Mauro Cataldi

Apoptosis induced in neuronal cells by oxidative stress: role played by caspases and intracellular calcium ions

Reactive oxygen species (ROS) have been implicated in the pathophysiology of many neurologic disorders and brain dysfunction. In the same pathological settings evidence has been provided in favour of a participation of intracellular Ca(2+) concentration altered homeostasis in the chain of events leading to neuronal apoptosis. In the present review literature reports and experimental data on the relationship between caspase activation and alteration of intracellular calcium concentrations in the mechanisms triggering neuronal apoptosis are discussed. The data gathered support the conclusion that during oxidative stress in neuronal cells the production of ROS triggers a mechanism that, through the release of cytochrome c from mitochondria and caspase-3 activation, leads to apoptosis; the concomitant ROS-mediated elevation of intracellular Ca(2+) concentration triggers caspase-2 activation but both events do not seem to be involved in cell death.

Resting state networks in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is typically described as a neurologic disorder affecting a cerebral network comprising the hippocampus proper and several anatomically related extrahippocampal regions. A new level of complexity was recently added to the study of this disorder by the evidence that TLE also appears to chronically alter the activity of several brain‐wide neural networks involved in the control of higher order brain functions and not traditionally linked to epilepsy. Recently developed brain imaging techniques such as functional magnetic resonance imaging (fMRI) analysis of resting state connectivity, have greatly contributed to these observations by allowing the precise characterization of several brain networks with distinct functional signatures in the resting brain, and therefore also known as “resting state networks.” These significant advances in imaging represent an opportunity to investigate the still elusive origins of the disabling cognitive and psychiatric manifestations of TLE, and could have important implications for its pathophysiology and, perhaps, its therapy. Herein we review recent studies in this field by focusing on resting state networks that have been implicated in the pathophysiology of psychiatric disorders and cognitive impairment in patients with epilepsy: the default mode network, the attention network, and the reward/emotion network.

Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: A randomized clinical trial

BACKGROUND AND AIMS In patients with chronic kidney disease (CKD), alterations in gut microbiome are posited to be responsible for gastrointestinal symptoms and generation of p-cresol, a uremic toxin that has been associated with CKD progression and cardiovascular mortality. This pilot study investigated whether Probinul-neutro®, a synbiotic that normalizes intestinal microflora, may lower plasma p-cresol concentrations and reduce gastrointestinal symptoms in non-dialyzed CKD patients. METHODS AND RESULTS This was a double-blind, randomized placebo-controlled trial. Thirty patients on 3-4 CKD stages were randomized to receive either Probinul neutro® or placebo for 4 weeks. Total plasma p-cresol concentration was assessed at baseline, and 15 and 30 days after treatment start. At the same study times, ease and frequency of defecation, upper and lower abdominal pain, stool shape, borborygmi, and flatus were quantified by subjective assessment questionnaires. Compared to baseline total plasma p-cresol median concentrations on 15th and 30th day were significantly lower in patients receiving Probinul-neutro® (2.31 and 0.78 vs. 3.05 μg/ml, p < 0.05; n = 18); no changes of plasma p-cresol concentrations were recorded in placebo-treated patients. No significant changes in gastrointestinal symptoms were observed during the study both in Probinul-neutro®-treated and placebo-treated patients. CONCLUSION Probinul-neutro® lowered total plasma p-cresol concentrations but did not ameliorate gastrointestinal symptoms in non-dialyzed CKD patients. Because high plasma concentrations of p-cresol in early phases of CKD are predictive of progression to end-stage renal disease, the results of our study suggest that synbiotics deserve attention as possible tools to delay CKD progression towards end-stage renal disease (ESRD). CLINICALTRIALSGOV IDENTIFIER NCT02008331.

ncx1, ncx2, and ncx3 Gene Product Expression and Function in Neuronal Anoxia and Brain Ischemia

Abstract:  Over the last few years, although extensive studies have focused on the relevant function played by the sodium–calcium exchanger (NCX) during focal ischemia, a thorough understanding of its role still remains a controversial issue. We explored the consequences of the pharmacological inhibition of this antiporter with conventional pharmacological approach, with the synthetic inhibitory peptide, XIP, or with an antisense strategy on the extent of brain damage induced by the permanent occlusion of middle cerebral artery (pMCAO) in rats. Collectively, the results of these studies suggest that ncx1 and ncx3 genes could be play a major role to limit the severity of ischemic damage probably as they act to dampen [Na+]i and [Ca2+]i overload. This mechanism seems to be normally activated in the ischemic brain as we found a selective upregulation of NCX1 and NCX3 mRNA levels in regions of the brain surviving to an ischemic insult. Despite this transcript increase, NCX1, NCX2, and NCX3 proteins undergo an extensive proteolytic degradation in the ipsilateral cerebral hemisphere. All together these results suggest that a rescue program centered on an increase NCX function and expression could halt the progression of the ischemic damage. On the basis of this evidence we directed our attention to the understanding of the transductional and transcriptional pathways responsible for NCX upregulation. To this aim, we are studying whether the brain isoform of Akt, Akt1, which is a downstream effector of neurotrophic factors, such as NGF can, in addition to affecting the other prosurvival cascades, also exert its neuroprotective effect by modulating the expression and activity of ncx1, ncx2, and ncx3 gene products.

Energy-restricted, n-3 polyunsaturated fatty acids-rich diet improves the clinical response to immuno-modulating drugs in obese patients with plaque-type psoriasis: a randomized control clinical trial

BACKGROUND & AIMS Low-grade systemic inflammation associated with obesity may worsen the clinical course of psoriasis. This study aimed to assess the effectiveness of an energy-restricted diet, enriched in n-3 polyunsaturated fatty acids (PUFAs) and poor in n-6 PUFAs, on metabolic markers and clinical outcome of obese patients with psoriasis. METHODS Forty-four obese patients with mild-to-severe plaque-type psoriasis treated with immuno-suppressive drugs were randomized to assume for six months either their usual diet or an energy-restricted diet (20 kcal/kg/ideal body weight/day) enriched of n-3 PUFAs (average 2.6 g/d). All patients continued their immuno-modulating therapy throughout the study. RESULTS At 3 and 6 months, a significant clinical improvement was observed in patients assuming the low-calorie high n-3 PUFAs diet respect to controls. Specifically Psoriasis Area Score Index (7.7 ± 3.7, 5.3 ± 4.3 and 2.6 ± 3.0, respectively; p < 0.05), itch scores (15.4 ± 13.5, 12.3 ± 12.1 and 1.8 ± 5.9, respectively; p < 0.05) and Dermatological Life Quality Index (19.5 ± 1.9, 11.4 ± 3.5 and 5.1 ± 1.6; respectively, p < 0.05) all decreased respect to baseline. In these subjects but not in controls, a significant decrease in body weight (93.8 ± 10.1, 85.8 ± 11.4 and 83.1 ± 12.1 kg, respectively; p < 0.05), waist circumference (112.7 ± 7.2, 106.1 ± 10.3 and 101.9 ± 10.4 cm; p < 0.05), serum triglycerides (141.8 ± 51.1, 100.5 ± 26.6 and 90.2 ± 34.5 mg/dL; respectively, p < 0.05), serum total cholesterol (198.3 ± 31.7, 171.4 ± 29.0 and 176.5 ± 20.5 mg/dL; respectively, p < 0.05) and n-6/n-3 ratio intake also occurred (5.1 ± 0.9, 2.0 ± 0.9 and 2.3 ± 1.1; respectively, p < 0.05). CONCLUSIONS In obese psoriatic patients, an energy-restricted diet designed to increase n-3 and reduce n-6 PUFAs, ameliorated the metabolic profile and, by increasing the response to immuno-modulating therapy, improved the clinical outcomes of the disease (ClinicalTrials.gov identifier: NCT01876875).

An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor

Urokinase receptor (uPAR) plays a key role in physiological and pathological processes sustained by an altered cell migration. We have developed peptides carrying amino acid substitutions along the Ser88‐Arg‐Ser‐Arg‐Tyr92 (SRSRY) uPAR chemotactic sequence. The peptide pyro glutamic acid (pGlu)‐Arg‐Glu‐Arg‐Tyr‐NH2 (pERERY‐NH2) shares the same binding site with SRSRY and competes with N‐formyl‐Met‐Leu‐Phe (fMLF) for binding to the G‐protein‐coupled N‐formyl‐peptide receptor (FPR). pERERY‐NH2 is a dose‐dependent inhibitor of both SRSRY‐ and fMLF‐directed cell migration, and prevents agonist‐induced FPR internalization and fMLF‐dependent ERK1/2 phosphorylation. pERERY‐NH2 is a new and potent uPAR inhibitor which may suggest the generation of new pharmacological treatments for pathological conditions involving increased cell migration.

ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na+/Ca2+exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells

J. Neurochem. (2012) 122, 911–922.

Histamine Receptors and Antihistamines: From Discovery to Clinical Applications

The synthesis and the identification of histamine marked a milestone in both pharmacological and immunological research. Since Sir Henry Dale and Patrick Laidlaw described some of its physiological effects in vivo in 1910, histamine has been shown to play a key role in the control of gastric acid secretion and in allergic disorders. Using selective agonists and antagonists, as well as molecular biology tools, four histamine receptors (H1R, H2R, H3R and H4R) have been identified. The Nobel Prize in Physiology and Medicine was awarded to Daniel Bovet in 1957 for the discovery of antihistamines (anti-H1R) and to Sir James Black in 1988 for the identification of anti-H2R antagonists. Anti-H1R and anti-H2R histamine receptor antagonists have revolutionized the treatment of certain allergic disorders and gastric acid-related conditions, respectively. More recently, anti-H3R antagonists have entered early-phase clinical trials for possible application in obesity and a variety of neurologic disorders. The preferential expression of H4R by several immune cells and its involvement in the development of allergic inflammation provide the rationale for the use of anti-H4R antagonists in allergic and in other immune-related disorders.

Glutamate-independent calcium toxicity: introduction.

It is widely accepted that a critical factor in determining neuronal death during cerebral ischemia is the progressive accumulation of intracellular Na+ ([Na+]i) and Ca2+ ([Ca2+]i) ions, which can precipitate necrosis and apoptosis of vulnerable neurons. Whereas the detrimental action of [Na+]i increase is attributable to both cell swelling and microtubular disorganization—2 phenomena that lead to cell necrosis1—a change in [Ca2+]i has been shown to be a key factor in ischemic brain damage, for it modulates several death pathways, including oxidative and nitrosative stress, mitochondrial dysfunction, and protease activation. Since Olney’s seminal work firstly suggested that excitatory aminoacids could elicit neurotoxicity,2 a large amount of work has been accumulated showing that glutamate extracellular concentrations briskly rise during acute brain injury, thus triggering an influx of Ca2+ and Na+ ions into neurons through ionotropic glutamate receptor subtypes. This evidence has led to the elaboration of the paradigm of glutamate excitotoxicity that explained ischemic neuronal cell death as a mere consequence of Na+ and Ca2+ influx through glutamate receptors.3 Although this theory has been guiding basic research in the field of neurodegeneration for almost 3 decades, more recently it has become the object of serious criticism and reassessment. What has aroused such skepticism among researchers has been the fact that although first, second, and third generation glutamate receptor antagonists have long yielded promising results in animal models of brain ischemia, they have failed to elicit a neuroprotective action in stroke and traumatic brain injury in humans.4 Therefore, the theory of excitotoxicity, though a fascinating paradigm, can only explain some of the events occurring in the acute phase of anoxic insult but cannot be seen as a major target for …

Plasma p-Cresol Lowering Effect of Sevelamer in Peritoneal Dialysis Patients: Evidence from a Cross-Sectional Observational Study

p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet. Because it has been reported that the phosphate binder sevelamer sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug. Conversely, no difference was observed among the different groups either in residual glomerular filtration rate, total weekly dialysis dose, total clearance, urine volume, protein catabolic rate, serum albumin or serum phosphate levels. Multiple linear regression analysis showed that none of these variables predicted plasma p-cresol concentrations that, instead, negatively correlated with the use of sevelamer. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect.