线粒体学与生物医学新前沿

近来大量研究证明,线粒体除了合成ATP能量之外还有多种极为重要新的细胞功能,包括生成活性氧,调节氧化还原电势和信号转导,调控基因表达和细胞凋亡等,并在生物的生长、发育、衰老、疾病、死亡以及生物进化等方面都有重要意义,成为当前生命科学和分子医学中一个新生长点和前沿。     

PD-L1在人子宫颈癌细胞异常表达并促T细胞凋亡

目的 探讨人子宫颈癌中负性协同刺激分子PD-L1的表达和它与肿瘤浸润淋巴细胞的关系以及PD-L1融合蛋白促宫颈癌患者外周血活化T细胞凋亡的作用.方法 采用免疫组化S-P法检测67例宫颈癌组织及20例正常宫颈组织中PD-L1的表达,分析PD-L1同临床病理特征的相关性,免疫荧光观察肿瘤浸润淋巴细胞数量,TUNEL法检测T细胞凋亡,体外实验将PD-L1融合蛋白细胞加入PHA刺激活化的宫颈癌患者外周血T细胞中共同培养,流式细胞术分析T细胞凋亡率和CD8+/CD4+T细胞比例.结论 正常子宫颈组织不表达PD-L1;宫颈癌组织中PD-L1的表达率为70％.宫颈癌PD-L1的表达与宫颈癌浸润深度相关(P＜0.05).PD-L1阳性病例肿瘤局部浸润淋巴细胞存在凋亡且CD8+T细胞数量明显减少;PD-L1融合蛋白组T细胞凋亡率明显高于抗PD-1组和空白对照组T细胞,分别为32.7％、18.3％和17.9％;CD8+T/CD4+T细胞的比值低于加入抗PD-1组和空白对照组,分别为0.864、0.894和0 907.结论 PD-L1在子宫颈癌中高表达且与肿瘤浸润程度及肿瘤浸润淋巴细胞数量减少有关,PD-L1能促进活化的T细胞尤其是CD8+T细胞的凋亡.     

生物耦合功能特性及其实现模式

生物在大自然优胜劣汰的法则下, 进化出与自身生长和生存环境高度适应的功能特性. 生物通过两个或两个以上不同部分的协同作用或不同因素的耦合作用有效地实现生物的各种功能, 充分展现其对生境的最佳适应性. 本文从仿生学角度, 分析了生物耦合功能、特性及其类别, 初步揭示了生物耦合功能实现的机制与模式, 最后, 展望了生物耦合功能仿生实现的工程技术前景     

CTGF在肺癌中的研究进展

结缔组织生长因子（CTGF／CCN2）属于即刻早期基因编码的CCN家族中的一员,参与正常细胞增殖、黏附、迁移、凋亡及新生血管形成,在创伤修复、纤维化疾病和肿瘤形成中也具有重要的作用。新近研究发现,CTGF在肺癌组织中表达较正常肺组织降低,与肺癌的发生、发展密切相关,被视为肺癌转移和预后的评价指标。本文简要介绍了CTGF的结构、功能及在其肺癌中的研究进展,以期为肺癌的临床治疗提供新的思路。     

美政府资助人类胚胎干细胞基础研究

美国国家卫生研究所已宣布,它将为三家研究机构提供 拨款,以资助它们进行人类胚胎干细胞的基础生物学研究。 胚胎干细胞能够分化形成人体所需的200多种细胞中的任何一种。利用干细胞的这一特性培育移植用细胞、组织或器官,在医疗上具有重要应用潜力。但美国国家卫生研究     

信号传导的研究对生命现象认识的推动作用

细胞内与细胞间的信号传导是生命现象的一种基本事件，它与生物的生长，发育，分化，遗传，学习，记等过程密切相关。疾病，衰老和死亡，作为生命现象的特殊形式或过程，其发生也是与信号传导始终密切相关联的。信号传导的相应的英文词为：ＳＩＧＮＡＬＩＮＧ或ＳＩＧＮＡＬ ＴＲＡＮＳＤＵＣＴＩＯＮ。     

肠型脂肪酸结合蛋白研究进展

肠型脂肪酸结合蛋白（I-FABP,FABP2）是脂肪酸结合蛋白超家族中的重要成员,主要参与机体对脂肪酸的吸收、转运、以及在细胞器内的再分布及利用。近年研究表明,FABP2与代谢性疾病、炎症性疾病、肠组织缺血损伤等密切相关,不但是肠组织损伤的敏感性标志,而且可以作为炎症严重程度的评价指标,并可能成为某些代谢性疾病的药物治疗靶点。     

器官芯片的制备及生物医学工程应用

器官芯片是在体外构建疾病(或正常)模型的一种新兴技术,近几年受到科研工作者和医务人员的广泛关注.相比构建模型的传统方法,具有便携性、高通量、可模拟在体微环境等优势,在研究疾病的发病机理、筛选药物等方面有着广阔的应用前景.本文介绍了器官芯片的发展历程,综述了器官芯片的主要结构及材料,通过分析现有器官芯片的结构,认为高度集...     

枸杞多糖对人肺腺癌 A549细胞增殖和凋亡的影响

目的探讨枸杞多糖(LBP)对体外培养的人肺腺癌细胞 A549的增殖抑制作用及其可能的作用机制.方法用不同浓度的LBP处理 A549细胞,MTT法检测24、48、72h时间点 LBP对 A549细胞的生长抑制率,实验设为对照组和实验组(1/2IC50作用48小时),MTT法绘制生长曲线、细胞计数计算倍增时间、流式细胞仪检测凋亡率及其细胞周期、RT PCR检测 SurvivinmRNA的变化、Westernblot检测 CyclinB1蛋白的变化,transwell体外侵袭实验观察药物对细胞体外侵袭的影响.结果 MTT显示不同浓度的LBP均能明显抑制 A549细胞的增殖且成剂量 效应关系,实验组细胞的倍增时间、凋亡率与对照组相比,均有统计学意义(P<0.05);LBP使细胞阻滞在 G2期,SurvivinmRNA表达和 CyclinB1蛋白的表达均降低,与对照组相比差异有显著性(P<0.05).结论 LBP可抑制 A549细胞的增殖,其机理可能与 LBP使 SurvivinmRNA表达下降引起细胞凋亡及 CyclinB1蛋白的表达降低造成细胞周期阻滞及抑制细胞的侵袭能力有关     

前列腺素E2受体生化性质及功能的研究进展

前列腺素E2受体(EP)是一类G蛋白偶联受体,主要与前列腺素E2(PGE2)结合,在多种疾病的发生中发挥作用.研究发现EP在机体几乎所有系统,如心血管系统、呼吸系统、生殖系统、神经系统等的病理反应中发挥重要作用,甚至与肿瘤的发生也有关联.研究并掌握EP相关性质对于临床疾病的治疗有着重要的意义,在国际上已成为研究和报道的热点.本文简要综述了关于EP前沿的研究成果,以期为广大研究者提供借鉴,为进一步阐释EP作用机制以及相关研究乃至临床治疗提供新的思路.     

Apoptosis and aging: increased resistance to apoptosis enhances the aging process

Apoptosis is a vital component in the evolutionarily conserved host defense system. Apoptosis is the guardian of tissue integrity by removing unfit and injured cells without evoking inflammation. However, apoptosis seems to be a double-edged sword since during low-level chronic stress, such as in aging, increased resistance to apoptosis can lead to the survival of functionally deficient, post-mitotic cells with damaged housekeeping functions. Senescent cells are remarkably resistant to apoptosis, and several studies indicate that host defense mechanisms can enhance anti-apoptotic signaling, which subsequently induces a senescent, pro-inflammatory phenotype during the aging process. At the molecular level, age-related resistance to apoptosis involves (1) functional deficiency in p53 network, (2) increased activity in the NF-κB-IAP/JNK axis, and (3) changes in molecular chaperones, microRNAs, and epigenetic regulation. We will discuss the molecular basis of age-related resistance to apoptosis and emphasize that increased resistance could enhance the aging process.     

The nuclear γ-H2AX apoptotic ring: implications for cancers and autoimmune diseases

Apoptosis is a fundamental process for metazoan development. It is also relevant to the pathophysiology of immune diseases and cancers and to the outcome of cancer chemotherapies, as well as being a target for cancer therapies. Apoptosis involves intrinsic pathways typically initiated by DNA damaging agents and engaging mitochondria, and extrinsic pathways typically initiated by “death receptors” and their ligands TRAIL and TNF at the cell surface. Recently, we discovered the apoptotic ring, which microscopically looks like a nuclear annular staining early in apoptosis. This ring is, in three-dimensional space, a thick intranuclear shell consisting of epigenetic modifications including histone H2AX and DNA damage response (DDR) proteins. It excludes the DNA repair factors usually associated with γ-H2AX in the DDR nuclear foci. Here, we summarize our knowledge of the apoptotic ring, and discuss its biological and pathophysiological relevance, as well as its value as a potential pharmacodynamic biomarker for anticancer therapies.     

The nuclear envelope: emerging roles in development and disease

The chromosomes of eukaryotic cells are separated from the cytoplasm by the nuclear envelope. The nuclear envelope includes two riveted membranes, plus embedded pore complexes that mediate nuclear import and export. In this sense, the nuclear envelope is truly a border zone. However, the envelope also links directly to chromosomes, and anchors two major infrastructures--the nuclear lamina and Tpr filaments--to the nuclear perimeter. Proteins of the nuclear envelope mediate a variety of fundamental activities, including DNA replication, gene expression and silencing, chromatin organization, cell division, apoptosis, sperm nuclear remodeling, the behavior of pronuclei, cell fate determination, nuclear migration and cell polarity. Furthermore, mutations in nuclear lamins and lamin-binding proteins cause tissue-specific inherited diseases. This special issue of Cell and Molecular Life Sciences is devoted to recent major advances in the characterization of nuclear envelope proteins and their roles. We offer here an overview of the topics covered in this issue of CMLS, and also discuss the emerging recognition that the nuclear envelope is an organelle critical for a wide range of genetic and developmental activity in multicellular organisms.     

Non-caspase proteases: triggers or amplifiers of apoptosis?

Caspases are the most important effectors of apoptosis, the major form of programmed cell death (PCD) in multicellular organisms. This is best reflected by the appearance of serious development defects in mice deficient for caspase-8, -9, and -3. Meanwhile, caspase-independent PCD, mediated by other proteases or signaling components has been described in numerous publications. Although we do not doubt that such cell death exists, we propose that it has evolved later during evolution and is most likely not designed to execute, but to amplify and speed-up caspase-dependent cell death. This review shall provide evidence for such a concept.     

Recently discovered functions of glucosylceramides in plants and fungi

Glycosphingolipids are ubiquitous membrane lipids of eukaryotic organisms and a few bacteria. Whereas inositol-containing glycosphingolipids are restricted to plants and fungi, galactosylceramide occurs only in fungi and animals. In contrast, glucosylceramide is the unique glycosphingolipid which plants, fungi and animals have in common. However, there are specific differences in the structure of the ceramide backbone of glucosylceramides from these organisms. A comparison of the structural features and the biosynthesis of glucosylceramides from plants, fungi and animals will contribute to our understanding of their functions, which so far have been analysed mainly in animals. The availability of nearly all genes involved in the biosynthesis of glucosylceramides enables the specific manipulation of glycosphingolipid metabolism by techniques of forward and reverse genetics. Application of this approach to unicellular organisms like yeasts, multicellular filamentous fungi, as well as to complex organisms like plants will reveal common and different glucosylceramide functions in these organisms. These glycolipids play a role both in intracellular processes and in cell-to-cell interactions. These interactions may occur between cells of a multicellular organism or between cells of different species, as in host-pathogen interactions.     

Cytoskeleton responses in wound repair

Wound repair on the cellular and multicellular levels is essential to the survival of complex organisms. In order to avoid further damage, prevent infection, and restore normal function, cells and tissues must rapidly seal and remodel the wounded area. The cytoskeleton is an important component of wound repair in that it is needed for actomyosin contraction, recruitment of repair machineries, and cell migration. Recent use of model systems and high-resolution microscopy has provided new insight into molecular aspects of the cytoskeletal response during wound repair. Here we discuss the role of the cytoskeleton in single-cell, embryonic, and adult repair, as well as the striking resemblance of these processes to normal developmental events and many diseases.     

Apoptosis-the story so far...

The process of programmed cell death, or apoptosis, has become one of the most intensively studied topics in biological sciences in the last two decades. Apoptosis as a common and universal mechanism of cell death, distinguishable from necrosis, is now a widely accepted concept after the landmark paper by Kerr, Wyllie and Currie in the early seventies [1]. Different components of the death machinery in eukaryotes are discussed in this issue.     

Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases

Loss of functional cardiomyocytes is a major underlying mechanism for myocardial remodeling and heart diseases, due to the limited regenerative capacity of adult myocardium. Apoptosis, programmed necrosis, and autophagy contribute to loss of cardiac myocytes that control the balance of cardiac cell death and cell survival through multiple intricate signaling pathways. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in cell death of cardiovascular diseases, such as myocardial infarction, cardiac hypertrophy, and heart failure. In addition, based on the view that mitochondrial morphology is linked to three types of cell death, ncRNAs are able to regulate mitochondrial fission/fusion of cardiomyocytes by targeting genes involved in cell death pathways. This review focuses on recent progress regarding the complex relationship between apoptosis/necrosis/autophagy and ncRNAs in the context of myocardial cell death in response to stress. This review also provides insight into the treatment for heart diseases that will guide novel therapies in the future.     

Regulation of mitochondrial dynamics: convergences and divergences between yeast and vertebrates

In eukaryotic cells, the shape of mitochondria can be tuned to various physiological conditions by a balance of fusion and fission processes termed mitochondrial dynamics. Mitochondrial dynamics controls not only the morphology but also the function of mitochondria, and therefore is crucial in many aspects of a cell’s life. Consequently, dysfunction of mitochondrial dynamics has been implicated in a variety of human diseases including cancer. Several proteins important for mitochondrial fusion and fission have been discovered over the past decade. However, there is emerging evidence that there are as yet unidentified proteins important for these processes and that the fusion/fission machinery is not completely conserved between yeast and vertebrates. The recent characterization of several mammalian proteins important for the process that were not conserved in yeast, may indicate that the molecular mechanisms regulating and controlling the morphology and function of mitochondria are more elaborate and complex in vertebrates. This difference could possibly be a consequence of different needs in the different cell types of multicellular organisms. Here, we review recent advances in the field of mitochondrial dynamics. We highlight and discuss the mechanisms regulating recruitment of cytosolic Drp1 to the mitochondrial outer membrane by Fis1, Mff, and MIEF1 in mammals and the divergences in regulation of mitochondrial dynamics between yeast and vertebrates.     

Alternative splicing of Bcl-2-related genes: functional consequences and potential therapeutic applications

Apoptosis is a morphologically distinct form of cell death. It is executed and regulated by several groups of proteins. Bcl-2 family proteins are the main regulators of the apoptotic process acting either to inhibit or promote it. More than 20 members of the family have been identified so far and most have two or more isoforms. Alternative splicing is one of the major mechanisms providing proteomic complexity and functional diversification of the Bcl-2 family proteins. Pro- and anti-apoptotic Bcl-2 family members should function in harmony for the regulation of the apoptosis machinery, and their relative levels are critical for cell fate. Any mechanism breaking down this harmony by changing the relative levels of these antagonistic proteins could contribute to many diseases, including cancer and neurodegenerative disorders. Recent studies have shown that manipulation of the alternative splicing mechanisms could provide an opportunity to restore the proper balance of these regulator proteins. This review summarises current knowledge on the alternative splicing products of Bcl-2-related genes and modulation of splicing mechanisms as a potential therapeutic approach.Received 5 January 2004; received after revision 31 March 2004; accepted 6 April 2004