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.

Machine Learning-Based Analysis Reveals Triterpene Saponins and Their Aglycones in Cimicifuga racemosa as Critical Mediators of AMPK Activation.

Cimicifuga racemosa (CR) extracts contain diverse constituents such as saponins. These saponins, which act as a defense against herbivores and pathogens also show promise in treating human conditions such as heart failure, pain, hypercholesterolemia, cancer, and inflammation. Some of these effects are mediated by activating AMP-dependent protein kinase (AMPK). Therefore, comprehensive screening for activating constituents in a CR extract is highly desirable. Employing machine learning (ML) techniques such as Deep Neural Networks (DNN), Logistic Regression Classification (LRC), and Random Forest Classification (RFC) with molecular fingerprint MACCS descriptors, 95 CR constituents were classified. Calibration involved 50 randomly chosen positive and negative controls. LRC achieved the highest overall test accuracy (90.2%), but DNN and RFC surpassed it in precision, sensitivity, specificity, and ROC AUC. All CR constituents were predicted as activators, except for three non-triterpene compounds. The validity of these classifications was supported by good calibration, with misclassifications ranging from 3% to 17% across the various models. High sensitivity (84.5-87.2%) and specificity (84.1-91.4%) suggest suitability for screening. The results demonstrate the potential of triterpene saponins and aglycones in activating AMP-dependent protein kinase (AMPK), providing the rationale for further clinical exploration of CR extracts in metabolic pathway-related conditions.

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.

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.

Impact of exercise on markers of B cell-related immunity: A systematic review.

BACKGROUND: B cells represent a crucial component of adaptive immunity that ensures long-term protection from infection by generating pathogen-specific immunoglobulins. Exercise alters B cell counts and immunoglobulin levels, but evidence-based conclusions on potential benefits for adaptive immunity are lacking. This systematic review assessed current literature on the impact of acute exercise and exercise training on B cells, immunoglobulins, and markers of secretory immunity in human biofluids. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, MEDLINE, Web of Science, and Embase were searched on March 8, 2023. Non-randomized controlled trials and crossover trials investigating the impact of acute exercise or exercise training on B cell counts and proportions, immunoglobulin levels, salivary flow rate, or secretory immunoglobulin A secretion rate were included. Quality and reporting of exercise training studies was assessed using the Tool for the Assessment of Study Quality and reporting in Exercise. Study characteristics, outcome measures, and statistically significant changes were summarized tabularly. RESULTS: Of the 67 eligible studies, 22 applied acute exercise and 45 applied exercise training. All included outcomes revealed significant alterations over time in acute exercise and exercise training context, but only a few investigations showed significant differences compared to control conditions. Secretory and plasma immunoglobulin A levels were most consistently increased in response to exercise training. CONCLUSION: B cell-related outcomes are altered by acute exercise and exercise training, but evidence-based conclusions cannot be drawn with high confidence due to the large heterogeneity in populations and exercise modalities. Well-designed trials with large sample sizes are needed to clarify how exercise shapes B cell-related immunity.

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.

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.

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.

Unraveling the Contribution of Serotonergic Polymorphisms, Prefrontal Alpha Asymmetry, and Individual Alpha Peak Frequency to the Emotion-Related Impulsivity Endophenotype.

The unique contribution of the serotonin transporter-linked polymorphic region (5-HTTLPR), intronic region 2 (STin2), and monoamine oxidase A (MAO-A) genes to individual differences in personality traits has been widely explored, and research has shown that certain forms of these polymorphisms relate to impulsivity and impulsivity-related disorders. Humans showing these traits are also described as having an asymmetrical prefrontal cortical activity when compared to others. In this explorative study, we examine the relationship between serotonergic neurotransmission polymorphisms, cortical activity features (prefrontal alpha asymmetry, individual alpha peak frequency [iAPF]), emotion-related and non-emotion-related impulsivity in humans. 5-HTTLPR, MAO-A, and STin2 polymorphisms were assessed in blood taken from 91 participants with high emotion-related impulsivity levels. Sixty-seven participants completed resting electroencephalography and a more comprehensive impulsivity index. In univariate analyses, iAPF correlated with both forms of emotion-related impulsivity. In multiple linear regression models, 5-HTTLPR polymorphism (model 1, adj. R2 = 15.2%) and iAPF were significant interacting predictors of emotion-related impulsivity, explaining a large share of the results' variance (model 2, adj. R2 = 21.2%). Carriers of the low transcriptional activity 5-HTTPLR and MAO-A phenotypes obtained higher emotion-related impulsivity scores than others did. No significant results were detected for non-emotion-related impulsivity or for a form of emotion-related impulsivity involving cognitive/motivational reactivity to emotion. Our findings support an endophenotypic approach to impulsivity, showing that tri-allelic 5-HTTLPR polymorphism, iAPF, and their interaction are relevant predictors of one form of emotion-related impulsivity.

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).

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 ).

Abdominal Obesity-Related Disturbance of Insulin Sensitivity Is Associated with CD8+ EMRA Cells in the Elderly.

Aging and overweight increase the risk of developing type 2 diabetes mellitus. In this cross-sectional study, we aimed to investigate the potential mediating role of T-EMRA cells and inflammatory markers in the development of a decreased insulin sensitivity. A total of 134 healthy older volunteers were recruited (age 59.2 (SD 5.6) years). T cell subpopulations were analyzed by flow cytometry. Furthermore, body composition, HOMA-IR, plasma tryptophan (Trp) metabolites, as well as cytokines and adipokines were determined. Using subgroup and covariance analyses, the influence of BMI on the parameters was evaluated. Moreover, correlation, multiple regression, and mediation analyses were performed. In the subgroup of participants with obesity, an increased proportion of CD8+EMRA cells and elevated concentrations of plasma kynurenine (KYN) were found compared to the lower-weight subgroups. Linear regression analysis revealed that an elevated HOMA-IR could be predicted by a higher proportion of CD8+EMRA cells and KYN levels. A mediation analysis showed a robust indirect effect of the Waist-to-hip ratio on HOMA-IR mediated by CD8+EMRA cells. Thus, the deleterious effects of abdominal obesity on glucose metabolism might be mediated by CD8+EMRA cells in the elderly. Longitudinal studies should validate this assumption and analyze the suitability of CD8+EMRA cells as early predictors of incipient prediabetes.

Exercise Diminishes Plasma Neurofilament Light Chain and Reroutes the Kynurenine Pathway in Multiple Sclerosis.

OBJECTIVE: To examine acute (single-bout) and training effects of high-intensity interval training (HIIT) vs standard exercise therapy (moderate continuous training [MCT]) on plasma neurofilament light chain (pNfL) and kynurenine (KYN) pathway of tryptophan degradation metabolites in persons with multiple sclerosis (pwMS). METHODS: Sixty-nine pwMS (Expanded Disability Status Scale score 3.0-6.0) were randomly assigned to a HIIT or an MCT group. Changes in pNfL and KYN pathway metabolites measured in blood plasma were assessed before, after, and 3 hours after the first training session as well as after the 3-week training intervention. RESULTS: Acute exercise reduced pNfL and increased the KYN pathway flux toward the neuroprotective kynurenic acid (KA). Changes in pNfL correlated positively with changes in KA and negatively with the quinolinic acid-to-KA ratio. HIIT consistently led to greater effects than MCT. Following the 3-week training intervention, the KYN pathway was activated in HIIT compared with MCT. CONCLUSION: Future studies and clinical assessments of pNfL should consider acute exercise as confounding factor for measurement reliability. Moreover, exercise-induced KYN pathway rerouting might mediate neuroprotection, potentially underlying the benefits in rehabilitation for pwMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that acute HIIT diminishes pNfL and increases KA levels, and 3 weeks of HIIT activate the KYN pathway in pwMS. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT03652519.

The Effect of Acute Physical Exercise on NK-Cell Cytolytic Activity: A Systematic Review and Meta-Analysis.

BACKGROUND: Data on changes in natural killer cell cytolytic activity (NKCA) in response to acute physical exercise are contradictory. OBJECTIVE: The aim of this systematic review, meta-analysis and meta-regression is to (1) examine the effect of acute physical exercise on NKCA, (2) shed more light on the moderating factors, and (3) test the assumption of NKCA suppression subsequent to performing sports. METHODS: Two comparisons of NKCA were performed: (1) pre- versus post-exercise and (2) pre-exercise versus recovery. Data were acquired through a systematic search of MEDLINE (via PubMed), Scopus, and SportDiscus. Studies were eligible for inclusion if the effect of acute physical exercise was assessed including a passive control group and reporting NKCA prior to and immediately after the trial, and during the first 2 h of recovery. To better explain between-study heterogeneity, a moderator analysis was conducted. RESULTS: Pooled estimate from 12 studies reporting 18 effect sizes show that NKCA is largely elevated by acute physical exercise (Hedges' g = 1.02, 95% CI 0.59-1.46, p < 0.01). Meta-regressions reveal that this effect is larger for endurance versus resistance exercise and increases with the intensity of exercise (both p < 0.01), whereas the blood material used in the assay (p = 0.71), and the quantitative change in NK-cell count (R2 = 0%, p = 0.55) do not play a significant role. Physical exercise does not affect the level of NKCA after the recovery period (g = 0.06, 95% CI - 0.37 to 0.50, p < 0.76). CONCLUSIONS: This work provides solid evidence for elevated NKCA through performing sports which returns to baseline during the first 1-2 h of recovery, but not below the pre-exercise values providing counterevidence to the assumption of temporarily reduced NKCA. Remarkably, the functional change in NKCA exists independently from the quantitative change in NK-cell count. PROSPERO registration number: CRD42020134257.

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.

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.

Effect of a Single Bout of Aerobic Exercise on Kynurenine Pathway Metabolites and Inflammatory Markers in Prostate Cancer Patients-A Pilot Randomized Controlled Trial.

The kynurenine (KYN) pathway gains growing research interest concerning the genesis, progression and therapy of solid tumors. Previous studies showed exercise-induced effects on metabolite levels along the KYN pathway. Modulations of the KYN pathway might be involved in the positive impact of exercise on prostate cancer progression and mortality. The objective of this trial was to investigate whether a single-physical exercise alters tryptophan (TRP) metabolism and related inflammatory markers in this population. We conducted a randomized controlled trial with 24 patients suffering from prostate cancer. While the control group remained inactive, the intervention group performed a 30-min aerobic exercise on a bicycle ergometer at 75% of individual VO2peak. Before (t0) and directly after the exercise intervention (t1) KYN, TRP, kynurenic acid, quinolinic acid as well as various inflammation markers (IL6, TNF-α, TGF-ß) were measured in blood serum. At baseline, the present sample showed robust correlations between TRP, KYN, quinolinic acid and inflammatory markers. Regarding the exercise intervention, interaction effects for TRP, the KYN/TRP ratio and TGF-ß were observed. The results show for the first time that acute physical exercise impacts TRP metabolism in prostate cancer patients. Moreover, baseline associations underline the relationship between inflammation and the KYN pathway in prostate cancer.

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.

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.