Acute exercise activates the AHR in peripheral blood mononuclear cells in an intensity-dependent manner.

The kynurenine pathway of tryptophan degradation generates several metabolites such as kynurenine or kynurenic acid that serve as endogenous ligands of the aryl hydrocarbon receptor (AHR). Due to its distinct biological roles particularly modulating the immune system, the AHR is a current therapeutic target across different inflammation-related diseases. Here, we show an acute exercise-induced increase in AHR ligand availability on a systemic level and a kynurenine pathway activation in peripheral blood mononuclear cells (PBMCs). Concurrently, the AHR is activated in PBMCs following acute exercise. Exercise effects on both, kynurenic acid and AHR activation in PBMCs were greater in response to high-intensity interval exercise (50 min., six three-minute intervals á 90% V̇O2peak, and three-minute intervals at 50% V̇O2peak in between) compared to workload-matched moderate intensity continuous exercise (50 min.). In conclusion, these data indicate a novel mechanistic link how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases.

HIIT Induces Stronger Shifts within the Peripheral T Cell Compartment Independent of Sex.

Acute exercise induces changes within the T-cell compartment, especially in cytotoxic CD8+ memory subsets, depending on exercise intensity and duration. It is unclear whether exercise-induced changes in major T-cell subsets differ in response to acute high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) and whether sex-specific effects exist. Twenty-four recreationally active runners (females: n=12, 27.8±4.1years, 54.4±4.6 ml*kg-1*min-1; males: n=12, 31.6±3.8years, 58.9±7.7 ml*kg-1*min-1) participated in this randomized controlled crossover study, and conducted an energy- and duration-matched HIIT and MICT session. Blood was sampled before (T1), immediately (T2) and 1 h after exercise (T3). Flow cytometry was used to identify T-cell populations. HIIT decreased the proportion of CD8+ T-cells more pronounced at T3 compared to MICT (p=0.007), induced a significantly stronger increase in the CD8+ effector memory (TEM) cell proportion at T2 (p=0.032), and decreased CD4+ central memory proportion more pronounced at T2 (p=0.029). A decrease below baseline CD8+ TEM proportion at T3 was observed only after HIIT (p<0.001). No interaction effects between sexes were revealed. Taken together, HIIT represents a more potent stimulus to induce shifts mainly within the cytotoxic CD8+ T-cell compartment, thereby giving implications to investigate the role of HIIT on the cell´s effector phenotype and function in more detail.

Photostability of sennosides and their aglycones in solution.

INTRODUCTION: Sennosides are the main active constituents of the dried leaves and/or pods of Senna alexandrina Mill. that are used as laxatives. A hypothesis is that aglycones are formed during the degradation of sennosides. However, it is unknown, whether this happens under visible light exposure and how photosensitive sennosides behave in solution. OBJECTIVES: Pure anthraquinone glycosides were tested on their behaviour during sample preparation in the lab under visible light exposure in dependence on the instability of the solvent. MATERIALS AND METHODS: Samples before and after exposure were analysed using UHPLC with UV/Vis and MS detection. RESULTS: Under visible light protection, the solutions were stable for 14 days at room temperature whereas a loss of 20%-60% was measured after 1 day of light exposure. The loss of sennosides due to degradation can be as fast as up to 2%-2.5% per hour, which might have a tremendous impact on phytochemical analysis results during the course of an analysis. The formation of aglycones was not observed in the degradation of sennosides and rhein-8-O-glucoside. CONCLUSION: Aglycones could not be found as a result of the forced degradation. The solutions of sennosides clearly need to be protected from light to obtain reliable analytical results, and light protection is a major point for the stability of liquid preparations.

12-week combined strength and endurance exercise attenuates CD8+ T-cell differentiation and affects the kynurenine pathway in the elderly: a randomized controlled trial.

BACKGROUND: Age-related accumulation of highly differentiated CD8+ effector memory re-expressing CD45RA (EMRA) T-cells and disruption of the kynurenine (KYN) pathway are associated with chronic inflammation and the development of insulin resistance. In this study the aim was to investigate the effects of 12-week combined strength and endurance exercise on CD8+ T-cell differentiation and KYN pathway metabolites. Ninety-six elderly subjects (f/m, aged 50-70) were randomized to a control (CON) or exercise (EX) group. The EX group completed combined strength and endurance training twice weekly for one hour each time at an intensity of 60% of the one-repetition maximum for strength exercises and a perceived exertion of 15/20 for endurance exercises. The EX group was also randomly subdivided into two groups with or without a concomitant balanced diet intervention in order to examine additional effects besides exercise alone. Before and after the intervention phase, the proportions of CD8+ T-cell subsets and levels of KYN pathway metabolites in peripheral blood were determined. RESULTS: The CD8+ EMRA T-cell subsets increased in the CON group but remained almost unchanged in the EX group (p = .02). Plasma levels of kynurenic acid (KA) increased in the EX group and decreased in the CON group (p = .03). Concomitant nutritional intervention resulted in lower levels of quinolinic acid (QA) compared with exercise alone (p = .03). Overall, there was a slight increase in the QA/KA ratio in the CON group, whereas it decreased in the EX group (p > .05). CONCLUSIONS: Combined strength and endurance training seems to be a suitable approach to attenuate CD8+ T-cell differentiation in the elderly and to redirect the KYN pathway towards KA. The clinical relevance of these effects needs further investigation.

Intensity- and time-matched acute interval and continuous endurance exercise similarly induce an anti-inflammatory environment in recreationally active runners: focus on PD-1 expression in Tregs and the IL-6/IL-10 axis.

PURPOSE: Acute exercise elicits a transient anti-inflammatory state during the early recovery period. Since recent studies reported on regimen-specific effects on immune-related humoral factors and cellular subsets, this study compared the effects of intensity- and time-matched acute interval and continuous exercise on peripheral anti-inflammatory cellular and humoral immune parameters with a particular focus on the PD-1 expression in CD4+ regulatory T cells (Tregs). METHODS: Twenty-four recreationally active runners (age: 29.7 ± 4.3 years, BMI: 22.2 ± 2.4, VO2peak: 56.6 ± 6.4 ml × kg-1 × min-1) participated in this crossover RCT. Each subject conducted a moderate continuous (MCE) and a high-intensity interval exercise (HIIE) session in a counterbalanced design. Blood was drawn before, immediately after, and 1 h after exercise. Treg subsets and levels of PD-1 and Foxp3 were assessed by flow cytometry. Serum levels of IL-10 and IL-6 were quantified by ELISA. RESULTS: PD-1 levels on Tregs increased within the recovery period after HIIE (p < .001) and MCE (p <  0.001). Total counts of Tregs (HIIE: p = 0.044; MCE: p = .021), naïve Tregs (HIIE: p  < 0.001; MCE: p  < 0.001), and PD-1+ effector Tregs (eTregs) (HIIE: p = .002) decreased 1 h after exercise. IL-10 increased 1 h after HIIE (p < 0.001) and MCE (p = 0.018), while IL-6 increased immediately after both HIIE (p = 0.031) and MCE (p = 0.021). Correlations between changes in IL-6 and IL-10 (p = 0.017, r = 0.379) and baseline VO2peak and Treg frequency (p = 0.002, r = 0.660) were identified. CONCLUSION: This is the first study that investigates PD-1 expression in circulating Tregs after acute exercise, revealing an increase in PD-1 levels on eTregs during the early recovery period after intensity- and time-matched HIIE and MCE. Future studies are needed to investigate the PD-1 signalosome in eTregs, together with the expression of key effector molecules (i.e., IL-10, TGF-ß, IL-35, CTLA-4) to elucidate PD-1-dependent changes in cellular function. Based on changes in serum cytokines, this study further reveals a regimen-independent establishment of an anti-inflammatory milieu and underpins the role of the IL-6/IL-10 axis.

Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti-oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune-responsive tumor entities.

Sleep problems and their interaction with physical activity and fatigue in hematological cancer patients during onset of high dose chemotherapy.

PURPOSE: Sleep problems reported by hematological cancer patients are usually linked to higher levels of cancer-related fatigue. Although the awareness of sleep problems in solid cancer patients is rising, there has been less attention to the issue in hematological cancer patients. The present study assesses the differences in sleep by comparing physical activity and fatigue levels among hematological cancer patients during the onset of chemotherapy. Furthermore, it investigates the relationship between sleep, physical activity, and fatigue through mediation analysis. METHODS: The recruited sample consists of 58 newly diagnosed hematological cancer patients (47.1 ± 15.4 yrs; 51.7% males). Subjects completed questionnaires assessing sleep (PSQI), physical activity (visual analogue scale), fatigue (MFI-20), anxiety, depression (HADS), and quality of life (EORTC QLQ-C30) within two weeks from starting treatment. RESULTS: The sample reported more sleep problems in comparison to the German population norm. The classification as good (ca 25%) or bad sleepers (ca 75%) showed less frequent physical activity (p = .04), higher fatigue (p = .032), anxiety (p = .003), depression (p = .011) and pain (p = .011) in bad sleepers. The mediation analysis revealed significant indirect effects of sleep on fatigue through physical activity habits. CONCLUSIONS: This study highlights the combined action of sleep problems and physical activity on fatigue during the onset of induction chemotherapy. These two parameters could represent meaningful intervention targets to improve a patient's status during chemotherapy. TRIAL REGISTRATION: The study was registered on the WHO trial register (DRKS00007824).

High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation.

In persons with multiple sclerosis (PwMS), the neutrophil-to-lymphocyte ratio (NLR) is associated with disability status, symptomatology and disease activity. High-intensity interval training (HIIT) improves many symptoms in PwMS and may positively influence disease progression. Here, we present results from a randomized controlled trial during inpatient rehabilitation on immediate (single bout) and training (3-week intervention) effects of HIIT versus moderate continuous training on NLR and related cellular inflammation markers. Only HIIT reduced the NLR over the 3-week intervention period. These training effects might be due to repetitive inflammatory states with compensatory anti-inflammatory counterbalancing after each HIIT session.

Learning to play golf for elderly people with subjective memory complaints: feasibility of a single-blinded randomized pilot trial.

BACKGROUND: Subjective Memory Complaints (SMC) in elderly people due to preclinical Alzheimer's Disease may be associated with dysregulation of the Kynurenine Pathway (KP), with an increase in neurotoxic metabolites that affect cognition. Golf is a challenging sport with high demands on motor, sensory, and cognitive abilities, which might bear the potential to attenuate the pathological changes of preclinical AD. This trial investigated the feasibility of learning to play golf for elderly with cognitive problems and its effects on cognitive functions and the KP. METHODS: In a 22-week single-blinded randomized controlled trial, elderly people with SMC were allocated to the golf (n = 25, 180 min training/week) or control group (n = 21). Primary outcomes were feasibility (golf exam, adherence, adverse events) and general cognitive function (Alzheimer's Disease Assessment Scale). Secondary outcomes include specific cognitive functions (Response Inhibition, Corsi Block Tapping Test, Trail Making Test), KP metabolites and physical performance (6-Minute-Walk-Test). Baseline-adjusted Analysis-of-Covariance was conducted for each outcome. RESULTS: 42 participants were analyzed. All participants that underwent the golf exam after the intervention passed it (20/23). Attendance rate of the golf intervention was 75 %. No adverse events or drop-outs related to the intervention occurred. A significant time*group interaction (p = 0.012, F = 7.050, Cohen's d = 0.89) was found for correct responses on the Response Inhibition task, but not for ADAS-Cog. Moreover, a significant time*group interaction for Quinolinic acid to Tryptophan ratios (p = 0.022, F = 5.769, Cohen's d = 0.84) in favor of the golf group was observed. An uncorrected negative correlation between attendance rate and delta Quinolinic acid to Kynurenic acid ratios in the golf group (p = 0.039, r=-0.443) was found as well. CONCLUSIONS: The findings indicate that learning golf is feasible and safe for elderly people with cognitive problems. Preliminary results suggest positive effects on attention and the KP. To explore the whole potential of golfing and its effect on cognitive decline, a larger cohort should be studied over a longer period with higher cardiovascular demands. TRIAL REGISTRATION: The trial was retrospectively registered (2nd July 2018) at the German Clinical Trials Register ( DRKS00014921 ).

Acute exercise impacts AhR and PD-1 levels of CD8+ T-cells-Exploratory results from a randomized cross-over trial comparing endurance versus resistance exercise.

PURPOSE: The programmed cell death protein 1 (PD-1) has become a promising target in cancer immunotherapy. PD-1 expression of CD8+ T-cells may be increased via the exploitation of aryl hydrocarbon receptor (AhR) signaling with kynurenine (KYN) as a ligand. Since exercise affects KYN metabolism, we exploratory investigated the influence of acute exercise bouts on AhR and PD-1 levels of CD8+ T-cells. METHOD: In this study, 24 healthy males (age: 24.6 ± 3.9 years; weight 83.9 ± 10.5 kg; height: 182.4 ± 6.2 cm) completed a single bout of endurance (EE) and resistance exercise (RE) in a randomly assigned order on separate days. Blood samples were drawn before (t0), after (t1), and 1 h after (t2) both conditions. T-cell populations, the level of cytoplasmic AhR, and surface PD-1 were assessed by flow cytometry. RESULTS: T-cell populations changed over time, indicated by an increase in the absolute numbers of CD3+ lymphocytes after EE (p < .001) and RE (p = .036) and in PD-1+ CD8+ T-cells after EE (p = .021). Proportions of T-cell populations changed only after EE (t0-t2: p = .029; t1-t2: p = .006). The level of cytoplasmic AhR decreased immediately after exercise in both exercise conditions (EE: p = .009; RE: p = .036). The level of surface PD-1 decreased 1 h after EE (p = .005). CONCLUSION: We analyzed the level of surface PD-1 and cytoplasmic AhR following acute physical exercise for the first time. Especially EE was observed to impact both AhR and PD-1 levels, undermining its role as the AhR-PD-1 axis modulator. These results provide new insights into the impact of exercise on AhR-signaling, which could potentially be relevant for various chronic diseases.

Cellular immune response to acute exercise: Comparison of endurance and resistance exercise.

OBJECTIVES: Exercise-induced cellular mobilization might play a role in treatment and prevention of several diseases. However, little is known about the impact of different exercise modalities on immune cell mobilization and clinical cellular inflammation markers. Therefore, the present study aimed to investigate differences between acute endurance exercise (EE) and resistance exercise (RE) on cellular immune alterations. METHODS: Twenty-four healthy men conducted an acute EE (cycling at 60% of peak power output) and RE (five exercise machines at 70% of the one-repetition maximum) session lasting 50 minutes in randomized order. Blood samples were collected before, after and one hour after exercise cessation. Outcomes included counts and proportions of leukocytes, neutrophils (NEUT), lymphocytes (LYM), LYM subsets, CD4/CD8 ratio, and the clinical cellular inflammation markers NEUT/LYM ratio (NLR), platelets/LYM ratio (PLR), and systemic immune inflammation index (SII). RESULTS: Alterations in all outcomes were revealed except for CD8+ T cells, CD4/CD8 ratio, NLR, and PLR. EE induced a stronger cellular immune response and provoked alterations in more immune cell populations than RE. SII was altered only after EE. CONCLUSION: An acute EE session causes a stronger mobilization of immune cells than RE. Additionally, SII represents an integrative marker to depict immunological alterations.

Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training.

INTRODUCTION: The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise. METHODS: 24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes. RESULTS: The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session. CONCLUSIONS: In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations.

Acute hypertrophic but not maximal strength loading transiently enhances the kynurenine pathway towards kynurenic acid.

PURPOSE: Due to distinct immuno- and neuro-modulatory properties, growing research interest focuses on exercise-induced alterations of the kynurenine (KYN) pathway in healthy and clinical populations. To date, knowledge about the impact of different acute strength exercise modalities on the KYN pathway is scarce. Therefore, we investigated the acute effects of hypertrophic (HYP) compared to maximal (MAX) strength loadings on the KYN pathway regulation. METHODS: Blood samples of twelve healthy males (mean age and weight: 23.5 ± 3.2 years; 77.5 ± 7.5 kg) were collected before (T0), immediately after (T1), and 1 h after completion (T2) of HYP (5 sets with 10 repetitions at 80% of 1RM) and MAX (15 sets with 1RM) loadings performed in a randomized cross-over design. Serum concentrations of tryptophan (TRP), KYN, kynurenic acid (KA), and quinolinic acid (QA) were assessed using high-performance liquid chromatography. RESULTS: The KA/KYN ratio increased from T0 to T1 (p = 0.01) and decreased from T1 to T2 (p = 0.011) in HYP, while it was maintained within MAX. Compared to MAX, serum concentrations of KA were greater in HYP at T1 (p = 0.014). Moreover, the QA/KA ratio was significantly lower in HYP than in MAX at T1 (p = 0.002). CONCLUSION: Acute HYP loading led to increases in the metabolic flux yielding KA, thereby possibly promoting immunosuppression and neuroprotection. Our findings emphasize the potential of acute HYP exercise as short-term modulator of KYN pathway downstream to KA in healthy males and need to be proven in other samples.

Influence of combined functional resistance and endurance exercise over 12 weeks on matrix metalloproteinase-2 serum concentration in persons with relapsing-remitting multiple sclerosis - a community-based randomized controlled trial.

BACKGROUND: The relevance of regular moderate to intense exercise for ameliorating psychomotor symptoms in persons with multiple sclerosis (pwMS) is becoming increasingly evident. Over the last two decades, emerging evidence from clinical studies and animal models indicate immune regulatory mechanisms in both periphery and the central nervous system that may underlie these beneficial effects. The integrity of the blood-brain barrier as the main structural interface between periphery and brain seems to play an important role in MS. Reducing the secretion of proteolytic matrix metalloproteinases (MMP), i.e. MMP-2, as disruptors of blood-brain barrier integrity could have profound implications for MS. METHODS: In this two-armed randomized controlled trial 64 participants with relapsing-remitting MS (RRMS) (EDSS 0-4.0) will be allocated to either an intervention group or a passive wait list control group. The intervention group will perform 60 min of combined functional resistance and endurance exercises 3x per week over a period of 12 weeks in a community-based and publicly available setting. Changes in serum concentration of MMP-2 will be the primary outcome. Secondary outcomes are numbers of immune cell subsets, soluble (anti-) inflammatory factors, physical capacity, cognitive performance, physical activity behavior, gait performance, and patient-reported outcomes. All outcome measures will be assessed at baseline and after week 12 with an additional blood sampling before, during and immediately after a single training session in week 6. DISCUSSION: To our knowledge, this will be the first RCT to investigate both the acute and chronic effects of a community-based intense functional resistance and endurance exercise regimen in persons with RRMS. Combining analysis of biological and cognitive or psychological outcomes may provide a better understanding of the MS-specific symptomology. TRIAL REGISTRATION: DRKS00017091; 05th of April, 2019; International Clinical Trials Registry Platform.

Influence of different rehabilitative aerobic exercise programs on (anti-) inflammatory immune signalling, cognitive and functional capacity in persons with MS - study protocol of a randomized controlled trial.

BACKGROUND: Studies have shown positive effects of therapeutic exercise on motor- and cognitive function as well as on psychosocial outcomes in persons with multiple sclerosis (MS). A reduction of inflammatory stress through physical exercise has been suspected as one key mechanism, mediating the positive effects of exercise in the context of MS. The primary objective of this trial is to investigate the acute and chronic effects of different exercise modalities on (anti-)inflammatory immune signalling as well as on cognitive and functional capacity in persons with MS. METHODS: A two armed single-blind randomized controlled design will investigate 72 persons with relapsing remitting or secondary progressive MS (EDSS 3.0-6.0), during 3 weeks of inpatient rehabilitation. Participants will be randomized into either a high-intensity interval training (HIIT) or a moderate continuous training group; the latter represents the local standard therapy (ST). Both groups will exercise 3x per week. The HIIT group will perform 5 × 1.5-min high-intensive exercise bouts at 95-100% of their maximum heart rate (HRmax) followed by active breaks of unloaded pedalling (60% HRmax) for 2 min. In contrast, the ST group will exercise for 24 min continuously at 65% of HRmax. The proportion of circulating regulatory T-cells will be measured as primary outcome. Secondary outcomes comprise numbers and proportions of further immune cells including Th17-cells, soluble factors ((anti-) inflammatory cytokines, tryptophan metabolites), endurance capacity, cognitive performance, processing skills for activities of daily living, fatigue, depression and healthcare-related quality of life. Outcomes will be assessed before (T0) and after (T3) the 3-week exercise intervention program. Blood samples of T0 will be taken immediately before the first exercise session. Additionally, blood samples for the soluble factors will be collected immediately after (T1) and three hours (T2) after the first exercise session of each group. DISCUSSION: This study will be the first to investigate both acute and chronic effects of aerobic exercise on immune function and disease associated biomarkers in persons with MS. Combining biological analyses with cognitive and functional capacity assessments may contribute to a better understanding of responses to rehabilitative training, needed to improve exercise recommendations for persons with MS. TRIAL REGISTRATION: This trial was prospectively registered at ClinicalTrials.gov ( NCT03652519 ; 29 August 2018).

Aqua cycling for immunological recovery after intensive, eccentric exercise.

PURPOSE: Alterations in immunological homeostasis induced by acute exercise have been frequently reported. In view of the growing amount of repetitive exercise stimuli in competitive sports, quick recovery plays a superior role. Therefore, we examined whether aqua cycling affects cellular immunological recovery. METHODS: After performing 300 countermovement jumps with maximal effort male sport students (n = 20; 24.4 ± 2.2 years) were randomized into either an aqua cycling (AC) or a passive recovery (P) group. AC pedaled in chest-deep water without resistance, while P lay in a supine position. Each recovery protocols lasted 30 min. Blood samples were taken at Baseline, Post-exercise, Post-recovery and 1 h (h), 2 h, 4 h, 24 h, 48 h and 72 h after recovery. Outcomes comprised white blood cell (WBC) counts, lymphocyte (LYM) counts and LYM subsets (CD4/CD8 ratio). Additionally, cellular inflammation markers (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII)) were calculated. RESULTS: In both groups, WBC, NLR and SII were significantly increased compared to Baseline up to and including 4 h after recovery. Significant interaction effects were found for WBC (Post-recovery, 2 h and 4 h), NLR (Post-recovery), SII (Post-recovery) and CD4/CD8 ratio (2 h) with values of AC being higher than of P. CONCLUSIONS: Interestingly, AC provoked a stronger but not prolonged immunological disturbance than P. NLR and SII may present simple, more integrative markers to screen exercise-induced alterations in immune homeostasis/recovery in athletes and clinical populations. More research is warranted to elucidate the clinical and practical relevance of these findings.

Acute Exercise Increases the Expression of KIR2DS4 by Promoter Demethylation in NK Cells.

Positive effects of exercise on cancer prevention and progression have been proposed to be mediated by stimulating natural killer (NK) cells. Because NK cell receptors are regulated by epigenetic modifications, we investigated whether acute aerobic exercise and training change promoter DNA methylation and gene expression of the activating KIR2DS4 and the inhibiting KIR3DL1 gene. Sixteen healthy women (50-60 years) performed a graded exercise test (GXT) and were randomized into either a passive control group or an intervention group performing a four-week endurance exercise intervention. Blood samples (pre-, post-GXT and post-training) were used for isolation of DNA/RNA of NK cells to assess DNA promoter methylation by targeted deep-amplicon sequencing and gene expression by qRT-PCR. Potential changes in NK cell subsets were determined by flow cytometry. Acute and chronic exercise did not provoke significant alterations of NK cell proportions. Promoter methylation decreased and gene expression increased for KIR2DS4 after acute exercise. A high gene expression correlated with a low methylation of CpGs that were altered by acute exercise. Chronic exercise resulted in a minor decrease of DNA methylation and did not alter gene expression. Acute exercise provokes epigenetic modifications, affecting the balance between the activating KIR2DS4 and the inhibiting KIR3DL1, with potential benefits on NK cell function.

Do Acute Exercise-Induced Activations of the Kynurenine Pathway Induce Regulatory T-Cells on the Long-Term? - A Theoretical Frame Work Supported by Pilot Data.

Regular physical activity and exercise interventions are suspected to have anti-inflammatory effects depending on exercise modality, thereby potentially reducing the risk and progress of several chronic diseases. Alterations in the kynurenine pathway may represent a link between inflammatory responses following acute exercise and chronic anti-inflammatory properties, such as increased levels of regulatory T-cells (Treg). Here, we hypothesize that acute exercise activates the kynurenine pathway and physical fitness is associated with proportions of circulating anti-inflammatory Treg in older healthy women. Nineteen older healthy female participants (55 years (SD: ± 5.6)) completed a cardiopulmonary incremental exercise test (CPET) with spirometry on a bicycle ergometer until exhaustion with maximum oxygen uptake (VO2max) as outcome. Blood samples were taken before (T0) and one minute after (T1) the CPET. Levels of tryptophan, serotonin and kynurenine were determined by enzyme-linked immunosorbent assays. Flow cytometry was used to identify proportions of T-cell subsets. Both, kynurenine (p = 0.003, d = 0.40) and the kynurenine/tryptophan ratio (p = 0.034, d = 0.48) increased significantly after acute exercise. Moreover, participants` VO2max was strongly correlated with Treg levels (p < 0.001, r = 0.689). This is the first study indicating a kynurenine pathway activation following acute exercise in older healthy women. The observed correlation between Treg levels and VO2max emphasizes a potential link between short-term upregulated kynurenine levels and longer-term anti-inflammatory properties of exercise. Future research is needed to clarify to what extend acute exercise-induced activations of the kynurenine pathway contribute to Treg differentiation.

High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: A randomized controlled trial.

BACKGROUND: Aerobic exercise can improve cognitive performance in healthy elderly people. OBJECTIVE: The aim of this study was to investigate the influence of a 3-week high-intensity aerobic exercise programme (high-intensity training group (HIT)) on cognitive performance in persons with multiple sclerosis (MS) compared with a standard exercise programme (control training (CT)). METHODS: A total of 60 persons with MS (Expanded Disability Status Scale (EDSS): 1.0-6.5) were randomized to a HIT group (3×/week for 20 minutes, including five 3-minute exercise intervals at 80% of peak oxygen uptake (VO2-peak)) or a CT group (continuously 5×/week for 30 minutes/session at 65% of VO2-peak). Cognitive performance was assessed using the Brief International Cognitive Assessment for MS at entry ( t0) and discharge ( t1). Furthermore, VO2-peak, brain-derived neurotrophic factor, serotonin and matrix metalloproteinases (MMP)-2 and -9 were measured. RESULTS: Compared to CT, HIT significantly improved verbal memory. Significant improvements over time in executive functions were found in both groups. Secondary outcomes indicated significant improvements in VO2-peak and a significant reduction in MMP-2 in the HIT group only. CONCLUSION: HIT represents a promising strategy to improve verbal memory and physical fitness in persons with MS. Further research is needed to determine the impact of exercise on biomarkers in MS.

Eight-week, multimodal exercise counteracts a progress of chemotherapy-induced peripheral neuropathy and improves balance and strength in metastasized colorectal cancer patients: a randomized controlled trial.

PURPOSES: Physical activity is supposed to decrease mortality of colorectal cancer (CRC) and is suggested to reduce side-effects of the disease and its treatment. However, the knowledge about the influence of exercise interventions on patients suffering from CRC and metastasized CRC (mCRC) is still sparse. One frequently observed side effect in mCRC is chemotherapy-induced peripheral neuropathy (CIPN). This randomized controlled trial investigated the influence of a supervised exercise program on CIPN in mCRC. METHODS: Thirty patients (stage IV) undergoing outpatient palliative treatment including a median of 23.5 chemotherapy cycles of various regimens were randomly assigned to an intervention or control group (IG, n = 17; CG, n = 13). The IG participated in an eight-week supervised exercise program, including endurance, resistance and balance training (2×/week for 60 min) whereas the CG received written standard recommendations to obtain physical fitness. CIPN was assessed using the FACT/GOG-NTX questionnaire. Moreover, endurance capacity (6MWT), strength (h1RM) and balance (GGT-Reha) were evaluated before (t 0) and after (t 1) the intervention as well as after 4 weeks follow-up (t2). RESULTS: Neuropathic symptoms remained stable in the IG over time, while CIPN significantly worsened in the CG from t 0 to t 1 and t 0 to t 2. In contrast to the CG, the IG significantly improved in strength and balance function. Changes in CIPN correlated with changes in balance. CONCLUSIONS: This is the first investigation showing positive effects of a multimodal exercise program on CIPN, balance and strength on mCRC patients in a palliative setting, thereby consequently increasing patients` quality of life. The results support earlier findings stating a positive influence of balance exercise on CIPN.