脂代谢与心血管疾病

<正>近年来,我国心血管病患病率显著上升,全国每年约有350万人死于心血管病,心血管病已成为是中国居民的首位死亡原因[1].众所周知,脂代谢异常是心血管疾病尤其是冠心病的独立危险因素,脂质代谢与动脉粥样硬化的发生发展密切相关[2-5].随着人们生活水平的提高、膳食习惯及生活方式的改变,脂代谢异常的发生率亦呈逐渐增加趋势.因     

胆汁酸受体FXR 的研究进展

法尼酯衍生物X受体(FXR)是一种胆汁酸受体,在胆汁酸代谢和胆固醇代谢中发挥重要作用,并有望成为降低胆固醇,治疗某些心血管病及肝脏疾病的治疗靶点。本文介绍了FXR的发现、FXR在调控胆汁酸和脂质代谢中的作用,以及FXR在心血管疾病治疗中的应用前景。     

法尼酯X受体在脂质代谢过程中的调控作用

法尼酯X受体(Farnesoid X Receptor,FXR)属于配体依赖的核转录因子,可被内源性配体胆汁酸激活,通过调节胆汁酸、胆固醇、脂蛋白及脂肪酸代谢维持血浆中脂质的稳态,从而达到调节脂质代谢的目的。最近研究发现FXR在脉管系统中也有表达活性,开辟了FXR调节脂质代谢的新途径。随着新配体及靶基因的发现,研究FXR的作用机制以及寻找对脂质代谢具有调控作用的FXR的配体,对于脂代谢异常和动脉粥样硬化的防治具有重要意义。本文综述了该领域的最新进展。     

肾小管脂毒性在糖尿病肾病发病机制中的研究进展

糖尿病肾病(diabetic nephropathy,DN)是糖尿病的重要并发症，是终末期肾病的重要病因。DN患者常伴脂质代谢紊乱。脂代谢紊乱可致肾小管内脂质分布异常，引起肾脏脂肪堆积、脂滴积累、肾小管损伤等一系列“脂毒性”现象，进而诱发DN肾脏炎症、纤维化等病理改变。作为肾脏中的高耗能结构，肾小管脂代谢产能对维持其正常生理功能具有重大意义。脂质能量代谢在DN发病机制中发挥不可或缺的作用，本文从胆固醇代谢引起DN肾小管脂毒性、脂肪酸代谢引起DN肾小管脂毒性、脂代谢异常在肾小管与肾小球间的“串扰”作用以及肾小管脂毒性靶向药物治疗等方面进行阐述，旨在为今后临床防治DN新角度与新方案的提出提供参考。     

运动与二甲双胍调节肝脏脂代谢的作用机制研究进展

肝脏脂代谢紊乱与2型糖尿病、肥胖症、心血管疾病等多种慢性病密切相关。运动与二甲双胍均可通过作用于不同组织器官调节机体脂代谢,是防治脂代谢异常相关疾病的有效手段。运动可减少肝脏脂质摄入与分泌、降低脂质合成、促进脂肪酸分解,二甲双胍可抑制肝脏糖异生及脂质合成,达到控糖减脂的作用。两者在激活AMPK信号通路、促进肝脏因子分泌方面表现为协同效应,而对线粒体复合物I活性的调节却表现为拮抗效应,两者联合作用于肝脏脂代谢的分子机制有待进一步研究。该文基于运动与二甲双胍调控肝脏脂代谢的生物学机制进行综述,为慢病预防和治疗提供新的思路与策略。     

脂滴包被蛋白2在动脉粥样硬化中的作用

动脉粥样硬化性心血管疾病严重威胁着人类生命健康,其中脂质代谢异常和炎症反应是其重要的发病机制。脂滴是细胞内储存脂质的一种亚细胞器,其表面存在多种脂滴包被蛋白,参与调控脂质动态平衡。脂滴包被蛋白2(Plin2)作为脂滴包被蛋白的一种,在脂质代谢的调节、脂肪酸的氧化及炎症反应等多种生理功能中发挥重要作用。近年来,越来越多的研究发现Plin2在动脉粥样硬化的发生发展中扮演着重要的角色。因此,本文主要综述Plin2在胆固醇代谢、脂质合成、自噬和炎症反应等过程中发挥的作用,进一步阐述其与动脉粥样硬化之间的关系。     

脂质组学在医药研究中的应用

脂质组学是对整体脂质进行系统分析的一门新兴学科,通过比较不同生理状态下脂代谢网络的变化,进而识别代谢调控中关键的脂生物标志物,最终揭示脂质在各种生命活动中的作用机制。电喷雾电离-质谱技术是脂质组学领域中最核心的研究手段,目前已能对各种脂质尤其是磷脂进行高分辨率、高灵敏度、高通量的分析。随着质谱技术的进步,脂质组学在疾病脂生物标志物的识别、疾病诊断、药物靶点及先导化合物的发现和药物作用机制的研究等方面已展现出广泛的应用前景。     

肠道微生物及其代谢产物与宿主脂质代谢研究进展

近年来,肠道微生物与宿主脂质代谢研究受到国内外的广泛关注.首先,肠道微生物多样性和组成在脂肪代谢紊乱动物模型、肥胖患者中均发生显著改变,而利用粪菌移植、益生菌以及营养干预重塑肠道菌群结构可以调控宿主脂质代谢.本文重点介绍了肠道微生物与宿主脂代谢的联系,并从短链脂肪酸、胆汁酸、氨基酸、内毒素和微生物节律等方面探讨了肠道微生物调控宿主脂代谢的潜在机制,以期为脂质代谢引起的疾病提供干预靶点.     

哺乳动物营养代谢的时间生物学研究进展

时间生物学主要是研究生物体内生理和行为的时间机制的学科,而这种机制主要是由生物钟调控的。研究表明,营养代谢的各个方面如葡萄糖转运、糖原异生、脂质合成及降解、氧化磷酸化等作用都受到生物钟核心转录机制的调控,并具有时间敏感性;相反,代谢信号也可以反馈调节生物钟系统,包括生物钟基因表达和行为活动。生物钟的紊乱会造成诸如心血管疾病、肥胖、糖尿病等多种疾病。本文从代谢与生物钟的相互关系、各类营养信号和营养素对生物钟的作用以及生物钟与营养代谢相关疾病的关系等多方面综述了哺乳动物营养代谢的时间生物学研究进展。     

中期因子与动脉粥样硬化

中期因子(midkine)是一种分泌型肝素结合生长因子,在炎症、肿瘤、代谢类疾病及胚胎的早期发育方面发挥着重要的作用。动脉粥样硬化(atherosclerosis)是一种常见的心血管疾病,迄今为止,其具体发病机制尚未完全阐明。研究表明,动脉粥样硬化是一种血管壁受损的慢性炎症性疾病,并与遗传、环境、脂质代谢相关。中期因子在脂质代谢、氧化应激及炎症等方面起重要作用,并与动脉粥样硬化密切相关。本文对中期因子在动脉粥样硬化发生发展中的作用的研究进展进行综述。     

Preparation of hair for measurement of elements by inductively coupled plasma-mass spectrometry (ICP-MS)

The preparation of hair for the determination of elements is a critical component of the analysis procedure. Open-beaker, closedvessel microwave, and flowthrough microwave digestion are methods that have been used for sample preparation and are discussed. A new digestion method for use with inductively coupled plasma-mass spectrometry (ICP-MS) has been developed. The method uses 0.2 g of hair and 3 mL of concentrated nitric acid in an atmospheric pressurelow-temperature microwave digestion (APLTMD) system. This preparation method is useful in handling a large numbers of samples per day and may be adapted to hair sample weights ranging from 0.08 to 0.3 g. After digestion, samples are analyzed by ICP-MS to determine the concentration of Li, Be, B, Na, Mg, Al, P, S, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ge, As, Se, Rb, Sr, Zr, Mo, Pd, Ag, Cd, Sn, Sb, I, Cs, Ba, Pt, Au, Hg, Tl, Pb, Bi, Th, and U. Benefits of the APLTMD include reduced contamination and sample handling, and increased precision, reliability, and sample throughput.     

Genetic Manipulation in Δku80 Strains for Functional Genomic Analysis of Toxoplasma gondii

Targeted genetic manipulation using homologous recombination is the method of choice for functional genomic analysis to obtain a detailed view of gene function and phenotype(s). The development of mutant strains with targeted gene deletions, targeted mutations, complemented gene function, and/or tagged genes provides powerful strategies to address gene function, particularly if these genetic manipulations can be efficiently targeted to the gene locus of interest using integration mediated by double cross over homologous recombination.Due to very high rates of nonhomologous recombination, functional genomic analysis of Toxoplasma gondii has been previously limited by the absence of efficient methods for targeting gene deletions and gene replacements to specific genetic loci. Recently, we abolished the major pathway of nonhomologous recombination in type I and type II strains of T. gondii by deleting the gene encoding the KU80 protein^1,2. The Δku80 strains behave normally during tachyzoite (acute) and bradyzoite (chronic) stages in vitro and in vivo and exhibit essentially a 100% frequency of homologous recombination. The Δku80 strains make functional genomic studies feasible on the single gene as well as on the genome scale^1-4.Here, we report methods for using type I and type II Δku80Δhxgprt strains to advance gene targeting approaches in T. gondii. We outline efficient methods for generating gene deletions, gene replacements, and tagged genes by targeted insertion or deletion of the hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) selectable marker. The described gene targeting protocol can be used in a variety of ways in Δku80 strains to advance functional analysis of the parasite genome and to develop single strains that carry multiple targeted genetic manipulations. The application of this genetic method and subsequent phenotypic assays will reveal fundamental and unique aspects of the biology of T. gondii and related significant human pathogens that cause malaria (Plasmodium sp.) and cryptosporidiosis (Cryptosporidium).     

A phylogenetic analysis of 100+ genera and 50+ families of euasterids based on morphological and molecular data with notes on possible higher level morphological synapomorphies

 A data matrix of 143 morphological and chemical characters for 142 genera of euasterids according to the APG system was compiled and complemented with rbcL and ndhF sequences for most of the genera. The data were subjected to parsimony analysis and support was assessed by bootstrapping. Strict consensus trees from analyses of morphology alone and morphology + rbcL + ndhF are presented. The morphological data recover several groups supported by molecular data but at the level of orders and above relationships are only superficially in agreement with molecular studies. The analyses provide support for monophyly of Gentianales, Aquifoliales, Apiales, Asterales, and Dipsacales. All data indicate that Adoxaceae are closely related to Dipsacales and hence they should be included in that order. The trees were used to assess some possible morphological synapomorphies for euasterids I and II and for the orders of the APG system. Euasterids I are generally characterised by opposite leaves, entire leaf margins, hypogynous flowers, “early sympetaly” with a ring-shaped corolla primordium, fusion of stamen filaments with the corolla tube, and capsular fruits. Euasterids II often have alternate leaves, serrate-dentate leaf margins, epigynous flowers, “late sympetaly” with distinct petal primordia, free stamen filaments, and indehiscent fruits. It is unclear which of these characters represent synapomorphies and symplesiomorphies for the two groups, respectively, and there are numerous expections to be interpreted as reversals and parallelisms. Received August 28, 2000 Accepted August 7, 2001     

Mechanisms and ecological consequences of plant defence induction and suppression in herbivore communities

Background Plants are hotbeds for parasites such as arthropod herbivores, which acquire nutrients and energy from their hosts in order to grow and reproduce. Hence plants are selected to evolve resistance, which in turn selects for herbivores that can cope with this resistance. To preserve their fitness when attacked by herbivores, plants can employ complex strategies that include reallocation of resources and the production of defensive metabolites and structures. Plant defences can be either prefabricated or be produced only upon attack. Those that are ready-made are referred to as constitutive defences. Some constitutive defences are operational at any time while others require activation. Defences produced only when herbivores are present are referred to as induced defences. These can be established via de novo biosynthesis of defensive substances or via modifications of prefabricated substances and consequently these are active only when needed. Inducibility of defence may serve to save energy and to prevent self-intoxication but also implies that there is a delay in these defences becoming operational. Induced defences can be characterized by alterations in plant morphology and molecular chemistry and are associated with a decrease in herbivore performance. These alterations are set in motion by signals generated by herbivores. Finally, a subset of induced metabolites are released into the air as volatiles and function as a beacon for foraging natural enemies searching for prey, and this is referred to as induced indirect defence.Scope The objective of this review is to evaluate (1) which strategies plants have evolved to cope with herbivores and (2) which traits herbivores have evolved that enable them to counter these defences. The primary focus is on the induction and suppression of plant defences and the review outlines how the palette of traits that determine induction/suppression of, and resistance/susceptibility of herbivores to, plant defences can give rise to exploitative competition and facilitation within ecological communities “inhabiting” a plant.Conclusions Herbivores have evolved diverse strategies, which are not mutually exclusive, to decrease the negative effects of plant defences in order to maximize the conversion of plant material into offspring. Numerous adaptations have been found in herbivores, enabling them to dismantle or bypass defensive barriers, to avoid tissues with relatively high levels of defensive chemicals or to metabolize these chemicals once ingested. In addition, some herbivores interfere with the onset or completion of induced plant defences, resulting in the plant’s resistance being partly or fully suppressed. The ability to suppress induced plant defences appears to occur across plant parasites from different kingdoms, including herbivorous arthropods, and there is remarkable diversity in suppression mechanisms. Suppression may strongly affect the structure of the food web, because the ability to suppress the activation of defences of a communal host may facilitate competitors, whereas the ability of a herbivore to cope with activated plant defences will not. Further characterization of the mechanisms and traits that give rise to suppression of plant defences will enable us to determine their role in shaping direct and indirect interactions in food webs and the extent to which these determine the coexistence and persistence of species.     

Angiosperm ovules: diversity, development, evolution

Background

Ovules as developmental precursors of seeds are organs of central importance in angiosperm flowers and can be traced back in evolution to the earliest seed plants. Angiosperm ovules are diverse in their position in the ovary, nucellus thickness, number and thickness of integuments, degree and direction of curvature, and histological differentiations. There is a large body of literature on this diversity, and various views on its evolution have been proposed over the course of time. Most recently evo–devo studies have been concentrated on molecular developmental genetics in ovules of model plants.

Scope

The present review provides a synthetic treatment of several aspects of the sporophytic part of ovule diversity, development and evolution, based on extensive research on the vast original literature and on experience from my own comparative studies in a broad range of angiosperm clades.

Conclusions

In angiosperms the presence of an outer integument appears to be instrumental for ovule curvature, as indicated from studies on ovule diversity through the major clades of angiosperms, molecular developmental genetics in model species, abnormal ovules in a broad range of angiosperms, and comparison with gymnosperms with curved ovules. Lobation of integuments is not an atavism indicating evolution from telomes, but simply a morphogenetic constraint from the necessity of closure of the micropyle. Ovule shape is partly dependent on locule architecture, which is especially indicated by the occurrence of orthotropous ovules. Some ovule features are even more conservative than earlier assumed and thus of special interest in angiosperm macrosystematics.     

Genome Similarity Implies that Citrus-Parasitic Burrowing Nematodes do not Represent a Unique Species

Burrowing nematodes from Central America, Dominican Republic, Florida, Guadeloupe, Hawaii, and Puerto Rico were characterized for their ability to parasitize citrus, but citrus parasites were found only in Florida. Sequence tag sites originally amplified from a citrus-parasitic burrowing nematode were polymorphic among 37 burrowing nematode isolates and were not correlated with citrus parasitism, nematode isolate collection site, or amplification of a 2.4-kb sequence tag site (DK#1). Results of a RAPD analysis and characterization of the isozymes phosphoglucose isomerase, lactate dehydrogenase, and malate dehydrogenase indicated that the burrowing nematode isolates were highly similar. Citrus parasitism in Florida appears to be associated with limited changes in the burrowing nematode genome. Findings did not substantiate a previous report that R. citrophilus was present in Hawaii. Overall, these data do not support assignment of sibling species status to burrowing nematodes that differ with respect to citrus parasitism.     

A Simple Protocol for Platelet-mediated Clumping of Plasmodium falciparum-infected Erythrocytes in a Resource Poor Setting

P. falciparum causes the majority of severe malarial infections. The pathophysiological mechanisms underlying cerebral malaria (CM) are not fully understood and several hypotheses have been put forward, including mechanical obstruction of microvessels by P. falciparum-parasitized red blood cells (pRBC). Indeed, during the intra-erythrocytic stage of its life cycle, P. falciparum has the unique ability to modify the surface of the infected erythrocyte by exporting surface antigens with varying adhesive properties onto the RBC membrane. This allows the sequestration of pRBC in multiple tissues and organs by adhesion to endothelial cells lining the microvasculature of post-capillary venules ¹. By doing so, the mature forms of the parasite avoid splenic clearance of the deformed infected erythrocytes ² and restrict their environment to a more favorable low oxygen pressure ³. As a consequence of this sequestration, it is only immature asexual parasites and gametocytes that can be detected in peripheral blood.Cytoadherence and sequestration of mature pRBC to the numerous host receptors expressed on microvascular beds occurs in severe and uncomplicated disease. However, several lines of evidence suggest that only specific adhesive phenotypes are likely to be associated with severe pathological outcomes of malaria. One example of such specific host-parasite interactions has been demonstrated in vitro, where the ability of intercellular adhesion molecule-1 to support binding of pRBC with particular adhesive properties has been linked to development of cerebral malaria ^4,5. The placenta has also been recognized as a site of preferential pRBC accumulation in malaria-infected pregnant women, with chondrotin sulphate A expressed on syncytiotrophoblasts that line the placental intervillous space as the main receptor ⁶. Rosetting of pRBC to uninfected erythrocytes via the complement receptor 1 (CD35)^7,8 has also been associated with severe disease ⁹.One of the most recently described P. falciparum cytoadherence phenotypes is the ability of the pRBC to form platelet-mediated clumps in vitro. The formation of such pRBC clumps requires CD36, a glycoprotein expressed on the surface of platelets. Another human receptor, gC1qR/HABP1/p32, expressed on diverse cell types including endothelial cells and platelets, has also been shown to facilitate pRBC adhesion on platelets to form clumps ¹⁰. Whether clumping occurs in vivo remains unclear, but it may account for the significant accumulation of platelets described in brain microvasculature of Malawian children who died from CM ¹¹. In addition, the ability of clinical isolate cultures to clump in vitro was directly linked to the severity of disease in Malawian ¹² and Mozambican patients ¹³, (although not in Malian ¹⁴).With several aspects of the pRBC clumping phenotype poorly characterized, current studies on this subject have not followed a standardized procedure. This is an important issue because of the known high variability inherent in the assay ¹⁵. Here, we present a method for in vitro platelet-mediated clumping of P. falciparum with hopes that it will provide a platform for a consistent method for other groups and raise awareness of the limitations in investigating this phenotype in future studies. Being based in Malawi, we provide a protocol specifically designed for a limited resource setting, with the advantage that freshly collected clinical isolates can be examined for phenotype without need for cryopreservation.     

Assessing burrowing, nest construction, and hoarding in mice

Deterioration in the ability to perform "Activities of daily living" (ADL) is an early sign of Alzheimer's disease (AD). Preclinical behavioural screening of possible treatments for AD currently largely focuses on cognitive testing, which frequently demands expensive equipment and lots of experimenter time. However, human episodic memory (the most severely affected aspect of memory in AD) is different to rodent memory, which seems to be largely non-episodic. Therefore the present ways of screening for new AD treatments for AD in rodents are intrinsically unlikely to succeed. A new approach to preclinical screening would be to characterise the ADL of mice. Fortuitously, several such assays have recently been developed at Oxford, and here the three most sensitive and well-characterised are presented. Burrowing was first developed in Oxford. It evolved from a need to develop a mouse hoarding paradigm. Most published rodent hoarding paradigms required a distant food source to be linked to the home cage by a connecting passage. This would involve modifying the home cage as well as making a mouse-proof connecting passage and food source. So it was considered whether it would be possible to put the food source inside the cage. It was found that if a container was placed on the floor it was emptied by the next morning., The food pellets were, however, simply deposited in a heap at the container entrance, rather than placed in a discrete place away from the container, as might be expected if the mice were truly hoarding them. Close inspection showed that the mice were performing digging ("burrowing") movements, not carrying the pellets in their mouths to a selected place as they would if truly hoarding them. Food pellets are not an essential substrate for burrowing; mice will empty tubes filled with sand, gravel, even soiled bedding from their own cage. Moreover, they will empty a full tube even if an empty one is placed next to it. Several nesting protocols exist in the literature. The present Oxford one simplifies the procedure and has a well-defined scoring system for nest quality. A hoarding paradigm was later developed in which the mice, rather than hoarding back to the real home cage, were adapted to living in the "home base" of a hoarding apparatus. This home base was connected to a tube made of wire mesh, the distal end of which contained the food source. This arrangement proved to yield good hoarding behaviour, as long as the mice were adapted to living in the "home base" during the day and only allowed to enter the hoarding tube at night.     

日本北海道虻类雌性外生殖器形态(双翅目：虻科)(英文)

【目的】利用日本北海道虻类评估和验证外生殖器在分类学上的意义。【方法】将虻类成虫标本浸渍在生理盐水中并置于双目显微镜下通过针和镊子在培养皿中进行解剖并绘图,观察第9背板、第10背板、尾叶、第8腹板、受精囊、受精囊管及生殖叉器的形态特征。【结果】在日本北海道共记录了虻科(Tabanidae) 3亚科7属38种。我们观察并描述了3亚科其中的6属24种的雌性外生殖器的主要特征。亚科之间存在明显差异;然而在一般情况下属之间很难建立一种方法来确定共同点;种之间只有在斑虻属Chrysops中有相似之处,其他属中则比较多样化。因此,亚科鉴定根据第9背板、第8腹板及受精囊足以进行区分,属及种鉴定需要结合第9背板、第10背板、尾叶、第8腹板、受精囊、受精囊管及生殖叉器各自的特征组合在一起才能区分开来。我们也制作了虻类外生殖器的检索表。【结论】和许多其他昆虫一样,外生殖器是虻科的重要分类特征,对于促进分类学和系统学的发展具有重要意义。本研究首次对分布在日本北海道的虻科雌性外生殖器进行了系统研究。     

外泌体在白血病中的重要调控作用

目前,白血病复发是患者死亡的主要原因之一。肿瘤细胞和微环境的相互作用,以及隐匿在骨髓中的肿瘤干细胞,促进了白血病的复发和向淋巴组织的转移,因此白血病的治疗、转移和复发问题受到广泛关注。外泌体是由绝大多数细胞分泌的双层脂质膜囊泡,可以调控细胞间的交流和信息传递。在白血病细胞、基质细胞和内皮细胞之间的相互联系中都涉及到外泌体,白血病细胞来源的外泌体存在于白血病患者的血浆中,能把其携带的白血病相关抗原及微小RNA呈递给靶细胞,促进白血病肿瘤细胞的增殖,有助于肿瘤细胞实现免疫逃避,保护白血病细胞抵抗化疗药物导致的细胞毒性作用,促进血管生成及肿瘤细胞的迁移。因此,外泌体与白血病的转移、治疗及预后密切相关,可以用来检测和监测白血病的进展。本文综述了外泌体的来源、形成与分泌机制,以及外泌体在白血病发生前、发展中、预后和免疫治疗中所扮演的重要角色。