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

Glio-vascular modifications caused by Aquaporin-4 deletion in the mouse retina

Aquaporin-4 (AQP4) is the Central Nervous System water channel highly expressed at the perivascular glial domain. In the retina, two types of AQP4 expressing glial cells take part in the blood-retinal barrier (BRB), astrocytes and Müller cells. The aim of the present study is to investigate the effect of AQP4 deletion on the retinal vasculature by looking at typical pathological hallmark such as BRB dysfunction and gliotic condition.AQP4 dependent BRB properties were evaluated by measuring the number of extravasations in WT and AQP4 KO retinas by Evans blue injection assay. AQP4 deletion did not affect the retinal vasculature, as assessed by Isolectin B4 staining, but caused BRB impairment to the deep plexus capillaries while the superficial and intermediate capillaries were not compromised. To investigate for gliotic responses caused by AQP4 deletion, Müller cells and astrocytes were analysed by immunofluorescence and western blot, using the Müller cell marker Glutamine Synthetase (GS) and the astrocyte marker GFAP. While GS expression was not altered in AQP4 KO retinas, a strong GFAP upregulation was found at the level of AQP4 KO astrocytes at the superficial plexus and not at Müller cells at the intermediate and deep plexi. These data, together with the upregulation of inflammatory markers (TNF-α, IL-6, IL-1β and ICAM-1) in AQP4 KO retinas indicated AQP4 deletion as responsible for a gliotic phenotype. Interestingly, no GFAP altered expression was found in AQP4 siRNA treated astrocyte primary cultures. All together these results indicate that AQP4 deletion is directly responsible for BRB dysfunction and gliotic condition in the mouse retina. The selective activation of glial cells at the primary plexus suggests that different regulatory elements control the reaction of astrocytes and Müller cells. Finally, GFAP upregulation is strictly linked to gliovascular crosstalk, as it is absent in astrocytes in culture. This study is useful to understand the role of AQP4 in the perivascular domain in the retina and its possible implications in the pathogenesis of retinal vascular diseases and of Neuromyelitis Optica, a human disease characterized by anti-AQP4 auto-antibodies

Potential role of the methylation of VEGF gene promoter in response to hypoxia in oxygen-induced retinopathy: beneficial effect of the absence of AQP4

Hypoxia-dependent accumulation of vascular endothelial growth factor (VEGF) plays a major role in retinal diseases characterized by neovessel formation. In this study, we investigated whether the glial water channel Aquaporin-4 (AQP4) is involved in the hypoxia-dependent VEGF upregulation in the retina of a mouse model of oxygen-induced retinopathy (OIR). The expression levels of VEGF, the hypoxia-inducible factor-1a (HIF-1a) and the inducible form of nitric oxide synthase (iNOS), the production of nitric oxide (NO), the methylation status of the HIF-1 binding site (HBS) in the VEGF gene promoter, the binding of HIF-1a to the HBS, the retinal vascularization and function have been determined in the retina of wild-type (WT) and AQP4 knock out (KO) mice under hypoxic (OIR) or normoxic conditions. In response to 5 days of hypoxia, WT mice were characterized by (i) AQP4 upregulation, (ii) increased levels of VEGF, HIF-1a, iNOS and NO, (iii) pathological angiogenesis as determined by engorged retinal tufts and (iv) dysfunctional electroretinogram (ERG). AQP4 deletion prevents VEGF, iNOS and NO upregulation in response to hypoxia thus leading to reduced retinal damage although in the presence of high levels of HIF-1a. In AQP4 KO mice, HBS demethylation in response to the beginning of hypoxia is lower than in WT mice reducing the binding of HIF-1a to the VEGF gene promoter. We conclude that in the absence of AQP4, an impaired HBS demethylation prevents HIF-1 binding to the VEGF gene promoter and the relative VEGF transactivation, reducing the VEGF-induced retinal damage in response to hypoxia

Drivers of farmers' adoption and continuation of climate-smart agricultural practices. A study from northeastern Italy

Abstract The EU rural development policy has addressed challenges related to climate change in agriculture by introducing public voluntary schemes, which financially support the adoption of climate-smart agricultural practices. Several factors, most of which are non-financial ones, drive adoption and continuation of these schemes by farmers. Despite the importance of these factors, only a few studies explore their role in the European context. This paper contributes to filling this gap from a twofold perspective. First, it investigates the role of the farming factors, technology accessibility, environmental features, policy design and social expertise at the territorial level on early adoption. Second, it sheds light on farmers' attitudes and motivations and on social pressure on their decision to continue or discontinue the practices, by surveying a sample of early adopters. Three schemes for the Veneto region rural development programme are considered: no tillage, fertiliser reduction, and water and fertiliser reduction. The results highlight that non-financial factors should be considered in order to design more effective schemes to prompt farmers to adopt and continue such practices over the long run. The paper also stresses the need to complement financial support with proactive information-based instruments

Centrality of Striatal Cholinergic Transmission in Basal Ganglia Function

Work over the past two decades revealed a previously unexpected role for striatal cholinergic interneurons in the context of basal ganglia function. The recognition that these interneurons are essential in synaptic plasticity and motor learning represents a significant step ahead in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction. Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum appears to be the trigger for pathophysiological changes occurring in basal ganglia disorders. Accordingly, there is now compelling evidence showing profound changes in cholinergic markers in these disorders, in particular Parkinson's disease and dystonia. Based on converging experimental and clinical evidence, we provide an overview of the role of striatal cholinergic transmission in physiological and pathological conditions, in the context of the pathogenesis of movement disorders

Synchrotron characterization of hexagonal and cubic lipidic phases loaded with azolate/phosphane gold(I) compounds: a new approach to the uploading of gold(I)-based drugs

none9Gold(I) phosphane compounds have recently attracted a renewed interest as potential new protagonists in cancer therapy. A class of phosphane gold(I) complexes containing azolate ligands has been successfully tested against several cancer cell lines and, in particular, against basal-like breast (BLB) cancer, a form characterized by strongly severe diagnosis and short life lapse after classic chemotherapy. Even though the anticancer activity of gold(I) phosphane compounds is thoroughly ascertained, no study has been devoted to the possibility of their delivery in nanovectors. Herein, nonlamellar lyotropic liquid crystalline lipid nanosystems, a promising class of smart materials, have been used to encapsulate gold(I) azolate/phosphane complexes. In particular, ((triphenylphosphine)-gold(I)-(4,5-dichloroimidazolyl-1H-1yl)) (C-I) and ((triphenylphosphine)-gold(I)-(4,5-dicyanoimidazolyl-1H-1yl)) (C-II) have been encapsulated in three different lipid matrices: monoolein (GMO), phytantriol (PHYT) and dioleoyl-phosphatidylethanolamine (DOPE). An integrated experimental approach involving X-ray diffraction and UV resonant Raman (UVRR) spectroscopy, based on synchrotron light and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, has been employed to establish the effects of drug encapsulation on the structure and phase behavior of the host mesophases. The results indicate that gold(I) complexes C-I and C-II are successfully encapsulated in the three lipid matrices as evidenced by the drug-induced phase transitions or by the changes in the mesophase lattice parameters observed in X-ray diffraction experiments and by the spectral changes occurring in UV resonant Raman spectra upon loading the lipid matrices with C-I and C-II.openPaola Astolfi, Michela Pisani, Elisabetta Giorgini, Barbara Rossi, Alessandro Damin, Francesco Vita, Oriano Francescangeli, Lorenzo Luciani, Rossana GalassiAstolfi, Paola; Pisani, Michela; Giorgini, Elisabetta; Rossi, Barbara; Damin, Alessandro; Vita, Francesco; Francescangeli, Oriano; Luciani, Lorenzo; Galassi, Rossan

The Outcome of Cholangitis After Percutaneous Biliary Drainage in Neoplastic Jaundice

The purpose of this paper is to evaluate factors affecting the outcome of cholangitis after PTBD in jaundiced cancer patients. Twenty nine patients with neoplastic jaundice (male/female ratio 13/16, median age 55 years) with full clinical data, were treated by PTBD and developed cholangitis at a median of 9 days later. Four patients (14%) died of biliary sepsis a median of one month after PTBD while the other 25 survived a median of 6 months, with one week median duration of cholangitis. The probability of the cholangitis resolving was analyzed by time to resolution and it was found that 50% and 100% of the recoveries occurred 5 and 9 months respectively from the onset of the complication

Lipid-rich histology in a basal-type immuno-profile breast carcinoma: a clinicopathological histochemical and immunohistochemical analysis of a case

We describe the clinicopathological and morphological features of an unusual breast carcinoma classifiable as a lipid-rich variant of ductal invasive carcinoma, with a basal-type immunohistochemical profile. Basal-type breast cancers show no hormonal receptor expression, rarely over-express HER-2 but exhibit molecular high weight cytokeratins, EGFR and c-kit positivity. Special stains and histochemistry tests were used to elucidate the nature of vescicles in the neoplastic cells. Sudan IV was performed on formalin-fixed tissue. Commercially available antibodies tested were: ER, PgR, EGFR, HER2, c-kit, high molecular weight cytokeratins. Cytoplasmic lipids were highlighted as red-orange droplets on Sudan IV staining. As for immunohistochemistry, the tumor showed no reactivity to ER, PgR and HER2 (triple negative), and diffuse and strong positivity to high weight cytokeratins, EGFR and c-kit, such as a basal-type breast carcinoma. A basaloid phenotype in a lipid-rich carcinoma has not been previously reported

Pituitary function and morphology in Fabry disease.

Endocrine abnormalities are known to affect patients with Fabry disease (FD). Pituitary gland theoretically represents an ideal target for FD because of high vascularization and low proliferation rate. We explored pituitary morphology and function in a cohort of FD patients through a prospectic, monocentric study at an Academic Tertiary Center. The study population included 28 FD patients and 42 sex and age-matched normal subjects. The protocol included a contrast enhancement pituitary MRI, the assessment of pituitary hormones, anti-pituitary, and anti-hypothalamus antibodies. At pituitary MRI, an empty sella was found in 11 (39%) FD patients, and in 2 (5%) controls (p < 0.001). Pituitary volume was significantly smaller in FD than in controls (p < 0.001). Determinants of pituitary volume were age and alpha-galactosidase enzyme activity. Both parameters resulted independently correlated at multivariate analysis. Pituitary function was substantially preserved in FD patients. Empty sella is a common finding in patients with FD. The major prevalence in the elderly supports the hypothesis of a progressive pituitary shrinkage overtime. Pituitary function seems not to be impaired in FD. An endocrine workup with pituitary hormone assessment should be periodically performed in FD patients, who are already at risk of cardiovascular complications

Optogenetic Activation of Striatopallidal Neurons Reveals Altered HCN Gating in DYT1 Dystonia

Summary: Firing activity of external globus pallidus (GPe) is crucial for motor control and is severely perturbed in dystonia, a movement disorder characterized by involuntary, repetitive muscle contractions. Here, we show that GPe projection neurons exhibit a reduction of firing frequency and an irregular pattern in a DYT1 dystonia model. Optogenetic activation of the striatopallidal pathway fails to reset pacemaking activity of GPe neurons in mutant mice. Abnormal firing is paralleled by alterations in motor learning. We find that loss of dopamine D2 receptor-dependent inhibition causes increased GABA input at striatopallidal synapses, with subsequent downregulation of hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. Accordingly, enhancing in vivo HCN channel activity or blocking GABA release restores both the ability of striatopallidal inputs to pause ongoing GPe activity and motor coordination deficits. Our findings demonstrate an impaired striatopallidal connectivity, supporting the central role of GPe in motor control and, more importantly, identifying potential pharmacological targets for dystonia