International Journal of Tryptophan Research最新文献

Parkinson's disease (PD) is identified as the most common neurodegenerative disorder of the central nervous system. Around 8.5 million individuals suffer from PD globally. Neuroinflammation triggers the activation of microglia, resulting in the release of numerous proinflammatory mediators. A major modulator of immune response in Parkinsonism is the kynurenine pathway (KP), probably linked to neurotoxic and inflammatory processes. Two types of compounds are produced by this pathway that act as neurotoxic and neuroprotective. Among these, kynurenic acid released by astrocytes acts as neuroprotective, and quinolinic acid released by microglia acts as neurotoxic by various mechanisms. Previous studies have shown that modulation of enzymes in this pathway can be a therapeutic approach for treating PD. Studies were performed to determine the effect of various drug treatments in inhibiting the enzymes of KP and preventing neurodegeneration. Pharmacological modulators of the KP enzymes will likely be a novel therapeutic approach for PD, and some of the KP metabolites may serve as predictive biomarkers.

Background: The accumulation of quinolinic acid (QUIN) in cerebrospinal fluid and serum may be used as a biomarker for various neuropsychiatric and inflammatory diseases. In this study, we developed a highly sensitive method to measure QUIN.

Methods: A reverse-phase high-performance liquid chromatography (HPLC) with fluorescence detection was established based on the enzymatic conversion of QUIN to nicotinic acid mononucleotide by recombinant quinolinic acid phosphoribosyltransferase, followed by the formation of fluorescent (BODIPY)-labeled deamido-NAD by recombinant nicotinic acid mononucleotide adenyltransferase.

Results: BODIPY-deamido-NAD was isocratically eluted within 6 minutes using reverse-phase chromatography and its chromatographic peak was resolved. The calibration range, precision, and analytical recovery of the QUIN assay are suitable for the analysis of biological fluids. Compared with published quantitation limits for QUIN measurement by HPLC, this method is at least 30-fold more sensitive and has a lower limit of detection of 5.0 nmol/L. The sensitivity was comparable to that previously reported for gas chromatography/mass spectrometry (GC/MS) and the quantitation results of QUIN from samples of cerebrospinal fluid correlated well with that of the GC/MS method.

Conclusions: We established a novel method to quantify QUIN in biological samples. Due to its high sensitivity and the fact that it does not rely on MS instrumentation, this method has the potential for widespread adoption in research laboratories.

Background: The effect of prolonged hyperglycemia on the sensory pathway of the nervous system has been the focus of numerous diabetes studies that aim at understanding the pathophysiology of the underlying inflammatory condition and neuropathy. In this study, we investigate the effects of prolonged hyperglycemia on the motoneurons of the ventral horn of the spinal cord, a lesser-studied area of the nervous system, with a focus on alterations in the Kynurenine Pathway (KP) as potential factors contributing to the induction, progression, and/or chronicity of diabetic neuropathy.

Methods: KP metabolites were identified and assessed by immunohistochemistry in cross-sections of the lumbar spinal cord of type 2 diabetes (T2D) streptozotocin-induced (STZ) adult Sprague-Dawley rats.

Results: Neuropathy, hyperglycemia, and gait alterations were associated to myelin loss in the spinal cord. KP metabolites were identified in glia, motoneuron, and non-motoneuron. The KP induction, as evidenced by enhanced L-kynurenine (L-KYN) fluorescence, appears to be associated with increased levels of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Notable differences in fluorescence merging of L-KYN with IFN-γ and TNF-α, of Quinolinic acid (QUIN) with 3-Hydroxykynurenine (3-HK), and of QUIN with advanced glycation end products (AGEs) were observed in the T2D group, contrasting with the control (P < .05). Additionally, in ventral horn cells, AGEs emerged as an added pro-inflammatory factor.

Conclusions: The KP is activated during diabetic neuropathy, and it displays divergent metabolic profiles in glia, motoneuron, and non-motoneuron, which differ from the controls. Their presence also evolves with time, indicating the dynamic nature of the process.

Feedback and other negative controls are important determinants of metabolic pathway activities. Other than inhibition of indoleamine 2,3-dioxygenase (IDO) by tryptophan (Trp) and nitric oxide (NO) and feedback inhibition of Trp 2,3-dioxygenase (TDO) by NAD(P)H, little is known of potential effects of Trp and kynurenine metabolites on the kynurenine (Kyn) pathway (KP). Whereas previous studies suggested that some Trp metabolites inhibit TDO activity in vitro, when administered in vivo to rats, inhibition is not always demonstrable, suggesting involvement of mitigating factors. To resolve this difference and provide indicators of likely interaction of Trp metabolites with TDO and IDO1, we performed molecular docking in silico of Trp and a range of its metabolites to these 2 KP enzymes. We found that Trp and many of its Kyn and 5-hydroxyindole metabolites docked to the active site of the TDO2 crystal structure, whereas no docking was observed with Kyn or kynurenic acid. Docking of NAD⁺(P⁺)H occurred at a different site, provisionally identified as the TDO allosteric site. By contrast, docking to IDO1 was limited to Trp, N'-formylkynurenine, 3-hydroxyanthranilic acid and picolinic acid. We conclude that bioinformatics can resolve controversial issues and identify amino acid residues at unexplored sites. The IDO1 effector nitric oxide (NO) docked to TDO as well as to IDO1. NO controls TDO2 and IDO1 activities in a dual fashion, through provision and limitation of the heme cofactor. We propose NO as a new TDO effector and discuss its role in control of TDO during acute inflammation. We propose TDO as an important player in the acute inflammatory responses in parallel with IDO1.

Background: Irritable Bowel Syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Tryptophan, an essential amino acid derived from dietary proteins, can be metabolized into various compounds by the gut microbiome. Emerging evidence suggests that tryptophan metabolites play a role in functional gastrointestinal disorders. However, the causal relationship between tryptophan metabolites and IBS remains to be fully elucidated.

Objective: This study aims to evaluate the potential causal relationship between tryptophan metabolites and IBS using Mendelian randomization (MR).

Methods: Instrumental variables (IVs) were selected from summary data of genome-wide association studies (GWAS) for tryptophan and IBS. SNPs potentially influencing MR results were excluded through outlier detection using MR-PRESSO. Bidirectional two-sample MR analyses were conducted using the inverse-variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode methods. The MR-Egger intercept test was employed to assess pleiotropy and heterogeneity among IVs, with visualization of the MR results through scatter plots, funnel plots, and forest plots.

Results: Genetically predicted tryptophan metabolites were not associated with the risk of IBS. In the reverse direction, genetically predicted IBS was associated with increased levels of tryptophan, serotonin, and kynurenine in the IVW analysis. Sensitivity and replication analyses confirmed these findings.

Conclusion: The findings of this Mendelian randomization study suggest that IBS may lead to elevated levels of tryptophan, serotonin, and kynurenine. These results have important implications for understanding the interplay between tryptophan metabolism and IBS in clinical settings. Further research is warranted to explore the underlying mechanisms.

Dengue, a widespread mosquito-borne disease, annually afflicts millions globally, posing substantial mortality risks. Preceding disease defervescence, a marked and transient surge in antibody-secreting cell (ASC) frequency correlates with disease severity, paralleled by heightened tryptophan degradation. Investigating details of this process through single-cell transcriptomics from public repositories, our data pinpoint CD14+ monocytes as principal IDO1 and IDO2 expressors, implicating them, rather than B cells, in initiating tryptophan metabolism. Interestingly, naive B cells exhibit altered gene expression indicative of early impact by tryptophan deficiency before defervescence with a potential impact on the B cell fate. Dengue-induced ASCs upregulated GCN2, PERK, eIF2a, ATF4 genes as well as BIM and CASP-3. However, the high expression of anti-apoptotic genes (FKBP8 [a CHOP-regulated gene], BCL-XL, BCL-2, MCL-1) allows enhanced ASC survival. Proliferation and differentiation-related genes (eIF4EBP1, RRM2, and HIF1a) were also upregulated in ASCs. These findings untangle how Dengue modulates the host metabolism and B-cell responses, although further research is needed to fully understand their implications on disease progression.

Background: In recent years, there has been a growing interest in exploring the potential contribution of tryptophan (TRP) metabolism via the kynurenine (KP) and serotonin (SP) pathways in Glioblastoma (GBM) biology. This study aims to address the association between pre-operative peripheral blood levels of TRP, kynurenine (KYN), 5-hydroxy-tryptophan (5-HTP), and serotonin (5-HT) and relevant oncological outcomes in GBM IDH-wt patients.

Methods: This is a single-center, retrospective clinical study. Serum from 62 adult patients undergoing maximal safe resection of newly diagnosed glioblastoma WHO-grade 4 IDH-wt (GBM) and n = 27 healthy controls were analyzed. The variables of interest were dichotomized via maximally selected rank statistics. Kaplan Meier and Cox multivariate regression analysis were conducted to explore the single contributions of these parameters in building a predictive model of overall survival (OS) and progression-free survival (PFS) in these patients.

Results: The mean baseline serum levels of 5-HT, KYN, and 5-HTP were significantly lower in GBM when compared to n = 27 healthy individuals (P < .001). Patients with 5-HT <78 ng/mL had a median OS of 14.4 months compared to 22.5 months in patients with increased levels (P = .01). Shorter OS was observed in patients with KYN <18 ng/mL (9.8 vs 17.5 months, P = .002), KYN/TRP <2.55 (11.4 vs 17.1, P = .002), 5-HTP/TRP <0.89 (11.5 vs 17.6 months, P = .02), and 5-HT/TRP <5.78 (13.4 vs 19.1 months, P = .002) compared to patients with high levels. Shorter PFS in patients with 5-HT <78 ng/mL (P = .04), KYN <18 ng/mL (P = .02), 5-HT/TRP <5.78 (P = .001), KYN/TRP <2.55 (P = .005). Reduced KYN, 5-HTP, and 5-HT were independent predictors of poor OS.

Conclusions: This study highlights an intriguing association between the degradation of TRP along the KP and SP and median survival times in GBM. Decreased KYN, 5-HTP, and 5-HT levels were associated with shorter OS.

Background: Biomarkers for psychological stress have been examined and the "gut-microbiota-brain axis" is currently attracting attention. An intervention study reported improvements in both the intestinal environment and psychological stress. However, the relationship between psychological stress scores and urinary 5-hydroxytryptamine (u-5-HT), produced by enterochromaffin cells in the intestinal tract, has not yet been investigated over time in healthy subjects under psychological stress. Therefore, the present study examined the relationship between subjective psychological stress (depression and anxiety) scores and u-5-HT levels over time in healthy women.

Methods: The effects of the objective structured clinical examination (OSCE), considered to be a uniform source of psychological stress, on u-5-HT levels were assessed 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 evaluate subjective stress 1 month, 1 week, and 1 day before and 1 week after the OSCE. Pearson's product-momentum correlation coefficient was used to calculate the correlation coefficient between u-5-HT levels, STAI, and SDS for each examined period.

Result: On the day before the OSCE, u-5-HT levels correlated with SDS and STAI (SDS: r = .524, P = .037, State-Anxiety: r = -.718, P = .002).

Conclusion: A correlation was observed between subjective psychological stress scores and u-5-HT levels in healthy women under psychological stress.

Background: The kynurenine pathway (KP) is an important hub in neuroimmune crosstalk that is dysregulated in persons with multiple sclerosis (pwMS) and modulated by exercise in a modality-specific manner.

Objectives: To compare changes in the KP metabolite profile of pwMS (1) following combined treatments including either high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) during a 3-week multimodal rehabilitation, (2) to evaluate exercise response in relation to baseline systemic inflammation, and (3) to investigate associations of kynurenines with physical capacity and clinical outcomes.

Methods: For this secondary analysis of a randomized controlled trial, serum concentrations of kynurenines at baseline and after 3 weeks were determined using targeted metabolomics (LC-MS/MS). Exercise-induced changes in the KP metabolite profile according to treatment and baseline systemic inflammation (neutrophil-to-lymphocyte ratio (NLR) <3.12 versus ⩾3.12) were investigated using covariance analyses.

Results: Regardless of treatment, concentrations of tryptophan and most kynurenines decreased over time. Quinolinic acid concentration increased (p < .001). Participants with low and high NLR revealed differential exercise-induced changes in concentrations of kynurenines and NLR. The systemic inflammation markers neopterin (p = .015) and NLR (p < .001) decreased in the whole group and in participants with high NLR, respectively.

Conclusions: Combined treatments including HIIT or MICT do not differentially modulate the KP metabolite profile, with both reducing concentrations of most kynurenines. Baseline systemic inflammation may impact exercise-induced changes in the KP metabolite profile and anti-inflammatory effects of exercise in pwMS.

Trial registration: clinicaltrials.gov (identifier: NCT04356248).

[This corrects the article DOI: 10.1177/11786469221128697.].