Oxidative stress and synaptic dysfunction in rodent models of Parkinson's disease

Parkinson's disease (PD) is a multifactorial disorder involving a complex interplay between a variety of genetic and environmental factors. In this scenario, mitochondrial impairment and oxidative stress are widely accepted as crucial neuropathogenic mechanisms, as also evidenced by the identification of PD-associated genes that are directly involved in mitochondrial function. The concept of mitochondrial dysfunction is closely linked to that of synaptic dysfunction. Indeed, compelling evidence supports the role of mitochondria in synaptic transmission and plasticity, although many aspects have not yet been fully elucidated. Here, we will provide a brief overview of the most relevant evidence obtained in different neurotoxin-based and genetic rodent models of PD, focusing on mitochondrial impairment and synaptopathy, an early central event preceding overt nigrostriatal neurodegeneration. The identification of early deficits occurring in PD pathogenesis is crucial in view of the development of potential disease-modifying therapeutic strategies

Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as “true” P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function

Hand rehabilitation with sonification techniques in the subacute stage of stroke

After a stroke event, most survivors suffer from arm paresis, poor motor control and other disabilities that make activities of daily living difficult, severely affecting quality of life and personal independence. This randomized controlled trial aimed at evaluating the efficacy of a music-based sonification approach on upper limbs motor functions, quality of life and pain perceived during rehabilitation. The study involved 65 subacute stroke individuals during inpatient rehabilitation allocated into 2 groups which underwent usual care dayweek) respectively of standard upper extremity motor rehabilitation or upper extremity treatment with sonification techniques. The Fugl-Meyer Upper Extremity Scale, Box and Block Test and the Modified Ashworth Scale were used to perform motor assessment and the McGill Quality of Life-it and the Numerical Pain Rating Scale to assess quality of life and pain. The assessment was performed at baseline, after 2weeks, at the end of treatment and at follow-up (1month after the end of treatment). Total scores of the Fugl-Meyer Upper Extremity Scale (primary outcome measure) and hand and wrist sub scores, manual dexterity scores of the affected and unaffected limb in the Box and Block Test, pain scores of the Numerical Pain Rating Scale (secondary outcomes measures) significantly improved in the sonification group compared to the standard of care group (time*group interaction<0.05). Our findings suggest that music-based sonification sessions can be considered an effective standardized intervention for the upper limb in subacute stroke rehabilitation

Dietary Vitamin E as a Protective Factor for Parkinson's Disease: Clinical and Experimental Evidence

Effective disease-modifying treatments are an urgent need for Parkinson's disease (PD). A putative successful strategy is to counteract oxidative stress, not only with synthetic compounds, but also with natural agents or dietary choices. Vitamin E, in particular, is a powerful antioxidant, commonly found in vegetables and other components of the diet. In this work, we performed a questionnaire based case-control study on 100 PD patients and 100 healthy controls. The analysis showed that a higher dietary intake of Vitamin E was inversely associated with PD occurrence independently from age and gender (OR = 1.022; 95% CI = 0.999–1.045; p < 0.05), though unrelated to clinical severity. Then, in order to provide a mechanistic explanation for such observation, we tested the effects of Vitamin E and other alimentary antioxidants in vitro, by utilizing the homozygous PTEN-induced kinase 1 knockout (PINK1−/−) mouse model of PD. PINK1−/− mice exhibit peculiar alterations of synaptic plasticity at corticostriatal synapses, consisting in the loss of both long-term potentiation (LTP) and long-term depression (LTD), in the absence of overt neurodegeneration. Chronic administration of Vitamin E (alpha-tocopherol and the water-soluble analog trolox) fully restored corticostriatal synaptic plasticity in PINK1−/− mice, suggestive of a specific protective action. Vitamin E might indeed compensate PINK1 haploinsufficiency and mitochondrial impairment, reverting some central steps of the pathogenic process. Altogether, both clinical and experimental findings suggest that Vitamin E could be a potential, useful agent for PD patients. These data, although preliminary, may encourage future confirmatory trials

Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia

Abstract Dystonia is a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions. Loss-of-function mutations in the GNAL gene have been identified to be the cause of "isolated" dystonia DYT25. The GNAL gene encodes for the guanine nucleotide-binding protein G(olf) subunit alpha (Gαolf), which is mainly expressed in the olfactory bulb and the striatum and functions as a modulator during neurotransmission coupling with D1R and A2AR. Previously, heterozygous Gαolf -deficient mice (Gnal+/−) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnal−/−) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnal+/−) with a 13 base pair deletion in the first exon of the rat Gnal splicing variant 2, a major isoform in both human and rat striatum. Gnal+/− rats showed early-onset phenotypes associated with impaired dopamine transmission, including reduction in locomotor activity, deficits in rotarod performance and an abnormal motor skill learning ability. At cellular and molecular level, we found down-regulated Arc expression, increased cell surface distribution of AMPA receptors, and the loss of D2R-dependent corticostriatal long-term depression (LTD) in Gnal+/− rats. Based on the evidence that D2R activity is normally inhibited by adenosine A2ARs, co-localized on the same population of striatal neurons, we show that blockade of A2ARs restores physiological LTD. This animal model may be a valuable tool for investigating Gαolf function and finding a suitable treatment for dystonia associated with deficient dopamine transmission

Treatment of Biofilm Communities: An Update on New Tools from the Nanosized World

Traditionally regarded as single cell organisms, bacteria naturally and preferentially build multicellular communities that enable them to react efficiently to external stimuli in a coordinated fashion and with extremely effective outcomes. These communities are bacterial biofilms, where single cells or microcolonies are embedded in self-built Extracellular Polymeric Substance (EPS), composed of different macromolecules, e.g., polysaccharides, proteins, lipids, and extracellular DNA (eDNA). Despite being the most common form in nature and having many biotechnologically useful applications, biofilm is often regarded as a life-threatening form of bacterial infection. Since this form of bacterial life is intrinsically more resistant to antibiotic treatment and antimicrobial resistance is reaching alarming levels, we will focus our attention on how nanotechnology made new tools available to the medical community for the prevention and treatment of these infections. After a brief excursus on biofilm formation and its main characteristics, different types of nanomaterials developed to prevent or counteract these multicellular forms of bacterial infection will be described. A comparison of different classifications adopted for nanodrugs and a final discussion of challenges and future perspectives are also presente

Health impact of the emissions from a refinery: case-control study on the adult population living in two municipalities in Lomellina, Italy

Background: In the municipalities of Sannazzaro de’ Burgondi and Ferrer Erbognone (District of Lomellina, Pavia, Lombardy, Italy), an oil refinery is operating since 1963. In 2008, the company running the plant (eni S.p.A.) asked the competent bodies the permission for building a new facility (“EST”). The present work is aimed at evaluating the ante-operam health impacts of the existing facility refinery. Methods: A case-control study design was implemented. Cases were subjects admitted to hospital in 2002-2014 due to acute respiratory, cardiovascular or gastrointestinal conditions. Controls were selected among those who had not been hospitalised in that timespan. Cases and controls had to be alive at enrolment, aged 20-64 years, and were frequency-matched by age, gender and municipality. Data were extracted from the health insurance registry and from Hospital Discharge Records (ATS Pavia). Enrolled subjects were asked to complete a mailed survey. Environmental exposure was the fallout of refinery emissions (PM10) at participants’ homes, as predicted by an AERMOD model. Results: 541 respondents (125 cases, 416 controls) were included in the analyses. Response bias was excluded. Individual PM10 exposure was not significantly different between cases and controls, while it was significantly associated with municipality (being higher in Sannazzaro). The crude effect estimate of PM10 over case/control status indicated a not-significant excess of hospitalisation with the increase in PM10 exposure. Multivariate analyses confirmed those results. Conclusion: Findings indicate a possible excess of hospitalisation risk in most exposed people, but the effect is not statistically significant and may be affected by bias

22Ne and 23Na ejecta from intermediate-mass stars: The impact of the new LUNA rate for 22Ne(p,gamma)23Na

We investigate the impact of the new LUNA rate for the nuclear reaction $^{22}$Ne$(p,\gamma)^{23}$Na on the chemical ejecta of intermediate-mass stars, with particular focus on the thermally-pulsing asymptotic giant branch (TP-AGB) stars that experience hot-bottom burning. To this aim we use the PARSEC and COLIBRI codes to compute the complete evolution, from the pre-main sequence up to the termination of the TP-AGB phase, of a set of stellar models with initial masses in the range $3.0\,M_{\odot} - 6.0\,M_{\odot}$, and metallicities $Z_{\rm i}=0.0005$, $Z_{\rm i}=0.006$, and $Z_{\rm i} = 0.014$. We find that the new LUNA measures have much reduced the nuclear uncertainties of the $^{22}$Ne and $^{23}$Na AGB ejecta, which drop from factors of $\simeq 10$ to only a factor of few for the lowest metallicity models. Relying on the most recent estimations for the destruction rate of $^{23}$Na, the uncertainties that still affect the $^{22}$Ne and $^{23}$Na AGB ejecta are mainly dominated by evolutionary aspects (efficiency of mass-loss, third dredge-up, convection). Finally, we discuss how the LUNA results impact on the hypothesis that invokes massive AGB stars as the main agents of the observed O-Na anti-correlation in Galactic globular clusters. We derive quantitative indications on the efficiencies of key physical processes (mass loss, third dredge-up, sodium destruction) in order to simultaneously reproduce both the Na-rich, O-poor extreme of the anti-correlation, and the observational constraints on the CNO abundance. Results for the corresponding chemical ejecta are made publicly available

Cytogenetic markers, DNA single-strand breaks, urinary metabolites, and DNA repair rates in styrene-exposed lamination workers.

The effect of occupational exposure to styrene on frequencies of chromosomal aberrations and binucleated cells with micronuclei and on single-strand break levels in peripheral blood lymphocytes was studied in 86 reinforced plastic workers and 42 control individuals (including 16 maintenance workers with intermittent, low-dose exposure). In these individuals, the irradiation-specific DNA repair rates and the repair rates of 8-oxoguanines were investigated. We assessed the exposure by measuring the concentrations of styrene in air and in blood and of mandelic acid, phenylglyoxylic acid, 4-vinyl phenol conjugates and regioisomeric phenyl hydroxyethyl mercapturic acids in urine. All these parameters correlated with one another. No clear relationship was found between the styrene exposure and the frequencies of chromosomal aberrations. Binucleated cells with micronuclei were moderately related to the parameters of styrene exposure. We found a negative correlation between all exposure parameters and single-strand breaks. The positive correlation between exposure parameters and DNA repair rates suggests that particular DNA repair pathways may be induced by styrene exposure

PARSEC: stellar tracks and isochrones with the PAdova and TRieste Stellar Evolution Code

We present the updated version of the code used to compute stellar evolutionary tracks in Padova. It is the result of a thorough revision of the major input physics, together with the inclusion of the pre-main sequence phase, not present in our previous releases of stellar models. Another innovative aspect is the possibility of promptly generating accurate opacity tables fully consistent with any selected initial chemical composition, by coupling the OPAL opacity data at high temperatures to the molecular opacities computed with our AESOPUS code (Marigo & Aringer 2009). In this work we present extended sets of stellar evolutionary models for various initial chemical compositions, while other sets with different metallicities and/or different distributions of heavy elements are being computed. For the present release of models we adopt the solar distribution of heavy elements from the recent revision by Caffau et al. (2011), corresponding to a Sun's metallicity Z=0.0152. From all computed sets of stellar tracks, we also derive isochrones in several photometric systems. The aim is to provide the community with the basic tools to model star clusters and galaxies by means of population synthesis techniques.Comment: To appear on MNRAS. While the full database is still being prepared, the first isochrones can be retrieved via http://stev.oapd.inaf.it/cm