HIF-1α和HIF-2α在低氧性肺动脉高压中的不同作用研究进展

低氧诱导因子家族(HIFs)是机体应对低氧环境时的主要调节因子,它们与低氧引起的肺组织细胞损伤以及异常增殖有关,其中又以低氧诱导因子-1α(HIF-1α)和低氧诱导因子-2α(HIF-2α)的作用最为明显。该文主要对HIF-1α、HIF-2α在结构功能上的异同和在低氧性肺动脉高压中作用的研究现状作一综述。     

低氧诱导因子1α在急性肺损伤发病机制中的研究进展

低氧诱导因子1a（HIF-1a)能与β亚基结合形成二聚体复合物，调节下游基因的表达参与低氧适应、机体炎症反应、免疫调节等，在急性肺损伤中发挥重要作用。本文就NF-kB/HIF-1a、ROS/HIF-1a、腺苷A2/HIF-1a途径与急性肺损伤发病机制的研究进展进行综述。     

HIF SUMO化在高原低氧适应中的作用

低氧诱导因子-1是参与调节机体氧平衡的重要核转录因子。作为一种蛋白质,它的主要亚基HIF-1α受到多种翻译后的化学修饰,如泛素化、类泛素化等的影响,从而使其蛋白的稳定性、入核以及对下游基因的促转录活性受到调节。因此,研究HIF-1α翻译后的修饰,不仅有助于理解类似转录因子自身的调控,更能对HIF-1作为一个高原病的治疗靶标提供思路。     

低氧诱导因子-1α对细胞信号、细胞凋亡的影响及研究进展

低氧诱导因子-1（hypoxia—induciblefactor-1，HIF-1）是普遍存在于人和哺乳动物细胞内的缺氧应答调控因子，通过调控一系列与缺氧适应有关基因的表达以保持机体的氧稳态。HIF-1（尤其是HIF-1α）的表达水平与糖酵解、细胞周期阻滞、细胞生存与增殖、血管新生、血管舒缩、红细胞生成、肿瘤生长和转移以及肿瘤多药耐药等许多生命活动密切相关。多数肿瘤具有缺氧的微环境。HIF-1α对于肿瘤的效应是多方面的：HIF-1α在上游调控诸多与肿瘤发生密切相关的基因；肿瘤在低氧条件下选择更恶性的表型；增加细胞突变率；增加与血管新生和肿瘤侵袭有关的基因表达；低氧条件下细胞更具有耐药倾向。因此HIF-1α已经成为一个治疗肿瘤的新的关键性靶点。细胞信号、细胞凋亡在多细胞生物的个体发育、自稳平衡等生理以及肿瘤、炎症等病理过程中具有重要意义，理解HIF-1α对于细胞信号、细胞凋亡的调节，对于开发特异性的肿瘤治疗有着现实意义。现就HIF-1α对细胞信号、细胞凋亡的影响及研究进展作一综述。     

基于低氧微环境的小分子激活前药与HIF-1抑制剂研究进展

低氧是实体瘤普遍存在的特征,是肿瘤细胞增殖、转移、侵袭、产生放疗抗性的重要原因。因此,肿瘤缺氧被认为是肿瘤诊断与治疗的一个重要靶点。低氧激活前药可在缺氧微环境下通过电子还原靶向低氧区域的肿瘤细胞,产生并释放细胞毒性代谢产物,从而杀死肿瘤细胞。目前已报道的低氧激活前药主要包括硝基化合物、醌类、氮氧化物、金属配合物、偶氮化合物五大类。而低氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)也在肿瘤细胞的低氧存活与发展中扮演重要角色,抑制HIF-1可抑制其下游基因主导的肿瘤血管生成、转移、耐药等生存发展进程。当前,已有低氧激活前药与HIF-1抑制剂正处于临床试验阶段,并表现出良好的抗肿瘤活性,并有可能在未来的肿瘤诊断与治疗中发挥重要作用。     

乙酰唑胺对低氧大鼠肺组织的保护作用

目的研究低氧环境下乙酰唑胺对大鼠肺组织低氧诱导因子-1α(HIF-1α)、血红素氧化酶1(HO-1)、Caspase-3 mRNA表达的影响。方法采用常压低氧实验建立大鼠低氧模型,单次腹腔注射乙酰唑胺,分别在低氧0,3,6 h后取肺组织,观察肺组织病理学变化,并检测低氧相关基因HIF-1α、Caspase-3、HO-1 mRNA的表达。结果随着低氧时间的延长,模型组大鼠肺组织HIF-1α、Caspase-3和HO-1 mRNA表达均呈升高趋势;与模型组比较,乙酰唑胺组大鼠肺组织HIF-1α、Caspase-3 mRNA的表达明显降低,而HO-1mRNA的表达却更加升高。结论乙酰唑胺可通过降低HIF-1α、Caspase-3 mRNA的表达、增加HO-1 mRNA的表达,对低氧大鼠的肺组织起到保护作用。     

低氧诱导因子1信号通路调控低氧性肺动脉高压研究进展

肺动脉高压(pulmonary hypertension, PH)是一种罕见且严重的进行性疾病，在无左心、肺实质或血栓栓塞性疾病的情况下，由远端肺小动脉肥厚性重构增加肺动脉压和肺血管阻力所致。低氧诱导因子1(hypoxia-inducible factor-1, HIF-1)调控大量与PH发生发展相关的基因，诱导肺血管生成、细胞增殖和迁移以及细胞能量代谢和利用等。HIF-1是低氧性PH发病机制的重要组成部分，在驱动肺血管和右心室重构的病理过程中发挥重要作用。本文就HIF-1在低氧性PH中的作用和调控及其在靶向治疗PH中的潜力进行系统阐述。     

低氧诱导因子抑制药在抗肿瘤方面的研究进展

低氧诱导因子抑制药(YC-1)是一种小分子物质,最初研究主要集中在心血管系统,如抗血小板聚集、收缩血管等方面。研究发现,YC-1能抑制低氧诱导因子-1α(HIF-1α)的表达,从而开启YC-1在抗肿瘤方面的研究。YC-1抗肿瘤作用是多方面的,包括细胞周期抑制和诱导肿瘤细胞凋亡、抗血管生成、抗炎性反应及抑制金属蛋白酶类(MMPs)等。     

人参皂苷Rg3对低氧条件诱导的Hep-2细胞作用机制的初步研究

目的:研究人参皂苷Rg3对低氧条件下人喉鳞癌细胞Hep-2中低氧诱导因子-1α(HIF-1α)及血管内皮生长因子(VEGF)表达的影响.方法:通过体外低氧培养Hep-2人喉鳞癌细胞株,同时设立阴性对照组和阳性对照组(顺铂).人参皂苷Rg3作用24 h后,应用免疫细胞化学技术和流式细胞技术检测Hep-2细胞HIF-1α和VEGF蛋白表达的变化;应用RT-PCR技术检测HIF-1α和VEGF mRNA表达的变化.结果:在低氧条件下,Rg3组和顺铂对照组的Hep-2细胞中的HIF-1α和VEGF蛋白表达低于阴性对照组(P<0.05);Rg3组的HIF-1α和VEGF mRNA水平明显低于阴性对照组(P<0.05),顺铂组的HIF-1α和VEGFmRNA水平无明显变化.结论:低氧条件下,人参皂苷Rg3抑制Hep-2细胞中的HIF-1α和VEGF蛋白和mRNA的表达,这可能是Rg3抗肿瘤作用的机制之一.     

HIF-2α在肺动脉高压中的研究进展

肺动脉高压(pulmonary hypertension, PH)是一种以肺血管阻力进行性增加、闭塞性血管重构为特征的疾病。低氧诱导因子-2α(hypoxia inducible factor-2 alpha, HIF-2α)是参与肺血管细胞异常增殖和肺血管重构过程的关键因子之一。本文主要从细胞水平、整体水平综述HIF-2α在PH发生中的作用及其机制,并对目前以HIF-2α为靶点治疗肺动脉高压的候选方案进行介绍,以期为PH发病机制的研究及有效治疗方法的筛选提供参考。     

Downregulation of hypoxia-related responses by novel antitumor histone deacetylase inhibitors in MDAMB231 breast cancer cells

The tumor microenvironment is characterized by a poor circulation which results in the selection of neoplastic cells that can grow or survive under hypoxic conditions. The relationship between hypoxia and histone deacetylase (HDAC) inhibitors has been previously established. In this work we evaluated the effects of novel HDAC inhibitors (the natural peptide FR235222 and three tetrapeptide analogs) in the human breast cancer cell line MDAMB231, cultured under hypoxia (2% O2 ? 14 mmHg) or normoxia (20% O2 ? 140 mmHg). First, we found that the novel HDAC inhibitors reduced cell proliferation in MDAMB231 cells at an extent which was similar or even higher than that exerted by the classic HDAC inhibitors trichostatin-A and suberoylanilide hydroxamic acid. More interestingly, the antiproliferative effects of the novel HDAC inhibitors were, in general, significantly higher in hypoxic cells than in normoxic controls. Hypoxic MDAMB231 cells expressed high levels of the hypoxia-inducible factor (HIF)-1α and HIF-1α-related genes, such as vascular endothelial growth factor, Bcl-2/E1B 19 kDa interacting protein-3, glucose transporter-1, carbonic anhydrase IX, as determined by Western blot analysis and qRT-PCR. Finally, we found that HIF-1α and HIF-1α-related genes were significantly downregulated by FR235222 and analogs. In conclusion, the identification of novel effects exerted by the HDAC inhibitors, characterized by a strong efficacy in inhibiting the expression of HIF-1α and its related genes, may have important implications in the pharmacological control of several tumors, including breast cancer, characterized by the presence of hypoxia, angiogenesis and metabolic derangements.     

Icariside II from Epimedium koreanum inhibits hypoxia-inducible factor-1alpha in human osteosarcoma cells

Hypoxia-inducible factor-1 (HIF-1) is an important tumor-selective therapeutic target for solid tumors. Icariside II was isolated from Epimedium koreanum through successive fractionation with ethyl acetate, n-butanol, chloroform and hexane, followed by gel column chromatography. Icariside II attenuated the protein level of HIF-1alpha induced by hypoxia in human osteosarcoma (HOS) cells in a concentration-dependent manner, probably by enhancing the interaction rate between von Hippel-Lindau (VHL) and HIF-1alpha. Furthermore, Icariside II down-regulated the levels of HIF-inducible genes involved in angiogenesis, metastasis, and glucose metabolism, such as vascular endothelial growth factor (VEGF), urokinase plasminogen activator receptor (uPAR), adrenomedullin (ADM), matrix metalloproteinase 2 (MMP2), aldolase A, and enolase 1 in HOS cells. Icariside II also inhibited the migration rate in HOS cells and tube formation rate in human umbilical vein endothelium cells (HUVECs). Overall, these results suggest the potential use of Icariside II as a therapeutic candidate against various diseases that involve overexpression of HIF-1alpha.     

缺氧诱导因子1α与核因子κB在炎症缺氧环境中相互作用研究进展

慢性炎症是一系列临床难治疾病（包括心血管损伤、炎性肠病、癌症等）的病理学基础,而缺氧是慢性炎症引起组织损伤的重要病理生理学机制。缺氧诱导因子1α（hypoxia inducible factor-1α,HIF-1α）对组织适应缺氧具有调节作用。缺氧时,HIF-1α通过激活适应性转录反应以协调低氧组织中的氧供应和代谢活性,此过程涉及血管生成因子和血管活性物质等细胞因子的上调。调节免疫应答和细胞凋亡的核因子κB（nuclear factor-κB,NF-κB）具有与HIF-1α类似的功能,即在低氧条件下通过改变氧依赖性羟脯氨酸化酶活性来调节缺氧状态。此文讨论了在多种炎症性疾病中HIF-1α与NF-κB激活通路之间的相互作用,以及HIF-1α和NF-κB通路作为炎症性疾病治疗靶点的潜力。     

A quassinoid 6alpha-tigloyloxychaparrinone inhibits hypoxia-inducible factor-1 pathway by inhibition of eukaryotic translation initiation factor 4E phosphorylation

Hypoxia-inducible factor-1 (HIF-1) is the central mediator of cellular responses to low oxygen and vital to many aspects of cancer biology. In a search for HIF-1 inhibitors, we identified a quassinoid 6alpha-tigloyloxychaparrinone (TCN) as an inhibitor of HIF-1 activation from Ailantus altissima. We here demonstrated the effect of TCN on HIF-1 activation induced by hypoxia or CoCl(2). TCN showed the potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1alpha protein dose-dependently, whereas it did not affect the expressions of HIF-1beta and topoisomerase-I. Furthermore, TCN prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor (VEGF) and erythropoietin. Further analysis revealed that TCN strongly inhibited HIF-1alpha protein synthesis, without affecting the expression level of HIF-1alpha mRNA or degradation of HIF-1alpha protein. Moreover, the levels of phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2), mitogen-activated protein (MAP) kinase-interacting protein kinase-1 (MNK1) and eukaryotic initiation factor 4E (eIF4E) were significantly suppressed by the treatment of TCN, without changing the total levels of these proteins. Our data suggested that TCN may exhibit anticancer activity by inhibiting HIF-1alpha translation through the inhibition of eIF4E phosphorylation pathway and thus provide a novel mechanism for the anticancer activity of quassinoids. TCN could be a new HIF-1-targeted anticancer agent and be effective on mammalian target of rapamycin (mTOR)-targeted cancer therapy, in which mTOR inhibition increases eIF4E phosphorylation.