糖皮质激素受体结构与功能研究进展

糖皮质激素受体（GR）是核受体超家族中的重要成员,也是一种典型的激素依赖性转录调节因子。与激素结合后通过与靶基因糖皮质激素反应元件（GRE）相互作用。从而调节靶基因的表达。引起各种生物学效应。近年对人GR（hGR)的分子结构与生物学作用的研究有一定进展。     

核因子κB与糖皮质激素受体途径的拮抗作用

免疫反应是机体重要的生理过程,在免疫反应的分子调控中有两个重要的调节节子：核因子－κB（NF－κB）和糖皮质激素受体（GR）。NF－κB是免疫反应的激活子,而GR是免疫反应的抑制子,两者互为生理拮抗剂。NF－κB与GR相互拮抗机制可能有三：NF－κB和GR直接作用;NF－κB与GR竞争性地与有限的转录辅因子相互作用;GCs上调IκBα基因的表达。在功能上,NF－κB与GR也是有相互拮抗。NF－κB与GR拮抗作用的生理意义主要表现在两方面：NF－κB与GR的拮抗作用是机体保持内环境稳定的基本调节机制之一;NF－κB与GR的拮抗作用是GCs可能的抗炎机制。     

糖皮质激素受体减少在休克发生中的作用——一个新假说

用放射配体结合法和单抗测定结果表明,各种原因所致的应激在人、大鼠和狗的各脏器都引起糖皮质激素受体（GR）减少。给大鼠注射RU486阻断GR的实验结果证明,GR减少导致受体水平上的肾上腺皮质功能不全,从而使内毒素血症和失血大鼠的病变明显加重。由此,我们提出了休克发生的GR减少假说。关于应激时GR减少的机制,除了血浆糖皮质激素水平升高使GR减少之外;很可能还是热休克反应的一个表现。     

大鼠海马神经元内11β-HSD1和GR的共存及其意义

本研究旨在探讨糖皮质激素代谢酶-11β-羟基类固醇脱氢酶Ⅰ型（11β-HSD1）和糖皮质激素受体（GR）在大鼠海马神经元内的共同分布及其意义。用免疫细胞化学方法研究显示,海马神经元内不仅存在11β-HSD1免疫反应物质,还存在GR免疫反应物质,而且11β-HSD1与GR共存于同一个海马神经元内,用Western印迹杂交和薄层层析（TLC）方法研究表明,地塞米松（DEX）可以促进11β-HSD1与GR共存于同一个海马神经元内,用Western印迹杂交和薄层层析（TLG）方法研究表明,地塞米松（DEX）可以促进11β-HSD1蛋白表达及其酶的活性,利用11β-HSD1基因启动子区序列构建的以CAT酶为报告基因的pBLCAT6质粒转染PC12细胞,证实DEX能够促进CAT酶的表达。以上糖皮质激素的作用均可为GR受体阻断剂RU38486所阻断,结果提示;糖皮质激素（GC）与GR结合后,可以作用于与其共存的11β-HSD1基因启动子区,使11β-HSD1表达增加,从而使更多的GC代谢产物转化为有活性的GC,此机制可能与保证GC在海马神经元内与亲和力较低的GR结合有关。     

脊椎动物脑发育中糖皮质激素受体功能的研究进展

糖皮质激素受体（glucocorticoid reccptor,GR）广泛分布在脊椎动物中枢神经系统的多个组织区域中,而且结构及功能保守。在与激素结合的状态下,受体能够特异性地与靶基因的启动子结合影响基因的表达,或通过激活G蛋白偶联的信号途径引起神经递质的释放。外界环境刺激和外源糖皮质激素暴露都能改变GR在脑中的表达,并对神经的发育及功能产生影响,同时也对学习、记忆以及情感等高级神经活动和行为起到重要的作用。该文对脊椎动物糖皮质激素受体的结构和在脑中的分布,以及对神经发育和功能的影响及其中的分子机制的最新研究进展进行综述。     

糖皮质激素受体的研究进展

糖皮质激素受体(glucocorticoid receptor,GR)在机体的生命活动中具有重要作用.它是激素核受体家族中的一个主要成员,同时也是一种重要的核转录因子,转录调控多种基因表达.糖皮质激素作用的发挥必须与糖皮质激素受体结合.糖皮质激素受体不仅能参与机体应激反应,而且具有抗炎抗免疫作用和促细胞凋亡作用.目前已知的GR有三种类型,分别为α、β和P型,糖皮质激素受体在应激及GC抵抗中扮演着重要的角色.     

干扰素诱导蛋白P56与糖皮质激素受体的相互作用及对其转录活性的影响

糖皮质激素受体（GR）在严重创伤早期及全身性炎症反应中具有重要作用,为寻找与GR相互作用的新的蛋白质,以期调节GR的功能活性,应用酵母双杂交技术,以糖皮质激素受体配体结合区（GR-LBD）为诱饵蛋白,在人骨髓cDNA文库中筛选到42个阳性克隆.测序结果表明,其中一个克隆为干扰素诱导蛋白P56的大部分编码序列（221～1 642 bp,编码第53位至第478位氨基酸）.利用酵母双杂交实验再次验证P56与GR具有结合作用.并用PCR方法从酵母质粒中扩增出P56片段,进行GST-P56原核融合蛋白表达与纯化,及真核表达与免疫共沉淀.蛋白质结合实验表明,P56与GR-LBD在体内外有结合作用.CAT报告基因检测表明P56抑制GR的转录激活能力.     

长期运动应激对人白细胞糖皮质激素受体的影响

自从Selye提出全身适应症的学说以来的半个多世纪,有关应激的研究已相当广泛和深入。生理性和病理性应激时,肾上腺糖皮质激素(GC)分泌增多已众所周知。但要全面认识应激时的GC效应,还必须研究应激时靶细胞对GC的反应,而糖皮质激素受体(GR)是靶细胞对GC反应的决定性因素。已有不少报道表明,急性的生理、病理性应激时,GR减少,但有关慢性应激时GR的变化,迄今未见报道。我们以长期经历运动应激的专业运动员为对象,研究了慢性应激对GR的影响。     

几种核受体核浆穿梭与调控机制

许多核受体属于核转录因子,它们在胞浆合成后快速地转运入核,同时还能够在核浆之间穿梭以行使其特定的生物学功能。核受体的核浆转运主要通过核膜上的核孔复合体,依靠运输载体Importins和Exportins介导以及Ran-GDP提供能量。现对糖皮质激素受体（GR）、雄激素受体（AR）和雌激素受体（ER）等核受体在核浆穿梭转运和调控机制等方面的研究进展进行综述,同时也介绍我们实验室最近发现的视黄素X受体（RXR）核浆穿梭转运的新功能。     

在应激低反应期新生大鼠的海马和视交叉上核核受体-MR、GR表达的变化

目的搞清新生大鼠HPA轴改变在应激低反应时期（stress hyporesponsive period、SHRP））的核受体-MR（盐皮质激素受体）和GR（糖皮质激素受体）在海马和视交叉上核（SCN）的表达变化。从而进一步了解新生大鼠发育时间对MR和GR的影响。方法本研究应用免疫荧光技术研究了生后4d（PD4）和生后12d（PD12）的新生大鼠海马和SCN的MR、GR的表达。同时采用RIA方法测定了血清中皮质类固醇的浓度水平。结果RIA结果显示在应激低反应期给予刺激,血清皮质类固醇水平没有明显改变。在海马,PD12较PD4,MR-和GR-i mmunoreactivity在CA1区表达增强;在齿状回没有明显变化;在海马门（hilus）减弱。而在海马的CA3区和SCN中,PD4 GR-ir强烈表达,在PD12却下降。同时也发现在hilus细胞出现GR和nestin（巢蛋白）阳性表达的共存,但是却没有发现MR和nestin的共存。结论新生大鼠阶段,发育时间对MR和GR的影响因区域不同影响不同。GR和nestin（巢蛋白）的共存为探讨在新生大鼠阶段GR对神经干细胞的分化有否影响提供了实验资料。本研究也为进一步研究新生大鼠应激低反应状态下海马及SCN与低活性的HPA轴的关系提供了形态学依据。     

Triterpenes from Alisma orientalis act as androgen receptor agonists,progesterone receptor antagonists,and glucocorticoid receptor antagonists

Alisma orientalis, a well-known traditional medicine, exerts numerous pharmacological effects including anti-diabetes, anti-hepatitis, and anti-diuretics but its bioactivity is not fully clear. Androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) are three members of nuclear receptor superfamily that has been widely targeted for developing treatments for essential diseases including prostate cancer and breast cancer. In this study, two triterpenes, alisol M 23-acetate and alisol A 23-acetate from Alisma orientalis were determined whether they may act as androgen receptor (AR), progesterone receptor (PR), or glucocorticoid receptor (GR) modulators. Indeed, in the transient transfection reporter assays, alisol M 23-acetate and alisol A 23-acetate transactivated AR in dose-dependent manner, while they transrepressed the transactivation effects exerted by agonist-activated PR and GR. Through molecular modeling docking studies, they were shown to respectively interact with AR, PR, or GR ligand binding pocket fairly well. All these results indicate that alisol M 23-acetate and alisol A 23-acetate from Alisma orientalis might possess therapeutic effects through their modulation of AR, PR, and GR pathways.     

Function-regulating pharmacophores in a sulfonamide class of glucocorticoid receptor agonists

A class of α-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks.     

Heterocyclic glucocorticoid receptor modulators with a 2,2-dimethyl-3-phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core

A series of heterocyclic glucocorticoid receptor (GR) modulators with 2,2-dimethyl-3-phenyl-N-(thiazol or thiadiazol-2-yl)propanamide core are described. Structure–activity relationships suggest a combination of H-bond acceptor and a 4-fluorophenyl moiety as being important structural components contributing to the glucocorticoid receptor binding and functional activity for this series of GR modulators.     

Discovery and optimization of novel, non-steroidal glucocorticoid receptor modulators

A virtual screening approach comprising a 3-D similarity search based on known GR modulators was used to identify a novel series of non-steroidal glucocorticoid receptor (GR) antagonists. Optimization of the initial hit to provide potent compounds which exhibit good selectivity against other steroidal nuclear hormone receptors is described.     

In vitro modulatory effects of functionalized pyrimidines and piperidine derivatives on Aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) activities

The development of biologically active molecules based on molecular recognition is an attractive and challenging task in medicinal chemistry and the molecules that can activate/deactivate certain receptors are of great medical interest. In this contribution, selected pyrimidine/piperidine derivatives were synthesized and tested for the ability to activate/deactivate Aryl hydrocarbon receptor (AhR) and Glucocorticoid receptor (GR). Tested compounds are shown to activate the receptors but to much lesser extent than positive controls, dioxin and dexamethasone for Ahr and GR, respectively. However, some of them antagonized the positive controls action. Although further in vivo studies are needed to fully characterize the bioactivities of these compounds, the reported in vitro evidences demonstrate that they might be used as the modulators of AhR and GR activities.     

Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids

Glucocorticoids regulate numerous physiological processes and are mainstays in the treatment of inflammation, autoimmune disease, and cancer. The traditional view that glucocorticoids act through a single glucocorticoid receptor (GR) protein has changed in recent years with the discovery of a large cohort of receptor subtypes arising from alternative processing of the GR gene. These isoforms differ in their expression, gene regulatory, and functional profiles. Post-translational modification of these proteins further expands GR diversity. Here, we discuss the origin and molecular properties of the GR isoforms and their contribution to the sensitivity and specificity of the glucocorticoid response.