Neuropathological role of alpha-synuclein: major contribution of inflammation in the evolution of both motor and non-motor symptoms of Parkinson’s disease

Neuroinflammation is nowadays considered a cardinal pathological feature of Parkinson’s disease (PD), in which glial cells lose their homeostatic function in favour of a pro-inflammatory profile. Such sustained glial response within the brain parenchyma is characterized by a chronic release of a number of pro-inflammatory mediators, likely driven by pathological interactions with toxic forms of α-Synuclein (αSyn). Moreover, the contribution of the peripheral immune system to PD neuropathology has been demonstrated, promoting the view of PD as a systemic pathology. While the contribution of inflammation to the neuropathology of motor symptoms has been ascertained, its role in non-motor symptoms is still under-investigated, particularly in relation to cognitive disturbances. Here, we targeted inflammation in PD by testing the immunomodulatory imide drug (IMiD) Pomalidomide (Pom) for its disease-modifying properties against motor deficits in a translational rat model of PD based on the intranigral infusion of toxic oligomers of human α-synuclein (H-αSynOs) (study I). Moreover, we investigated the contribution of neuroinflammation in PD cognitive symptoms, in the same PD preclinical model (study II). Study I: The neuroprotective effect of Pom (20 mg/kg; i.p. three times/week for two months) was tested in the early stage of the disease. We found that the infusion of H-αSynOs induced an impairment in motor performance that was fully rescued by Pom, as assessed via a battery of motor tests. Moreover, H-αSynOs-infused rats displayed a 40–45% cell loss within the substantia nigra (SN), that was largely abolished by Pom. The inflammatory response to H-αSynOs infusion and the Pom treatment was evaluated both in CNS and peripherally. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the cytokine Tumour Necrosis Factor (TNF)-α. In contrast, Pom inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine Interleukin (IL)-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with a dysregulated production of serum cytokines and chemokines, that was largely restored by Pom. Study II: We asked whether the H-αSynOs-based model of PD is an effective tool to study PD-related cognitive disturbances, thus investigating the contribution of neuroinflammation. We show that H-αSynOs-infused rats displayed memory deficits three months after the infusion. These were underpinned by an altered electrophysiological neuronal activity and altered expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) in cognitive regions, such as the anterior cingulate cortex (ACC). Moreover, the brain of cognitively impaired rats showed a neuroinflammatory response in the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. Such neuroinflammatory response was epitomized by the acquisition of a pro-inflammatory phenotype by microglia cells, as indicated by the increased levels of TNF-α. Taken together, results of the present study indicate that neuroinflammation is a common feature of both motor and non-motor aspects of PD, and suggest that targeting inflammation might represent a novel therapeutic strategy to treat the disease as a whole

Induction of Activity-Regulated Cytoskeleton-Associated Protein and c-Fos Expression in an Animal Model of Anorexia Nervosa

Anorexia nervosa (AN) is a complex eating disorder characterized by reduced caloric intake to achieve body-weight loss. Furthermore, over-exercise is commonly reported. In recent years, animal models of AN have provided evidence for neuroplasticity changes in specific brain areas of the mesocorticolimbic circuit, which controls a multitude of functions including reward, emotion, motivation, and cognition. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates several forms of synaptic plasticity and has been linked to neuropsychiatric illness. Since the role of Arc in AN has never been investigated, in this study we evaluated whether the anorexic-like phenotype reproduced by the activity-based anorexia (ABA) model may impact its expression in selected brain regions that belong to the mesocorticolimbic circuit (i.e., prefrontal cortex, nucleus accumbens, and hippocampus). The marker of neuronal activation c-Fos was also assessed. We found that the expression of both markers increased in all the analyzed brain areas of ABA rats in comparison to the control groups. Moreover, a negative correlation between the density of Arc-positive cells and body-weight loss was found. Together, our findings suggest the importance of Arc and neuroplasticity changes within the brain circuits involved in dysfunctional behaviors associated with AN

Combined measure of salivary alpha-synuclein species as diagnostic biomarker for Parkinson's disease

Parkinson's disease (PD) diagnosis is still vulnerable to bias, and a definitive diagnosis often relies on post-mortem neuropathological diagnosis. In this regard, alpha-synuclein (αsyn)-specific in vivo biomarkers remain a critical unmet need, based on its relevance in the neuropathology. Specifically, content changes in αsyn species such as total (tot-αsyn), oligomeric (o-αsyn), and phosphorylated (p-αsyn) within the cerebrospinal fluid (CSF) and peripheral fluids (i.e., blood and saliva) have been proposed as PD biomarkers possibly reflecting the neuropathological outcome. Here, we measured the p-αsyn levels in the saliva from 15 PD patients along with tot-αsyn, o-αsyn and their ratios, and compared the results with those from 23 healthy subjects (HS), matched per age and sex. We also calculated the optimal cutoff values for different αsyn species to provide information about their capability to discriminate PD from HS. We found that p-αsyn was the most abundant alpha-synuclein species in the saliva. While p-αsyn concentration did not differ between PD and HS when adjusted for total salivary proteins, the ratio p-αsyn/tot-αsyn was largely lower in PD patients than in HS. Moreover, the concentration of o-αsyn was increased in the saliva of PD patients, and tot-αsyn did not differ between PD and HS. The ROC curves indicated that no single αsyn form or ratio could provide an accurate diagnosis of PD. On the other hand, the ratio of different items, namely p-αsyn/tot-αsyn and o-αsyn, yielded more satisfactory diagnostic accuracy, suggesting that the combined measure of different species in the saliva may show more promises as a diagnostic means for PD

Nanocrystals as an effective strategy to improve Pomalidomide bioavailability in rodent

Pomalidomide (POM) is an FDA-approved immunomodulatory imide drug (IMiDs) an it is effectively used in the treatment of multiple myeloma. IMiDs are analogs of the drug thalidomide and they have been repurposed for the treatment of several diseases such as psoriatic arthritis and Kaposi Sarcoma. In recent years, IMiDs have been also evaluated as a new treatment for neurological disorders with an inflammatory and neuroinflammatory component. POM draws particular interest for its potent anti-TNF-α activity at significantly lower concentrations than the parent compound thalidomide. However, POM's low water solubility underpins its low gastrointestinal permeability resulting in irregular and poor absorption. The purpose of this work was to prepare a POM nanocrystal-based formulation that could efficiently improve POM's plasma and brain concentration after intraperitoneal injection. POM nanocrystals prepared as a nanosuspension by the media milling method showed a mean diameter of 219 nm and a polydispersity index of 0.21. POM's nanocrystal solubility value (22.97 µg/mL) in phosphate buffer was about 1.58 folds higher than the POM raw powder. Finally, in vivo studies conducted in adult Male Sprague-Dawley rats indicated that POM nanocrystal ensured higher and longer-lasting drug levels in plasma and brain when compared with POM coarse suspension

Entrapment of Citrus limon var. pompia Essential Oil or Pure Citral in Liposomes Tailored as Mouthwash for the Treatment of Oral Cavity Diseases

This work aimed at developing a mouthwash based on liposomes loading Citrus limon var. pompia essential oil or citral to treat oropharyngeal diseases. Vesicles were prepared by dispersing phosphatidylcholine and pompia essential oil or citral at increasing amounts (12, 25 and 50 mg/mL) in water. Transparent vesicle dispersions were obtained by direct sonication avoiding the use of organic solvents. Cryogenic transmission electron microscopy (cryo-TEM) confirmed the formation of unilamellar, spherical and regularly shaped vesicles. Essential oil and citral loaded liposomes were small in size (~110 and ~100 nm, respectively) and negatively charged. Liposomes, especially those loading citral, were highly stable as their physico-chemical properties did not change during storage. The formulations were highly biocompatible against keratinocytes, were able to counteract the damages induced in cells by using hydrogen peroxide, and able to increase the rate of skin repair. In addition, liposomes loading citral at higher concentrations inhibited the proliferation of cariogenic bacteriu

The Impact of Bariatric Surgery on the Muscle Mass in Patients with Obesity: 2-Year Follow-up

Bariatric surgery; Morbid obesity; Sarcopenic obesityCirugía bariátrica; Obesidad mórbida; Obesidad sarcopénicaCirurgia bariàtrica; Obesitat mòrbida; Obesitat sarcopènicaPurpose Bariatric surgery (BS) induces a significant and sustained weight loss in patients with severe obesity (SO). Nevertheless, apart from significantly reducing body fat, fat-free mass (FFM) might also be lost. At present, there is little and controversial data in the literature regarding the impact of BS on FFM. In recent years, bioimpedance (BIA) has emerged as a reliable test to assess body composition easily to use in the daily clinical practice. On the bases, the aim of the present study is to evaluate the impact of BS on the FFM, evaluated by means of BIA. Material and Methods This is a prospective, observational study, including consecutive patients with SO that underwent BS between February 2018 and February 2019 at our center. At baseline, 1, 6, 12, and 24 months after the BS, all the patients underwent complete medical history, physical and anthropometric evaluation, and body composition assessment by means of BIA (using Bodystat QuadScan4000®). Results Eighty-five patients with SO were recruited, 72.9% females, aged 45.54 ± 9.98 years, pre-BS BMI 43.87 ± 6.52 kg/m2. FFM significantly decreased continuously after BS at all timepoints. The loss of FFM 24 months post-BS accounted for approximately 21.71 ± 13.9% of the total weight loss, and was independent of BS technique or protein metabolism. Pre-BS HOMA-IR and FFM were independent predictors of FFM at 24 months. Conclusions Significant and early loss of FFM in patients with SO that undergo BS was seen, not related to protein metabolism parameters or the BS technique used, suggesting an independent mechanism.Open Access Funding provided by Universitat Autonoma de Barcelona. This study was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria, PI20/01806). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Modeling Parkinson's Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers.

The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson's disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Porous Ni Photocathodes Obtained by Selective Corrosion of Ni-Cu Films: Synthesis and Photoelectrochemical Characterization

In this work, a dealloying technique is proposed as a synthesis method to obtain highly porous Nickel electrodes starting from Ni-Cu co-deposit: pulsed corrosion is applied adopting different corrosion and relaxation times. Different morphologies, pore size distribution and residual copper amount were obtained depending on the corrosion conditions. For the developed electrodes, the surface roughness factor, Rf, was evaluated by electrochemical impedance spectroscopy (EIS). The hydrogen evolution reaction (HER) on these electrodes was evaluated by means of steady-state polarization curves, and the related parameters were derived by Tafel analysis. Finally, a thin layer of NiO on the porous structures was obtained to exploit the semiconductor characteristic of the oxide, so that an extra-photopotential was obtained by the simulated solar light action. Results demonstrate greater apparent activity of the developed electrodes towards HER in comparison with commercial smooth Ni electrode, which can be mainly attributed to the large Rf obtained with the proposed technique