Plasma amino acids and neopterin in healthy persons with Down’s syndrome

In persons with Down’s syndrome (DS) immunological abnormalities as well as hypothyroidism and Alzheimer type dementia are frequently observed. In addition, the activity of the enzyme cystathionine beta-synthase (CBS) is over-expressed which results in an altered homocysteine metabolism

Effects of interferon-alpha on the inflammatory response of swine peripheral blood mononuclear cells

Interferon-\u3b1 (IFN-\u3b1) at low concentrations had been previously shown to control the expression of inflammatory cytokine genes in swine pulmonary alveolar macrophages. In the first part of this study, cultured swine peripheral blood mononuclear cells (PBMCs) were supplemented with IFN-\u3b1 at low/moderate concentrations, and then stimulated with lipopolysaccharide (LPS). The expression of IFN-\u3b1, IFN-\u3b3, IL-1\u392, TNF-\u3b1, and IL-6 genes was determined by real-time PCR. IFN-\u3b1 at low/moderate concentrations did not significantly reduce the expression of any cytokine gene under study, with clear trends though to a concentration-dependent reduction of IL-1\u392 gene expression and to a concentration-dependent increase of IFN-\u3b3 gene expression. In vivo, orally administered IFN-\u3b1 was shown instead to modulate the inflammatory response to early weaning in uncultured PBMCs of specific pathogen-free piglets. As opposed to the in vitro model, the oral IFN-\u3b1 treatment reduced after weaning the expression of the IFN-\u3b3 gene (P < 0.08) and increased that of the IL-1\u392 gene (P < 0.05). There was also a trend to a reduced expression of both IL-6 and TNF-\u3b1. The above modulation of cytokine genes expression and the greater daily mean weight gain of treated piglets highlight important regulatory properties of oral IFN-\u3b1 in the response to the weaning stress

Lymphomonocyte alpha-synuclein levels in aging and in Parkinson disease

In this study we employed an ELISA assay to measure alpha-synuclein protein in lymphomonocytes from 78 PD patients and 78 controls. We correlated protein levels with demographic and clinical characteristics and with the chymotryptic and tryptic activities of the 20S proteasome. Alpha-synuclein levels were not significantly different between patients and controls. In control subjects, alpha-synuclein protein levels increased significantly with age and were significantly higher in men compared to women. Proteasome activity was not significantly different between cases and controls. In control group, the 20S chymotryptic activity tended to decrease significantly with increasing age, though it was not correlated to alpha-synuclein levels. The 20S tryptic activity was not significantly correlated to age, but was inversely correlated to alpha-synuclein levels. Our findings suggest that alpha-synuclein levels in lymphomonocytes are affected by age, gender, and by the 20S proteasome activity in control subjects, but they are not useful as a diagnostic biomarker for PD

Prenatal N-acetyl-cysteine administration moderates the long-term negative effects of maternal obesity in adolescent male and female mouse offspring

Obesity during pregnancy may affect offspring developmental trajectories representing a risk factor for mental health. Amongst the mechanisms called into question inflammation, oxidative stress and the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis appear as the most suitable. We investigated the emotional phenotype of male and female offspring of dams exposed to a high-fat diet (HFD, a mouse model of maternal obesity) before and during pregnancy. We also tested the efficacy of N-acetyl-cysteine (NAC – an antioxidant) in preventing the negative effects of HFD. We focused on adolescence, an age of main vulnerability for the onset of psychopathologies. Female C57BL/6N mice were fed HFD for 13 weeks and, after 5 weeks, were also exposed to NAC (1 g/kg b.w.) via drinking water, until delivery. Emotionality was assessed in 35-45-day-old adolescent mice by means of the elevated-plus-maze (EPM) and social interaction tests (SIT). A forced swimming test was used both to evaluate depressive-like behaviour as well as a stressful challenge to measure HPA axis reactivity. NAC was effective in moderating body weight gain in HFD-treated dams. Prenatal HFD reduced exploratory behaviours in the EPM in periadolescent offspring; NAC administration resulting in increased social interactions in the offspring of HFD dams. Analyses of depression-like behaviours, HPA axis functionality and brain transcriptomics are currently ongoing for mechanistic insight. Data from these studies indicate that the long-term effects of maternal obesity may be mediated by changes in oxidative stress and point to NAC as a potential preventive strategy. ERANET-NEURON-JTC 2018 (Mental Disorders) Project ‘‘EMBED”

Prenatal N-acetyl-cysteine administration alleviates the long-term effects of maternal obesity of adolescent male and female mouse offspring

Introduction. High-fat diet (HFD) consumption during pregnancy may act as a prenatal stressor affecting foetal brain developmental and representing an important risk factor for mental health. Indeed, offspring of obese mothers are prenatally over-exposed to increased levels of oxidative stress, hormones and pro-inflammatory cytokines, that all together can dramatically alter the development of neuronal circuits involved in the regulation of behaviour and mood. N-acetyl-cysteine (NAC) is a promising antioxidant compound that has revealed beneficial effects in the treatment of psychopathology. Aim. The aim of this study was to evaluate the general neurodevelopment, the social behaviour and the emotional phenotype of male and female offspring of dams exposed to a HFD (a mouse model of maternal obesity) before and during pregnancy. Furthermore, we tested the efficacy of prenatal NAC administration in preventing the negative effects of maternal HFD. We focused on adolescence, an age of main vulnerability for the onset of psychopathologies. Methods. Female C57BL/6N mice were fed either HFD (energy 5.56 kcal/g, fat 58%, carbohydrate 25.5% and protein 16.4%) or control diet (CD, energy 4.07 kcal/g, fat 10.5%, carbohydrate 73.1% and protein 16.4%) for 13 weeks and, after 5 weeks, were also exposed to NAC (1 g/kg body weight) via drinking water, until delivery. The general neurodevelopment of offspring was assessed through the Homing test at post-natal day (PND) 10; emotionality and social behaviour were assessed during adolescence (PND 35-45) by means of the elevated-plus-maze (EPM) and social interaction tests (SIT). A forced swimming test was used both to evaluate depressive-like behaviour as well as a stressful challenge to measure hypothalamic-pituitary-adrenal (HPA) axis reactivity. Transcriptomic analysis on hippocampus were performed in order to identify mechanisms of action of both HFD and NAC. Data were analysed using parametric analysis of variance (ANOVA) with Prenatal diet (HFD vs. CD), Prenatal treatment (NAC vs. WATER), Sex (females vs. males) as between subjects factors and time blocks as within-subjects repeated measures (i.e. body weight). Post hoc comparisons were performed using the Tukey’s test. Results. NAC was effective in moderating body weight gain in HFD-fed dams (Diet x Treatment x time p=0.0078, post hoc HFD-WATER vs. HFD-NAC p&lt;0.05). Neither HFD or NAC affected neurodevelopment of offspring at PND 10. Prenatal HFD reduced exploratory behaviours in the EPM (main effect of Prenatal diet in frequency of crossings p=0.0001; frequency of head dipping p=0.0292; frequency of wall-rearing p=0.0255) and decreased sociability (Prenatal diet x Prenatal treatment in the duration of sniff the cospecific subject p=0.0002, post hoc CD-WATER vs. HFD-WATER p&lt;0.05) in the SIT in periadolescent offspring. Prenatal NAC administration was effective in preventing social anxiety in offspring of HFD-fed dams (post hoc HFD-WATER vs. HFD NAC p&lt;0.05). HPA axis functionality and brain transcriptomics are currently ongoing for mechanistic insight. Conclusions. Data from this study indicate that the long-term effects of maternal obesity may be mediated by changes in oxidative stress and point to NAC as a potential preventive strategy. ERANET-NEURON-JTC 2018 (Mental Disorders) Project ‘‘EMBED”

Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease

Several lines of evidence implicate a central role for alpha-synuclein (aSN) in the pathogenesis of Parkinson's disease (PD). Besides rare genetic mutations, post-translational mechanisms, such as oxidative stress-related nitration, may alter the protein properties in terms of propensity to aggregate or be degraded. Our group previously described increased reactive oxygen species (ROS) production within easily accessible peripheral blood mononuclear cells (PBMCs) in PD patients compared to healthy elderly subjects. In the present work, we demonstrated a significant induction of nitrotyrosine (NT)-modifications of aSN within PBMCs derived from individuals with idiopathic PD compared to controls, while aSN protein appeared similarly expressed in the two populations. The amount of NT-modified aSN within PBMCs was positively correlated with intracellular ROS concentration and inversely related to daily dosage of levodopa, making its measurement potentially relevant for disease-intervention studies. Neither aSN expression nor its NT-modifications showed any correlation to specific REP1 genotypes, polymorphic variants within aSN gene promoter whose association to PD susceptibility may occur through the modulation of aSN protein expression. Moreover, although NT-modified aSN has been linked to enhanced propensity to aggregate, we failed to detect an increased presence of insoluble aSN aggregates in PBMCs from PD subjects relative to controls, despite a lack of changes in the ubiquitin-proteasome expression or activity. Nonetheless, a significant activation of the autophagy response was identified within PBMCs from PD individuals, which could represent a protective mechanism against abnormal protein accumulation and may explain the lack of aSN aggregation. We discuss the relevance of these findings with respect to PD pathogenesis and biomarker development