A caspase-3-dependent pathway is predominantly activated by the excitotoxin pregnenolone sulfate and requires early and late cytochrome c release and cell-specific caspase-2 activation in the retinal cell death

This study investigates the implication of mitochondria- and caspase-dependent pathways in the death of retinal neurones exposed to the neurosteroid pregnenolone sulfate (PS) shown to evoke apoptosis and contribute to amplification and propagation of excitotoxicity. After a brief PS challenge of intact retinas, caspase-3 and caspase-2 activation and cytochrome c release occur early and independent of changes in the oxidative state measured by superoxide dismutase activity. The temporal and spatial relationship of these events suggests that a caspase-3-dependent pathway is activated in response to cytochrome c release and requires caspase-2 activation and a late cytochrome c release in speci…

Pregnenolone sulfate, a naturally occurring excitotoxin involved in delayed retinal cell death.

The present study was designed to investigate the neurosteroid pregnenolone sulfate (PS), known for its ability to modulate NMDA receptors and interfere with acute excitotoxicity, in delayed retinal cell death. Three hours after exposure of the isolated and intact retina to a 30-min PS pulse, DNA fragmentation as assessed by genomic DNA gel electrophoresis and a modified in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method appeared concurrently with an increase in superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels. At 7 h, the increased amount of DNA laddering was accompanied by a higher number of TUN…

Chronic pharmacological treatment in takotsubo cardiomyopathy.

Abstract Background Takotsubo cardiomyopathy is a disorder that has been appreciated only recently. In most of reported cases, this syndrome mimes an acute myocardial infarction. Till this moment no data are available from literature about the treatment in the acute phase of this disease. Aim of the study In our multicentric experience we have retrospectively looked at the benefits of a treatment with ACE-inhibitors, beta-blockers, Aspirin and calcium channels blockers, started until the early phases of the disease and continued for 30 days, in 36 patients affected by Takotsubo cardiomyopathy. We chose as endpoint of the study the efficacy of the used drug in improving left ventricular myoc…

Film sottili di precursori del pentacene per applicazioni in transistori flessibili

Pregnenolone sulfate modulates NMDA receptors, inducing and potentiating acute excitotoxicity in isolated retina

Pregnenolone sulfate (PS) acts as a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptor-mediated responses. In the retina, we previously observed that the synthesis of pregnenolone and PS increases after stimulation of NMDA receptors and blockade of the synthesis reduces retinal cell death. This study was carried out to explore in the isolated and intact retina the possible role of PS in NMDA-induced excitotoxicity. Lactate dehydrogenase (LDH) measurements and morphological analysis revealed that a 90-min exogenous application of PS at 0.1-500 microM concentrations potentiated NMDA-induced cell death and at 50-500 microM concentrations caused cytotoxicity. After 45 min, ei…

Size, stability and activity of ß amyloid intermediates of fibrillogenesis

Retinal oxidation, apoptosis and age- and sex-differences in the mnd mutant mouse, a model of neuronal ceroid lipofuscinosis

Retinal degeneration is an early and progressive event in many forms of neuronal ceroid lipofuscinoses (NCLs), a heterogeneous group of neurodegenerative disorders with unknown pathogenesis. We here used the mutant motor neuron degeneration (mnd) mouse, a late-infantile NCL variant, to investigate the retinal oxidative state and apoptotic cell death as a function of age and sex. Total superoxide dismutase (SOD) activities and thiobarbituric acid-reactive substance (TBARS) levels revealed progressive increases in retinal oxyradicals and lipid peroxides of mnd mice of both sexes. Female mnd retinas showed a higher oxidation rate and consistently exhibited the 4-hydroxy-2-nonenal (4-HNE)-adduc…

RUPTURE OF A LEFT SINUS OF VALSALVA ANEURYSM INTO THE PULMONARY ARTERY: A CASE REPORT

Human neuroblastoma SH-SY5Y cell line: neurosteroid-producing cell line relying on cytoskeletal organization.

Pregnenolone, the precursor of all steroids, is synthesized by CNS structures. The synthesis requires an obligatory step involving cholesterol transport to mitochondrial cytochrome P450-cholesterol side chain cleavage (cytP450scc), although the underlying mechanism(s) are still mostly unknown. We used the human neuroblastoma SH-SY5Y cell line to investigate cytP450scc expression and activity and to establish a role of cytoskeleton in pregnenolone synthesis. Immunocytochemical and biochemical approaches revealed that undifferentiated as well as differentiated cells either by retinoic acid (RA) or phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), possess cytP450scc and rapidly synthes…

The effect of Trehalose on the Alpha-Crystallin Aggregates

RUPTURE OF THE ATHEROSCLEROTIC PLAQUE: IS CHLAMYDIA PNEUMONIAE A POSSIBLE AGENT?

BACKGROUND: The natural history of atherosclerosis has not clearly been elucidated yet. Some works reported that flogosis plays a role in plaque instability. Why does this inflammatory process start? We investigated the correlation between Chlamydia pneumoniae acute infection and plaque rupture. METHODS: We compared blood concentrations of IgM anti-Chlamydia pneumoniae in patients affected by acute myocardial infarction (AMI) and in patients affected by stable angina. RESULTS: Our results showed a minimal statistical difference, with a more positive value in patients with AMI. Subsequently, the group affected by AMI was divided into two subgroups with and without plaque rupture: the subgrou…

Retinal oxidation and apoptosis in the motor neuron degeneration mouse, a model of neuronal ceroid lipofuscinosis

Neurosteroidogenesis in Rat Retinas

Neurosteroids (steroids synthesized in the CNS) function by modulating neurotransmission. To establish an experimental model for investigation of neurosteroid synthesis and regulation, independent of blood-borne steroids, we examined the steroidogenic activity of isolated rat retinas. We identified progesterone, pregnenolone, dehydroepiandrosterone, desoxycorticosterone, 3 alpha,5 alpha-tetrahydrodesoxycorticosterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone, 17-hydroxyprogesterone, and 17-hydroxypregnenolone together with their esterified forms. As pregnenolone is the precursor of all steroids, its formation was studied in detail as an index of a steroid-synthesizing tissue. Pregnenolon…

Rupture of the atherosclerotic plaque: is Chlamydia pneumoniae a possible agent?

Ventricular tachycardia in non-compaction of left ventricle: Is this a frequent complication?

Background: Isolated left ventricular non-compaction is the result of incomplete myocardial morphogenesis, leading to persistence of the embryonic myocardium. The condition is recognized by an excessively prominent trabecular meshwork and deep intertrabecular recesses of the left ventricle. Whether these intertrabecular recesses are a favorable substrate for ventricular arrhythmias is unclear. Some reports have found that the fatal ventricular arrhythmias may occur in approximately half of the patients. In this report we investigated about this association. Methods and Results: In total we evaluated a continuous series of 238 patients affected by non-compaction. Periodic Holter monitoring w…

Induction of neurosteroid synthesis by NMDA receptors in isolated rat retina: a potential early event in excitotoxicity

Here we investigated the possible regulation of neurosteroidogenesis by N-methyl-D-aspartic acid (NMDA) receptor activation and addressed the hypothesis that neurosteroid synthesis may be involved in acute excitotoxicity. In the isolated retina, exposure to NMDA modified pregnenolone and pregnenolone sulphate formation. This effect was dose and time dependent, the synthesis being increased by relatively moderate NMDA doses (1-100 microM) within 30 min exposure and reduced to its control value by 60 min or by raising drug concentrations. NMDA-stimulated neurosteroid synthesis was blocked by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate (MK-801) and 3(2-ca…

A CLINICAL CASE OF CORONARY FISTULA CANALIZED IN ACCESSORY CHAMBER COMMUNICATING WITH RIGHT ATRIUM

Identification of an Antigen Related to the Sea Urchin RNA-Binding Protein LP54 in Mammalian Central Nervous System

LP54 is an RNA-binding protein involved in localization of maternal messengers in sea urchin egg and embryos. Using a polyclonal antibody directed against Paracentrotus lividus LP54 we detected a 66-kDa cross-reacting antigen in undifferentiated and differentiated SH-SY5Y human neuroblastoma cells. After treatment of undifferentiated cells with detergent, the 66-kDa antigen was found to be enriched in the cytoskeletal fraction. By Western blot the expression of this antigen was also analyzed in regions of the CNS and in tissues of the adult rat and its exclusive presence in the hippocampus and thalamus was revealed. The immunoreactivity with P. lividus antibody against LP54 in hippocampal l…

Neurosteroids in the Retina

Steroids may have a powerful role in neuronal degeneration. Recent research has revealed that steroids may influence the onset and progression of some retinal disorders as well as neurodegenerative diseases and, as in brain, they accumulate in the retina via a local synthesis (neurosteroids) and metabolism of blood-circulating steroid hormones. Their crucial role as neurodegenerative and neuroprotective agents has been also upheld in a retinal excitotoxic paradigm. These findings are reviewed especially from the emerging perspective that after an insult local changes in steroidogenic responses and consequent neurosteroid availability might turn out to be offensive or defensive cellular adap…

gamma-Aminobutyric acid type A/benzodiazepine receptors regulate rat retina neurosteroidogenesis.

Abstract It has been previously shown that retinal ganglion cells have the ability to synthesize steroids including neuroactive steroids such as pregnenolone sulfate. Since ganglion cells possess GABAA/benzodiazepine (BZ) receptors and neurosteroids modulate retinal GABAA receptor function, we investigated the role of these receptors in isolated rat retina neurosteroidogenesis. Ligands for central-type BZ receptors stimulated retinal pregnenolone synthesis. Clonazepam was the most potent ligand examined acting at nanomolar concentrations. Moreover, the effective steroidogenesis stimulatory dose (ED50) for these ligands and theKi to inhibit [3-H]flunitrazepam binding showed a coefficient of …

LA CHLAMYDIA PNEUMONIAE È CORRELABILE CON LA ROTTURA DELLA PLACCA ATEROSCLEROTICA? RUPTURE OF THE ATHEROSCLEROTIC PLAQUE: IS CHLAMYDIA PNEUMONIAE A POSSIBLE AGENT?

Background. The natural history of atherosclerosis has not clearly been elucidated yet. Some works reported that flogosis plays a role in plaque instability. Why does this inflammatory process start? We investigated the correlation between Chlamydia pneumoniae acute infection and plaque rupture. Methods. We compared blood concentrations of IgM anti-Chlamydia pneumoniae in patients affected by acute myocardial infarction (AMI) and in patients affected by stable angina. Results. Our results showed a minimal statistical difference, with a more positive value in patients with AMI. Subsequently, the group affected by AMI was divided into two subgroups with and without plaque rupture: the subgrou…

INIBITORI DEL SISTEMA RENINA-ANGIOTENSINA E FIBRILLAZIONE ATRIALE: UNO STUDIO RETROSPETTIVO SU 187 PAZIENTI

LA PREVENZIONE DELLA CARDIOPATIA ISCHEMICA

INSUFFICIENZA CARDIACA ACUTA E CARDIOMIOPATIE: UN CASO CLINICO

Isolated noncompaction of left ventricular myocardium is a rare congenital heart disease, characterized by an excessive prominence of trabecular meshwork, spaced out by deep intertrabecular recesses, consequent to the arrest of the normal myocardial embryogenesis. Although there are numerous descriptions, the pathophysiological effects of the structural alterations, like the clinical spectrum and the evolution of the disease, are not fully clarified. In this paper we evaluated the natural history of the disease, the family incidence and the alterations of the systolic and diastolic function. An interesting case report is described concerning a patient affected by noncompaction and atrial fi…

Surface Chemistry Effects on the Early Growth Stages of Pentacene Films from a Soluble Precursor on Silicon-Based Materials

LA CHLAMYDIA PNEUMONIAE E’ CORRELABILE CON LA ROTTURA DELLA PLACCA ATEROSCLEROTICA?

CHLAMIDYA PNEUMONIAE AND VULNERABLE PLAQUE: DOES EXIST A CORRELATION?

Influenza del Cu II sull’autoorganizzazione gerarchica di AB(25-35) e dei suoi derivati [C-amidati o N-acetilati]

Expression of vesicle-associated membrane-protein-associated protein B cleavage products in peripheral blood leukocytes and cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis

Background and purpose Vesicle-associated membrane-protein-associated protein B (VAPB) is an endoplasmic reticulum (ER) resident protein participating in ER function, vesicle trafficking, calcium homeostasis and lipid transport. Its N-terminal domain, named MSP, is cleaved and secreted, serving as an extracellular ligand. VAPB mutations are linked to autosomal-dominant motor neuron diseases, including amyotrophic lateral sclerosis (ALS) type 8. An altered VAPB function is also suspected in sporadic ALS (SALS). Methods The expression pattern of VAPB cleavage and secreted products in the peripheral blood leukocytes (PBL) and cerebrospinal fluid (CSF) of SALS patients and neurological controls…