血管生成素在细胞凋亡调节中的作用机制（英文）

血管生成素(angiogenin,ANG)是一种核糖核酸酶;最近研究证明,作为一种抗凋亡因子,ANG参与各种抗细胞凋亡过程.ANG对内源性及外源性相关信号途径中的重要分子,如Bcl-2抗凋亡蛋白具有调节作用.此外,ANG对内、外部信号途径中的重要环节——p53依赖的凋亡也具有调节作用.     

血管生成素与炎症性疾病

血管生成素（angiogenin,ANG）是首个被发现来源于肿瘤的具有血管生成能力的蛋白质,但其在炎症中的作用机制尚未完全阐明. 研究表明, ANG在炎症性疾病的发生发展中起重要作用,并与炎症的调控密切相关,而慢性炎症正是导致肿瘤形成、生长和转移的因素之一. 本文以ANG与炎症的关联为基础,结合我们的工作阐述ANG在炎症性疾病特别是肿瘤中的作用和调控机制,明确ANG与蛋白质的相互作用、对信号通路的调控及核内作用是其发挥功能的重要机制,也可能是调控肿瘤炎症的重要机制. 因而,深入研究ANG与炎症的关系不仅可加深我们对ANG兼具抗炎、抗新生血管双重功能的认识,更可为炎症性疾病的治疗提供潜在的作用靶点和新的思路和方法.     

JNK介导的信号转导途径以及活性氧在其中的作用

JNK是一个受外界应激因素调控的信号分子,调节包括凋亡在内的一系列细胞内的反应,但目前越来越多的报道证实了JNK信号途径具有促凋亡和抗凋亡的双重功能,这种双重功能受到细胞类型、刺激物的种类、剂量和持续时间以及胞内其他信号途径的影响。活性氧作为一种常见的外界应激因素也部分参与了JNK信号途径的激活,对细胞的生死产生了重要的影响。本文将主要总结JNK介导的信号转导途径及活性氧在这一途径中所发挥的作用。     

细胞抗凋亡作用及其信号转导途径

细胞抗凋亡是生物机体为了适应环境变化,维持生理平衡的一种主动的自我保护行为。凋亡或抗凋亡均是多样性、偶联性、多途径的信号转导过程。细胞抗凋亡的信号转导是在内外生存因子的刺激下,激活P13K／AKT,ERK,NF—kB。NO等多种信号偶联途径,抑制细胞的凋亡。     

血管生长素与治疗性血管生成的研究进展

血管生长素(angiogenin,ANG) 是一种分泌性的单链碱性蛋白质,由123个氨基酸组成,分子量为14.4kD,广泛分布在人体中.ANG属于核糖核酸酶超家族中的一员,具有低核糖核酸酶活性.研究证实,ANG是一种有效的促血管生成因子,参与血管生成的各个阶段,是其它血管生成因子诱导新血管生成的枢纽,在缺血性疾病的治疗方面显示出巨大的潜能.本文对ANG在治疗性血管生成方面的研究进展作一综述.     

光对植物生物钟的调节

植物中的许多生理和生化反应都表现出一种内源的近似于24小时的昼夜节律现象,这些昼夜节律现象受生物钟的调节.高等植物的生物钟系统由输入途径、中央振荡器、输出途径以及一个阀门效应器组成.光信号通过光敏色素和隐花色素进入生物钟,使中央振荡器产生振荡,改变生物钟的输出信号,引起各种生理反应.本文综述了光信号对高等植物生物钟的调节作用和转导途径.     

细胞凋亡信号途径与免疫系统之间的串流

细胞凋亡作为一种生命体的主要细胞死亡方式,在清除多余或受感染细胞中发挥重要作用.尽管在组织或胚胎正常发育过程中,细胞凋亡诱导免痉反应比较温和,但在病毒感染或者对死亡受体(death receptor.DR)进行刺激时凋亡可以触发强烈的天然和获得性免疫反应.凋亡信号途径中的分子与免疫系统有着复杂的相互作用.本文综述了有关凋亡性死亡在诱导炎症,维持免疫系统动态平衡,促进免疫应答以及凋亡信号途径和免疫系统抗病毒机制相互关系等方面的研究成果,分析细胞凋亡所诱发免疫效应的机制.     

保护基因HO在组织细胞中的作用及其机制研究进展

血红素加氧酶(HO)是血红素降解过程中的限速酶,将血红素降解为胆绿素、CO和游离铁。HO有三种同工酶,HO—1为诱导型,而HO—2和HO—3呈结构性表达。HO—1是一种分布广泛的应激蛋白,具有抗炎、抗凋亡、抗增生效应。各组织细胞中HO—1受不同的应激而诱导,通过上调HO—1基因表达来防御由细胞因子诱导的氧化应激和凋亡。HO—1的细胞保护机制目前尚未明确,可能涉及CO、NO等信号分子,抗凋亡基因的表达,以及NF—κB与p38MAPK信号转导途径的介导。本文就HO在组织细胞中的作用及其可能的机制进行综述。     

血管生成素的结构与功能的研究进展

血管生成素(angiogenin,ANG)是一种有效的血管生成因子,是RNase超家族中惟一具有促血管生成能力的成员,也是目前已知的所有血管生成因子中独具核糖核酸酶活性的因子。ANG具有3个功能元件,即RNase活性中心、细胞表面结合位点及核定位序列。ANG参与血管生成的各个阶段,是其他血管生成因子诱导新血管生成的枢纽,其作用受到受体调节。在肿瘤的发生、发展及恶化过程中,ANG也具有非常重要的作用。通过对ANG促血管生成及细胞增殖机制的研究,为治疗肿瘤提供了多种靶点和途径。     

真菌中一氧化氮生物合成、降解及功能的研究进展

一氧化氮是一个有较高活性的自由基气体分子,无论在动植物还是微生物中,作为一个细胞内和细胞间的信号传导分子,它在许多的生理和病理过程中都发挥着双向的调节作用.研究发现真菌细胞可以合成一氧化氮,适当浓度的一氧化氮在真菌细胞内发挥多种重要的生物学功能,一旦一氧化氮过量累积,这个自由基分子会对细胞造成伤害,导致细胞凋亡.一氧化氮介导生成的环鸟苷酸(cGMP)作为一种重要的第二信使分子涉及到真菌细胞内多种信号途径的调控,调节了整个真菌类群的生长发育、形态发生、孢子形成和萌发、繁殖和细胞凋亡的过程,影响了真菌整个生命周期的生理活动.到目前为止,尽管一氧化氮在动植物中作用的机制得到了广泛的研究,但一氧化氮在真菌中的研究报道很有限.关于一氧化氮在真菌中的合成和降解途径,一氧化氮介导的信号传导机制的研究还不透彻,它在真菌细胞内的功能和毒理还有待于更深入的研究.     

Simple shifts in redox/thiol balance that perturb blood coagulation.

The biological chemistry that underlies and regulates the blood coagulation cascade is not fully understood. To begin to understand this, we performed clotting assays under various redox conditions. By varying the amount of oxidant and/or antioxidant in these assays, we observed that both the intrinsic/tenase complex and the extrinsic pathways were susceptible to shifts in the thiol/redox balance. We established a dichotomy where blood clotting via the intrinsic pathway was sensitive to oxidation whereas the tissue factor or extrinsic pathway was more sensitive to reduction. These differential inhibitory effects present a conceptual mechanism for selective modulation of the activities of clotting factors specific for the respective pathways. These data also suggest that blood clotting may be influenced by unidentified redox or thiol equilibria.     

Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner

Loss-of-function mutations in angiogenin (ANG) gene were discovered in amyotrophic lateral sclerosis (ALS) patients and ANG has been shown to prevent neuronal death both in vitro and in vivo. The neuro-protective activity of ANG was brought about partially by inhibiting stress-induced apoptosis. ANG attenuates both the extrinsic and the intrinsic apoptotic signals by activating Nf-κb-mediated cell survival pathway and Bcl-2-mediated anti-apoptotic pathway. Here we report that ANG inhibits nuclear translocation of apoptosis inducing factor (AIF), an important cell death-executing molecule known to play a dominant role in neurodegenerative diseases. ANG inhibits serum withdrawal-induced apoptosis by attenuating a series of Bcl-2-dependent events including caspase-3 activation, poly ADP-ribose polymerase-1 (PARP-1) cleavage, and AIF nuclear translocation.     

NFκB signaling regulates embryonic and adult neurogenesis

Both embryonic and adult neurogenesis involves the self-renewal/proliferation,survival,migration and lineage differentiation of neural stem/progenitor cells.Such dynamic process is tightly regulated by...     

Heparan sulfate regulates self-renewal and pluripotency of embryonic stem cells

Embryonic stem (ES) cell self-renewal and pluripotency are maintained by several signaling cascades and by expression of intrinsic factors, such as Oct3/4 and Nanog. The signaling cascades are activated by extrinsic factors, such as leukemia inhibitory factor, bone morphogenic protein, and Wnt. However, the mechanism that regulates extrinsic signaling in ES cells is unknown. Heparan sulfate (HS) chains are ubiquitously present as the cell surface proteoglycans and are known to play crucial roles in regulating several signaling pathways. Here we investigated whether HS chains on ES cells are involved in regulating signaling pathways that are important for the maintenance of ES cells. RNA interference-mediated knockdown of HS chain elongation inhibited mouse ES cell self-renewal and induced spontaneous differentiation of the cells into extraembryonic endoderm. Furthermore, autocrine/paracrine Wnt/beta-catenin signaling through HS chains was found to be required for the regulation of Nanog expression. We propose that HS chains are important for the extrinsic signaling required for mouse ES cell self-renewal and pluripotency.     

Hypothesis: A New Role for the Renin-Angiotensin System in Ureteric Bud Branching

Branching morphogenesis in the developing mammalian kidney involves growth and branching of the ureteric bud (UB), leading to formation of its daughter collecting ducts, calyces, pelvis and ureters. Even subtle defects in the efficiency and/or accuracy of this process have profound effects on the ultimate development of the kidney and result in congenital abnormalities of the kidney and urinary tract. This review summarizes current knowledge regarding a number of genes known to regulate UB development and emphasizes an emerging role for the renin-angiotensin system (RAS) in renal branching morphogenesis. Mutations in the genes encoding components of the RAS in mice cause renal papillary hypoplasia, hydronephrosis, and urinary concentrating defect. These findings imply that UB-derived epithelia are targets for angiotensin (ANG) II actions during metanephric kidney development. Here, it is proposed that papillary hypoplasia in RAS-deficient mice is secondary to an intrinsic defect in the development of the renal medulla. This hypothesis is based on the following observations: a) UB and surrounding stroma express angiotensinogen (AGT) and ANG II AT1 receptors in vivo; b) ANG II stimulates UB cell process extension, branching and cord formation in collagen gel cultures in vitro; and c) AT1 blockade inhibits ANG II-induced UB cell branching. It is further postulated that ANG II is a novel stroma-derived factor involved in stroma/UB cross-talk which regulates UB branching morphogenesis.     

Anaplasma phagocytophilum delays spontaneous human neutrophil apoptosis by modulation of multiple apoptotic pathways

Anaplasma phagocytophilum infects human neutrophils and inhibits the intrinsic pathway of spontaneous neutrophil apoptosis by protecting mitochondrial membrane integrity. In the present study, we investigated the molecular signalling of the extrinsic pathway and the interaction between the intrinsic and extrinsic pathways in the inhibition of spontaneous human neutrophil apoptosis by A. phagocytophilum. Cell surface Fas clustering during spontaneous neutrophil apoptosis was significantly blocked by A. phagocytophilum infection. The cleavage of pro-caspase 8, caspase 8 activation and the cleavage of Bid, which links the intrinsic and extrinsic pathways, in the extrinsic pathway of spontaneous neutrophil apoptosis were inhibited by A. phagocytophilum infection. Inhibition of this pathway was active as the cleavage of pro-caspase 8 and Bid in anti-Fas-induced neutrophil apoptosis was also inhibited by A. phagocytophilum infection. Likewise, A. phagocytophilum infection inhibited the pro-apoptotic Bax translocation to mitochondria, activation of caspase 9, the initiator caspase in the intrinsic pathway, and the degradation of a potent caspase inhibitor, X-chromosome-linked inhibitor of apoptosis protein (XIAP), during spontaneous neutrophil apoptosis. These data point to a novel mechanism induced by A. phagocytophilum involving both extrinsic and intrinsic pathways to ensure to delay the apoptosis of host neutrophils.     

The heat shock protein 27 (Hsp27) operates predominantly by blocking the mitochondrial-independent/extrinsic pathway of cellular apoptosis

Heat shock protein 27 (Hsp27) is a molecular chaperone protein which regulates cell apoptosis by interacting directly with the caspase activation components in the apoptotic pathways. With the assistance of the Tat protein transduction domain we directly delivered the Hsp27 into the myocardial cell line, H9c2 and demonstrate that this protein can reverse hypoxia-induced apoptosis of cells. In order to characterize the contribution of Hsp27 in blocking the two major apoptotic pathways operational within cells, we exposed H9c2 cells to staurosporine and cobalt chloride, agents that induce mitochondria-dependent (intrinsic) and -independent (extrinsic) pathways of apoptosis in cells respectively. The Tat-Hsp27 fusion protein showed a greater propensity to inhibit the effect induced by the cobalt chloride treatment. These data suggest that the Hsp27 predominantly exerts its protective effect by interfering with the components of the extrinsic pathway of apoptosis. These authors contributed equally to this work.     

Hypothesis: A New Role for the Renin-Angiotensin System in Ureteric Bud Branching

Branching morphogenesis in the developing mammalian kidney involves growth and branching of the ureteric bud (UB), leading to formation of its daughter collecting ducts, calyces, pelvis and ureters. Even subtle defects in the efficiency and/or accuracy of this process have profound effects on the ultimate development of the kidney and result in congenital abnormalities of the kidney and urinary tract. This review summarizes current knowledge regarding a number of genes known to regulate UB development and emphasizes an emerging role for the renin-angiotensin system (RAS) in renal branching morphogenesis. Mutations in the genes encoding components of the RAS in mice cause renal papillary hypoplasia, hydronephrosis, and urinary concentrating defect. These findings imply that UB-derived epithelia are targets for angiotensin (ANG) II actions during metanephric kidney development. Here, it is proposed that papillary hypoplasia in RAS-deficient mice is secondary to an intrinsic defect in the development of the renal medulla. This hypothesis is based on the following observations: (a) UB and surrounding stroma express angiotensinogen (AGT) and ANG II AT₁ receptors in vivo; (b) ANG II stimulates UB cell process extension, branching and cord formation in collagen gel cultures in vitro; and (c) AT₁ blockade inhibits ANG II-induced UB cell branching. It is further postulated that ANG II is a novel stroma-derived factor involved in stroma/UB cross-talk which regulates UB branching morphogenesis.Key Words: kidney development, branching morphogenesis, renin-angiotensin, stromal mesenchyme, ureteric bud     

Stress-induced apoptosis: Toward a symmetry with receptor-mediated cell death

Apoptosis is a form of programmed cell death executed by caspases activated along signalling pathways initiated by ligation of cell-surface death receptors ( extrinsic pathway ) or by perturbation of the mithocondrial membrane promoted by physical or chemical stress agents ( intrinsic pathway ). In metazoans, this evolutionary conserved, genetically controlled process has a role in a variety of physiological settings, as development, homeostasis of tissues and maintenance of the organism integrity. When deranged by impaired regulation or inappropriate activation apoptosis contributes to the pathogenesis of diseases as autoimmunity, cancer, restenosis, ischaemia, heart failure and neurodegenerative disorders. In this review we will present a survey of the stress-induced intrinsic, mithochondrial, pathway and, based on recent experimental data, we will propose a view compatible with an emergent conceptual symmetry between the two apoptogenic extrinsic and intrinsic pathways. Elements of symmetry present in both the apoptogenic signalling pathways include: early activation of initiator caspases (feed-forwarded by a direct or post-mitocondrial effector caspase-mediated amplification loop in some cell types) and mitochondrial membrane permeabilization with required release of antagonists of active caspase inhibitors (IAPs) in high-level IAPs-expressing cells and apoptosome-mediated amplification of the caspase cascade more or less needed in different cell types.     

Game and players: mitochondrial apoptosis and the therapeutic potential of ursodeoxycholic acid

Apoptosis represents a universal and exquisitely efficient cellular suicide pathway essential for a variety of normal biological processes ranging from embryonic development to ageing. In fact, tissue homeostasis is dependent on the perfect balance between positive and negative signals that determines the decision between life and death. Therefore, any imbalance can result in a wide range of pathologic disorders associated with unwanted apoptosis or cell growth. During the apoptotic process, the molecular players interact closely with each other in ways relevant to accelerate or interrupt the cellular death process. In addition, two major pathways of apoptosis activation have been recognized as the "intrinsic" mitochondrial pathway and the "extrinsic" death receptor pathway. Although these pathways act independently to initiate apoptosis, a delicate balance and cross-talk between the extrinsic and intrinsic pathways is thought to occur in many cell types. Interestingly, we have shown that ursodeoxycholic acid (UDCA), an endogenous hydrophilic bile acid, is a potent inhibitor of apoptosis by either stabilizing the mitochondrial membrane or modulating the expression of specific upstream targets. Herein, we review the main effectors involved in the death machinery, describe how they interact to regulate apoptosis, and discuss the main pathways that control cell death and survival. Further, we address multiple interesting targets as well as the potential application of UDCA as a therapeutic modality for apoptosis-related disorders.