Academic literature on the topic 'Kynurenine - Metabolism'
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Journal articles on the topic "Kynurenine - Metabolism"
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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.
Dissertations / Theses on the topic "Kynurenine - Metabolism"
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Owe-Young, Robert School of Medicine UNSW. "Kynurenine pathway metabolism at the blood-brain barrier." Awarded by:University of New South Wales. School of Medicine, 2006. http://handle.unsw.edu.au/1959.4/26183.
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A major product of HIV-infected and cytokine-stimulated monocytic-lineage cells is quinolinic acid (QUIN), a neurotoxic metabolite of the kynurenine pathway (KP) of L-tryptophan (L-Trp) metabolism. Despite the large number of neurotoxins found in HIV patients with AIDS Dementia Complex (ADC), only QUIN correlates with both the presence and severity of ADC. With treatment, cerebrospinal fluid (CSF) QUIN concentrations decrease proportionate to the degree of clinical and neuropsychological improvement. As endothelial cells (EC) of the blood-brain barrier (BBB) are the first brain-associated cell that a bloodborne pathogen would encounter, this project examined the BBB response to KP metabolites, as these are implicated in damage of the CNS associated with ADC. Using RT-PCR and HPLC/gas chromatographymass spectrometry (GC-MS), I found that cultured primary human BBB EC and pericytes constitutively expressed the KP. EC synthesised kynurenic acid (KA) constitutively, and after immune activation, kynurenine (KYN). Pericytes produced small amounts of picolinic acid and after immune activation, KYN. An SV40-transformed BBB EC showed no KP expression. By contrast, human umbilical vein EC only expressed low levels of KA after immune activation, however human dermal microvascular EC showed a similar constitutive and inducible KP to that in BBB EC. As T cells are central to primary HIV infection, I also examined KP expression in two CD4+ and one CD4- cell lines, but none showed either constitutive or inducible KP expression. I next examined how QUIN might interact with BBB EC. There was no binding of 3H-QUIN to cultured primary human BBB EC, however a biologically relevant concentration of QUIN induced changes in gene expression which adversely affected EC function, possibly mediated by lipid peroxidation and oxidative stress. The upregulated genes were of the heat shock protein family, and the downregulated genes were associated with regulation of cell adhesion, tight junction and cytoskeletal stability, metalloproteinase (MMP) regulation, apoptosis and G protein signaling. Immunofluorescence showed that QUIN induced morphological changes in BBB EC consistent with the changes in gene expression. Gelatin zymography showed that this was not mediated by MMPs, as constitutive MMP expression was unchanged. These data provide strong evidence for QUIN directly damaging the BBB in the context of HIV infection.
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Skouras, Christos. "Kynurenine metabolism and organ dysfunction in human acute pancreatitis." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28898.
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BACKGROUND: Acute pancreatitis (AP) is a sterile initiator of systemic inflammation that can trigger multiple organ dysfunction syndrome (MODS). In the acute phase of AP, the kynurenine pathway of tryptophan metabolism plays an important role in the genesis of AP-MODS in experimental animal models, but it is unknown whether the pathway is activated in human AP. Human data are required to support the rationale for kynurenine 3- monooxygenase (KMO) inhibition as a treatment for AP-MODS and reinforce the translational potential. Additionally, as respiratory dysfunction is frequent in severe AP, the role of lung ultrasonography in severity stratification deserves investigation. Furthermore, the effect of AP-MODS on long-term survival is unknown. OBJECTIVES: My objectives were to: 1) Define the temporal and quantitative relationship of kynurenine metabolites with the onset and severity of APMODS, 2) Investigate the value of lung ultrasonography in the early diagnosis of respiratory dysfunction in human AP-MODS, and 3) Examine whether early AP-MODS impacts on long-term survival. METHODS: 1) A prospective, observational, clinical experimental medicine study titled “Inflammation, Metabolism, and Organ Failure in Acute Pancreatitis” (IMOFAP) was performed. For 90 days, consecutive patients with a potential diagnosis of AP were recruited and venous blood was sampled at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. Kynurenine metabolite concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and analysed in the context of clinical data, disease severity indices, and cytokine profiles. 2) In a nested cohort within IMOFAP, 41 participants underwent lung ultrasonography to evaluate whether this imaging modality can detect respiratory dysfunction in AP. 3) Survival data for a prospectively maintained database of patients with AP was analysed after accounting for in-hospital deaths. RESULTS: 1) During the IMOFAP study, 79 patients were recruited with an elevated serum amylase, of which 57 patients met the diagnostic criteria for AP; 9 had severe disease. Temporal profiling revealed early tryptophan depletion and contemporaneous elevation of plasma concentrations of 3- hydroxykynurenine, which paralleled systemic inflammation and AP severity. 2) Lung ultrasonography findings correlated with respiratory dysfunction. 3) 694 patients were followed up for a median of 8.8 years. AP-MODS conferred a deleterious effect on overall survival which persisted after the exclusion of inhospital deaths (10.0 years, 95% C.I. = 9.4-10.6 years) compared to AP without MODS (11.6 years, 95% C.I. = 11.2-11.9 years; P = 0.001). This effect was independent of age. CONCLUSIONS: In the acute phase of AP, metabolic flux through KMO is elevated and proportionate to AP severity. Lung ultrasonography may be a useful technique for evaluating AP-MODS. AP-MODS is an independent predictor of long-term mortality. Together, this work reinforces the rationale for investigating early phase KMO inhibition as a therapeutic strategy in humans.
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Milne, Gavin D. S. "Inhibition studies of kynurenine 3-monooxygenase." Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/4101.
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Kynurenine 3-monooxygenase (K3MO) lies on the kynurenine pathway, the major pathway for the catabolism of L-tryptophan. It converts kynurenine to 3-hydroxy kynurenine. Inhibition of K3MO is important in several neurological diseases and there is evidence that inhibition of K3MO could also be targeted for the prevention of multiple organ failure, secondary to acute pancreatitis. A structure activity relationship based upon the 1,2,4-oxadiazoles motif was carried out which revealed amide 207 as an inhibitor of P. fluorescens K3MO. Further structure activity relationships were developed based upon 207. This revealed 3,4-dichloro substitution in 235 and 245 as optimum for inhibition. Co-crystalisation of these inhibitors with P. fluorescens K3MO revealed their interactions with the enzyme. It also highlighted new, potential interactions between the inhibitors and K3MO. This led to the synthesis of 271 and 272, which were also potent inhibitors of K3MO. These amides were successfully co-crystalised with P. fluorescens K3MO. Further development of the amides followed, with amide 282 providing the most potent inhibitor of P. fluorescens K3MO to date (Kᵢ = 29.1 nM).
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Pisar, Mazura Md. "The role of kynurenine metabolism in the development of the central nervous system." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5550/.
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Prenatal exposure to maternal infection has been thought as a major risk factor for neurodevelopmental brain damage and thus contributes to the pathophysiology of neurodegenerative diseases including schizophrenia and autism. The mechanisms of aberrant neurodevelopmental processes on the offspring, in which primary cerebral insults occur during early brain development, are not fully understood. In the present investigation, maternal infection was modelled in timed-pregnant rats at embryonic day (E) 14, 16 and 18 by administering intraperitoneal injections of polyriboinosinic-polyribocytidilic acid,poly(I:C), a viral mimetic double stranded RNA complex which activates Toll-Like-Receptor-3 (TLR-3). The aim was to examine the impact of maternal inflammatory response on the regulation of expression of neurodevelopmental proteins that play important roles in many neurodevelopment aspects, including maintenance of synaptic plasticity, intracellular signalling and neurogenesis which may be relevant in cognitive and behavioural functions. An examination of embryo brains 5 h after maternal poly(I:C) showed significant differences in expression of the NMDA receptor NR2 subunits. The expression of NR2A subunits was reduced, whereas infection induced during pregnancy enhanced NR2B subunit expression. Expression levels of both subunits at postnatal day 21 (P21) were not affected by prenatal poly(I:C) exposure. In utero viral challenge led to significant changes among neurogenesis factor only at P21. In the fetal brain, acute poly(I:C) exposure had no effect on the expression of SHH, PCNA and also SOX2 proteins. However, when poly(I:C) was administered during mid and late gestation in the rodent model, long term effects of prenatal viral challenge on survival and maintenance of cell in the brain as indicated by the expression of SOX2 and SHH was clearly demonstrable. Expression of SOX2 level was increased,while SHH was significantly decreased, suggesting possible increase in the number of cells and changes in the rate of differentiation, respectively. The results demonstrate that poly(I:C) challenge in pregnant dams results in selective molecular changes in the brain, with transient alteration in the levels of NMDA receptor subunit NR2A and NR2B in the foetal brain, and also affecting molecules associated with cell genesis processes at later stages of developmental age of offspring. On the other hand, recent pharmacological interest in kynurenines with respect to CNS diseases has mainly focussed on two neuroactive molecules: quinolinic acid (QUIN) and kynurenic acid (KYNA). Manipulation of the kynurenine pathway and its neuroactive metabolites has been associated with N-methyl-D-aspartate (NMDA) receptor neurotoxicity and dysfunction which linked to the development of various neurological disorders. An early developmental event has been proposed to precipitate alterations in the NMDA receptor function. In this respect, early development during the gestational period of rats is most suitable for investigating the modulating effect of kynurenine pathway inhibition by compound Ro61-8048 (3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphomide) an inhibitor of kynurenine-3-monooxygenase (KMO) in shifting the balance towards the production of neuroprotective, kynurenic acid. Western blots were generated to indicate the expression of a range of proteins relevant to different aspects of CNS development including neuritogenesis, axon guidance, maintenance of synaptic plasticity, intracellular signalling and cell proliferation and migration. Within 5 h of Ro61-8048, there was a significant decrease in NR2A expression and increased NR2B in the embryo brains, with subsequent changes in SHH and NFB at 24 h post treatment. The litters were left undisturbed until weaning on P21 and other groups were allowed to develop to P60, at which time they euthanized and the brains removed for analysis. At P21, western blot analysis revealed significantly increased protein expression of the NR2A and NR2B subunits and postsynaptic density protein (PSD95). Among several neurodevelopmental proteins, the expression of NFB and proliferating cell nuclear antigen (PCNA) was increased, while reduced level of SHH was detected. We demonstrate here persisting changes in NR2A expression, with reduced level in the hippocampus while a raised level was noted in the cortex suggesting prenatal modulation of kynurenine pathway causes long lasting modifications of NMDA receptor composition and function. It is important to note that kynurenine pathway inhibition can generate a consistent set of long term changes in the SHH in which the levels of this protein remained repressed in some regional areas of the brain including hippocampus, cerebellum and cortex. We show that there are some common pathways that are affected by kynurenine pathway inhibition, and this early modulation tends to disrupt critical molecular processes that are known to be actively occurring at each specific developmental time. Overall, given these selective and differing developmental profile, an early life modulation of the kynurenine pathway might be expected to cause a sufficient disturbance of biological processes that are actively occurring at the time of exposure and also able to leave a series of molecular changes that persist into adulthood. This disruption is likely to influence the resulting physiology of the adolescent and adult brain and subsequently can lead to impairments in social behaviour. It is hoped that this study provides a broad analysis of the long term molecular effects of developmental kynurenine metabolism, and that it allows for a viable opportunity of potential therapeutic targets for disease intervention.
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Marchi, Alexandre Froes. "Produção de quinurenina em modelos experimentais de restrição de sono e obesidade." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9141/tde-03062015-165904/.
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A via das Quinureninas (Via Quin) representa a principal via catabólica do metabolismo do triptofano (Trp) e é essencial para diversos processos fisiológicos. No fígado, o Trp é catalisado por triptofano 2,3-dioxigenase (TDO) quinurenina (Quin). A mesma reação também pode ser catalisada pela enzima indolamina 2,3-dioxigenase (IDO), produzida por células imunológicas. Em alguns processos patológicos, há um aumento do consumo de Trp pela Via Quin, que gera compostos que estão relacionados ao processo de imunotolerância. No presente estudo, foram selecionados dois modelos que mimetizam situações associadas às alterações da resposta imunológica: a restrição de sono e a obesidade. A partir do conhecimento das alterações na resposta imune nessas condições, geramos a hipótese de que parte do mecanismo se dê a partir da indução do catabolismo de Trp pela via Quin. Desse modo, foram investigadas as concentrações séricas e hepáticas de Trp nesses modelos experimentais, modelos esses que foram utilizados em outros projetos do nosso grupo de pesquisa. Não houve diferença significativa na concentração de Quin sérica e hepática entre os camundongos C57BL/6J restritos de sono (3 hs/15 dias), privação de sono paradoxal (72 hs) e período rebote (24 hs). A razão Quin/Trp também não diferiu entre os grupos RS e controle. Igualmente não houve diferenças estatísticas na concentração de Quin plasmática nos modelos privação de sono paradoxal e período rebote realizados em ratos Wistar. O mesmo foi observado em camundongos Swiss e camundongos C57BL/6J submetidos a protocolos experimentais de obesidade: ração hiperlipídica (21 dias) e de síndrome metabólica (20 semanas de ração hiperlipídica). Tais resultados sugerem que as alterações na resposta imunológica nesses quadros não estão associadas ao catabolismo de Trp.The Kynurenine pathway (Kyn pathway) is the major catabolic pathway of tryptophan metabolism (Trp) and it is essential for many physiological processes. In the liver, Trp is catalyzed by tryptophan 2,3-dioxygenase (TDO), producing kynurenine (Kyn). The same reaction can also be catalyzed by the enzyme indoleamine 2,3-dioxygenase (IDO), produced by immune cells. In some pathological conditions, there is a high Trp consumption by Kyn pathway, that generate compounds related to immune tolerance. In this study, we chose two models strongly associated with changes in the immune response: sleep restriction and obesity. From the knowledge that there are immune response alterations in those conditions, we generated the hypotesis that in part, those alterations are correlated with induction the Trp catabolism by Kyn pathway. Thus, serum and liver concentrations of Trp and Kyn were investigated in these experimental models that have been used in other projects of our research group. There was no significant difference in concentration of Kyn in serum and liver among mice C57BL/6J induced to restricted sleep (3 hours / 15 days), paradoxical sleep deprivation (72 hours) and rebound period (24 hours). The Kyn/Trp ratio did not differ between control group and RS group. Also there were no statistical differences in plasma concentration of Kyn in paradoxical sleep deprivation and rebound period models performed in rats Wistar. The same profile was also observed in Swiss e C57BL/6J mice subjected to experimental obesity protocols: fat diet (21 days) and metabolic syndrome (20 weeks of fat diet). These results suggest that changes in the immune response in the conditions tested above are not associated with Trp catabolism.
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Yan, Edwin B., Tony Frugier, Chai K. Lim, Benjamin Heng, Gayathri Sundaram, May Tan, Jeffrey V. Rosenfeld, David W. Walker, Gilles J. Guillemin, and Maria C. Morganti-Kossmann. "Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans." BioMed Central, 2015. http://hdl.handle.net/10150/610324.
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ABSTRACT: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. METHODS: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.
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Jonker, Anneliene. "Synthetic Lethality and Metabolism in Ewing Sarcoma : Knowledge Through Silence." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T039/document.
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Le sarcome de Ewing est la seconde tumeur pédiatrique de l’os la plus fréquente. Elle est caractérisée par une translocation chromosomique résultant à la fusion de EWSR1 avec un membre de la famille ETS. Chez 85% des patients, cette fusion conduit à l’expression de la protéine chimérique EWS-FLI1 qui est l’oncogène majeur de ce sarcome. Ce dernier agit principalement par son action transcriptionelle sur des cibles qui lui sont propres. Au niveau thérapeutique, le sarcome d’Ewing est traité par chimiothérapie, chirurgie locale et par radiothérapie. La survie à long terme des patients est de l’ordre de 70%, mais beaucoup plus basse pour les patients métastatiques et quasi nulle lors d’une récidive. Parmi maintes caractéristiques, certains cancers présentent une dérégulation énergétique. L’influence d’EWS-FLI1 sur cet aspect n’a fait l’objet d’aucune étude dans le contexte du sarcome d’Ewing. Nous avons donc étudié par profilage métabolomique des cellules de sarcome d’Ewing en présence ou en absence d’EWS-FLI1. En comparant ces deux conditions, des modulations du profil énergétique relatif au cycle de Krebs, des précurseurs de le glycosylation ainsi que des métabolites de la voie de la méthionine et du tryptophane ont été observés. En parallèle, grâce à un crible de banque de shRNAs réalisé dans des conditions expérimentales similaires à l’étude métabolomique (lignée d’Ewing avec ou sans EWS-FLI1), nous avons pu identifier des gènes présentant des caractéristiques « synthétique létales », c'est-à-dire tuant uniquement les cellules du sarcome d’Ewing en présence de son oncogèneEwing sarcoma, the second most commonly occurring pediatric bone tumor, is most often characterized by a chromosomal translocation between EWSR1 and FLI1. The gene fusion EWS-FLI1 accounts for 85% of all Ewing sarcoma and is considered the major oncogene and master regulator of Ewing sarcoma. EWS-FLI1 is a transcriptional modulator of targets, both directly and indirectly. Ewing sarcoma is aggressively treated with chemotherapy, localized surgery and radiation and has an overall survival of about 70%, however, survival for metastasis or relapsed cases remains low. One of the cancer hallmarks, metabolic deregulation, is most likely partly dependent on EWS-FLI1 in Ewing sarcoma cells. In order to get a better understanding of Ewing sarcoma biology and oncogenesis, it might be of high interest to investigate the influence of EWS-FLI1 in Ewing sarcoma cells. We therefore performed a global metabolic profiling of Ewing sarcoma cells with or without inhibition of EWS-FLI1. Several changes in the energy metabolism were observed throughout this study; the observed changes were consistent with an energy profile that moved from a cancer cell energy metabolism towards the energy metabolism of a more normal cell upon EWS-FLI1 inhibition, primarily based on the TCA cycle. Levels of TCA intermediates, glycosylation precursors, methionine pathway metabolites and amino acids, especially changes in the tryptophan metabolic pathway, were altered upon EWS-FLI1 inhibition. Parallel to this study, we performed a high-throughput synthetic lethality screen, in order to not only identify essential genes for cell survival and proliferation, but also to identify new synthetic lethal targets that could specifically target Ewing sarcoma cells carrying the EWS-FLI1 fusion gene
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Vallius, Laura I. "Modulating the immune system by amino acid depletion : IDO and beyond." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:eb1a1987-4121-4042-be82-2aafb67c9941.
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Amino acid availability plays an important role in modulating the activity of T-cells. One of the pathways employed by T-cells to sense nutrient levels is the “mammalian target of rapamycin” (mTOR) pathway that is inhibited in response to nutrient depletion. Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme along the tryptophan catabolising kynurenine pathway. T-cells are very sensitive to lack of this essential amino acid in their microenvironment and this confers strong immunomodulatory properties to cells expressing active IDO. It therefore has a significant physiological role as a homeostatic mechanism used in mammalian organisms to dampen excessive activation of the immune system but is also used as an immune evasion mechanism by many cancers. In this study, we investigated the IDO inhibitory properties and mechanism of action of the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) that potentially forms a negative feedback loop in the kynurenine pathway. We studied the molecule in enzymatic assays, in live cells and discovered that it inhibits IDO in an indirect way via the formation of hydrogen peroxide. Secondly, we looked at the effects of tryptophan and its metabolites on T-cell proliferation and mTOR activity, and discovered a metabolite that inhibits T-cell proliferation. Lastly we examined mechanisms of T-cell suppression employed by myeloid derived suppressor cells (MDSCs), focusing on their ability to deplete amino acids from their microenvironment. We were able to exclude tryptophan consumption as a suppressive mechanism and established that by manipulating extracellular concentrations of several amino acids other than arginine and cysteine – that are known to be utilised by MDSCs - we were able to reduce their inhibitory properties. In summary, we have described in detail how 3-HAA inhibits IDO in in vitro assays, outlined how some tryptophan metabolites can inhibit T-cell proliferation, and clarified aspects of suppressive mechanism employed by MDSCs.
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Mizdrak, Jasminka. "Human lens chemistry: UV filters and age-related nuclear cataract." Australia : Macquarie University, 2007. http://hdl.handle.net/1959.14/16855.
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"A thesis submitted in partial fulfillment of the requirements for the award of the degree of Doctor of Philosophy".Thesis (PhD) -- Macquarie University, Division of Environmental and Life Sciences, Dept. of Chemistry and Biomolecular Sciences, 2007.
Bibliography: p. 243-277.
Introduction -- A convenient synthesis of 30HKG -- Facile synthesis of the UV filter compounds 30HKyn and AHBG -- Synthesis, identification and quantification of novel human lens metabolites -- Modification of bovine lens protein with UV filters and related metabolites -- Effect of UV light on UV filter-treated lens proteins -- Conclusions and future directions.
The kynurenine-based UV filters are unstable under physiological conditions and undergo side chain deamination, resulting in α,β-unsaturated carbonyl compounds. These compounds can react with free or protein bound nucleophiles in the lens via Michael addition. The key sites of the UV filters kynurenine (Kyn) and 3-hydroxykynurenine (3OHKyn) modification in human lenses include cysteine (Cys), and to a lesser extent, lysine (Lys) and histidine (His) residues. Recent in vivo studies have revealed that 3-hydroxykynurenine-O-β-D-glucoside (3OHKG) binds to Cys residues of lens crystallins in older normal human lenses. As a result of this binding, human lens proteins become progressively modified by UV filters in an age-dependent manner, contributing to changes that occur with the development of age-related nuclear (ARN) cataract. Upon exposure to UV light, free UV filters are poor photosensitisers, however the role of protein-bound species is less clear. It has been recently demonstrated that Kyn, when bound to lens proteins, becomes more susceptible to photo-oxidation by UV light. Therefore, the investigation of 3OHKG binding to lens proteins, and the effect of UV light on proteins modified with 3OHKG and 3OHKyn, were major aims of this study. As a result of the role of these compounds as UV filters and their possible involvement in ARN cataract formation, it is crucial to understand the nature, concentration and modes of action of the UV filters and their metabolites present in the human lenses. Therefore, an additional aim was to investigate human lenses for the presence of novel kynurenine-based human lens metabolites and examine their reactivity.--As 3OHKG is not commercially available, to conduct protein binding studies, an initial aim of this study was to synthesise 3OHKG (Chapter 2). Through the expansion and optimisation of a literature procedure, 3OHKG was successfully synthesised using commercially available and inexpensive reagents, and applying green chemistry principles, where toxic and corrosive reagents were replaced with benign reagents and solvent-free and microwave chemistry was used. A detailed investigation of different reaction conditions was also conducted, resulting in either the improvement of reaction yields or reaction time compared to the literature method. Applying the same synthetic strategy, and using key precursors from the synthesis of 3OHKG, the UV filters 3OHKyn and 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid-O-β-D-glucoside (AHBG), were also successfully synthesised (Chapter 3).
Chapter 4 describes the investigation of both normal and cataractous human lenses in an attempt to identify novel human lens metabolites derived from deaminated Kyn and 3OHKyn (Chapter 4, Part A). Initially, 4-(2-aminophenyl)-4-oxobutanoic acid (AHA), glutathionyl-kynurenine (GSH-Kyn), kynurenine yellow (Kyn yellow), 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid (AHB), glutathionyl-3-hydroxykynurenine (GSH-3OHKyn) and 3-hydroxykynurenine yellow (3OHKyn yellow) were synthesised and human lenses were examined for their presence. AHA and AHB were synthesised from similar precursors to those used in the synthesis of 3OHKG, while the GSH adducts and yellow compounds were synthesised from Kyn and 3OHKyn via base induced deamination. Following isolation and structural elucidation, AHA, AHB and GSH-Kyn were confirmed as novel human lens metabolites. They were quantified in low pmol/mg lens (dry mass) levels in normal and cataractous lenses of all ages, while GSH-3OHKyn, Kyn yellow and 3OHKyn yellow were not detected. In contrast to AHA, the lens metabolites AHB, GSH-Kyn and GSH-3OHKyn were found to be unstable at physiological pH. The spectral properties of these compounds suggest that they may act as UV filters. --Chapter 4 (Part B) also describes the identification and characterisation of a novel human lens UV filter, cysteinyl-3-hydroxykynurenine -O-β-D-glucoside (Cys-3OHKG). An authentic standard was synthesised via Michael addition of cysteine to deaminated 3OHKG. Cys-3OHKG was detected in low pmol/mg lens (dry mass) levels in normal lenses only after the 5th decade of life and was absent in cataractous lenses. Cys-3OHKG showed rapid decomposition at physiological pH.
Chapter 5 describes the identification and quantification of amino acids involved in covalent binding of 3OHKG to lens proteins. Model studies with bovine lens proteins and 3OHKG at pH 7.2 and 9.5 were undertaken. The amino acid adducts were identified via total synthesis and spectral analysis, and subsequently quantified upon acid hydrolysis of the modified lens proteins. Under both pH conditions, 3OHKG was found to react with lens proteins predominantly via Cys residues with low levels of binding also detected at Lys residues. Comparative studies with Kyn (pH 9.5) and 3OHKyn (pH 7.2 and 9.5) resulted in modified lens proteins at Cys residues, with only minor modification at Lys residues at pH 9.5. The extent of modification was found to be significantly higher at pH 9.5 in all cases. His adducts were not identified. 3OHKG-, Kyn- and 3OHKyn-modified lens proteins were found to be coloured and fluorescent, resembling those of aged and ARN cataractous lenses. In contrast, AHB and AHA, which can not form α,β-unsaturated carbonyl compounds, resulted in non-covalent modification of lens proteins. AHB may contribute to lens colouration and fluorescence as further reactions of this material yielded species that have similar characteristics to those identified from 3OHKyn modification. These species are postulated to arise via auto-oxidation of the o-aminophenol moiety present in both 3OHKyn and AHB.--In Chapter 6, the potential roles of 3OHKG and 3OHKyn, and the related species AHA and AHB, in generating reactive oxygen species and protein damage following illumination with UV light was examined. The UV filter compounds were examined in both their free and protein-bound forms. Kyn-modified proteins were used as a positive control. Exposure of these compounds to UV light (λ 305-385 nm) has been shown to generate H2O2 and protein-bound peroxides in a time-dependent manner, with shorter wavelengths generating more peroxides. The yields of peroxides were observed to be highly dependent on the nature of the UV filter compound and whether these species were free or protein bound, with much higher levels being detected with the bound species. Thus, protein-bound 3OHKyn yielded higher levels of peroxide than 3OHKG, with these levels, in turn, higher than for the free UV filter compounds. AHB-treated lens proteins resulted in formation of low but statistically significant levels of peroxides, while AHA-treated lens proteins resulted in insignificant peroxide formation. The consequences of these photochemical reactions have been examined by quantifying protein-bound tyrosine oxidation products (3,4-dihydroxyphenylalanine [DOPA], di-tyrosine [di-Tyr]) and protein cross-linking. 3OHKG-modified proteins gave elevated levels of di-Tyr, but not DOPA, whereas 3OHKyn-modified protein gave the inverse. DOPA formation was observed to be independent of illumination and most likely arose via o-aminophenol auto-oxidation. AHB- and AHA-treated lens proteins resulted in statistically insignificant di-Tyr formation, while a light independent increase in DOPA was observed for both samples. Both reducible (disulfide) and non-reducible cross-links were detected in modified proteins following illumination. These linkages were present at lower levels in modified, but non-illuminated proteins, and absent from unmodified protein samples.
This work has provided an optimised synthetic procedure for 3OHKG and other lens metabolites (Chapters 2 and 3). Four novel lens metabolites have been identified and quantified in normal and cataractous human lenses (Chapter 4). Subsequent experiments, described in Chapter 5, identified the major covalent binding sites of 3OHKG to lens proteins, while AHA and AHB showed non-covalent binding. Further work described in Chapter 6 showed that protein-bound 3OHKG, Kyn and 3OHKyn were better photosensitisers of oxidative damage than in their unbound state. Together, this research has provided strong evidence that post-translational modifications of lens proteins by kynurenine-based metabolites and their interaction with UV light appear, at least in part, responsible for the age-dependent colouration of human lenses and an elevated level of oxidative stress in older lenses. These processes may contribute to the progression of ARN cataract.
Mode of access: World Wide Web.
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Boulet-Le, Gouar Lysiane. "Etude de la voie catabolique du tryptophane dans différentes conditions pathologiques : exemple de la phénylcétonurie et perspectives dans les maladies cardiovasculaires Is tryptophan metabolism involved in sleep apnea-relatedcardiovascular co-morbidities and cancer progression? Neuropathology of Kynurenine Pathway of Tryptophan Metabolism Simultaneous determination of tryptophan and 8 metabolites in humanplasma by liquid chromatography/tandem mass spectrometry." Thesis, Université Grenoble Alpes, 2020. http://www.theses.fr/2020GRALV040.
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Le métabolisme du tryptophane (Trp) a été investigué dans différentes pathologies, incluant les maladies cardiovasculaires, la cancérologie et les maladies neurodégénératives. Le Trp, acide aminé essentiel, est catabolisé en périphérie et au niveau central selon 2 voies : celle des kynurénines, quantitativement majoritaire et impliquée dans les cardiopathies et la tolérance immune, et celle de la sérotonine, connue pour son implication dans la dépression et le sommeil. Dans le cadre de ce travail, nous nous sommes intéressés à l’implication de cette voie métabolique dans la phénylcétonurie (PCU) et les maladies cardiovasculaires.Dans la première partie de ce travail, nous avons mis au point une technique analytique de dosage de 9 métabolites de la voie du Trp, incluant ses 2 voies cataboliques. La méthode proposée, en HPLC-MS/MS, est fiable, reproductible, peu coûteuse, avec un processus pré-analytique simple et une durée d’analyse de 15 min. Ses critères sont conformes aux exigences du laboratoire selon les recommandations de la norme NF EN ISO 15189.Dans la deuxième partie, nous nous sommes intéressés au métabolisme du Trp dans la phénylcétonurie (PCU ; OMIM 261600). Cette maladie, due à un déficit de la phénylalanine hydroxylase hépatique (PAH ; EC 1.14.16.1), entraine une accumulation de phénylalanine (Phe) associée à un déficit en tyrosine. Cette pathologie, causant principalement un profond retard mental (QI < 50), est traitable grâce à l’instauration le plus précocement possible d’un régime restreint en Phe.Plusieurs éléments rapprochent le métabolisme du Trp de celui de la Phe, que ce soient les transporteurs, cofacteurs et enzyme chaperone communs, ou les inhibitions de l’une des voies par des métabolites de l’autre voie. De plus, certains adultes atteints de PCU présentent des dysfonctions neuropsychologiques inexpliquées par leur concentration de Phe sanguine, ce qui pourrait être dû à des modifications de la voie métabolique du Trp, plusieurs kynurénines possédant des propriétés neuroactives.Nous avons mis en évidence une modification du métabolisme du Trp dans une population phénylcétonurique adulte française (n=151 patients), avec en particulier une diminution des concentrations sanguines de kynurénine (KYN) et d’acide 3-hydroxykynurénique (3HK) par rapport à notre population de référence (p-value < 0.0001), ces résultats étant modulés par le type de régime suivi.La troisième partie de notre travail a consisté en l’évaluation du métabolisme du Trp dans le contexte des maladies cardiovasculaires. La prévention de ces pathologies est un enjeu de santé publique majeur, et se base sur la maitrise des facteurs de risque, dont le syndrome d’apnées obstructives du sommeil (SAOS) qui touche 6 à 17% des adultes à travers le monde. Ce syndrome se caractérise par un collapsus pharyngé partiel ou total, une fragmentation du sommeil et une augmentation des efforts respiratoires et donc des séquences d’hypoxie – réoxygénations (hypoxie intermittente) responsables d’une inflammation de bas grade. Plusieurs études explorant les maladies cardiovasculaires et le métabolisme du Trp ont été publiées récemment, mais très peu apportaient un lien mécanistique. Nous présentons ici les prochaines études cliniques et pré-cliniques que nous souhaitons mener dans ce domaine, afin de caractériser les modifications du métabolisme du Trp dans le SAOS traité ou non, mais également lors de l’hypoxie intermittente (modèle animal du SAOS) ou lors d’un réentrainement à l’effort.Il est à présent évident que la voie métabolique du Trp est impliquée dans différentes conditions pathologiques. Nous avons mis en évidence lors de ce travail ses modifications dans la PCU. L’impact physiopathologique des modifications observées reste cependant à explorer dans de nombreuses pathologiesTryptophan (Trp) metabolism was investigated in various pathology, including cardiovascular diseases, cancerology and neurodegenerative diseases. Trp, an essential aminoacid, is catabolized into two major pathways: kynurenine (KYN) pathway represents 98% of Trp catabolism and is involved in cardiopathy and immune tolerance, as serotonin (5HT) pathway is implicated in depression and sleep. In this work, we have studied Trp pathway in phenylketonuria (PKU) and cardiovascular diseases.Firstly, we developed a simple method for quantification of Trp and 8 of its metabolites, involved in both KYN and 5HT pathways, using liquid chromatography coupled to tandem mass spectrometry. This method, with a quick chromatographic runtime (15 min) and simple sample preparation, has been validated according to NF EN ISO 15189 criteria.Secondly, we explored Trp metabolism in phenylketonuria (OMIM 261600), a pathology caused by deficiency of phenylalanine hydroxylase enzyme (EC 1.14.16.1), that catalyses hydroxylation of phenylalanine (Phe) to tyrosine. Early low-Phe diet treatment, results in the prevention of severe mental retardation (IQ < 50) seen in untreated PKU patients.Many similarities between Trp and Phe metabolisms exist: transporters, cofactor and chaperone enzyme, and inhibition of one pathway by metabolites of the other pathway. As some of these metabolites have neuroactive properties, they should be considered in neurological impairment seen in this pathology and not totally explained by blood Phe concentrations.We assessed here a change of Trp metabolism in 151 adult PKU patients, with diminution of plasmatic concentrations of KYN and 3-hydroxykynurenic acid (3HK) in PKU patients compared to general population (P < .0001). These modifications were modified by diet type.In third line, we evaluated Trp metabolism in cardiovascular diseases. Prevention of these diseases representes a serious public health issue, based on diminution of co-morbidities like obstructive sleep apnoea (OSA). This syndrome affects 6-17% of adults worldwide, and is characterized by complete or partial pharyngeal collapse, sleep fragmentation and increased respiratory efforts, resulting in intermittent hypoxia and low-grade inflammation. Recent studies have explored Trp metabolism in cardiovascular diseases, but mainly in epidemiologic studies. We highlighted here clinical and preclinical studies that we will conducted in this field, in the way to characterized Trp modification in treated or untreated OSA, intermittent hypoxia (animal model of OSA) and exercise training.Trp metabolism is clearly involved in various pathological conditions. In this work, we have highlighted its modification in PKU. Physiopathological impact of these modifications have to been explored in various pathologies
Books on the topic "Kynurenine - Metabolism"
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Robert, Schwarcz, Young Simon N, and Brown Raymond R, eds. Kynurenine and serotonin pathways: Progress in tryptophan research. New York: Plenum Press, 1991.
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Lázló, Vécsei, ed. Kynurenines in the brain: From experiments to clinics. Hauppauge, NY: Nova Science Publishers, 2005.
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Mirza, Sarwarbeg. The hepatic and the peripheral metabolism of tryptophan via the kynurenine pathway in children with biliary atresiaand with orthotopic liver transplant: The assessment of the relationship between the levels of the kynurenine metabolites, neopterin, biopterin and liver function tests. [Guildford]: University of Surrey, 1995.
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Mittal, Sandeep. Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, 2016.
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Mittal, Sandeep. Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, 2015.
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Mittal, Sandeep. Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, 2015.
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Schwarcz, Robert, Simon N. Young, and Raymond R. Brown. Kynurenine and Serotonin Pathways: Progress in Tryptophan Research. Springer, 2012.
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Schwarcz, Robert, Simon N. Young, and Raymond R. Brown. Kynurenine and Serotonin Pathways: Progress in Tryptophan Research. Springer London, Limited, 2013.
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(Editor), Robert Schwarcz, Simon N. Young (Editor), and Raymond R. Brown (Editor), eds. Kynurenine and Serotonin Pathways (Advances in Experimental Medicine and Biology). Springer, 1991.
Find full textBook chapters on the topic "Kynurenine - Metabolism"
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Rudzite, V., and E. Jurika. "Kynurenine and Lipid Metabolism." In Advances in Experimental Medicine and Biology, 463–66. Boston, MA: Springer New York, 1991. http://dx.doi.org/10.1007/978-1-4684-5952-4_45.
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Shibata, Katsumi. "Nutritional Aspects of Tryptophan Metabolism." In Targeting the Broadly Pathogenic Kynurenine Pathway, 31–43. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-11870-3_3.
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Guillemin, Gilles J., Stephen J. Kerr, George A. Smythe, Patricia J. Armati, and Bruce J. Brew. "Kynurenine Pathway Metabolism in Human Astrocytes." In Advances in Experimental Medicine and Biology, 125–31. Boston, MA: Springer US, 1999. http://dx.doi.org/10.1007/978-1-4615-4709-9_18.
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Juhász, Csaba, and Sandeep Mittal. "Molecular Imaging of Tryptophan Metabolism in Tumors." In Targeting the Broadly Pathogenic Kynurenine Pathway, 373–89. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-11870-3_28.
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Lim, Chai K., and Gilles J. Guillemin. "The Next Decade in Tryptophan Metabolism Research." In Targeting the Broadly Pathogenic Kynurenine Pathway, 419–25. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-11870-3_31.
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Michelhaugh, Sharon K., Anthony R. Guastella, and Sandeep Mittal. "Overview of the Kynurenine Pathway of Tryptophan Metabolism." In Targeting the Broadly Pathogenic Kynurenine Pathway, 3–9. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-11870-3_1.
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Frédérick, Raphaël. "Inhibition of the Kynurenine Pathway of Tryptophan Metabolism." In Targeting the Broadly Pathogenic Kynurenine Pathway, 393–406. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-11870-3_29.
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Rudzite, V., G. Sileniece, D. Liepina, A. Dalmane, and R. Zirne. "Impairment of Kynurenine Metabolism in Cardiovascular Disease." In Advances in Experimental Medicine and Biology, 663–67. Boston, MA: Springer New York, 1991. http://dx.doi.org/10.1007/978-1-4684-5952-4_89.
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Gostner, Johanna M., Kathrin Becker, Barbara Sperner-Unterweger, Florian Überall, Dietmar Fuchs, and Barbara Strasser. "Role of Tryptophan Metabolism in Mood, Behavior, and Cognition." In Targeting the Broadly Pathogenic Kynurenine Pathway, 75–89. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-11870-3_6.
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Badawy, Abdulla A. B. "Tryptophan Metabolism and the Hepatic Kynurenine Pathway in Health and Disease." In Targeting the Broadly Pathogenic Kynurenine Pathway, 11–30. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-11870-3_2.
Full textConference papers on the topic "Kynurenine - Metabolism"
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Gosker, Harry R., Gerard Clarke, John F. Cryan, and Annemie M. Schols. "Impaired skeletal muscle kynurenine metabolism in patients with COPD." In ERS International Congress 2018 abstracts. European Respiratory Society, 2018. http://dx.doi.org/10.1183/13993003.congress-2018.pa940.
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Castro-Portuguez, Raul, Samuel Freitas, and George L. Sutphin. "Abstract LB-241: Kynurenine metabolism as a biomarker and therapeutic target in hepatocellular carcinoma (HCC)." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-lb-241.
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Coma, Silvia, Jill Cavanaugh, James Nolan, Jeremy Tchaicha, Karen McGovern, Everett Stone, Candice Lamb, et al. "Abstract 3757: Targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-3757.
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Subramanian, Chitra, Thekkelnaycke M. Rajendiran, Tanu Soni, and Mark S. Cohen. "Abstract 5481: Targeting the kynurenine pathway as a novel metabolic treatment for head and neck cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5481.
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Zhang, Michelle, Everett Stone, Todd A. Triplett, Kendra Triplett, Candice Lamb, Christos S. Karamitros, John Blazek, George Georgiou, and Mark G. Manfredi. "Abstract 5570: A novel approach to targeting the IDO/TDO pathway through degradation of the immunosuppressive metabolite kynurenine." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-5570.
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