Extracellular Guanosine 5'-Triphosphate Induces Human Muscle Satellite Cells to Release Exosomes Stuffed With Guanosine.

The extracellular guanosine 5'-triphosphate, GTP, has been demonstrated to be an enhancer of myogenic cell differentiation in a murine cell line, not yet in human muscle cells. Our hypothesis was that GTP could influence also human skeletal muscle regeneration, specifically in the first phases. We tested GTP stimulus on human muscle precursor cells established in culture by human satellite cells derived from Vastus Lateralis of three young male. Our data show that extracellular GTP (a) up-regulated miRNA (specifically miR133a and miR133b) and myogenic regulator factor and (b) induces human myogenic precursor cells to release exosomes stuffed with guanosine based molecules (mainly guanosine) in the extracellular milieu. We think that probably these exosomes could be addressed to influence by means of their content (mainly guanosine) in paracrine or autocrine manner the surrounding cells and/or at distance other muscles or tissues.

Synthesis and Antioxidant Properties of Novel Memantine Derivatives.

BACKGROUND: Medicinal chemistry methodologies are presently used to develop multifunctional molecules which simultaneously reduce oxidative stress, excitotoxicity, metal dyshomeostasis, and neuroinflammation that characterize neuropathological conditions, such as Alzheimer's Disease. RESULTS: Memantine (MEM) derivatives 1-6 were designed and synthesized as novel multifunctional entities with antioxidant and neuroprotective capabilities to manage neurodegenerative diseases, such as Alzheimer's Disease. In vitro neuroprotective studies were performed by using astroglial GL15 cell line to assess antioxidant capability of MEM derivatives 1-6. CONCLUSION: Our outcomes showed that compounds 1 and 5 (at the concentration of 10 µM), containing as antioxidant portion residues of N-acetyl-Cys-OH and N-acetyl-Cys(Allyl)-OH, respectively, revealed a significant neuroprotective activity against oxidative stress, as assessed by NBT assays.

The Regenerative Potential of Female Skeletal Muscle upon Hypobaric Hypoxic Exposure.

AIM: The aim of this study was to determine whether a 14-day trekking expeditions, in high altitude hypoxic environment, triggers redox disturbance at the level of satellite cells (adult stem cells) in young women. METHODS: We collected muscle biopsies from Vastus Lateralis muscle for both single fiber analysis and satellite cells isolation. The samples collected before (PRE-Hypoxia) and after (POST-Hypoxia) the trekking in the Himalayas were compared. Satellite cells were investigated for oxidative stress (oxidant production, antioxidant enzyme activity, and lipid damage), mitochondrial potential variation, gene profile of HIF, and myogenic transcription factors (Pax7, MyoD, myogenin), and miRNA expression (miR-1, miR-133, miR-206). RESULTS: The nuclear domain analysis showed a significant fusion and consequent reduction of the Pax7(+) satellite cells in the single mature fibers. The POST-Hypoxia myoblasts obtained by two out of six volunteers showed high superoxide anion production and lipid peroxidation along with impaired dismutase and catalase and mitochondrial potential. The transcription profile and miRNA expression were different for oxidized and non-oxidized cells. CONCLUSIONS: The present study supports the phenomenon of hypobaric-hypoxia-induced oxidative stress and its role in the impairment of the regenerative capacity of satellite cells derived from the V. Lateralis muscle of young adult female subjects.

Low Intensity Exercise Training Improves Skeletal Muscle Regeneration Potential.

PURPOSE: The aim of this study was to determine whether 12 days of low-to-moderate exercise training at low altitude (598 m a.s.l.) improves skeletal muscle regeneration in sedentary adult women. METHODS: Satellite cells were obtained from the vastus lateralis skeletal muscle of seven women before and after this exercise training at low altitude. They were investigated for differentiation aspects, superoxide anion production, antioxidant enzymes, mitochondrial potential variation after a depolarizing insult, intracellular Ca(2+) concentrations, and micro (mi)RNA expression (miR-1, miR-133, miR-206). RESULTS: In these myogenic populations of adult stem cells, those obtained after exercise training, showed increased Fusion Index and intracellular Ca(2+) concentrations. This exercise training also generally reduced superoxide anion production in cells (by 12-67%), although not in two women, where there was an increase of ~15% along with a reduced superoxide dismutase activity. miRNA expression showed an exercise-induced epigenetic transcription profile that was specific according to the reduced or increased superoxide anion production of the cells. CONCLUSIONS: The present study shows that low-to-moderate exercise training at low altitude improves the regenerative capacity of skeletal muscle in adult women. The differentiation of cells was favored by increased intracellular calcium concentration and increased the fusion index. This low-to-moderate training at low altitude also depicted the epigenetic signature of cells.

Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer's disease.

The approved treatments for Alzheimer's disease (AD) exploit mainly a symptomatic approach based on the use of cholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Natural antioxidant compounds, able to pass through the blood-brain barrier (BBB), have been extensively studied as useful neuroprotective agents. A novel approach towards excitotoxicity protection and oxidative stress associated with excess ß amyloid (Aß) preservation in AD is represented by selective glutamatergic antagonists that possess as well antioxidant capabilities. In the present work, GSH (1) or (R)-α-lipoic acid (LA) (2) have been covalently linked with the NMDA receptor antagonists memantine (MEM). The new conjugates, proposed as potential antialzheimer drugs, should act both as glutamate receptor antagonists and radical scavenging agents. The physico-chemical properties and "in vitro" membrane permeability, the enzymatic and chemical stability, the demonstrated "in vitro" antioxidant activity associated to the capacity to inhibit Aß(1-42) aggregation makes at least compound 2 a promising candidate for treatment of AD patients.