International Journal of Tryptophan Research最新文献

Alzheimer's disease (AD) is associated with progressive endogenous neurotoxicity and hampered inflammatory regulation. The kynurenine (Kyn) pathway, which is controlled by tryptophan 2,3-dioxygenase (TDO), produces neuroactive and anti-inflammatory metabolites. Age-related Kyn pathway activation might contribute to AD pathology in humans, and inhibition of TDO was found to reduce AD-related cellular toxicity and behavioral deficits in animal models. To further explore the effect of aging on the Kyn pathway in the context of AD, we analyzed Kyn metabolite profiles in serum and brain tissue of the APP23 amyloidosis mouse model. We found that aging had genotype-independent effects on Kyn metabolite profiles in serum, cortex, hippocampus and cerebellum, whereas serum concentrations of many Kyn metabolites were reduced in APP23 mice. Next, to further establish the role of TDO in AD-related behavioral deficits, we investigated the effect of long-term pharmacological TDO inhibition on cognitive performance in APP23 mice. Our results indicated that TDO inhibition reversed recognition memory deficits without producing measurable changes in cerebral Kyn metabolites. TDO inhibition did not affect spatial learning and memory or anxiety-related behavior. These data indicate that age-related Kyn pathway activation is not specific for humans and could represent a cross-species phenotype of aging. These data warrant further investigation on the role of peripheral Kyn pathway disturbances and cerebral TDO activity in AD pathophysiology.

Fear is an indispensable characteristic of any infectious disease, and the alarm will be further amplified when the infection spreads uncontrollable, unpredictable, and global. The novel corona virus (SARS CoV-2) lead Covid-19, has been declared as a global emergency by WHO as it has affected millions of people with a high mortality rate. The non-availability of medicine for Covid-19 and the various control measures such as social distancing, self-isolation, house quarantine, and the new normal implementation by different nations across the world to control the spread of Covid-19 made people vulnerable to fear and anxiety. As a result, considerable number of Covid-19-related suicidal deaths has been reported across the world during this pandemic. There have been several studies which describe the psychosocial aspects of suicidal ideation. However, the research on the biological aspects of suicidal ideation/suicidal risk factors that are related to pandemic are unreported. Hence this review article is intended to provide a comprehensive analysis of suicidal deaths during Covid-19 and also aimed to addresses the possible link between suicidal ideation and different factors, including psycho-social, behavioral, neurobiological factors (proximal, distal, and inflammatory) and immunity. The alterations in glutamatergic and GABAergic neurotransmitters had upregulated the GABARB3, GABARA4, GABARA3, GABARR1, GABARG2, and GAD2 gene expressions in suicidal victims. The changes in the Kynurenine (KYN) pathway, Hypothalamus-Pituitary-Adrenal axis (HPA axis) hyperactivation, and dysregulation of serotonin biosynthesis would significantly alter the brain chemistry in people with suicide ideation.

Saturated fat ingestion has previously been linked to increases in inflammation. However the relationship between saturated fatty acid (SFA) intake and the kynureine:tryptophan ratio ([Kyn]:[Trp]), a marker of inflammation, has not been previously investigated. This study evaluated in healthy, middle aged, individuals (men = 48, women = 52), potential relationships between SFA intake, red blood cell (RBC) membrane SFAs and monounsaturated fatty acids (MUFA), the [Kyn]:[Trp] ratio, C-reactive protein (CRP), TNF-α and Δ9 desaturase activity. [Kyn]:[Trp] was positively associated with increases in Total fat (P = .034) intake, including Total SFA (P = .029) and Total MUFA (P = .042) intakes. Unexpectedly the [Kyn]:[Trp] ratio was inversely associated with the percentage of Total SFA (P = .004) and positively associated with percentage of Total MUFA (P = .012) present in the RBC membrane. We found a positive association between Δ9 desaturase activity, responsible for the desaturation of a various SFAs to MUFAs, and [Kyn]:[Trp] (P = .008). [Kyn]:[Trp] was also positively associated with CRP (P = .044), however no significant relationship between [Kyn]:[Trp] and TNF-α was found. This study shows for the first time that SFA consumption increases inflammatory pathways linked to increased tryptophan to kynurenine conversion, even in healthy humans. Our data also suggests that SFA linked increases in inflammation occur concomitantly with an upregulation of Δ9 desaturase activity resulting in increased desaturation of SFA substrates to their MUFA derivatives.

Melatonin (MLT) is a well-known pineal hormone possessed with remarkable biological activities. However, its low oral bioavailability and high first-pass metabolism rate are important pharmacokinetics problems. Therefore, 5 MLT derivatives (1-5) were designed and synthesised in our group to solve these problems. In this work, in silico analysis of all synthetic derivatives for pharmacokinetic and drug-likeness parameters were predicted by SwissADME software. The results revealed that all derivatives (1-5) met the requirements for ideal oral bioavailability and CNS drugs. The molecular docking showed that the acetyl-MLT derivative (1) and the un-substitution at N1-position derivative 5 would be substrates of CYP1A2, while the lipophilic substituted N1-position derivatives 2-4 could not be metabolised by CYP1A2. Moreover, all N-amide derivatives (1-4) were hydrolysed and released less than 2.33% MLT after 4-hour incubation in 80% human plasma. It seemed that these derivatives preferred to behave like drugs rather than prodrugs of MLT. These findings confirmed that the addition of bulky groups at the N1-position of the MLT core could prolong the half-life, increase drug absorption and penetrate the blood brain barrier into the CNS.

The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites suggested to be involved in a wide variety of diseases and disorders, however, technical challenges in reliably detecting these metabolites hampers cross-comparisons. The main objective of this study was to develop an accurate, robust and precise bioanalytical method for simultaneous quantification of ten plasma kynurenine metabolites. As a secondary aim, we applied this method on blood samples taken from healthy subjects conducting 1 session of sprint interval exercise (SIE). It is well accepted that physical exercise is associated with health benefits and reduces risks of psychiatric illness, diabetes, cancer and cardiovascular disease, but also influences the peripheral and central concentrations of kynurenines. In line with this, we found that in healthy old adults (n = 10; mean age 64 years), levels of kynurenine increased 1 hour (P = .03) after SIE, while kynurenic acid (KYNA) concentrations were elevated after 24 hours (P = .02). In contrast, no significant changes after exercise were seen in young adults (n = 10; mean age 24 years). In conclusion, the described method performs well in reliably detecting all the analyzed metabolites in plasma samples. Furthermore, we also detected an age-dependent effect on the degree by which a single intense training session affects kynurenine metabolite levels.

Tryptophan metabolism plays essential roles in both immunomodulation and cancer development. Indoleamine 2,3-dioxygenase, a rate-limiting enzyme in the metabolic pathway, is overexpressed in different types of cancer. To get a better understanding of the involvement of tryptophan metabolism in cancer development, we evaluated the expression and pairwise correlation of 62 genes in the metabolic pathway across 12 types of cancer. Only gene AOX1, encoding aldehyde oxidase 1, was ubiquitously downregulated, Furthermore, we observed that the 62 genes were widely and strongly correlated in normal controls, however, the gene pair correlations were significantly lost in tumor patients for all 12 types of cancer. This implicated that gene pair correlation coefficients of the tryptophan metabolic pathway could be applied as a prognostic and/or diagnostic biomarker for cancer.

Aim: To analyze indoleamine 2,3-dioxygenase (IDO) production in the cell culture supernatant of phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from type 2 DM (T2DM) patients and investigate IDO's association to pro- and anti-inflammatory cytokines.

Subjects and methods: PBMC samples were collected from 21 T2DM patients and 17 normoglycemic participants, then stimulated with PHA for 3 days. Cytokine and IDO concentrations were measured in the PBMC culture supernatants. In vitro production of TNF-α, IL-6, interferon-γ, and IL-10 were measured using multiplex immunoassay. IDO concentration was assessed using ELISA. To assess how PHA stimulation altered IDO production and to minimize the unstimulated baseline effect of T2DM, we subtracted the PHA-stimulated IDO concentration from the unstimulated one. IBM SPSS version 23 was used for statistical analysis.

Results: The IDO concentrations in the PBMC culture supernatants were significantly higher in T2DM patients regardless of whether they were unstimulated (P < .001) or PHA-stimulated (P = .012). Reduced IDO production was observed in 52.8% of T2DM patients and was associated with older age and lower interferon-γ levels. Conversely, 42.8% of T2DM patients showed increased IDO concentrations, which were correlated with the IL-6/IL-10 ratio (r = 0.683, P = .021) and interferon-γ/IL-10 ratio (r = 0.517, P = .077).

Conclusion: The interferon-γ level was reduced in the PBMC culture supernatant of T2DM patients with reduced IDO production. Reduced IDO production in T2DM patients following PHA stimulation was associated with older age and, notably, higher baseline IDO concentrations. Since IDO is primarily produced by dendritic cells, reduced IDO production after PHA stimulation may indicate dendritic cell dysfunction.

Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.

The serotonergic precursor tryptophan and the dopaminergic precursor tyrosine have been shown to be important modulators of mood, behaviour and cognition. Specifically, research on the function of tryptophan has characterised this molecule as particularly relevant in the context of pathological disorders such as depression. Moreover, a large body of evidence has now been accumulated to suggest that tryptophan may also be involved in executive function and reward processing. Despite some clear differentiation with tryptophan, the data reviewed in this paper illustrates that tyrosine shares similar functions with tryptophan in the regulation of executive function and reward, and that these processes in turn, rather than acting in isolation, causally influence each other.

Type 1 diabetes (T1D) is characterized by anomalous functioning of the immuno regulatory, tryptophan-catabolic enzyme indoleamine 2,3 dioxygenase 1 (IDO1). In T1D, the levels of kynurenine-the first byproduct of tryptophan degradation via IDO1-are significantly lower than in nondiabetic controls, such that defective immune regulation by IDO1 has been recognized as potentially contributing to autoimmunity in T1D. Because tryptophan catabolism-and the production of immune regulatory catabolites-also occurs via the gut microbiota, we measured serum levels of tryptophan, and metabolites thereof, in pediatric, diabetic patients after a 3-month oral course of Lactobacillus rhamnosus GG. Daily administration of the probiotic significantly affected circulating levels of tryptophan as well as the qualitative pattern of metabolite formation in the diabetic patients, while it decreased inflammatory cytokine production by the patients. This study suggests for the first time that a probiotic treatment may affect systemic tryptophan metabolism and restrain proinflammatory profile in pediatric T1D.