糖皮质激素受体及其在器官移植排斥反应中的作用

糖皮质激素GlucocordicoidsGC是一类具有重要生理及药理作用的甾体激素它除了调节三大营养物质的代谢外还参与机体的应激反应,调节免疫,在器官移植排斥反应的预防和治疗中有十分重要的地位。GC通过与其受体GR结合而发挥作用。本文将从受体及受体后的分子水平来讨论GC及GR的作用     

大鼠脑液压伤后磷脂酶A2与糖皮质激素受体的变化

目的：观察鼠脑外伤后局部组织、磷脂酶A2（PLA2）、糖皮质激素受体（GR）脑含水量变化。方法：应用鼠脑液压伤动物模型,采用GR放射配基结合分析法和PLA2快速测定法,测定伤侧鼠脑组织PLA2、GR和脑含水量变化。结果：伤后1hPLA2增加,12－24h形成高峰,随之缓慢减少直至72h。GR伤后6－12h明显减少,72h恢复至对照组70％水平。脑含水量伤后6h逐渐上升。结论：（1）创伤后脑缺血脑水肿是PLA2高张力的基础。（2）GR减少是PLA2抑制作用低下的重要因素,早期至72hPLA2与GR改变呈负相关,糖皮质激素（GC）对PLA2的抑制作用与GR水平密切相关。（3）早期大剂量应用地塞米松（DEX）对于降低PLA2,促进GR恢复,减轻脑水肿有显著疗效。     

糖皮质激素受体与新型糖皮质激素受体调节剂的研究进展

外源性糖皮质激素（GCs）在临床上广泛用于治疗炎症性疾病，其机制主要通过糖皮质激素受体（GR）发挥作用。但长期大量的使用GCs引起的不良反应使得GCs的使用受到限制，学术界正不断努力寻找更安全的GR调节剂。通过对GR的作用机制及长期使用GCs导致的不良反应进行介绍，同时，总结了近年来更安全的新型GR调节剂的研究进展，以期为新型GR配体的研发提供参考。     

糖皮质激素对人卵巢癌细胞系3AO增殖分化及对糖皮质激素受体表达的影响

目的：观察不同浓度地塞米松（Dex)对人卵巢癌细胞系（3AO）增殖及分化的影响及其对糖皮质激素受体（GR）的调节作用。方法：以不同浓度Dex处理3AO细胞,采用活细胞计数法观察细胞增殖,用氨基安替比林法测定碱性磷酸酶（AKP）活性;用酶联免疫法测定细胞标志抗原CA125水平的变化;用放射配体结合法测定GR的表达。结果：Dex对3AO细胞的增殖有抑制作用,同时伴有细胞形态的变化及AKP活性增高和CA125的表达下降。Dex对3AO细胞AKP活性的诱导作用可被RU486所阻断。在3AO细胞中存在糖皮质激素受体（GR）,Dex对GR结合活性有下调作用。结论：Dex对3AO细胞有增殖抑制和诱导分化作用,这种作用是通过GR来介导的。     

糖皮质激素及其受体与分娩启动的关系

目的 探讨糖皮质激素(GC)及其受体(GR)与分娩启动的关系.方法 40例是月剖宫产孕妇均分为临产后剖宫产(A)组及选择性剖宫产(B)组.孕妇均无妊娠合并症及并发症,孕期未使用GC.检测血清及羊水中GC水平.采用免疫组化和RT-PCR技术检测胎盘、胎膜组织GR-α和GR-β的表达.结果 A组血清GC水平明显高于B组(P＜0.05).两组胎盘组织几乎无GR表达;A组胎膜绀织中GR-β表达明显低于B组,GR-α/GR-β比例高于B组(P＜0.05).结论 临产后血清GC增加,胎膜上GR-β的表达降低,GR-α/GR-β增高,可能与分娩启动相关.     

慢性肾炎患者白细胞糖皮质激素受体测定及临床意义

本文用放射配体结合法测定２５例慢性肾炎患者治疗前、后外周血白细胞糖皮质激素受体（ＧＣＲ），用放免法测定其血浆糖皮质激素（ＧＣ）水平。结果与正常人差异无显著性。ＧＣＲ含量与ＧＣ的生物效应强度平行，某些患者有ＧＣ抵抗现象     

婴儿痉挛症患儿外周血单核细胞糖皮质激素受体α及βmRNA的表达及意义

目的 探讨糖皮质激素受体(GR)基因亚型表达在婴儿痉挛症(IS)患儿发病机制中的作用.方法 采用反转录聚合酶链反应(RT-PCR)检测IS患儿及正常对照儿童外周血单核细胞(PBMC)sGRα和βmRNA的表达,并分析其与IS患儿对糖皮质激素(GC)的疗效相关性.结果 30例患儿中,对GC治疗显效者19例,有效率为63.3％.无效者11例,占36.7％.IS组PBMCs GRαmRNA的表达水平低于正常对照组(P＜0.05);显效组GRα mRNA的表达水平与无效组比较差异无显著性(P＞0.05).IS组GRβ mRNA的表达水平与正常对照组无显著性差异(P＞0.05);显效组GRβ mRNA的表达水平与无效组无显著性差异(P＞0.05).结论 GRα mRNA的降低可能参与了IS的发病机制,未发现GC治疗IS疗效与GR mRNA表达水平之间的关系.     

糖皮质激素受体mRNA在儿童原发性肾病综合征中的表达意义

目的:探讨不同类型糖皮质激素(GC)对儿童原发性肾病综合征(PNS)患者糖皮质激素受体(GR)的影响。方法:正常儿童为对照组(N组)20例;55例初治PNS患儿随机分为泼尼松组(A组)17例,曲安西龙组(B组)20例,甲基泼尼松龙组(C组)18例,均给予相应GC治疗并在0、4及8周时取静脉血,通过半定量逆转录-聚合酶链反应(RT-PCR)检测外周血单个核细胞(PBMCs)中GRα和GRβ的mRNA表达水平。结果:未经GC治疗时PNS组GRα低于N组,GRβ高于N组,差异有统计学意义(P<0.05)。各组患儿经GC治疗后,GRα、GRβ指标组间、时间效应差异均有统计学意义(P<0.05或P<0.01);GRα指标时间与组间无交互作用(P>0.05),GRβ指标时间与组间存在交互作用(P<0.05)。55例PNS患儿中GC耐药组6例,敏感组49例,2组患儿经GC治疗后,GRα、GRβ指标组间、时间效应差异均有统计学意义(P<0.05或P<0.01);各组GRα指标时间与组间效应无交互作用(P>0.05),但GRβ指标时间与组间存在交互作用(P<0.05)。结论:在调节GR的表达水平上甲基泼尼松龙治疗PNS效果较好。     

COPD患者氧化应激与糖皮质激素受体水平的相关性

目的探讨不同时期COPD患者全身氧化应激水平的变化及其与糖皮质激素受体的相关性。方法测定40例急性加重期COPD患者（A组）、30例稳定期COPD患者（B组）、15例健康吸烟者（C组）血浆中MDA、GSH含量,SOD活性,及外周血有核细胞糖皮质激素受体水平。结果①A组、B组、C组间：①血浆MDA含量呈下降趋势;②血浆GSH含量、SOD活性呈上升趋势;②外周血有核细胞GR水平呈递增趋势;③GR与血SOD、MDA、GSH的相关系数分别为0.593、-0.561、0.663,P〈0.05。结论①COPD患者在全身水平存在氧化/抗氧化失衡,尤以急性加重期患者更为明显;②COPD患者氧化应激增加是导致外周血有核细胞糖皮质激素受体水平下降的原因之一。     

应激与衰老及相关神经系统疾患的研究进展

慢性应激或长期外源性应激激素皮质类固醇处理可以引起机体神经精神系统功能失调，导致衰老过程加速、学习记忆障碍、阿尔茨海默病、抑郁等疾患，其中应激激素对海马的选择性损伤是导致这些疾患发生的关键原因，表现为海马出现糖皮质激素（GC）受体下调、神经元萎缩甚至缺失等退化性变化，其机制可能与GC及继发性释放的兴奋性氨基酸（EAA）协同作用，最终使神经营养因子（如NGF）表达低下有关。本文就慢性应激诱发衰老及相关疾患机制的研究进行综述。     

激素性糖尿病发病机制研究进展

糖皮质激素在临床上使用广泛,但是其带来的不良反应却不可忽视,激素性糖尿病作为糖皮质激素使用常见的不良反应严重影响了激素的使用,糖皮质激素诱导胰岛素抵抗是目前公认的激素性糖尿病的发病机制,糖皮质激素可以通过抑制胰岛素信号通路,减少脂联素、骨钙素的分泌,增加5羟色胺（5-HT）分泌等多种途径诱导胰岛素的抵抗。此外激素还可以通过抑制胰高血糖素样肽-1（GLP-1）、葡萄糖依赖性促胰岛素多肽（GIP）的作用减少胰岛素的分泌造成糖代谢紊乱,进一步发展为激素性糖尿病。     

Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays

Synthetic glucocorticoids (GCs) have been widely used in the treatment of a broad range of inflammatory diseases, but their clinic use is limited by undesired side effects such as metabolic disorders, osteoporosis, skin and muscle atrophies, mood disorders and hypothalamic-pituitary-adrenal (HPA) axis suppression. Selective glucocorticoid receptor modulators (SGRMs) are expected to have promising anti-inflammatory efficacy but with fewer side effects caused by GCs. Here, we reported HT-15, a prospective SGRM discovered by structure-based virtual screening (VS) and bioassays. HT-15 can selectively act on the NF-κB/AP1-mediated transrepression function of glucocorticoid receptor (GR) and repress the expression of pro-inflammation cytokines (i.e., IL-1β, IL-6, COX-2, and CCL-2) as effectively as dexamethasone (Dex). Compared with Dex, HT-15 shows less transactivation potency that is associated with the main adverse effects of synthetic GCs, and no cross activities with other nuclear receptors. Furthermore, HT-15 exhibits very weak inhibition on the ratio of OPG/RANKL. Therefore, it may reduce the side effects induced by normal GCs. The bioactive compound HT-15 can serve as a starting point for the development of novel therapeutics for high dose or long-term anti-inflammatory treatment.     

炎症性疾病中糖皮质激素抵抗机制的研究进展

糖皮质激素因其强效的抗炎作用在临床上广泛使用,但是使用中发现在严重哮喘、慢性阻塞性肺病、急性淋巴细胞白血病、间质性肺病等炎症性疾病中有部分患者存在激素抵抗,限制了糖皮质激素的使用及预后。激素治疗患者存在糖皮质激素激素抵抗主要是由于糖皮质激素受体蛋白表达差异、基因多态性和基因突变、细胞转录因子的异常等引起的。不同疾病存在的糖皮质激素抵抗的机制也存在差异,对于哮喘和间质性肺病患者糖皮质激素抵抗主要是由于糖皮质受体基因多态性,急性淋巴细胞白血病患者主要是受体蛋白的表达差异,而糖皮质激素对于慢性阻塞性肺病患者可能无效。     

Recent advances in the discovery of 11beta-HSD1 inhibitors

Glucocorticoids are steroid hormones that regulate several physiological processes, and modulation of glucocorticoid action has been implicated as a potential treatment for a variety of diseases, including metabolic syndrome, inflammation and age-related cognitive decline. 11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is an enzyme that is involved in glucocorticoid regulation by catalyzing the conversion of inactive cortisone to its active form cortisol. Rodent models have demonstrated that the inhibition of 11b-HSD1 can improve components of metabolic syndrome, such as insulin resistance and dyslipidemia, and several laboratories are exploring small-molecule 11b-HSD1 inhibitors as a treatment for metabolic syndrome, as well as for type 2 diabetes. This review discusses progress in the development of key chemical classes of 11b-HSD1 inhibitors, with a focus on advanced compounds and recently disclosed structures.     

Tissue-specific glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)--a promising drug target for the treatment of metabolic syndrome

Obesity is closely associated with the Metabolic Syndrome, which includes insulin resistance, glucose intolerance, dyslipidemia and hypertension. The best predictor of these morbidities is not the total body fat mass but the quantity of visceral (e.g. omental, mesenteric) fat. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Indeed, patients with Cushing-s syndrome (a rare disease characterized by systemic glucocorticoid excess originating from the adrenal or pituitary tumors) or receiving glucocorticoid therapy develop reversible visceral fat obesity. The role of glucocorticoids in prevalent forms of human obesity, however, has remained obscure, because circulating glucocorticoid concentrations are not elevated in the majority of obese subjects. Glucocorticoid action on target tissue depends not only on circulating levels but also on intracellular concentration. Locally enhanced action of gluccorticoids in adipose tissue and skeletal muscle has been demonstrated in the Metabolic Syndrome. Evidence has accumulated that enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11beta-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. Furthermore, fat-specific 11beta-HSD1 transgenic mice, those have increased enzyme activity to a similar extent seen in obese humans, develop visceral obesity with insulin and leptin resistance, dyslipidemia and hypertension. In adipocytes, both antidiabetic PPARgamma agonists and LXRalpha agonists significantly reduce 11beta-HSD1 mRNA and enzyme activity, suggesting that suppression of 11beta-HSD1 in adipose tissue may be one of the mechanisms by which these drugs exert beneficial metabolic effects. Recently reported selective inhibitors of 11beta-HSD1 can ameliorate severe hyperglycemia in the genetically diabetic obese mice. In summary, 11beta-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome.     

The glucocorticoid receptor: a revisited target for toxins

The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy.     

From excess adiposity to insulin resistance: The role of free fatty acids

With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses. A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors. As a consequence, more free fatty acids (FFA) are released into the portal system. Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance. Excess of circulating FFA, TNF-α and other factors induces insulin resistance. FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serine-phosphorylation and tyrosine-dephosphorylation of IRS-1, causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling. Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes.     

Novel ligands of steroid hormone receptors

The development of novel ligands for steroid hormone receptors has become a burgeoning field with tremendous potential in numerous human therapies. Novel structures offer the advantage of greatly improved proprietary position, as well as the potential for highly selective compounds with fewer side effects and reduced metabolic liabilities. This opinion details the recent progress in the area of non-steroidal ligands of the principal steroid receptors. Published intellectual property associated with established areas such as oestrogen and androgen receptors have been updated, and new patents detailing ligands for progesterone, glucocorticoid and mineralocorticoid receptors are also discussed. A wide variety of structures are disclosed along with data in comparison with steroidal references. These novel structural families have strong potential, and these compounds will likely grow into complementary pharmacophores of defined function and enhanced therapeutic utility.