PPARγ激动剂与小胶质细胞和中枢神经系统炎症变性疾病的关系

过氧化物酶体增殖物活化受体γ(PPARγ)是一种核转录因子,属由配体激活的Ⅱ型核受体超家族的成员。PPARγ除参与脂质代谢、胰岛素抵抗、脂肪细胞分化、动脉粥样硬化和肿瘤生成外,还参与炎症反应及免疫调节。PPARγ激动剂能通过PPARγ依赖或非依赖机制抑制活化的小胶质细胞、保护神经元、促进活化的小胶质细胞凋亡从而控制中枢神经系统(CNS)炎症变性疾病如阿茨海默病(AD)、帕金森病(PD)和多发性硬化(MS)。提示PPARγ激动剂有可能成为一类很有治疗CNS炎症性及退行性变性疾病前景的药物。     

阿尔茨海默病中炎症反应的研究进展

阿尔茨海默病(AD)是常见的痴呆类型之一,AD的认知功能损害和行为损害严重危害老年人的健康。关于AD的发病机制,存在多种学说。越来越多的研究表明,在AD疾病进程中伴随着广泛的炎症反应,炎症反应与其他机制紧密联系,起到至关重要的作用。文中主要从小胶质细胞、星形胶质细胞、单核细胞、炎症介质等方面对目前AD神经炎症反应的研究进展进行综述。     

泛素特异性蛋白酶11在中枢神经系统疾病中的作用研究进展

泛素特异性蛋白酶11(USP11)是泛素特异性蛋白酶(USPs)家族成员之一, 通过介导底物的去泛素化过程, 抑制靶蛋白的泛素-蛋白酶体降解, 进而参与细胞周期进程、DNA损伤修复、细胞死亡、自噬、信号传导、免疫炎症反应及大脑皮层发育等多种病理生理过程的调节。研究表明, USP11在中枢神经系统(CNS)疾病的发生发展进程中具有重要作用。本文围绕USP11的结构、功能及其在CNS疾病中的作用机制研究进展进行综述, 以期为靶向USP11治疗相关疾病提供新的思路。     

Alzheimer病的免疫学研究进展

Alzheimer 病(AD)除了具有大脑皮质萎缩、神经细胞缺失、神经纤维缠结、炎性斑(SP)和脑血管β-淀粉样蛋白(Aβ)沉积的病理特征以外,还伴随着一个缓慢的炎性病理改变过程[1].随着分子免疫学和分子病理学技术的飞速发展,在AD患者脑内发现存在大量与炎症反应有关的免疫分子.其中关于白细胞介素(IL)、趋化因子、转化生长因子(TGF)以及补体等在AD免疫炎症反应中作用的研究较为深入,并取得了许多新的进展.为阐明AD的发病机制,澄清免疫学变化在AD慢性炎症过程中的作用极为重要.     

载脂蛋白E基因多态性在缺血性脑卒中中的研究进展

正缺血性脑卒中(ischemic stroke,IS)是遗传和环境因素相互作用导致脑组织血流异常所引起的兴奋性氨基酸毒性、线粒体功能障碍、细胞凋亡、炎症反应等病理过程,最终造成脑组织缺血坏死的疾病。已有多项研究表明载脂蛋白E(apolipoprotein E,Apo E)通过其基因多态性和受体介导途径影响中枢神经系统(central nerve system,CNS)脂质代谢平衡、炎症反应、氧化应激、血脑屏障完整性、线粒体功能及细胞凋亡     

小胶质细胞在阿尔茨海默病发病机制中的作用

研究表明,β淀粉样蛋白(amyloid beta-peptide,Aβ)沉积激活小胶质细胞引起的炎症反应是阿尔茨海默病(Akheimer disease,AD)的核心病理机制之一,小胶质细胞在其发病机制中起着重要的作用。小胶质细胞被Ap激活,释放大量细胞因子和炎性介质,促进老年斑(senile plaques,SP)、神经原纤维缠结(neurofibrillary tangles,NFTs)的形成,导致神经元损伤、死亡,促使AD发生、发展。     

空气污染致中枢神经系统炎症的细胞机制研究进展

空气污染一直被认为与呼吸系统和心血管系统疾病相关,近年来研究表明空气污染也是中枢神经系统(CNS)疾病的来源。最新的研究证据显示,中枢神经系统中小胶质细胞的激活可产生神经毒性物质,并参与炎症反应和免疫应答;血脑屏障具有识别空气污染的屏障功能并产生促炎信号;星型胶质细胞激活后也可产生神经炎性介质。本文对空气污染致中枢神经系统炎症的细胞机制进行综述。     

IL-6与Alzheimer病研究进展

<正> 随着人口老龄化的发展,老年性痴呆的代表性疾病—Alzheimer病(AD)越来越受到人们的重视。AD是一种慢性进行性神经系统变性疾病,其病理特征是在大脑皮层和海马区域出现神经炎性斑(NP),神经洗维缠结(NFT).McGeer等提出AD的神经退行性变可能是脑内免疫和炎症反应不适当激活所致。近年来,随着分子免疫学和分子病理学技术的发展,发现在AD患者脑内存在大量与炎症反应有关的细胞因子。其中关于IL-6在AD免疫炎症反应中的作用研究较多。现就近几年的文献做一综述,以期为AD的诊断和治疗提供新的理论依据。     

中枢神经系统小胶质细胞的研究进展

中枢神经系统(CNS)中的小胶质细胞源于造血系统,是CNS的胶质细胞,又有着单核吞噬细胞的属性。在正常情况下,它对周围神经组织起着连续监视作用以维持CNS的稳态,小胶质细胞微小的异常也会引起机体的功能障碍;而当疾病或损伤发生时,失去了神经元的抑制作用,活化后的小胶质细胞作为CNS中的定植炎症细胞参与炎症反应与免疫应答。     

自噬调控机制对多发性硬化的影响

多发性硬化(multiple sclerosis,MS)是中枢神经系统(central nervous system,CNS)自身免疫性脱髓鞘疾病,是导致年轻人致残的最主要的CNS疾病,发病机制尚不明确。自噬(autophagy)是细胞降解和回收利用细胞内生物大分子与细胞器的过程,是细胞重要的自稳机制,已经发现其在神经退行性疾病细胞代谢中有重要作用,如阿尔兹海默病,同时,自噬也参与进自身免疫的调节,也许对于MS的疾病病理过程有重要作用。     

Neuroimaging in epilepsy in tropics

Epilepsy is a major public health problem in many tropical countries. Also, some of the tropical diseases are major contributors to the higher prevalence of epilepsy in these countries. The etiologic factors responsible for epilepsy in these countries are quite different from those in the developed world. This article discusses the etiologic factors and neuroimaging of epilepsy in light of the conditions in these tropical countries.     

癫痫与抑郁关系的研究进展

抑郁是癫痫患者中常见的精神障碍,严重地影响了患者的生活质量。传统的观点认为癫痫患者因为存在着诸多社会学问题易出现抑郁倾向,癫痫和抑郁是单向的联系,但大量的研究已经证明癫痫和抑郁之间存在双向的联系,一种异常状态的存在可能易转化为另一种异常状态的发展。癫痫和抑郁存在着共同的发病机制。本文主要就癫痫和抑郁的双向联系以及抗抑郁药物在癫痫患者中的应用进行阐述。     

Sudanophilic lipid accumulation in astrocytes in periventricular leukomalacia in monkeys

Summary Sudanophilic lipid accumulation is a characteristic feature of periventricular leukomalacia (PVL) of infants. At least two types of lipid-containing cells have been identified, one being the macrophage, the other the pre-myelin glial cell. A third type of lipid-containing cell has been seen in two monkeys with spontaneous PVL. Electron microscopically this cell appears to be an astrocyte. This probably represents a reaction of the astrocyte to hypoxia and may be the equivalent of the hypertrophic astrocytes found in human infants.Supported in part by NIH grant HDO 8633 and the Regional Primate Research Center Grant RR-00166     

Increase in cathepsin D activity in rat brain in aging

Cathepsin D-like activity in homogenates of five brain areas of 3-month-old and 24-month-old Fischer 344 rats was measured. With hemoglobin as substrate at pH 3.2, more than 90% of the activity was inhibited by pepstatin. In each area studied, activity was more than twice as high in the old rat brain: 140-160% higher in the cortex, cerebellum, pons-medulla, and striatum and 90-100% higher in the hippocampus and spinal cord. The greatly increased metabolic capacity in the absence of an increase in protein turnover may have a role in age-related pathological degeneration in the brain.     

Characteristics of nociceptors in the periodontium--an in vitro study in rats

Recent studies have indicated that nociceptors can be classified into various types according to their physiological properties. These studies have clarified that the frequency distribution of various nociceptor types is different among body sites and animal species. In the present study, we investigated the physiological properties of rat's periodontal nociceptors in an in vitro jaw-nerve preparation. Responses were recorded from functional single filaments in the inferior alveolar nerve. To determine the nociceptor type, calibrated von Frey filaments, heat, and bradykinin (BK) stimuli were used. We found five subtypes of nociceptors in the periodontal ligaments of the lower incisor: Adelta-high threshold mechanonociceptors (Adelta-HTM, n=28), Adelta-mechanoheat nociceptors (Adelta-MH, n=6), Adelta-polymodal nociceptors (Adelta-POLY, n=26), C-high threshold mechanonociceptors (C-HTM, n=3) and C-polymodal nociceptors (C-POLY, n=4). Most nociceptors were Adelta-innervated, while only a small number of C-innervated nociceptors were found. The present results suggest that periodontal nociceptors transmit mainly fast pain, and may thus play a role in rapid detection of injure-related stimuli during mastication.     

Gender in Voice Perception in Autism

Deficits in the perception of social stimuli may contribute to the characteristic impairments in social interaction in high functioning autism (HFA). Although the cortical processing of voice is abnormal in HFA, it is unclear whether this gives rise to impairments in the perception of voice gender. About 20 children with HFA and 20 matched controls were presented with voice fragments that were parametrically morphed in gender. No differences were found in the perception of gender between the two groups of participants, but response times differed significantly. The results suggest that the perception of voice gender is not impaired in HFA, which is consistent with behavioral findings of an unimpaired voice-based identification of age and identity by individuals with autism. The differences in response times suggest that individuals with HFA use different perceptual approaches from those used by typically developing individuals.     

Defects in Bioenergetic Coupling in Schizophrenia

Synaptic neurotransmission relies on maintenance of the synapse and meeting the energy demands of neurons. Defects in excitatory and inhibitory synapses have been implicated in schizophrenia, likely contributing to positive and negative symptoms as well as impaired cognition. Recently, accumulating evidence has suggested that bioenergetic systems, important in both synaptic function and cognition, are abnormal in psychiatric illnesses such as schizophrenia. Animal models of synaptic dysfunction demonstrated endophenotypes of schizophrenia as well as bioenergetic abnormalities. We report findings on the bioenergetic interplay of astrocytes and neurons and discuss how dysregulation of these pathways may contribute to the pathogenesis of schizophrenia, highlighting metabolic systems as important therapeutic targets.     

Ethnic disparities in problem behaviour in adolescence contribute to ethnic disparities in social class in adulthood

BACKGROUND: It is important for prevention of social class disparities to know how ethnic disparities in social class arise among migrant children. We contribute to this understanding by examining the role of problem behaviour in adolescence. METHODS: Prospective observational study with 753 Dutch native and 217 Turkish migrant adolescents (11-18 year) followed for 10 years. Internalising and externalising problems were assessed in adolescence and employment status and occupational level were assessed in adulthood. The difference in odds ratios (OR) before and after adjustment for internalising and externalising problems was an indication of the predictive value of disparities in internalising and externalising problems for the development of social class disparities. RESULTS: A total of 135 (62%) of the Turkish and 602 (80%) of the Dutch adults were employed. Internalising and externalising problems were not associated with employment status. Of the employed, 65 (48%) Turkish and 179 (30%) Dutch adults worked in low-level occupations (p < 0.0001). Internalising and externalising problems were associated with both ethnicity and occupation. The OR for low-level occupation for Turkish adults was 1.78 (1.19-2.65), indicating ethnic disparities. Adjustment for internalising problems lowered the OR with 36% to 1.50 (0.97-2.31), and adjustment for externalising problems lowered it with 8% to 1.72 (1.15-2.57). Findings were similar for men and women and did not vary by age. CONCLUSIONS: Ethnic disparities in occupational level in adulthood could partly be attributed to disparities in mental health between Turkish migrants and Dutch natives in adolescence. Prevention of ethnic disparities in mental health at young age may therefore also contribute to the prevention of occupational differences in adulthood.     

Progress in neuroprotection in Parkinson's disease

Slowing or aborting the progress of neurodegeneration in Parkinson's disease (PD) remains the most important unmet need of this disorder. There are several recent developments in trial design and also in drugs under investigation for possible neuroprotective effect. Emphasis has been placed on clinical as opposed to imaging end-points and these include change in a clinical rating scale, e.g. United Parkinson's disease Rating Scale (UPDRS), or time to additional therapy. The introduction of the delayed-start, or wash-in, trial design adds an additional dimension to drug evaluation for neuroprotection. Compounds that have been recently tested in clinical trial include the monoamine oxidase-B inhibitor rasagiline, the anti-apoptotic agents TCH346 and CEP1347, and the promitochondrial agent creatine. The dopamine agonists have been evaluated for a neuroprotective effect using imaging end-points. Perhaps the most important and simplest concept for neuroprotection has been the theory that early dopaminergic support for the degenerating dopaminergic system per se provides significant long-term clinical benefit for PD patients.     

Changes in parasympathetic system in medulla oblongata in male pigs in the course of tachycardia-induced cardiomyopathy

Background

Autonomic imbalance constituting a fundamental feature of heart failure (HF) has been assessed mainly at the periphery. Changes in the functioning of autonomic centers in the brain remain unclear. We investigated the molecular elements of parasympathetic system, i.e. α7 nicotinic acetylcholine receptor (α7nAChR) and enzymes metabolizing acetylcholine (acetylcholinesterase, AChE, choline acetyltransferase, ChAT) in medulla oblongata (MO) of male pigs with chronic tachycardia-induced cardiomyopathy.

Methods

The mRNA levels of AChE, ChAT, α7nAChR and X-box binding protein 1 (spliced form, XBP1s) in MO were analyzed using qPCR, AChE and ChAT activities using spectrophotometry, proteasome activity using fluorometry, and the protein level of α7nAChR using Western blotting.

Results

The development of systolic HF was accompanied by an increase in circulating catecholamines, a decrease in the AChE and α7nAChR mRNA in MO, an increase in AChE activity (all p < 0.05), and no change in either the mRNA or activity of ChAT. Both circulating catecholamine levels and AChE activity were inversely related to systolic function of left myocardial ventricle (p < 0.05). The level of α7nAChR protein in MO and its cytoplasmatic fraction were higher in pigs with moderate and severe HF as compared to the other animals (p < 0.01). There was no difference in proteasome activity in MO between diseased and healthy animals, whereas the XBP1s mRNA decreased during HF progression (p < 0.05).

Conclusions

Molecular elements of parasympathetic system are changed within the medulla oblongata during the progression of systolic non-ischemic heart failure in male pigs, indicating a functional link between MO and heart in HF.