International Journal of Tryptophan Research最新文献

In recent years, kynurenine metabolites generated by tryptophan catabolism have gained increasing attention in the context of brain diseases. The question of importance is whether there is a relationship between peripheral and central levels of these metabolites. Some of these compounds do not cross the blood-brain barrier; in particular, kynurenic acid, and most analyses of kynurenines from psychiatric patients have been performed using plasma samples. In the present study, we recruited 30 healthy volunteers with no history of psychiatric or neurological diagnosis, to analyze tryptophan, kynurenine, kynurenic acid, and quinolinic acid levels in CSF and plasma. In addition, kynurenic acid was analyzed in urine. The most important finding of this study is that CSF kynurenic acid levels do not correlate with those in plasma or urine. However, we found a correlation between plasma kynurenine and CSF kynurenic acid. Further, plasma kynurenine and plasma quinolinic acid were correlated. Our findings clarify the distribution of tryptophan and its metabolites in various body compartments and may serve as a guide for the analysis of these metabolites in humans. The most significant finding of the present study is that a prediction of brain kynurenic acid by of the analysis of the compound in plasma cannot be made.

Traumatic experiences and fetal development influence tryptophan (TRP) and its neuroactive byproduct, kynurenic acid (KYNA). Maternal TRP metabolite levels during pregnancy vary by fetal sex, with higher concentrations in mothers carrying male fetuses. This pilot study aimed to explore the relationship between offspring sex, maternal childhood trauma, and maternal salivary KYNA and TRP levels during pregnancy. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine KYNA and TRP levels in maternal saliva samples collected from 35 late-pregnancy participants. Maternal childhood trauma was assessed using the Childhood Trauma Questionnaire, including subscales for emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. Among mothers pregnant with boys, salivary KYNA significantly correlated with physical and emotional neglect, and salivary TRP with emotional neglect. No significant correlations were found in mothers who delivered female offspring. Significant associations of childhood trauma and offspring sex were found for salivary KYNA but not TRP concentrations. Mothers with higher trauma levels who delivered boys exhibited higher levels of salivary KYNA compared to those with lower trauma levels. Moreover, mothers with higher trauma levels who delivered boys had higher salivary KYNA levels than those with higher trauma levels who delivered girls. This pilot study provides evidence of an association between maternal childhood trauma and TRP metabolism, measured in saliva, especially in mothers pregnant with boys. However, longitudinal studies with larger sample sizes are required to confirm these results.

Introduction: Limited clinical efficiency of current medications warrants search for new antipsychotic agents. Deorphanized G-protein coupled receptor (GPR)109A has not attracted much of attention of schizophrenia researchers. We analyzed literature and our data on endogenous agonists of GPR109A, beta-hydroxybutyrate (BHB), anthranilic (AA), butyric (BA), and nicotinic (NA) acids, in individuals with schizophrenia.

Data: Sex specific differences: plasma AA levels were 27% higher in female than in male patients and correlated with PANSS before 6 weeks of antipsychotics treatment (r = .625, P < .019, Spearman's test). There was no sex specific differences of plasma AA levels after treatment. AA plasma levels inversely correlated (-.58, P < .005) with PANSS scores in responders to treatment (at least, 50% improvement) but not in nonresponders. Preclinical studies suggested antipsychotic effect of BHB and BA. Clinical studies observed antipsychotic effect of NA; benzoate sodium, an AA precursor; and interventions associated with BHB upregulation (eg, fasting and ketogenic diets).

Discussion: Upregulation of GPR109A, an anti-inflammatory and neuroprotective receptor, inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that breakdown myelin, lipid-based insulating axonal sheath that protects and promotes nerve conduction. Brain cPLA2 is upregulated in individuals with schizophrenia and subjects at high-risk for development of psychosis. Lower myelin content is associated with cognitive decline in individuals with schizophrenia. Therefore, GPR109A might exert antipsychotic effect via suppression of cPLA2, and, consequently, preservation of myelin integrity. Future research might explore antipsychotic effects of (1) human pegylated kynureninase, an enzyme that catalyzes formation of AA from kynurenine (Kyn); (2) inhibitors of Kyn conversion into kynurenic acid, for example, KYN5356, to patients with already impaired Kyn conversion into 3-hydroxykynurenine; (3) synthetic GPR 109A agonists, for example, MK-1903 and SCH900271 and GSK256073, that underwent clinical trials as anti-dyslipidemia agents. GPR109A expression, that might be a new endophenotype of schizophrenia, especially associated with cognitive impairment, needs thorough assessment.

The kynurenine pathway is the primary route for tryptophan catabolism and has received increasing attention as its association with inflammation and the immune system has become more apparent. This review provides a broad overview of the kynurenine pathway in respiratory diseases, from the initial observations to the characterization of the different cell types involved in the synthesis of kynurenine metabolites and the underlying immunoregulatory mechanisms. With a focus on respiratory infections, the various attempts to characterize the kynurenine/tryptophan (K/T) ratio as an inflammatory marker are reviewed. Its implication in chronic lung inflammation and its exacerbation by respiratory pathogens is also discussed. The emergence of preclinical interventional studies targeting the kynurenine pathway opens the way for the future development of new therapies.

Background: Around 10% of people who had COVID-9 infection suffer from persistent symptoms such as fatigue, dyspnoea, chest pain, arthralgia/myalgia, sleep disturbances, cognitive dysfunction and impairment of mental health. Different underlying pathomechanisms appear to be involved, in particular inflammation, alterations in amino acid metabolism, autonomic dysfunction and gut dysbiosis.

Aim: As routine tests are often inconspicuous in patients with Long COVID (LC), similarly to patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), accessible biomarkers indicating dysregulation of specific pathways are urgently needed to identify underlying pathomechanisms and enable personalized medicine treatment. Within this pilot study we aimed to proof traceability of altered metabolism by urine analysis.

Patients and methods: Urine metabolome analyses were performed to investigate the metabolic signature of patients with LC (n = 25; 20 women, 5 men) in comparison to healthy controls (Ctrl, n = 8; 7 women, 1 man) and individuals with ME/CFS (n = 8; 2 women, 6 men). Concentrations of neurotransmitter precursors tryptophan, phenylalanine and their downstream metabolites, as well as their association with symptoms (fatigue, anxiety and depression) in the patients were examined.

Results and conclusion: Phenylalanine levels were significantly lower in both the LC and ME/CFS patient groups when compared to the Ctrl group. In many LC patients, the concentrations of downstream metabolites of tryptophan and tyrosine, such as serotonin, dopamine and catecholamines, deviated from the reference ranges. Several symptoms (sleep disturbance, pain or autonomic dysfunction) were associated with certain metabolites. Patients experiencing fatigue had lower levels of kynurenine, phenylalanine and a reduced kynurenine to tryptophan ratio (Kyn/Trp). Lower concentrations of gamma-aminobutyric acid (GABA) and higher activity of kynurenine 3-monooxygenase (KMO) were observed in patients with anxiety. Conclusively, our results suggest that amino acid metabolism and neurotransmitter synthesis is disturbed in patients with LC and ME/CFS. The identified metabolites and their associated dysregulations could serve as potential biomarkers for elucidating underlying pathomechanisms thus enabling personalized treatment strategies for these patient populations.

The kynurenine pathway (KP) is the main pathway of tryptophan (TRP) metabolism that generates energy for multiple cellular processes. The activity of this pathway has been shown to be dysregulated in multiple human diseases. The resultant modulation of metabolites has been suggested to comprise biomarkers to track disease progression or could identify new therapeutic targets. While metabolite changes can be measured readily in blood, there is limited knowledge on the effect of blood matrices and sample processing time may have on the stability of KP metabolites. Understanding the stability of KP metabolites in blood is integral to obtaining accurate KP data to correlate with clinical pathology. Hence, the aim of this study was to assess the concentration of KP metabolites in matched whole blood, plasma and serum. The impact of pre-analytical sample processing time in the various blood matrices was also analysed. Serum and plasma had the higher concentration of KP metabolites compared to whole blood. Furthermore, concentrations of KP metabolites declined when the collected blood was processed after 24 hours storage at 4°C. Our study shows that that type of blood matrix and the time to processing have an impact on the stability of the KP metabolites. Serum or plasma are the preferred choice of matrix and the isolation of these matrices from whole blood is best performed immediately after collection for optimal analytical KP data.

In this systematic review and meta-analysis, a normative dataset is generated from the published literature on the kynurenine pathway in control participants extracted from case-control and methodological validation studies. Study characteristics were mapped, and studies were evaluated in terms of analytical rigour and methodological validation. Meta-analyses of variance between types of instruments, sample matrices and metabolites were conducted. Regression analyses were applied to determine the relationship between metabolite, sample matrix, biological sex, participant age and study age. The grand mean concentrations of tryptophan in the serum and plasma were 60.52 ± 15.38 μM and 51.45 ± 10.47 μM, respectively. The grand mean concentrations of kynurenine in the serum and plasma were 1.96 ± 0.51 μM and 1.82 ± 0.54 μM, respectively. Regional differences in metabolite concentrations were observed across America, Asia, Australia, Europe and the Middle East. Of the total variance within the data, mode of detection (MOD) accounted for up to 2.96%, sample matrix up to 3.23%, and their interaction explained up to 1.53%; the latter of which was determined to be negligible. This review was intended to inform future empirical research and method development studies and successfully synthesised pilot data. The pilot data reported in this study will inform future precision medicine initiatives aimed at targeting the kynurenine pathway by improving the availability and quality of normative data.

The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand's battery, emphasizing the different responses triggered by these high diverse molecules. Among them, several members of the kynurenine pathway (one key process of tryptophan catabolism) are AhR agonists and are subsequently involved in regulatory functions. We will finally display the interplay between Tryptophan (Trp) catabolism and dysregulation in metabolic pathways drawing hypothesis on the involvement of the AhR pathway in these cancer-related processes.

The aryl hydrocarbon receptor (AHR) exerts major roles in xenobiotic metabolism, and in immune and barrier tissue homeostasis. How AHR activity is regulated by the availability of endogenous ligands is poorly understood. Potent AHR ligands have been shown to exhibit a negative feedback loop through induction of CYP1A1, leading to metabolism of the ligand. Our recent study identified and quantified 6 tryptophan metabolites (eg, indole-3-propionic acid, and indole-3-acetic acid) in mouse and human serum, generated by the host and gut microbiome, that are present in sufficient concentrations to individually activate the AHR. Here, these metabolites are not significantly metabolized by CYP1A1/1B1 in an in vitro metabolism assay. In contrast, CYP1A1/1B metabolizes the potent endogenous AHR ligand 6-formylindolo[3,2b]carbazole. Furthermore, molecular modeling of these 6 AHR activating tryptophan metabolites within the active site of CYP1A1/1B1 reveal metabolically unfavorable docking profiles with regard to orientation with the catalytic heme center. In contrast, docking studies confirmed that 6-formylindolo[3,2b]carbazole would be a potent substrate. The lack of CYP1A1 expression in mice fails to influence serum levels of the tryptophan metabolites examined. In addition, marked induction of CYP1A1 by PCB126 exposure in mice failed to alter the serum concentrations of these tryptophan metabolites. These results suggest that certain circulating tryptophan metabolites are not susceptible to an AHR negative feedback loop and are likely important factors that mediate constitutive but low level systemic human AHR activity.

For the fluorometric determination of picolinic acid in human serum, HPLC-postcolumn UV irradiation using zinc acetate has been developed. Picolinic acid in serum sample was separated on a Capcell Pak C18. The mobile phase consisted of 0.1 mol/L sodium phosphate solution (adjusted to pH 3.0) containing 3.0 mmol/L zinc acetate and 3.5 mmol/L trimethylamine, and delivered at a flow rate of 0.8 mL/minutes. In order to stabilize the retention time (6.5 minutes), a back pressure tube (0.4 m × 0.13 mm i.d.) was attached after the photoreaction tube. Column effluent was irradiated with ultraviolet light to produce fluorescence, excitation wavelength of 336 nm and emission wavelength of 448 nm. The calibration graph for picolinic acid showed linearity when the amount was in the range of 0.89 to 455 pmol, and the detection limit (S/N = 3) was determined to be 0.30 pmol. The pretreatment of serum sample consisted of deproteinized by perchloric acid, potassium hydroxide, and mobile phase. The mean recovery of picolinic acid from serum was 99.0%. Using this procedure, the concentration of picolinic acid in serum of a healthy subject was determined.