Recent Advances in the Treatment of Neurodegenerative Diseases Based on GSH Delivery Systems

Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease(AD), are a group of pathologies characterized by a progressive and specific loss of certain brain cell populations. Oxidative stress, mitochondrial dysfunction, and apoptosis play interrelated roles in these disorders. It is well documented that free radical oxidative damage, particularly on neuronal lipids, proteins, DNA, and RNA, is extensive in PD and AD brains. Moreover, alterations of glutathione (GSH) metabolism in brain have been implicated in oxidative stress and neurodegenerative diseases. As a consequence, the reduced GSH levels observed in these pathologies have stimulated a number of researchers to find new potential approaches for maintaining or restoring GSH levels. Unfortunately, GSH delivery to the central nervous system (CNS) is limited due to a poor stability and low bioavailability. Medicinal-chemistry- and technology-based approaches are commonly used to improve physicochemical, biopharmaceutical, and drug delivery properties of therapeutic agents. This paper will focus primarily on these approaches used in order to replenish intracellular GSH levels, which are reduced in neurodegenerative diseases. Here, we discuss the beneficial properties of these approaches and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically from PD and AD

Study of cardiomyogenic potential of human Amniotic Fluid Stem Cells

It has been shown that Amniotic fluid stem cells (AFSCs) have characteristics intermediate between pluripotent embryonic and lineage-restricted adult stem cells, and are non-tumorigenic and low immunogenic. Moreover, they are obtained without destroying human embryos, so that preventing most of the ethical and social controversy. Human AFSCs express some genes specific of both embryonic (OCT3/4, NANOG, c-MYC) and primordial germ stem cells (Fragilis, Stella, c-KIT). We have demonstrated that hAFSCs form in vitro embryoid bodies (EBs) and express markers of three germ layers. Studies reported the ability of hAFSCs to differentiate in vitro into adipocytes and osteocytes, but only few data are available on their cardiomyogenic potential. Aim of this study is to analyze hAFSCs differentiation through the cardiac pathway. Embryonic Bodies (EBs) were obtained from hAFSCs cultured in presence of ascorbic acid and 5-aza-2’-deoxycytidine. Cardiomyogenic potential of hAFSCs and EBs was explored by WB and immunoflorescent analyses of specific markers. Simultaneous quantitative detection and cellular localization analysis of cardiomyogenic markers were conducted with an ImageStream multispectral imaging flow cytometer (Amnis-Seattle, WA) equipped with IDEAS statistical software. We evidenced that both AFSCs and EBs at early stage express Nkx2.5, a transcription factor expressed by cardiomyocytes precursor cells. Moreover, ImageStream imaging cytometer analysis evidenced that EBs formation was accompanied by an up-regulation of Nkx2.5 expression (36.54±1.83% and 64.68±3.23% positive cells in hAFSC and EBs respectively, p<.005) and by a significant nuclear translocation (12.98±0.64% and 37.98±1.9% nuclear positive cells in hAFSC and EBs respectively, p<.005). Microscopical analysis evidenced inside the EBs cells positive for the presence of cardiac α-Myosin heavy chain protein structurally organized in oriented filaments. Moreover, we detected cells expressing Connexin43. These results evidenced that EBs obtained from hAFSCs cultured in permissive conditions terminally differentiate into cardiomyocytes and suggest them as possible model to study the cardiac differentiation

Human Cardiopoietic Amniotic Fluid cell population: characterization and terminal differentiation

Rationale. Human amniotic fluid-derived (hAF) stem cells are considered a novel class of multipotent stem cells, sharing characteristics of both embryonic and adult stem cells. In fact, they proliferate rapidly, are able to differentiate into cells of all the embryonic germ layers, but do not form teratoma. It has been already reported that the embryoid bodies (EBs) obtained from hAFs have a cardiac potential, but it has not been described a functional terminal differentiation in cardiomyocytes (CMs) yet. Objective. Aim of this study was to foster the cardiomyogenic potential of hAFs in order to obtain a cellular population with morphological and functional features of CMs. Methods and Results. AFCs were exposed sequentially to inducing factors (Ascorbic Acid, 5-Azacytidine, BMP4, ActivinA, VEGF) up to 15 days and differentiation was monitored. Only the hAF samples expressing the multipotency markers SSEA4, OCT4 and CD90 (CardiopoieticAF) responded to the differentiation process loosing their stemness and increasing the cardiac nuclear factors NKX2.5 and GATA4. After the differentiation cells expressed high levels of the sarcomeric proteins (cTnT, αMHC and αSA), the gap junction marker Connexin43 and both atrial and ventricular markers; moreover, up to 90% of the cells was positive for CACNA1C and SERCA2a, cardiac calcium pumps involved in the excitation/contraction coupling, and about 30% of the CardiopoieticAF-derived cells presented spontaneous intracellular Ca2+ waves and Ca2+ fluctuation in response to caffeine or adrenergic stimulation. Some spontaneous beating foci were also observed. Conclusion. Our results demonstrate that CardiopoietichAFs can fully differentiate into a homogenous population of CM-like cells, characterized by cardiac-specific molecular, structural, and functional properties. Thus, CardiopoietichAFs can hold great promise for the development of in vitro models of cardiac genetic disorders, for drug discovery and testing, and for the emerging field of cardiovascular regenerative medicine

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe

Effects of cognitive feedback, emotional induction and social pressure on decisions related to cognitive performance with economic reward.

The main aim of this study was to investigate whether the effect of induced affective states, obtained through a false (positive vs. negative) feedback in a cognitive task, influenced participants’ choices in a consecutive cognitive task. We also investigated a possible effect of ‘social pressure’ on individual preferences, by introducing information about the percentage of difficulty level choices provided by other participants. The 3 x 2 experimental design involved the manipulation of two between-subjects variables: feedback (positive vs. negative) and social pressure (none vs. prudent vs. hazardous); 180 undergraduates (90 males), with mean age 23.99 (SD=2.89) participated in the experiment as unpaid volunteers. As expected, results showed that the feedback manipulation was highly effective. Results also showed that participants who received a negative feedback chose less difficult tasks, while those receiving a positive feedback preferred more difficult tasks. Some emotions partially mediated such effect. Instead, social pressure did not affect participants’ choice

Contextual information and reappraisal of negative emotional events

In this study the effect of the contextual-information induced reappraisal on modifying the emotional response elicited by failure has been investigated. To an academic or job setting failure (control condition)it has been added one of two types of contextual information (knowing that many other people failed the same task and knowing that it would be possible to try the failed task again) affecting three dimensions of failure appraisal: responsibility, sharing, and remediability. In an experimental condition both information were added. Four hundred and eighty undergraduates participated in this study. The experimental design was a 2 (negative emotional event) x 4 (contextual information) between-subjects design. The first variable was included in the design as covariate. We expected that generalized failure should imply a decrease of responsibility and an increase of sharing, the possibility of retrying should imply an increase in the remediability, and that the presence of both types of information should produce all the abovementioned effects. Our findings substantially corroborated the hypotheses

A Potent (R)-alpha-bis-lipoyl Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human Neuroblastoma Cells

A novel bis-lipoyl derivative containing 8-hydroxyquinoline scaffold (LA-HQ-LA, 5) was synthesized as a new multifunctional drug candidate with antioxidant, chelant, and neuroprotective properties for the treatment of neurodegenerative diseases. We have investigated the potential effectiveness of LA-HQ-LA against the cytotoxicity induced by 6-OHDA and H2O2 on human neuroblastoma SH-SY5Y cell line. Our outcomes showed that LA-HQ-LA resulted in significant neuroprotective and antioxidant effects against H2O2- and 6-OHDA-induced neurotoxicity in human neuroblastoma SH-SY5Y cells, as assessed by MTT assay. In particular, it showed potent neuroprotective effects against 6-OHDA in RA/PMA differentiated cells at all the tested concentrations