STIM1: A new player in nuclear dynamics? Lessons learnt from tubular aggregate myopathy.

Two recent papers have highlighted that STIM1, a key component of Store-operated Ca2+-entry, is able to translocate to the nucleus and participate in nuclear Ca-handling and in DNA repair. These finding opens new avenues on the role that this Ca-sensing protein may have in health and disease.

Astroglial calcium signaling and homeostasis in tuberous sclerosis complex.

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities.

Getting everyone to agree on gene signatures for murine macrophage polarization in vitro.

Macrophages, key players in the innate immune system, showcase remarkable adaptability. Derived from monocytes, these phagocytic cells excel in engulfing and digesting pathogens and foreign substances as well as contributing to antigen presentation, initiating and regulating adaptive immunity. Macrophages are highly plastic, and the microenvironment can shaper their phenotype leading to numerous distinct polarized subsets, exemplified by the two ends of the spectrum: M1 (classical activation, inflammatory) and M2 (alternative activation, anti-inflammatory).

Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell-target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD-related memory deficits, neuropathology, and neuroinflammation.

Do France, Germany, and Italy agree on the added therapeutic value of medicines?

Objectives: The Health Technology Assessment (HTA) of medicines is performed separately at the country level with some differences, but Italy, France, and Germany have implemented price and reimbursement systems strongly focused on the Added Therapeutic Value (ATV). This study investigates the level of agreement on ATV assessments by Agenzia Italiana del Farmaco (AIFA), Haute Autorité de Santé (HAS), and Gemeinsamer Bundesausschuss (G-BA).

Methods: A database was created collecting all information about drugs with innovativeness status requests in Italy from July 2017 to December 2022 and populated with the corresponding HAS and G-BA ATV assessments.

The endoplasmic reticulum stress and unfolded protein response in Alzheimer's disease: A calcium dyshomeostasis perspective.

Protein misfolding is prominent in early cellular pathology of Alzheimer's disease (AD), implicating pathophysiological significance of endoplasmic reticulum stress/unfolded protein response (ER stress/UPR) and highlighting it as a target for drug development. Experimental data from animal AD models and observations on human specimens are, however, inconsistent. ER stress and associated UPR are readily observed in in vitro AD cellular models and in some AD model animals.

Inhibition of NHE1 transport activity and gene transcription in DRG neurons in oxaliplatin-induced painful peripheral neurotoxicity.

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na/H exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pH) homeostasis in many cell types, including nociceptors.

Immortalized hippocampal astrocytes from 3xTg-AD mice, a new model to study disease-related astrocytic dysfunction: a comparative review.

Alzheimer's disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD, emphasizing the urgent need for a comprehensive understanding of cell-specific pathology. Astrocytes, principal homeostatic cells of the central nervous system, are key players in the pathogenesis of neurodegenerative diseases, including AD.

Immortalized Alzheimer's Disease Astrocytes: Characterization of Their Proteolytic Systems.

Alzheimer's disease (AD) is a progressive neurodegeneration with dysfunctions in both the ubiquitin-proteasome system (UPS) and autophagy. Astroglia participation in AD is an attractive topic of research, but molecular patterns are partially defined and available in vitro models have technical limitations. Immortalized astrocytes from the hippocampus of 3xTg-AD and wild-type mice (3Tg-iAstro and WT-iAstro, respectively) have been obtained as an attempt to overcome primary cell line limitations and this study aims at characterizing their proteolytic systems, focusing on UPS and autophagy.

Calcineurin Signalling in Astrocytes: From Pathology to Physiology and Control of Neuronal Functions.

Calcineurin (CaN), a Ca/calmodulin-activated serine/threonine phosphatase, acts as a Ca-sensitive switch regulating cellular functions through protein dephosphorylation and activation of gene transcription. In astrocytes, the principal homeostatic cells in the CNS, over-activation of CaN is known to drive pathological transcriptional remodelling, associated with neuroinflammation in diseases such as Alzheimer's disease, epilepsy and brain trauma. Recent reports suggest that, in physiological conditions, the activity of CaN in astrocytes is transcription-independent and is required for maintenance of basal protein synthesis rate and activation of astrocytic Na/K pump thereby contributing to neuronal functions such as neuronal excitability and memory formation.

Implications of Oncology Trial Design and Uncertainties in Efficacy-Safety Data on Health Technology Assessments.

Background: Advances in cancer medicines have resulted in tangible health impacts, but the magnitude of benefits of approved cancer medicines could vary greatly. Health Technology Assessment (HTA) is a multidisciplinary process used to inform resource allocation through a systematic value assessment of health technology. This paper reviews the challenges in conducting HTA for cancer medicines arising from oncology trial designs and uncertainties of safety-efficacy data.

Time-Trends of Drug-Drug Interactions among Elderly Outpatients in the Piedmont Region (Italy): A Population-Based Study.

Adverse drug reactions (ADRs) are a major health problem in the primary care setting, particularly among the elderly population. While the high frequency of ADRs in the elderly has several causes, a major and common determinant is polypharmacy, which can in turn increase the risk of drug-drug interactions (DDIs). In this paper, we analyzed the drugs prescriptions dispensed to elderly outpatients, to assess changes in the prevalence of selected DDIs in the period 2013−2019.

CIC-39Na reverses the thrombocytopenia that characterizes tubular aggregate myopathy.

Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.

STIM1 and ORAI1 mutations leading to tubular aggregate myopathies are sensitive to the Store-operated Ca-entry modulators CIC-37 and CIC-39.

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps.

Calcineurin Controls Cellular Prion Protein Expression in Mouse Astrocytes.

Prion diseases arise from the conformational conversion of the cellular prion protein (PrP) into a self-replicating prion isoform (PrP). Although this process has been studied mostly in neurons, a growing body of evidence suggests that astrocytes express PrP and are able to replicate and accumulate PrP. Currently, prion diseases remain incurable, while downregulation of PrP represents the most promising therapy due to the reduction of the substrate for prion conversion.