食欲素神经肽在应激过程中的作用

食欲素因其在调节能量代谢、睡眠和唤醒等生理功能中的作用而备受关注.近年来研究逐渐发现,食欲素参与应激和奖赏过程的调节,特别是其在药物成瘾过程中的作用是目前的研究热点.主要介绍食欲素系统与应激相关系统之间的神经联系,阐述了其在应激相关的生理、神经内分泌与行为反应中的作用.并进一步介绍了食欲素系统在应激诱发药物成瘾复吸过程中的作用.食欲素对应激反应的调控作用具有相对特异性,受应激的种类、其他应激相关神经递质系统及食欲素神经元的投射通路等多种因素影响.     

大鼠慢性多重应激模型的建立

目的:建立大鼠慢性多重应激模型,为研究应激性疾病提供实验模型.方法:健康雄性SD大鼠随机分为模型组(n=10)和对照组(n=10).模型组采用脉冲随机变动的噪声、夜间光照、足底电击以及强迫游泳和束缚的复合刺激为应激源,对大鼠实施刺激,观察行为变化,检测心率、血压、体重增长速率、食物利用率,测定血清ACTH和皮质酮并进行分析.结果:慢性多重应激大鼠由实验之初的兴奋状态逐渐进入抑制状态,血压心率上升,体重增长缓慢,食物利用率降低,血清ACTH和皮质酮增高.结论:慢性多重应激大鼠一般行为、基本生理体征和下丘脑-垂体-肾上腺轴(HPA)功能发生改变,应激反应处于持续亢奋状态,该模型是较稳定较理想的应激模型.     

慢性复合应激后FGF-2的表达变化及其对神经发生的影响

应激是机体在内外环境剧变的刺激下所产生的综合应答状态,包括精神、神经、内分泌和免疫等各方面的变化。近年来许多研究发现应激与神经发生存在着一定的联系,同时碱性成纤维细胞生长因子（basic fibroblast growth factor,FGF-2）是一种重要的血管原性促有丝分裂剂,对神经细胞也有显著的作用,能促进神经元的存活和轴突的生长。本室以往研究发现慢性复合应激可促进大鼠海马神经发生,本研究通过观察慢性复合应激后大鼠海马FGF-2表达的变化,来探讨慢性复合应激对FGF-2表达的影响及其与海马神经发生的联系。     

荷人卵巢上皮性癌裸鼠慢性心理应激模型中移植瘤蛋白质组研究

心理社会因素对肿瘤患者的影响已经引起了国内外学者的密切关注, 长期生活在不良心理应激状态下能促进恶性肿瘤的发生和发展已成定论, 但对其具体机制尚不完全清楚. 为探讨慢性心理应激影响肿瘤发生发展的分子学机制, 建立荷人卵巢癌裸鼠慢性心理应激模型. 通过双向电泳和nanoUPLC-ESI-MS/MS, 在裸鼠移植瘤组织中发现了20种明显差异表达蛋白, 其中相比对照组, 应激组有14种蛋白表达上调, 5种表达下调, 而1种蛋白只在应激组裸鼠皮下移植瘤中被发现; Western blotting验证结果与蛋白质组学一致. 本研究为揭示心理和肿瘤的关系提供了新的分子方面的依据.     

饮酒通过内质网应激促进小鼠乳腺癌恶性进展

目的通过动物实验及体外实验探索饮酒是否促进乳腺癌恶性进展,且这一作用是否与其诱导的慢性应激有关。方法利用小鼠乳腺癌移植瘤模型,体内观察2%乙醇慢性处理的小鼠乳腺癌E0771细胞对体内细胞生长转移的影响;利用体外细胞学实验观察0.2%乙醇慢性诱导对小鼠乳腺癌细胞E0771增殖、迁移及非锚定生长能力的影响;同时用分子生物学方法探索细胞内ROS水平及慢性内质网应激蛋白如p-e IF2a、Bip、XBP1-s等蛋白表达水平是否发生改变。结果与对照组相比,饮酒组小鼠体内肿瘤生长速度加快,转移增加;体外酒精处理可以显著促进乳腺癌细胞增殖、迁移等恶性生物学行为,酒精慢性处理可以诱导ROS、内质网应激活化蛋白p-e IF2a、Bip、XBP1-s表达上升。结论饮酒可能通过诱导乳腺癌细胞内质网应激促进其恶性进展。     

创伤后应激障碍机制的研究进展

创伤后应激障碍(Post-traumatic stress disorder;PTSD)是一种由严重强烈的伤害事件造成的精神障碍,随着近年来社会应激事件的增多和自然灾害的发生,创伤应激障碍的发病率逐渐增高。同时为了研究对应的治疗方法,人们对创伤应激障碍的机制进行了更深入的探索,也有了新的进展。本文着重从激素、神经营养因子、免疫系统等方面来总结创伤后应激障碍发生的生物学机制。激素方面,PTSD主要与交感肾上腺髓质系统(Sympatho-adrenomedullarysystem,SAS)和下丘脑-垂体-肾上腺轴(Hypothalamicpituitary-adrenal axis,HPA)的功能异常有关;神经营养因子方面,其产生与分泌的异常增加或减少可能是PTSD产生的重要机制;免疫系统方面,PTSD可能与免疫系统相关的蛋白质、细胞的数量和功能变化有关。整合神经生物学与分子生物学、表观遗传学、蛋白质组学及分子影像学的成果将对PTSD的研究产生推动作用。     

螺旋藻对慢性应激大鼠结肠菌群和体重的影响

目的观察螺旋藻对慢性应激大鼠结肠菌群和体重的保健作用。方法采用SD大鼠慢性应激模型,实验期为7周。用平板计数法检测大鼠肠道菌群。结果慢性应激大鼠粪便中发生明显的以双歧杆菌数量下降为特征的菌群失调现象,进食含5%螺旋藻饲料的大鼠粪便中双歧杆菌数量显著增加,肠杆菌相应减少,体重相应增加。结论在慢性应激条件下,饲喂螺旋藻能够有效维持大鼠肠道微生态平衡,促进大鼠生长。     

大鼠慢性束缚应激后肠道病理及其菌群变化

基于慢性束缚应激法建立大鼠慢性应激模型,结合苏木精-伊红染色和肠道细菌基因间重复序列(enterobacterial repetitive intergenic consensus,ERIC)-PCR技术观察大鼠肠道组织病理及菌群变化规律。选取10只健康雄性sprague-dawley(SD)大鼠,随机分为对照组和模型组,每组5只。对照组正常饲养,模型组采用束缚筒每天束缚应激4 h,连续造模30 d,造模前后记录大鼠的体重并于造模后进行行为学评估,采用脱臼法处死并收集大鼠肠道组织及其内容物,包被切片后进行HE染色,肠道内容物初步分离后提取基因组DNA并采用ERIC-PCR检测菌群变化规律。结果显示,与对照组相比,应激模型组大鼠体重、穿越次数、直立次数、理毛次数均显著降低,强迫游泳不动时间显著延长、糖水偏爱显著降低;造模后大鼠肠道微绒毛结构破损严重,细胞核轻微固缩且深染,肠道菌群变化明显,出现了多个特征性变化条带。采用慢性束缚应激法并结合行为学评估成功建立了大鼠慢性应激模型,结合病理学检测和肠道菌群表达谱变化为基于慢性应激相关疾病的研究提供了重要参考,具有一定的应用价值。     

固醇调节素结合蛋白与动脉粥样硬化关系的研究进展

动脉粥样硬化(Atherosclerosis,AS)的发生与血浆胆固醇水平、血管平滑肌细胞(Vascular smooth muscle cell,VSMC)密切相关.经研究证明,血浆胆固醇水平和VSMC是AS发病的关键因素.血浆胆固醇水平过高会促进AS的发生、发展;VSMC、向内膜迁移、增殖形成新生内膜也在AS的发生、发展中起重要作用.固醇调节素结合蛋白(Sterol regulatory element binding protein,SREBP)在调节胆固醇合成及代谢的平衡和稳态中起独有的重要作用,其过度表达将引起脂代谢的紊乱,造成非脂肪组织的脂质积聚,促进AS的发生和发展;而且,SREBP与VSMC之间存在一定的相互关系,SREBP在VSMC表达并参与VSMC盼迁移和增殖,在AS中发挥了重要作用.     

应激与自杀、睡眠障碍的关系

自杀是复杂且致死率高的重要公共健康问题,应激和睡眠障碍均为自杀的重要风险因素,且三者之间具有密切的关联。由于应激和睡眠障碍具有可改变性,了解应激、睡眠和自杀的关系及其生理机制,有助于了解自杀的病理基础,探寻识别和干预自杀的关键靶点,促进对自杀的预防和干预。本文介绍有关应激、自杀、睡眠关联的最新研究结果,分别从 HPA轴功能、多胺应激反应系统等神经生理基础,以及基因、表观遗传修饰等遗传学的角度探讨三者关联的生理机制,探索该领域的研究挑战及未来的研究方向。     

Diet and Atherosclerosis in Apolipoprotein E-Deficient Mice

Atherosclerosis is a multifactorial, long-lasting process in humans. Accordingly, animal models in which more rapid changes occur can be useful for the study of this process. Among such models are apolipoprotein E-deficient (apoE?/?) mice, which give insight into the human process. ApoE?/? mice show impaired clearing of plasma lipoproteins and develop atherosclerosis in a short time, and hence they are an excellent model in which to assess the impact of dietary factors. This review considers lipid metabolism and inflammation as well as nutritional constituents affecting atherosclerosis, with reference to apoE?/? mice, and discusses the mechanisms through which they act.     

A Murine Model of Obesity With Accelerated Atherosclerosis

The epidemic of obesity sweeping developed nations is accompanied by an increase in atherosclerotic cardiovascular diseases. Dyslipidemia, diabetes, hypertension, and obesity are risk factors for cardiovascular disease. However, delineating the mechanism of obesity‐accelerated atherosclerosis has been hampered by a paucity of animal models. Similar to humans, apolipoprotein E–deficient (apoE^?/?) mice spontaneously develop atherosclerosis over their lifetime. To determine whether apoE^?/? mice would develop obesity with accelerated atherosclerosis, we fed mice diets containing 10 (low fat (LF)) or 60 (high fat (HF)) kcal % from fat for 17 weeks. Mice fed the HF diet had a marked increase in body weight and atherosclerotic lesion formation compared to mice fed the LF diet. There were no significant differences between groups in serum total cholesterol, triglycerides, or leptin concentrations. Plasma concentrations of the acute‐phase reactant serum amyloid A (SAA) are elevated in both obesity and cardiovascular disease. Accordingly, plasma SAA concentrations were increased fourfold (P < 0.01) in mice fed the HF diet. SAA was associated with both pro‐ and antiatherogenic lipoproteins in mice fed the HF diet compared to those fed the LF diet, in which SAA was primarily associated with the antiatherogenic lipoprotein high‐density lipoprotein (HDL). Moreover, SAA was localized with apoB‐containing lipoproteins and biglycan in the vascular wall. Taken together, these data suggest male apoE‐deficient mice are a model of metabolic syndrome and that chronic low level inflammation associated with increased SAA concentrations may mediate atherosclerotic lesion formation.     

Role of Nrf2 in the pathogenesis of atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the vascular arterial walls. A number of studies have revealed the biological and genetic bases of atherosclerosis, and over 100 genes influence atherosclerosis development. Nrf2 plays an important role in oxidative stress response and drug metabolism, but the Nrf2 signaling pathway is closely associated with atherosclerosis development. During atherosclerosis progression, Nrf2 signaling modulates many physiological and pathophysiological processes, such as lipid homeostasis regulation, foam cell formation, macrophage polarization, redox regulation and inflammation. Interestingly, Nrf2 exhibits both pro- and anti-atherogenic effects in experimental animal models. These observations make the Nrf2 pathway a promising target to prevent atherosclerosis.     

动脉粥样硬化中单核细胞膜流动性研究

为研究动脉粥样硬化中单核细胞膜流动性的变化,本实验选用20只新西兰白兔建立动物粥样硬化模型,提取模型组与对照组兔外周血中单核细胞,通过荧光漂白恢复技术检测单核细胞膜流动性,并结合动脉粥样硬化动物模型病理切片揭示其与动脉粥样硬化相关性。结果显示动物动脉粥样硬化模型建立成功,模型组单核细胞膜的荧光恢复率和扩散系数均低于对照组。本研究揭示了单核细胞细胞膜的流动性与动脉粥样硬化的发生有关,为今后深入探究单核细胞与动脉粥样硬化关系提供实验基础。     

Decreased Naive and Increased Memory CD4+ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis

Background

Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4⁺ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.

Methods and Findings

We examined cross-sectional relationships of circulating CD4⁺ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4⁺ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].

Conclusions

These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4⁺ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.     

Vitamin D Deficiency Induces High Blood Pressure and Accelerates Atherosclerosis in Mice

Multiple epidemiological studies link vitamin D deficiency to increased cardiovascular disease (CVD), but causality and possible mechanisms underlying these associations are not established. To clarify the role of vitamin D-deficiency in CVD in vivo, we generated mouse models of diet-induced vitamin D deficiency in two backgrounds (LDL receptor- and ApoE-null mice) that resemble humans with diet-induced hypertension and atherosclerosis. Mice were fed vitamin D-deficient or -sufficient chow for 6 weeks and then switched to high fat (HF) vitamin D-deficient or –sufficient diet for 8–10 weeks. Mice with diet-induced vitamin D deficiency showed increased systolic and diastolic blood pressure, high plasma renin, and decreased urinary sodium excretion. Hypertension was reversed and renin was suppressed by returning chow-fed vitamin D-deficient mice to vitamin D-sufficient chow diet for 6 weeks. On a HF diet, vitamin D-deficient mice had ∼2-fold greater atherosclerosis in the aortic arch and ∼2–8-fold greater atherosclerosis in the thoracic and abdominal aorta compared to vitamin D-sufficient mice. In the aortic root, HF-fed vitamin D-deficient mice had increased macrophage infiltration with increased fat accumulation and endoplasmic reticulum (ER) stress activation, but a lower prevalence of the M1 macrophage phenotype within atherosclerotic plaques. Similarly, peritoneal macrophages from vitamin D-deficient mice displayed an M2-predominant phenotype with increased foam cell formation and ER stress. Treatment of vitamin D-deficient mice with the ER stress reliever PBA during HF feeding suppressed atherosclerosis, decreased peritoneal macrophage foam cell formation, and downregulated ER stress proteins without changing blood pressure. Thus, we suggest that vitamin D deficiency activates both the renin angiotensin system and macrophage ER stress to contribute to the development of hypertension and accelerated atherosclerosis, highlighting vitamin D replacement as a potential therapy to reduce blood pressure and atherosclerosis.     

Association of Early Atherosclerosis with Vascular Wall Shear Stress in Hypercholesterolemic Zebrafish

Although atherosclerosis is a multifactorial disease, the role of hemodynamic information has become more important. Low and oscillating wall shear stress (WSS) that changes its direction is associated with the early stage of atherosclerosis. Several in vitro and in vivo models were proposed to reveal the relation between the WSS and the early atherosclerosis. However, these models possess technical limitations in mimicking real physiological conditions and monitoring the developmental course of the early atherosclerosis. In this study, a hypercholesterolaemic zebrafish model is proposed as a novel experimental model to resolve these limitations. Zebrafish larvae are optically transparent, which enables temporal observation of pathological variations under in vivo condition. WSS in blood vessels of 15 days post-fertilisation zebrafish was measured using a micro particle image velocimetry (PIV) technique, and spatial distribution of lipid deposition inside the model was quantitatively investigated after feeding high cholesterol diet for 10 days. Lipids were mainly deposited in blood vessel of low WSS. The oscillating WSS was not induced by the blood flows in zebrafish models. The present hypercholesterolaemic zebrafish would be used as a potentially useful model for in vivo study about the effects of low WSS in the early atherosclerosis.     

治疗动脉粥样硬化的靶位:A类清道夫受体

动脉粥样硬化性心血管疾病是危害人类健康的常见疾病之一。A类清道夫受体是动脉粥样硬化发生和发展过程中的主要参与者之一,介导巨噬细胞内吞修饰的低密度脂蛋白,形成泡沫细胞,有明显的致动脉粥样硬化作用,是治疗动脉粥样硬化的潜在靶点。另外A类清道夫受体还参与机体的防御过程。重点综述了A类清道夫受体各成员结构及其在动脉粥样硬化中的生理作用和在新药研发方面的应用与展望。     

5-脂氧化酶与动脉粥样硬化的研究进展

动脉粥样硬化（AS）及其并发症是当今世界上导致死亡的最常见的病因之一。AS发病机制有多种学说,其中动脉粥样硬化是一种慢性炎症性疾病的学说已为广大学者所接受。白三烯（LTs）是促进炎症反应的脂类调控因子,在心血管组织中具有强烈的致炎作用,5-脂氧化酶（5-LO）能够氧化花生四烯酸生成LTs等花生酸类物质。近年对动脉粥样硬化的研究中发现5-LO途径及其下游产物LTs对AS的形成、发展及动脉粥样硬化斑块的不稳定性有重要作用。本文结合国内外文献,对5-LO基因结构、蛋白结构和代谢活性等生物学特性以及5-LO及其下游产物与动脉粥样硬化发生、发展的关系进行了总结,对了解和研究动脉粥样硬化疾病及其治疗具有重要意义。