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排序方式: 共有572条查询结果,搜索用时 15 毫秒
41.
André R. A. Marques Jan Aten Roelof Ottenhoff Cindy P. A. A. van Roomen Daniela Herrera Moro Nike Claessen María Fernanda Vinueza Veloz Kuikui Zhou Zhanmin Lin Mina Mirzaian Rolf G. Boot Chris I. De Zeeuw Herman S. Overkleeft Yildiz Yildiz Johannes M. F. G. Aerts 《PloS one》2015,10(8)
The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1
-/-) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1
-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1
-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1
-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC. 相似文献
42.
Mario Di Staso Giovanni Luca Gravina Luigi Zugaro Pierluigi Bonfili Lorenzo Gregori Pietro Franzese Francesco Marampon Francesca Vittorini Roberto Moro Vincenzo Tombolini Ernesto Di Cesare Carlo Masciocchi 《PloS one》2015,10(6)
Purpose
aim of this study was to identify outcomes in pain relief and quality of life in patients with a solitary painful osseous metastasis treated by radiotherapy, cryoablation or the combination using a propensity score matching study design.Materials and Methods
175 patients with painful bone metastases were included in the study. Twenty-five of them underwent a radiation course (20 Gy in five daily fractions) 15 days after the cryoablation. These subjects were retrospectively matched by propensity analysis with a group of subjects treated by radiotherapy (125 subjects) and with a group treated byCryoablation (25 subjects). The pain relief in terms of complete response, rate of subjects requiring analgesics after treatments and the changes in self-rated quality of life were measured. Informed consent was obtained from the subject and the study was approved by the local Ethical Committee.Results
An higher proportion of subjects treated by cryoablation (32%) or cryoablation followed by RT (72%;) experienced a complete response compared with patients treated by radiotherapy alone (11.2%). After Bonferroni correction strategy, the addition of radiotherapy to cryoablation significantly improved the rate of complete response compared with cryoablation alone (p = 0.011) and this paralleled with an improved self-rated quality of life. Seventeen subjects (13.6%) of patients in the radiotherapy group, 9 (36%) in the cryoablation group, and 19 (76)% in the cryoablation- radiotherapy group did not require narcotic medications.Conclusions
The addition of radiotherapy to cryoablation favorably impacts on perceived pain, with a favorable toxicity profile. However, our data should be interpreted with caution and could serve as a framework around which to design future trials. 相似文献43.
Flavia Serpieri Andre Inocencio Jose Marcelino de Oliveira Alécio A. PimentaJr. Angélica Garbuio Jorge Kalil Marcelo M. Brigido Ana Maria Moro 《Molecular biotechnology》2010,45(3):218-225
Two humanized monoclonal antibody constructs bearing the same variable regions of an anti-CD3 monoclonal antibody, whole IgG
and FvFc, were expressed in CHO cells. Random and site-specific integration were used resulting in similar expression levels.
The transfectants were selected with appropriate selection agent, and the surviving cells were plated in semi-solid medium
for capture with FITC-conjugated anti-human IG antibody and picked with the robotic ClonePix FL. Conditioned media from selected
clones were purified by affinity chromatography and characterized by SDS-PAGE, Western-blot, SEC-HPLC, and isoelectric focusing.
Binding to the target present in healthy human mononuclear cells was assessed by flow cytometry, as well as by competition
between the two constructs and the original murine monoclonal antibody. The humanized constructs were not able to dislodge
the murine antibody while the murine anti-CD3 antibody could dislodge around 20% of the FvFc or IgG humanized versions. Further
in vitro and in vivo pre-clinical analyses will be carried out to verify the ability of the humanized versions to demonstrate
the immunoregulatory profile required for a humanized anti-CD3 monoclonal antibody. 相似文献
44.
Enrico Moro Rosella Tomanin Adelaide Friso Nicola Modena Natascia Tiso Maurizio Scarpa Francesco Argenton 《Matrix biology》2010,29(1):43-50
Sulfated glycosaminoglycan chains of extracellular matrix and cell membrane-tethered proteoglycans exert specific cellular functions by interacting with a broad spectrum of morphogens and growth factors.In humans, a congenital impaired catabolism of sulfated glycosaminoglycans is associated with severe metabolic disorders. Here, we report on the identification and characterization of a zebrafish iduronate sulfatase orthologue. By knocking down its function with antisense morpholino oligos, we demonstrate that iduronate sulfatase plays a critical role during early vertebrate development and its downregulation may be responsible for severe developmental defects, including a misshapen trunk and abnormal craniofacial cartilages. We show that the altered cartilage patterning is mediated by depauperation of sox10-expressing neural crest cell precursors. Through the application of a transactivation reporter assay, we also provide a molecular proof that increased TGFβ (Transforming Growth Factor β) signalling is tightly associated with downregulation of iduronate sulfatase function. Our results provide an insight into the early biological impairments underlying the Hunter syndrome and suggest the use of zebrafish as a novel tool to better understand lysosomal storage disorder pathogenesis. 相似文献
45.
Seil M El Ouaaliti M Fontanils U Etxebarria IG Pochet S Dal Moro G Marino A Dehaye JP 《Purinergic signalling》2010,6(4):405-416
The response to ATP of peritoneal macrophages from wild-type (WT) and P2X7-invalidated (KO) mice was tested. Low concentrations (1–100 μM) of ATP transiently increased the intracellular concentration
of calcium ([Ca2+]i) in cells from both mice. The inhibition of the polyphosphoinositide-specific phospholipase C with U73122 inhibited this
response especially in WT mice suggesting that the responses coupled to P2Y receptors were potentiated by the expression of
P2X7 receptors. One millimolar ATP provoked a sustained increase in the [Ca2+]i only in WT mice. The response to 10 μM ATP was potentiated and prolonged by ivermectin in both mice. One millimolar ATP increased
the influx of extracellular calcium, decreased the intracellular concentration of potassium ([K+]i) and stimulated the secretion of interleukin-1β (IL-1β) only in cells from WT mice. Ten micromolar ATP in combination with
3 μM ivermectin reproduced these responses both in WT and KO mice. The secretion of IL-1β was also increased by nigericin
in WT mice and the secretory effect of a combination of ivermectin with ATP in KO mice was suppressed in a medium containing
a high concentration of potassium. In WT mice, 150 μM BzATP stimulated the uptake of YOPRO-1. Incubation of macrophages from
WT and KO mice with 10 μM ATP resulted in a small increase of YOPRO-1 uptake, which was potentiated by addition of 3 μM ivermectin.
The uptake of this dye was unaffected by pannexin-1 blockers. In conclusion, prolonged stimulation of P2X4 receptors by a combination of low concentrations of ATP plus ivermectin produced a sustained activation of the non-selective
cation channel coupled to this receptor. The ensuing variations of the [K+]i triggered the secretion of IL-1β. Pore formation was also triggered by activation of P2X4 receptors. Higher concentrations of ATP elicited similar responses after binding to P2X7 receptors. The expression of the P2X7 receptors was also coupled to a better response to P2Y receptors. 相似文献
46.
Polak J Moro C Bessière D Hejnova J Marquès MA Bajzova M Lafontan M Crampes F Berlan M Stich V 《Journal of lipid research》2007,48(10):2236-2246
The acute in vitro and in vivo effects of long-chain fatty acids (LCFAs) on the regulation of adrenergic lipolysis were investigated in human adipose tissue. The effect of a 2 h incubation, without or with LCFA (200 mumol/l), on basal and hormonally induced lipolysis was tested in vitro on isolated fat cells. The lipolytic response to epinephrine was enhanced by suppression of the antilipolytic alpha(2)-adrenergic effect. Then, healthy lean and obese male subjects performed a 45 min exercise bout at 50% of their heart rate reserve either after an overnight fast or 3 h after a high-fat meal (HFM: 95% fat, 5% carbohydrates). Subcutaneous adipose tissue lipolysis was measured by microdialysis in the presence or absence of an alpha-antagonist (phentolamine). In vivo, a HFM increased plasma levels of nonesterified fatty acids in lean and obese subjects. In both groups, the HFM did not alter hormonal responses to exercise. Under fasting conditions, the alpha(2)-adrenergic antilipolytic effect was more pronounced in obese than in lean subjects. The HFM totally suppressed the alpha(2)-adrenergic antilipolytic effect in lean and obese subjects during exercise. LCFAs per se, in vitro as well as in vivo, suppress alpha(2)-adrenergic-mediated antilipolysis in adipose tissue. LCFA-mediated suppression of antilipolytic pathways represents another mechanism whereby a high fat content in the diet might increase adipose tissue lipolysis. 相似文献
47.
48.
Salmonella spp. bacteria are responsible for some of the most important zoonoses worldwide. Because Dermanyssus gallinae (DeGeer) (Acari: Dermanyssidae) has been recently reported to be an experimental vector of Salmonella Enteritidis, it would be of benefit to evaluate the presence of this bacterium in mites. A molecular detection tool associating a simple filter-based DNA preparation with a specific 16S rDNA Salmonella sp. polymerase chain reaction (PCR) amplification was described. The limit of detection with this method was 2 x 10(4) bacteria per mite. To adapt this technique for large-scale studies, two sizes of mite pools were tested and a preliminary investigation was carried out on mites from 16 currently or previously contaminated farms. Mites sampled from one farm of each type were positive for Salmonella, suggesting that Dermanyssus could act as a reservoir between flocks. In further investigations, it will be necessary to carry out a large-scale study to assess the role of D. gallinae in the epidemiology of avian salmonellosis. 相似文献
49.
Bobba A Atlante A Moro L Calissano P Marra E 《Apoptosis : an international journal on programmed cell death》2007,12(9):1597-1610
The involvement and the role of nitric oxide (NO) as a signaling molecule in the course of neuronal apoptosis, whether unique
or modulated during the progression of the apoptotic program, has been investigated in a cellular system consisting of cerebellar
granule cells (CGCs) where apoptosis can be induced by lowering extracellular potassium. Several parameters involved in NO
signaling pathway, such as NO production, neuronal nitric oxide synthase (nNOS) expression, and cyclic GMP (cGMP) production
were examined in the presence or absence of different inhibitors. We provide evidence that nitric oxide has dual and opposite
effects depending on time after induction of apoptosis. In an early phase, up to 3 h of apoptosis, nitric oxide supports survival
of CGCs through a cGMP-dependent mechanism. After 3 h, nNOS expression and activity decreased resulting in shut down of NO
and cGMP production. Residual NO then contributes to the apoptotic process by reacting with rising superoxide anions leading
to peroxynitrite production and protein inactivation. We conclude that whilst NO over-production protects neurons from death
in the early phase of neuronal damage, its subsequent reduction may contribute to neuronal degeneration and ultimate cell
death. 相似文献
50.
DC Andrade C Henriquez–Olguín AR Beltrán MA Ramírez C Labarca M Cornejo C álvarez R Ramírez-Campillo 《Biology of sport / Institute of Sport》2015,32(2):123-128
The purpose of this study was to compare the acute effects of general, specific and combined warm-up (WU) on explosive performance. Healthy male (n = 10) subjects participated in six WU protocols in a crossover randomized study design. Protocols were: passive rest (PR; 15 min of passive rest), running (Run; 5 min of running at 70% of maximum heart rate), stretching (STR; 5 min of static stretching exercise), jumping [Jump; 5 min of jumping exercises – 3x8 countermovement jumps (CMJ) and 3x8 drop jumps from 60 cm (DJ60)], and combined (COM; protocols Run+STR+Jump combined). Immediately before and after each WU, subjects were assessed for explosive concentric-only (i.e. squat jump – SJ), slow stretch-shortening cycle (i.e. CMJ), fast stretch-shortening cycle (i.e. DJ60) and contact time (CT) muscle performance. PR significantly reduced SJ performance (p =0.007). Run increased SJ (p =0.0001) and CMJ (p =0.002). STR increased CMJ (p =0.048). Specific WU (i.e. Jump) increased SJ (p =0.001), CMJ (p =0.028) and DJ60 (p =0.006) performance. COM increased CMJ performance (p =0.006). Jump was superior in SJ performance vs. PR (p =0.001). Jump reduced (p =0.03) CT in DJ60. In conclusion, general, specific and combined WU increase slow stretch-shortening cycle (SSC) muscle performance, but only specific WU increases fast SSC muscle performance. Therefore, to increase fast SSC performance, specific fast SSC muscle actions must be included during the WU. 相似文献