NR4A孤儿核受体亚家族与动脉粥样硬化

核受体家族是一组能在生物体内调控发育、代谢、炎症、免疫等多种生物作用的转录因子。NR4A孤儿核受体亚家族由高度同源的3种受体：Nur77、Nurr1和NOR1组成。这些进化上保守而又古老的受体可被环境中的刺激信号快速诱导,作为非配体依赖的转录因子和早期反应基因行使功能。早期研究发现NR4A在调控分化、增殖以及凋亡上起关键作用。近年发现3种NR4A受体在动脉粥样硬化病变中均有表达并被认为是在动脉粥样硬化中调节基因表达的关键转录因子之一。     

核因子-κB与细胞凋亡关系的研究进展

核因子-κB是一类具有多向转录调节作用的核蛋白因子,存在于多种组织的多种细胞中,具有广泛的生物学活性,激活后参与许多基因的转录调控,在感染、炎症反应、氧化应激、细胞增生、细胞凋亡等过程中发挥作用.近年的研究表明NF-κB与细胞凋亡的关系密切,其参与多种凋亡相关基因的转录调控,在肿瘤的发生、发展过程中发挥重要作用.许多高表达NF-κB的细胞表现出对放疗、化疗、细胞因子介导的凋亡的抵抗作用,而现在又发现NF-κB具有促进细胞凋亡的作用.因而NF-κB与细胞凋亡存在双向调节关系:既可抑制细胞凋亡,也可促进细胞凋亡.是抑制凋亡,还是促进凋亡依赖于细胞类型和刺激因素的不同,但具体机制还不十分清楚.本文对其与细胞凋亡关系的研究作一综述,同时也为进一步改善肿瘤的有效治疗提供理论基础.     

动脉粥样硬化药物治疗的新靶点——核受体Nur77和类视黄醇X受体

核受体(nuclear receptor,NR)是一类在生物体内广泛分布、配体依赖的转录因子,其成员众多,构成了一个大家族,可分为4大类:类固醇激素受体、甲状腺激素和维生素D受体、孤儿核受体(orphannuclear receptors,ONR)及可被代谢中间产物激活的受体。NR与相应的配体及其辅调节因子相互作用,调控基因的协调表达,从而在机体的生长发育、新陈代谢、细胞分化和凋亡、免疫反应及体内许多生理过程中发挥重要作用[1]。     

过氧化物酶体增殖物激活受体γ与胃肠肿瘤研究进展

过氧化物酶体增殖物激活受体(PPAR)γ属于核激素受体超家族中的一员,它在调控细胞的生长、分化及凋亡等方面起重要作用。配体激活的PPARγ可抑制肿瘤细胞的生长和转移,促进肿瘤细胞分化和凋亡。此文就PPARγ与胃肠肿瘤的研究进展作一综述。     

Twist基因在非小细胞肺癌中的研究进展

Twist作为碱性螺旋-环-螺旋转录因子的家族成员,在胚胎发育过程中通过转录激活或抑制下游靶基因对细胞的迁移和分化发挥重要的调节作用.Twist基因在多种肿瘤中存在高表达,参与多种信号通路及肿瘤上皮-间质转化的调控,与肿瘤的发生、侵袭转移、血管生成、凋亡抵抗及肿瘤细胞耐药等密切相关,是多种肿瘤的不良预后因子.本文对Twist基因在非小细胞肺癌发生发展、侵袭转移及肿瘤细胞耐药等方面的研究进展作一综述.     

孤儿核受体Nur77与肺部疾病

Nur77作为NR4A孤儿核受体超家族的一员,可被多种激素、炎症反应和生长因子诱导表达,具有复杂的生物学功能,参与细胞的增殖、分化和凋亡过程.其中值得注意的是Nur77可通过由细胞核向细胞质移位介导一种新的细胞凋亡机制.大量研究表明Nur77与多种肺部疾病发病机制关系密切,如呼吸机过度通气引发的肺部炎症性损伤,镉中毒诱发的肺组织细胞凋亡和肺动脉高压血管平滑肌细胞增殖的负反馈调节机制等.此外,Nur77还与肺癌的发生发展有关,同时也参与维甲酸的抗肺癌机制.因此,本文就Nur77及其与肺部疾病的关系作一综述.     

孤儿核受体NR4A亚家族在血管细胞中的作用

在过去的几年里，发现了参与动脉粥样硬化（AS）的新基因，其中包括不同的核受体（NR）:过氧化物酶体增殖蛋白激酶受体（PPAR），RXR，RAR。NR乃一个大家族，是配体激活的转录因子，调控复杂的基因程序，涉及发育的几乎所有领域并在生理学中扮演重要角色。现就该NR亚家族在血管细胞中的功能作一介绍。     

Toll样受体，核因子-κB与肿瘤

Toll样受体（TLRs）是新近发现的存在于哺乳动物细胞表面，在天然免疫中发挥重要作用的一种细胞跨膜蛋白受体，亦是病原模式识别受体之一。核因子-κB（NF-κB）是广泛存在于哺乳动物细胞中的一种重要转录调控因子，与多种基因启动子中含有的κB序列结合，发挥转录因子作用，激活多种与细胞生长或凋亡相关的细胞因子转录。TLRs通过对病原相关分子模式（PAMPs）进行模式识别，经一系列信号传导分子最终激活NF-κB。近年来一些研究发现，多种肿瘤细胞表面表达TLRs,TLRs介导的信号通路可能参与肿瘤的发生、发展。TLRs／NF-κB通路在肿瘤生物学上的这种新功能为肿瘤的治疗提供了新的策略。     

孤儿核受体NR4A1表达对氧-葡萄糖剥夺诱导培养大鼠小脑颗粒神经元凋亡的影响

目的 探讨孤儿核受体NR4A1表达对氧-葡萄糖剥夺(oxy gen-glucose deprivation,OGD)诱导培养大鼠小脑颗粒神经元凋亡的影响及其可能机制.方法 大鼠小脑颗粒细胞原代培养7～8 d后给予OGD处理.应用四甲基偶氮唑蓝法检测细胞活性,流式细胞术检测细胞凋亡率,蛋白质印迹法检测NR4A1、胱天蛋白酶-3和细胞色素c蛋白表达,实时定量聚合酶链反应检测NR4A1mRNA表达.用编码NR4A1的慢病毒载体转染大鼠小脑颗粒神经元,并检测转染大鼠小脑颗粒神经元OGD后凋亡率以及细胞色素c和胱天蛋白酶-3表达.结果 随着OGD时间的延长,培养大鼠小脑颗粒神经元活性显著性降低,凋亡率显著性增高,NR4A1 mRNA和蛋白以及胱天蛋白酶-3和细胞色素c蛋白表达均显著性上调.转染NR4A1的大鼠小脑颗粒神经元过表达NR4A1,OGD后凋亡率显著性降低,胱天蛋白酶-3和细胞色素c蛋白表达显著性下调.结论 NR4A1过表达能通过下调胱天蛋白酶-3和细胞色素c表达减少OGD诱导的大鼠小脑颗粒神经元凋亡.     

配体依赖过氧化物酶体增殖活化受体γ通路在类风湿关节炎发病中的作用

过氧化物酶体增殖活化受体(peroxisome proliferator-activated receptors,PPAR)γ是配体依赖核转录因子超家族成员,是调控细胞及组织代谢的关键因子[1],参与脂肪细胞形成、分化,维持脂质代谢、血糖平衡,并参与调控细胞增生、分化、凋亡和炎症反应,在炎症和免疫反应中发挥重要作用,与肥胖、胰岛素抵抗、高血压、2型糖尿病、动脉粥样硬化、炎症性疾病等密切相关[2].近年研究表明配体依赖PPARγ通路亦参与调控类风湿关节炎(rheumatoid arthritis,RA)滑膜炎及关节骨破坏这两个关键的致病环节,本文对此进行综述.     

Effects of estrogens on striatal damage after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in male and female mice

Nurr1, NGFI-B, and Nor1 form the NR4A subfamily of orphan nuclear receptors. The NR4A receptors are immediate early genes that can be rapidly induced in response to a variety of stimuli in many cell types, for example, in osteoblasts. Nurr1 regulates the differentiation of osteoblasts and the expression of several osteoblastic genes. Fibroblast growth factor 8b (FGF-8b) regulates osteoblastic differentiation. We show here that treatment of preosteoblastic MC3T3-E1 cells or mouse bone marrow mesenchymal cells with FGF-8b induces the expression of NR4A receptors rapidly and in a dose-dependent manner. This induction involves mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI-3K), and protein kinase C (PKC) pathways. FGF-8b stimulates the proliferation of MC3T3-E1 cells. This effect is enhanced by overexpression of Nurr1 and NGFI-B whereas it is abolished by a dominant negative Nurr1 variant. In conclusion, FGF-8b induces the expression of NR4A orphan nuclear receptors that are involved in mediating the growth promoting effect of FGF-8b in osteoblasts.     

Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer

Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.     

Frequent loss of estrogen and progesterone receptors in human prostatic tumors determined by quantitative real-time PCR

Relative gene expression of the estrogen receptors (ER)-alpha (NR3A1) and ER-beta (NR3A2) along with progesterone receptors PR-A and PR-B (NR3C3) was determined by quantitative real-time PCR in a previously characterized panel of paired human prostate tumor and surrounding unaffected tissue (Prostate 54:275). In approximately half of these cases, a 10-fold or greater reduction in the relative mRNA levels of ER-beta but not ER-alpha was found in the cancer as compared to normal tissue, which was also observed with unpaired samples. Immunohistochemical staining for ER-beta and ER-alpha closely paralleled mRNA expression patterns for both receptors in paired samples. Reduced relative expressions of PR-B and total PR-A and PR-B isoforms were also observed in prostate tumor as compared to unaffected tissue, implying a potential role of PR in prostate tissue. The relative decrease in ER-beta is greater than that observed in prior studies, suggesting that paired samples more accurately reflect differences within individual cases. These findings favor the concept that ER-beta mediates anti-proliferative signals and its loss in prostatic tumor promotes proliferation of these cells.     

Regulation of calcium signaling in lung cancer

Lung cancer is the most common malignant tumor in the world. Calcium is a ubiquitous cellular signal, which is crucial in cancer. This review presents regulation of calcium signaling in lung cancer. Altered expression of specific Ca(2+) channels and Ca(2+)-binding proteins are characterizing features of lung cancer, which regulate cell signaling pathway leading to cell proliferation or apoptosis. Chemoresistance is frequent in lung cancer. Altered endoplasmic reticulum Ca(2+) homeostasis of lung cancer cell is correlated with drug resistance. Hypoxia has a vital role in tumor angiogenesis, metastasis, apoptosis. And Ca(2+) channels are open induced by hypoxia with the increase of Ca(2+) influx causing tumor growth.     

蛋白激酶C抑制剂联合顺铂治疗非小细胞肺癌的实验研究

目的 初步探讨蛋白激酶C(PKC)抑制剂白屈菜红碱(CH)与化疗药物顺铂联合应用在非小细胞肺癌(NSCLC)治疗中的作用及其可能的机制.方法 应用四甲基偶氮唑蓝试验及流式细胞术分别检测CH、顺铂以及CH与顺铂联用对人NSCLC细胞株A549增殖和凋亡的影响.用裸鼠移植瘤实验检测CH、顺铂以及CH与顺铂联用对A549细胞成瘤性的影响.应用人肺腺癌细胞株A549细胞构建裸鼠皮下移植瘤模型,用随机数字表法将24只倚瘤裸鼠分为CH组、顺铂组、CH+顺铂组及生理盐水对照组,每组5只,裸鼠分别腹腔注射CH、顺铂、CH+顺铂和生理盐水(共3周,顺铂及生理盐水每周注射1次,CH每周注射2次),观察移植瘤的生长情况.结果 CH可抑制NSCLC细胞株A549增殖,浓度增加其细胞毒作用亦增强,CH与顺铂联用呈协同或相加作用;CH组、顺铂组及CH+顺铂组A549细胞的凋亡率分别为(5.36±0.70)%、(5.23±0.55)%及(17.28±2.17)%,均高于对照组的(2.75±0.35)%(t=7.88,P＜0.05),CH+顺铂组A549细胞的凋亡率分别高于CH组及顺铂组(t=5.62,P＜0.05);裸鼠移植瘤体内实验结果表明,CH及顺铂均町抑制移植瘤的生长,CH+顺铂组的抑瘤率(80.5%)高于CH组(72.4%)及顺铂(64.3%)组(t=11.34,P＜0.01).结论 CH与顺铂联用对A549细胞及裸鼠移植瘤有显著的协同抗肿瘤作用,其作用机制可能是通过增强对A549细胞增殖的抑制以及诱导其凋亡而实现.