The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical Implications

Non-alcoholic fatty liver disease (NAFLD) represents a predominant hepatopathy that is rapidly becoming the most common cause of hepatocellular carcinoma worldwide. The close association with metabolic syndrome's extrahepatic components has suggested the nature of the systemic metabolic-related disorder based on the interplay between genetic, nutritional, and environmental factors, creating a complex network of yet-unclarified pathogenetic mechanisms in which the role of insulin resistance (IR) could be crucial. This review detailed the clinical and pathogenetic evidence involved in the NAFLD-IR relationship, presenting both the classic and more innovative models. In particular, we focused on the reciprocal effects of IR, oxidative stress, and systemic inflammation on insulin-sensitivity disruption in critical regions such as the hepatic and the adipose tissue, while considering the impact of genetics/epigenetics on the regulation of IR mechanisms as well as nutrients on specific insulin-related gene expression (nutrigenetics and nutrigenomics). In addition, we discussed the emerging capability of the gut microbiota to interfere with physiological signaling of the hormonal pathways responsible for maintaining metabolic homeostasis and by inducing an abnormal activation of the immune system. The translation of these novel findings into clinical practice could promote the expansion of accurate diagnostic/prognostic stratification tools and tailored pharmacological approaches

Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes

IntroductionTrained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations.Materials and methodsWe extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production.ResultsMonocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels.DiscussionOverall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort

Left Ventricular Non-Compaction Spectrum in Adults and Children: From a Morphological Trait to a Structural Muscular Disease

Left ventricular non-compaction (LVNC) is an extremely heterogeneous disorder with a highly variable clinical presentation, morphologic appearance at imaging testing, and prognosis. It is still unclear whether LVNC should be classified as a separate cardiomyopathy or if it is a mere morphological trait shared by many phenotypically distinct cardiomyopathies. Moreover, the hypertrabeculated phenotype may be reversible in some cases, possibly reflecting the left ventricular physiological response of the cardiac muscle to chronic overload. The current diagnostic criteria have several limitations, leaving many patients in a grey area. Here, we review the available literature on LVNC in order to provide an overview of the current knowledge on this complex disorder

Left Ventricular Non-Compaction Spectrum in Adults and Children: From a Morphological Trait to a Structural Muscular Disease

Left ventricular non-compaction (LVNC) is an extremely heterogeneous disorder with a highly variable clinical presentation, morphologic appearance at imaging testing, and prognosis. It is still unclear whether LVNC should be classified as a separate cardiomyopathy or if it is a mere morphological trait shared by many phenotypically distinct cardiomyopathies. Moreover, the hypertrabeculated phenotype may be reversible in some cases, possibly reflecting the left ventricular physiological response of the cardiac muscle to chronic overload. The current diagnostic criteria have several limitations, leaving many patients in a grey area. Here, we review the available literature on LVNC in order to provide an overview of the current knowledge on this complex disorder

Structural investigation of a C-terminal EphA2 receptor mutant: Does mutation affect the structure and interaction properties of the Sam domain?

Ephrin A2 receptor (EphA2) plays a key role in cancer, it is up-regulated in several types of tumors and the process of ligand-induced receptor endocytosis, followed by degradation, is considered as a potential path to diminish tumor malignancy. Protein modulators of this mechanism are recruited at the cytosolic Sterile alpha motif (Sam) domain of EphA2 (EphA2-Sam) through heterotypic Sam-Sam associations. These interactions engage the C-terminal helix of EphA2 and close loop regions (the so called End Helix side). In addition, several studies report on destabilizing mutations in EphA2 related to cataract formation and located in/or close to the Sam domain. Herein, we analyzed from a structural point of view, one of these mutants characterized by the insertion of a novel 39 residue long polypeptide at the C-terminus of EphA2-Sam. A 3D structural model was built by computational methods and revealed partial disorder in the acquired C-terminal tail and a few residues participating in an α-helix and two short β-strands. We investigated by CD and NMR studies the conformational properties in solution of two peptides encompassing the whole C-terminal tail and its predicted helical region, respectively. NMR binding experiments demonstrated that these peptides do not interact relevantly with either EphA2-Sam or its interactor Ship2-Sam. Molecular dynamics (MD) simulations further indicated that the EphA2 mutant could be represented only through a conformational ensemble and that the C-terminal tail should not largely wrap the EphA2-Sam End-Helix interface and affect binding to other Sam domains

Wearable cardioverter-defibrillator (life-vest): A feasible bridging treatment in adult congenital heart disease

Wearable cardioverter-defibrillators (WCDs) are currently used in patients at temporarily heightened risk for sudden cardiac death (SCD) who are temporarily unable to receive an implantable cardioverter-defibrillator (ICD). WCD can safely record and terminate life-threatening arrhythmias through a non-invasive electrode-based system. The current clinical indications for WCD use are varied and keep evolving as experience with this technology increases

Characterization of linear mimetic peptides of Interleukin-22 from dissection of protein interfaces

Interleukin-22 (IL-22) belongs to the family of IL-10 cytokines and is involved in a wide number of human diseases, including inflammatory disorders and cancer pathology. The ligand-receptor complex IL-22/IL-22R plays a key role in several pathways especially in the regulation and resolution of immune responses. The identification of novel compounds able to modulate IL-22/IL-22R complex could open the route to new therapeutic strategies in multiple human diseases. In this study, we designed and characterized IL-22 derived peptides at protein interface regions: several sequences revealed able to interfere with the protein complex with IC50 in the micromolar range as evaluated through Surface Plasmon Resonance (SPR) experiments. Their conformational characterization was carried out through Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies, shedding new light into the features of IL-22 fragments and on structural determinants of IL-22/IL-22R1 recognition. Finally, several peptides were tested on human keratinocyte cultures for evaluating their ability to mimic the activation of molecular pathways downstream to IL-22R in response to IL-22 binding

Safety and efficacy of non-vitamin K antagonist oral anticoagulants for prevention of thromboembolism in adults with systemic right ventricle: Results from the NOTE international registry

BACKGROUND Patients with systemic right ventricle (sRV), including transposition of great arteries (TGA) after atrial switch procedure and congenitally corrected transposition of great arteries (ccTGA), may require anticoagulation for thromboembolism (TE) prevention. In the absence of data on non-vitamin K antagonist oral anticoagulants (NOACs), vitamin K antagonists (VKAs) remain the agent of choice. We investigated the safety, efficacy and feasibility of NOACs treatment in adults with sRV in a worldwide study. METHODS This is an international multicentre prospective study, using data from the NOTE registry on adults with sRV taking NOACs between 2014 and 2019. The primary endpoints were TE and major bleeding (MB). The secondary endpoint was minor bleeding. RESULTS A total of 76 patients (42.5 ± 10.0 years, 76% male) with sRV (74% TGA, 26% ccTGA) on NOACs were included in the study. During a median follow-up of 2.5 years (IQR1.5-3.9), TE events occurred in 3 patients (4%), while no MB episodes were reported. Minor bleeding occurred in 9 patients (12%). NOAC treatment cessation rate was 1.4% (95%CI:0.3-4%) during the first year of follow-up. All the patients with TE events had a CHA$_{2}$DS$_{2}$-VASc score ≥ 2 and impaired sRV systolic function at baseline. The total incidence of major events during follow-up was significantly lower compared to historical use of VKAs or aspirin before study inclusion (1.4% (95%CI:0.29-4%) vs 6,9% (95%CI:2.5-15.2%); p = .01). CONCLUSIONS In this prospective study, NOACs appear to be well-tolerated, with excellent efficacy and safety at mid-term in patients with sRV