Non-coding RNA and pseudogenes in neurodegenerative diseases: “The (un)Usual Suspects”

Neurodegenerative disorders and cancer are severe diseases threatening human health. The glaring differences between neurons and cancer cells mask the processes involved in their pathogenesis. Defects in cell cycle, DNA repair, and cell differentiation can determine unlimited proliferation in cancer, or conversely, compromise neuronal plasticity, leading to cell death and neurodegeneration. Alteration in regulatory networks affecting gene expression contribute to human diseases onset, including neurodegenerative disorders, and deregulation of non-coding RNAs – particularly microRNAs (miRNAs) – is supposed to have a significant impact. Recently, competitive endogenous RNAs (ceRNAs) – acting as sponges – have been identified in cancer, indicating a new and intricate regulatory network. Given that neurodegenerative disorders and cancer share altered genes and pathways, and considering the emerging role of miRNAs in neurogenesis, we hypothesize ceRNAs may be implicated in neurodegenerative diseases. Here we propose, and computationally predict, such regulatory mechanism may be shared between the diseases. It is predictable that similar regulation occurs in other complex diseases, and further investigation is needed

PPARG: Gene Expression Regulation and Next-Generation Sequencing for Unsolved Issues

Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most extensively studied ligand-inducible transcription factors (TFs), able to modulate its transcriptional activity through conformational changes. It is of particular interest because of its pleiotropic functions: it plays a crucial role in the expression of key genes involved in adipogenesis, lipid and glucid metabolism, atherosclerosis, inflammation, and cancer. Its protein isoforms, the wide number of PPARγ target genes, ligands, and coregulators contribute to determine the complexity of its function. In addition, the presence of genetic variants is likely to affect expression levels of target genes although the impact of PPARG gene variations on the expression of target genes is not fully understood. The introduction of massively parallel sequencing platforms—in the Next Generation Sequencing (NGS) era—has revolutionized the way of investigating the genetic causes of inherited diseases. In this context, DNA-Seq for identifying—within both coding and regulatory regions of PPARG gene—novel nucleotide variations and haplotypes associated to human diseases, ChIP-Seq for defining a PPARγ binding map, and RNA-Seq for unraveling the wide and intricate gene pathways regulated by PPARG, represent incredible steps toward the understanding of PPARγ in health and disease

Hepatic Insulin Resistance in Hyperthyroid Rat Liver: Vitamin E Supplementation Highlights a Possible Role of ROS

Thyroid hormones are normally involved in glycaemic control, but their excess can lead to altered glucose metabolism and insulin resistance (IR). Since hyperthyroidism-linked increase in ROS results in tissue oxidative stress that is considered a hallmark of conditions leading to IR, it is conceivable a role of ROS in the onset of IR in hyperthyroidism. To verify this hypothesis, we evaluated the effects of vitamin E on thyroid hormone-induced oxidative damage, insulin resistance, and on gene expression of key molecules involved in IR in the rat liver. The factors involved in oxidative damage, namely the total content of ROS, the mitochondrial production of ROS, the activity of antioxidant enzymes, the in vitro susceptibility to oxidative stress, have been correlated to insulin resistance indices, such as insulin activation of hepatic Akt and plasma level of glucose, insulin and HOMA index. Our results indicate that increased levels of oxidative damage ROS content and production and susceptibility to oxidative damage, parallel increased fasting plasma level of glucose and insulin, reduced activation of Akt and increased activation of JNK. This last result suggests a role for JNK in the insulin resistance induced by hyperthyroidism. Furthermore, the variation of the genes Pparg, Ppara, Cd36 and Slc2a2 could explain, at least in part, the observed metabolic phenotypes. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

In Vitro-Generated Hypertrophic-Like Adipocytes Displaying PPARG Isoforms Unbalance Recapitulate Adipocyte Dysfunctions In Vivo

Reduced neo-adipogenesis and dysfunctional lipid-overloaded adipocytes are hallmarks of hypertrophic obesity linked to insulin resistance. Identifying molecular features of hypertrophic adipocytes requires appropriate in vitro models. We describe the generation of a model of human hypertrophic-like adipocytes directly comparable to normal adipose cells and the pathologic evolution toward hypertrophic state. We generate in vitro hypertrophic cells from mature adipocytes, differentiated from human mesenchymal stem cells. Combining optical, confocal, and transmission electron microscopy with mRNA/protein quantification, we characterize this cellular model, confirming specific alterations also in subcutaneous adipose tissue. Specifically, we report the generation and morphological/molecular characterization of human normal and hypertrophic-like adipocytes. The latter displays altered morphology and unbalance between canonical and dominant negative (PPARGΔ5) transcripts of PPARG, paralleled by reduced expression of PPARγ targets, including GLUT4. Furthermore, the unbalance of PPARγ isoforms associates with GLUT4 down-regulation in subcutaneous adipose tissue of individuals with overweight/obesity or impaired glucose tolerance/type 2 diabetes, but not with normal weight or glucose tolerance. In conclusion, the hypertrophic-like cells described herein are an innovative tool for studying molecular dysfunctions in hypertrophic obesity and the unbalance between PPARγ isoforms associates with down-regulation of GLUT4 and other PPARγ targets, representing a new hallmark of hypertrophic adipocytes

White light emitting silsesquioxane based materials: The importance of a ligand with rigid and directional arms

The synthesis of a novel polyhedral oligomeric silsesquioxane functionalized with eight rigid and directional terpyridine-based arms (Ter-POSS) was successfully achieved via a Sonogashira reaction. The POSS based ligand was extensively characterized using different techniques including 1H, 13C and 29Si NMR as well as UV-Vis and fluorescence spectroscopies. The assembly of these nano-caged units in the presence of different transition metal ions (Fe2+, Zn2+ and Cu2+) as well as of a cation from the lanthanides (Eu3+) was investigated using absorption and emission spectroscopies. The final materials display an evident emission in different regions of the visible spectrum as a function of the cation employed. Additional insights into the structural organization of Ter-POSS in the presence of metal cations were obtained via molecular mechanics and molecular dynamics simulations. The polymeric material resulting from the complexation with europium displays a white light emission ascribed to the presence of combined contributions from the blue, green and red regions. The final self-assembled organizations display an increased quantum yield with the highest value (29.6%) obtained in the presence of Zn2+. Moreover, the white-light emitting europium-based nanostructure exhibits one of the highest quantum yields reported in the literature for similar solids

Heart failure: Pilot transcriptomic analysis of cardiac tissue by RNA-sequencing

Background: Despite left ventricular (LV) dysfunction contributing to mortality in chronic heart failure (HF), the molecular mechanisms of LV failure continues to remain poorly understood and myocardial biomarkers have yet to be identified. The aim of this pilot study was to investigate specific transcriptome changes occurring in cardiac tissues of patients with HF compared to healthy condition patients to improve diagnosis and possible treatment of affected subjects. Methods: Unlike other studies, only dilated cardiomyopathy (DCM) (n = 2) and restrictive cardiomyopathy (RCM) (n = 2) patients who did not report family history of the disease were selected with the aim of obtaining a homogeneous population for the study. The transcriptome of all patients were studied by RNA-sequencing (RNA-Seq) and the read counts were adequately filtered and normalized using a recently developed user-friendly tool for RNA-Seq data analysis, based on a new graphical user interface (RNA-SeqGUI). Results: By using this approach in a pairwise comparison with healthy donors, we were able to identify DCM- and RCM-specific expression signatures for protein-coding genes as well as for long noncoding RNAs (lncRNAs). Differential expression of 5 genes encoding different members of the mediator complex was disclosed in this analysis. Interestingly, a significant alteration was found for genes which had never been associated with HF until now, and 27 lncRNA/mRNA pairs that were significantly altered in HF patients. Conclusions: The present findings revealed specific expression pattern of both protein-coding and lncRNAs in HF patients, confirming that new LV myocardial biomarkers could be reliably identified using Next-Generation Sequencing-based approaches

The health care for diabetic persons in Italy: the QUADRI survey

To obtain regional and national data on the quality of diabetes care within the Italian National Health Service, a national survey among persons with diabetes was conducted in 2004. A sample of 3,426 diabetic patients (age 18-64 years) were interviewed using a standardized questionnaire. The population was middle-aged (median age 57 years), had a low educational level, and was followed primarily in public diabetes centres. A total of 54% reported having hypertension but 14% were not on treatment; for hypercholesterolemia, the corresponding figures were 44% and 26%. Of the 72% who were overweight or obese, 51% were trying to lose weight; 26% currently smoked. Only 66% of patients had undergone haemoglobin A1c testing in the past four months (among the 67% who had ever heard of test); 30% suffered from microvascular or macrovascular complications. Only 5% received all eight main tests recommended by the guidelines within the specified intervals. Our study demonstrates that diabetic patients receive less than optimal care, they are engaged in unhealthy behaviours and received inadequate treatment for comorbidities, and that the translation of guidelines into clinical practice was unsatisfactory. These data have been used to formulate national and regional policy regarding integrated case management to improve the quality of diabetes care

Psychological treatments and psychotherapies in the neurorehabilitation of pain. Evidences and recommendations from the italian consensus conference on pain in neurorehabilitation

BACKGROUND: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. OBJECTIVES: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. METHODS: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. RESULTS: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. CONCLUSIONS: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the pape