Actin instability alters red blood cell mechanics and Piezo1 channel activity.

The organization and dynamics of the spectrin-actin membrane cytoskeleton play a crucial role in determining the mechanical properties of red blood cells (RBC). RBC are subjected to various forces that induce deformation during blood microcirculation. Such forces also regulate membrane tension, leading to Piezo1 channel activation, which is functionally linked to RBC dehydration through calcium influx and subsequent activation of Gardos channels, ultimately resulting in variations in RBC volume.

Ferritin adsorption onto chrysotile asbestos fibers influences the protein secondary structure.

Asbestos fiber exposure triggers chronic inflammation and cancer. Asbestos fibers can adsorb different types of proteins. The mechanism of this adsorption, not yet completely understood, has been studied in detail mainly with serum albumin and was shown to induce structural changes in the bound protein.

Effect of Synthetic Vitreous Fiber Exposure on TMEM16A Channels in a Oocyte Model.

Many years ago, asbestos fibers were banned and replaced by synthetic vitreous fibers because of their carcinogenicity. However, the toxicity of the latter fibers is still under debate, especially when it concerns the early fiber interactions with biological cell membranes. Here, we aimed to investigate the effects of a synthetic vitreous fiber named FAV173 on the oocyte membrane, the cell model we have already used to characterize the effect of crocidolite asbestos fiber exposure.

A Pharmacological Investigation of the TMEM16A Currents in Murine Skeletal Myogenic Precursor Cells.

TMEM16A is a Ca-activated Cl channel expressed in various species and tissues. In mammalian skeletal muscle precursors, the activity of these channels is still poorly investigated. Here, we characterized TMEM16A channels and investigated if the pharmacological activation of Piezo1 channels could modulate the TMEM16A currents in mouse myogenic precursors.

Asbestos Fibers Enhance the TMEM16A Channel Activity in Xenopus Oocytes.

Background: The interaction of asbestos fibers with target cell membranes is still poorly investigated. Here, we detected and characterized an enhancement of chloride conductance in oocyte cell membranes induced by exposure to crocidolite (Croc) asbestos fibers.

Methods: A two-microelectrode voltage clamp technique was used to test the effect of Croc fiber suspensions on outward chloride currents evoked by step membrane depolarization.

Ferruginous bodies exert a strong proinflammatory effect.

One of the main problems related to ferruginous-asbestos bodies (ABs) exposure is their potential pathogenetic role in asbestos-related diseases. The aim of this study was to examine whether purified ABs, might stimulate inflammatory cells. ABs were isolated by exploiting their magnetic properties, therefore avoiding the strong chemical treatment usually employed for this purpose.

Asbestos fibers promote iron oxidation and compete with apoferritin enzymatic activity.

Asbestos fibers interact with many different proteins and may affect either their structure or functions. The aim of this study was to determine whether ferritin absorbed onto fibers might modify its ferroxidase activity. By measuring apo-ferritin ferroxidase activity, data demonstrated that ferritin in the presence of fibers did not significantly modify this enzymatic activity.

Challenges in the Development of Intravenous Neurokinin-1 Receptor Antagonists: Results of a Safety and Pharmacokinetics Dose-Finding, Phase 1 Study of Intravenous Fosnetupitant.

Oral NEPA is the fixed-combination antiemetic comprising netupitant (neurokinin-1 receptor antagonist [NK RA]) and palonosetron (5-hydroxytryptamine-3 receptor antagonist [5-HT RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water-soluble N-phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK RA water solubility, preventing the occurrence of hypersensitivity and infusion-site reactions associated with these products.

Neuronal Agrin Promotes Proliferation of Primary Human Myoblasts in an Age-Dependent Manner.

Neuronal agrin, a heparan sulphate proteoglycan secreted by the α-motor neurons, promotes the formation and maintenance of the neuromuscular junction by binding to Lrp4 and activating muscle-specific kinase (MuSK). Neuronal agrin also promotes myogenesis by enhancing differentiation and maturation of myotubes, but its effect on proliferating human myoblasts, which are often considered to be unresponsive to agrin, remains unclear. Using primary human myoblasts, we determined that neuronal agrin induced transient dephosphorylation of ERK1/2, while c-Abl, STAT3, and focal adhesion kinase were unresponsive.

Nerve-dependent distribution of subsynaptic type 1 inositol 1,4,5-trisphosphate receptor at the neuromuscular junction.

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are enriched at postsynaptic membrane compartments of the neuromuscular junction (NMJ), surrounding the subsynaptic nuclei and close to nicotinic acetylcholine receptors (nAChRs) of the motor endplate. At the endplate level, it has been proposed that nerve-dependent electrical activity might trigger IP3-associated, local Ca2+ signals not only involved in excitation-transcription (ET) coupling but also crucial to the development and stabilization of the NMJ itself. The present study was undertaken to examine whether denervation affects the subsynaptic IP3R distribution in skeletal muscles and which are the underlying mechanisms.

A preliminary study on the role of Piezo1 channels in myokine release from cultured mouse myotubes.

It has long been known that regular physical exercise induces short and long term benefits reducing the risk of cardiovascular disease, diabetes, osteoporosis, cancer and improves sleep quality, cognitive level, mobility, autonomy in enderly. More recent is the evidence on the endocrine role of the contracting skeletal muscle. Exercise triggers the release of miokines, which act in autocrine, paracrine and endocrine ways controlling the activity of muscles but also of other tissues and organs such as adipose tissue, liver, pancreas, bones, and brain.

The State of the Art of Piezo1 Channels in Skeletal Muscle Regeneration.

Piezo1 channels are highly mechanically-activated cation channels that can sense and transduce the mechanical stimuli into physiological signals in different tissues including skeletal muscle. In this focused review, we summarize the emerging evidence of Piezo1 channel-mediated effects in the physiology of skeletal muscle, with a particular focus on the role of Piezo1 in controlling myogenic precursor activity and skeletal muscle regeneration and vascularization. The disclosed effects reported by pharmacological activation of Piezo1 channels with the selective agonist Yoda1 indicate a potential impact of Piezo1 channel activity in skeletal muscle regeneration, which is disrupted in various muscular pathological states.

Preliminary Observations on Skeletal Muscle Adaptation and Plasticity in Homer 2 Mice.

Homer represents a diversified family of scaffold and transduction proteins made up of several isoforms. Here, we present preliminary observations on skeletal muscle adaptation and plasticity in a transgenic model of Homer 2 mouse using a multifaceted approach entailing morphometry, quantitative RT-PCR (Reverse Transcription PCR), confocal immunofluorescence, and electrophysiology. Morphometry shows that muscle (SOL), at variance with muscle (EDL) and muscle (FDB), displays sizable reduction of fibre cross-sectional area compared to the WT counterparts.

"Time window" effect of Yoda1-evoked Piezo1 channel activity during mouse skeletal muscle differentiation.

Aim: Mechanosensitive Piezo1 ion channels emerged recently as important contributors to various vital functions including modulation of the blood supply to skeletal muscles. The specific Piezo1 channel agonist Yoda1 was shown to regulate the tone of blood vessels similarly to physical exercise. However, the direct role of Piezo1 channels in muscle function has been little studied so far.

Pharmacokinetics and safety evaluation of oral Palonosetron in Chinese healthy volunteers: A phase 1, open-label, randomized, cross-over study.

Purpose: Palonosetron hydrochloride is a specific 5-HT3 receptor antagonist, used to prevent chemotherapy-induced nausea and vomiting (CINV), and is a known chemical entity currently registered in the oral and IV forms in several countries worldwide.

Methods: Single-center, single-dose, 3-treatment, open-label, randomized, 3-period, phase-I cross-over study, conducted in 18 individuals (16 males and 2 females). The primary objective was to assess the pharmacokinetic profile of Palonosetron 0.

A phase 1 pharmacokinetic study of oral NEPA, the fixed combination of netupitant and palonosetron, in Chinese healthy volunteers.

Purpose: Oral NEPA, the only fixed-combination antiemetic, is composed of the neurokinin-1 receptor antagonist netupitant (300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (0.50 mg). This study was conducted to evaluate the pharmacokinetic profile of netupitant and its main metabolites M1 and M3, and palonosetron in Chinese subjects.

Pharmacokinetic profile and safety of intravenous NEPA, a fixed combination of fosnetupitant and palonosetron, in cancer patients: Prevention of chemotherapy-induced nausea and vomiting associated with highly emetogenic chemotherapy.

NEPA is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.

Interplay Between Cholinergic and Adenosinergic Systems in Skeletal Muscle.

Since the pioneering works of Ricardo Miledi, the neuromuscular junction represents the best example of a synapse where ACh is the neurotransmitter acting on nicotinic ACh receptors. ATP, co-released with ACh, is promptly degraded to Ado, which acts as a modulator of the cholinergic synaptic activity. Consequently, both ACh and adenosine play a crucial role in controlling the nerve-muscle communication.

A "noisy" electrical stimulation protocol favors muscle regeneration in vitro through release of endogenous ATP.

An in vitro system of electrical stimulation was used to explore whether an innovative "noisy" stimulation protocol derived from human electromyographic recordings (EMGstim) could promote muscle regeneration. EMGstim was delivered to cultured mouse myofibers isolated from Flexor Digitorum Brevis, preserving their satellite cells. In response to EMGstim, immunostaining for the myogenic regulatory factor myogenin, revealed an increased percentage of elongated myogenin-positive cells surrounding the myofibers.

On the mechanism of the electrophysiological changes and membrane lesions induced by asbestos fiber exposure in Xenopus laevis oocytes.

The so-called amphibole asbestos fibers are enriched with mineral iron ions, able to stimulate ROS production. We recently reported that crocidolite asbestos was able to interact with the cell membranes of Xenopus laevis oocytes, to alter their electrical membrane properties. Here, we found that applied iron ions (Fe) or HO (for ROS generation) mimicked these effects, suggesting that at least one effect of iron-containing asbestos fiber exposure was mediated by ROS production.

Timing flexibility of oral NEPA, netupitant-palonosetron combination, administration for the prevention of chemotherapy-induced nausea and vomiting (CINV).

Purpose: The administration timing of antiemetic and chemotherapeutic regimens is often determined by regulatory indications, based on registration studies. Oral NEPA, fixed combination of the neurokinin-1 receptor antagonist (NKRA) netupitant and the 5-hydroxytryptamine-3 RA (5-HTRA) palonosetron, is recommended to be administered approximately 60 min before chemotherapy. Reducing chair time for chemotherapy administration at oncology day therapy units would improve facility efficiency without compromising patient symptom management.

Complementary Pharmacokinetic Profiles of Netupitant and Palonosetron Support the Rationale for Their Oral Fixed Combination for the Prevention of Chemotherapy-Induced Nausea and Vomiting.

NEPA is the first fixed-combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant (netupitant; 300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (palonosetron; 0.50 mg). This study evaluated the pharmacokinetic profiles of netupitant and palonosetron.

Adenosine Promotes Endplate nAChR Channel Activity in Adult Mouse Skeletal Muscle Fibers via Low Affinity P1 Receptors.

Adenosine is a powerful modulator of skeletal neuromuscular transmission, operating via inhibitory or facilitatory purinergic-type P1 receptors. To date, studies have been focused mainly on the effect of adenosine on presynaptic P1 receptors controlling transmitter release. In this study, using two-microelectrode voltage-clamp and single-channel patch-clamp recording techniques, we have explored potential postsynaptic targets of adenosine and their modulatory effect on nicotinic acetylcholine receptor (nAChR)-mediated synaptic responses in adult mouse skeletal muscle fibers in vitro.

Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice.

Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release.