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CONTEXT: Sarcopenia describes the age-related decline in skeletal muscle mass and strength that is driven, at least in part, by an imbalance between rates of muscle protein synthesis (MPS) and muscle protein breakdown. An expanding body of literature has examined the effect of omega-3 polyunsaturated fatty acid (n-3 PUFA) ingestion on MPS rates in older adults, with mixed findings. OBJECTIVE: The aim of this systematic review and meta-analysis was to investigate the effectiveness of n-3 PUFA ingestion in stimulating rates of MPS and whole-body protein synthesis in healthy adults and clinical populations. DATA SOURCES: Searches were conducted of the PubMed, Web of Science, Cochrane Library, and Scopus databases from inception until December 2022 for articles on randomized controlled trials comparing the effect of n-3 PUFA ingestion vs a control or placebo on rates of MPS and whole-body protein synthesis. The search yielded 302 studies, of which 8 were eligible for inclusion. DATA EXTRACTION: The random effects inverse-variance model was used and standardized mean differences (SMDs) with 95%CIs were calculated to assess the pooled effect. Risk of bias was assessed by the Cochrane Risk-of-Bias 2 tool. DATA ANALYSIS: The main analysis indicated no effect of n-3 PUFA supplementation on MPS rates (k = 6; SMD: 0.03; 95%CI, -0.35 to 0.40; I2 = 30%; P = .89). Subgroup analysis based on age, n-3 PUFA dose, duration of supplementation, and method used to measure fractional synthetic rate also revealed no effect of n-3 PUFA ingestion on MPS. In contrast, the main analysis demonstrated an effect of n-3 PUFA ingestion on increasing whole-body protein synthesis rates (k = 3; SMD: 0.51; 95%CI, 0.12-0.90; I2 = 0%; P = .01). CONCLUSIONS: n-3 PUFA ingestion augments the stimulation of whole-body protein synthesis rates in healthy adults and clinical populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. 42022366986.
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The oncogene and drug metabolism enzyme glutathione S-transferase P (GSTP) is also a GSH-dependent chaperone of signal transduction and transcriptional proteins with key role in liver carcinogenesis. In this study, we explored this role of GSTP in hepatocellular carcinoma (HCC) investigating the possible interaction of this protein with one of its transcription factor and metronome of the cancer cell redox, namely the nuclear factor erythroid 2-related factor 2 (Nrf2). Expression, cellular distribution, and function as glutathionylation factor of GSTP1-1 isoform were investigated in the mouse model of N-nitrosodiethylamine (DEN)-induced HCC and in vitro in human HCC cell lines. The physical and functional interaction of GSTP protein with Nrf2 and Keap1 were investigated by immunoprecipitation and gene manipulation experiments. GSTP protein increased its liver expression, enzymatic activity and nuclear levels during DEN-induced tumor development in mice; protein glutathionylation (PSSG) was increased in the tumor masses. Higher levels and a preferential nuclear localization of GSTP protein were also observed in HepG2 and Huh-7 hepatocarcinoma cells compared to HepaRG non-cancerous cells, along with increased basal and Ebselen-stimulated levels of free GSH and PSSG. GSTP activity inhibition with the GSH analogue EZT induced apoptotic cell death in HCC cells. Hepatic Nrf2 and c-Jun, two transcription factors involved in GSTP expression and GSH biosynthesis, were induced in DEN-HCC compared to control animals; the Nrf2 inhibitory proteins Keap1 and ß-TrCP also increased and oligomeric forms of GSTP co-immunoprecipitated with both Nrf2 and Keap1. Nrf2 nuclear translocation and ß-TrCP expression also increased in HCC cells, and GSTP transfection in HepaRG cells induced Nrf2 activation. In conclusion, GSTP expression and subcellular distribution are modified in HCC cells and apparently contribute to the GSH-dependent reprogramming of the cellular redox in this type of cancer directly influencing the transcriptional system Nrf2/Keap1.
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Carcinoma Hepatocelular , Gutatión-S-Transferasa pi , Proteína 1 Asociada A ECH Tipo Kelch , Neoplasias Hepáticas , Factor 2 Relacionado con NF-E2 , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Animales , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Gutatión-S-Transferasa pi/metabolismo , Gutatión-S-Transferasa pi/genética , Masculino , Línea Celular Tumoral , Células Hep G2 , Glutatión/metabolismoRESUMEN
The aim of this research was to validate the effectiveness of the Healthy Fatty Index (HFI) regarding some foods of animal origin (meat, processed, fish, milk products, and eggs) typical of the Western diet and to compare these results with two consolidated indices (atherogenic-AI, and thrombogenic-TI) in the characterization of the nutritional features of their lipids. The fatty acids profile (% of total fatty acids and mg/100 g) of 60 foods, grouped in six subclasses, was used. The AI, TI, and HFI indexes were calculated, and the intraclass correlation coefficients and the degree of agreement were evaluated using different statistical approaches. The results demonstrated that HFI, with respect to AI and TI, seems better able to consider the complexity of the fatty acid profile and the different fat contents. HFI and AI are the two most diverse indices, and they can provide different food classifications. AI and IT exhibit only a fair agreement in regards to food classification, confirming that such indexes are always to be considered indissolubly and never separately, in contrast to the HFI, which can stand alone.
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Oxidative stress (OS) develops in critically ill patients as a metabolic consequence of the immunoinflammatory and degenerative processes of the tissues. These induce increased and/or dysregulated fluxes of reactive species enhancing their pro-oxidant activity and toxicity. At the same time, OS sustains its own inflammatory and immunometabolic pathogenesis, leading to a pervasive and vitious cycle of events that contribute to defective immunity, organ dysfunction and poor prognosis. Protein damage is a key player of these OS effects; it generates increased levels of protein oxidation products and misfolded proteins in both the cellular and extracellular environment, and contributes to forms DAMPs and other proteinaceous material to be removed by endocytosis and proteostasis processes of different cell types, as endothelial cells, tissue resident monocytes-macrophages and peripheral immune cells. An excess of OS and protein damage in critical illness can overwhelm such cellular processes ultimately interfering with systemic proteostasis, and consequently with innate immunity and cell death pathways of the tissues thus sustaining organ dysfunction mechanisms. Extracorporeal therapies based on biocompatible/bioactive membranes and new adsorption techniques may hold some potential in reducing the impact of OS on the defective proteostasis of patients with critical illness. These can help neutralizing reactive and toxic species, also removing solutes in a wide spectrum of molecular weights thus improving proteostasis and its immunometabolic corelates. Pharmacological therapy is also moving steps forward which could help to enhance the efficacy of extracorporeal treatments. This narrative review article explores the aspects behind the origin and pathogenic role of OS in intensive care and critically ill patients, with a focus on protein damage as a cause of impaired systemic proteostasis and immune dysfunction in critical illness.
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Enfermedad Crítica , Estrés Oxidativo , Proteostasis , Humanos , Estrés Oxidativo/fisiología , Inmunidad Innata , Deficiencias en la Proteostasis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Cell therapy for muscular dystrophy has met with limited success, mainly due to the poor engraftment of donor cells, especially in fibrotic muscle at an advanced stage of the disease. We developed a cell-mediated exon skipping that exploits the multinucleated nature of myofibers to achieve cross-correction of resident, dystrophic nuclei by the U7 small nuclear RNA engineered to skip exon 51 of the dystrophin gene. We observed that co-culture of genetically corrected human DMD myogenic cells (but not of WT cells) with their dystrophic counterparts at a ratio of either 1:10 or 1:30 leads to dystrophin production at a level several folds higher than what predicted by simple dilution. This is due to diffusion of U7 snRNA to neighbouring dystrophic resident nuclei. When transplanted into NSG-mdx-Δ51mice carrying a mutation of exon 51, genetically corrected human myogenic cells produce dystrophin at much higher level than WT cells, well in the therapeutic range, and lead to force recovery even with an engraftment of only 3-5%. This level of dystrophin production is an important step towards clinical efficacy for cell therapy.
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Distrofina , Distrofia Muscular de Duchenne , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Distrofina/genética , Exones , Vectores Genéticos , Ratones Endogámicos mdx , Músculos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapiaRESUMEN
AIM: Force expression is characterized by an interplay of biological and molecular determinants that are expected to differentiate males and females in terms of maximal performance. These include muscle characteristics (muscle size, fiber type, contractility), neuromuscular regulation (central and peripheral factors of force expression), and individual genetic factors (miRNAs and gene/protein expression). This research aims to comprehensively assess these physiological variables and their role as determinants of maximal force difference between sexes. METHODS: Experimental evaluations include neuromuscular components of isometric contraction, intrinsic muscle characteristics (proteins and fiber type), and some biomarkers associated with muscle function (circulating miRNAs and gut microbiome) in 12 young and healthy males and 12 females. RESULTS: Male strength superiority appears to stem primarily from muscle size while muscle fiber-type distribution plays a crucial role in contractile properties. Moderate-to-strong pooled correlations between these muscle parameters were established with specific circulating miRNAs, as well as muscle and plasma proteins. CONCLUSION: Muscle size is crucial in explaining the differences in maximal voluntary isometric force generation between males and females with similar fiber type distribution. Potential physiological mechanisms are seen from associations between maximal force, skeletal muscle contractile properties, and biological markers.
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MicroARNs , Caracteres Sexuales , Masculino , Humanos , Femenino , Contracción Muscular/fisiología , Músculo Esquelético/fisiología , Fibras Musculares Esqueléticas , Contracción Isométrica/fisiología , ElectromiografíaRESUMEN
(1) Background: Cadmium (Cd) is a potentially toxic element with a long half-life in the human body (20-40 years). Cytotoxicity mechanisms of Cd include increased levels of oxidative stress and apoptotic signaling, and recent studies have suggested that these aspects of Cd toxicity contribute a role in the pathobiology of non-alcoholic fatty liver disease (NAFLD), a highly prevalent ailment associated with hepatic lipotoxicity and an increased generation of reactive oxygen species (ROS). In this study, Cd toxicity and its interplay with fatty acid (FA)-induced lipotoxicity have been studied in intestinal epithelium and liver cells; the cytoprotective function of melatonin (MLT) has been also evaluated. (2) Methods: human liver cells (HepaRG), primary murine hepatocytes and Caco-2 intestinal epithelial cells were exposed to CdCl2 before and after induction of lipotoxicity with oleic acid (OA) and/or palmitic acid (PA), and in some experiments, FA was combined with MLT (50 nM) treatment. (3) Results: CdCl2 toxicity was associated with ROS induction and reduced cell viability in both the hepatic and intestinal cells. Cd and FA synergized to induce lipid droplet formation and ROS production; the latter was higher for PA compared to OA in liver cells, resulting in a higher reduction in cell viability, especially in HepaRG and primary hepatocytes, whereas CACO-2 cells showed higher resistance to Cd/PA-induced lipotoxicity compared to liver cells. MLT showed significant protection against Cd toxicity either considered alone or combined with FFA-induced lipotoxicity in primary liver cells. (4) Conclusions: Cd and PA combine their pro-oxidant activity to induce lipotoxicity in cellular populations of the gut-liver axis. MLT can be used to lessen the synergistic effect of Cd-PA on cellular ROS formation.
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Melatonina , Enfermedad del Hígado Graso no Alcohólico , Ratones , Humanos , Animales , Ácidos Grasos no Esterificados , Cadmio/farmacología , Melatonina/farmacología , Especies Reactivas de Oxígeno , Células CACO-2 , Hepatocitos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Ácidos Grasos/farmacología , Ácido Palmítico/farmacología , Ácido Oléico/farmacologíaRESUMEN
OBJECTIVE: Protein-energy malnutrition and the subsequent muscle wasting (sarcopenia) are common ageing complications. It is knowing to be also associated with dementia. Our programme will test the cytoprotective functions of vitamin E combined with the cortisol-lowering effect of chocolate polyphenols (PP), in combination with muscle anabolic effect of adequate dietary protein intake and physical exercise to prevent the age-dependent decline of muscle mass and its key underpinning mechanisms including mitochondrial function, and nutrient metabolism in muscle in the elderly. METHODS AND ANALYSIS: In 2020, a 6-month double-blind randomised controlled trial in 75 predementia older people was launched to prevent muscle mass loss, in respond to the 'Joint Programming Initiative A healthy diet for a healthy life'. In the run-in phase, participants will be stabilised on a protein-rich diet (0.9-1.0 g protein/kg ideal body weight/day) and physical exercise programme (high-intensity interval training specifically developed for these subjects). Subsequently, they will be randomised into three groups (1:1:1). The study arms will have a similar isocaloric diet and follow a similar physical exercise programme. Control group (n=25) will maintain the baseline diet; intervention groups will consume either 30 g/day of dark chocolate containing 500 mg total PP (corresponding to 60 mg epicatechin) and 100 mg vitamin E (as RRR-alpha-tocopherol) (n=25); or the high polyphenol chocolate without additional vitamin E (n=25). Muscle mass will be the primary endpoint. Other outcomes are neurocognitive status and previously identified biomolecular indices of frailty in predementia patients. Muscle biopsies will be collected to assess myocyte contraction and mitochondrial metabolism. Blood and plasma samples will be analysed for laboratory endpoints including nutrition metabolism and omics. ETHICS AND DISSEMINATION: All the ethical and regulatory approvals have been obtained by the ethical committees of the Azienda Ospedaliera Universitaria Integrata of Verona with respect to scientific content and compliance with applicable research and human subjects' regulation. Given the broader interest of the society toward undernutrition in the elderly, we identify four main target audiences for our research activity: national and local health systems, both internal and external to the project; targeted population (the elderly); general public; and academia. These activities include scientific workshops, public health awareness campaigns, project dedicated website and publication is scientific peer-review journals. TRIAL REGISTRATION NUMBER: NCT05343611.