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1
Maget, Alexander, Martina Platzer, Susanne A. Bengesser, Frederike T. Fellendorf, Armin Birner, Robert Queissner, Carlo Hamm, et al. "Differences in Kynurenine Metabolism During Depressive, Manic, and Euthymic Phases of Bipolar Affective Disorder." Current Topics in Medicinal Chemistry 20, no. 15 (June 1, 2020): 1344–52. http://dx.doi.org/10.2174/1568026619666190802145128.
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Background & Objectives: The kynurenine pathway is involved in inflammatory diseases. Alterations of this pathway were shown in psychiatric entities as well. The aim of this study was to determine whether specific changes in kynurenine metabolism are associated with current mood symptoms in bipolar disorder. Methods: Sum scores of the Hamilton Depression Scale, Beck Depression Inventory, and Young Mania Rating Scale were collected from 156 bipolar individuals to build groups of depressive, manic and euthymic subjects according to predefined cut-off scores. Severity of current mood symptoms was correlated with activities of the enzymes kynurenine 3-monooxygenase (ratio of 3-hydroxykynurenine/ kynurenine), kynurenine aminotransferase (ratio of kynurenic acid/ kynurenine) and kynureninase (ratio of 3-hydroxyanthranilic acid/ 3-hydroxykynurenine), proxied by ratios of serum concentrations. Results: Individuals with manic symptoms showed a shift towards higher kynurenine 3-monooxygenase activity (χ2 = 7.14, Df = 2, p = .028), compared to euthymic as well as depressed individuals. There were no differences between groups regarding activity of kynurenine aminotransferase and kynureninase. Within the group of depressed patients, Hamilton Depression Scale and kynurenine aminotransferase showed a significant negative correlation (r = -0.41, p = .036), displaying lower metabolism in the direction of kynurenic acid. Conclusion: Depression severity in bipolar disorder seems to be associated with a decreased synthesis of putative neuroprotective kynurenic acid. Furthermore, higher kynurenine 3-monooxygenase activity in currently manic individuals indicates an increased inflammatory state within bipolar disorder with more severe inflammation during manic episodes. The underlying pathophysiological mechanisms of the different affective episodes could represent parallel mechanisms rather than opposed processes.
2
Chen, Yiquan, and Gilles J. Guillemin. "Kynurenine Pathway Metabolites in Humans: Disease and Healthy States." International Journal of Tryptophan Research 2 (January 2009): IJTR.S2097. http://dx.doi.org/10.4137/ijtr.s2097.
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Tryptophan is an essential amino acid that can be metabolised through different pathways, a major route being the kynurenine pathway. The first enzyme of the pathway, indoleamine-2,3-dioxygenase, is strongly stimulated by inflammatory molecules, particularly interferon gamma. Thus, the kynurenine pathway is often systematically up-regulated when the immune response is activated. The biological significance is that 1) the depletion of tryptophan and generation of kynurenines play a key modulatory role in the immune response; and 2) some of the kynurenines, such as quinolinic acid, 3-hydroxykynurenine and kynurenic acid, are neuroactive. The kynurenine pathway has been demonstrated to be involved in many diseases and disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, AIDS dementia complex, malaria, cancer, depression and schizophrenia, where imbalances in tryptophan and kynurenines have been found. This review compiles most of these studies and provides an overview of how the kynurenine pathway might be contributing to disease development, and the concentrations of tryptophan and kynurenines in the serum, cerebrospinal fluid and brain tissues in control and patient subjects.
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Badawy, Abdulla A. B., and Samina Bano. "Tryptophan Metabolism in Rat Liver after Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors." International Journal of Tryptophan Research 9 (January 2016): IJTR.S38190. http://dx.doi.org/10.4137/ijtr.s38190.
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Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureninase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK. 3-HAA stimulated TDO, but inhibited kynureninase activity from K and 3-HK. Trp (50 mg/kg) increased kynurenine metabolite concentrations and KAT from K, and exerted a temporary stimulation of TDO. The kynureninase inhibitors BSZ and CBD also inhibited KAT, but stimulated TDO. BSZ abolished or strongly inhibited the Trp-induced increases in liver Trp and kynurenine metabolites. The potential effects of these changes in conditions of immune activation, schizophrenia, and other disease states are discussed.
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Majláth, Zsófia, and László Vécsei. "A kinureninrendszer és a stressz." Orvosi Hetilap 156, no. 35 (August 2015): 1402–5. http://dx.doi.org/10.1556/650.2015.30246.
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The kynurenine pathway is the main route of tryptophan degradation which gives rise to several neuroactive metabolites. Kynurenic acid is an endogenous antagonist of excitatory receptors, which proved to be neuroprotective in the preclinical settings. Kynurenines have been implicated in the neuroendocrine regulatory processes. Stress induces several alterations in the kynurenine metabolism and this process may contribute to the development of stress-related pathological processes. Irritable bowel disease and gastric ulcer are well-known disorders which are related to psychiatric comorbidity and stress. In experimental conditions kynurenic acid proved to be beneficial by reducing inflammatory processes and normalizing microcirculation in the bowel. Further investigations are needed to better understand the relations of stress and the kynurenines, with the aim of developing novel therapeutic tools for stress-related pathologies. Orv. Hetil., 2015, 156(35), 1402–1405.
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Hafstad Solvang, Stein-Erik, Jan Erik Nordrehaug, Dag Aarsland, Johannes Lange, Per Magne Ueland, Adrian McCann, Øivind Midttun, Grethe S. Tell, and Lasse Melvaer Giil. "Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia." International Journal of Tryptophan Research 12 (January 2019): 117864691987788. http://dx.doi.org/10.1177/1178646919877883.
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Introduction: Circulating tryptophan (Trp) and its downstream metabolites, the kynurenines, are potentially neuroactive. Consequently, they could be associated with neuropsychiatric symptoms and cognitive prognosis in patients with dementia. Objective: The objective of this study was to assess associations between circulating kynurenines, cognitive prognosis, and neuropsychiatric symptoms. Methods: We measured baseline serum Trp, neopterin, pyridoxal 5′-phosphate (PLP), and 9 kynurenines in 155 patients with mild dementia (90 with Alzheimer’s disease, 65 with Lewy body dementia). The ratios between kynurenine and Trp and kynurenic acid (KA) to kynurenine (KKR) were calculated. The Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were administered at baseline and annually over 5 years. Associations between baseline metabolite concentrations with MMSE and the NPI total score were assessed using a generalized structural equation model (mixed-effects multiprocess model), adjusted for age, sex, current smoking, glomerular filtration rate, and PLP. Post hoc associations between KKRs and individual NPI items were assessed using logistic mixed-effects models. False discovery rate (0.05)–adjusted P values ( Q values) are reported. Results: Kynurenine had a nonlinear quadratic relationship with the intercept of the MMSE scores over 5 years ( Q < 0.05), but not with the slope of MMSE decline. Kynurenine was associated with a higher NPI total score over time ( Q < 0.001). Post hoc, both KKR and KA were associated with more hallucinations ( Q < 0.05). Conclusions: Kynurenine has a complex relationship with cognition, where both low and high levels were associated with poor cognitive performance. A higher KKR indicated risk for neuropsychiatric symptoms, especially hallucinations.
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Gawel, Kinga. "A Review on the Role and Function of Cinnabarinic Acid, a “Forgotten” Metabolite of the Kynurenine Pathway." Cells 13, no. 5 (March 5, 2024): 453. http://dx.doi.org/10.3390/cells13050453.
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In the human body, the majority of tryptophan is metabolized through the kynurenine pathway. This consists of several metabolites collectively called the kynurenines and includes, among others, kynurenic acid, L-kynurenine, or quinolinic acid. The wealth of metabolites, as well as the associated molecular targets and biological pathways, bring about a situation wherein even a slight imbalance in the kynurenine levels, both in the periphery and central nervous system, have broad consequences regarding general health. Cinnabarinic acid (CA) is the least known trace kynurenine, and its physiological and pathological roles are not widely understood. Some studies, however, indicate that it might be neuroprotective. Information on its hepatoprotective properties have also emerged, although these are pioneering studies and need to be replicated. Therefore, in this review, I aim to present and critically discuss the current knowledge on CA and its role in physiological and pathological settings to guide future studies.
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Büki, Alexandra, Gabriella Kekesi, Gyongyi Horvath, and László Vécsei. "A Potential Interface between the Kynurenine Pathway and Autonomic Imbalance in Schizophrenia." International Journal of Molecular Sciences 22, no. 18 (September 16, 2021): 10016. http://dx.doi.org/10.3390/ijms221810016.
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Schizophrenia is a neuropsychiatric disorder characterized by various symptoms including autonomic imbalance. These disturbances involve almost all autonomic functions and might contribute to poor medication compliance, worsened quality of life and increased mortality. Therefore, it has a great importance to find a potential therapeutic solution to improve the autonomic disturbances. The altered level of kynurenines (e.g., kynurenic acid), as tryptophan metabolites, is almost the most consistently found biochemical abnormality in schizophrenia. Kynurenic acid influences different types of receptors, most of them involved in the pathophysiology of schizophrenia. Only few data suggest that kynurenines might have effects on multiple autonomic functions. Publications so far have discussed the implication of kynurenines and the alteration of the autonomic nervous system in schizophrenia independently from each other. Thus, the coupling between them has not yet been addressed in schizophrenia, although their direct common points, potential interfaces indicate the consideration of their interaction. The present review gathers autonomic disturbances, the impaired kynurenine pathway in schizophrenia, and the effects of kynurenine pathway on autonomic functions. In the last part of the review, the potential interaction between the two systems in schizophrenia, and the possible therapeutic options are discussed.
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Szűcs, Edina, Azzurra Stefanucci, Marilisa Pia Dimmito, Ferenc Zádor, Stefano Pieretti, Gokhan Zengin, László Vécsei, Sándor Benyhe, Marianna Nalli, and Adriano Mollica. "Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists." Biomolecules 10, no. 2 (February 12, 2020): 284. http://dx.doi.org/10.3390/biom10020284.
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Kynurenine (kyn) and kynurenic acid (kyna) are well-defined metabolites of tryptophan catabolism collectively known as “kynurenines”, which exert regulatory functions in host-microbiome signaling, immune cell response, and neuronal excitability. Kynurenine containing peptides endowed with opioid receptor activity have been isolated from natural organisms; thus, in this work, novel opioid peptide analogs incorporating L-kynurenine (L-kyn) and kynurenic acid (kyna) in place of native amino acids have been designed and synthesized with the aim to investigate the biological effect of these modifications. The kyna-containing peptide (KA1) binds selectively the μ-opioid receptor with a Ki = 1.08 ± 0.26 (selectivity ratio μ/δ/κ = 1:514:10,000), while the L-kyn-containing peptide (K6) shows a mixed binding affinity for μ, δ, and κ-opioid receptors, with efficacy and potency (Emax = 209.7 + 3.4%; LogEC50 = −5.984 + 0.054) higher than those of the reference compound DAMGO. This novel oligopeptide exhibits a strong antinociceptive effect after i.c.v. and s.c. administrations in in vivo tests, according to good stability in human plasma (t1/2 = 47 min).
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Myint, A. M. "Role of Tryptophan-kynurenine Pathway in Depression: Psychopathological Aspect." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70521-8.
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It was reported that cytokines such as IFN-γ reduce the synthesis of 5-HT by stimulating the activity of indoleamine 2,3 dioxygenase (IDO) enzyme which degrades tryptophan to kynurenine. Kynurenine is further metabolized to kynurenic acid (KYNA), 3-hydroxykynurenine (3OHK) and quinolinic acid (QA) by kynurenine aminotransferase (KAT), kynurenine 3-monooxygenase (KMO) and kynureninase. Both KMO and kynureninase are also shown to be activated by IFNγ. The 3OHK is neurotoxic apoptotic while QA is the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist. Conversely KYNA is an antagonist of all three ionotropic excitatory amino acid receptors and considered neuroprotective. In the brain, tryptophan catabolism occurs in the astrocytes and. The astrocytes are shown to produce mainly KYNA whereas microglia and macrophages produced mainly 3OHK and QA. The astrocytes have been demonstrated to metabolise the QA produced by the neighbouring microglia.Tryptophan breakdown has been found to be increased but KYNA, the neuroprotective metabolite is decreased in both blood and cerebrospinal fluid of the patients with major depression compared to healthy controls. Moreover, the ratio between KYNA and 3OHK showed significant correlation with response to treatment. These findings lead to the hypothesis an imbalance neuroprotection-neurodegener-ation in terms of kynurenine metabolites and their immunological and biochemical interactions in the brain might further induce the apoptosis of the neuroprotective astrocytes and the vulnerability to stress is thereby enhanced.
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Zakharov, Gennady A., Alexander V. Zhuravlev, Tatyana L. Payalina, Nikolay G. Kamyshev, and Elena V. Savvateeva-Popova. "The influence of D. melanogaster mutations of the kynurenine pathway of tryptophan metabolism on locomotor behavior and expression of genes belonging to glutamatergic and cholinergic systems." Ecological genetics 9, no. 2 (June 15, 2011): 65–73. http://dx.doi.org/10.17816/ecogen9265-73.
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Disbalance of kynurenines produced by Drosophila mutations of the kynurenine pathway of tryptophan metabolism influences the locomotor behavior in larvae. The most pronounced is the effect of accumulation of kynurenic acid in the mutant cinnabar manifested as sharp reduction of general level of locomotor activity. The mutations seem to act through modulatory influences of kynurenines on signal cascades governed by ionotropic glutamatergic and cholinergic receptors. Expression of receptor genes in the mutants shows age-related changes pointing to gradual evolvement of consequences of kynurenines disbalance.
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Fukuwatari, Tsutomu. "Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid." Nutrients 12, no. 5 (May 13, 2020): 1403. http://dx.doi.org/10.3390/nu12051403.
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Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan catabolism, acts as an antagonist for both the α7 nicotinic acetylcholine receptor and glycine coagonist sites of the N-methyl-d-aspartic acid receptor at endogenous brain concentrations. Elevation of brain kynurenic acid levels reduces the release of neurotransmitters such as dopamine and glutamate, and kynurenic acid is considered to be involved in psychiatric disorders such as schizophrenia and depression. Thus, the control of kynurenine pathway, especially kynurenic acid production, in the brain is an important target for the improvement of brain function or the effective treatment of brain disorders. Astrocytes uptake kynurenine, the immediate precursor of kynurenic acid, via large neutral amino acid transporters, and metabolize kynurenine to kynurenic acid by kynurenine aminotransferases. The former transport both branched-chain and aromatic amino acids, and the latter have substrate specificity for amino acids and their metabolites. Recent studies have suggested the possibility that amino acids may suppress kynurenic acid production via the blockade of kynurenine transport or via kynurenic acid synthesis reactions. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with elevated kynurenic acid levels.
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Alberts, Charl, Maja Owe-Larsson, and Ewa M. Urbanska. "New Perspective on Anorexia Nervosa: Tryptophan-Kynurenine Pathway Hypothesis." Nutrients 15, no. 4 (February 18, 2023): 1030. http://dx.doi.org/10.3390/nu15041030.
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Anorexia nervosa (AN), affecting up to 4% of all females and 0.3% of all males globally, remains the neuropsychiatric disorder with the highest mortality rate. However, the response to the current therapeutic options is rarely satisfactory. Considering the devastating prognosis of survival among patients with AN, further research aimed at developing novel, more effective therapies for AN is essential. Brain and serum tryptophan is mostly converted along the kynurenine pathway into multiple neuroactive derivatives, whereas only 1–2% is used for the synthesis of serotonin. This narrative review provides an update on the experimental and clinical research data concerning the metabolism of tryptophan along the kynurenine pathway in anorexia nervosa based on the available literature. We propose that in AN, lower levels of L-kynurenine and kynurenic acid result in diminished stimulation of the aryl hydrocarbon receptor, which could contribute to abnormally low body weight. The impact of L-kynurenine supplementation on anorexia in animal models and the effects of changes in tryptophan and downstream kynurenines on the clinical progression of AN require further investigation. Moreover, prospective clinical studies on larger cohorts of restrictive and binge-eating/purging AN patients and assessing the potential benefit of L-kynurenine as an add-on therapeutic agent, should follow.
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Ervik, Arne Olav, Stein-Erik Hafstad Solvang, Jan Erik Nordrehaug, Per Magne Ueland, Øivind Midttun, Audun Hildre, Adrian McCann, Ottar Nygård, Dag Aarsland, and Lasse Melvaer Giil. "The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia." International Journal of Tryptophan Research 12 (January 2019): 117864691988563. http://dx.doi.org/10.1177/1178646919885637.
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Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain. Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis. Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia Study of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney U tests and linear mixed-effects models were used for statistical analysis. Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele ( P-value of the interactions < .05). Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.
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Mieszkowski, Jan, Paulina Brzezińska, Błażej Stankiewicz, Andrzej Kochanowicz, Bartłomiej Niespodziński, Joanna Reczkowicz, Tomasz Waldziński, et al. "Direct Effects of Vitamin D Supplementation on Ultramarathon-Induced Changes in Kynurenine Metabolism." Nutrients 14, no. 21 (October 25, 2022): 4485. http://dx.doi.org/10.3390/nu14214485.
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In humans, most free tryptophan is degraded via kynurenine pathways into kynurenines. Kynurenines modulate the immune system, central nervous system, and skeletal muscle bioenergetics. Consequently, kynurenine pathway metabolites (KPMs) have been studied in the context of exercise. However, the effect of vitamin D supplementation on exercise-induced changes in KPMs has not been investigated. Here, we analyzed the effect of a single high-dose vitamin D supplementation on KPMs and tryptophan levels in runners after an ultramarathon. In the study, 35 amateur runners were assigned into two groups: vitamin D supplementation group, administered 150,000 IU vitamin D in vegetable oil 24 h before the run (n = 16); and control (placebo) group (n = 19). Blood was collected for analysis 24 h before, immediately after, and 24 h after the run. Kynurenic, xanthurenic, , quinolinic, and picolinic acids levels were significantly increased after the run in the control group, but the effect was blunted by vitamin D supplementation. Conversely, the decrease in serum tryptophan, tyrosine, and phenylalanine levels immediately after the run was more pronounced in the supplemented group than in the control. The 3-hydroxy-l-kynurenine levels were significantly increased in both groups after the run. We conclude that vitamin D supplementation affects ultramarathon-induced changes in tryptophan metabolism.
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Theofylaktopoulou, Despoina, Arve Ulvik, Øivind Midttun, Per Magne Ueland, Stein Emil Vollset, Ottar Nygård, Steinar Hustad, Grethe S. Tell, and Simone J. P. M. Eussen. "Vitamins B2and B6as determinants of kynurenines and related markers of interferon-γ-mediated immune activation in the community-based Hordaland Health Study." British Journal of Nutrition 112, no. 7 (August 8, 2014): 1065–72. http://dx.doi.org/10.1017/s0007114514001858.
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Vitamins B2and B6are cofactors in the kynurenine pathway. Many of the kynurenines are neuroactive compounds with immunomodulatory effects. In the present study, we aimed to investigate plasma concentrations of vitamins B2and B6as determinants of kynurenines and two markers of interferon-γ-mediated immune activation (kynurenine:tryptophan ratio (KTR) and neopterin). We measured the concentrations of vitamins B2and B6vitamers, neopterin, tryptophan and six kynurenines (i.e. kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid) in plasma from 7051 individuals. Dietary intake of vitamins B2and B6was assessed using a validated FFQ. Associations were investigated using partial Spearman's correlations, generalised additive models, and segmented or multiple linear regression. The B2vitamer, riboflavin, was positively associated with 3-hydroxyanthranilic acid and xanthurenic acid, with correlation coefficients, as obtained by segmented regression, of 0·20 (95 % CI 0·16, 0·23) and 0·24 (95 % CI 0·19, 0·28), at riboflavin concentrations below the median value (13·0 nmol/l). The vitamin B6vitamer, pyridoxal 5′-phosphate (PLP), was positively associated with most kynurenines at PLP concentrations < 39·3–47·0 nmol/l, and inversely associated with 3-hydroxykynurenine with the association being more prominent at PLP concentrations < 18·9 nmol/l. Riboflavin and PLP were associated with xanthurenic acid only at relatively low, but normal concentrations of both vitamers. Lastly, PLP was negatively correlated with neopterin and KTR. These results demonstrate the significant and complex determination of kynurenine metabolism by vitamin status. Future studies on B-vitamins and kynurenines in relation to chronic diseases should therefore integrate data on relevant biomarkers related to B-vitamins status and tryptophan metabolism.
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HEYES, Melvyn P., Cai Y. CHEN, Eugene O. MAJOR, and Kuniaki SAITO. "Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types." Biochemical Journal 326, no. 2 (September 1, 1997): 351–56. http://dx.doi.org/10.1042/bj3260351.
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Substantial increases in the tryptophan–kynurenine pathway metabolites, L-kynurenine and the neurotoxin quinolinic acid, occur in human brain, blood and systemic tissues during immune activation. Studies in vitrohave shown that not all human cells are capable of synthesizing quinolinate. To investigate further the mechanisms that limit L-kynurenine and quinolinate production, the activities of kynurenine pathway enzymes and the ability of different human cells to convert pathway intermediates into quinolinate were compared. Stimulation with interferon γ substantially increased indoleamine 2,3-dioxygenase activity and L-kynurenine production in primary peripheral blood macrophages and fetal brains (astrocytes and neurons), as well as cell lines derived from macrophage/monocytes (THP-1), U373MG astrocytoma, SKHEP1 liver and lung (MRC-9). High activities of kynurenine 3-hydroxylase, kynureninase or 3-hydroxyanthranilate 3,4-dioxygenase were found in interferon-γ-stimulated macrophages, THP-1 cells and SKHEP1 cells, and these cells made large amounts of quinolinate when supplied with L-tryptophan, L-kynurenine, 3-hydroxykynurenine or 3-hydroxyanthranilate. Quinolinate production by human fetal brain cultures and U373MG cells was restricted by the low activities of kynurenine 3-hydroxylase, kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase, and only small amounts of quinolinate were synthesized when cultures were supplied with L-tryptophan or 3-hydroxyanthranilate. In MRC-9 cells, quinolinate was produced only from 3-hydroxykynurenine and 3-hydroxyanthranilate, consistent with their low kynurenine 3-hydroxylase activity. The results are consistent with the notion that indoleamine 2,3-dioxygenase is an important regulatory enzyme in the production of L-kynurenine and quinolinate. Kynurenine 3-hydroxylase and, in some cells, kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase are important determinants of whether a cell can make quinolinate.
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Trepci, Ada, Sophie Imbeault, Victoria L. Wyckelsma, Håkan Westerblad, Sigurd Hermansson, Daniel C. Andersson, Fredrik Piehl, et al. "Quantification of Plasma Kynurenine Metabolites Following One Bout of Sprint Interval Exercise." International Journal of Tryptophan Research 13 (January 2020): 117864692097824. http://dx.doi.org/10.1177/1178646920978241.
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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.
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Ruddick, Jon P., Andrew K. Evans, David J. Nutt, Stafford L. Lightman, Graham A. W. Rook, and Christopher A. Lowry. "Tryptophan metabolism in the central nervous system: medical implications." Expert Reviews in Molecular Medicine 8, no. 20 (August 2006): 1–27. http://dx.doi.org/10.1017/s1462399406000068.
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The metabolism of the amino acid l-tryptophan is a highly regulated physiological process leading to the generation of several neuroactive compounds within the central nervous system. These include the aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), products of the kynurenine pathway of tryptophan metabolism (including 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid and kynurenic acid), the neurohormone melatonin, several neuroactive kynuramine metabolites of melatonin, and the trace amine tryptamine. The integral role of central serotonergic systems in the modulation of physiology and behaviour has been well documented since the first description of serotonergic neurons in the brain some 40 years ago. However, while the significance of the peripheral kynurenine pathway of tryptophan metabolism has also been recognised for several decades, it has only recently been appreciated that the synthesis of kynurenines within the central nervous system has important consequences for physiology and behaviour. Altered kynurenine metabolism has been implicated in the pathophysiology of conditions such as acquired immunodeficiency syndrome (AIDS)-related dementia, Huntington's disease and Alzheimer's disease. In this review we discuss the molecular mechanisms involved in regulating the metabolism of tryptophan and consider the medical implications associated with dysregulation of both serotonergic and kynurenine pathways of tryptophan metabolism.
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Holthuijsen, Daniëlle D. B., Martijn J. L. Bours, Eline H. van Roekel, Stéphanie O. Breukink, Maryska L. G. Janssen-Heijnen, Eric T. P. Keulen, Per M. Ueland, et al. "Longitudinal Associations of Adherence to the Dietary World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and Dutch Healthy Diet (DHD) Recommendations with Plasma Kynurenines in Colorectal Cancer Survivors after Treatment." Nutrients 14, no. 23 (December 3, 2022): 5151. http://dx.doi.org/10.3390/nu14235151.
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The tryptophan-kynurenine pathway has been linked to cancer aetiology and survivorship, and diet potentially affects metabolites of this pathway, but evidence to date is scarce. Among 247 stage I-III CRC survivors, repeated measurements were performed at 6 weeks, 6 months, and 1 year post-treatment. Adherence to the World Cancer Research Fund/ American Institute for Cancer Research (WCRF) and Dutch Healthy Diet (DHD) recommendations was operationalized using seven-day dietary records. Plasma kynurenines of nine metabolites were analysed. Longitudinal associations of adherence to these dietary patterns and plasma kynurenines were analysed using confounder-adjusted linear mixed-models. In general, higher adherence to the dietary WCRF/AICR and DHD recommendations was associated with lower concentrations of kynurenines with pro-oxidative, pro-inflammatory, and neurotoxic properties (3-hydroxykynurenine (HK) and quinolinic acid (QA)), and higher concentrations of kynurenines with anti-oxidative, anti-inflammatory, and neuroprotective properties (kynurenic acid (KA) and picolinic acid (Pic)), but associations were weak and not statistically significant. Statistically significant positive associations between individual recommendations and kynurenines were observed for: nuts with kynurenic-acid-to-quinolinic-acid ratio (KA/QA); alcohol with KA/QA, KA, and xanthurenic acid (XA); red meat with XA; and cheese with XA. Statistically significant inverse associations were observed for: nuts with kynurenine-to-tryptophan ratio (KTR) and hydroxykynurenine ratio; alcohol with KTR; red meat with 3-hydroxyanthranilic-to-3-hydroxykynurenine ratio; ultra-processed foods with XA and KA/QA; and sweetened beverages with KA/QA. Our findings suggest that CRC survivors might benefit from adhering to the dietary WCRF and DHD recommendations in the first year after treatment, as higher adherence to these dietary patterns is generally, but weakly associated with more favourable concentrations of kynurenines and their ratios. These results need to be validated in other studies.
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Ashoura, Norah E., Joseph Dekker, Todd A. Triplett, Kendra Garrison, John Blazeck, Christos Karamitros, Candice Lamb, et al. "The Force Awakens: Illuminating the Role of Kynurenine in Cancer Progression and Treatment." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 240.16. http://dx.doi.org/10.4049/jimmunol.204.supp.240.16.
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Abstract Cancer is the second leading cause of death in the United States, with an estimated 40% of all Americans expected to be diagnosed with cancer in their lifetime. Despite progress in treatment options, major obstacles in current therapies must be overcome to limit their harmful side effects on patients. To evade immune clearance, many cancers elevate tryptophan (Trp) catabolism in the tumor microenvironment (TME) by upregulating the enzyme indoleamine 2,3-dioxygenase (IDO). As a result, cancer cells (1) monopolize extracellular tryptophan and (2) release L-kynurenine into the TME, an independent immune signal. This change in metabolism generates immune suppression in the TME, but whether the cause arises from Trp depletion or the accumulation of the IDO product kynurenine (L-Kyn) remains highly controversial. Kynurenine is known to induce immunosuppressive phenotypes through aryl hydrocarbon receptor (AhR) activation. However, the functional role of this binding is still poorly understood, despite an explosion of interest and information in the field. Our strategy uses the enzyme kynureninase (KynU) to degrade kynurenine into non-toxic products, thereby restoring anti-tumor immunity without harming the tryptophan metabolism of healthy cells. Moreover, this work aims to determine kynurenine’s molecular effect on T cells to better understand why its depletion successfully relieves tumor burden.
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Marković, Miloš, Tatjana Nikolić, and Sanja Totić-Poznanović. "The kynurenine pathway of tryptophan catabolism and schizophrenia." Medicinski podmladak 74, no. 2 (2023): 12–17. http://dx.doi.org/10.5937/mp74-40330.
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The development of new therapeutic options focused on the recovery of patients with schizophrenia is primarily conditioned by elucidating the biological underpinnings of the disorder. The kynurenine pathway of tryptophan catabolism is the focus of psychiatric research since its catabolites have neuroactive properties, and one of the most important is the effect of kynurenic acid as the only endogenous NMDA receptor antagonist. According to the kynurenine hypothesis, there is an imbalance of excitatory and neuroprotective metabolites of the kynurenine pathway in patients with schizophrenia. It is postulated that excessive production of kynurenic acid leads to excessive blockade of NMDA glutamate and alpha-7 nicotinic receptors, acting as a trigger for the development of psychotic symptoms and neurocognitive deficits. This paper aims to review the kynurenine hypothesis of schizophrenia, important findings of studies exploring metabolites of the kynurenine pathway in patients with schizophrenia, and findings from the research on the potential impact of proinflammatory cytokines on the kynurenine pathway.
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Nozaki, Kazuhiko, and M. Flint Beal. "Neuroprotective Effects of L-Kynurenine on Hypoxia—Ischemia and NMDA Lesions in Neonatal Rats." Journal of Cerebral Blood Flow & Metabolism 12, no. 3 (May 1992): 400–407. http://dx.doi.org/10.1038/jcbfm.1992.57.
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Kynurenic acid is the only known endogenous excitatory amino acid receptor antagonist in the central nervous system. In the present study, we examined whether increasing brain concentrations of kynurenic acid by loading with its precursor l-kynurenine, or blocking its excretion with probenecid, could exert neuroprotective effects. Neuroprotective effects were examined in a neonatal model of hypoxia–ischemia, and following intrastriatal injection of N-methyl-d-aspartate (NMDA). Seven-day-old rats underwent unilateral ligation of the carotid artery, followed by exposure to 8% oxygen for 1.5 h. l-kynurenine administered 1 h before the hypoxia–ischemia showed a dose-dependent significant neuroprotective effect, with complete protection at a dose of 300 mg kg−1. The induction of c-fos immunoreactivity in cerebral cortex was also blocked by this dose of l-kynurenine. Probenecid alone had moderate neuroprotective effects, while a combination of a low dose of probenecid with doses of 50–200 mg kg−1 of l-kynurenine showed significant dose-dependent neuroprotection. Kynurenine dose-dependently protected against NMDA neurotoxicity in 7-day-old rats. Neurochemical analysis confirmed that l-kynurenine with or without probenecid markedly increased concentrations of kynurenic acid in cerebral cortex of 7-day-old rats. These results show for the first time that pharmacologic manipulation of endogenous concentrations of kynurenic acid can exert neuroprotective effects.
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Martin, Kyle S., Michele Azzolini, and Jorge Lira Ruas. "The kynurenine connection: how exercise shifts muscle tryptophan metabolism and affects energy homeostasis, the immune system, and the brain." American Journal of Physiology-Cell Physiology 318, no. 5 (May 1, 2020): C818—C830. http://dx.doi.org/10.1152/ajpcell.00580.2019.
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Tryptophan catabolism through the kynurenine pathway generates a variety of bioactive metabolites. Physical exercise can modulate kynurenine pathway metabolism in skeletal muscle and thus change the concentrations of select compounds in peripheral tissues and in the central nervous system. Here we review recent advances in our understanding of how exercise alters tryptophan-kynurenine metabolism in muscle and its subsequent local and distal effects. We propose that the effects of kynurenine pathway metabolites on skeletal muscle, adipose tissue, immune system, and the brain suggest that some of these compounds could qualify as exercise-induced myokines. Indeed, some of the more recently discovered biological activities for kynurenines include many of the best-known benefits of exercise: improved energy homeostasis, promotion of an anti-inflammatory environment, and neuroprotection. Finally, by considering the tissue expression of the different membrane and cytosolic receptors for kynurenines, we discuss known and potential biological activities for these tryptophan metabolites.
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Beier, Ulf H., Michelle D. Cully, Peter J. Siska, Katrin Singer, Jing Jiao, Tara TeSlaa, William J. Quinn, et al. "Fatty acid depletion is a reversible cause of kynurenine induced T cell apoptosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 137.1. http://dx.doi.org/10.4049/jimmunol.202.supp.137.1.
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Abstract Metabolic conditions in the tumor microenvironment (TME) are a barrier for anti-tumor immunotherapy. The TME metabolite kynurenine binds aryl hydrocarbon receptor which has been linked to immunosuppressive effects. We questioned if kynurenines could be utilized for therapeutic immunosuppression, and examined the effect of kynurenines on human and murine effector T cell (Teff) metabolism and function. We co-stimulated C57BL/6 Teff for three days and measured bioenergetic function with Seahorse. Injection of 1 mM L- or D-kynurenine reduced extracellular acidification by 4.2 ±0.2 and 7.1 ±0.4% over 1 hr, respectively (p<0.05). Next, we labeled activated Teff with 60 mg/dL [13C] glucose for 3 hr. We observed a 44.2% and 49.3% reduction of [13C]-glucose derived M+3 pyruvate production with D- and L-kynurenine, respectively (p<0.05, 3/group). We also noted a reduction in lipid pools, with a 56.5/33.8%, 40.1/43.9%, 52.5/43.6%, and 70.7/43.2% decline in the palmitate, oleate, lineolate, and myristate with L-/D-kynurenine, respectively. These data pointed to an important role for lipid catabolism in kynurenine rich environments. We observed, that 3-day co-stimulated Teffs ±1 mM L- or D-kynurenine had 98.9 ±0.55 or 97.3 ±0.55% cell death (vs. 69.7 ±18.84% in untreated Teff, 4/grp). Addition of 0.2–0.6 mM oleate/palmitate rescued the apoptosis phenotype, restoring Teff viability and proliferation. Our results show lipid consumption as a reversible cause of kynurenine-induced Teff apoptosis, indicating Teff apoptosis as a potential in vitro artifact of low lipid content in traditional cell culture media, the immune modulatory potential of TME fatty acids, or the possible use of kynurenines to induce lipid catabolism therapeutically.
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Saito, Kuniaki, Suwako Fujigaki, Melvyn P. Heyes, Katsumi Shibata, Masao Takemura, Hidehiko Fujii, Hisayasu Wada, Akio Noma, and Mitsuru Seishima. "Mechanism of increases in l-kynurenine and quinolinic acid in renal insufficiency." American Journal of Physiology-Renal Physiology 279, no. 3 (September 1, 2000): F565—F572. http://dx.doi.org/10.1152/ajprenal.2000.279.3.f565.
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Marked increases in metabolites of thel-tryptophan-kynurenine pathway, l-kynurenine and quinolinic acid (Quin), were observed in serum and cerebrospinal fluid (CSF) of both the rat and human with renal insufficiency. The mechanisms responsible for their accumulation after renal insufficiency were investigated. In patients with chronic renal insufficiency, elevated levels of serum l-kynurenine and Quin were reduced by hemodialysis. In renal-insufficient rats, Quin andl-kynurenine levels in serum, brain, and CSF were also increased parallel to the severity of renal insufficiency. Urinary excretion of Quin (3.5-fold) and l-kynurenine (2.8-fold) was also increased. Liver l-tryptophan 2,3-dioxygenase activity (TDO), a rate-limiting enzyme of the kynurenine pathway, was increased in proportion to blood urea nitrogen and creatinine levels. Kynurenine 3-hydroxylase and quinolinic acid phosphoribosyltransferase were unchanged, but the activities of kynureninase, 3-hydroxyanthranilate dioxygenase, and aminocarboxymuconate-semialdehyde decarboxylase (ACMSDase) were significantly decreased. Systemic administrations of pyrazinamide (ACMSDase inhibitor) increased serum Quin concentrations in control rats, demonstrating that changes in body ACMSDase activities in response to renal insufficiency are important factors for the determination of serum Quin concentrations. We hypothesize the following ideas: that increased serum l-kynurenine concentrations are mainly due to the increased TDO and decreased kynureninase activities in the liver and increased serum Quin concentrations are due to the decreased ACMSDase activities in the body after renal insufficiency. The accumulation of CSFl-kynurenine is caused by the entry of increased seruml-kynurenine, and the accumulation of CSF Quin is secondary to Quin from plasma and/or Quin precursor into the brain.
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Sadok, Ilona, and Katarzyna Jędruchniewicz. "Dietary Kynurenine Pathway Metabolites—Source, Fate, and Chromatographic Determinations." International Journal of Molecular Sciences 24, no. 22 (November 14, 2023): 16304. http://dx.doi.org/10.3390/ijms242216304.
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Tryptophan metabolism plays an essential role in human health. In mammals, about 95% of dietary tryptophan is metabolized through the kynurenine pathway, which is associated with the development of several pathologies, including neurodegeneration. Some of the kynurenine pathway metabolites are agonists of the aryl hydrocarbon receptor involved in metabolic functions, inflammation, and carcinogenesis. Thus, their origins, fates, and roles are of widespread interest. Except for being produced endogenously, these metabolites can originate from exogenous sources (e.g., food) and undergo absorption in the digestive tract. Recently, a special focus on exogenous sources of tryptophan metabolites was observed. This overview summarizes current knowledge about the occurrence of the kynurenine pathway metabolites (kynurenines) in food and the analytical method utilized for their determination in different food matrices. Special attention was paid to sample preparation and chromatographic analysis, which has proven to be a core technique for the detection and quantification of kynurenines. A discussion of the fate and role of dietary kynurenines has also been addressed. This review will, hopefully, guide further studies on the impact of dietary kynurenines on human health.
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Kozhevnikova, M. V., A. V. Krivova, E. O. Korobkova, A. A. Ageev, K. M. Shestakova, N. E. Moskaleva, S. A. Appolonova, E. V. Privalova, and Yu N. Belenkov. "Comparative analysis of tryptophan and downstream metabolites of the kynurenine and serotonin pathways in patients with arterial hypertension and coronary artery disease." Kardiologiia 62, no. 11 (November 30, 2022): 40–48. http://dx.doi.org/10.18087/cardio.2022.11.n2283.
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Aim To compare serum concentrations of tryptophane (Trp) and its metabolites in subjects with no cardiovascular disease (CVD) and patients with СVD, including arterial hypertension (AH) and ischemic heart disease (IHD).Material and methods This study included 131 participants; 58 participants (11 of them with documented peripheral atherosclerosis) were included into the AH group, 46 participants were included into the IHD group, and 27 participants with no signs of CVD were included into the control group. Plasma concentrations of Trp and its metabolites were measured by high-performance liquid chromatography in combination with a triple quadrupole analyzer.Results Comparison of the three study groups revealed significant differences in concentrations of Trp (р=0.029), kynurenine (p<0.001), kynurenine/Trp ratio (p<0.001), quinolinic acid (р=0.007), kynurenic acid (р=0.003), serotonin (p<0.001), and 5‑hydroxyindoleacetic acid (5‑HIAA) (р=0.011). When the AH group was subdivided into subgroups without and with documented peripheral atherosclerosis, the intergroup differences remained for concentrations of kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, serotonin, and 5‑HIAA. Also, correlations were found between concentrations of Trp metabolites and laboratory and instrumental data, primarily inflammatory markers. Conclusion Analysis of serum concentrations of Trp and its metabolites in CVD patients showed increases in kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, and 5‑HIAA along with decreases in concentrations of Trp and serotonin in the groups of AH, AH with documented peripheral atherosclerosis, and IHD.
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Ala, Moein, and Seyed Parsa Eftekhar. "The Footprint of Kynurenine Pathway in Cardiovascular Diseases." International Journal of Tryptophan Research 15 (January 2022): 117864692210966. http://dx.doi.org/10.1177/11786469221096643.
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Kynurenine pathway is the main route of tryptophan metabolism and produces several metabolites with various biologic properties. It has been uncovered that several cardiovascular diseases are associated with the overactivation of kynurenine pathway and kynurenine and its metabolites have diagnostic and prognostic value in cardiovascular diseases. Furthermore, it was found that several kynurenine metabolites can differently affect cardiovascular health. For instance, preclinical studies have shown that kynurenine, xanthurenic acid and cis-WOOH decrease blood pressure; kynurenine and 3-hydroxyanthranilic acid prevent atherosclerosis; kynurenic acid supplementation and kynurenine 3-monooxygenase (KMO) inhibition improve the outcome of stroke. Indoleamine 2,3-dioxygenase (IDO) overactivity and increased kynurenine levels improve cardiac and vascular transplantation outcomes, whereas exacerbating the outcome of myocardial ischemia, post-ischemic myocardial remodeling, and abdominal aorta aneurysm. IDO inhibition and KMO inhibition are also protective against viral myocarditis. In addition, dysregulation of kynurenine pathway is observed in several conditions such as senescence, depression, diabetes, chronic kidney disease (CKD), cirrhosis, and cancer closely connected to cardiovascular dysfunction. It is worth defining the exact effect of each metabolite of kynurenine pathway on cardiovascular health. This narrative review is the first review that separately discusses the involvement of kynurenine pathway in different cardiovascular diseases and dissects the underlying molecular mechanisms.
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Shestopalov, A. V., O. P. Shatova, M. S. Karbyshev, A. M. Gaponov, N. E. Moskaleva, S. A. Appolonova, A. V. Tutelyan, V. V. Makarov, S. M. Yudin, and S. A. Roumiantsev. "“Kynurenine switch” and obesity." Bulletin of Siberian Medicine 20, no. 4 (January 3, 2022): 103–11. http://dx.doi.org/10.20538/1682-0363-2021-4-103-111.
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Aim. To assess the concentrations of bacterial and eukaryotic metabolites mainly involved in indole, kynurenine, and serotonin pathways of tryptophan metabolism in a cohort of patients with obesity. Materials and methods. Using high-performance liquid chromatography with mass spectrometric detection, the concentrations of several serum metabolites, such as kynurenine, kynurenic acid, anthranilic acid, xanthurenic acid, quinolinic acid, 5-hydroxyindole-3-acetate, tryptamine, serotonin, indole-3-lactate, indole-3-acetate, indole-3- butyrate, indole-3-carboxaldehyde, indole-3-acrylate, and indole-3-propionate, were analyzed in a cohort of obese patients compared with healthy volunteers.Results. It was found that serum levels of tryptophan metabolites of microbial and eukaryotic origin were significantly increased in obese patients. Therefore, the concentration of kynurenine in the blood serum in obese patients was 2,413 ± 855 nmol / l, while in healthy volunteers of the same age group, the level of kynurenine in the blood serum was 2,122 ± 863 nmol / l. In obese patients, two acids formed due to kynurenine metabolism; the concentrations of kynurenic and quinolinic acids were increased in the blood serum. The concentration of kynurenic acid in the blood serum in obese patients was 21.1 ± 9.26 nmol / l, and in healthy patients, it was 16.8 ± 8.37 nmol / l. At the same time, the level of quinolinic acid in the blood serum in obese patients was 73.1 ± 54.4 nmol / l and in healthy volunteers – 56.8 ± 34.1 nmol / l. Normally, the level of quinolinic acid is 3.4 times higher than the concentration of kynurenic acid, and in case of obesity, there is a comparable increase in these acids in the blood serum.From indole derivatives, mainly of microbial origin, the concentrations of indole-3-lactate, indole-3-butyrate, and indole-3-acetate were significantly increased in the blood serum of obese patients. In obese patients, the serum concentration of 5-hydroxyindole-3-acetate was elevated to 74.6 ± 75.8 nmol / l (in healthy volunteers – 59.4 ± 36.6 nmol / l); indole-3-lactate – to 523 ± 251 nmol / l (in healthy volunteers – 433 ± 208 nmol / l); indole-3-acetate – to 1,633 ± 1,166 nmol / l (in healthy volunteers – 1,186 ± 826 nmol / l); and indole-3-butyrate – to 4.61 ± 3.31 nmol / l (in healthy volunteers – 3.85 ± 2.51 nmol / l).Conclusion. In case of obesity, the utilization of tryptophan was intensified by both the microbiota population and the macroorganism. It was found that obese patients had higher concentrations of kynurenine, quinolinic and kynurenic acids, indole-3-acetate, indole-3-lactate, indole-3-butyrate, and 5-hydroxyindole-3-acetate. Apparently, against the background of increased production of proinflammatory cytokines by adipocytes in obese patients, the “kynurenine switch” was activated which contributed to subsequent overproduction of tryptophan metabolites involved in the immune function of the macroorganism.
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Berthon, Céline, Michaela Fontenay, Selim Corm, Isabelle Briche, Michel Lhermitte, and Bruno Quesnel. "Metabolites of Tryptophan Catabolism Are Elevated in Sera of Patients with Myelodysplastic Syndromes and Inhibit Hematopoietic Progenitor Amplification." Blood 120, no. 21 (November 16, 2012): 3843. http://dx.doi.org/10.1182/blood.v120.21.3843.3843.
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Abstract Abstract 3843 Introduction: Tryptophan catabolism, which is mediated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), produces kynurenine, which blocks T-cell activation and induces immunosuppression. Kynurenine itself is converted by downstream enzymes into secondary catabolites that also have toxic effects on T cells. Tryptophan catabolism is elevated in many cancers, including acute myeloid leukemia (AML). However, tryptophan catabolites that are downstream of kynurenine have never been investigated in hematological malignancies. Methods: We evaluated the serum levels of primary and secondary tryptophan catabolites in a cohort of patients with myelodysplastic syndromes (MDS). Sera were isolated from 132 adult MDS patients after informed consent was obtained in accordance with the Helsinki Declaration. The levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and anthranilic acid in the sera were quantified using HPLC. For erythroid cell expansion, CD34+ cells were collected and isolated from the mononuclear cell fractions of cytapheresis products from 3 healthy donors and cultured in liquid medium under erythroid conditions with tryptophan catabolites. Results: The MDS patients showed significantly lower levels of tryptophan and higher levels of kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and anthranilic acid compared with the healthy controls. We also compared the kynurenine and tryptophan levels in the MDS patients with our previous cohort of 112 patients with primary AML. The kynurenine/tryptophan ratios were significantly higher in the MDS patients (median 0.0468 vs. 0.0676). The tryptophan catabolites correlated with cytopenia; higher kynurenine levels were associated with lower hemoglobin levels and higher blast counts and were associated with presence of dysgranulopoiesis. Lower tryptophan levels were found in patients with platelet transfusion dependency. Kynurenic acid levels were higher in patients with dysmegakaryopoiesis. High 3-hydroxyanthranilic and kynurenic acid levels were associated with severe thrombopenia below 20 G/L. IPSS score, cytogenetic, and WHO diagnosis did not associated with any tryptophan catabolite level. The tryptophan catabolites inhibited progenitor expansion during the in vitro culture of hematopoietic cells and reduced the numbers of granulocytes and erythroblasts. Conclusions: Thus, MDS patients are characterized by high tryptophan catabolism resulting in elevated primary and secondary metabolites, which both have inhibitory effects on hematopoiesis. These results suggest that IDO or TDO inhibitors should be investigated in MDS. Disclosures: No relevant conflicts of interest to declare.
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Allison, David J., Joshua P. Nederveen, Tim Snijders, Kirsten E. Bell, Dinesh Kumbhare, Stuart M. Phillips, Gianni Parise, and Jennifer J. Heisz. "Exercise training impacts skeletal muscle gene expression related to the kynurenine pathway." American Journal of Physiology-Cell Physiology 316, no. 3 (March 1, 2019): C444—C448. http://dx.doi.org/10.1152/ajpcell.00448.2018.
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Exercise positively impacts mood and symptoms of depression; however, the mechanisms underlying these effects are not fully understood. Recent evidence highlights a potential role for skeletal muscle-derived transcription factors to influence tryptophan metabolism, along the kynurenine pathway, which has important implications in depression. This has important consequences for older adults, whose age-related muscle deterioration may influence this pathway and may increase their risk for depression. Although exercise training has been shown to improve skeletal muscle mass in older adults, whether this also translates into improvements in transcription factors and metabolites related to the kynurenine pathway has yet to be examined. The aim of the present study was to examine the influence of a 12-wk exercise program on skeletal muscle gene expression of transcription factors, kynurenine aminotransferase (KAT) gene expression, and plasma concentrations of tryptophan metabolites (kynurenines) in healthy older men over 65 yr of age. Exercise training significantly increased skeletal muscle gene expression of transcription factors (peroxisome proliferator-activated receptor-γ coactivator 1α, peroxisome proliferator-activated receptor-α, and peroxisome proliferator-activated receptor-δ: 1.77, 1.99, 2.18-fold increases, respectively, P < 0.01] and KAT isoforms 1–4 (6.5, 2.1, 2.2, and 2.6-fold increases, respectively, P ≤ 0.01). Concentrations of plasma kynurenines were not altered. These results demonstrate that 12 wk of exercise training significantly altered skeletal muscle gene expression of transcription factors and gene expression related to the kynurenine pathway, but not circulating kynurenine metabolites in older men. These findings warrant future research to determine whether distinct exercise modalities or varying intensities could induce a shift in the kynurenine pathway in depressed older adults.
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Sadok, Ilona, and Magdalena Staniszewska. "Electrochemical Determination of Kynurenine Pathway Metabolites—Challenges and Perspectives." Sensors 21, no. 21 (October 28, 2021): 7152. http://dx.doi.org/10.3390/s21217152.
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In recent years, tryptophan metabolism via the kynurenine pathway has become one of the most active research areas thanks to its involvement in a variety of physiological processes, especially in conditions associated with immune dysfunction, central nervous system disorders, autoimmunity, infection, diabetes, and cancer. The kynurenine pathway generates several metabolites with immunosuppressive functions or neuroprotective, antioxidant, or toxic properties. An increasing body of work on this topic uncovers a need for reliable analytical methods to help identify and quantify tryptophan metabolites at physiological concentrations in biological samples of different origins. Recent methodological advances in the fabrication and application of electrochemical sensors promise a rise in the future generation of novel analytical systems. This work summarizes current knowledge and provides important suggestions with respect to direct electrochemical determinations of kynurenine pathway metabolites (kynurenines) in complex biological matrices. Measurement challenges, limitations, and future opportunities of electroanalytical methods to advance study of the implementation of kynurenines in disease conditions are discussed.
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Schlittler, Maja, Michel Goiny, Leandro Z. Agudelo, Tomas Venckunas, Marius Brazaitis, Albertas Skurvydas, Sigitas Kamandulis, et al. "Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans." American Journal of Physiology-Cell Physiology 310, no. 10 (May 15, 2016): C836—C840. http://dx.doi.org/10.1152/ajpcell.00053.2016.
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Physical exercise has emerged as an alternative treatment for patients with depressive disorder. Recent animal studies show that exercise protects from depression by increased skeletal muscle kynurenine aminotransferase (KAT) expression which shifts the kynurenine metabolism away from the neurotoxic kynurenine (KYN) to the production of kynurenic acid (KYNA). In the present study, we investigated the effect of exercise on kynurenine metabolism in humans. KAT gene and protein expression was increased in the muscles of endurance-trained subjects compared with untrained subjects. Endurance exercise caused an increase in plasma KYNA within the first hour after exercise. In contrast, a bout of high-intensity eccentric exercise did not lead to increased plasma KYNA concentration. Our results show that regular endurance exercise causes adaptations in kynurenine metabolism which can have implications for exercise recommendations for patients with depressive disorder.
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Colle, R., C. Verstuyft, D. David, P. Chanson, and E. Corruble. "Peripheral tryptophan and serotonin and kynurenine pathways in major depression: A case-control study." European Psychiatry 64, S1 (April 2021): S328. http://dx.doi.org/10.1192/j.eurpsy.2021.880.
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IntroductionThe tryptophan pathway along with its two branches of metabolism to serotonin and kynurenine seems to be affected in major depression. In depressed patients, peripheral levels of tryptophan, serotonin, kynurenine and their metabolite remain unclear.ObjectivesTherefore, peripheral tryptophan and metabolites of serotonin and kynurenine were investigated extensively in 173 patients suffering from a current major depressive episode (MDE) and compared to 214 healthy controls (HC).MethodsFasting plasma levels of 11 peripheral metabolites were quantified: tryptophan, serotonin pathway (serotonin, its precursor 5-hydroxy-tryptophan and its metabolite the 5-hydroxy-indole acetic acid), and kynurenine pathway (kynurenine and six of its metabolites including anthranilic acid, kynurenic acid, nicotinamide, picolinic acid, xanthurenic acid and 3-hydroxy-anthranilic acid).Results60 (34.7%) patients were antidepressant drug free. Tryptophan levels did not differ between MDE patients and HC. Serotonin and its precursor (5-hydroxy-tryptophan) levels were lower in MDE patients than HC. Whereas, its metabolite (5-hydroxy-indole acetic acid) levels were within the standard range. Kynurenine and four of its metabolites (kynurenic acid, nicotinamide, picolinic acid and xanthurenic acid) were lower in MDE patients.ConclusionsThis study uses the largest ever sample of MDE patients, with an extensive assessment of peripheral tryptophan metabolism in plasma. These findings provide new insights into the peripheral signature of MDE. The reasons for these changes should be further investigated. These results might suggest a better stratification of patients and different therapeutic strategies therapeutic strategies.
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Wickström, Ronny, Åsa Fowler, Michel Goiny, Vincent Millischer, Sofia Ygberg, and Lilly Schwieler. "The Kynurenine Pathway is Differentially Activated in Children with Lyme Disease and Tick-Borne Encephalitis." Microorganisms 9, no. 2 (February 4, 2021): 322. http://dx.doi.org/10.3390/microorganisms9020322.
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In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions.
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Nagy, Bence M., Chandran Nagaraj, Andreas Meinitzer, Neha Sharma, Rita Papp, Vasile Foris, Bahil Ghanim, et al. "Importance of kynurenine in pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 5 (November 1, 2017): L741—L751. http://dx.doi.org/10.1152/ajplung.00517.2016.
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The tryptophan metabolite kynurenine is significantly increased in pulmonary arterial hypertension (PAH) patients, and it is a potent vasodilator of systemic arteries. Our aim was to investigate the role of kynurenine in the pulmonary circulation. Serum tryptophan, kynurenine, and kynurenic acid levels were measured in 20 idiopathic PAH (IPAH) patients, 20 healthy controls, and 20 patients with chronic lung disease or metabolic syndrome without PH. Laser-dissected pulmonary arteries from IPAH and control lungs were tested for the expression of indoleamine-2, 3-dioxygenase (IDO), the rate-limiting enzyme for the conversion from tryptophan to kynurenine. Acute effects of kynurenine were tested in pulmonary vascular preparations, two different models of chronic pulmonary hypertension (PH), and in human pulmonary arterial smooth muscle cells (hPASMCs). In IPAH vs. control serum, kynurenine was significantly elevated (3.6 ± 0.2 vs. 2.6 ± 0.1 µM, P < 0.0001), and strongly associated with PH (area under the curve = 0.86), but kynurenine levels were not elevated in lung disease and metabolic syndrome. Among all investigated tryptophan metabolites, kynurenine displayed the strongest correlation with mean pulmonary arterial pressure (mPAP) (ρ: 0.770, P < 0.0001). Tryptophan was significantly decreased in IPAH lungs; however, IDO expression was not changed. In hPASMCs, kynurenine increased both cAMP and cGMP; in intrapulmonary arteries, it relaxed the preconstriction via NO/cGMP and cAMP pathways, and in two models of established PH, it acutely decreased the mPAP. Our data suggest that kynurenine elevation might be specifically associated with mPAP; kynurenine acts on hPASMCs in synergy with NO and exerts acute pulmonary vasodilatation in chronic PH models. Kynurenine might provide both a new biomarker and a new therapeutic option for PH.
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Baran, H., J. A. Hainfellner, and B. Kepplinger. "Kynurenic Acid Metabolism in Various Types of Brain Pathology in HIV-1 Infected Patients." International Journal of Tryptophan Research 5 (January 2012): IJTR.S10627. http://dx.doi.org/10.4137/ijtr.s10627.
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Kynurenic acid, an intermediate metabolite of L-kynurenine, is a competitive antagonist of inotropic excitatory amino acid (EAA) receptors as well as a non competitive antagonist of 7 alpha nicotine cholinergic receptors and its involvement in memory deficit and cognition impairment has been suggested. Alterations of kynurenic acid metabolism in the brain after HIV-1 (human immunodeficiency virus type-1) infection have been demonstrated. The present study evaluates the biosynthetic machinery of kynurenic acid e.g. the content of L-kynurenine and kynurenic acid, as well as the activity of enzymes synthesizing kynurenic acid, kynurenine aminotransferase I (KAT I) and kynurenine aminotransferase II (KAT II) in the frontal cortex and cerebellum of HIV-1 infected patients in relation to different types of pathology classified as follows: HIV in brain (HIV); opportunistic infection (OPP); infarction of brain (INF); malignant lymphoma of brain (LY); and glial dystrophy (GD) and of control (CO) subjects. Of all investigated pathologies the most frequent was OPP (65%), followed by HIV (26%), LY, INF, and GD (each 22%, respectively). Further, 68% of HIV-1 patients had bronchopneumonia, the highest incidence of which, at 60%, was seen in the OPP and LY group. Kynurenic acid was increased significantly in the frontal cortex of LY (392% of CO, P < 0.001), HIV (231% of CO, P < 0.01) and GD (193% of CO, P < 0.05), as well as in the cerebellum of GD (261% of CO, P < 0.01). A significant increase of L-kynurenine was observed in the frontal cortex of LY (385% of CO, P < 0.001) and INF (206% of CO, P < 0.01), and in the cerebellum of GD, LY, OPP and HIV (between 177% and 147% of CO). The KAT I activity increased significantly in the frontal cortex of all pathological subgroups, ie OPP = 420% > INF > LY > HIV > GD = 192% of CO. In the cerebellum, too, all pathological subgroups showed marked increase of KAT I activity (OPP = 320% > LY, HIV > GD > INF = 176% of CO). On contrary, the activity of KAT II was moderately, but significantly, higher in the frontal cortex of INF and OPP; in the cerebellum of HIV, OPP and LY it was comparable to the control, while mildly reduced in INF and GD. Interestingly, normal subjects with the diagnosis of bronchopneumonia were characterized by high kynurenic acid metabolism in the brain, too. Correlation analyses between kynurenine parameters revealed association between high ratio KAT I/KAT II and increased kynurenic acid level and lower L-kynurenine in the frontal cortex and cerebellum of HIV and LY subgroups. The present study revealed a different pattern of alteration of kynurenic acid metabolism in frontal cortex and cerebellum among investigated pathological subgroups of HIV-1 infected patients. Interestingly, a marked enhancement of kynurenic acid metabolism in the brain has been found with occurrence of bronchopneumonia. This finding indicates a notable association between impaired conditions of oxygen availability and enhancement of kynurenic acid formation in the human brain. These observation(s) might have an impact on the understanding of pathological processes in the brain after HIV-1 infection involving the development of neuropsychiatric and neurological symptoms, including memory and cognition impairment.
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Stone, Trevor W., and Richard O. Williams. "Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface." Cancers 15, no. 11 (May 24, 2023): 2895. http://dx.doi.org/10.3390/cancers15112895.
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The mechanisms underlying a relationship between inflammation and cancer are unclear, but much emphasis has been placed on the role of tryptophan metabolism to kynurenine and downstream metabolites, as these make a substantial contribution to the regulation of immune tolerance and susceptibility to cancer. The proposed link is supported by the induction of tryptophan metabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), in response to injury, infection or stress. This review will summarize the kynurenine pathway and will then focus on the bi-directional interactions with other transduction pathways and cancer-related factors. The kynurenine pathway can interact with and modify activity in many other transduction systems, potentially generating an extended web of effects other than the direct effects of kynurenine and its metabolites. Conversely, the pharmacological targeting of those other systems could greatly enhance the efficacy of changes in the kynurenine pathway. Indeed, manipulating those interacting pathways could affect inflammatory status and tumor development indirectly via the kynurenine pathway, while pharmacological modulation of the kynurenine pathway could indirectly influence anti-cancer protection. While current efforts are progressing to account for the failure of selective IDO1 inhibitors to inhibit tumor growth and to devise means of circumventing the issue, it is clear that there are wider factors involving the relationship between kynurenines and cancer that merit detailed consideration as alternative drug targets.
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Ciapała, Katarzyna, and Ewelina Rojewska. "Kinurenines in Central Nervous System under neuropathic pain – clinical implications from basic research." BÓL 20, no. 3 (January 16, 2020): 32–39. http://dx.doi.org/10.5604/01.3001.0013.7396.
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Central nervous system disorders are often accompanied by changes in tryptophan metabolism. Kynurenine pathway is known to be the main route by which this essential amino acid is catabolized to a plenty of metabolites. Intermediates of this cascade are responsible for a wide spectrum of effects, including endogenous regulation of neuronal excitability and immune cells response. Excessive or disrupted activation of the pathway can lead to the accumulation of neurotoxic compounds, and in consequence, contributes to the development of various type of pathologies. These aspects shed new light on the kynurenine pathway as a promising target for development of new therapeutic strategies. Following work briefly characterizes the kynurenine pathway and discusses the neurobiological functions of kynurenines, with particular focus on their role in the development and persistence of neuropathic pain. It is also presenting the potential clinical implications of modulation of the kynurenine pathway in pharmacological therapy of chronic pain.
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Guo, Song, L. Vecsei, and Messoud Ashina. "The L-kynurenine signalling pathway in trigeminal pain processing: A potential therapeutic target in migraine?" Cephalalgia 31, no. 9 (May 18, 2011): 1029–38. http://dx.doi.org/10.1177/0333102411404717.
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Introduction: In recent years the kynurenine family of compounds, metabolites of tryptophan, has become an area of intensive research because of its neuroactive properties. Two metabolites of this family have become of interest in relation to migraine and pain processing. Discussion: Experimental studies have shown that kynurenic acid (KYNA) plays an important role in the transmission of sensory impulses in the trigeminovascular system and that increased levels of KYNA decrease the sensitivity of the cerebral cortex to cortical spreading depression. Furthermore, another metabolite of the kynurenine family, L-kynurenine, exerts vasodilating effects similar to nitric oxide by increasing cyclic guanosine monophosphate. Conclusion: This review summarizes current knowledge of the role of kynurenine signalling in trigeminal and central pain processing, including its therapeutic prospects in migraine treatment.
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Ramos-Chávez, L. A., R. Lugo Huitrón, D. González Esquivel, B. Pineda, C. Ríos, D. Silva-Adaya, L. Sánchez-Chapul, G. Roldán-Roldán, and V. Pérez de la Cruz. "Relevance of Alternative Routes of Kynurenic Acid Production in the Brain." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/5272741.
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The catabolism of tryptophan has gained great importance in recent years due to the fact that the metabolites produced during this process, with neuroactive and redox properties, are involved in physiological and pathological events. One of these metabolites is kynurenic acid (KYNA), which is considered as a neuromodulator since it can interact with NMDA, nicotinic, and GPR35 receptors among others, modulating the release of neurotransmitters as glutamate, dopamine, and acetylcholine. Kynureninate production is attributed to kynurenine aminotransferases. However, in some physiological and pathological conditions, its high production cannot be explained just with kynurenine aminotransferases. This review focuses on the alternative mechanism whereby KYNA can be produced, either from D-amino acids or by means of other enzymes as D-amino acid oxidase or by the participation of free radicals. It is important to mention that an increase in KYNA levels in processes as brain development, aging, neurodegenerative diseases, and psychiatric disorders, which share common factors as oxidative stress, inflammation, immune response activation, and participation of gut microbiota that can also be related with the alternative routes of KYNA production, has been observed.
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Laura, Orsatti, Thomas Stiehl, Katharina Dischinger, Roberto Speziale, Pamela Di Pasquale, Edith Monteagudo, Carsten Mueller-Tidow, Aleksandar Radujkovic, Peter Dreger, and Thomas Luft. "Kynurenine Pathway Activation and Deviation in Fibrosing Chronic Graft-Versus-Host Disease." Blood 138, Supplement 1 (November 5, 2021): 3895. http://dx.doi.org/10.1182/blood-2021-152793.
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Abstract Background: Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication after allogeneic stem cell transplantation (allo-SCT), and its pathophysiology is poorly understood. Kynurenine and its metabolites were shown to associate with both, interferon-gamma (IFNg) activation and fibrosis. This study investigates the interplay between members of the IFNγ pathway and Kynurenin-derived metabolites in cGVHD. Methods: Using a liquid chromatography tandem mass spectrometry approach on sera obtained on day+100 (n=430) and/or at onset of cGVHD symptoms (n=196) of our prospectively collected biobank after alloSCT, we measured concentrations of Kyn pathway metabolites (kynurenin (Kyn), anthranilic acid (AA), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), and 3-hydroxy-anthranilic acid (3-HAA). We also measured C-X-C chemokine ligand 9 (CXCL9), interleukin (IL-)18, tryptophane (Trp) and indoleamine-2,3-dioxygenase (IDO) by ELISA. Results: We observed increased CXCL9 and IDO levels, and increased activity of the Kynurenine pathway in both non-severe and severe cGVHD. Interestingly, severe fibrosing cGVHD differed from any other form of cGVHD in a significant pathway shift toward AA and KA. This resulted in a reduced 3-HAA/AA ratio. A score consisting of low 3-HAA/AA ratio and high KA serum levels at onset of mild cGVHD symptoms predicted risk specifically of severe fibrosing cGVHD. This altered pathway in severe fibrosing cGVHD correlated with reduced activity of the Vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. Our results are consistent with a triple-hit model for fibrosing cGVHD including low activity of kynurenine monooxygenase (KMO, Vitamin B2 and B6 dependent) in the context of high IL18 serum levels and CXCL9-induced IDO activation (Figure 1). Conclusion: Chronic GVHD associates with an IFNg signature and increased activity of the Kynurenin pathway. KA and 3-HAA/AA defined the first molecular distinction between fibrosing and non-fibrosing cGVHD. The mechanism may involve Vitamin B2/B6 deficiency, and high CXCL9 and IL18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGHVD and provides a rationale for translational trials on prophylactic Vitamin B2/B6 supplementation for cGVHD prevention. Figure 1: Triple hit model of fibrosing cGVHD (Hypothesis): Severe fibrosing cGVHD associates with a strong CXCL9-induced activation of IDO. The result of this activation is influenced by a reduced activity of kynurenine monooxygenase (KMO), either due to genetic polymorphisms or lack of Vitamin B2, and further aggravated by lack of Vitamin B6. The resulting metabolic deviation increases AA concentrations and reduces the 3-HAA/AA ratio. Finally, high IL-18 associates with increased serum KA. These three hits result in a metabolic situation with high KA and a low ratio 3-HAA/AA that predicts risk of fibrosing cGVHD. Figure 1 Figure 1. Disclosures Mueller-Tidow: Janssen Cilag: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bioline: Consultancy, Research Funding.
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Jonsson, William O., Jonathan Ponette, Oscar Horwath, Tomas Rydenstam, Karin Söderlund, Björn Ekblom, Michele Azzolini, Jorge L. Ruas, and Eva Blomstrand. "Changes in plasma concentration of kynurenine following intake of branched-chain amino acids are not caused by alterations in muscle kynurenine metabolism." American Journal of Physiology-Cell Physiology 322, no. 1 (January 1, 2022): C49—C62. http://dx.doi.org/10.1152/ajpcell.00285.2021.
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Administration of branched-chain amino acids (BCAA) has been suggested to enhance mitochondrial biogenesis, including levels of PGC-1α, which may, in turn, alter kynurenine metabolism. Ten healthy subjects performed 60 min of dynamic one-leg exercise at ∼70% of Wmax on two occasions. They were in random order supplied either a mixture of BCAA or flavored water (placebo) during the experiment. Blood samples were collected during exercise and recovery, and muscle biopsies were taken from both legs before, after, and 90 and 180 min following exercise. Ingestion of BCAA doubled their concentration in both plasma and muscle while causing a 30%–40% reduction ( P < 0.05 vs. placebo) in levels of aromatic amino acids in both resting and exercising muscle during 3-h recovery period. The muscle concentration of kynurenine decreased by 25% ( P < 0.05) during recovery, similar in both resting and exercising leg and with both supplements, although plasma concentration of kynurenine during recovery was 10% lower ( P < 0.05) when BCAA were ingested. Ingestion of BCAA reduced the plasma concentration of kynurenic acid by 60% ( P < 0.01) during exercise and recovery, whereas the level remained unchanged with placebo. Exercise induced a three- to fourfold increase ( P < 0.05) in muscle content of PGC-1α1 mRNA after 90 min of recovery under both conditions, whereas levels of KAT4 mRNA and protein were unaffected by exercise or supplement. In conclusion, the reduction of plasma levels of kynurenine and kynurenic acid caused by BCAA were not associated with any changes in the level of muscle kynurenine, suggesting that kynurenine metabolism was altered in tissues other than muscle.
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Ciapała, Katarzyna, Joanna Mika, and Ewelina Rojewska. "The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives." International Journal of Molecular Sciences 22, no. 20 (October 13, 2021): 11055. http://dx.doi.org/10.3390/ijms222011055.
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Accumulating evidence suggests the key role of the kynurenine pathway (KP) of the tryptophan metabolism in the pathogenesis of several diseases. Despite extensive research aimed at clarifying the mechanisms underlying the development and maintenance of neuropathic pain, the roles of KP metabolites in this process are still not fully known. Although the function of the peripheral KP has been known for several years, it has only recently been acknowledged that its metabolites within the central nervous system have remarkable consequences related to physiology and behavior. Both the products and metabolites of the KP are involved in the pathogenesis of pain conditions. Apart from the neuroactive properties of kynurenines, the KP regulates several neurotransmitter systems in direct or indirect ways. Some neuroactive metabolites are known to have neuroprotective properties (kynurenic acid, nicotinamide adenine dinucleotide cofactor), while others are toxic (3-hydroxykynurenine, quinolinic acid). Numerous animal models show that modulation of the KP may turn out to be a viable target for the treatment of diseases. Importantly, some compounds that affect KP enzymes are currently described to possess analgesic properties. Additionally, kynurenine metabolites may be useful for assessing response to therapy or as biomarkers in therapeutic monitoring. The following review describes the molecular site of action and changes in the levels of metabolites of the kynurenine pathway in the pathogenesis of various conditions, with a particular emphasis on their involvement in neuropathy. Moreover, the potential clinical implications of KP modulation in chronic pain therapy as well as the directions of new research initiatives are discussed.
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Mor, Adrian, Krystyna Pawlak, Bartlomiej Kalaska, Tomasz Domaniewski, Beata Sieklucka, Marta Zieminska, Bogdan Cylwik, and Dariusz Pawlak. "Modulation of the Paracrine Kynurenic System in Bone as a New Regulator of Osteoblastogenesis and Bone Mineral Status in an Animal Model of Chronic Kidney Disease Treated with LP533401." International Journal of Molecular Sciences 21, no. 17 (August 19, 2020): 5979. http://dx.doi.org/10.3390/ijms21175979.
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An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.
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Schwarcz, Robert, Ann Foo, Korrapati V. Sathyasaikumar, and Francesca M. Notarangelo. "The Probiotic Lactobacillus reuteri Preferentially Synthesizes Kynurenic Acid from Kynurenine." International Journal of Molecular Sciences 25, no. 7 (March 26, 2024): 3679. http://dx.doi.org/10.3390/ijms25073679.
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The gut–brain axis is increasingly understood to play a role in neuropsychiatric disorders. The probiotic bacterium Lactobacillus (L.) reuteri and products of tryptophan degradation, specifically the neuroactive kynurenine pathway (KP) metabolite kynurenic acid (KYNA), have received special attention in this context. We, therefore, assessed relevant features of KP metabolism, namely, the cellular uptake of the pivotal metabolite kynurenine and its conversion to its primary products KYNA, 3-hydroxykynurenine and anthranilic acid in L. reuteri by incubating the bacteria in Hank’s Balanced Salt solution in vitro. Kynurenine readily entered the bacterial cells and was preferentially converted to KYNA, which was promptly released into the extracellular milieu. De novo production of KYNA increased linearly with increasing concentrations of kynurenine (up to 1 mM) and bacteria (107 to 109 CFU/mL) and with incubation time (1–3 h). KYNA neosynthesis was blocked by two selective inhibitors of mammalian kynurenine aminotransferase II (PF-048559989 and BFF-122). In contrast to mammals, however, kynurenine uptake was not influenced by other substrates of the mammalian large neutral amino acid transporter, and KYNA production was not affected by the presumed competitive enzyme substrates (glutamine and α-aminoadipate). Taken together, these results reveal substantive qualitative differences between bacterial and mammalian KP metabolism.
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Baran, Halina, Gabriele Amann, Barbara Lubec, and Gert Lubec. "Kynurenic Acid and Kynurenine Aminotransferase in Heart." Pediatric Research 41, no. 3 (March 1997): 404–10. http://dx.doi.org/10.1203/00006450-199703000-00017.
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Stone, Trevor W. "Kynurenic acid antagonists and kynurenine pathway inhibitors." Expert Opinion on Investigational Drugs 10, no. 4 (April 2001): 633–45. http://dx.doi.org/10.1517/13543784.10.4.633.
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Goeden, Nick, Francesca M. Notarangelo, Ana Pocivavsek, Sarah Beggiato, Alexandre Bonnin, and Robert Schwarcz. "Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid." Developmental Neuroscience 39, no. 6 (2017): 519–28. http://dx.doi.org/10.1159/000481168.
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The kynurenine pathway (KP), the major catabolic route of tryptophan in mammals, contains several neuroactive metabolites, including kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). KP metabolism, and especially the fate of KYNA, during pregnancy is poorly understood, yet it may play a significant role in the development of psychiatric disorders later in life. The present study was designed to investigate the prenatal features of KP metabolism in vivo, with special focus on KYNA. To this end, pregnant CD-1 mice were treated systemically with kynurenine (100 mg/kg), KYNA (10 mg/kg), or saline on embryonic day 18. As expected, administration of either kynurenine or KYNA increased KYNA levels in the maternal plasma and placenta. Maternal kynurenine treatment also raised kynurenine levels in the fetal plasma and brain, demonstrating the ability of this pivotal KP metabolite to cross the placenta and increase the levels of both KYNA and 3-HK in the fetal brain. In contrast, maternal administration of KYNA caused only a small, nonsignificant elevation in KYNA levels in fetal plasma and brain. Complementary experiments using an ex vivo placental perfusion procedure confirmed the significant transplacental transfer of kynurenine and demonstrated that only a very small fraction of maternal kynurenine is converted to KYNA in the placenta and released into the fetal compartment under physiological conditions. Jointly, these results help to clarify the contributions of the maternal circulation and the placenta to fetal KYNA in the late prenatal period.
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Nicholas, Dequina A., Lorena M. Salto, Kristen Lavelle, Joy Wilson, W. Lawrence Beeson, Anthony Firek, William H. R. Langridge, Zaida Cordero-MacIntyre, and Marino De Leon. "En Balance: The Contribution of Physical Activity to the Efficacy of Spanish Diabetes Education of Hispanic Americans with Type 2 Diabetes." Journal of Diabetes Research 2020 (April 21, 2020): 1–8. http://dx.doi.org/10.1155/2020/4826704.
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Purpose. En Balance, a culturally sensitive diabetes education program, improves glycemic control in Hispanics with type 2 diabetes. The program emphasized diet, physical activity, and other factors important for glycemic control. However, the individual contributions of these education factors are unclear. The purpose of this study is to assess the contribution of physical activity to the success of En Balance in improving the health of Mexican Americans with type 2 diabetes. Methods. A retrospective study was conducted with plasma samples collected pre- and post-3-month study. Samples from 58 (18 males and 40 females) Hispanic subjects with type 2 diabetes were analyzed for the concentration of kynurenines, known to decrease in response to exercise. After three months, health outcomes for the active group (decreased kynurenines) and the rest of the cohort were evaluated by paired Wilcoxon signed-rank test. Results. Half of the subjects had increased kynurenine levels at the end of the educational program. We found that the subjects in the active group with decreased kynurenine concentrations displayed statistically greater improvements in fasting blood glucose, A1C, cholesterol, and triglycerides despite weight loss being higher in the group with increased kynurenine concentrations. Conclusions. En Balance participants with decreased kynurenine levels had significantly improved glycemic control. These data suggest that physical activity significantly contributes to the success of the En Balance education program. This analysis indicates that diabetes public health educators should emphasize the benefit of physical activity on glycemic control even in the absence of major weight loss.