The Experts below are selected from a list of 10284 Experts worldwide ranked by ideXlab platform
Dietmar Fuchs - One of the best experts on this subject based on the ideXlab platform.
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Tryptophan Metabolism and related pathways in psychoneuroimmunology the impact of nutrition and lifestyle
Neuropsychobiology, 2020Co-Authors: Johanna M Gostner, Simon Geisler, Marlies Stonig, Lisa Mair, Barbara Spernerunterweger, Dietmar FuchsAbstract:In the past, accelerated Tryptophan breakdown was considered to be a feature of clinical conditions, such as infection, inflammation, and malignant disease. More recently, however, the focus has changed to include the additional modulation of Tryptophan Metabolism by changes in nutrition and microbiota composition. The regulation of Tryptophan concentration is critical for the maintenance of systemic homeostasis because it integrates essential pathways involved in nutrient sensing, metabolic stress response, and immunity. In addition to Tryptophan being important as a precursor for the synthesis of the neurotransmitter serotonin, several catabolites along the kynurenine axis are neuroactive. This emphasizes the importance of the immunometabolic fate of this amino acid for processes relevant to neuropsychiatric symptoms. In humans, besides hepatic catabolism, there is usually a strong relationship between immune activation-associated Tryptophan breakdown and increased levels of biomarkers, such as neopterin, which has particular relevance for both acute and chronic diseases. A shift towards neopterin synthesis during oxidative stress may indicate a corresponding decrease in tetrahydrobiopterin, a cofactor of several mono-oxygenases, providing a further link between Tryptophan Metabolism and serotonergic and catecholaminergic neurotransmission. The psychoneuroimmunological consequences of Tryptophan Metabolism and the susceptibility of this pathway to modulation by a variety of nutritional and lifestyle-related factors have important implications for the development of both diagnostic and treatment options.
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Tryptophan Metabolism and its relationship with central nervous system toxicity in people living with hiv switching from efavirenz to dolutegravir
Journal of NeuroVirology, 2019Co-Authors: Dietmar Fuchs, Michael R Keegan, Alan Winston, Chris Higgs, Adriano Boasso, Mark T NelsonAbstract:The mechanisms underlying central nervous system (CNS) toxicities in antiretroviral-treated persons living with HIV (PLWH) remain elusive. We investigated the associations between markers of Tryptophan Metabolism and measurements of CNS toxicity in PLWH. In a prospective study, virologically suppressed PLWH receiving efavirenz-containing antiretroviral regimens with ongoing CNS toxicity were switched to dolutegravir-containing regimens and followed up for 12 weeks. Plasma Tryptophan and kynurenine concentrations and the kynurenine/Tryptophan ratio were calculated. Ten CNS toxicities were graded according to the ACTG adverse events scale. Scores ranged from 0 (none) to 3 (severe) and were summed, giving a total from 0 to 30. Paired-samples t tests and linear mixed model analyses were conducted to assess changes in, and relationships between, laboratory and clinical parameters. Mean kynurenine plasma concentration increased from baseline to week 12 (2.15 to 2.50 μmol/L, p = 0.041). No significant changes were observed for Tryptophan (54.74 to 56.42 μmol/L, p = 1.000) or kynurenine/Tryptophan ratio (40.37 to 41.08 μmol/L, p = 0.276). Mean CNS toxicity score decreased from 10.00 to 4.63 (p < 0.001). Plasma kynurenine concentration correlated with CNS toxicity score: for every 1 μmol/L increase in kynurenine concentration observed, a 1.7 point decrease was observed in CNS toxicity score (p < 0.038). A similar trend was observed for the kynurenine/Tryptophan ratio: for every 1 μmol/mmol increase observed in kynurenine/Tryptophan ratio, a 0.1 point decrease was observed in CNS toxicity score (p = 0.054). Switching from efavirenz to dolutegravir was associated with increases in plasma kynurenine concentration and improvements in CNS toxicity scores. Underlying mechanisms explaining the rise in kynurenine concentrations need to be established.
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Tryptophan Metabolism in allergic disorders
International Archives of Allergy and Immunology, 2016Co-Authors: Johanna M Gostner, K Becker, Heinz Kofler, Barbara Strasser, Dietmar FuchsAbstract:Allergic diseases such as asthma and rhinitis, as well the early phase of atopic dermatitis, are characterized by a Th2-skewed immune environment. Th2-type cytokines are upregulated in allergic inflammation, whereas there is downregulation of the Th1-type immune response and related cytokines, such as interferon-x03B3; (IFN-x03B3;). The latter is a strong inducer of indoleamine 2,3-dioxygenase-1 (IDO-1), which degrades the essential amino acid Tryptophan, as part of an antiproliferative strategy of immunocompetent cells to halt the growth of infected and malignant cells, and also of T cells - an immunoregulatory intervention to avoid overactivation of the immune system. Raised serum Tryptophan concentrations have been reported in patients with pollen allergy compared to healthy blood donors. Moreover, higher baseline Tryptophan concentrations have been associated with a poor response to specific immunotherapy. It has been shown that the increase in Tryptophan concentrations in patients with pollen allergy only exists outside the pollen season, and not during the season. Interestingly, there is only a minor alteration of the kynurenine to Tryptophan ratio (Kyn/Trp, an index of Tryptophan breakdown). The reason for the higher Tryptophan concentrations in patients with pollen allergy outside the season remains a matter of discussion. To this regard, the specific interaction of nitric oxide (NO∙) with the Tryptophan-degrading enzyme IDO-1 could be important, because an enhanced formation of NO∙ has been reported in patients with asthma and allergic rhinitis. Importantly, NO∙ suppresses the activity of the heme enzyme IDO-1, which could explain the higher Tryptophan levels. Thus, inhibitors of inducible NO∙ synthase should be reconsidered as candidates for antiallergic therapy out of season that may abrogate the arrest of IDO-1 by decreasing the production of NO∙. Considering its association with the pathophysiology of atopic disease, Tryptophan Metabolism may play a relevant role in the pathophysiology of allergic disorders.
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disturbed Tryptophan Metabolism in cardiovascular disease
Current Medicinal Chemistry, 2014Co-Authors: Harald Mangge, Ingeborg Stelzer, Eva Z Reininghaus, Daniel Weghuber, Teodor T Postolache, Dietmar FuchsAbstract:Atherosclerosis (AS), a major pathologic consequence of obesity, is the main etiological factor of cardiovascular disease (CVD), which is the most common cause of death in the western world. A systemic chronic low grade immune- mediated inflammation (scLGI) is substantially implicated in AS and its consequences. In particular, proinflammatory cytokines play a major role, with Th1-type cytokine interferon-γ (IFN-γ) being a key mediator. Among various other molecular and cellular effects, IFN-γ activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, dendritic, and other cells, which, in turn, decreases serum levels of the essential amino acid Tryptophan (TRP). Thus, people with CVD often have increased serum kynurenine to Tryptophan ratios (KYN/TRP), a result of an increased TRP breakdown. Importantly, increased KYN/TRP is associated with a higher likelihood of fatal cardiovascular events. A scLGI with increased production of the proinflammatory adipokine leptin, in combination with IFN-γ and interleukin-6 (IL-6), represents another central link between obesity, AS, and CVD. Leptin has also been shown to contribute to Th1-type immunity shifting, with abdominal fat being thus a direct contributor to KYN/TRP ratio. However, TRP is not only an important source for protein production but also for the generation of one of the most important neurotransmitters, 5-hydroxytryptamine (serotonin), by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. In prolonged states of scLGI, availability of free serum TRP is strongly diminished, affecting serotonin synthesis, particularly in the brain. Additionally, accumulation of neurotoxic KYN metabolites such as quinolinic acid produced by microglia, can contribute to the development of depression via NMDA glutamatergic stimulation. Depression had been reported to be associated with CVD endpoints, but it most likely represents only a secondary loop connecting excess adipose tissue, scLGI and cardiovascular morbidity and mortality. Accelerated catabolism of TRP is further involved in the pathogenesis of the anemia of scLGI. The pro-inflammatory cytokine IFN-γ suppresses growth and differentiation of erythroid progenitor cells, and the depletion of TRP limits protein synthesis and thus hemoglobin production, and, through reduction in oxygen supply, may contribute to ischemic vascular disease. In this review we discuss the impact of TRP breakdown and the related complex mechanisms on the prognosis and individual course of CVD. Measurement of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio will contribute to a better understanding of the interplay between inflammation, metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorable outcome in patients with CVD. The review leads to a novel framework for successful therapeutic modification of several cardinal pathophysiological processes leading to adverse cardiovascular outcome.
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monitoring Tryptophan Metabolism in chronic immune activation
Clinica Chimica Acta, 2006Co-Authors: Katharina Schrocksnadel, Barbara Wirleitner, Christiana Winkler, Dietmar FuchsAbstract:The essential amino acid Tryptophan is a constituent of proteins and is also a substrate for two important biosynthetic pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by Tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides. The latter pathway is initiated by the enzymes Tryptophan pyrrolase (Tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). TDO is located in liver cells, whereas IDO is expressed in a variety of cells including monocyte-derived macrophages and dendritic cells and is preferentially induced by Th1-type cytokine interferon-gamma. Tryptophan depletion via IDO is part of the cytostatic and antiproliferative activity mediated by interferon-gamma in cells. In vivo Tryptophan concentration can be measured by HPLC by monitoring its natural fluorescence (285 nm excitation and 365 nm emission wavelength). IDO activity is characterized best by the kynurenine to Tryptophan ratio which correlates with concentrations of immune activation markers such as neopterin. Low serum/plasma Tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated Tryptophan conversion. Thus, in states of persistent immune activation, low Tryptophan concentration may contribute to immunodeficiency. Decreased serum Tryptophan can also effect serotonin biosynthesis and thus contribute to impaired quality of life and depressive mood. As such, monitoring Tryptophan Metabolism in chronic immunopathology provides a better understanding of the association between immune activation and IDO and its role in the development of immunodeficiency, anemia and mood disorders.
Stephane Burtey - One of the best experts on this subject based on the ideXlab platform.
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the aryl hydrocarbon receptor activating effect of uremic toxins from Tryptophan Metabolism a new concept to understand cardiovascular complications of chronic kidney disease
Toxins, 2014Co-Authors: Marion Sallee, Laetitia Dou, Claire Cerini, Stephane Poitevin, Philippe Brunet, Stephane BurteyAbstract:Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from Tryptophan Metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from Tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from Tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a “dioxin-like” effect.
Yingyong Zhao - One of the best experts on this subject based on the ideXlab platform.
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gut microbiota derived Tryptophan Metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation
Cellular and Molecular Life Sciences, 2021Co-Authors: Jingru Liu, Hua Miao, Deqiang Deng, Nosratola D Vaziri, Yingyong ZhaoAbstract:The gut microbiota has a crucial effect on regulating the intestinal mucosal immunity and maintaining intestinal homeostasis both in health and in disease state. Many effects are mediated by gut microbiota-derived metabolites and Tryptophan, an essential aromatic amino acid, is considered important among many metabolites in the crosstalk between gut microbiota and the host. Kynurenine, serotonin, and indole derivatives are derived from the three major Tryptophan Metabolism pathways modulated by gut microbiota directly or indirectly. Aryl hydrocarbon receptor (AHR) is a cytoplasmic ligand-activated transcription factor involved in multiple cellular processes. Tryptophan metabolites as ligands can activate AHR signaling in various diseases such as inflammation, oxidative stress injury, cancer, aging-related diseases, cardiovascular diseases (CVD), and chronic kidney diseases (CKD). Accumulated uremic toxins in the body fluids of CKD patients activate AHR and affect disease progression. In this review, we will elucidate the relationship between gut microbiota-derived uremic toxins by Tryptophan Metabolism and AHR activation in CKD and its complications. This review will provide therapeutic avenues for targeting CKD and concurrently present challenges and opportunities for designing new therapeutic strategies against renal fibrosis.
John F Cryan - One of the best experts on this subject based on the ideXlab platform.
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serotonin Tryptophan Metabolism and the brain gut microbiome axis
Behavioural Brain Research, 2015Co-Authors: Siobhain M Omahony, Gerard Clarke, Yuliya E Borre, Timothy G Dinan, John F CryanAbstract:The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on Tryptophan Metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host Tryptophan Metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.
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a distinct profile of Tryptophan Metabolism along the kynurenine pathway downstream of toll like receptor activation in irritable bowel syndrome
Frontiers in Pharmacology, 2012Co-Authors: Gerard Clarke, John F Cryan, Declan P Mckernan, Gabor Gaszner, Eamonn Martin Quigley, Timothy G DinanAbstract:Irritable bowel syndrome (IBS), a disorder of the brain-gut axis, is characterised by the absence of reliable biological markers. Tryptophan is an essential amino acid that serves as a precursor to serotonin but which can alternatively be metabolised along the kynurenine pathway leading to the production of other neuroactive agents. We previously reported an increased degradation of Tryptophan along this immunoresponsive pathway in IBS. Recently, altered cytokine production following activation of specific members of the toll-like receptor (TLR) family (TLR1-9) has also been demonstrated in IBS. However, the relationship between TLR activation and kynurenine pathway activity in IBS is unknown. In this study, we investigated whether activation of specific TLRs elicits exaggerated kynurenine production in IBS patients compared to controls. Whole blood from IBS patients and healthy controls was cultured with a panel of nine different TLR agonists for 24 hours. Cell culture supernatants were then analysed for both Tryptophan and kynurenine concentrations, as were plasma samples from both cohorts. IBS subjects had an elevated plasma kynurenine:Tryptophan ratio compared to healthy controls. Furthermore, we demonstrated a differential downstream profile of kynurenine production subsequent to TLR activation in IBS patients compared to healthy controls. This profile included alterations at TLR1/2, TLR2, TLR3, TLR5, TLR7 and TLR8. Our data expands on our previous understanding of altered Tryptophan Metabolism in IBS and suggests that measurement of Tryptophan metabolites downstream of TLR activation may ultimately find utility as components of a biomarker panel to aid gastroenterologists in the diagnosis of IBS. Furthermore, these studies implicate the modulation of TLRs as means through which aberrant Tryptophan Metabolism along the kynurenine pathway can be controlled, a novel potential therapeutic strategy in this and other disorders.
Marion Sallee - One of the best experts on this subject based on the ideXlab platform.
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the aryl hydrocarbon receptor activating effect of uremic toxins from Tryptophan Metabolism a new concept to understand cardiovascular complications of chronic kidney disease
Toxins, 2014Co-Authors: Marion Sallee, Laetitia Dou, Claire Cerini, Stephane Poitevin, Philippe Brunet, Stephane BurteyAbstract:Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from Tryptophan Metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from Tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from Tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a “dioxin-like” effect.
