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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.
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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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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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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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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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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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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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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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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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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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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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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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Kepplinger, Berthold, Halina Baran, Brenda Sedlnitzky-Semler, Nagy-Roland Badawi, and Helene Erhart. "Stochastic Resonance Activity Influences Serum Tryptophan Metabolism in Healthy Human Subjects." International Journal of Tryptophan Research 4 (January 2011): IJTR.S7986. http://dx.doi.org/10.4137/ijtr.s7986.
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Background Stochastic resonance therapy (SRT) is used for rehabilitation of patients with various neuropsychiatric diseases. An alteration in tryptophan metabolism along the kynurenine pathway has been identified in the central and peripheral nervous systems in patients with neuroinflammatory and neurodegenerative diseases and during the aging process. This study investigated the effect of SRT as an exercise activity on serum tryptophan metabolites in healthy subjects. Methods Serum L-tryptophan, L-kynurenine, kynurenic acid, and anthranilic acid levels were measured one minute before SRT and at one, 5, 15, 30, and 60 minutes after SRT. We found that SRT affected tryptophan metabolism. Serum levels of L-tryptophan, L-kynurenine, and kynurenic acid were significantly reduced for up to 60 minutes after SRT. Anthranilic acid levels were characterized by a moderate, non significant transient decrease for up to 15 minutes, followed by normalization at 60 minutes. Tryptophan metabolite ratios were moderately altered, suggesting activation of metabolism after SRT. Lowering of tryptophan would generally involve activation of tryptophan catabolism and neurotransmitter, protein, and bone biosynthesis. Lowering of kynurenic acid by SRT might be relevant for improving symptoms in patients with neuropsychiatric disorders, such as Parkinson's disease, Alzheimer's disease, schizophrenia, and depression, as well as certain pain conditions.
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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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Aarsland, Tore Ivar Malmei, Johanne Telnes Instanes, Maj-Britt Rocio Posserud, Arve Ulvik, Ute Kessler, and Jan Haavik. "Changes in Tryptophan-Kynurenine Metabolism in Patients with Depression Undergoing ECT—A Systematic Review." Pharmaceuticals 15, no. 11 (November 19, 2022): 1439. http://dx.doi.org/10.3390/ph15111439.
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The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a systematic review with aims of summarizing changes in Trp and/or kynurenines after ECT and assessing methodological issues. The inclusion criterium was measures of Trp and/or kynurenines before and after ECT. Animal studies and studies using Trp administration or Trp depletion were excluded. Embase, MEDLINE, PsycInfo and PubMed were searched, most recently in July 2022. Outcomes were levels of Trp, kynurenines and ratios before and after ECT. Data on factors affecting Trp metabolism and ECT were collected for interpretation and discussion of the reported changes. We included 17 studies with repeated measures for a total of 386 patients and 27 controls. Synthesis using vote counting based on the direction of effect found no evidence of effect of ECT on any outcome variable. There were considerable variations in design, patient characteristics and reported items. We suggest that future studies should include larger samples, assess important covariates and determine between- and within-subject variability. PROSPERO (CRD42020187003).
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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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Bhat, Abid, Ananda Staats Pires, Vanessa Tan, Saravana Babu Chidambaram, and Gilles J. Guillemin. "Effects of Sleep Deprivation on the Tryptophan Metabolism." International Journal of Tryptophan Research 13 (January 2020): 117864692097090. http://dx.doi.org/10.1177/1178646920970902.
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Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.
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Simonato, Manuela, Stefano Dall’Acqua, Caterina Zilli, Stefania Sut, Romano Tenconi, Nicoletta Gallo, Paolo Sfriso, et al. "Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome." Biomedicines 9, no. 11 (November 19, 2021): 1724. http://dx.doi.org/10.3390/biomedicines9111724.
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Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.
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Huhn, M., M. Herrero San Juan, B. Melcher, C. Dreis, K. Schmidt, J. M. Pfeilschifter, M. Vieth, J. Stein, and H. H. Radeke. "P110 Identification of the tryptophan metabolite 3-hydroxyanthranilic acid as a novel tool for the differentiation of Crohn’s disease phenotypes." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S190—S191. http://dx.doi.org/10.1093/ecco-jcc/jjz203.239.
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Abstract Background The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise question regarding the unclarified heterogeneity of disease pathomechanisms. While biomarkers for the differentiation of Crohn’s disease (CD) vs. ulcerative colitis (UC) have been suggested, specific markers for a subclassification of CD phenotypes are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterise potential biomarkers focusing on the downstream metabolites of kynurenine metabolism. The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise question regarding the unclarified heterogeneity of disease pathomechanisms. While biomarkers for the differentiation of Crohn’s disease (CD) vs. ulcerative colitis (UC) have been suggested, specific markers for a subclassification of CD phenotypes are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterise potential biomarkers focusing on the downstream metabolites of kynurenine metabolism. Methods Using immunohistochemical staining, we analysed and compared the mucosal tryptophan immune metabolism in biotic samples from patients with UC (n = 11), CD (n = 11) and healthy control (n = 12). Localisation-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. Results As expected, we found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T-cell markers in the ileum compared with the colon. In line with this finding, we identified kynureninase as a modulator of immunosuppressive kynurenine levels specifically in the ileum of patients with CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in CD ileum samples. Conclusion Highlighting the heterogeneity of the different phenotypes of CD, we identified 3-hydroxyanthranilic acid as a potential mucosal biomarker allowing the localisation-specific differentiation of ileum or colon inflammation in patients with CD. Moreover, we characterised the kynurenine-degrading enzyme kynureninase as a modulator of immunosuppression and chronic inflammation with potential therapeutic relevance.
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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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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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Dehhaghi, Mona, Hamed Kazemi Shariat Panahi, and Gilles J. Guillemin. "Microorganisms, Tryptophan Metabolism, and Kynurenine Pathway: A Complex Interconnected Loop Influencing Human Health Status." International Journal of Tryptophan Research 12 (January 2019): 117864691985299. http://dx.doi.org/10.1177/1178646919852996.
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The kynurenine pathway is important in cellular energy generation and limiting cellular ageing as it degrades about 90% of dietary tryptophan into the essential co-factor NAD+ (nicotinamide adenine dinucleotide). Prior to the production of NAD+, various intermediate compounds with neuroactivity (kynurenic acid, quinolinic acid) or antioxidant activity (3-hydroxykynurenine, picolinic acid) are synthesized. The kynurenine metabolites can participate in numerous neurodegenerative disorders (Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease) or other diseases such as AIDS, cancer, cardiovascular diseases, inflammation, and irritable bowel syndrome. Recently, the role of gut in affecting the emotional and cognitive centres of the brain has attracted a great deal of attention. In this review, we focus on the bidirectional communication between the gut and the brain, known as the gut-brain axis. The interaction of components of this axis, namely, the gut, its microbiota, and gut pathogens; tryptophan; the kynurenine pathway on tryptophan availability; the regulation of kynurenine metabolite concentration; and diversity and population of gut microbiota, has been considered.
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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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Castro-Portuguez, Raul, Jeremy Meyers, Sam Freitas, Hope Dang, Emily Turner, Destiny DeNicola, Luis Espejo, and George Sutphin. "Kynurenine Metabolism Lifespan Extension Mediated by Oxidative Stress Response and Hypoxic Response in C. elegans." Innovation in Aging 5, Supplement_1 (December 1, 2021): 679–80. http://dx.doi.org/10.1093/geroni/igab046.2557.
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Abstract Aging is characterized by a progressive decline in the normal physiological functions of an organism, ultimately leading to mortality. Metabolic changes throughout the aging process disrupt the balance and homeostasis of the cell. The kynurenine metabolic pathway is the sole de novo biosynthetic pathway for producing NAD+ from ingested tryptophan. Altered kynurenine pathway activity is associated with both aging and a variety of age-associated diseases, and kynurenine-based interventions can extend lifespan in Caenorhabditis elegans. Our laboratory recently demonstrated knockdown of the kynurenine pathway enzymes kynureninase (KYNU) or 3-hydroxyanthranilic acid dioxygenase (HAAO) increases lifespan by 20-30% in C elegans. However, the mechanism of how these interventions may modulate response against different stressors during the aging process has yet to be explored. Fluorescent reporter strains show the stress-responsive transcription factors skn-1 (ortholog of NRF2/NFE2L2; oxidative stress response) and hif-1 (ortholog of HIF1A; hypoxic stress response) to be highly upregulated when the kynurenine pathway is inhibited. We also demonstrated the increase expression of gst-4 and gcs-1 (transcriptional targets skn-1), which are involved in production of the antioxidant glutathione (GSH), as well as upregulation of cysl-2 (transcriptional target of hif-1), a regulator of cysteine biosynthesis from serine. We hypothesize that lifespan extension resulting from kynurenine pathway inhibition is mediated, at least in part, by upregulation of these transcription factors, providing elevated defense against oxidative stress and hypoxic stress.
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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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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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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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Navrotskaya, V. V., and Yu Yu Sapota. "Analysis of the role of kynurenine metabolism in drosophila viability control at the high sugar diet influence." Faktori eksperimental'noi evolucii organizmiv 26 (September 1, 2020): 72–76. http://dx.doi.org/10.7124/feeo.v26.1244.
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Aim. To analyze viability and life span of drosophila at genetic and pharmacological inhibition of tryptophan-kynurenine metabolism, when cultivating on the standard nutritive medium and at a high sugar diet. Methods. Wild type stock and the stock with vermilion mutation have been used. Viability (number of individuals, mortality at the pupal stage) and median life span of imagoes have been determined. Results. High sugar diet has been found to negatively affect the viability of drosophila, leading to increased mortality at the pupal stage and decrease of males’ life span; wild-type stock is less resistant to the influence of such diet as compared with mutant stock. Berberine (an inhibitor of tryptophan dioxygenase) when added to the high sugar nutritive medium reduces the negative effect of a high sugar diet on life span of the wild-type stock: males’ life span reaches control values and in females life span is even more than in the control. Conclusions. Decrease of kynurenines content in the flies organisms (both at the genetic and pharmacological inhibition of tryptophan-kynurenine metabolism) may attenuate negative influence of the high sugar diet.
Keywords: drosophila, viability, life span, kynurenine pathway of tryptophan metabolism, high sugar diet.
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Kanova, Marcela, and Pavel Kohout. "Tryptophan: A Unique Role in the Critically Ill." International Journal of Molecular Sciences 22, no. 21 (October 28, 2021): 11714. http://dx.doi.org/10.3390/ijms222111714.
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Tryptophan is an essential amino acid whose metabolites play key roles in diverse physiological processes. Due to low reserves in the body, especially under various catabolic conditions, tryptophan deficiency manifests itself rapidly, and both the serotonin and kynurenine pathways of metabolism are clinically significant in critically ill patients. In this review, we highlight these pathways as sources of serotonin and melatonin, which then regulate neurotransmission, influence circadian rhythm, cognitive functions, and the development of delirium. Kynurenines serve important signaling functions in inter-organ communication and modulate endogenous inflammation. Increased plasma kynurenine levels and kynurenine-tryptophan ratios are early indicators for the development of sepsis. They also influence the regulation of skeletal muscle mass and thereby the development of polyneuromyopathy in critically ill patients. The modulation of tryptophan metabolism could help prevent and treat age-related disease with low grade chronic inflammation as well as post intensive care syndrome in all its varied manifestations: cognitive decline (including delirium or dementia), physical impairment (catabolism, protein breakdown, loss of muscle mass and tone), and mental impairment (depression, anxiety or post-traumatic stress disorder).
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Rentschler, Katherine M., Annalisa M. Baratta, Audrey L. Ditty, Nathan T. J. Wagner, Courtney J. Wright, Snezana Milosavljevic, Jessica A. Mong, and Ana Pocivavsek. "Prenatal Kynurenine Elevation Elicits Sex-Dependent Changes in Sleep and Arousal During Adulthood: Implications for Psychotic Disorders." Schizophrenia Bulletin 47, no. 5 (April 5, 2021): 1320–30. http://dx.doi.org/10.1093/schbul/sbab029.
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Abstract Dysregulation of the kynurenine pathway (KP) of tryptophan catabolism has been implicated in psychotic disorders, including schizophrenia and bipolar disorder. Kynurenic acid (KYNA) is a KP metabolite synthesized by kynurenine aminotransferases (KATs) from its biological precursor kynurenine and acts as an endogenous antagonist of N-methyl-D-aspartate and α7-nicotinic acetylcholine receptors. Elevated KYNA levels found in postmortem brain tissue and cerebrospinal fluid of patients are hypothesized to play a key role in the etiology of cognitive symptoms observed in psychotic disorders. Sleep plays an important role in memory consolidation, and sleep disturbances are common among patients. Yet, little is known about the effect of altered KP metabolism on sleep–wake behavior. We presently utilized a well-established experimental paradigm of embryonic kynurenine (EKyn) exposure wherein pregnant dams are fed a diet laced with kynurenine the last week of gestation and hypothesized disrupted sleep–wake behavior in adult offspring. We examined sleep behavior in adult male and female offspring using electroencephalogram and electromyogram telemetry and determined sex differences in sleep and arousal in EKyn offspring. EKyn males displayed reduced rapid eye movement sleep, while female EKyn offspring were hyperaroused compared to controls. We determined that EKyn males maintain elevated brain KYNA levels, while KYNA levels were unchanged in EKyn females, yet the activity levels of KAT I and KAT II were reduced. Our findings indicate that elevated prenatal kynurenine exposure elicits sex-specific changes in sleep–wake behavior, arousal, and KP metabolism.
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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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Fellendorf, F., M. Platzer, A. Birner, R. Queissner, S. Bengesser, M. Lenger, A. Maget, et al. "Tryptophan metabolism in bipolar disorder." European Psychiatry 65, S1 (June 2022): S110. http://dx.doi.org/10.1192/j.eurpsy.2022.310.
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Introduction Immune mediated inflammatory processes are involved in the aetiopathogenesis of bipolar disorder (BD) and weight associated comorbidities. Tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) along the kynurenine axis concomitant with a pro-inflammatory state was found more active in BD but also associated with overweight/obesity. Objectives Aims of our study were to investigate 1.) the tryptophan metabolism in BD compared to mentally healthy controls, 2.) differences in weight classes, 3.) in a longitudinal setting, dependent on the incidence of BD episodes and euthymia. Methods At the Medical University Graz anthropometric and clinical data as well as peripheral tryptophan and kynurenine were assessed in serum samples of 226 individuals with BD and 142 controls. For 75 individuals with BD a longitudinal assessment with three samples was performed. Serum concentrations of tryptophan and kynurenine were determined by reverse-phase high-performance liquid chromatography. The kynurenine/tryptophan was used as a proxy for IDO-1 activity. Results showed a higher kynurenine/tryptophan ratio in BD compared to controls and in overweight compared to normal weight persons. Levels remained stable over time. In the longitudinal course, no differences were found between individuals who were constantly euthymic or not as well who had an illness episode or none. Conclusions Findings indicate that IDO-1 activity might constitute more a trait and not a state marker of BD. Accelerated tryptophan breakdown along the kynurenine axis may be further facilitated by overweight. This may increase the risk of accumulation of neurotoxic metabolites which impacts BD symptomatology, cognition, and somatic comorbidities. Disclosure No significant relationships.
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Noakes, Rowland R. "Effects of Tranilast on the Urinary Excretion of Kynurenic and Quinolinic Acid under Conditions of L Tryptophan Loading." International Journal of Tryptophan Research 6 (January 2013): IJTR.S12797. http://dx.doi.org/10.4137/ijtr.s12797.
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The pathogenesis of morphea and other cutaneous sclerosing disorders remain poorly understood. Although they are considered to be autoimmune disorders, abnormal tryptophan metabolism may be involved. Current therapy is directed to supressing the autoimmune response. Demonstration of a therapeutic response to manipulation of the kynurenine pathway would both support a role for abnormal tryptophan metabolism and offer additional targets for therapy. Tranilast is a 3-hydroxyanthranilic acid derivative known to target the kynurenine pathway. The aim of this study was to see if tranilast lowered the urinary excretion of the kynurenine metabolites kynurenic and quinolinic acid under condition of L tryptophan loading in a volunteer. Mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol/mol creatinine, respectively. This rose to 5.6 and 3.8 mmol/mol creatinine respectively under conditions of L tryptophan loading 2 grams daily. Adding 1 g of tranilast daily lowered the values to 2.0 and 2.9 mmol/mol creatinine, respectively. These data suggest that tranilast acts as a competitive inhibitor of either indoleamine 2, 3-dioxygenase (IDO), tryptophan 2, 3 di-oxygenase (TDO) or both. As it involved only 1 subject, the results may not be representative of the larger population and must be considered preliminary.
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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.
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Hestad, Knut, Jan Alexander, Helge Rootwelt, and Jan O. Aaseth. "The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases." Biomolecules 12, no. 7 (July 18, 2022): 998. http://dx.doi.org/10.3390/biom12070998.
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Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.
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Hartai, Z., P. Klivenyi, T. Janaky, B. Penke, L. Dux, and L. Vecsei. "Kynurenine metabolism in multiple sclerosis." Acta Neurologica Scandinavica 112, no. 2 (August 2005): 93–96. http://dx.doi.org/10.1111/j.1600-0404.2005.00442.x.
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Baran, H., K. Jellinger, and L. Deecke. "Kynurenine metabolism in Alzheimer's disease." Journal of Neural Transmission 106, no. 2 (March 17, 1999): 165–81. http://dx.doi.org/10.1007/s007020050149.
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Badawy, Abdulla A.-B., Sarah L. Lake, and Donald M. Dougherty. "Mechanisms of the Pellagragenic Effect of Leucine: Stimulation of Hepatic Tryptophan Oxidation by Administration of Branched-Chain Amino Acids to Healthy Human Volunteers and the Role of Plasma Free Tryptophan and Total Kynurenines." International Journal of Tryptophan Research 7 (January 2014): IJTR.S18231. http://dx.doi.org/10.4137/ijtr.s18231.
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The pellagragenic effect of leucine (Leu) has been proposed to involve modulation of L-tryptophan (Trp) metabolism along the hepatic kynurenine pathway. Here, we discuss some of the mechanisms suggested and report the effects in healthy volunteers of single doses of Leu (4.05–6.75 g) administered in a 16-amino acid mixture on concentrations of plasma Trp and its kynurenine metabolites. Flux of Trp through Trp 2,3-dioxygenase (TDO) is dose-dependently enhanced most probably by Leu and can be attributed to TDO activation. Trp oxidation is better expressed using plasma total kynurenines, rather than kynurenine, and free, rather than total, Trp. Increased hepatic Trp oxidation may be an additional mechanism of action of branched-chain amino acids in the acute Trp depletion test. Inhibition of intestinal absorption or hepatic uptake of Trp by Leu can be excluded. Potential mechanisms of the aggravation of pellagra symptoms by Leu are discussed.
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Chojnacki, Cezary, Tomasz Popławski, Jan Chojnacki, Michał Fila, Paulina Konrad, and Janusz Blasiak. "Tryptophan Intake and Metabolism in Older Adults with Mood Disorders." Nutrients 12, no. 10 (October 18, 2020): 3183. http://dx.doi.org/10.3390/nu12103183.
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The role of serotonin in the pathogenesis of depression is well-documented, while the involvement of other tryptophan (TRP) metabolites generated in the kynurenine pathway is less known. The aim of this study was to assess the intake and metabolism of TRP in elderly patients with mood disorders. Ninety subjects in three groups, 30 subjects each, were enrolled in this study: controls (healthy young adults, group I) and elderly individuals without (group II) or with (group III) symptoms of mild and moderate depression, as assessed by the Hamilton Depression Rating Scale (HAM-D) and further referred to as mood disorders. The average TRP intake was evaluated with the nutrition calculator. Urinary levels of TRP, 5-hydroxyindoleacetic acid (5-HIAA), L-kynurenine (KYN), kynurenic acid (KynA), xanthurenic acid (XA), and quinolinic acid (QA) were determined by liquid chromatography with tandem mass spectrometry and related to creatinine level. The average daily intake of TRP was significantly lower in group III than the remaining two groups, but group III was also characterized by higher urinary levels of KYN, KynA, XA, and QA as compared with younger adult individuals and elderly patients without mood disorders. Therefore, mild and moderate depression in the elderly may be associated with a lower intake of TRP and changes in its kynurenine metabolic pathway, which suggests a potential dietary TRP-based intervention in this group of patients.
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Kiluk, Małgorzata, Janina Lewkowicz, Dariusz Pawlak, and Anna Tankiewicz-Kwedlo. "Crosstalk between Tryptophan Metabolism via Kynurenine Pathway and Carbohydrate Metabolism in the Context of Cardio-Metabolic Risk—Review." Journal of Clinical Medicine 10, no. 11 (June 4, 2021): 2484. http://dx.doi.org/10.3390/jcm10112484.
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Scientific interest in tryptophan metabolism via the kynurenine pathway (KP) has increased in the last decades. Describing its metabolites helped to increase their roles in many diseases and disturbances, many of a pro-inflammatory nature. It has become increasingly evident that KP can be considered an important part of emerging mediators of diabetes mellitus and metabolic syndrome (MS), mostly stemming from chronic systemic low-grade inflammation resulting in the aggravation of cardiovascular complications. An electronic literature search of PubMed and Embase up to March 2021 was performed for papers reporting the effects of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), anthranilic acid (AA), and quinolinic acid (QA), focusing on their roles in carbohydrate metabolism and the cardiovascular system. In this review, we discussed the progress in tryptophan metabolism via KP research, focusing particular attention on the roles in carbohydrate metabolism and its complications in the cardiovascular system. We examined the association between KP and diabetes mellitus type 2 (T2D), diabetes mellitus type 1 (T1D), and cardiovascular diseases (CVD). We concluded that tryptophan metabolism via KP serves as a potential diagnostic tool in assessing cardiometabolic risk for patients with T2D.
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Vecchiarelli, Haley A., Chaitanya P. Gandhi, and Matthew N. Hill. "Acute Psychological Stress Modulates the Expression of Enzymes Involved in the Kynurenine Pathway throughout Corticolimbic Circuits in Adult Male Rats." Neural Plasticity 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/7215684.
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Tryptophan is an essential dietary amino acid that is necessary for protein synthesis, but also serves as the precursor for serotonin. However, in addition to these biological functions, tryptophan also serves as a precursor for the kynurenine pathway, which has neurotoxic (quinolinic acid) and neuroprotective (kynurenic acid) metabolites. Glucocorticoid hormones and inflammatory mediators, both of which are increased by stress, have been shown to bias tryptophan along the kynurenine pathway and away from serotonin synthesis; however, to date, there is no published data regarding the effects of stress on enzymes regulating the kynurenine pathway in a regional manner throughout the brain. Herein, we examined the effects of an acute psychological stress (120 min restraint) on gene expression patterns of enzymes along the kynurenine pathway over a protracted time-course (1–24 h post-stress termination) within the amygdala, hippocampus, hypothalamus, and medial prefrontal cortex. Time-dependent changes in differential enzymes along the kynurenine metabolism pathway, particularly those involved in the production of quinolinic acid, were found within the amygdala, hypothalamus, and medial prefrontal cortex, with no changes seen in the hippocampus. These regional differences acutely may provide mechanistic insight into processes that become dysregulated chronically in stress-associated disorders.
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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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Tanaka, Bohár, and Vécsei. "Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism." Molecules 25, no. 3 (January 28, 2020): 564. http://dx.doi.org/10.3390/molecules25030564.
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Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer’s disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.
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Naz, Bhat, Ståhl, Forsslund, Sköld, Wheelock, and Wheelock. "Dysregulation of the Tryptophan Pathway Evidences Gender Differences in COPD." Metabolites 9, no. 10 (October 1, 2019): 212. http://dx.doi.org/10.3390/metabo9100212.
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Increased activity of indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase (TPH) have been reported in individuals with chronic obstructive pulmonary disease (COPD). We therefore investigated the effect of gender stratification upon the observed levels of tryptophan metabolites in COPD. Tryptophan, serotonin, kynurenine, and kynurenic acid were quantified in serum of never-smokers (n = 39), smokers (n = 40), COPD smokers (n = 27), and COPD ex-smokers (n = 11) by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). The individual metabolite associations with lung function, blood, and bronchoalveolar lavage (BAL) immune-cell composition, as well as chemokine and cytokine levels, were investigated. Stratification by gender and smoking status revealed that the observed alterations in kynurenine and kynurenic acid, and to a lesser extent serotonin, were prominent in males, irrespective of COPD status (kynurenine p = 0.005, kynurenic acid p = 0.009, and serotonin p = 0.02). Inferred serum IDO activity and kynurenine levels decreased in smokers relative to never-smokers (p = 0.005 and p = 0.004, respectively). In contrast, inferred tryptophan hydroxylase (TPH) activity and serotonin levels showed an increase with smoking that reached significance with COPD (p = 0.01 and p = 0.01, respectively). Serum IDO activity correlated with blood CXC chemokine ligand 9 (CXCL9, p = 0.0009, r = 0.93) and chemokine (C-C motif) ligand 4 (CCL4.(p = 0.04, r = 0.73) in female COPD smokers. Conversely, serum serotonin levels correlated with BAL CD4+ T-cells (%) (p = 0.001, r = 0.92) and CD8+ T-cells (%) (p = 0.002, r = −0.90) in female COPD smokers, but not in male COPD smokers (p = 0.1, r = 0.46 and p = 0.1, r = −0.50, respectively). IDO- and TPH-mediated tryptophan metabolites showed gender-based associations in COPD, which were primarily driven by smoking status.
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Sutphin, George, Hope Dang, Luis Espejo, Raul Castro-Portuguez, Bradford Hull, Jeremy Meyers, Emily Turner, and Destiny DeNicola. "Targeting kynurenine metabolism to reduce inflammation and enhance stress response during aging." Innovation in Aging 5, Supplement_1 (December 1, 2021): 682. http://dx.doi.org/10.1093/geroni/igab046.2565.
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Abstract Aberrant kynurenine pathway metabolism is increasingly linked to aging and age-associated disease. Kynurenine metabolic activity increases with age and becomes dysregulated during various forms of age-associated pathology in humans. By manipulating one or more kynurenine pathway enzymes and metabolites, we have extended lifespan up to 40% in Caenorhabditis elegans. In particular, elevating physiological levels of the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) by directly supplementing 3HAA or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends C. elegans lifespan by ~30%. 3HAA delivered chronically in chow similarly extends lifespan in aged C57BL/6 mice. In ongoing work, we are investigating the mechanisms underlying the benefits of multiple kynurenine pathway interventions using tools in C. elegans, mice, and human cell culture. We have preliminary evidence for activation of broad-spectrum cellular stress response, enhanced immune function, and reduced inflammation. Among other roles, the kynurenine pathway is the sole metabolic route for de novo synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan in Eukaryotic cells. We are examining the regulatory interaction between kynurenine metabolism and the two NAD+ recycling pathways, Salvage and Preiss-Handler, both as potential mechanistic mediators and as possible parallel targets for combined interventions with synergistic benefits in aging. We are further evaluating the impact of these interventions in several models of specific age-associated diseases, including sepsis, chronic inflammation, stroke, Alzheimer’s disease, and cancer. Finally, we are developing pharmaceutical strategies to replicate key genetic and metabolic interventions within the kynurenine pathway that can be readily translated into clinical applications.
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Hartai, Zsuzsanna, Peter Klivenyi, Tamas Janaky, Botond Penke, Laszlo Dux, and Laszlo Vecsei. "Peripheral Kynurenine Metabolism in Focal Dystonia." Medicinal Chemistry 3, no. 3 (May 1, 2007): 285–88. http://dx.doi.org/10.2174/157340607780620707.
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REINHARD, J. F. "Pharmacological Manipulation of Brain Kynurenine Metabolism." Annals of the New York Academy of Sciences 1035, no. 1 (December 1, 2004): 335–49. http://dx.doi.org/10.1196/annals.1332.020.
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Kolodziej, Lukasz R., Ewa M. Paleolog, and Richard O. Williams. "Kynurenine metabolism in health and disease." Amino Acids 41, no. 5 (October 23, 2010): 1173–83. http://dx.doi.org/10.1007/s00726-010-0787-9.
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Braidy, Nady, and Ross Grant. "Kynurenine pathway metabolism and neuroinflammatory disease." Neural Regeneration Research 12, no. 1 (2017): 39. http://dx.doi.org/10.4103/1673-5374.198971.
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Fellendorf, Frederike T., Johanna M. Gostner, Melanie Lenger, Martina Platzer, Armin Birner, Alexander Maget, Robert Queissner, et al. "Tryptophan Metabolism in Bipolar Disorder in a Longitudinal Setting." Antioxidants 10, no. 11 (November 10, 2021): 1795. http://dx.doi.org/10.3390/antiox10111795.
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Immune-mediated inflammatory processes and oxidative stress are involved in the aetiopathogenesis of bipolar disorder (BD) and weight-associated comorbidities. Tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) along the kynurenine axis concomitant with a pro-inflammatory state was found to be more active in BD, and associated with overweight/obesity. This study aimed to investigate tryptophan metabolism in BD compared to controls (C), stratified by weight classes, in a longitudinal setting, dependent on the incidence of BD episodes. Peripheral tryptophan, kynurenine, and neopterin were assessed in the serum of 226 BD individuals and 142 C. Three samples in a longitudinal assessment were used for 75 BD individuals. Results showed a higher kynurenine/tryptophan in both BD compared to C and overweight compared to normal weight persons. Levels remained stable over time. In the longitudinal course, no differences were found between individuals who were constantly euthymic or not, or who had an illness episode or had none. Findings indicate that tryptophan, kynurenine, and IDO-1 activity may play a role in pathophysiology in BD but are not necessarily associated with clinical manifestations. Accelerated tryptophan breakdown along the kynurenine axis may be facilitated by being overweight. This may increase the risk of accumulation of neurotoxic metabolites, impacting BD symptomatology, cognition, and somatic comorbidities.