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Elisa Bisicchia Laura Latini Virve Cavallucci Valeria Sasso Vanessa Nicolin Marco Molinari Marcello D’Amelio Maria Teresa Viscomi 《Molecular neurobiology》2017,54(7):4896-4907
Spinal cord injuries (SCIs) are devastating conditions of the central nervous system (CNS) for which there are no restorative therapies. Neuronal death at the primary lesion site and in remote regions that are functionally connected to it is one of the major contributors to neurological deficits following SCI.Disruption of autophagic flux induces neuronal death in many CNS injuries, but its mechanism and relationship with remote cell death after SCI are unknown. We examined the function and effects of the modulation of autophagy on the fate of axotomized rubrospinal neurons in a rat model of spinal cord dorsal hemisection (SCH) at the cervical level. Following SCH, we observed an accumulation of LC3-positive autophagosomes (APs) in the axotomized neurons 1 and 5 days after injury. Furthermore, this accumulation was not attributed to greater initiation of autophagy but was caused by a decrease in AP clearance, as demonstrated by the build-up of p62, a widely used marker of the induction of autophagy. In axotomized rubrospinal neurons, the disruption of autophagic flux correlated strongly with remote neuronal death and worse functional recovery. Inhibition of AP biogenesis by 3-methyladenine (3-MA) significantly attenuated remote degeneration and improved spontaneous functional recovery, consistent with the detrimental effects of autophagy in remote damage after SCH. Collectively, our results demonstrate that autophagic flux is blocked in axotomized neurons on SCI and that the inhibition of AP formation improves their survival. Thus, autophagy is a promising target for the development of therapeutic interventions in the treatment of SCIs. 相似文献
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Solano AF Leipnitz G De Bortoli GM Seminotti B Amaral AU Fernandes CG Latini AS Dutra-Filho CS Wajner M 《Free radical research》2008,42(8):707-715
The present work investigated the in vitro effects of isovaleric acid (IVA) and isovalerylglycine (IVG), which accumulate in isovaleric acidemia (IVAcidemia), on important parameters of oxidative stress in supernatants and mitochondrial preparations from brain of 30-day-old rats. IVG, but not IVA, significantly increased TBA-RS and chemiluminescence values in cortical supernatants. Furthermore, the addition of free radical scavengers fully prevented IVG-induced increase of TBA-RS. IVG also decreased GSH concentrations, whereas IVA did not modify this parameter in brain supernatants. Furthermore, IVG did not alter lipid peroxidation or GSH concentrations in mitochondrial preparations, indicating that the generation of oxidants by IVG was dependent on cytosolic mechanisms. On the other hand, IVA significantly induced carbonyl formation both in supernatants and purified mitochondrial preparations from rat brain, with no effect observed for IVG. Therefore, it is presumed that oxidative damage may be at least in part involved in the pathophysiology of the neuropathology of IVAcidemia. 相似文献
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Bordignon V Bultrini S Prignano G Sperduti I Piperno G Bonifati C Filippetti M Toma L Latini A Di Cecio M Giuliani A Vocaturo A Trento E D' Agosto G Francesconi F Cataldo A Vento A Cilenti V Berardesca E Ameglio F Cordiali Fei P Ensoli F 《Journal of biological regulators and homeostatic agents》2011,25(2):213-220
The early diagnosis and treatment of individuals harboring M. tuberculosis is key to ensuring the effectiveness of health programs aimed at the elimination of tuberculosis (TB). Monitoring for TB also has other important health care implications for the related immune pathology caused by the chronic inflammatory response to M. tuberculosis. Moreover, the recent introduction of biologic therapies for the treatment of several immune-mediated inflammatory diseases has shown unexpected high frequencies of reactivation of latent TB. The present cross-sectional study is aimed at estimating the prevalence of latent tuberculosis infection (LTBI) in different groups of subjects, either undergoing a routine program of screening for TB or a clinical monitoring of autoimmune or lung disorders, by analyzing their immune response in vitro to a pool of different M. tuberculosis antigens through an IFN-gamma-release assay (IGRA). We consecutively tested 1,644 subjects including health care workers (931), healthy immigrants from different countries (93), patients with a diagnosis of psoriasis (405), patients with lung inflammatory disease (60) or lung neoplasia (32) and a group of HIV-1 infected Italian subjects (120). The prevalence of IGRAs positive responses among health care workers was 8.9 percent. In comparison, significantly higher frequencies were found in healthy immigrant subjects (33.3%), similar to those found in inflammatory broncho-pneumopathies (34.5%) or lung cancer (29.6%). Interestingly, an unexpected high prevalence was also found in patients affected by psoriasis (18.0%), while HIV-infected subjects had values comparable to those of health care workers (10.8%). An age cut-off was determined and applied for each group by receiver operating characteristic (ROC) curves in order to perform the statistical analysis among age-comparable groups. Multivariate analysis showed that the age and clinical conditions such as having a diagnosis of psoriasis or a lung inflammatory disease were independent risk factors for developing an IGRA positive response. This study highlights an unprecedented high prevalence of IGRA positive responses among patients affected by psoriasis and emphasizes the need for a preliminary assessment of LTBI before the administration of any biologic therapy based on cytokine antagonists such as anti-TNF-alpha. Moreover, screening for LTBI should be routinely performed in the presence of a chronic pulmonary disease. 相似文献
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A novel multisite confocal system for rapid Ca2+ imaging from submicron structures in brain slices
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Luiza Filipis Karima Ait Ouares Philippe Moreau Dimitrii Tanese Valeria Zampini Andrea Latini Chun Bleau Charlie Bleau Jeremy Graham Marco Canepari 《Journal of biophotonics》2018,11(3)
In brain slices, resolving fast Ca2+ fluorescence signals from submicron structures is typically achieved using 2‐photon or confocal scanning microscopy, an approach that limits the number of scanned points. The novel multiplexing confocal system presented here overcomes this limitation. This system is based on a fast spinning disk, a multimode diode laser and a novel high‐resolution CMOS camera. The spinning disk, running at 20 000 rpm, has custom‐designed spiral pattern that maximises light collection, while rejecting out‐of‐focus fluorescence to resolve signals from small neuronal compartments. Using a 60× objective, the camera permits acquisitions of tens of thousands of pixels at resolutions of ~250 nm per pixel in the kHz range with 14 bits of digital depth. The system can resolve physiological Ca2+ transients from submicron structures at 20 to 40 μm below the slice surface, using the low‐affinity Ca2+ indicator Oregon Green BAPTA‐5N. In particular, signals at 0.25 to 1.25 kHz were resolved in single trials, or through averages of a few recordings, from dendritic spines and small parent dendrites in cerebellar Purkinje neurons. Thanks to an unprecedented combination of temporal and spatial resolution with relatively simple implementation, it is expected that this system will be widely adopted for multisite monitoring of Ca2+ signals. 相似文献
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The Intra-Hippocampal Leucine Administration Impairs Memory Consolidation and LTP Generation in Rats
Viviane Glaser Valeria P. Carlini Laura Gabach Marisa Ghersi Susana Rubiales de Barioglio Oscar A. Ramirez Mariela F. Perez Alexandra Latini 《Cellular and molecular neurobiology》2010,30(7):1067-1075
Leucine accumulates in fluids and tissues of patients affected by maple syrup urine disease, an inherited metabolic disorder,
predominantly characterized by neurological dysfunction. Although, a variable degree of cognition/psychomotor delay/mental
retardation is found in a considerable number of individuals affected by this deficieny, the mechanisms underlying the neuropathology
of these alterations are still not defined. Therefore, the aim of this study was to investigate the effect of acute intra-hippocampal
leucine administration in the step-down test in rats. In addition, the leucine effects on the electrophysiological parameter,
long-term potentiation generation, and on the activities of the respiratory chain were also investigated. Male Wistar rats
were bilaterally administrated with leucine (80 nmol/hippocampus; 160 nmol/rat) or artificial cerebrospinal fluid (controls)
into the hippocampus immediately post-training in the behavioral task. Twenty-four hours after training in the step-down test,
the latency time was evaluated and afterwards animals were sacrificed for assessing the ex vivo biochemical measurements.
Leucine-treated animals showed impairment in memory consolidation and a complete inhibition of long-term potentiation generation
at supramaximal stimulation. In addition, a significant increment in complex IV activity was observed in hippocampus from
leucine-administered rats. These data strongly indicate that leucine compromise memory consolidation, and that impairment
of long-term potentiation generation and unbalance of the respiratory chain may be plausible mechanisms underlying the deleterious
leucine effect on cognition. 相似文献
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Investigations into the Adenosine Outflow from Hippocampal Slices Evoked by Ischemia-Like Conditions 总被引:13,自引:2,他引:11
Felicita Pedata Serena Latini Anna Maria Pugliese Giancarlo Pepeu 《Journal of neurochemistry》1993,61(1):284-289
Abstract: The characteristics of adenosine and inosine outflow evoked by 5 min of ischemia-like conditions in vitro (superfusion with glucose-free Krebs solution gassed with 95% N2/5% CO2) were investigated on rat hippocampal slices. The viability of the slices after “ischemia” was evaluated by extracellular recording of the evoked synaptic responses in the CA1 region. The evoked dendritic field potentials were abolished after 5 min of superfusion under “ischemia” but a complete recovery occurred after 5 min of reperfusion with normal oxygenated Krebs solution. No recovery took place after 10 min of “ischemia.” The addition of the adenosine A, receptor antagonist 8-phenylthe- ophylline to the superfusate antagonized the depression of the evoked field potentials caused by 5 min of “ischemia.” Five minutes of “ischemia” brought about a six- and fivefold increase in adenosine and inosine outflow, respectively, within 10 min. Tetrodotoxin reduced the outflow of adenosine and inosine by 42 and 33%, respectively, whereas the removal of Ca2+ caused a further increase. The NMDA receptor antagonist d (-)-2-amino-7- phoshonoheptanoic acid and the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione brought about small, not statistically significant decreases of adenosine and inosine outflow. The glutamate uptake inhibitor dihydrokainate did not affect the outflow of adenosine and inosine. Inhibition of ecto-5′-nucleotidase by α, β-methylene ADP and GMP did not affect basal adenosine outflow but potentiated “ischemia”-evoked adenosine outflow. It is concluded that ischemia-like conditions in vitro evoke a Ca2+-independent adenosine and inosine outflow, through a mechanism that partly depends on propagated nervous activity but does not involve excitatory amino acids. The efflux of adenosine is probably responsible for the depression of the evoked synaptic electrical activity during “ischemia” in the hippocampal slices. 相似文献
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Erik Tandberg Askevold Lars Gullestad St?le Nymo John Kjekshus Arne Yndestad Roberto Latini John G. F. Cleland John J. V. McMurray P?l Aukrust Thor Ueland 《PloS one》2015,10(8)