真菌鞘脂代谢及其与抗真菌药物关系研究进展

鞘脂是真核细胞中普遍存在的成分,它在真核细胞的胞吞、胞饮、信号转导、细胞的生长、凋亡、分化、衰老等过程中起着非常重要的作用.该文论述了真菌鞘脂代谢的途径及参与其合成的相关酶和基因,并比较了真菌与哺乳动物鞘脂代谢途径的不同,旨在为研究新型无公害抗真菌药物提供理论依据.     

脂筏--细胞信号转导发生的平台

在脂筏和胞膜窖中存在有多种参与细胞信号转导的跨膜蛋白质,在细胞内或／和细胞外信号的刺激下。脂筏能改变蛋白质的大小和组成,有助于特异的蛋白质与蛋白质之间的相互作用,从而导致了信号级联反应的激活。脂筏在细胞信号转导事件中的重要作用已越来越受到人们的关注。     

鞘脂类与细胞信号传导的研究进展

当前生命科学研究中的一个中心问题是关于细胞代谢、生长、发育、适应、防御和凋亡等的调节机制,以及调控异常与疾病,特别是与一些重大疾病,如肿瘤、心血管病、糖尿病以及老年性痴呆等的关联.这些问题与生物信号分子所携带的信息的细胞内的传递有关.我们已经知道,细胞中存在着遣传信息传递系统,即由DNA(基因)转录成mRNA再翻译成蛋白质过程所形成的信息流,控制着生物体生长发育和新陈代谢.此外,细胞中还存在一个调节细胞代谢、生长、增殖、凋亡和各种功能活动的信号转导系统,它们由能接收信号的特定的受体、受体后的信号转导途径及其作用的终端所组成.它们能够对各种胞外信号分子,如激素、神经递质、细胞因子以及药物等起反应,通过细胞内的信号转导过程,调节代谢酶、离子通道、转录因子等的活性,产生各种生物效应.不同的信号转导通路间具有相互的联系和作用,形成复杂的网络.了解信号转导系统的组成及信号转导的机制,对于深入认识生命过程和揭示生命的本质具有重要意义,同时由于信号转导的失控可导致多种疫病,因此有关信号转导过程的研究还有助于阐明疾病的发生和发展的机制,并为新药的设计和发展新的治疗方法提供思路,达到预防和治疗疾病的目的.     

鞘脂代谢及其相关疾病研究进展

近年对鞘脂代谢及其产物的研究越来越多.鞘脂及其代谢产物不仅是构成细胞膜的重要结构分子,而且参与调节细胞的生长、分化、衰老和细胞程序性死亡等许多重要的信号转导过程,使细胞产生各种不同的生物学功能.该文综述了鞘脂代谢途径的重要酶,鞘脂及其代谢产物的功能,以及它们与相关疾病的研究进展,并就其存在的问题和今后可能的研究方向做出展望.为鞘脂代谢的过程和鞘脂相关疾病的生理病理学研究提供重要的理论依据.     

液相串联质谱法同时定量检测生物样本中鞘脂类化合物

鞘脂类中的主要活性分子鞘氨醇1-磷酸（S1P）,可通过介导细胞增殖、分化和迁移等发挥广泛的生物学功能|同时,S1P可在相关酶的作用下转变为其它形式.本文旨在建立一种简便的鞘脂类的制备方法,并结合液相串联质谱（LC-MS/MS）快速检测生物样本中纳克水平的鞘脂类化合物. 采用甲醇沉淀或经典的脂质提取方法获得鞘脂类化合物,再采用LC-MS/MS在多反应监测模式（MRM）下进行定量分析. 实验结果表明,甲醇沉淀法可简便快捷地获得血浆或脂蛋白中鞘氨醇类化合物; S1P、二氢鞘氨醇（DH-S1P）和鞘氨醇（SPH）的定量限分别为110.5、215.6和44.3 pg;人血浆中S1P、DH-S1P和SPH的含量分别为257.8±49.4 nmol/L、93.5±17.3 nmol/L和44.6± 7.4 nmol/L, 鞘脂类化合物在人血浆脂蛋白上的分布存在显著性差异|在ApoE-/-小鼠血浆中S1P、DH-S1P和SPH的含量分别为590.1±78.2 nmol/L、197.8±60.6 nmol/L和35.4±16.7 nmol/L|每1×106个人脐静脉内皮细胞（EA.hy926）中,S1P和SPH的含量分别为103.7±21.8 pg和16.3±5.3 ng.甲醇沉淀法结合LC-MS/MS可简便快捷地对血浆和脂蛋白中的鞘脂类化合物进行定量检测. 该方法特别适用于大量生物样本中鞘脂类的快速定量分析.     

鞘脂与细胞凋亡

随着生物技术的不断发展,近年来对鞘脂类物质的研究不断深入。鞘脂质除了在细胞骨架的迁移、血管发生、胚胎发育和信号转导等方面起重要作用外,最近的研究发现鞘脂及其代谢物(神经酰胺、鞘氨醇、鞘氨醇-1-磷酸)能诱导多种肿瘤和恶性增殖细胞(如腺癌、结肠癌、肝肿瘤、肺癌、鼻咽癌等)的凋亡。本文着重对鞘脂与细胞凋亡相关的最新研究进展进行综述。     

鞘氨醇单胞菌的研究进展

鞘氨醇单胞菌(Sphingomonas)不仅细胞膜含有比脂多糖更疏水的鞘糖脂,而且具有高效的代谢调控机制和基因调控能力,使其在威兰胶合成、环境修复和促进植物生长等方面具有巨大的应用潜力。目前国内在鞘氨醇单胞菌代谢机制方面的研究尚无新突破。本文主要综述了鞘氨醇单胞菌的系统分类、基因组学、基因调控机制及其应用等方面的研究,从基因层面分析鞘氨醇单胞菌产威兰胶的合成机制,为后续鞘氨醇单胞菌高密度发酵、工业化生产等研究提供理论基础,以便进一步发掘其在生物技术上的应用潜力。     

肿瘤鞘脂代谢异常与肿瘤细胞对维甲酸类药物耐药性

维甲酸类药物对多种癌症有效,其作用包括诱导凋亡、抑制生长、促进分化等,这主要通过调节维甲酸受体包括维甲酸受体(retinoic acid receptor,RAR)和维甲酸X受体(rexinoid X receptor,RXR)的表达实现。目前发现,一些患者癌细胞的RAR、RXR或RAR/RXR表达缺乏,可能导致癌细胞对维甲酸产生耐药性。鞘脂代谢异常和维甲酸类受体表达缺失密切相关,在癌细胞对维甲酸产生耐药性中发挥着重要作用。本文就鞘脂代谢异常与维甲酸受体表达异常及维甲酸类药物耐药的相关性做一简要综述。     

鞘脂类对胰岛素信号的调控——Ⅱ型糖尿病研究的新兴领域

胰岛素抵抗是Ⅱ型糖尿病的病理基础之一,近年来已成为Ⅱ型糖尿病研究的关键和热点．众多研究发现,机体内鞘脂类物质水平的改变直接影响胰岛素信号的强弱．神经酰胺和神经节苷脂GM3对胰岛素信号具有负向调控作用,介导胰岛素抵抗的形成,该调节效应依赖于细胞膜上微囊蛋白．1-磷酸鞘氨醇则通过氧化还原途径增强胰岛素信号．微囊蛋白功能性活动和1-磷酸鞘氨醇的介导作用均与钙信号相关,因此,可通过实时检测细胞外钙内流和细胞内钙瞬间变化,从离子通道水平进一步探索鞘脂类调节胰岛素信号的相关机制．本文综述了鞘脂类物质调控胰岛素信号的机制,干预鞘脂类水平和改善胰岛素抵抗的策略,将为鞘脂类物质在Ⅱ型糖尿病预防和治疗的研究及应用提供有力的帮助．     

植物鞘脂的结构、代谢途径及其功能

众所周知, 鞘脂是生物膜结构的重要组成成分, 随着鞘脂在动物和酵母中的深入研究发现, 鞘脂及其代谢产物是一类很重要的活性分子, 它们参与调节细胞的生长、分化、衰老和细胞程序性死亡等许多重要的信号转导过程。鞘脂在植物中的研究最近几年才开始, 植物鞘脂的功能还不十分清楚。最近的研究发现, 鞘脂及其代谢产物在植物中也起着很重要的信号分子作用。该文详细总结了鞘脂在植物中的结构、代谢途径和主要生物学功能, 并结合实验室的工作对植物鞘脂的功能研究进行了展望。     

Sphingolipids in mitochondria

Sphingolipids are bioactive lipids found in cell membranes that exert a critical role in signal transduction. In recent years, it has become apparent that sphingolipids participate in growth, senescence, differentiation and apoptosis. The anabolism and catabolism of sphingolipids occur in discrete subcellular locations and consist of a strictly regulated and interconnected network, with ceramide as the central hub. Altered sphingolipid metabolism is linked to several human diseases. Hence, an advanced knowledge of how and where sphingolipids are metabolized is of paramount importance in order to understand the role of sphingolipids in cellular functions. In this review, we provide an overview of sphingolipid metabolism. We focus on the distinct pathways of ceramide synthesis, highlighting the mitochondrial ceramide generation, transport of ceramide to mitochondria and its role in the regulation of mitochondrial-mediated apoptosis, mitophagy and implications to disease. We will discuss unanswered questions and exciting future directions. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.     

Sphingolipids in colon cancer

Colorectal cancer is one of the major causes of death in the western world. Despite increasing knowledge of the molecular signaling pathways implicated in colon cancer, therapeutic outcomes are still only moderately successful. Sphingolipids, a family of N-acyl linked lipids, have not only structural functions but are also implicated in important biological functions. Ceramide, sphingosine and sphingosine-1-phosphate are the most important bioactive lipids, and they regulate several key cellular functions. Accumulating evidence suggests that many cancers present alterations in sphingolipids and their metabolizing enzymes. The aim of this review is to discuss the emerging roles of sphingolipids, both endogenous and dietary, in colon cancer and the interaction of sphingolipids with WNT/β-catenin pathway, one of the most important signaling cascades that regulate development and homeostasis in intestine. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

Sphingolipids and lifespan regulation

Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipids so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

Sphingolipids in tumor metastases and angiogenesis

This review article summarizes data on the involvement of sphingolipids (sphingosine-1-phosphate, sphingosine-1-phosphocholine, neutral glycosphingolipids, and gangliosides) in tumor metastases and angiogenesis.     

Sphingolipids from Conyza canadensis

Sphingolipid 1 and its corresponding beta-D-glucopyranoside derivative 2 have been isolated from the ethylacetate fraction of Conyza canadensis along with beta-sitosterol 3, stigmasterol 4, beta-sitosterol 3-O-beta-D-glucoside 5 and harmine 6, reported for the first time from this species. The structures of 1 and 2 were elucidated through spectroscopy including two-dimensional NMR.     

Sphingolipids and cell death

Sphingolipids (SLs) have been considered for many years as predominant building blocks of biological membranes with key structural functions and little relevance in cellular signaling. However, this view has changed dramatically in recent years with the recognition that certain SLs such as ceramide, sphingosine 1-phosphate and gangliosides, participate actively in signal transduction pathways, regulating many different cell functions such as proliferation, differentiation, adhesion and cell death. In particular, ceramide has attracted considerable attention in cell biology and biophysics due to its key role in the modulation of membrane physical properties, signaling and cell death regulation. This latter function is largely exerted by the ability of ceramide to activate the major pathways governing cell death such as the endoplasmic reticulum and mitochondria. Overall, the evidence so far indicates a key function of SLs in disease pathogenesis and hence their regulation may be of potential therapeutic relevance in different pathologies including liver diseases, neurodegeneration and cancer biology and therapy.     

Sphingolipids and lysosomal pathologies

Endocytosed (glyco)sphingolipids are degraded, together with other membrane lipids in a stepwise fashion by endolysosomal enzymes with the help of small lipid binding proteins, the sphingolipid activator proteins (SAPs), at the surface of intraluminal lysosomal vesicles. Inherited defects in a sphingolipid-degrading enzyme or SAP cause the accumulation of the corresponding lipid substrates, including cytotoxic lysosphingolipids, such as galactosylsphingosine and glucosylsphingosine, and lead to a sphingolipidosis. Analysis of patients with prosaposin deficiency revealed the accumulation of intra-endolysosmal vesicles and membrane structures (IM). Feeding of prosaposin reverses the storage, suggesting inner membrane structures as platforms of sphingolipid degradation. Water soluble enzymes can hardly attack sphingolipids embedded in the membrane of inner endolysosomal vesicles. The degradation of sphingolipids with few sugar residues therefore requires the help of the SAPs, and is strongly stimulated by anionic membrane lipids. IMs are rich in anionic bis(monoacylglycero)phosphate (BMP). This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

Sphingolipids of influenza viruses.

Total lipid of four egg grown influenza viruses (A2-Asia, A2-England, A2-Taiwan and fowl plague virus) were extracted with chloroform-methanol. After mild alkali treatment of the extracts, glycosphingolipids and sphingomyelin were separated by a silicic acid column, and finally purified by thin layer chromatography. Fatty acid, sphingosine and carbohydrate components of individual lipid classes were then analysed by gas-liquid chromatography. Nearly identical results were obtained with all viruses investigated. Approximately 20% of the total lipid was monohexosylceramide, distributed equally between glucosyl- and galactosyl- analogues. Lactosylceramide and oligohexosylceramides were found in much smaller concentrations (approx. 2%). About 15% of the total lipid was attributed to sphingomyelin. A large proportion of fatty acids (around 25% in sphingomyelin and 60% in glycolipids) belonged to the long chain (C19-C26) normal- and 2-hydroxy series. C18-sphingosine was found to be the only base present in all lipid classes investigated.