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1.
Matthew E. Downs Amanda Buch Carlos Sierra Maria Eleni Karakatsani Shangshang Chen Elisa E. Konofagou Vincent P. Ferrera 《PloS one》2015,10(5)
Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500kHz, 200–400 kPa, 4–5μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4–20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of’ visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4–5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used. 相似文献
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Three major glycan fractions of 580 kDa (g580), 150 kDa (g150), and 2 kDa (g2) were isolated and purified from Lytechinus pictus sea urchin embryos at the mesenchyme blastula stage by gel filtration and high pressure liquid chromatography. Chemical analysis, by gas chromatography, revealed that g580 is highly sulfated and rich in N-acetylglucosamine, N-acetylgalactosamine, glucuronic acid, and fucose. The g150 fraction is less acidic than g580 and contains high amounts of amino sugars, xylose, and mannose. The g2 fraction is neutral, rich in N-acetylglucosamine, mannose, and galactose. The g580 and g150 fractions are resistant to glycosaminoglycan-degrading enzymes, indicating that they are distinct from the glycosaminoglycans. The g580 fraction resembles, with respect to chemical composition, a previously characterized 200 kDa sponge adhesion glycan (g200). The binding of the monoclonal antibody Block 2, which recognizes a repetitive epitope on g200, as well as of the anti-g580 polyclonal antibodies to both g580 and g200 indicated that these two glycans share similar antigenic determinants. The Fab fragments of the Block 2 antibody, which previously have been shown to inhibit cell adhesion in sponges, also blocked the reaggregation of dissociated sea urchin mesenchyme blastula cells. These results indicate that g580 carries a carbohydrate epitope, similar to the sponge adhesion epitope of g200, which is involved in sea urchin embryonal cell adhesion. 相似文献
4.
Michael E. Maragoudakis Eva Pipili-Synetos Eleni Sakkoula Dimitris Panagiotopoulos Nancy Craniti John M. Matsoukas 《Letters in Peptide Science》1996,3(4):227-232
Summary We have recently shown that thrombin promotes angiogenesis by a mechanism independent of fibrin formation. In the present paper, we investigated the effect of the thrombin-receptor-activating tetradecapeptide (TRAP1–14, S42FLLRNPNDKYEPF55) for its effects on angiogenesis in the chick chorioallantoic membrane (CAM) system of angiogenesis. A dose-dependent promotion of angiogenesis is evident with TRAP. In contrast, a thrombin-receptor-derived tripeptide analogue H-Phe-Pro-Arg-OH (FPR), which was designed based on the S42FLLR46 sequence, caused an inhibition of angiogenesis in the CAM, and when it was combined with TRAP it caused a complete reversal of the angiogenesis-promoting effect of TRAP. These results indicate that the proteolytic exposure of the receptor N-terminal tetradecapeptide by thrombin can activate the post-thrombotic events related to angiogenesis. These events can be modulated by constrained peptide analogues such as FPR. 相似文献
5.
Eleni Theodosiou Kateřina Purchartová Haralambos Stamatis Fragiskos Kolisis Vladimír Křen 《Phytochemistry Reviews》2014,13(1):1-18
Over the past years, great advances have been made on the development of novel delivery systems for bioactive natural compounds, in parallel to their structural modification via chemical, chemo-enzymatic and enzymatic methodologies. These approaches give rise to novel formulations and derivatives that often display advantages over the parental molecule, such as enhanced bioavailability and pharmacological activity, due to improved dissolution and stability. Silymarin components suffer from poor solubility in water and lipid media and their resorption in the intestine is rather limited. Moreover, silybin undergoes intensive Phase II metabolism and is rapidly excreted in bile and urine, leading to low therapeutic efficacy. This work aims to present the current status of available silymarin formulations, and to highlight successful efforts for the biotransformation of its constituent flavonolignans towards the synthesis of novel derivatives. Herein, various pharmaceutical formulations that aim at the bioavailability improvement of these fascinating phytochemicals, i.e., liposomes, phytosomes, self-microemulsifying drug delivery systems, solid dispersions systems, dripping pills, nanosuspensions, floating tablets, and micronization, are reviewed. Silybin (semi)synthetic derivatives prepared by chemical or enzymatic methods, such as fatty acid conjugates, silybin bishemisuccinate, silybin glycosides, silybin sulfates, silybinic acid, and 2,3-dehydrosilybin, are also discussed in detail. Additionally, this work attempts to direct the attention towards the pharmacological implications of optically pure silybin A and silybin B and their biotransformation reactions, both Phase I and II, in relation to bioavailability. 相似文献
6.
Mumtsidu E Makhov AM Roessle M Bathke A Tucker PA 《Journal of structural biology》2007,160(2):157-167
Bluetongue virus (BTV) non-structural protein 2 (NS2) belongs to a class of highly conserved proteins found in members of the orbivirus genus of the reoviridae. NS2 forms large multimeric complexes, localizes to cytoplasmic inclusion bodies in the infected cells and binds non-sequence specifically single-stranded RNA (ssRNA). Due to its ability to bind ssRNA, it has been suggested that the protein is involved in the selection and condensation of the BTV ssRNA segments prior to genome encapsidation. We have previously determined the crystal structure of the 177 amino acid N-terminal domain, sufficient for ssRNA binding ability of NS2, to 2.4A resolution. The C-terminal domain, as determined at low resolution using small-angle X-ray scattering, is an elongated dimer. This domain expressed in insect cells is phosphorylated at S249 and S259. Electron microscopy of the full-length protein shows a variety of species with the largest having a ring-like appearance. Based on the electron micrographs, the crystal structure of the N-terminal domain and the structure of the C-terminal domain reported here, we propose a model for a decamer of the full-length protein. This decamer changes conformation upon binding of a non-hydrolysable ATP analogue. 相似文献
7.
Eleni N. Tsakiri Gerasimos P. Sykiotis Issidora S. Papassideri Evangelos Terpos Meletios A. Dimopoulos Vassilis G. Gorgoulis Dirk Bohmann Ioannis P. Trougakos 《Aging cell》2013,12(5):802-813
The ubiquitin–proteasome system is central to the regulation of cellular proteostasis. Nevertheless, the impact of in vivo proteasome dysfunction on the proteostasis networks and the aging processes remains poorly understood. We found that RNAi‐mediated knockdown of 20S proteasome subunits in Drosophila melanogaster resulted in larval lethality. We therefore studied the molecular effects of proteasome dysfunction in adult flies by developing a model of dose‐dependent pharmacological proteasome inhibition. Impaired proteasome function promoted several ‘old‐age’ phenotypes and markedly reduced flies' lifespan. In young somatic tissues and in gonads of all ages, loss of proteasome activity induced higher expression levels and assembly rates of proteasome subunits. Proteasome dysfunction was signaled to the proteostasis network by reactive oxygen species that originated from malfunctioning mitochondria and triggered an Nrf2‐dependent upregulation of the proteasome subunits. RNAi‐mediated Nrf2 knockdown reduced proteasome activities, flies' resistance to stress, as well as longevity. Conversely, inducible activation of Nrf2 in transgenic flies upregulated basal proteasome expression and activity independently of age and conferred resistance to proteotoxic stress. Interestingly, prolonged Nrf2 overexpression reduced longevity, indicating that excessive activation of the proteostasis pathways can be detrimental. Our in vivo studies add new knowledge on the proteotoxic stress‐related regulation of the proteostasis networks in higher metazoans. Proteasome dysfunction triggers the activation of an Nrf2‐dependent tissue‐ and age‐specific regulatory circuit aiming to adjust the cellular proteasome activity according to temporal and/or spatial proteolytic demands. Prolonged deregulation of this proteostasis circuit accelerates aging. 相似文献
8.
Eleni Panousopoulou Richard A. Tyson Till Bretschneider Jeremy B.A. Green 《Developmental biology》2013
Convergent extension (CE) is a conserved morphogenetic movement that drives axial lengthening of the primary body axis and depends on the planar cell polarity (PCP) pathway. In Drosophila epithelia, a polarised subcellular accumulation of PCP core components, such as Dishevelled (Dvl) protein, is associated with PCP function. Dvl has long been thought to accumulate in the mediolateral protrusions in Xenopus chordamesoderm cells undergoing CE. Here we present a quantitative analysis of Dvl intracellular localisation in Xenopus chordamesoderm cells. We find that, surprisingly, accumulations previously observed at mediolateral protrusions of chordamesodermal cells are not protrusion-specific but reflect yolk-free cytoplasm and are quantitatively matched by the distribution of the cytoplasm-filling lineage marker dextran. However, separating cell cortex-associated from bulk Dvl signal reveals a statistical enrichment of Dvl in notochord–somite boundary-(NSB)-directed protrusions, which is dependent upon NSB proximity. Dvl puncta were also observed, but only upon elevated overexpression. These puncta showed no statistically significant spatial bias, in contrast to the strongly posteriorly-enriched GFP-Dvl puncta previously reported in zebrafish. We propose that Dvl distribution is more subtle and dynamic than previously appreciated and that in vertebrate mesoderm it reflects processes other than protrusion as such. 相似文献
9.
Eleni A. Charmpila Maximilian Wagner Bettina Reichenbacher 《Journal of fish biology》2021,98(5):1450-1455
Otolith morphology is a widely accepted tool for species identification in teleost fish, but whether this holds true for very small species remains to be explored. Here, the saccular otoliths of the cryptobenthic Mediterranean clingfish Gouania (Gobiesocidae) are described for the first time. The new data, although preliminary, indicate that otolith morphology and morphometry support the recognition of the recently differentiated five species of Gouania in the Mediterranean Sea. Furthermore, otoliths of phylogenetically closely related Gouania species resemble each other more than do those of the more distantly related species. 相似文献
10.
Alexandros E. Giakoustidis Kokona Koliakou Eleni Kaldrymidou Stavros Iliadis Nickolaos Antoniadis 《Free radical research》2013,47(2):180-188
Intestinal ischemia/reperfusion (I/R) produces reactive oxygen species (ROS) activating signal transduction and apoptosis. The aim of this study was to evaluate the effect of (?)-epigallocatechin-3-gallate (EGCG) administration in inhibition of apoptosis by attenuating the expression of NF-kB, c-Jun and caspace-3 in intestinal I/R. Thirty male wistar rats were used. Group A sham operation, B I/R, C I/R-EGCG 50 mg/kg ip. Intestinal ischemia was induced for 60 min by clamping the superior mesenteric artery. Malondialdehyde (MDA), myeloperoxidase (MPO), light histology, Fragment End Labelling of DNA (TUNEL), immunocytochemistry for NF-kB, c-Jun and caspace-3 analysis in intestinal specimens were performed 120 min after reperfusion. Apoptosis as indicated by TUNEL and Caspace-3, NF-kB and c-Jun was widely expressed in I/R group but only slightly expressed in EGCG treated groups. MDA and MPO showed a marked increase in the I/R group and a significant decrease in the EGCG treated group. Light histology showed preservation of architecture in the EGCG treated group. In conclusion, EGCG pre-treatment is likely to inhibit intestinal I/R-induced apoptosis by down-regulating the expression of NF-kB, c-Jun and caspase-3. 相似文献