HIF-1通路在低氧对成肌细胞增殖分化影响中的作用

氧是在环境中存在的并在发育过程中起作用的信号分子,调控着细胞的能量代谢、生长和分化。骨骼肌中存在着具有自我更新和分化为肌纤维能力的成肌细胞,出生后成肌细胞在骨骼肌的损伤修复和维持中起重要作用。尽管氧在几乎所有高级生命活动中具有重要作用,但有关氧水平对成肌细胞增殖和分化的影响的研究甚少。体内生理性和病理性微环境的氧浓度是处于低水平的,本文就低氧对成肌细胞增殖和分化的影响,以及HIF-1信号通路在其中的作用进行了综述。     

造血干细胞发育过程中的信号通路调控

血液系统是维持机体生命活动最重要的系统之一,为机体提供所需的氧气和营养物质,通过物质交换维持内环境的稳态,同时为机体提供免疫防御与保护。血细胞是血液的重要组成成分,机体中成熟血细胞类型起源于具有自我更新及分化潜能的多能成体干细胞—造血干细胞(hematopoietic stem cells,HSCs)。造血干细胞及各类血细胞产生、发育及成熟的过程称为造血过程,该过程开始于胚胎发育早期并贯穿整个生命过程,任一阶段出现异常都可能导致血液疾病的发生。因此,深入探究造血发育过程及其调控机制对于认识并治疗血液疾病至关重要。近年来,以小鼠(Mus musculus)和斑马鱼(Danio rerio)作为动物模型来研究造血发育取得了一系列的进展。其中,BMP、Notch和Wnt等信号通路对造血干细胞的命运决定和产生发挥了重要作用。本文对这些信号通路在小鼠和斑马鱼造血过程中的调控作用进行系统总结,以期能够完善造血发育过程的调控网络并为临床应用提供指导。     

HIF-1α信号通路在肿瘤细胞调控中的研究进展

缺氧诱导因子(HIF-1α)是肿瘤细胞生长过程中重要的调控因子,研究其作用机制有利于实现对肿瘤细胞增殖的抑制作用。HIF-1α可引起多种基因转录,使肿瘤细胞耐受低氧环境,进而使癌症患者在治疗过程中产生耐受反应,最终影响治疗效果,甚至放弃治疗。因此,以HIF-1α为靶点是治疗肿瘤的重要手段和方法。本文对HIF-1α的基本概况及其主要信号通路(PI3K通路、HSP90通路及MAPK通路)以及不同通路抑制剂(如LY294002、17AAG、PD98059、U0126、SB203580、SP600125等)进行综述,并对HIF-1α的应用前景进行展望。     

HIF-1alpha信号通路在肿瘤细胞调控中的研究进展

缺氧诱导因子（HIF-1alpha）是肿瘤细胞生长过程中重要的调控因子,研究其作用机制有利于实现对肿瘤细胞增殖的抑制作用。 HIF-1alpha可引起多种基因转录,使肿瘤细胞耐受低氧环境,进而使癌症患者在治疗过程中产生耐受反应,最终影响治疗效果,甚至 放弃治疗。因此,以HIF-1alpha为靶点是治疗肿瘤的重要手段和方法。本文对HIF-1alpha的基本概况及其主要信号通路（PI3K 通路、 HSP90 通路及MAPK通路）以及不同通路抑制剂（如LY294002、17AAG、PD98059、U0126、SB203580、SP600125 等）进行综述,并 对HIF-1alpha的应用前景进行展望。     

RELM调控信号通路在低氧与炎症中的作用研究进展

抵抗素样分子(resistin like molecule,RELM)家族是一类富含半胱氨酸的分泌蛋白,其结构在进化过程中十分保守,然而其分布却有着较大的种属和组织特异性。目前国内外对该蛋白家族的关注越来越多,该蛋白家族成员在低氧与炎症相关生理病理过程中起到不可忽视的作用,其在血管生长、平滑肌增殖、气道炎症、肠道免疫等方面的作用已有相关研究。本文就RELM家族成员的结构、分布特点、调控方式、下游信号通路和生物学功能,重点对其在人与鼠类的区别与联系以及该家族与低氧和炎症的关系作一综述。     

Neuregulin／Erb信号转导通路在神经发育中的作用

Neuregulins(NRG)是一在结构上相类似的多肽家族,它们由四个不同的基因编码。NRG有三种异构体（NRG1、2和3）。这些异构体在及脑内有高表达,包括发育中的脑和成熟的脑。这些异构体中,对NRG1研究最为广泛。NRG1对神经系统的发育有多种重要的调节作用。它能促进胶质细胞的生化和分化;也能调节小脑、颗粒细胞沿胶质细胞的迁移。在突触形成过程中,NRG1可诱导以下三种受体的表达：神经肌肉接头和中枢 神经系统内的乙酰胆碱受体的表达;小脑胶质细胞中NMDA受体的NR2C亚单位的表达;小脑胶质细胞中GABAA受体的表达。近年来的研究表明,NRG受体多分布于突触后膜致密区,提示NRG可能对突触的可塑性有重要的作用。本文综述了NRG的研究进展,特别对其功能及其信号转导机制有较多的讨论。     

低氧与神经干细胞

由于氧在能量代谢和内环境稳定中起重要调节作用,所以地球上绝大多数生命都离不开氧（YunZhong,2002）。作为重要的生理病理调节因素,氧浓度改变的影响可以贯穿整个生命过程：从胚胎发育到成体正常功能的维持,多种病变,衰老退变等。NSCs不仅存在于发育中的哺乳动物中枢神经系统中,而且也存在于几乎所有成年哺乳动物,包括人类的神经系统中。     

Notch信号转导通路对神经干细胞的调控

神经干细胞增殖、分化机制研究为神经系统疾病治疗提供了新的途径,具有巨大的潜在应用价值和理论研究意义。已发现Notch信号对神经干细胞的维持和抑制分化发挥着决定性作用,Notch信号由Notch受体、DSL(Delta／Serrate／LAG-2)配体,CSL(CBFl／Suppressor of Haidess(Su(H))／LAG-1)DNA结合蛋白和一些蛋白水解酶组成。本文主要综述了Notch信号通路及其在调控神经干细胞的增殖、分化中的作用。     

HIF-1在卵巢黄体发育过程中对血管新生的调控作用

在哺乳动物中,卵巢黄体（corpus luteum,CL）是由破裂排卵后的卵泡所形成的,也是血管增生比较激烈的地方。尤其是在卵巢黄体早期发育阶段,这种快速形成的致密毛细血管网可以确保产生激素的细胞获得氧气、营养和合成激素等所必要的前体,同时释放大量的激素用于早期妊娠的建立和维持。目前的研究已经表明,血管内皮生长因子（vascular endothel ial growth factor,VEGF）作为重要的促血管生成因子,在卵巢黄体发育过程中对血管增生具有至关重要的调节作用,而VEGF作为转录因子HIF－1的下游靶基因,受缺氧诱导因子HIF－1信号通路的调控。该文一方面对卵巢黄体发育过程中VEGF依赖性血管增生的调控机制进行概述,另一方面就转录因子H1F－1对VEGF的转录激活调控机制进行系统阐述,从而揭示HIF－1对卵巢黄体发育过程dgVEGF依赖性血管新生的调控作用,为进一步研究哺乳动物卵巢黄体发育过程中血管增生的分子调控机制提供坚实的理论基础。     

HIF-1调控低氧性肺动脉高压北大核心CSCD

低氧性肺动脉高压(hypoxia-induced pulmonary hypertension,HPH)是多种慢性病高原病发病的中心环节,严重影响疾病的病程和预后。其主要特点是低氧刺激下诱发过度的肺血管收缩反应和异常的肺血管结构重塑,导致慢性肺源性心脏病的发生。低氧诱导因子-1(hypoxia inducible factor-1,HIF-1)被认为是低氧环境下感受氧变化的重要转录调控因子,可调控多种低氧相关靶基因表达,影响肺血管重塑过程。本文就低氧下HIF-1在低氧性肺动脉高压形成中的研究进展做一综述。     

Notch信号通路对神经干细胞增殖分化的作用

神经干细胞作为一种具有自我更新能力和多向分化潜能的细胞,它的增殖和分化受到多种源于自身或外在、邻近或远程细胞信号通路的调控,各种细胞因子及胞间通讯在神经干细胞的增殖和分化中发挥着重要的作用。近年来的多种研究表明,Notch信号通路正是这样一种可以通过相邻细胞的配体与受体相互作用,从而传递信号,进一步发挥其生物学功能的重要信号通路。该通路参与了神经干细胞维持自我形态及向多种具有不同功能的神经细胞分化的过程．对于研究神经干细胞的增殖和分化具有巨大的意义。该文将就当前Notch信号通路对神经干细胞增殖分化影响的相关研究进行简要综述。     

Mild Hypoxia Enhances Proliferation and Multipotency of Human Neural Stem Cells

Background

Neural stem cells (NSCs) represent an optimal tool for studies and therapy of neurodegenerative diseases. We recently established a v-myc immortalized human NSC (IhNSC) line, which retains stem properties comparable to parental cells. Oxygen concentration is one of the most crucial environmental conditions for cell proliferation and differentiation both in vitro and in vivo. In the central nervous system, physiological concentrations of oxygen range from 0.55 to 8% oxygen. In particular, in the in the subventricular zone niche area, it''s estimated to be 2.5 to 3%.

Methodology/Principal Findings

We investigated in vitro the effects of 1, 2.5, 5, and 20% oxygen concentrations on IhNSCs both during proliferation and differentiation. The highest proliferation rate, evaluated through neurosphere formation assay, was obtained at 2.5 and 5% oxygen, while 1% oxygen was most noxious for cell survival. The differentiation assays showed that the percentages of β-tubIII+ or MAP2+ neuronal cells and of GalC+ oligodendrocytes were significantly higher at 2.5% compared with 1, 5, or 20% oxygen at 17 days in vitro. Mild hypoxia (2.5 to 5% oxygen) promoted differentiation into neuro-oligodendroglial progenitors as revealed by the higher percentage of MAP2+/Ki67+ and GalC+/Ki67+ residual proliferating progenitors, and enhanced the yield of GABAergic and slightly of glutamatergic neurons compared to 1% and 20% oxygen where a significant percentage of GFAP+/nestin+ cells were still present at 17 days of differentiation.

Conclusions/Significance

These findings raise the possibility that reduced oxygen levels occurring in neuronal disorders like cerebral ischemia transiently lead to NSC remaining in a state of quiescence. Conversely, mild hypoxia favors NSC proliferation and neuronal and oligodendroglial differentiation, thus providing an important advance and a useful tool for NSC-mediated therapy of ischemic stroke and neurodegenerative diseases like Parkinson''s disease, multiple sclerosis, and Alzheimer''s disease.     

缺氧诱导因子-1在病毒感染中的作用

缺氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)是一种由β亚单位和α亚单位组成的异二聚体转录因子,其表达产物参与细胞的许多生理过程。越来越多的研究提示HIF-1在病毒感染中发挥着重要作用。通过检索相关文献,对人病毒感染中HIF-1活性改变及其在病毒感染中的作用进行了综述,为研究HIF-1在病毒感染中的作用提供参考。     

Small ncRNA Expression and Regulation Under Hypoxia in Neural Progenitor Cells

Small non-coding RNA (ncRNA) plays critical roles in a large number of cellular processes, including neural development, cell survival and cell determination. Our previous work showed that low oxygen promoted the survival and proliferation of neural progenitor cells (NPCs) in vitro. In this study, we examine the expression and regulation of small ncRNAs in the hypoxia-driven proliferation of NPCs. The expression profiles of ncRNAs in NPCs under hypoxia were detected using microarray analysis. Results of significance analysis of microarrays (SAM) revealed that 15 small RNAs were up-regulated at least threefold and 11 were down-regulated under hypoxic conditions. The differentially expressed small ncRNAs were confirmed by quantitative RT-PCR, and miR-210 was observed to be highly expressed in NPCs under hypoxic conditions. Further study showed that hypoxia-inducible factor (HIF)-1α had a direct impact on the putative promoter regions of miR-210. From these results, we conclude that some small ncRNAs participate in the regulation of the proliferation of NPCs under hypoxia and that miR-210 is directly regulated by HIF-1α.     

BRCA-1 基因与神经干细胞

乳腺癌易感基因(Breast cancer susceptibility gene,Brca-1)是肿瘤抑制基因家族中的一员,它是乳腺癌特异性抑癌基因,1994年Miki等[1]采用定位克隆方法首次将Brca-1分离出来。Brca-1能防止细胞过快地或失去控制地生长和分化,在调节细胞进程、DNA损伤修复、细胞生长与凋亡及转录活化和抑制等多种生物学途径都发挥重要作用,Korhonen等2003年报道Brca-1基因可促进体外培养的大鼠来源的神经干细胞的增殖。     

A Novel Role for the Hypoxia Inducible Transcription Factor HIF-1alpha: Critical Regulation of Inflammatory Cell Function

No abstract available.     

不同类型神经细胞对低氧的敏感性研究*

Objective: In order to illustrate the hypoxia-induced changes of neural cells in inflammatory response, oxidative stress, and energy metabolism process and to compare the sensitivity of neural cells’ responses to hypoxia. Methods: Different types of neural cells (BV2, N9, Gl261, HT22) were treated with hypoxia (0.1% O₂, 5% CO₂) for 0-24 hours. Cell proliferation was detected by Cell Counting Kit-8 method and cell viability was assayed by CellTiter-Glo Luminescent Cell Viability Assay. Total RNA was extracted by Trizol reagent, and the inflammation, oxidative stress, and energy metabolism-related genes expression were measured by quantitative real-time PCR and Western blot. The ROS production was detected by flow cytometer with fluorescence probe. Results: Hypoxia stimulation decreased cell proliferation and cell viability. The hypoxia-induced changes of microglial cells (BV2 and N9) were mainly involved in inflammatory response and glucose metabolism process. The changes of astrocytes Gl261 and neural cell HT22 were mainly involved in glucose metabolism process. Hypoxia stimulation significantly increased oxidative stress in microglia and astrocytes. Conclusion: Different types of neural cells have different degrees of sensitivity in response to hypoxic stimulation. In terms of energy metabolism and inflammatory response, microglia are more sensitive to hypoxia treatment, which is manifested as a significant up-regulation of glycolytic enzymes and inflammation genes, whereas microglia and astrocytes are more sensitive to hypoxia treatment in terms of oxidative stress, which is indicated by their quick response and significant increase of ROS production.