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Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts  [PDF]
Anna Király,Tímea Váradi,Tímea Hajdu,Ralph Rühl,Carlos M. Galmarini,János Sz?ll?si,Peter Nagy
Marine Drugs , 2013, DOI: 10.3390/md11124858
Abstract: The mechanism of action of elisidepsin (PM02734, Irvalec ?) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug’s binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin.
Lipid Rafts: Keys to Sperm Maturation, Fertilization, and Early Embryogenesis  [PDF]
Natsuko Kawano,Kaoru Yoshida,Kenji Miyado,Manabu Yoshida
Journal of Lipids , 2011, DOI: 10.1155/2011/264706
Abstract: Cell membranes are composed of many different lipids and protein receptors, which are important for regulating intracellular functions and cell signaling. To orchestrate these activities, the cell membrane is compartmentalized into microdomains that are stably or transiently formed. These compartments are called “lipid rafts”. In gamete cells that lack gene transcription, distribution of lipids and proteins on these lipid rafts is focused during changes in their structure and functions such as starting flagella movement and membrane fusion. In this paper, we describe the role of lipid rafts in gamete maturation, fertilization, and early embryogenesis. 1. Introduction Fertilization is the process in which 2 different gamete cells, a sperm and an oocyte, unite to produce a zygote. For fertilization to be successful, these gamete cells must differentiate and activate specific signaling pathways. For example, after sperm has differentiated completely, various extracellular factors such as epididymosomes and albumin alter the structure and function of the plasma membrane of the sperm. In addition, in terminally differentiated gamete cells, various sterols, sphingolipids, glycolipids, and glycosylphosphatidylinositol- (GPI-) anchored proteins are localized on cell membrane microdomains that are called lipid rafts. Lipid raft components are often examined by using detergent-resistant membrane domains (DRMs), which enrich these components so that their distributions and functions can be visualized on the cell surface by using putative raft markers [1, 2]. Since lipid rafts in gametes contain signaling proteins that regulate intracellular functions and cell signaling, these domains are important for sperm maturation, fertilization, and early embryogenesis [3, 4]. In this paper, we discuss the role of lipid rafts in reproductive biology. 2. Sperm Maturation and Membrane Modification Sperm are highly differentiated haploid cells with a head and a tail (flagellum) [5]. The head consists of a nucleus, an acrosome, and a small amount of cytoplasm, while the tail consists of a motility apparatus, mitochondria, an axoneme, and cytoskeletal structures. Although these structures are necessary for sperm to swim and fertilize oocytes, these structures are not functional after spermatogenesis until the plasma membrane is modified during epididymal transit (Figure 1(a)) [6]. In mammals, the sperm mature in the epididymis; however, in other animals, sperms mature in the spermiduct [7]. Previous studies have demonstrated that the modifications of the sperm plasma membrane that
Systemic Compensatory Response to Neonatal Estradiol Exposure Does Not Prevent Depletion of the Oocyte Pool in the Rat  [PDF]
Clémentine Chalmey, Franck Giton, Frédéric Chalmel, Jean Fiet, Bernard Jégou, Séverine Mazaud-Guittot
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082175
Abstract: The formation of ovarian follicles is a finely tuned process that takes place within a narrow time-window in rodents. Multiple factors and pathways have been proposed to contribute to the mechanisms triggering this process but the role of endocrine factors, especially estrogens, remains elusive. It is currently hypothesized that removal from the maternal hormonal environment permits follicle formation at birth. However, experimentally-induced maintenance of high 17β-estradiol (E2) levels leads to subtle, distinct, immediate effects on follicle formation and oocyte survival depending on the species and dose. In this study, we examined the immediate effects of neonatal E2 exposure from post-natal day (PND) 0 to PND2 on the whole organism and on ovarian follicle formation in rats. Measurements of plasma E2, estrone and their sulfate conjugates after E2 exposure showed that neonatal female rats rapidly acquire the capability to metabolize and clear excessive E2 levels. Concomitant modifications to the mRNA content of genes encoding selected E2 metabolism enzymes in the liver and the ovary in response to E2 exposure indicate that E2 may modify the neonatal maturation of these organs. In the liver, E2 treatment was associated with lower acquisition of the capability to metabolize E2. In the ovary, E2 depleted the oocyte pool in a dose dependent manner by PND3. In 10 μg/day E2-treated ovaries, apoptotic oocytes were observed in newly formed follicles in addition to areas of ovarian cord remodeling. At PND6, follicles without any visible oocyte were present and multi-oocyte follicles were not observed. Our study reveals a major species-difference. Indeed, neonatal exposure to E2 depletes the oocyte pool in the rat ovary, whereas in the mouse it is well known to increase oocyte survival.
TFIIB Co-Localizes and Interacts with α-Tubulin during Oocyte Meiosis in the Mouse and Depletion of TFIIB Causes Arrest of Subsequent Embryo Development  [PDF]
Hui Liu, Feng-Xia Yin, Chun-Ling Bai, Qi-Yuan Shen, Zhu-Ying Wei, Xin-Xin Li, Hao Liang, Shorgan Bou, Guang-Peng Li
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080039
Abstract: TFIIB (transcription factor IIB) is a transcription factor that provides a bridge between promoter-bound TFIID and RNA polymerase II, and it is a target of various transcriptional activator proteins that stimulate the pre-initiation complex assembly. The localization and/or attachment matrix of TFIIB in the cytoplast is not well understood. This study focuses on the function of TFIIB and its interrelationship with α-tubulins in a mouse model. During oocyte maturation TFIIB distributes throughout the entire nucleus of the germinal vesicle (GV). After progression to GV breakdown (GVBD), TFIIB and α-tubulin co-localize and accumulate in the vicinity of the condensed chromosomes. During the MII stage, the TFIIB signals are more concentrated at the equatorial plate and the kinetochores. Colcemid treatment of oocytes disrupts the microtubule (MT) system, although the TFIIB signals are still present with the altered MT state. Injection of oocytes with TFIIB antibodies and siRNAs causes abnormal spindle formation and irregular chromosome alignment. These findings suggest that TFIIB dissociates from the condensed chromatids and then tightly binds to microtubules from GVBD to the MII phase. The assembly and disassembly of TFIIB may very well be associated with and driven by microtubules. TFIIB maintains its contact with the α-tubulins and its co-localization forms a unique distribution pattern. Depletion of Tf2b in oocytes results in a significant decrease in TFIIB expression, although polar body extrusion does not appear to be affected. Knockdown of Tf2b dramatically affects subsequent embryo development with more than 85% of the embryos arrested at the 2-cell stage. These arrested embryos still maintain apparently normal morphology for at least 96h without any obvious degeneration. Analysis of the effects of TFIIB in somatic cells by co-transfection of BiFC plasmids pHA-Tf2b and pFlag-Tuba1α further confirms a direct interaction between TFIIB and α-tubulins.
Glycolytic Metabolites Are Critical Modulators of Oocyte Maturation and Viability  [PDF]
Lloyd Berger, Andrew Wilde
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077612
Abstract: The maturation of an oocyte into an egg is a key step in preparation for fertilization. In Xenopus, oocyte maturation is independent of transcription, being regulated at the level of translation and post-translational modifications of proteins. To identify factors involved in the maturation process we used two-dimensional differential gel electrophoresis to compare the proteome of oocytes and eggs. Protein abundance changes were observed in multiple cellular pathways during oocyte maturation. Most prominent was a general reduction in abundance of enzymes in the glycolytic pathway. Injection into oocytes of the glycolytic intermediates glyceraldehyde-3-phosphate, phosphoenolpyruvate and glucose-6-phosphate prevented oocyte maturation. Instead, these metabolites stimulated ROS production and subsequent apoptosis of the oocyte. In contrast, all other metabolites tested had no effect on oocyte maturation and did not induce apoptosis. These data suggest that a subset of glycolytic metabolites have the capacity to regulate oocyte viability.
Rafts - the current picture  [cached]
Micha? Grzybek,Agnieszka Kozubek,Patrycja Dubielecka,Aleksander F. Sikorski
Folia Histochemica et Cytobiologica , 2011, DOI: 10.5603/4622
Abstract: Although evidences that cell membrane contains microdomains are accumulating, the exact properties, diversity and levels of organization of small lipid patches built mainly of cholesterol and sphingomyelin, termed rafts, remain to be elucidated. Our understanding of the cell membrane is increasing with each new raft feature discovered. Nowadays rafts are suggested to act as sites of cell signaling events, to be a part of protein sorting machinery but also they are used by several pathogens as gates into the cells. It is still unclear how rafts are connected to the membrane skeleton and cytoskeleton and with how many different types of rafts are we actually dealing with. This review summarizes some of the most recent discoveries trying to make a view of the complex raft properties.
Oocyte Maturation Process and Affecting Factors  [cached]
Yurdun Kuyucu,Ozgul Tap
Arsiv Kaynak Tarama Dergisi , 2009,
Abstract: Normal female fertility depends on normally occuring oogenesis and maturation progress. Oogenesis and folliculogenesis are different progresses but occure in a harmony and at the same time. Oogenesis includes the events that take place matur ovum produced from primordial germ cells. Although folliculogenesis includes the stages primordial, primary, secondary, matur (Graaf) follicules in the influece of gonadotropines and local growth factors. During oocyte maturation meiosis is distrupted till the puberty. Under LH influence it starts again and first meiosis completes before ovulation. Oocyte maturation can be regarded as the process of coming metaphase II from prophase I of oocyte at the puberty and can be studied as nuclear and cytoplasmic maturation. Meiosis is completed when fertilization occures and zygot is formed. In this article oogenesis, folliculogenesis and oocyte maturation process are summerized with related studies and reiews are revised. [Archives Medical Review Journal 2009; 18(4.000): 227-240]
Rafts, Nanoparticles and Neural Disease  [PDF]
Vishal Gulati,Ron Wallace
Nanomaterials , 2012, DOI: 10.3390/nano2030217
Abstract: This review examines the role of membrane rafts in neural disease as a rationale for drug targeting utilizing lipid-based nanoparticles. The article begins with an overview of methodological issues involving the existence, sizes, and lifetimes of rafts, and then examines raft function in the etiologies of three major neural diseases—epilepsy, Parkinson’s disease, and Alzheimer’s disease—selected as promising candidates for raft-based therapeutics. Raft-targeting drug delivery systems involving liposomes and solid lipid nanoparticles are then examined in detail.
How Capillary Rafts Sink  [PDF]
S. Protiere,M. Abkarian,J. Aristoff,H. Stone
Physics , 2010,
Abstract: We present a fluid dynamics video showing how capillary rafts sink. Small objects trapped at an interface are very common in Nature (insects walking on water, ant rafts, bubbles or pollen at the water-air interface, membranes...) and are found in many multiphase industrial processes. Thanks to Archimedes principle we can easily predict whether an object sinks or floats. But what happens when several small particles are placed at an interface between two fluids. In this case surface tension also plays an important role. These particles self-assemble by capillarity and thus form what we call a "capillary raft". We show how such capillary rafts sink for varying sizes of particles and define how this parameter affects the sinking process.
Space Asymmetry Directs Preferential Sperm Entry in the Absence of Polarity in the Mouse Oocyte  [PDF]
Nami Motosugi,Jens-Erik Dietrich,Zbigniew Polanski,Davor Solter,Takashi Hiiragi
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0040135
Abstract: Knowledge about the mechanism that establishes embryonic polarity is fundamental in understanding mammalian development. In re-addressing several controversial claims, we recently proposed a model in which mouse embryonic polarity is not specified until the blastocyst stage. Before fertilization, the fully differentiated oocyte has been characterized as “polarized,” and we indeed observed that the sperm preferentially enters the polar body half. Here we show that preferential sperm entry is not due to an intrinsic polarity of the oocyte, since fertilization takes place uniformly when the zona pellucida is removed. We suggest that the term “asymmetry” denotes morphological differences, whereas “polarity” in addition implies developmental consequences. Thus, the mouse oocyte can be considered “asymmetric” but “non-polarized.” The penetration through the zona pellucida is also random, and a significant proportion of sperm binds to the oocyte membrane at a point distant from the zona penetration site. Time-lapse recordings confirmed that sperm swim around the perivitelline space before fertilization. Experimental enlargement of the perivitelline space in the non-polar body half increased the regional probability of fertilization. Based on these experiments, we propose a model in which the space asymmetry exerted by the first polar body and the zona pellucida directs sperm entry preferentially to the polar body half, with no need for oocyte polarity.
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