PubMed Health⌕ Search

Biomedical subjects

E Fava

Publications and source records attributed to E Fava.

At least 19 recordsLinked to original sources
PubMed1999

Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis.

Under pathological conditions, the mode of cell death, apoptosis or necrosis, is relevant for the subsequent fate of the tissue. Cell demise may be shaped by endogenous mediators such as nitric oxide (NO) which interfere with subroutines of the death program. Here we show that apoptosis of Jurkat cells elicited by either staurosporine (STS) or anti-CD95 antibodies in glucose-free medium is converted to necrosis by NO donors. In the presence of NO, release of mitochondrial cytochrome c was delayed and activation of execution caspases was prevented. Stimulated cells died nonetheless. The switch in the mode of cell death was due to NO-dependent failure of mitochondrial energy production. Restoration of intracellular ATP by glucose supplementation recovered the cells' ability to activate caspases and undergo apoptosis. In this system, the apoptosis/necrosis conversion promoted by NO was not mediated by cyclic guanosine monophosphate-dependent mechanisms, poly-(ADP-ribose)-polymerase (PARP) activation, or inhibition of caspases due to S-nitrosylation and glutathione depletion. In contrast, depleting intracellular ATP with rotenone, an inhibitor of mitochondrial complex I mimicked the effect of NO. The findings presented here suggest that NO can decide the shape of cell death by lowering intracellular ATP below the level required to allow the coordinated execution of apoptosis.

Adenosine Triphosphate↗
PubMed1999

Nitric oxide inhibits execution of apoptosis at two distinct ATP-dependent steps upstream and downstream of mitochondrial cytochrome c release.

The endogenous mediator nitric oxide (NO) blocked apoptosis of Jurkat cells elicited by staurosporine, anti-CD95 or chemotherapeutics, and switched death to necrosis. The switch in the mode of cell death was dependent on the ATP loss elicited by NO. This affected two distinct steps of the apoptotic cascade. First, the release of cytochrome c from mitochondria was delayed by NO. Second, processing of procaspases-3/7 to the active proteases was prevented even after cytochrome c had been released. Thus, NO interferes with execution steps of apoptosis both upstream and downstream of cytochrome c release.

Adenosine Triphosphate↗
PubMed1998

Confocal scanning laser microscopy of the follicular epithelium in ovarioles of the stick insect Carausius morosus.

Ovarian follicles of the stick insect Carausius morosus were analyzed by confocal laser microscopy and immunocytochemistry with a view to studying cell polarity in the follicular epithelium. Such probes as anti-alpha-tubulin antibodies and Rh-phalloidin were employed to establish how the follicle cell cytoskeleton changes during ovarian development. Data show that alpha-tubulin prevails over the basal end, while F-actin appears more abundant along the apical end of the follicle cells. This finding was further corroborated by immunogold cytochemistry, showing that label along the basal end is primarily associated with microtubules, while that along the apical end is due to follicle cell microvilli interdigitating with the oocyte plasma membrane. A monoclonal antibody specifically raised against a vitellin polypeptide was used to investigate the role the follicular epithelium might play in relation to vitellogenin (Vg) uptake by the oocyte. Data show that under these conditions label is restricted to the intercellular channels of the follicular epithelium, thus providing further support to the notion that Vg enters the oocyte through the extracellular pathway leading from the basement lamina to the oocyte surface. By contrast, the use of a monoclonal antibody raised against a fat-body-derived protein of 85 kDa that is specifically sulfated within the follicle cells provides evidence for the existence of an alternative way of gaining access to the oocyte surface, that is by transcytosis through the follicular cell epithelium. These findings confirm our earlier observations on stick insect ovarioles whereby polarization in the follicular epithelium is primarily addressed to sustain a transcytotic vesicular traffic between opposite poles of the follicle cell of Vg toward the oocyte surface.

Animals↗
PubMed1998

1-Methyl-4-phenylpyridinium induces autocrine excitotoxicity, protease activation, and neuronal apoptosis.

The pathogenesis of several neurodegenerative diseases may involve indirect excitotoxic mechanisms, where glutamate receptor overstimulation is a secondary consequence of initial functional defects of neurons (e.g., impairment of mitochondrial energy generation). The neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and other mitochondrial inhibitors (e.g., rotenone or 3-nitropropionic acid) elicited apoptosis in cerebellar granule cell cultures via stimulation of autocrine excitotoxicity. Cell death, increase in intracellular Ca2+ concentration, release of cytochrome c, and all biochemical and morphological signs of apoptosis were prevented by blockade of the N-methyl-D-aspartate receptor with noncompetitive, glycine-site or glutamate-site inhibitors. In addition, MPP+-induced apoptosis was reduced by high Mg2+ concentrations in the medium or by inhibiting exocytosis with clostridial neurotoxins. Two classes of cysteine proteases were involved in the execution of cell death: caspases and calpains. Inhibitors of either class of proteases prevented cell death, cleavage of intracellular proteins (i.e., fodrin), and the appearance of typical features of apoptosis such as phosphatidylserine translocation or DNA fragmentation. However, protease inhibitors did not interfere with the initial intracellular Ca2+ concentration increase. We suggest that MPP+ as well as other mitochondrial inhibitors trigger indirect excitotoxic processes, which lead to Ca2+ overload, protease activation, and subsequent neuronal apoptosis.

1-Methyl-4-phenylpyridinium↗
PubMed1997

Peroxynitrite and nitric oxide donors induce neuronal apoptosis by eliciting autocrine excitotoxicity.

Endogenous generation of nitric oxide and its congeners, including peroxynitrite (ONOO-), has been implicated in the mechanism of neuron loss in neurodegenerative diseases. Accordingly, nitric oxide donors and ONOO- can elicit both apoptosis and necrosis in neuron cultures. Here we show that nitric oxide donors and ONOO- are each able to trigger apoptosis of mouse cerebellar granule cells by an excitotoxic mechanism requiring exocytosis and NMDA receptor-mediated intracellular Ca2+ overload. This conclusion is supported by the following findings. Apoptosis was induced by various nitric oxide donors or by direct addition of ONOO- to differentiated cerebellar granule cell cultures that were sensitive to NMDA toxicity, but not in cerebellar granule cells that did not display NMDA-induced cell death (i.e. early days in culture) or in various glial cell populations. Donors of ONOO- or nitric oxide stimulated a sustained increase in intracellular Ca2+, which was prevented by inhibitors of NMDA receptors, such as MK-801 and 5-phospho-aminovaleric acid, or by dampening neuronal electrical activity with high concentrations of extracellular Mg2+. Moreover, these treatments and the exposure of cerebellar granule cells in nominally Ca2+-free media prevented apoptotic cell death. Both the intracellular Ca2+ increase and apoptosis elicited by ONOO- or the nitric oxide donors were prevented by blocking exocytosis with tetanus toxin or botulinum neurotoxin C.

Animals↗
PubMed1997

Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide.

BACKGROUND: Excitotoxicity and excess generation of nitric oxide (NO) are believed to be fundamental mechanisms in many acute and chronic neurodegenerative disorders. Disturbance of Ca2+ homeostasis and protein nitration/nitrosylation are key features in such conditions. Recently, a family of proteases collectively known as caspases has been implicated as common executor of a variety of death signals. In addition, overactivation of poly-(ADP-ribose) polymerase (PARP) has been observed in neuronal excitotoxicity. We therefore designed this study to investigate whether triggering of caspase activity and/or activation of PARP played a role in cerebellar granule cell (CGC) apoptosis elicited by peroxynitrite (ONOO-) or NO donors. MATERIALS AND METHODS: CGC from wild-type or PARP -/- mice were exposed to various nitric oxide donors. Caspase activation and its implications for membrane alterations, Ca2+ homeostasis, intracellular proteolysis, chromatin degradation, and cell death were investigated. RESULTS: CGC exposed to NO donors undergo apoptosis, which is mediated by excess synaptic release of excitotoxic mediators. This excitotoxic mechanism differs from direct NO toxicity in some other neuronal populations and does not involve PARP activation. Inhibition of caspases with different peptide substrates prevented cell death and the related features, including intracellular proteolysis, chromatin breakdown, and translocation of phosphatidylserine to the outer surface of the cell membrane. Increased Ca2+ influx following N-methyl-D-aspartate (NMDA) receptor (NMDA-R) activation was not inhibited by caspase inhibitors. CONCLUSIONS: In CGC, NO donors elicit apoptosis by a mechanism involving excitotoxic mediators, Ca2+ overload, and subsequent activation of caspases.

Animals↗
PubMed1992

Provoking agents, vulnerability factors and depression in an Italian setting: a replication of Brown and Harris's model.

The aetiological model of depression proposed by Brown and Harris in 1978 was examined in a sample of 120 women in Milan, using the same method for the assessment of life stresses. The role of provoking agents (severe events and major difficulties) was found to be similar to that of the earlier study. There was some evidence that lack of an intimate relationship with a husband or a boyfriend acted as a vulnerability factor, increasing the risk of depression in the face of provoking agents. The overall results support the Brown-Harris aetiological model in a quite different cultural setting.

Adolescent↗
PubMed1992

The training of the psychiatrist in relation to the new trends in psychiatry.

One of the most important things to realize about modern Psychiatry is that many factors are involved in the pathogenesis and especially in the evolution of mental diseases. The results of epidemiological research and the development of different schools with separate specializations have shown the importance of extrasubjective factors such as family environment, social context, life events and life stressors, and therefore the need to find therapeutic strategies which are able to influence the different areas. From this wide spectrum arises the necessity for a functional integration of the different therapeutic areas in the operative context, also because of the nonhomogeneity and the frequent random choice of reference models by the operators and the mental health services. In this study we propose a training model which allows the achievement of this integration ability at an operative level, and which at the same time defines its limits.

Community Mental Health Centers↗
PubMed1988

Monitoring of brain function by means of evoked potentials in cerebral aneurysm surgery.

Deliberate arterial hypotension is currently used to operate upon cerebral aneurysms. However, it is not ascertained whether this practice is really safe for all patients, especially those presenting with preoperative vasospasm. 50 patients, requiring surgical treatment for cerebral aneurysm, have been submitted, during surgery, to the recording of Somatosensory Evoked Potentials (SEPs) on median nerve stimulation. This technique allows the functional evaluation of neural pathways mediating the somatosensory stimuli and of primary somatosensory cortex; it is known that a decrease of cerebral perfusion may affect the SEP waveforms in terms of reduced subcortical conduction velocity (i.e., increased central conduction time, CCT) and of reduced cortical response amplitude. These changes may be apparent before a permanent neurological damage is produced. Preoperative SEP recording demonstrated a prolonged CCT, possibly related to vasospasm, in 9 patients, a normal clinical evaluation notwithstanding (grade I and II). During intraoperative deliberate hypotension, a SEP change has always been produced. No postoperative damage has been observed, however, as long as the CCT did not exceed 9 msec for 10 minutes (maximum normal CCT value is 6.7 msec) and as the cortical response had been visible throughout the whole surgical procedure. The critical value of CCT has been reached at a mean arterial pressure (MAP) lower than 60 Torr in patients with a normal preoperative SEP recording; at the opposite, in patients presenting with a prolonged preoperative CCT, the value of 9 msec was arrived at with a MAP value that is generally accepted as safe for all patients (75 Torr).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1984

Cat posture on a tilted platform.

The posture of cats trained to stand freely on a platform was studied during static tilts (up to +/- 30 degrees). Vertical projection of the center of mass on the support surface, as well as limb orientation in space and degree of limb flexion, varied minimally with platform tilt angle. The limbs' main axes were kept almost lined up with the vertical. This data indicates that postural control is simplified by strong internal constraints which limit the number of possible postural configurations. The mechanical advantages of this postural strategy are also considered. Finally, the data are discussed in the context of previously held views on the role of vestibular and neck reflex control of posture in intact animals.

Adaptation, Physiological↗
PubMed1984

A study of the relationship between muscle length, tension-time area and stiffness in cat areflexic soleus.

The relationship between muscle length and both tension-time area and stiffness were studied in the isolated cat soleus muscle during tetanic isometric contraction at different stimulus rates. The results show that: The area subtending the tension curve remains constant in a range of 8-10 mm of muscle length, for stimulation frequencies between 15 and 66 Hz. The muscle stiffness, measured using different amplitude stretches, remains constant over changes in muscle length of 10 mm. The stiffness is higher for smaller stretches than for larger ones. The data therefore show an approximately constant tension-time area and no significant changes in stiffness for variations in muscle length that exceed the physiological length variations during quiet standing. These results are discussed in the context of postural mechanisms.

Animals↗
PubMed1983

Properties of the spike afterhyperpolarization in pyramidal tract neurons.

Features of the spike afterhyperpolarization (AHP) recorded intracellularly have been analyzed in fast pyramidal tract neurons of cats. Cell input conductance increases during the AHP, possibly because of a change in potassium conductance, as suggested by an AHP equilibrium potential 10--15 mV negative to the resting membrane potential. When more spikes are evoked in succession, AHPs following the first one are strongly reduced in amplitude. The effect is virtually maximal (30--50% of the control) after a single spike and fades out by 200-400 ms after the last spike. At short interspike intervals the initial time course of the depression is hidden by summation occurring between consecutive AHPs.

Animals↗