myocardial ischemia, spontaneous hypertension, and hypoxic pulmonary hypertension. In the vascular system, H(2)S exerts biphasic regulation of a vascular tone with varying effects based on its concentration and in the presence of nitric oxide. Over the past decade, several H(2)S-releasing compounds (NaHS, Na(2)S, GYY4137, etc.) have been utilized to test the effect of exogenous H(2)S under different physiological and pathological situations in vivo and in vitro. H(2)S has been found to promote angiogenesis and to protect against atherosclerosis and hypertension, while excess H(2)S may promote inflammation in septic or hemorrhagic shock. H(2)S-releasing compounds and inhibitors of H(2)S synthesis hold promise in alleviating specific disease conditions. This comprehensive review covers in detail the effects of H(2)S on the cardiovascular system, especially in disease situations, and also the various underlying mechanisms.