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BACKGROUND: Extracellular vesicles (EVs) are proposed to play a role in the development of cardiovascular diseases (CVDs) and are considered emerging markers of CVDs. n-3 PUFAs are abundant in oily fish and fish oil and are reported to reduce CVD risk, but there has been little research to date examining the effects of n-3 PUFAs on the generation and function of EVs. OBJECTIVES: We aimed to investigate the effects of fish oil supplementation on the number, generation, and function of EVs in subjects with moderate risk of CVDs. METHODS: A total of 40 participants with moderate risk of CVDs were supplemented with capsules containing either fish oil (1.9 g/d n-3 PUFAs) or control oil (high-oleic safflower oil) for 12 wk in a randomized, double-blind, placebo-controlled crossover intervention study. The effects of fish oil supplementation on conventional CVD and thrombogenic risk markers were measured, along with the number and fatty acid composition of circulating and platelet-derived EVs (PDEVs). PDEV proteome profiles were evaluated, and their impact on coagulation was assessed using assays including fibrin clot formation, thrombin generation, fibrinolysis, and ex vivo thrombus formation. RESULTS: n-3 PUFAs decreased the numbers of circulating EVs by 27%, doubled their n-3 PUFA content, and reduced their capacity to support thrombin generation by >20% in subjects at moderate risk of CVDs. EVs derived from n-3 PUFA-enriched platelets in vitro also resulted in lower thrombin generation, but did not alter thrombus formation in a whole blood ex vivo assay. CONCLUSIONS: Dietary n-3 PUFAs alter the number, composition, and function of EVs, reducing their coagulatory activity. This study provides clear evidence that EVs support thrombin generation and that this EV-dependent thrombin generation is reduced by n-3 PUFAs, which has implications for prevention and treatment of thrombosis. CLINICAL TRIAL REGISTRY: This trial was registered at clinicaltrials.gov as NCT03203512.
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Coagulación Sanguínea , Plaquetas , Estudios Cruzados , Vesículas Extracelulares , Ácidos Grasos Omega-3 , Humanos , Vesículas Extracelulares/metabolismo , Ácidos Grasos Omega-3/farmacología , Masculino , Femenino , Persona de Mediana Edad , Método Doble Ciego , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos , Suplementos Dietéticos , Enfermedades Cardiovasculares/prevención & control , Adulto , Aceites de Pescado/farmacología , Aceites de Pescado/administración & dosificación , Anciano , Ácidos Grasos/metabolismoRESUMEN
In this study, we explore the impact of alkali metal ions (Li+, Na+, K+, Rb+, and Cs+) on the hydration structure of water using molecular dynamics simulations carried out with MB-nrg potential energy functions (PEFs). Our analyses include radial distribution functions, coordination numbers, dipole moments, and infrared spectra of water molecules, calculated as a function of solvation shells. The results collectively indicate a highly local influence of all of the alkali metal ions on the hydrogen-bond network established by the surrounding water molecules, with the smallest and most densely charged Li+ ion exerting the most pronounced effect. Remarkably, the MB-nrg PEFs demonstrate excellent agreement with available experimental data for the position and size of the first solvation shells, underscoring their potential as predictive models for realistic simulations of ionic aqueous solutions across various thermodynamic conditions and environments.
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Introduction: Every-other-day fasting (EODF) is a classical intermittent fasting (IF) mode with neuroprotective effects that promotes motor function recovery after spinal cord injury (SCI) in rats. However, its dynamic effects on the gut microbiota and spinal cord transcriptome remain unknown. Methods: In this study, 16S rRNA sequencing and RNA-seq analysis were used to investigate the effects of ad libitum (AL) and EODF dietary modes on the structural characteristics of rat gut microbiota in rats and the spinal cord transcriptome at various time points after SCI induction. Results: Our results showed that both dietary modes affected the bacterial community composition in SCI rats, with EODF treatment inducing and suppressing dynamic changes in the abundances of potentially anti-inflammatory and pro-inflammatory bacteria. Furthermore, the differentially expressed genes (DEGs) enriched after EODF intervention in SCI rats were associated with various biological events, including immune inflammatory response, cell differentiation, protein modification, neural growth, and apoptosis. In particular, significant spatiotemporal differences were apparent in the DEGs associated with neuroprotection between the EODF and AL interventions. These DGEs were mainly focused on days 1, 3, and 7 after SCI. The relative abundance of certain genera was significantly correlated with DEGs associated with neuroprotective effects in the EODF-SCI group. Discussion: Our results showed that EODF treatment may exert neuroprotective effects by modulating the transcriptome expression profile following SCI in rats. Furthermore, gut microbiota may be partially involved in mediating these effects.
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The development of molecular models with quantum-mechanical accuracy for predictive simulations of biomolecular systems has been a long-standing goal in the field of computational biophysics and biochemistry. As a first step toward a transferable force field for biomolecules entirely derived from "first-principles", we introduce a data-driven many-body energy (MB-nrg) potential energy function (PEF) for N-methylacetamide (NMA), a peptide bond capped by two methyl groups that is commonly used as a proxy for the protein backbone. The MB-nrg PEF is shown to accurately describe the energetics and structural properties of an isolated NMA molecule, including the normal modes of both cis and trans isomers and the energy variation along the isomerization path, as well as the multidimensional potential energy landscape of the NMA-H2O dimer in the gas phase. Importantly, we show that the MB-nrg PEF is fully transferable, enabling molecular dynamics simulations of NMA in solution with quantum-mechanical accuracy. Comparisons with results obtained with a popular pairwise-additive force field for biomolecules and a classical polarizable PEF demonstrate the ability of the MB-nrg PEF to accurately represent many-body effects in NMA-H2O interactions at both short and long distances, which is key to guaranteeing full transferability from the gas phase to the liquid phase.
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Simulación de Dinámica Molecular , Proteínas , Proteínas/química , Acetamidas/químicaRESUMEN
The hydration structure of Na+ and K+ ions in solution is systematically investigated using a hierarchy of molecular models that progressively include more accurate representations of many-body interactions. We found that a conventional empirical pairwise additive force field that is commonly used in biomolecular simulations is unable to reproduce the extended X-ray absorption fine structure (EXAFS) spectra for both ions. In contrast, progressive inclusion of many-body effects rigorously derived from the many-body expansion of the energy allows the MB-nrg potential energy functions (PEFs) to achieve nearly quantitative agreement with the experimental EXAFS spectra, thus enabling the development of a molecular-level picture of the hydration structure of both Na+ and K+ in solution. Since the MB-nrg PEFs have already been shown to accurately describe isomeric equilibria and vibrational spectra of small ion-water clusters in the gas phase, the present study demonstrates that the MB-nrg PEFs effectively represent the long-sought-after models able to correctly predict the properties of ionic aqueous systems from the gas to the liquid phase, which has so far remained elusive.
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Agua , Iones/química , Modelos Moleculares , Agua/químicaRESUMEN
Background: Extracellular vesicles (EVs) are submicron membrane-bound vesicles released from various cells, which are emerging as a potential novel biomarker in cardiovascular diseases (CVDs) due to their procoagulatory and prothrombotic properties. However, there is little information about the relationships between circulating EVs and conventional and thrombogenic risk markers of CVDs. Objective: To investigate the relationships between circulating EVs, conventional cardiovascular risk markers and thrombogenic markers in subjects with moderate risk of CVDs. Design: Subjects (n = 40) aged 40-70 years with moderate risk of CVDs were recruited and assessed for body mass index, blood pressure and plasma lipid profile, as well as platelet aggregation, clot formation, thrombin generation and fibrinolysis. Numbers of circulating EVs were assessed by Nanoparticle Tracking Analysis and flow cytometry. A range of assays were used to assess the procoagulatory activity of plasma and circulating EVs. Results: Circulating EV numbers were positively associated with body mass index, blood pressure, plasma triacylglycerol concentration and overall CVD risk. Higher circulating EV numbers were also associated with increased thrombin generation and enhanced clot formation, and EVs isolated from subjects with moderate CVD risk promoted thrombin generation ex vivo. Higher numbers of endothelial-derived EVs were associated with a greater tendency for clot lysis. Plasma triacylglycerol concentration and diastolic blood pressure independently predicted circulating EV numbers, and EV numbers independently predicted aspects of thrombin generation and clot formation and 10-year CVD risk. Conclusion: Circulating EVs were strongly associated with both conventional and thrombogenic risk markers of CVDs, and also with overall CVD risk, highlighting a potentially important role for EVs in CVDs.
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OBJECTIVE: There is currently no effective treatment for spinal cord injuries (SCIs). Previous studies have shown that every-other-day fasting (EODF), a dietary restriction method, can reduce SCI size and promote motor function recovery, making it a potential novel treatment. However, the mechanism that underlies the positive impact of EODF on SCI remains unclear. Caspase-dependent apoptosis and necroptosis, which involve receptor-interacting protein kinase (RIPK), drive the loss of nerve cells and restrict motor function recovery after SCI. Dietary restriction has a significant inhibitory effect on Caspase and RIPK expression. This study aimed to investigate whether the EODF diet achieves a neuroprotective effect by inhibiting Caspase-dependent apoptosis and RIPK-dependent necroptosis after SCI. METHODS: The model rats underwent EODF for 4 weeks before SCI or started EODF diet immediately after SCI. Immunoblotting and immunohistochemical analyses were used to assess the impact of the intervention on protein expression. Apoptosis in the spinal cord was detected by TdT-mediated dUTP nick-end labeling. RESULTS: Immunoblotting analysis results revealed that the levels of both RIPK1 and RIPK3 proteins in the injury zone were reduced at 6, 12, and 24 hours and at 3 and 7 days after SCI, respectively. Immunohistochemistry results showed that EODF reduced the expression of Caspase-3 and Bax proteins, while prophylactic EODF decreased the rate of apoptosis detected by TdT-mediated dUTP nick-end labeling within 3 days after SCI. CONCLUSIONS: These findings indicate that the mechanism by which EODF exerts neuroprotective effects may be related to the simultaneous inhibition of apoptosis and necroptosis in SCI.
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Fármacos Neuroprotectores , Traumatismos de la Médula Espinal , Animales , Apoptosis , Humanos , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/fisiología , Médula EspinalRESUMEN
BACKGROUND: Fasting and caloric restriction have a potential means of anti-inflammatory, as they can decrease the level of systemic inflammation. Although encouraging results have been obtained in animal experiments, there is no consensus on whether these results are applicable to human. The objective of this systematic review and meta-analysis is to analyze the influence of fasting and caloric restriction on inflammation levels in humans. METHODS: The systematic review and meta-analysis will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The following eight databases will be searched:(The retrieval time is from the establishment of each database to December 2020): PubMed, the Cochrane Library, Embase, Web of Science, China National Knowledge infrastructure (CNKI), China Biology Medicine (CBM), Wan Fang Data, the Chinese Science and Technology Periodical Database (VIP). Relevant data will be performed by Revman 5.3 software provided (Cochrane Collaboration) and Stata 14.0 statistical software. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSIONS: This systematic review will provide evidence to judge the effectiveness of fasting and calorie restriction in human subjects, so as to provide a sound basis for future research and lifestyle promotion. INPLASY REGISTRATION NUMBER: INPLASY202130026.