International Journal of Tryptophan Research最新文献

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. Here we present an investigation of AHR activation using a complex mixture of tryptophan metabolites to examine the biological relevance of circulating tryptophan metabolites. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of a cell-based model for rheumatoid arthritis. We present data that reframe AHR biology to include the presence of a mixture of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.

Honey is a natural product with beneficial properties to health and has different characteristics depending on the region of production and collection, flowering, and climate. The presence of precursor amino acids of- and biogenic amines can be important in metabolomic studies of differentiation and quality of honey. We analyzed 65 honeys from 11 distinct regions of the State of Santa Catarina (Brazil) as to the profile of amino acids and biogenic amines by HPLC. The highest L-tryptophan (Trp), 5-hydroxytryptophan (5-OH-Trp), and tryptamine (Tryp) levels were detected in Cfb climate and harvested in 2019. Although we have found high content of serotonin, dopamine, and L-dopa in Cfb climate, the highest values occurred in honey produced during the summer 2018 and at altitudes above 900 m. Results indicate that the amino acids and biogenic amine levels in honeys are good indicators of origin. These data warrant further investigation on the honey as source of amino acids precursor of serotonin, melatonin, and dopamine, what can guide the choice of food as source of neurotransmitters.

Protein dynamics governs most of the fundamental processes in the human body. Particularly, the dynamics of loops located near an active site can be involved in the positioning of the substrate and the reaction mechanism. The understanding of the functioning of dynamic loops is therefore a challenge, and often requires the use of a multi-disciplinary approach mixing, for example, crystallographic experiments and molecular dynamics simulations. In the present work, the dynamic behavior of the JK-loop of the human indoleamine 2,3-dioxygenase 1 hemoprotein, a target for immunotherapy, is investigated. To overcome the lack of knowledge on this dynamism, the study reported here is based on 3 crystal structures presenting different conformations of the loop, completed with molecular dynamics trajectories and MM-GBSA analyses, in order to trace the reaction pathway of the enzyme. In addition, the crystal structures identify an exo site in the small unit of the enzyme, that is populated redundantly by the substrate or the product of the reaction. The role of this newer reported exo site still needs to be investigated.

Background: To establish a method to prevent and manage fatigue caused by psychological and physical stress in young females, early detection factors, such as understanding of fatigue and causes of psychological and physical stress, as well as a review of early management of psychiatric disease, are important. With increasing knowledge regarding the diverse causes of stress, it is important to select biomarkers with consideration of the types of stress burden and mechanisms underlying the development of physical symptoms. The methods used to search for stress characteristics is an issue that needs to be addressed. However, consensus regarding objective assessment methods for impaired mental health is lacking.

Methods: We examined the effects of an objective structured clinical examination (OSCE), considered to be a uniform source of psychological and physical stress, on biomarkers of oxidative stress and fatigue in 16 third-year female medical university students (21.3 ± 2.1 years old) in Japan with a normal menstrual cycle. A self-administered questionnaire consisting of Zung's Self-rating Depression Scale (SDS) and State-Trait Anxiety Inventory (STAI) was used to assess subjective stress. Furthermore, stress-related biomarkers (urinary 8-hydroxy-2'-deoxyguanosine [u-8-OHdG], urinary 5-hydroxytryptamine [u-5-HT], and salivary human herpesvirus-6 [s-HHV-6]) were examined at 1 month, 1 week, and 1 day before, and 1 week after the OSCE.

Results: The results indicated that the OSCE did not have effects on u-8-OHdG, a biomarker of oxidative stress. However, u-5-HT and s-HHV-6 were found to be elevated in examinations performed prior to the OSCE.

Conclusions: The present findings suggest that u-5-HT and s-HHV-6 levels can be used for objective assessment of mental and physical fatigue in young females, including that produced not only by knowledge regarding an upcoming OSCE, but also by skill and attitude aspects related to that examination.

Tryptophan and its bioactive metabolites are associated with health conditions such as systemic inflammation, cardiometabolic diseases, and neurodegenerative disorders. There are dynamic interactions among metabolites of tryptophan. The interactions between metabolites, particularly those that are strong and temporally reproducible could be of pathophysiological relevance. Using a targeted metabolomics approach, the concentration levels of tryptophan and 18 of its metabolites across multiple pathways was quantified in 24-hours urine samples at 2 time-points, age 17 years (baseline) and 18 years (follow-up) from 132 (52% female) apparently healthy adolescent participants of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study. In sex-specific analyses, we applied 2 network approaches, the Gaussian graphical model and Bayesian network to (1) explore the network structure for both time-points, (2) retrieve strongly related metabolites, and (3) determine whether the strongly related metabolites were temporally reproducible. Independent of selected covariates, the 2 network approaches revealed 5 associations that were strong and temporally reproducible. These were novel relationships, between kynurenic acid and indole-3-acetic acid in females and between kynurenic acid and xanthurenic acid in males, as well as known relationships between kynurenine and 3-hydroxykynurenine, and between 3-hydroxykynurenine and 3-hydroxyanthranilic acid in females and between tryptophan and kynurenine in males. Overall, this epidemiological study using network-based approaches shed new light into tryptophan metabolism, particularly the interaction of host and microbial metabolites. The 5 observed relationships suggested the existence of a temporally stable pattern of tryptophan and 6 metabolites in healthy adolescent, which could be further investigated in search of fingerprints of specific physiological states. The metabolites in these relationships may represent a multi-biomarker panel that could be informative for health outcomes.

The immunomodulatory capacity of mental stress is one of the basic concepts of psychoneuroimmunology. The current prospective longitudinal study was designed to evaluate the effect of acute mental stress on neurotransmitter precursor amino acid levels in individuals with depression at 2 time points. Ten physically healthy patients with a diagnosis of major depressive episode and Montgomery-Åsberg Depression Rating Scale scores (MADRAS) ⩾20 points at inclusion were assessed on 2 study days (once with higher MADRAS scores, once with lower MADRAS scores; median 34.5 days apart) and subjected to a standardized acute mental stress test on each study day. Blood was collected at 4 time points: once prior to and at 3 time points (0, 30 minutes, 60 minutes) following mental stress. Neurotransmitter precursor amino acid levels, that is kynurenine/tryptophan (KYN/TRP) and phenylalanine/tyrosine (PHE/TYR), as well as neopterin and nitrite were analyzed in a total of 80 individual blood samples. Regression and correlation analyses were performed. Regression analyses of PHE/TYR (R ² = .547) and KYN/TRP (R ² = .440) in relation to MADRAS depression severity showed a quadratic curve fit. This was reflected by a negative linear correlation between MADRAS scores and PHE/TYR as well as KYN/TRP in the lower score range (r = -.805, P < .001 and r = -.586, P < .001 respectively) and a positive correlation in the higher MADRAS score range (r = .713, P < .001 and r = .379, P = .016 respectively). No effect of acute mental stress was found. This analysis exemplifies the implications of sampling as well as data distributions on results. The crosstalk of biological mechanisms that orchestrate metabolic and immunological signaling may vary depending on depression severity resulting in non-linear associations that may explain the heterogeneity of results found in the literature.

Excess of brain kynurenic acid (KYNA), a neuroactive metabolite of the kynurenine pathway, is known to elicit cognitive dysfunction. In the present study, we investigated spatial working memory in mice with elevated levels of KYNA, induced by targeted deletion of kynurenine 3-monooxygenase (KMO), as well as long-term potentiation (LTP) of field excitatory postsynaptic potentials (fEPSPs) in hippocampal brain slices from these mice. The KMO knock-out (KMO^-/-) mice performed more poorly in the spatial working memory task as compared to their wild-type (WT) counterparts, as reflected by fewer correct choices in a T-maze. Both fEPSPs, or LTP, did not significantly differ between the 2 mouse strains. However, administration of PF-04859989, a kynurenine aminotransferase (KAT) II inhibitor, limiting the production of KYNA, facilitated fEPSP and enhanced LTP to a greater extent in hippocampal slices from KMO^-/- mice compared to WT mice. The results of the present study point to an essential role for KYNA in modulating LTP in the hippocampus of KMO^-/- mice which may account for their dysfunctional spatial working memory.