Silvia Leoncini | University of Siena / Università di Siena (original) (raw)
Papers by Silvia Leoncini
Frontiers in neurology, Jun 17, 2024
Mediators of Inflammation, 2014
Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk r... more Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk rate for sudden cardiac death. A subclinical myocardial biventricular dysfunction has been recently reported in RTT by our group and found to be associated with an enhanced oxidative stress (OS) status. Here, we tested the effects of the naturally occurring antioxidants-3 polyunsaturated fatty acids (-3 PUFAs) on echocardiographic parameters and systemic OS markers in a population of RTT patients with the typical clinical form. A total of 66 RTT girls were evaluated, half of whom being treated for 12 months with a dietary supplementation of-3 PUFAs at high dosage (docosahexaenoic acid ∼71.9 ± 13.9 mg/kg b.w./day plus eicosapentaenoic acid ∼115.5 ± 22.4 mg/kg b.w./day) versus the remaining half untreated population. Echocardiographic systolic longitudinal parameters of both ventricles, but not biventricular diastolic measures, improved following-3 PUFAs supplementation, with a parallel decrease in the OS markers levels. No significant changes in the examined echocardiographic parameters nor in the OS markers were detectable in the untreated RTT population. Our data indicate that-3 PUFAs are able to improve the biventricular myocardial systolic function in RTT and that this functional gain is partially mediated through a regulation of the redox balance.
Oxidative Medicine and Cellular Longevity (Web), 2015
PubMed, Feb 1, 2014
The oxidative stress (OS) hypothesis is able to explain several features of Rett syndrome (RTT), ... more The oxidative stress (OS) hypothesis is able to explain several features of Rett syndrome (RTT), a pervasive development disorder almost exclusively affecting females mainly caused by a mutation in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. In particular, the generation of an OS imbalance is related to MeCP2 gene mutation type, as well as natural history, clinical heterogeneity of the disease, and is compatible with the potential reversibility of the disease observed in the RTT animal models. In addition, our findings indicate the importance of blood as a suitable biological fluid for detecting markers of central nervous system oxidative damage in RTT and underline the key role of interaction between organic chemists, OS biochemists, and clinicians in revealing potential new markers of the disease and identifying potential new targets and interventional strategies aimed at improving the quality of life of these patients, affected by a so far incurable disease. Further efforts in the near future are needed in order to dissect the "black box" of the molecular events likely linking the MeCP2 gene mutation to OS derangement and subsequent disease expression.
Journal of Proteomics, 2017
Mediators of Inflammation, 2013
The mechanism of action of omega-3 polyunsaturated fatty acids (-3 PUFAs) is only partially known... more The mechanism of action of omega-3 polyunsaturated fatty acids (-3 PUFAs) is only partially known. Prior reports suggest a partial rescue of clinical symptoms and oxidative stress (OS) alterations following-3 PUFAs supplementation in patients with Rett syndrome (RTT), a devastating neurodevelopmental disorder with transient autistic features, affecting almost exclusively females and mainly caused by sporadic mutations in the gene encoding the methyl CpG binding protein 2 (MeCP2) protein. Here, we tested the hypothesis that-3 PUFAs may modify the plasma proteome profile in typical RTT patients with MECP2 mutations and classic phenotype. A total of 24 RTT girls at different clinical stages were supplemented with-3 PUFAs as fish oil for 12 months and compared to matched healthy controls. The expression of 16 proteins, mainly related to acute phase response (APR), was changed at the baseline in the untreated patients. Following-3 PUFAs supplementation, the detected APR was partially rescued, with the expression of 10 out of 16 (62%) proteins being normalized.-3 PUFAs have a major impact on the modulation of the APR in RTT, thus providing new insights into the role of inflammation in autistic disorders and paving the way for novel therapeutic strategies.
Free Radical Biology and Medicine, Aug 1, 2019
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Frontiers in Neurology, Mar 29, 2022
Background: Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopme... more Background: Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopmental disorder almost exclusively affecting females. RTT is linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Our aim was to assess the clinical relevance of apneas during sleep-wakefulness cycle in a population with RTT and the possible impact of apneas on circulating oxidative stress markers. Methods: Female patients with a clinical diagnosis of typical RTT (n = 66), MECP2 gene mutation, and apneas were enrolled (mean age: 12.5 years). Baseline clinical severity, arterial blood gas analysis, and red blood cell count were assessed. Breathing was monitored during the wakefulness and sleep states (average recording time: 13 ± 0.5 h) with a portable polygraphic screening device. According to prevalence of breath holdings, the population was categorized into the wakefulness apnea (WA) and sleep apnea (SA) groups, and apnea-hypopnea index (AHI) was calculated. The impact of respiratory events on oxidative stress was assessed by plasma and intra-erythrocyte non-protein-bound iron (P-NPBI and IE-NPBI, respectively), and plasma F 2-isoprostane (F 2-IsoP) assays. Results: Significant prevalence of obstructive apneas with values of AHI > 15 was present in 69.7% of the population with RTT. The group with SA showed significantly increased AHI values > 15 (p = 0.0032), total breath holding episodes (p = 0.007), and average SpO 2 (p = 0.0001) as well as lower nadir SpO 2 (p = 0.0004) compared with the patients with WAs. The subgroups of patients with WA and SA showed no significant differences in arterial blood gas analysis variables (p > 0.089). Decreased mean cell hemoglobin (MCH) (p = 0.038) was observed in the group with WAs. P-NPBI levels were significantly higher in the group with WA than in that with SAs (p = 0.0001). Stepwise multiple linear regression models showed WA being related to nadir SpO 2 , average SpO 2 , and P-NPBI (adjusted R 2 = 0.613, multiple correlation Leoncini et al. WA-Related P-NPBI in Rett Syndrome coefficient = 0.795 p < 0.0001), and P-NPBI being related to average SpO 2 , blood PaCO 2 , red blood cell mean corpuscular volume (MCV), age, and topiramate treatment (adjusted R 2 = 0.551, multiple correlation coefficient = 0.765, p < 0.0001). Conclusion: Our findings indicate that the impact of apneas in RTT is uneven according to the sleep-wakefulness cycle, and that plasma redox active iron represents a potential novel therapeutic target.
In condizioni fisiologiche, i globuli rossi - cellule dalle dimensioni di 7-8 m (millesimo di mm)... more In condizioni fisiologiche, i globuli rossi - cellule dalle dimensioni di 7-8 m (millesimo di mm) - mostrano una caratteristica forma a disco biconcavo (discociti), di importanza chiave per tutte le loro funzioni, quali la deformabilità (per adattarsi alle sinuosità della rete circolatoria), e lo scambio di ossigeno (O2), ma sono molto suscettibili a cambiamenti morfologici, con conseguente perdita della loro funzionalità. Tra i fattori che causano alterazioni morfologiche ci possono essere i cambiamenti di osmolarità, di pH, condizioni di ipossia e presenza di ossidanti (sostanze o molecole che possono indurre stress ossidativo) [1-5]. I globuli rossi a causa degli alti livelli di ferro cellulare e della proprietà dell’emoglobina ad auto-ossidarsi, sono una costante sorgente di produzione di ossidanti (radicali liberi dell’ossigeno come l’anione superossido) [6,7] e di ferro in forma libera (NPBI), cioè non legato a proteine, redox attivo. Stress ossidativo (SO) e ipossia possono portare ad alterazioni nella forma dei globuli rossi in pazienti adulti con malattia polmonare cronica ostruttiva (COPD) [7,8]. Nella forma tipica della sindrome di Rett (RTT ) il nostro gruppo ha dimostrato la presenza di ipossia cronica, alterati scambi di gas a livello polmonare, aumentato SO e lesioni morfologiche polmonari, simili a quelle evidenziabili nella malattia polmonare interstiziale associata a bronchiolite respiratoria dei fumatori (RB-ILD) [9,10]. Nonostante i globuli rossi svolgano un ruolo fondamentale nel trasporto e scambio di O2 nei mammiferi, finora non esistevano informazioni sulla morfologia dei globuli rossi nelle bimbe e ragazze affette da RTT . In particolare, nei nostri precedenti studi avevamo dimostrato che lo SO è in grado di indurre nei globuli rossi rilascio di NPBI, formazione di metemoglobina (Met-Hb) e alterazioni ossidative dei lipidi (perossidazione lipidica) e delle proteine di membrana [11]. Quindi nel presente studio abbiamo valutato se lo SO possa indurre cambiamenti morfologici e danno ossidativo nei globuli rossi di pazienti Rett con forma classica. La forma dei globuli rossi in pazienti RTT e in soggetti sani è stata correlata ai marker di SO, stato di ossigenazione, scambi gassosi polmonari e vari parametri cardiorespiratori
Free Radical Biology and Medicine, Sep 1, 2004
F 2-isoprostanes, prostaglandin F 2-like compounds formed by free radical-catalyzed lipid peroxid... more F 2-isoprostanes, prostaglandin F 2-like compounds formed by free radical-catalyzed lipid peroxidation, are considered the most reliable markers of oxidative stress. It has been repeatedly suggested that newborns are exposed to conditions of oxidative stress resulting from the change from a low oxygen pressure in utero to a high oxygen pressure at birth. We measured the levels of F 2-isoprostanes in plasma of newborns by gas chromatography/mass spectrometry and we found that F 2-isoprostanes are significantly higher in term newborns compared to healthy adults. The greatest values were found in preterm newborns in whom F 2-isoprostanes are even higher than in term babies. Moreover a significant inverse correlation was found between the plasma levels of isoprostanes and the gestational age. A quite normal level of isoprostanes was found in the mothers both at delivery and during pregnancy. Placental total F 2-isoprostanes (sum of free plus esterified) were significantly higher in preterm compared to term deliveries and such a difference might account for the difference in plasma isoprostanes. Plasma non-protein-bound iron is higher in preterm than in term newborns, even if no correlation was found with plasma F 2-isoprostanes. Erythrocyte desferrioxamine-chelatable iron content (0 time) and release (24 h of aerobic incubation) are higher in newborns than in adults and in preterm than in term newborns, but again no correlation was found with plasma F 2-isoprostanes. The marked increase in plasma isoprostanes suggests that oxidative stress is a feature of the physiopathological changes seen in the perinatal period.
Springer eBooks, 2014
Rett syndrome (RTT) is a relatively rare form of autism, affecting almost exclusively females, wh... more Rett syndrome (RTT) is a relatively rare form of autism, affecting almost exclusively females, which is caused in the overwhelming majority of cases by the X-linked methyl-CpG binding protein 2 gene (MeCP2) gene and for which no definitive cure exists to date. RTT can be considered a very interesting natural model of autism spectrum disorder, ultimately ending up in a neuronal disease, with reduced brain size, smaller neuronal soma, presynaptic abnormalities, and postsynaptic morphological defects resulting in an overall decrease in synapse number and creating an abnormal excitatory/inhibitory balance. Ongoing investigations by our group have pointed out a previously unrecognized role of oxidative imbalance in the pathogenesis of this condition characterized by wide phenotypic variability. Here, we explore the potential value as biomarkers for a series of F2-IsoP-like molecules, termed F4-neuroprostanes (F4-NeuroPs) and representing the oxidation end-products from docosahexaenoic acid (DHA C22:6 ω-3), an essential constituent of the nervous tissue which is particularly enriched in neuronal membranes. Our investigations, performed in a large RTT patients cohort, indicate that plasma F4-NeuroPs concentrations are proportional to phenotype severity and type of MeCP2 mutation. These data underline the unrecognized role of oxidative damage in the pathogenesis of this genetic model of autism, and indicate the potential value of plasma F4-NeuroPs as a potential biomarker helpful in screening the disease
Journal of the Siena Academy of Sciences, Jul 27, 2017
Herd immunity towards measles, one of the 20 most lethal diseases in human history, has been rece... more Herd immunity towards measles, one of the 20 most lethal diseases in human history, has been recently challenged on a global scale. Despite a missing causal relationship, vaccine fear has triggered a global anti vaccine movement. We investigated i) the extent of the vaccination-autism false belief in a selected Italian population from two geographical areas with and without an ongoing epidemics for a potentially vaccination-preventable infectious disease (Neisseria meningitidis, groups C and B); ii) the corresponding information source; and iii) the belief in a possible global conspiracy. Four different population sub-categories (I-general population; II-parents of autistic children; III-paramedics; IV-physicians, biologists and pharmacists; n=424) were administered anonymous questionnaires. A total of 30.1% of the general population and the 54.5% of autism parents participants believed in a vaccine-autism relationship (P<0.0001). The web was the major information source for the general population (35.3%). A total of 41.6% of the general population believes in a cover up of potential conflicts of interests by the Institutions. The belief in the autism-vaccination link was also positively related to the parenthood of an autistic child (OR:5.78, 95%CI: 2.36 to 14.12). We conclude that, against scientific evidence, information source and emotional involvement are major influencers of the misperception in the vaccine-autism paradigm, potentially fuelling the resurgence of vaccinepreventable diseases with major public health consequences.
Current Proteomics, Jan 18, 2016
Neuroscience Research, Apr 1, 2016
Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome ... more Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50kDa protein i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5.
Free Radical Research, Nov 23, 2016
IsoPs, F 2-dihomo-isoprostanes; F 2-IsoPs, F 2-Isoprostanes; F 4-Neuro-Ps, F 4-neuroprostanes; IE... more IsoPs, F 2-dihomo-isoprostanes; F 2-IsoPs, F 2-Isoprostanes; F 4-Neuro-Ps, F 4-neuroprostanes; IE-NPBI, intraerythrocyte non-protein bound iron; IREs, iron responsive elements; NPBI, nonprotein bound iron; OS, oxidative stress; P-NPBI, plasma non-protein bound iron; RBC, erythrocytes; RCPM, Raven's colored progressive matrices; ROS, reactive oxygen species; STI, serum total iron; tert-BHP, tert-butyl hydroperoxide; TIBC, total iron-binding capacity.
Mediators of Inflammation, 2014
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the ... more Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n = 228) and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ∼80% (184/228) of patients versus ∼18% of healthy controls, with "high" (39.8%) and "low" (34.8%) patterns dominating over "mixed" (19.6%) and "simple mismatch" (5.9%) types. Increased plasma levels of nonprotein-bound iron (NPBI), F 2-isoprostanes (F 2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F 2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.
Mediators of Inflammation, 2013
Autism spectrum disorders (ASDs) are a complex group of neurodevelopment disorders steadily risin... more Autism spectrum disorders (ASDs) are a complex group of neurodevelopment disorders steadily rising in frequency and treatment refractory, where the search for biological markers is of paramount importance. Although red blood cells (RBCs) membrane lipidomics and rheological variables have been reported to be altered, with some suggestions indicating an increased lipid peroxidation in the erythrocyte membrane, to date no information exists on how the oxidative membrane damage may affect cytoskeletal membrane proteins and, ultimately, RBCs shape in autism. Here, we investigated RBC morphology by scanning electron microscopy in patients with classical autism, that is, the predominant ASDs phenotype (age range: 6-26 years), nonautistic neurodevelopmental disorders (i.e., "positive controls"), and healthy controls (i.e., "negative controls"). A high percentage of altered RBCs shapes, predominantly elliptocytes, was observed in autistic patients, but not in both control groups. The RBCs altered morphology in autistic subjects was related to increased erythrocyte membrane F 2-isoprostanes and 4-hydroxynonenal protein adducts. In addition, an oxidative damage of the erythrocyte membrane-actin protein was evidenced. Therefore, the combination of erythrocyte shape abnormalities, erythrocyte membrane oxidative damage, and-actin alterations constitutes a previously unrecognized triad in classical autism and provides new biological markers in the diagnostic workup of ASDs.
European Journal of Echocardiography, Nov 23, 2011
Rett syndrome (RTT) is a rare neurodevelopmental disorder frequently linked to methyl-CpG-binding... more Rett syndrome (RTT) is a rare neurodevelopmental disorder frequently linked to methyl-CpG-binding protein 2 (MeCP2) gene mutations. RTT is associated with a 300-fold increased risk of sudden cardiac death. Rhythm abnormalities and cardiac dysautonomia do not to fully account for cardiac mortality. Conversely, heart function in RTT has not been explored to date. Recent data indicate a previously unrecognized role of MeCP2 in cardiomyocytes development. Besides, increased oxidative stress markers (OS) have been found in RTT. We hypothesized that (i) RTT patients present a subclinical biventricular dysfunction and (ii) the myocardial dysfunction correlate with OS. Methods and results We evaluated typical (n ¼ 72) and atypical (n ¼ 20) RTT female and healthy controls (n ¼ 92). Main outcome measurements were (i) echocardiographic biventricular systo-diastolic parameters; (ii) correlation between echocardiographic measures and OS levels, i.e. plasma and intra-erythrocyte non-protein-bound iron (NPBI) and plasma F2-Isoprostanes (F2-IsoPs). A significant reduction in longitudinal biventricular function (tricuspid annular plane systolic excursion, mitral annular plane systolic excursion, S ′ of lateral and septal mitral annulus, S ′ of tricuspidal annulus) was evidenced in RTT patients vs. controls. No significant changes in the LV ejection fraction were found. Peak-early filling parameters (E, E ′ of lateral mitral annulus, E ′ of tricuspidal annulus) and right ventricular systolic pressure were reduced. A-wave, E/A, and E/E ′ were normal. OS markers were increased, but only F2-IsoPs correlated to LV systolic dysfunction. Conclusion These data indicate a previously unrecognized subclinical systo-diastolic biventricular myocardial dysfunction in typical and atypical RTT patients. A reduced preload is evidenced. The biventricular dysfunction is partially related to OS damage.
Genes and Nutrition, Mar 8, 2012
Evidence of enhanced oxidative stress (O.S.) and lipid peroxidation has been reported in patients... more Evidence of enhanced oxidative stress (O.S.) and lipid peroxidation has been reported in patients with Rett syndrome (RTT), a relatively rare neurodevelopmental disorder progressing in 4-stages, and mainly caused by loss-of-function mutations in the methyl-CpG-binding protein 2. No effective therapy for preventing or arresting the neurologic regression in the disease in its various clinical presentations is available. Based on our prior evidence of enhanced O.S. and lipid peroxidation in RTT patients, herein we tested the possible therapeutic effects of x-3 polyunsaturated fatty acids (x-3 PUFAs), known antioxidants with multiple effects, on the clinical Electronic supplementary material The online version of this article (
Acta Diabetologica, Mar 25, 2011
An increased oxidative stress and a decreased life span of erythrocytes (RBCs) are reported in pa... more An increased oxidative stress and a decreased life span of erythrocytes (RBCs) are reported in patients with diabetes. Aim of this study was to assess in RBCs from patients with type 2 diabetes whether downstream effector mechanisms of apoptosis, such as activation of caspase-3, is operative, and whether an iron-related oxidative imbalance, occurring inside RBCs and in plasma, could be involved in caspase-3 activation. In 26 patients with type 2 diabetes and in 12 healthy subjects, oxidative stress was evaluated by means of different markers; non-protein-bound iron, methemoglobin and glutathione were determined in RBCs, and non-protein-bound iron was also determined in plasma. Erythrocyte caspase-3 activation was evaluated by an immunosorbent enzyme assay. Arterial hypertension, demographic and standard biochemical data were also evaluated. The results show, for the first time, that type 2 diabetic RBCs put into motion caspase-3 activation, which is significantly higher than in control RBCs. Such an effector mechanism of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;eryptosis&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; was positively correlated to blood glucose levels and to the increased plasma NPBI level. Caspase-3 activation was also positively correlated to occurrence of arterial hypertension. The results suggest that an extracellular oxidative milieu can be responsible for erythrocyte caspase-3 activation in patients with type 2 diabetes. In turn, caspase-3 activation can be envisaged as a novel mechanism which, by impairing the maintenance of erythrocyte shape and function, might contribute to the shortened life span of RBCs from patients with type 2 diabetes and to hemorheological disorders observed in these patients.
Frontiers in neurology, Jun 17, 2024
Mediators of Inflammation, 2014
Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk r... more Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk rate for sudden cardiac death. A subclinical myocardial biventricular dysfunction has been recently reported in RTT by our group and found to be associated with an enhanced oxidative stress (OS) status. Here, we tested the effects of the naturally occurring antioxidants-3 polyunsaturated fatty acids (-3 PUFAs) on echocardiographic parameters and systemic OS markers in a population of RTT patients with the typical clinical form. A total of 66 RTT girls were evaluated, half of whom being treated for 12 months with a dietary supplementation of-3 PUFAs at high dosage (docosahexaenoic acid ∼71.9 ± 13.9 mg/kg b.w./day plus eicosapentaenoic acid ∼115.5 ± 22.4 mg/kg b.w./day) versus the remaining half untreated population. Echocardiographic systolic longitudinal parameters of both ventricles, but not biventricular diastolic measures, improved following-3 PUFAs supplementation, with a parallel decrease in the OS markers levels. No significant changes in the examined echocardiographic parameters nor in the OS markers were detectable in the untreated RTT population. Our data indicate that-3 PUFAs are able to improve the biventricular myocardial systolic function in RTT and that this functional gain is partially mediated through a regulation of the redox balance.
Oxidative Medicine and Cellular Longevity (Web), 2015
PubMed, Feb 1, 2014
The oxidative stress (OS) hypothesis is able to explain several features of Rett syndrome (RTT), ... more The oxidative stress (OS) hypothesis is able to explain several features of Rett syndrome (RTT), a pervasive development disorder almost exclusively affecting females mainly caused by a mutation in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. In particular, the generation of an OS imbalance is related to MeCP2 gene mutation type, as well as natural history, clinical heterogeneity of the disease, and is compatible with the potential reversibility of the disease observed in the RTT animal models. In addition, our findings indicate the importance of blood as a suitable biological fluid for detecting markers of central nervous system oxidative damage in RTT and underline the key role of interaction between organic chemists, OS biochemists, and clinicians in revealing potential new markers of the disease and identifying potential new targets and interventional strategies aimed at improving the quality of life of these patients, affected by a so far incurable disease. Further efforts in the near future are needed in order to dissect the "black box" of the molecular events likely linking the MeCP2 gene mutation to OS derangement and subsequent disease expression.
Journal of Proteomics, 2017
Mediators of Inflammation, 2013
The mechanism of action of omega-3 polyunsaturated fatty acids (-3 PUFAs) is only partially known... more The mechanism of action of omega-3 polyunsaturated fatty acids (-3 PUFAs) is only partially known. Prior reports suggest a partial rescue of clinical symptoms and oxidative stress (OS) alterations following-3 PUFAs supplementation in patients with Rett syndrome (RTT), a devastating neurodevelopmental disorder with transient autistic features, affecting almost exclusively females and mainly caused by sporadic mutations in the gene encoding the methyl CpG binding protein 2 (MeCP2) protein. Here, we tested the hypothesis that-3 PUFAs may modify the plasma proteome profile in typical RTT patients with MECP2 mutations and classic phenotype. A total of 24 RTT girls at different clinical stages were supplemented with-3 PUFAs as fish oil for 12 months and compared to matched healthy controls. The expression of 16 proteins, mainly related to acute phase response (APR), was changed at the baseline in the untreated patients. Following-3 PUFAs supplementation, the detected APR was partially rescued, with the expression of 10 out of 16 (62%) proteins being normalized.-3 PUFAs have a major impact on the modulation of the APR in RTT, thus providing new insights into the role of inflammation in autistic disorders and paving the way for novel therapeutic strategies.
Free Radical Biology and Medicine, Aug 1, 2019
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Frontiers in Neurology, Mar 29, 2022
Background: Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopme... more Background: Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopmental disorder almost exclusively affecting females. RTT is linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Our aim was to assess the clinical relevance of apneas during sleep-wakefulness cycle in a population with RTT and the possible impact of apneas on circulating oxidative stress markers. Methods: Female patients with a clinical diagnosis of typical RTT (n = 66), MECP2 gene mutation, and apneas were enrolled (mean age: 12.5 years). Baseline clinical severity, arterial blood gas analysis, and red blood cell count were assessed. Breathing was monitored during the wakefulness and sleep states (average recording time: 13 ± 0.5 h) with a portable polygraphic screening device. According to prevalence of breath holdings, the population was categorized into the wakefulness apnea (WA) and sleep apnea (SA) groups, and apnea-hypopnea index (AHI) was calculated. The impact of respiratory events on oxidative stress was assessed by plasma and intra-erythrocyte non-protein-bound iron (P-NPBI and IE-NPBI, respectively), and plasma F 2-isoprostane (F 2-IsoP) assays. Results: Significant prevalence of obstructive apneas with values of AHI > 15 was present in 69.7% of the population with RTT. The group with SA showed significantly increased AHI values > 15 (p = 0.0032), total breath holding episodes (p = 0.007), and average SpO 2 (p = 0.0001) as well as lower nadir SpO 2 (p = 0.0004) compared with the patients with WAs. The subgroups of patients with WA and SA showed no significant differences in arterial blood gas analysis variables (p > 0.089). Decreased mean cell hemoglobin (MCH) (p = 0.038) was observed in the group with WAs. P-NPBI levels were significantly higher in the group with WA than in that with SAs (p = 0.0001). Stepwise multiple linear regression models showed WA being related to nadir SpO 2 , average SpO 2 , and P-NPBI (adjusted R 2 = 0.613, multiple correlation Leoncini et al. WA-Related P-NPBI in Rett Syndrome coefficient = 0.795 p < 0.0001), and P-NPBI being related to average SpO 2 , blood PaCO 2 , red blood cell mean corpuscular volume (MCV), age, and topiramate treatment (adjusted R 2 = 0.551, multiple correlation coefficient = 0.765, p < 0.0001). Conclusion: Our findings indicate that the impact of apneas in RTT is uneven according to the sleep-wakefulness cycle, and that plasma redox active iron represents a potential novel therapeutic target.
In condizioni fisiologiche, i globuli rossi - cellule dalle dimensioni di 7-8 m (millesimo di mm)... more In condizioni fisiologiche, i globuli rossi - cellule dalle dimensioni di 7-8 m (millesimo di mm) - mostrano una caratteristica forma a disco biconcavo (discociti), di importanza chiave per tutte le loro funzioni, quali la deformabilità (per adattarsi alle sinuosità della rete circolatoria), e lo scambio di ossigeno (O2), ma sono molto suscettibili a cambiamenti morfologici, con conseguente perdita della loro funzionalità. Tra i fattori che causano alterazioni morfologiche ci possono essere i cambiamenti di osmolarità, di pH, condizioni di ipossia e presenza di ossidanti (sostanze o molecole che possono indurre stress ossidativo) [1-5]. I globuli rossi a causa degli alti livelli di ferro cellulare e della proprietà dell’emoglobina ad auto-ossidarsi, sono una costante sorgente di produzione di ossidanti (radicali liberi dell’ossigeno come l’anione superossido) [6,7] e di ferro in forma libera (NPBI), cioè non legato a proteine, redox attivo. Stress ossidativo (SO) e ipossia possono portare ad alterazioni nella forma dei globuli rossi in pazienti adulti con malattia polmonare cronica ostruttiva (COPD) [7,8]. Nella forma tipica della sindrome di Rett (RTT ) il nostro gruppo ha dimostrato la presenza di ipossia cronica, alterati scambi di gas a livello polmonare, aumentato SO e lesioni morfologiche polmonari, simili a quelle evidenziabili nella malattia polmonare interstiziale associata a bronchiolite respiratoria dei fumatori (RB-ILD) [9,10]. Nonostante i globuli rossi svolgano un ruolo fondamentale nel trasporto e scambio di O2 nei mammiferi, finora non esistevano informazioni sulla morfologia dei globuli rossi nelle bimbe e ragazze affette da RTT . In particolare, nei nostri precedenti studi avevamo dimostrato che lo SO è in grado di indurre nei globuli rossi rilascio di NPBI, formazione di metemoglobina (Met-Hb) e alterazioni ossidative dei lipidi (perossidazione lipidica) e delle proteine di membrana [11]. Quindi nel presente studio abbiamo valutato se lo SO possa indurre cambiamenti morfologici e danno ossidativo nei globuli rossi di pazienti Rett con forma classica. La forma dei globuli rossi in pazienti RTT e in soggetti sani è stata correlata ai marker di SO, stato di ossigenazione, scambi gassosi polmonari e vari parametri cardiorespiratori
Free Radical Biology and Medicine, Sep 1, 2004
F 2-isoprostanes, prostaglandin F 2-like compounds formed by free radical-catalyzed lipid peroxid... more F 2-isoprostanes, prostaglandin F 2-like compounds formed by free radical-catalyzed lipid peroxidation, are considered the most reliable markers of oxidative stress. It has been repeatedly suggested that newborns are exposed to conditions of oxidative stress resulting from the change from a low oxygen pressure in utero to a high oxygen pressure at birth. We measured the levels of F 2-isoprostanes in plasma of newborns by gas chromatography/mass spectrometry and we found that F 2-isoprostanes are significantly higher in term newborns compared to healthy adults. The greatest values were found in preterm newborns in whom F 2-isoprostanes are even higher than in term babies. Moreover a significant inverse correlation was found between the plasma levels of isoprostanes and the gestational age. A quite normal level of isoprostanes was found in the mothers both at delivery and during pregnancy. Placental total F 2-isoprostanes (sum of free plus esterified) were significantly higher in preterm compared to term deliveries and such a difference might account for the difference in plasma isoprostanes. Plasma non-protein-bound iron is higher in preterm than in term newborns, even if no correlation was found with plasma F 2-isoprostanes. Erythrocyte desferrioxamine-chelatable iron content (0 time) and release (24 h of aerobic incubation) are higher in newborns than in adults and in preterm than in term newborns, but again no correlation was found with plasma F 2-isoprostanes. The marked increase in plasma isoprostanes suggests that oxidative stress is a feature of the physiopathological changes seen in the perinatal period.
Springer eBooks, 2014
Rett syndrome (RTT) is a relatively rare form of autism, affecting almost exclusively females, wh... more Rett syndrome (RTT) is a relatively rare form of autism, affecting almost exclusively females, which is caused in the overwhelming majority of cases by the X-linked methyl-CpG binding protein 2 gene (MeCP2) gene and for which no definitive cure exists to date. RTT can be considered a very interesting natural model of autism spectrum disorder, ultimately ending up in a neuronal disease, with reduced brain size, smaller neuronal soma, presynaptic abnormalities, and postsynaptic morphological defects resulting in an overall decrease in synapse number and creating an abnormal excitatory/inhibitory balance. Ongoing investigations by our group have pointed out a previously unrecognized role of oxidative imbalance in the pathogenesis of this condition characterized by wide phenotypic variability. Here, we explore the potential value as biomarkers for a series of F2-IsoP-like molecules, termed F4-neuroprostanes (F4-NeuroPs) and representing the oxidation end-products from docosahexaenoic acid (DHA C22:6 ω-3), an essential constituent of the nervous tissue which is particularly enriched in neuronal membranes. Our investigations, performed in a large RTT patients cohort, indicate that plasma F4-NeuroPs concentrations are proportional to phenotype severity and type of MeCP2 mutation. These data underline the unrecognized role of oxidative damage in the pathogenesis of this genetic model of autism, and indicate the potential value of plasma F4-NeuroPs as a potential biomarker helpful in screening the disease
Journal of the Siena Academy of Sciences, Jul 27, 2017
Herd immunity towards measles, one of the 20 most lethal diseases in human history, has been rece... more Herd immunity towards measles, one of the 20 most lethal diseases in human history, has been recently challenged on a global scale. Despite a missing causal relationship, vaccine fear has triggered a global anti vaccine movement. We investigated i) the extent of the vaccination-autism false belief in a selected Italian population from two geographical areas with and without an ongoing epidemics for a potentially vaccination-preventable infectious disease (Neisseria meningitidis, groups C and B); ii) the corresponding information source; and iii) the belief in a possible global conspiracy. Four different population sub-categories (I-general population; II-parents of autistic children; III-paramedics; IV-physicians, biologists and pharmacists; n=424) were administered anonymous questionnaires. A total of 30.1% of the general population and the 54.5% of autism parents participants believed in a vaccine-autism relationship (P<0.0001). The web was the major information source for the general population (35.3%). A total of 41.6% of the general population believes in a cover up of potential conflicts of interests by the Institutions. The belief in the autism-vaccination link was also positively related to the parenthood of an autistic child (OR:5.78, 95%CI: 2.36 to 14.12). We conclude that, against scientific evidence, information source and emotional involvement are major influencers of the misperception in the vaccine-autism paradigm, potentially fuelling the resurgence of vaccinepreventable diseases with major public health consequences.
Current Proteomics, Jan 18, 2016
Neuroscience Research, Apr 1, 2016
Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome ... more Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50kDa protein i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5.
Free Radical Research, Nov 23, 2016
IsoPs, F 2-dihomo-isoprostanes; F 2-IsoPs, F 2-Isoprostanes; F 4-Neuro-Ps, F 4-neuroprostanes; IE... more IsoPs, F 2-dihomo-isoprostanes; F 2-IsoPs, F 2-Isoprostanes; F 4-Neuro-Ps, F 4-neuroprostanes; IE-NPBI, intraerythrocyte non-protein bound iron; IREs, iron responsive elements; NPBI, nonprotein bound iron; OS, oxidative stress; P-NPBI, plasma non-protein bound iron; RBC, erythrocytes; RCPM, Raven's colored progressive matrices; ROS, reactive oxygen species; STI, serum total iron; tert-BHP, tert-butyl hydroperoxide; TIBC, total iron-binding capacity.
Mediators of Inflammation, 2014
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the ... more Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n = 228) and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ∼80% (184/228) of patients versus ∼18% of healthy controls, with "high" (39.8%) and "low" (34.8%) patterns dominating over "mixed" (19.6%) and "simple mismatch" (5.9%) types. Increased plasma levels of nonprotein-bound iron (NPBI), F 2-isoprostanes (F 2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F 2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.
Mediators of Inflammation, 2013
Autism spectrum disorders (ASDs) are a complex group of neurodevelopment disorders steadily risin... more Autism spectrum disorders (ASDs) are a complex group of neurodevelopment disorders steadily rising in frequency and treatment refractory, where the search for biological markers is of paramount importance. Although red blood cells (RBCs) membrane lipidomics and rheological variables have been reported to be altered, with some suggestions indicating an increased lipid peroxidation in the erythrocyte membrane, to date no information exists on how the oxidative membrane damage may affect cytoskeletal membrane proteins and, ultimately, RBCs shape in autism. Here, we investigated RBC morphology by scanning electron microscopy in patients with classical autism, that is, the predominant ASDs phenotype (age range: 6-26 years), nonautistic neurodevelopmental disorders (i.e., "positive controls"), and healthy controls (i.e., "negative controls"). A high percentage of altered RBCs shapes, predominantly elliptocytes, was observed in autistic patients, but not in both control groups. The RBCs altered morphology in autistic subjects was related to increased erythrocyte membrane F 2-isoprostanes and 4-hydroxynonenal protein adducts. In addition, an oxidative damage of the erythrocyte membrane-actin protein was evidenced. Therefore, the combination of erythrocyte shape abnormalities, erythrocyte membrane oxidative damage, and-actin alterations constitutes a previously unrecognized triad in classical autism and provides new biological markers in the diagnostic workup of ASDs.
European Journal of Echocardiography, Nov 23, 2011
Rett syndrome (RTT) is a rare neurodevelopmental disorder frequently linked to methyl-CpG-binding... more Rett syndrome (RTT) is a rare neurodevelopmental disorder frequently linked to methyl-CpG-binding protein 2 (MeCP2) gene mutations. RTT is associated with a 300-fold increased risk of sudden cardiac death. Rhythm abnormalities and cardiac dysautonomia do not to fully account for cardiac mortality. Conversely, heart function in RTT has not been explored to date. Recent data indicate a previously unrecognized role of MeCP2 in cardiomyocytes development. Besides, increased oxidative stress markers (OS) have been found in RTT. We hypothesized that (i) RTT patients present a subclinical biventricular dysfunction and (ii) the myocardial dysfunction correlate with OS. Methods and results We evaluated typical (n ¼ 72) and atypical (n ¼ 20) RTT female and healthy controls (n ¼ 92). Main outcome measurements were (i) echocardiographic biventricular systo-diastolic parameters; (ii) correlation between echocardiographic measures and OS levels, i.e. plasma and intra-erythrocyte non-protein-bound iron (NPBI) and plasma F2-Isoprostanes (F2-IsoPs). A significant reduction in longitudinal biventricular function (tricuspid annular plane systolic excursion, mitral annular plane systolic excursion, S ′ of lateral and septal mitral annulus, S ′ of tricuspidal annulus) was evidenced in RTT patients vs. controls. No significant changes in the LV ejection fraction were found. Peak-early filling parameters (E, E ′ of lateral mitral annulus, E ′ of tricuspidal annulus) and right ventricular systolic pressure were reduced. A-wave, E/A, and E/E ′ were normal. OS markers were increased, but only F2-IsoPs correlated to LV systolic dysfunction. Conclusion These data indicate a previously unrecognized subclinical systo-diastolic biventricular myocardial dysfunction in typical and atypical RTT patients. A reduced preload is evidenced. The biventricular dysfunction is partially related to OS damage.
Genes and Nutrition, Mar 8, 2012
Evidence of enhanced oxidative stress (O.S.) and lipid peroxidation has been reported in patients... more Evidence of enhanced oxidative stress (O.S.) and lipid peroxidation has been reported in patients with Rett syndrome (RTT), a relatively rare neurodevelopmental disorder progressing in 4-stages, and mainly caused by loss-of-function mutations in the methyl-CpG-binding protein 2. No effective therapy for preventing or arresting the neurologic regression in the disease in its various clinical presentations is available. Based on our prior evidence of enhanced O.S. and lipid peroxidation in RTT patients, herein we tested the possible therapeutic effects of x-3 polyunsaturated fatty acids (x-3 PUFAs), known antioxidants with multiple effects, on the clinical Electronic supplementary material The online version of this article (
Acta Diabetologica, Mar 25, 2011
An increased oxidative stress and a decreased life span of erythrocytes (RBCs) are reported in pa... more An increased oxidative stress and a decreased life span of erythrocytes (RBCs) are reported in patients with diabetes. Aim of this study was to assess in RBCs from patients with type 2 diabetes whether downstream effector mechanisms of apoptosis, such as activation of caspase-3, is operative, and whether an iron-related oxidative imbalance, occurring inside RBCs and in plasma, could be involved in caspase-3 activation. In 26 patients with type 2 diabetes and in 12 healthy subjects, oxidative stress was evaluated by means of different markers; non-protein-bound iron, methemoglobin and glutathione were determined in RBCs, and non-protein-bound iron was also determined in plasma. Erythrocyte caspase-3 activation was evaluated by an immunosorbent enzyme assay. Arterial hypertension, demographic and standard biochemical data were also evaluated. The results show, for the first time, that type 2 diabetic RBCs put into motion caspase-3 activation, which is significantly higher than in control RBCs. Such an effector mechanism of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;eryptosis&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; was positively correlated to blood glucose levels and to the increased plasma NPBI level. Caspase-3 activation was also positively correlated to occurrence of arterial hypertension. The results suggest that an extracellular oxidative milieu can be responsible for erythrocyte caspase-3 activation in patients with type 2 diabetes. In turn, caspase-3 activation can be envisaged as a novel mechanism which, by impairing the maintenance of erythrocyte shape and function, might contribute to the shortened life span of RBCs from patients with type 2 diabetes and to hemorheological disorders observed in these patients.