Developed in 1992, the flow-mediated dilation test is now the most commonly used noninvasive assessment of vascular endothelial function in humans. Since its inception, scientists have refined their ...understanding of the physiology, analysis, and interpretation of this measurement. Recently, a significant growth of knowledge has added to our understanding and implementation of this clinically relevant research methodology. Therefore, this tutorial provides timely insight into recent advances and practical information related to the ultrasonic assessment of vascular endothelial function in humans.
Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of ...flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans.
Abstract
Context
Type 1 diabetes (T1D) negatively affects both the endothelin system and muscle oxidative capacity. The endothelin pathway is a critical regulator of microcirculatory function and may ...exhibit sexual dichotomy by which healthy premenopausal women have greater endothelin-B receptor (ETBR) function compared to men. Moreover, T1D may differentially alter muscle oxidative capacity in men and women; however, whether ETBR function is impaired in women compared to men with T1D and its relationship with muscle oxidative capacity has yet to be explored.
Objective
The purpose of this investigation was to determine if ETBR-mediated dilation is impaired in women compared to men with T1D and if this is related to their skeletal muscle oxidative capacity.
Methods
Men (n = 9; glycated hemoglobin A1c HbA1c = 7.8 ± 1.0%) and women (N = 10 women; HbA1c = 8.4 ± 1.3%) with uncomplicated T1D were recruited for this investigation. Near-infrared spectroscopy (NIRS) and intradermal microdialysis (750 nM BQ-123 + ET-1 10−20–10−8 mol/L) were used to evaluate skeletal muscle oxidative capacity and assess ETBR-mediated vasodilation, respectively.
Results
Skeletal muscle oxidative capacity was significantly lower (P = .031) in women compared with men with T1D. However, ETBR-mediated dilation induced a significantly greater (P = .012) vasodilatory response in women compared to men with T1D, and the area under the curve was negatively associated with skeletal muscle oxidative capacity (r = −.620; P = .042).
Conclusion
Compared to men with uncomplicated T1D, muscle oxidative capacity was lower and ETBR-mediated vasodilation was higher in women with uncomplicated T1D. ETBR-induced vasodilatory capacity was inversely related to skeletal muscle oxidative capacity, suggesting there may be compensatory mechanisms occurring to preserve microvascular blood flow in women with T1D.
Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen ...levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exosomes, key mediators of cell‐cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via the secretion of ...exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O2•− to H2O2 whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise‐induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks of volunteer wheel exercise. A single bout of exercise in humans also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing models, which was associated with a decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3−/− mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H2O2 levels in a heparin‐binding domain‐dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3−/− mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3‐dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease.
Abstract Background About 50% of Americans and 60% to 70% of US military personnel use dietary supplements, some of which have been associated with adverse events (AEs). Nutritional supplements like ...sport drinks and sport bars/gels are also commonly used by athletes and service members. Previous dietary supplement and nutritional supplement surveys were conducted on Army, Air Force, and Coast Guard personnel. Objective The aim of this cross-sectional study was to investigate dietary and nutritional supplement use in Navy and Marine Corps personnel, including the prevalence, types, factors associated with use, and AEs. Design A random sample of 10,000 Navy and Marine Corps personnel were contacted. Service members were asked to complete a detailed questionnaire describing their personal characteristics, supplement use, and AEs experienced. Results In total, 1,708 service members completed the questionnaire during August through December 2014, with 1,683 used for analysis. Overall, 73% reported using dietary supplements one or more times per week. The most commonly used dietary supplements (used one or more times per week) were multivitamins/multiminerals (48%), protein/amino acids (34%), combination products (33%), and individual vitamins and minerals (29%). About 31% of service members reported using five or more dietary supplements. Sport drinks and sport bars/gels were used by 45% and 23% of service members, respectively. Monthly expenditures on dietary supplements averaged $39; 31% of service members spent ≥$50/mo. Multivariate logistic regression modeling indicated that female sex (women/men; odds ratio OR=1.76, 95% CI 1.32 to 2.36), higher educational level (college degree/no college degree; OR=2.23, 95% CI 1.62 to 3.30), higher body mass index (calculated as kg/m2 ) (≥30/<25; OR=1.67, 95% CI 1.06 to 2.63), and a greater amount of resistance training (≥271/0 to 45 min/week; OR=2.85, 95% CI 1.94 to 4.17) were associated with dietary supplement use. Twenty-two percent of dietary supplement users and 6% of nutritional supplement users reported one or more AEs. For combination products alone, 29% of users reported one or more AEs. Conclusions The prevalence of dietary supplement use in Navy and Marine Corps personnel was considerably higher than reported in civilian investigations for almost all types of dietary supplements, although similar to most other military services. Factors associated with dietary supplement use were similar to those reported in previous military and civilian investigations. Prevalence of self-reported AEs was very high, especially for combination products.
Dietary supplements (DSs) are used by 50% of Americans and 70% of United States military service members (SMs); some have adverse effects (AEs). This cross-sectional investigation examined AEs ...associated with specific DSs. A stratified random sample of SMs from the Air Force, Army, Marine Corps, and Navy was obtained. Volunteers completed a questionnaire reporting AEs for 96 generic and 62 specific DSs. The highest prevalence (≥1 AE) in specific DS categories was 35% prohormones, 33% weight loss supplements, 26% pre/post workout supplements, 14% herbal products, 12% multivitamin/multiminerals, 11% protein/amino acids, 9% muscle building supplements, 7% other DSs, 6% joint health products, and 5% individual vitamins/minerals. Specific DSs of concern (with proportion reporting AEs) included: Libido Max® (35%), Hydroxycut Hardcore® (33%), OxyElite® (33%), Roxylean® (31%), Growth Factor 9® (30%), Super HD® (29%), Hydroxycut Advanced® (29%), Lipo 6® (28%), The Ripper® (27%), Test Booster® (27%), Xenadrine Xtreme Thermogenic® (27%), C4 Extreme® (26%), and C4 Original® (25%). Products marketed for weight loss, use before/after workout, and prohormones had the highest AE prevalence. DSs can contain substances with independent/additive AEs and/or interact with other ingredients or prescribed medications. Methods described here could provide a continuous surveillance system detecting dangerous DSs entering the market.
•Over 26,000 Service members reported on adverse effects of dietary supplements.•A number of individual dietary supplements were associated with adverse events.•18% of pre/post workout, 15% of fat/weight loss users reported ≥1 adverse event.•10% of body building, 8% of prohormone supplement users reported ≥1 adverse event.•Study provides a model for a surveillance system to detect dangerous supplements.
This longitudinal study examined associations between chronic medical conditions (CMCs) and persistent dietary supplement (DS) use. On two separate occasions, 1.3 ± 0.2 years apart, military service ...members (SMs) (n = 5778) completed identical questionnaires concerning their DS use in the past 6 months and their demographic and lifestyle characteristics. Medical conditions were obtained from a medical surveillance system six months before the first questionnaire and during the period between questionnaires. Diagnoses were grouped into 19 major (largely systemic) and 9 specific CMCs. Conditions diagnosed in both periods (CMCs) were examined in relation to DS use reported on both questionnaires (persistent DS use). After adjustment for demographic and lifestyle factors, higher odds of persistent DS use were found in 7 of the 19 major CMCs and 5 of the 9 specific CMCs. SMs with a CMC had 1.25 (95% confidence interval 95%CI = 1.10–1.41) higher adjusted odds of persistent DS use. The three specific CMCs with the highest adjusted odds of persistent DS use were anxiety (odds ratio OR = 2.30, 95%CI = 1.36–3.89), depression (OR = 2.12, 95%CI = 1.20–3.73), and gastroesophageal reflux disease (OR = 2.02, 95%CI = 1.02–4.04). Among DS categories, participants with a CMC had higher adjusted odds of persistent vitamins or mineral use (OR = 1.31, 95% CI = 1.12–1.53). Participants with CMCs had a higher prevalence of persistent DS use, especially individual vitamin and mineral use.
The ongoing COVID-19 pandemic has revealed the shortfalls in our understanding of how to treat coronavirus infections. With almost 7 million case fatalities of COVID-19 globally, the catalog of ...FDA-approved antiviral therapeutics is limited compared to other medications, such as antibiotics. All-trans retinoic acid (RA), or activated vitamin A, has been studied as a potential therapeutic against coronavirus infection because of its antiviral properties. Due to its impact on different signaling pathways, RA's mechanism of action during coronavirus infection has not been thoroughly described. To determine RA's mechanism of action, we examined its effect against a mouse coronavirus, mouse hepatitis virus strain A59 (MHV). We demonstrated that RA significantly decreased viral titers in infected mouse L929 fibroblasts and RAW 264.7 macrophages. The reduced viral titers were associated with a corresponding decrease in MHV nucleocapsid protein expression. Using interferon regulatory factor 3 (IRF3) knockout RAW 264.7 cells, we demonstrated that RA-induced suppression of MHV required IRF3 activity. RNA-seq analysis of wildtype and IRF3 knockout RAW cells showed that RA upregulated calcium/calmodulin (CaM) signaling proteins, such as CaM kinase kinase 1 (CaMKK1). When treated with a CaMKK inhibitor, RA was unable to upregulate IRF activation during MHV infection. In conclusion, our results demonstrate that RA-induced protection against coronavirus infection depends on IRF3 and CaMKK.
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