New Findings What is the central question of this study?What are the characteristics of the NK cell response following acute moderate‐intensity aerobic exercise in prostate cancer survivors and is there a relationship between stress hormones and NK cell mobilization? What is the main finding and its importance?NK cell numbers and proportions changed similarly between prostate cancer survivors and controls following acute exercise. Consecutive training sessions can likely be used without adverse effects on the immune system during prostate cancer treatment. Abstract Prostate cancer treatment affects multiple physiological systems, although the immune response during exercise has been minimally investigated. The objective was to characterize the natural killer (NK) cell response following acute exercise in prostate cancer survivors. Prostate cancer survivors on androgen deprivation therapy (ADT) and those without (PCa) along with non‐cancer controls (CON) completed a moderate intensity cycling bout. NK cells were phenotyped before and 0, 2 and 24 h after acute exercise using flow cytometry. CD56 total NK cell frequency increased by 6.2% at 0 h (P < 0.001) and decreased by 2.5% at 2 h (P < 0.01) with similar findings in CD56dim cells. NK cell counts also exhibited a biphasic response. Independent of exercise, ADT had intracellular interferon γ (IFNγ) expression that was nearly twofold higher than CON (P < 0.01). PCa perforin expression was reduced by 11.4% (P < 0.05), suggesting these cells may be more prone to degranulation. CD57− NK cells demonstrated increased perforin and IFNγ frequencies after exercise with no change within the CD57+ populations. All NK and leukocyte populations returned to baseline by 24 h. NK cell mobilization and egress with acute exercise appear normal, as cell counts and frequencies in prostate cancer survivors change similarly to CON. However, lower perforin proportions (PCa) and higher IFNγ expression (ADT) may alter NK cytotoxicity and require further investigation. The return of NK cell proportions to resting levels overnight suggests that consecutive training sessions can be used without adverse effects on the immune system during prostate cancer treatment.
Collegiate athletes are exposed to varying levels of academic and physical stressors, placing them at increased risk for stress-activated latent viral infections. However, the impact of allostatic stress load on the immune response to maximal exercise in athletes remains largely unknown. This study examined the effects of a 7-mo training period and cytomegalovirus (CMV) serostatus on immune cell response to high-intensity swim tests within a group of collegiate swimmers. Samples were collected from 15 National Collegiate Athletic Association Division I swimmers (9 men, 6 women: 19.87 ± 0.64 yr) before and after exhaustive in-pool swims at 2 time points (V1: immediately post-season 1 and V3: beginning of season 2). An additional off-season (V2) time point was collected in a subset of 9 swimmers. Natural killer (NK) cell, B cell, and T cells were quantified by flow cytometry. Linear mixed models were used to determine the effects of exercise, time point, and CMV serostatus (α = 0.05). Resting senescent CD8+ T cells were higher in CMV-seropositive participants at V3 ( P = 0.005). CMV-seronegative participants had a decrease in resting senescent CD8+ T cells from V1 to V3 ( P = 0.021). After acute exercise, CMV-seropositive participants had lower naïve CD8+ T cells ( P < 0.001) and higher senescent CD8+ T cells ( P < 0.001). Increased cumulative stress levels did not appear to affect B-cell and NK-cell compartments. Immune response to exercise was impacted by CMV serostatus and allostatic stress load. Young CMV-seropositive athletes exposed to elevated stressors should be monitored to determine long-term effects of training and academic stressors. NEW & NOTEWORTHY Allostatic stress load is associated with impaired immune response to maximal exercise in cytomegalovirus (CMV)-seropositive subjects but not in CMV-seronegative young healthy adults.
Background Enhanced metabolic plasticity and diversification of energy production is a hallmark of highly proliferative breast cancers. This contributes to poor pharmacotherapy efficacy, recurrence, and metastases. We have previously identified a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 that selectively reduces bioenergetic coupling efficiency and is orally available. Here, we evaluated the antineoplastic properties of uncoupling oxidative phosphorylation from ATP production in breast cancer using BAM15. Methods The anticancer effects of BAM15 were evaluated in human triple-negative MDA-MB-231 and murine luminal B, ERα-negative EO771 cells as well as in an orthotopic allograft model of highly proliferative mammary cancer in mice fed a standard or high fat diet (HFD). Untargeted transcriptomic profiling of MDA-MB-231 cells was conducted after 16-h exposure to BAM15. Additionally, oxidative phosphorylation and electron transfer capacity was determined in permeabilized cells and excised tumor homogenates after treatment with BAM15. Results BAM15 increased proton leak and over time, diminished cell proliferation, migration, and ATP production in both MDA-MB-231 and EO771 cells. Additionally, BAM15 decreased mitochondrial membrane potential, while inducing apoptosis and reactive oxygen species accumulation in MDA-MB-231 and EO771 cells. Untargeted transcriptomic profiling of MDA-MB-231 cells further revealed inhibition of signatures associated with cell survival and energy production by BAM15. In lean mice, BAM15 lowered body weight independent of food intake and slowed tumor progression compared to vehicle-treated controls. In HFD mice, BAM15 reduced tumor growth relative to vehicle and calorie-restricted weight-matched controls mediated in part by impaired cell proliferation, mitochondrial respiratory function, and ATP production. LC-MS/MS profiling of plasma and tissues from BAM15-treated animals revealed distribution of BAM15 in adipose, liver, and tumor tissue with low abundance in skeletal muscle. Conclusions Collectively, these data indicate that mitochondrial uncoupling may be an effective strategy to limit proliferation of aggressive forms of breast cancer. More broadly, these findings highlight the metabolic vulnerabilities of highly proliferative breast cancers which may be leveraged in overcoming poor responsiveness to existing therapies.
Exercise has long been considered crucial for improving cardiometabolic health. However, recent research also highlights the benefits of exercise on improving immune function in adults of all ages (Duggal et al., 2019). Given the immune system's complexity, the mechanisms linking regular exercise to enhanced immune function are likely multi-dimensional. Cross-sectional studies have shown that individuals who participate in lifelong physical
Background Physiological and psychological stress slow healing from experimental wounds by impairing immune function. Objective To determine whether supplemental protein and multi-nutrient supplementation improve wound healing markers following acute stress induced by acute sleep restriction. Methods In this single-blind, cross-over study of generally healthy young adults (18 males/2 females; 19.7±2.30 years [mean±SD]), experimental wounds were created by removing the top layer of forearm blisters induced via suction after 48-h of 72-h sleep restriction (2-h nightly sleep), a protocol previously shown to delay wound healing. Skin barrier restoration (measured by trans-epidermal water loss, TEWL) assessed wound healing up to 10 days post-blistering, and local immune responses were evaluated by serial measurement of cytokine concentrations in fluid collected at wound sites for 48-h post-blistering. Participants consumed controlled, isocaloric diets with either 0.900 g·kg−1·d−1 protein plus placebo (PLA) or 1.50 g·kg−1·d−1 protein plus multi-nutrient beverage (NUT; L-arginine: 20.0 g·d−1, L-glutamine: 30.0 g·d−1, omega-3 fatty acids: 1.00 g·d−1, zinc sulfate: 24.0 mg·d−1, cholecalciferol: 800 IU·d−1 and vitamin C: 400 mg·d−1) during sleep restriction and for 4 days afterwards. Results Skin barrier restoration (primary outcome) was shorter for NUT [(median, interquartile range) (3.98, 1.17 days)] compared to PLA (5.25, 1.05 days) (P = 0.001). Cytokines from wound fluid (secondary outcome) increased over time (main effect of time P≤0.001), except IL-13 (P = 0.07); however, no effects of treatment were observed. Conclusions Supplemental nutrition may promote wound healing following sleep restriction in healthy adults including military personnel, the latter of which also have a high incidence of wounds and infection. Clinical trials registration: clinicaltrials.gov #NCT03525184.
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