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Wnt signaling in stem cells and lung cancer. Wnt信号在干细胞和肺癌中的作用
Pub Date : 2006-01-01 DOI: 10.1007/2789_2007_043
B He, D M Jablons

The Wnt signal transduction pathway plays important roles during embryo development, regulating cell proliferation and survival of immature cells. However, its improper function can lead to harmful consequences for humans, such as aberrant cell proliferation and, therefore, cancer. Increasing evidence suggests that stem cells may be the source of mutant cells that cause cancers to develop and proliferate. Wnt signaling has been shown to promote self-renewal in both gut epithelial and hematopoietic stem cells (HSCs) and to trigger critical pathways in carcinogenesis. Although the function of stem cells in solid tumor development is unclear, the Wnt pathway's role in determining the fate and self-renewal potential of cancer stem cells suggests a critical role in carcinogenesis. The development of new inhibitors, such as antibodies or small molecules, to inhibit this pathway may be of great therapeutic utility against cancer.

Wnt信号转导通路在胚胎发育、调节细胞增殖和未成熟细胞存活过程中发挥重要作用。然而,它的功能不当会给人类带来有害的后果,比如异常的细胞增殖,从而导致癌症。越来越多的证据表明,干细胞可能是导致癌症发展和增殖的突变细胞的来源。Wnt信号已被证明可以促进肠道上皮细胞和造血干细胞(hsc)的自我更新,并触发致癌的关键途径。尽管干细胞在实体瘤发展中的功能尚不清楚,但Wnt通路在决定癌症干细胞的命运和自我更新潜力方面的作用表明,它在癌变中起着关键作用。开发新的抑制剂,如抗体或小分子,来抑制这一途径可能对癌症有很大的治疗效用。
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引用次数: 28
Bone morphogenetic proteins regulate tumorigenicity in human glioblastoma stem cells. 骨形态发生蛋白调节人胶质母细胞瘤干细胞的致瘤性。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2007_044
S G M Piccirillo, A L Vescovi

Human glioblastomas appear to be established and expanded by cancer stem cells, which are endowed with tumour-initiating and perpetuating ability. We report that bone morphogenetic proteins (BMPs), amongst which BMP4 elicits the strongest effect, activate their cognate receptors (BMPRs) and trigger the Smad but not the MAP38 kinase signalling cascade in cells isolated from human glioblastomas (GBMs). This is followed by a reduction in proliferation and increased expression of differentiated neural markers, without affecting cell viability. The concomitant reduction in the clonogenic ability, both in the size of the CD133+ side population and in the growth kinetics of GBM cells, indicates that BMP4 triggers a reduction in the in vitro cancer stem cell (CSC) pool. Accordingly, transient ex vivo exposure to BMP4 abolishes the capacity of transplanted GBM cells to establish intracerebral GBMs. Most important, in vivo delivery of BMP4 effectively blocks the tumour growth and associated mortality which occur in 100% of control mice in less than 12 weeks, following intracerebral grafting of human GBM cells. These findings show that the BMP-BMPR signalling system, which controls the activity of normal brain stem cells, may also act as a key inhibitory regulator of cancer-initiating, GBM stem-like cells and identifies BMP4 as a novel, non-cytotoxic therapeutic effector, which may be used to prevent growth and recurrence of GBMs in humans.

人类胶质母细胞瘤似乎是由癌症干细胞建立和扩大的,癌症干细胞被赋予了肿瘤启动和延续的能力。我们报道了骨形态发生蛋白(BMPs),其中BMP4的作用最强,在人胶质母细胞瘤(GBMs)分离的细胞中激活其同源受体(BMPRs)并触发Smad而不是MAP38激酶信号级联。随后是增殖减少和分化神经标记物表达增加,而不影响细胞活力。在CD133+侧群体的大小和GBM细胞的生长动力学中,克隆生成能力的伴随降低表明BMP4触发了体外癌症干细胞(CSC)池的减少。因此,短暂的体外暴露于BMP4会消除移植的GBM细胞建立脑内GBM的能力。最重要的是,在脑内移植人类GBM细胞后,体内递送BMP4有效地阻断了肿瘤生长和相关死亡率,在不到12周的时间内,100%的对照小鼠发生了相关死亡率。这些发现表明,BMP-BMPR信号系统,控制正常脑干细胞的活性,也可能作为癌症启动的关键抑制调节剂,GBM干细胞样细胞,并确定BMP4作为一种新的,非细胞毒性治疗效应,可用于预防人类GBM的生长和复发。
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引用次数: 74
QSAR modeling of GPCR ligands: methodologies and examples of applications. GPCR配体的QSAR建模:方法和应用实例。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2006_003
A Tropsha, S X Wang

GPCR ligands represent not only one of the major classes of current drugs but the major continuing source of novel potent pharmaceutical agents. Because 3D structures of GPCRs as determined by experimental techniques are still unavailable, ligand-based drug discovery methods remain the major computational molecular modeling approaches to the analysis of growing data sets of tested GPCR ligands. This paper presents an overview of modern Quantitative Structure Activity Relationship (QSAR) modeling. We discuss the critical issue of model validation and the strategy for applying the successfully validated QSAR models to virtual screening of available chemical databases. We present several examples of applications of validated QSAR modeling approaches to GPCR ligands. We conclude with the comments on exciting developments in the QSAR modeling of GPCR ligands that focus on the study of emerging data sets of compounds with dual or even multiple activities against two or more of GPCRs.

GPCR配体不仅代表了当前药物的主要类别之一,而且是新型强效药物的主要持续来源。由于通过实验技术确定的GPCR的3D结构仍然不可用,基于配体的药物发现方法仍然是主要的计算分子建模方法,用于分析已测试GPCR配体的增长数据集。本文介绍了现代定量结构活动关系(QSAR)模型的研究概况。我们讨论了模型验证的关键问题,以及将成功验证的QSAR模型应用于可用化学数据库的虚拟筛选的策略。我们提出了几个应用验证的QSAR建模方法对GPCR配体的例子。最后,我们对GPCR配体的QSAR建模的令人兴奋的发展进行了评论,这些研究集中在对两种或两种以上GPCR具有双重甚至多重活性的化合物的新兴数据集的研究上。
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引用次数: 15
Privileged structures in GPCRs. gpcr中的特权结构。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2006_004
R P Bywater

Certain kinds of ligand substructures recur frequently in pharmacologically successful synthetic compounds. For this reason they are called privileged structures. In seeking an explanation for this phenomenon, it is observed that the privileged structure represents a generic substructure that matches commonly recurring conserved structural motifs in the target proteins, which may otherwise be quite diverse in sequence and function. Using sequence-handling tools, it is possible to identify which other receptors may respond to the ligand, as dictated on the one hand by the nature of the privileged substructure itself or by the rest of the ligand in which a more specific message resides. It is suggested that privileged structures interact with the partially exposed receptor machinery responsible for the switch between the active and inactive states. Depending on how they have been designed to interact, one can predispose these substructures to favour either one state or the other; thus privileged structures can be used to create either agonists or antagonists. In terms of the mechanism of recognition, the region that the privileged structures bind to are rich in aromatic residues, which explains the prevalence of aromatic groups and atoms such as sulphur or halogens in many of the ligands. Finally, the approach described here can be used to design drugs for orphan receptors whose function has not yet been established experimentally.

某些类型的配体亚结构在药理学上成功的合成化合物中经常重复出现。因此,它们被称为特权结构。在寻找对这一现象的解释时,我们观察到特权结构代表了与目标蛋白中经常重复出现的保守结构基序相匹配的一般亚结构,否则这些亚结构在序列和功能上可能是相当不同的。利用序列处理工具,可以确定哪些其他受体可能对配体产生反应,一方面是由特权亚结构本身的性质决定的,另一方面是由配体中含有更特定信息的其余部分决定的。这表明特权结构与部分暴露的受体机制相互作用,负责在活跃和不活跃状态之间切换。根据它们是如何被设计成相互作用的,人们可以使这些子结构倾向于一种状态或另一种状态;因此,特权结构可用于制造激动剂或拮抗剂。在识别机制方面,特权结构结合的区域富含芳香残基,这解释了许多配体中普遍存在芳香基团和硫或卤素等原子。最后,本文描述的方法可用于设计孤儿受体的药物,其功能尚未在实验中建立。
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引用次数: 6
Isoindolones and related N-heterocycles via palladium nanoparticle-catalyzed 3-component cascade reactions. 钯纳米颗粒催化的异吲哚酮及其相关n -杂环化合物的级联反应。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2007_029
R Grigg, V Sridharan

Non-phosphine-containing cyclopalladated N-heterocycles possessing either sp2 C-Pd(II) or sp3 C-Pd(II) bonds and simple Pd(II) salts are precursors of Pd(0) nanoparticles whose initial morphology is dependent on the nature of the precursor. Addition of polyvinylpyrrolidone (pvp) dramatically increases catalyst lifetime. Nanoparticle generation can be achieved at ambient temperature in the presence of carbon monoxide by a process akin to the water-gas shift reaction. Allene also lowers the temperature required for nanoparticle generation. 3-Component catalytic cascades employing one or both of these substrates provide access to a variety of 5- and 6-membered N-heterocycles including isoindolones, N-aminoisoindolones, phthalazones, dihydroisoquinolines, and isoquinolones.

具有sp2 C-Pd(II)或sp3 C-Pd(II)键和简单Pd(II)盐的不含磷化氢的环钯化n杂环是Pd(0)纳米粒子的前驱体,其初始形态取决于前驱体的性质。聚乙烯吡咯烷酮(pvp)的加入显著提高了催化剂的使用寿命。纳米颗粒的生成可以在一氧化碳存在的环境温度下通过类似于水气转换反应的过程来实现。烯还降低了纳米颗粒生成所需的温度。采用一种或两种底物的三组分催化级联反应提供了多种5元和6元n -杂环化合物,包括异吲哚酮、n -氨基异吲哚酮、邻苯二酮、二氢异喹啉和异喹诺酮。
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引用次数: 0
Scale-up in microwave-accelerated organic synthesis. 放大微波加速有机合成。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2007_032
H Lehmann

Microwave-assisted organic chemistry has received strong exposure in the literature over the last decade, and nowadays more and more research chemists are successfully applying microwave technology to organic reactions on a small scale. However, the efficient application of this technology to cover the specific needs of larger-scale preparations, e.g., in a kilo lab, remains to be shown. We therefore initiated a study to investigate the scalability of microwave technology. Two different microwave systems designed for large-scale operation were evaluated in order to characterize strengths and weaknesses of each instrument with regard to scale-up. Special focus was directed on temperature/pressure limits, handling of suspensions, ability to rapidly heat and cool, robustness, and overall processing time. Based on the results of this study, a batch microwave reactor with a reaction volume of approximately 1.1 1 was purchased and installed in the kilo lab. Several reactions have been performed successfully on a 50- to 100-g scale in our laboratory, showing that a scale-up from a 15 ml scale to a 1-1 scale is feasible. In general, a significant reduction of reaction time was achievable, in some cases yields and selectivity were also improved. Nevertheless, a major weakness of the available systems is the limited vessel size, which is, in most cases, far below a suitable reaction volume required for work in a kilo lab.

近十年来,微波辅助有机化学在文献中得到了广泛的关注,如今越来越多的研究化学家成功地将微波技术应用于小范围的有机反应中。然而,这项技术的有效应用,以满足大规模制剂的具体需要,例如,在一公斤实验室,仍有待证明。因此,我们开始研究微波技术的可扩展性。为大规模操作而设计的两种不同的微波系统进行了评估,以表征每种仪器在放大方面的优缺点。特别关注的是温度/压力限制,悬浮液的处理,快速加热和冷却的能力,坚固性和整体处理时间。根据研究结果,购买了反应体积约为1.1的间歇式微波反应器并安装在基洛实验室。在我们的实验室中,在50至100克的规模上成功地进行了几次反应,表明从15毫升的规模扩大到1-1的规模是可行的。总的来说,可以显著缩短反应时间,在某些情况下收率和选择性也有所提高。然而,现有系统的一个主要弱点是容器尺寸有限,在大多数情况下,远远低于在一公斤实验室工作所需的合适反应体积。
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引用次数: 6
The role of GPCR dimerisation/oligomerisation in receptor signalling. GPCR二聚/寡聚在受体信号传导中的作用。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2006_007
G Milligan, M Canals, J D Pediani, J Ellis, J F Lopez-Gimenez

A wide range of techniques have been employed to examine the quaternary structure of G-protein-coupled receptors (GPCRs). Although it is well established that homo-dimerisation is common, recent studies have sought to explore the physical basis of these interactions and the role of dimerisation in signal transduction. Growing evidence hints at the existence of higher-order organisation of individual GPCRs and the potential for hetero-dimerisation between pairs of co-expressed GPCRs. Here we consider how both homo-dimerisation/oligomerisation and hetero-dimerisation can regulate signal transduction through GPCRs and the potential consequences of this for function of therapeutic medicines that target GPCRs. Hetero-dimerisation is not the sole means by which co-expressed GPCRs may regulate the function of one another. Heterologous desensitisation may be at least as important and we also consider if this can be the basis for physiological antagonism between pairs of co-expressed GPCRs. Although there may be exceptions (Meyer et al. 2006), a great deal of recent evidence has indicated that most G-protein-coupled receptors (GPCRs) do not exist as monomers but rather as dimers or, potentially, within higher-order oligomers (Milligan 2004b; Park et al. 2004). Support for such models has been provided by a range of studies employing different approaches, including co-immunoprecipitation of differentially epitope-tagged but co-expressed forms of the same GPCR, co-operativity in ligand binding and a variety of resonance energy transfer techniques (Milligan and Bouvier 2005). Only for the photon receptor rhodopsin has the organisational structure of a GPCR been studied in situ. The application of atomic force microscopy to murine rod outer segment discs indicated that rhodopsin is organised in a series of parallel arrays of dimers (Liang et al. 2003) and based on this, molecular models were constructed to try to define and interpret regions of contact between the monomers (Fotiadis et al. 2004). Only for relatively few other GPCRs are details of the molecular basis of dimerisation available but within this limited data set, recent studies on the dopamine D2 receptor suggest a means by which information on the binding of an agonist can be transmitted between the two elements of the dimer via the dimer interface (Guo et al. 2005). Although the availability of cDNAs encoding molecularly defined GPCRs has allowed high-throughput screening for ligands that modulate GPCR function, this is performed almost exclusively in heterologous cell lines transfected to express only the specific GPCR of interest. Given that the human genome contains some 400-450 genes encoding non-chemosensory GPCRs, it is clear that any individual cell of the body may express a considerable number of GPCRs. Interactions between these, either via hetero-dimerisation, via heterologous desensitisation or via the integration of downstream signals can potentially alter the pharmacology, sen

广泛的技术已经被用来检查g蛋白偶联受体(gpcr)的四级结构。虽然同源二聚化很常见,但最近的研究试图探索这些相互作用的物理基础以及二聚化在信号转导中的作用。越来越多的证据表明,存在单个gpcr的高阶组织,并且在共表达的gpcr对之间存在异二聚化的潜力。在这里,我们考虑了同源二聚化/寡聚化和异二聚化如何通过gpcr调节信号转导,以及这对靶向gpcr的治疗药物功能的潜在影响。异二聚化并不是共表达gpcr调节彼此功能的唯一途径。异源脱敏可能至少同样重要,我们也考虑这是否可以成为共表达gpcr对之间生理拮抗的基础。尽管可能有例外(Meyer et al. 2006),但最近的大量证据表明,大多数g蛋白偶联受体(gpcr)不是作为单体存在,而是作为二聚体存在,或者可能存在于高阶低聚物中(Milligan 2004b;Park et al. 2004)。采用不同方法的一系列研究为这些模型提供了支持,包括对带有不同表位标记但共表达形式的相同GPCR的共免疫沉淀、配体结合的协同性和各种共振能量转移技术(Milligan and Bouvier 2005)。只有对光子受体视紫红质的组织结构进行了原位研究。原子力显微镜在小鼠棒外段圆盘上的应用表明,视紫红质是由一系列平行的二聚体阵列组成的(Liang et al. 2003),并在此基础上构建了分子模型,试图定义和解释单体之间的接触区域(Fotiadis et al. 2004)。只有相对较少的其他gpcr具有二聚化的分子基础细节,但在这有限的数据集中,最近对多巴胺D2受体的研究表明,通过二聚体界面,可以在二聚体的两个元素之间传递激动剂结合的信息(Guo et al. 2005)。虽然编码分子定义的GPCR的cdna的可用性允许高通量筛选调节GPCR功能的配体,但这几乎只在转染仅表达感兴趣的特定GPCR的异源细胞系中进行。鉴于人类基因组包含约400-450个编码非化学感觉gpcr的基因,很明显,人体的任何单个细胞都可能表达相当数量的gpcr。它们之间的相互作用,无论是通过异源二聚化、异源脱敏还是通过下游信号的整合,都可能改变受体激动剂的药理学、敏感性和功能,从而产生不同的反应。在本文中,我们将使用具体的例子来考虑同源二聚化/寡聚化在GPCR功能中的作用,以及共表达GPCR对之间的直接异源二聚化或异源脱敏是否会影响受体对的功能。
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引用次数: 60
Deorphanization of G-protein-coupled receptors. g蛋白偶联受体的去孤儿化。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2006_008
M Parmentier, M Detheux

G-protein-coupled receptors constitute one of the major families of drug targets. Orphan receptors, for which the ligands and function are still unknown, are an attractive set of future targets for presently unmet medical needs. Screening strategies have been developed over the years in order to identify the natural ligands of these receptors. Natural or chimeric G-proteins that can redirect the natural coupling of receptors toward intracellular calcium release are frequently used. Potential problems include poor expression or trafficking to the cell surface, constitutive activity of the receptors, or the presence of endogenous receptors in the cell types used for functional expression, leading to nonspecific responses. Many orphan receptors characterized over the last 10 years have been associated with previously known bioactive molecules. However, new and unpredicted biological mediators have also been purified from complex biological sources. A few old and recent examples, including nociceptin, chemerin, and the F2L peptide are illustrated. Future challenges for the functional characterization of the remaining orphan receptors include the potential requirement of specific proteins necessary for quality control, trafficking or coupling of specific receptors, the possible formation of obligate heterodimers, and the possibility that some constitutively active receptors may lack ligands or respond only to inverse agonists. Adapted expression and screening strategies will be needed to deal with these issues.

g蛋白偶联受体是药物靶点的主要家族之一。孤儿受体,其配体和功能仍然未知,是目前未满足的医疗需求的一组有吸引力的未来目标。筛选策略已经发展了多年,以确定这些受体的天然配体。通常使用天然或嵌合g蛋白,它们可以将受体的自然偶联转向细胞内钙释放。潜在的问题包括表达不良或运输到细胞表面,受体的组成活性,或用于功能表达的细胞类型中存在内源性受体,导致非特异性反应。在过去的10年里,许多孤儿受体被发现与以前已知的生物活性分子有关。然而,新的和不可预测的生物介质也从复杂的生物来源纯化。一些旧的和最近的例子,包括痛觉啡、趋化素和F2L肽。对剩余孤儿受体的功能表征的未来挑战包括对质量控制所需的特定蛋白质的潜在需求,特定受体的运输或偶联,专性异二聚体的可能形成,以及一些构成活性受体可能缺乏配体或仅对逆激动剂有反应的可能性。需要适应的表达和筛选策略来处理这些问题。
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引用次数: 14
Estradiol action in atherosclerosis and reendothelialization. 雌二醇在动脉粥样硬化和再内皮化中的作用。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2006_017
J F Arnal, H Laurell, F Lenfant, V Douin-Echinard, L Brouchet, P Gourdy

Whereas hormonal replacement/menopause therapy (HRT) in postmenopausal women increases coronary artery disease risk, epidemiological studies (protection in premenopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of estrogens is thus required. The atheroprotective effect of E2 is absent in mice deficient in mature T and B lymphocytes, demonstrating the crucial role of the endothelium/immune system pair. The immunoinflammatory system appears to play a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas E2 favors an anti-inflammatory effect in vitro (cultured cells), it elicits in vivo a proinflammation at the level of several subpopulations of the immunoinflammatory system, which could contribute to plaque destabilization. Endothelium appears to be an important target for E2, since it potentiates endothelial NO and prostacyclin production, thus promoting beneficial effects such as vasorelaxation and inhibition of platelet aggregation. Prostacyclin, but not NO, appear to be involved in the atheroprotective effect of E2, which also accelerates endothelial regrowth, thus favoring vascular healing. Finally, most of these E2 effects are mediated by estrogen receptor alpha and are independent of estrogen receptor beta. In summary, a better understanding of the mechanisms of estrogens on the normal and atheromatous arteries is required and should help to optimize the prevention of cardiovascular disease after menopause. These mouse models should help to screen existing and future selective estrogen receptor modulators (SERMs).

虽然绝经后妇女的激素替代/更年期治疗(HRT)增加了冠状动脉疾病的风险,但流行病学研究(对绝经前妇女的保护)和实验研究(预防动物脂肪条纹的形成)表明雌二醇(E2)具有主要的动脉粥样硬化保护作用。因此,需要了解雌激素的有害和有益作用。E2的动脉粥样硬化保护作用在缺乏成熟T淋巴细胞和B淋巴细胞的小鼠中不存在,这表明内皮/免疫系统对的关键作用。免疫炎症系统似乎在脂肪条纹沉积的发展以及动脉粥样硬化斑块的破裂中起关键作用。虽然E2在体外(培养细胞)具有抗炎作用,但在体内,它在免疫炎症系统的几个亚群水平上引发炎症,这可能有助于斑块的不稳定。内皮似乎是E2的重要靶标,因为它增强了内皮NO和前列环素的产生,从而促进了血管松弛和抑制血小板聚集等有益作用。前列环素,而不是NO,似乎参与E2的动脉粥样硬化保护作用,E2也加速内皮细胞再生,从而有利于血管愈合。最后,大多数E2效应是由雌激素受体α介导的,不依赖于雌激素受体β。总之,更好地了解雌激素对正常动脉和动脉粥样硬化动脉的作用机制是必要的,并有助于优化绝经后心血管疾病的预防。这些小鼠模型应该有助于筛选现有的和未来的选择性雌激素受体调节剂(SERMs)。
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引用次数: 5
Functional effects and molecular mechanisms of subtype-selective ERalpha and ERbeta agonists in the cardiovascular system. 亚型选择性erα和erβ激动剂在心血管系统中的功能作用和分子机制。
Pub Date : 2006-01-01 DOI: 10.1007/2789_2006_018
P A Arias-Loza, V Jazbutyte, K H Fritzemeier, C Hegele-Hartung, L Neyses, G Ertl, T Pelzer

Gender differences in the development of cardiovascular disease suggested for a protective function of estrogens in heart disease. The negative or neutral outcome of clinical trials on hormone replacement therapy provides clear evidence that the role of female sex hormones in the cardiovascular system is more complex than previously thought. In particular, the function of estrogens can not be understood without detailed knowledge on the specific function of both estrogen receptor subtypes in the heart and in the vasculature. In here, we review recent studies on subtype selective ERalpha and ERbeta agonists in different animal models of hypertension, cardiac hypertrophy and vascular inflammation. The results indicate that the activation of specific ER subtypes confers specific as well as redundant protective effects in hypertensive heart disease that might ultimately translate into novel treatment options for hypertensive heart disease.

心血管疾病发展中的性别差异提示雌激素在心脏病中的保护功能。激素替代疗法临床试验的负面或中性结果提供了明确的证据,表明女性性激素在心血管系统中的作用比以前认为的要复杂得多。特别是,如果不详细了解雌激素受体亚型在心脏和脉管系统中的具体功能,就无法了解雌激素的功能。本文综述了近年来在高血压、心肌肥厚和血管炎症的不同动物模型中,亚型选择性erα和erβ激动剂的研究进展。结果表明,特定内质网亚型的激活对高血压心脏病具有特异性和冗余的保护作用,最终可能转化为高血压心脏病的新治疗选择。
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引用次数: 3
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