Role of Vitamin E and the Orexin System in Neuroprotection.

Microglia are the first line of defense at the level of the central nervous system (CNS). Phenotypic change in microglia can be regulated by various factors, including the orexin system. Neuroinflammation is an inflammatory process mediated by cytokines, by the lack of interaction of specific receptors such as the OX2-OX2R complex, caused by systemic tissue damage or, more often, associated with direct damage to the CNS. Chronic activation of microglia could lead to long-term neurodegenerative diseases. This review aims to explore how tocopherol (vitamin E) and the orexin system may play a role in the prevention and treatment of microglia inflammation and, consequently, in neurodegenerative diseases thanks to its antioxidant properties. The results of animal and in vitro studies provide evidence to support the use of tocopherol for a reduction in microglia inflammation as well as a greater activation of the orexinergic system. Although there is much in vivo and in vitro evidence of vitamin E antioxidant and protective abilities, there are still conflicting results for its use as a treatment for neurodegenerative diseases that speculate that vitamin E, under certain conditions or genetic predispositions, can be pro-oxidant and harmful

The Metabolic Rearrangements of Bariatric Surgery: Focus on Orexin-A and the Adiponectin System

The accumulation of adipose tissue represents one of the characteristics of obesity, increasing the risk of developing correlated obesity diseases such as cardiovascular disease, type 2 diabetes, cancer, and immune diseases. Visceral adipose tissue accumulation leads to chronic low inflammation inducing an imbalanced adipokine secretion. Among these adipokines, Adiponectin is an important metabolic and inflammatory mediator. It is also known that adipose tissue is influenced by Orexin-A levels, a neuropeptide produced in the lateral hypothalamus. Adiponectin and Orexin-A are strongly decreased in obesity and are associated with metabolic and inflammatory pathways. The aim of this review was to investigate the involvement of the autonomic nervous system focusing on Adiponectin and Orexin-A after bariatric surgery. After bariatric surgery, Adiponectin and Orexin-A levels are strongly increased independently of weight loss showing that hormone increases are also attributable to a rearrangement of metabolic and inflammatory mediators. The restriction of food intake and malabsorption are not sufficient to clarify the clinical effects of bariatric surgery suggesting the involvement of neuro-hormonal feedback loops and also of mediators such as Adiponectin and Orexin-A

The Orexin-A serum levels are strongly modulated by physical activity intervention in diabetes mellitus patients

The Orexin-A (hypocretin-1) is a neuropeptide secreted by neurons in the lateral hypothalamus. This protein regulates physiological and behavioural processes that have an essential impact on energy balance and metabolic status, physical activity, blood glucose levels, and food intake. Furthermore, that orexin-A regulates insulin sensitivity, energy expenditure and metabolic rate and is involved in immune processes and then regulate inflammatory response, with an anti-inflammatory action. Diabetes mellitus (T2DM) is a worldwide health problem associated with obesity and sedentary lifestyle. High glycaemic levels and lipid serum profile, low col-HDL, or hypertension and increased body mass index (BMI) are significantly associated with increased T2DM risk and with increased cardiovascular mortality and morbidity in T2DM patients. For these reasons the aim of this study is to evaluate the biochemical and anthropometric parameters, orexin-A levels by ELISA test and western blotting analysis, and inflammatory cytokines levels such as TNF-a, IL-8 and IL-10 by ELISA test in subjects affected by diabetes mellitus following an accurate physical activity program at baseline, after 3 months and after 6 months. We found that there is a ameliorate of many anthropometric and biochemical parameters; furthermore, there is a statistical increase of orexin-A serum levels already after 3 months compared to baseline in T2DM subjects and also there is a strongly modulation in inflammatory cytokines expression. These found indicates that the physical activity has beneficial effects not only on anthropometric and biochemical parameters but also on orexin-A levels, and then on CNS

The beneficial effects of physical activity and weight loss on human colorectal carcinoma cell lines

Recent studies have demonstrated that obesity is a significant risk factor for the development of several malignancies such as cancer. Colorectal cancer is among the most common cancers worldwide and is strong linked to obesity. A healthy lifestyle, characterized by hypocaloric diet and physical activity, is important to reduce a chronic inflammation, oxidative stress and metabolic disorders typical of obesity (Messina et al, 2018; Messina et al, 2017; Messina et al, 2015). It is well known that the chronic inflammation state and oxidative stress are responsible for the aging and development of many diseases, such as cancer. Dysregulation of cytokine’s secretion probably participates in the establishment of cancer in obese patients. The aim of this study is to analyse the effects of sera from obese patients subjected to a physical activity program before and after weight loss on cell viability, apoptosis and oxidative stress in HCT116 carcinoma cell line treated for 24, 48 and 72 hours through MTT test. We analysed the expression of cytokines in HCT116 cells. We found that sera from obese after physical activity intervention compared to treatment with sera from obese patients before physical activity intervention reduce the survival rate of HCT116 cells through induction of apoptosis and oxidative stress. Finally, we found a reduction of mRNA levels corresponding to the pro-inflammatory IL-6 and IL-8 cytokines together with an increase of the anti-inflammatory IL-10 cytokine. We can conclude that the physical activity has numerous beneficial effects also in colorectal cancer cell, indeed the physical activity and weight loss in obese subjects have an inhibitory and anti-inflammatory effects in a short period on carcinoma cell line

The rootstock shape microbial diversity and functionality in the rhizosphere of Vitis vinifera L. cultivar Falanghina

The rhizosphere effect occurring at the root-soil interface has increasingly been shown to play a key role in plant fitness and soil functionality, influencing plants resilience. Here, for the first time, we investigated whether the rootstock genotype on which Vitis vinifera L. cultivar Falanghina is grafted can influence the rhizosphere microbiome. Specifically, we evaluated to which extent the 5BB and 1103P rootstocks are able to shape microbial diversity of rhizosphere environment. Moreover, we explored the potential function of microbial community and its shift under plant genotype influence. We investigated seven vineyards subjected to the same pedo-climatic conditions, similar age, training system and management and collected twelve rhizosphere soil samples for metagenomic analyses and composite soil samples for physical-chemical properties. In this study, we used 16S rRNA gene-based metagenomic analysis to investigate the rhizosphere bacterial diversity and composition. Liner discriminant analysis effect size (LEFSe) was conducted for metagenomic biomarker discovery. The functional composition of sampled communities was determined using PICRUSt, which is based on marker gene sequencing profiles. Soil analyses involved the determination of texture, pH, Cation Exchange Capacity (CSC), Organic Carbon (OC), electrical conductivity (EC), calcium (Ca), magnesium (Mg), potassium (K) content, Phosphorous (P), nitrogen (N). The latter revealed that soil features were quite homogenous. The metagenomic data showed that the bacterial alpha-diversity (Observed OTUs) significantly increased in 1103P rhizosphere microbiota. Irrespective of cultivar, Pseudomonadota was the dominant phylum, followed by Actinomycetota > Bacteroidota > Thermoproteota. However, Actinomycetota was the major marker phyla differentiating the rhizosphere microbial communities associated with the different rootstock types. At the genus level, several taxa belonging to Actinomycetota and Alphaproteobacteria classes were enriched in 1103P genotype rhizosphere. Investigating the potential functional profile, we found that most key enzyme-encoding genes involved in N cycling were significantly more abundant in 5BB rootstock rhizosphere soil. However, we found that 1103P rhizosphere was enriched in genes involved in C cycle and Plant Growth Promotion (PGP) functionality. Our results suggest that the different rootstocks not only recruit specific bacterial communities, but also specific functional traits within the same environment

TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy

Tubulinopathies constitute a family of neurodevelopmental/neurodegenerative disorders caused by mutations in several genes encoding tubulin isoforms. Loss-of-function mutations in TBCE, encoding one of the five tubulin-specific chaperones involved in tubulin folding and polymerization, cause two rare neurodevelopmental syndromes, hypoparathyroidism-retardation-dysmorphism and Kenny-Caffey syndrome. Although a missense mutation in Tbce has been associated with progressive distal motor neuronopathy in the pmn/pmn mice, no similar degenerative phenotype has been recognized in humans. We report on the identification of an early-onset and progressive neurodegenerative encephalopathy with distal spinal muscular atrophy resembling the phenotype of pmn/pmn mice and caused by biallelic TBCE mutations, with the c.464T>A (p.Ile155Asn) change occurring at the heterozygous/homozygous state in six affected subjects from four unrelated families originated from the same geographical area in Southern Italy. Western blot analysis of patient fibroblasts documented a reduced amount of TBCE, suggestive of rapid degradation of the mutant protein, similarly to what was observed in pmn/pmn fibroblasts. The impact of TBCE mutations on microtubule polymerization was determined using biochemical fractionation and analyzing the nucleation and growth of microtubules at the centrosome and extracentrosomal sites after treatment with nocodazole. Primary fibroblasts obtained from affected subjects displayed a reduced level of polymerized α-tubulin, similarly to tail fibroblasts of pmn/pmn mice. Moreover, markedly delayed microtubule re-polymerization and abnormal mitotic spindles with disorganized microtubule arrangement were also documented. Although loss of function of TBCE has been documented to impact multiple developmental processes, the present findings provide evidence that hypomorphic TBCE mutations primarily drive neurodegeneration

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M.S

Adherence issues related to sublingual immunotherapy as perceived by allergists

Objectives: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence. Methods: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10. Results: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists. Conclusion: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers. © 2010 Scurati et al, publisher and licensee Dove Medical Press Ltd

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock