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International Journal of Molecular... Sep 2022In recent decades, neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar, etc., have become a global health concern, causing various... (Review)
Review
In recent decades, neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar, etc., have become a global health concern, causing various detrimental influences on patients. Tryptophan is an important amino acid that plays an indisputable role in several physiological processes, including neuronal function and immunity. Tryptophan's metabolism process in the human body occurs using different pathways, including the kynurenine and serotonin pathways. Furthermore, other biologically active components, such as serotonin, melatonin, and niacin, are by-products of Tryptophan pathways. Current evidence suggests that a functional imbalance in the synthesis of Tryptophan metabolites causes the appearance of pathophysiologic mechanisms that leads to various neuropsychiatric diseases. This review summarizes the pharmacological influences of tryptophan and its metabolites on the development of neuropsychiatric disorders. In addition, tryptophan and its metabolites quantification following the neurotransmitters precursor are highlighted. Eventually, the efficiency of various biomarkers such as inflammatory, protein, electrophysiological, genetic, and proteomic biomarkers in the diagnosis/treatment of neuropsychiatric disorders was discussed to understand the biomarker application in the detection/treatment of various diseases.
Topics: Depressive Disorder, Major; Humans; Kynurenine; Proteomics; Serotonin; Tryptophan
PubMed: 36077360
DOI: 10.3390/ijms23179968 -
International Journal of Molecular... May 2022Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...].
Tryptophan is a rate-limiting essential amino acid and a unique building block of peptides and proteins [...].
Topics: Amino Acids, Essential; Nutritional Status; Peptides; Tryptophan
PubMed: 35628285
DOI: 10.3390/ijms23105455 -
Journal of Translational Medicine Apr 2023Lactobacillus has been demonstrated to serve a protective role in intestinal injury. However, the relationship between Lactobacillus murinus (L. murinus)-derived...
BACKGROUND
Lactobacillus has been demonstrated to serve a protective role in intestinal injury. However, the relationship between Lactobacillus murinus (L. murinus)-derived tryptophan metabolites and intestinal ischemia/reperfusion (I/R) injury yet to be investigated. This study aimed to evaluate the role of L. murinus-derived tryptophan metabolites in intestinal I/R injury and the underlying molecular mechanism.
METHODS
Liquid chromatograph mass spectrometry analysis was used to measure the fecal content of tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. Immunofluorescence, quantitative RT-PCR, Western blot, and ELISA were performed to explore the inflammation protective mechanism of tryptophan metabolites in WT and Nrf2-deficient mice undergoing intestinal I/R, hypoxia-reoxygenation (H/R) induced intestinal organoids.
RESULTS
By comparing the fecal contents of three L. murinus-derived tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. We found that the high abundance of indole-3-lactic acid (ILA) in the preoperative feces was associated with better postoperative intestinal function, as evidenced by the correlation of fecal metabolites with postoperative gastrointestinal function, serum I-FABP and D-Lactate levels. Furthermore, ILA administration improved epithelial cell damage, accelerated the proliferation of intestinal stem cells, and alleviated the oxidative stress of epithelial cells. Mechanistically, ILA improved the expression of Yes Associated Protein (YAP) and Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) after intestinal I/R. The YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of ILA, both in vivo and in vitro. Additionally, we found that ILA failed to protect epithelial cells from oxidative stress in Nrf2 knockout mice under I/R injury.
CONCLUSIONS
The content of tryptophan metabolite ILA in the preoperative feces of patients is negatively correlated with intestinal function damage under CPB surgery. Administration of ILA alleviates intestinal I/R injury via the regulation of YAP and Nrf2. This study revealed a novel therapeutic metabolite and promising candidate targets for intestinal I/R injury treatment.
Topics: Mice; Animals; NF-E2-Related Factor 2; Tryptophan; Reperfusion Injury; Oxidative Stress; Microbiota; Ischemia
PubMed: 37072757
DOI: 10.1186/s12967-023-04109-3 -
Journal of Separation Science Aug 2017The kynurenine pathway generates multiple tryptophan metabolites called collectively kynurenines and leads to formation of the enzyme cofactor nicotinamide adenine... (Review)
Review
The kynurenine pathway generates multiple tryptophan metabolites called collectively kynurenines and leads to formation of the enzyme cofactor nicotinamide adenine dinucleotide. The first step in this pathway is tryptophan degradation, initiated by the rate-limiting enzymes indoleamine 2,3-dioxygenase, or tryptophan 2,3-dioxygenase, depending on the tissue. The balanced kynurenine metabolism, which has been a subject of multiple studies in last decades, plays an important role in several physiological and pathological conditions such as infections, autoimmunity, neurological disorders, cancer, cataracts, as well as pregnancy. Understanding the regulation of tryptophan depletion provide novel diagnostic and treatment opportunities, however it requires reliable methods for quantification of kynurenines in biological samples with complex composition (body fluids, tissues, or cells). Trace concentrations, interference of sample components, and instability of some tryptophan metabolites need to be addressed using analytical methods. The novel separation approaches and optimized extraction protocols help to overcome difficulties in analyzing kynurenines within the complex tissue material. Recent developments in chromatography coupled with mass spectrometry provide new opportunity for quantification of tryptophan and its degradation products in various biological samples. In this review, we present current accomplishments in the chromatographic methodologies proposed for detection of tryptophan metabolites and provide a guide for choosing the optimal approach.
Topics: Chromatography; Humans; Kynurenine; Tryptophan
PubMed: 28590049
DOI: 10.1002/jssc.201700184 -
Chemistry (Weinheim An Der Bergstrasse,... Apr 2020Pd-mediated reactions have emerged as a powerful tool for the site-selective and bioorthogonal late-stage diversification of amino acids, peptides and related compounds.... (Review)
Review
Pd-mediated reactions have emerged as a powerful tool for the site-selective and bioorthogonal late-stage diversification of amino acids, peptides and related compounds. Indole moieties of tryptophan derivatives are susceptible to C H-activation, whereas halogenated aromatic amino acids such as halophenylalanines or halotryptophans provide a broad spectrum of different functionalisations. The compatibility of transition-metal-catalysed cross-couplings with functional groups in peptides, other biologically active compounds and even proteins has been demonstrated. This Review primarily compiles the application of different cross-coupling reactions to modify halotryptophans, halotryptophan containing peptides or halogenated, biologically active compounds derived from tryptophan. Modern approaches use regio- and stereoselective biocatalytic strategies to generate halotryptophans and derivatives on a preparative scale. The combination of bio- and chemocatalysis in cascade reactions is given by the biocompatibility and bioorthogonality of Pd-mediated reactions.
Topics: Amino Acids; Catalysis; Halogenation; Peptides; Tryptophan
PubMed: 31544296
DOI: 10.1002/chem.201903756 -
Nutrients Nov 2019Tryptophan depletion is common in hemodialysis patients. The cause of this depletion remains largely unknown, but reduced nutritional tryptophan intake, losses during...
Tryptophan depletion is common in hemodialysis patients. The cause of this depletion remains largely unknown, but reduced nutritional tryptophan intake, losses during dialysis or an increased catabolism due to an inflammatory state are likely contributors. Currently, little is known about tryptophan homeostasis in hemodialysis patients. We assessed dietary tryptophan intake, measured plasma tryptophan during dialysis, and measured the combined urinary and dialysate excretion of tryptophan in 40 hemodialysis patients (66 ± 15 years and 68% male). Patients had low tryptophan concentrations (27 ± 9 µmol/L) before dialysis. Mean dietary tryptophan intake was 4454 ± 1149 µmol/24 h. Mean urinary tryptophan excretion was 15.0 ± 12.3 μmol/24 h, dialysate excretion was 209 ± 67 μmol/24 h and combined excretion was 219 ± 66 µmol/24 h, indicating only 5% of dietary tryptophan intake was excreted. No associations were found between plasma tryptophan concentration and tryptophan intake, plasma kynurenine/tryptophan ratio or inflammatory markers. During dialysis, mean plasma tryptophan concentration increased 16% to 31 ± 8 µmol/L. Intradialytic increase in plasma tryptophan was associated with a lower risk of mortality, independent of age, sex and dialysis vintage (HR: 0.87 [0.76-0.99]; = 0.04). Tryptophan intake was well above the dietary recommendations and, although tryptophan was removed during dialysis, mean plasma tryptophan increased during dialysis. The cause of this phenomenon is unknown, but it appears to be protective.
Topics: Aged; Aged, 80 and over; Diet; Diet Records; Female; Humans; Kynurenine; Male; Middle Aged; Renal Dialysis; Tryptophan
PubMed: 31766383
DOI: 10.3390/nu11122851 -
Bioscience Reports Sep 2015Tryptophan (Trp) requirements in pregnancy are several-fold: (1) the need for increased protein synthesis by mother and for fetal growth and development; (2) serotonin... (Review)
Review
Tryptophan (Trp) requirements in pregnancy are several-fold: (1) the need for increased protein synthesis by mother and for fetal growth and development; (2) serotonin (5-HT) for signalling pathways; (3) kynurenic acid (KA) for neuronal protection; (4) quinolinic acid (QA) for NAD(+) synthesis (5) other kynurenines (Ks) for suppressing fetal rejection. These goals could not be achieved if maternal plasma [Trp] is depleted. Although plasma total (free + albumin-bound) Trp is decreased in pregnancy, free Trp is elevated. The above requirements are best expressed in terms of a Trp utilization concept. Briefly, Trp is utilized as follows: (1) In early and mid-pregnancy, emphasis is on increased maternal Trp availability to meet the demand for protein synthesis and fetal development, most probably mediated by maternal liver Trp 2,3-dioxygenase (TDO) inhibition by progesterone and oestrogens. (2) In mid- and late pregnancy, Trp availability is maintained and enhanced by the release of albumin-bound Trp by albumin depletion and non-esterified fatty acid (NEFA) elevation, leading to increased flux of Trp down the K pathway to elevate immunosuppressive Ks. An excessive release of free Trp could undermine pregnancy by abolishing T-cell suppression by Ks. Detailed assessment of parameters of Trp metabolism and disposition and related measures (free and total Trp, albumin, NEFA, K and its metabolites and pro- and anti-inflammatory cytokines in maternal blood and, where appropriate, placental and fetal material) in normal and abnormal pregnancies may establish missing gaps in our knowledge of the Trp status in pregnancy and help identify appropriate intervention strategies.
Topics: Animals; Female; Humans; Immune Tolerance; Immunity; Metabolic Networks and Pathways; Pregnancy; Pregnancy Complications; Tryptophan
PubMed: 26381576
DOI: 10.1042/BSR20150197 -
Reproductive Sciences (Thousand Oaks,... Apr 2022Preeclampsia (PE) is a hypertensive pregnancy, which is a leading cause of maternal and fetal morbidity and mortality during pregnancy. L-Tryptophan (Trp) is an...
Preeclampsia (PE) is a hypertensive pregnancy, which is a leading cause of maternal and fetal morbidity and mortality during pregnancy. L-Tryptophan (Trp) is an essential amino acid, which can be metabolized into various biologically active metabolites. However, the levels of many circulating Trp-metabolites in human normotensive pregnancies (NT) and PE are undetermined. This study quantified the levels of Trp-metabolites in maternal and umbilical vein sera from women with NT and PE. Paired maternal and umbilical blood samples were collected from singleton pregnant patients. Twenty-five Trp-metabolites were measured in serum samples using liquid chromatography with tandem mass spectrometry. The effects of L-kynurenine (Kyn) and indole-3-lactic acid (ILA), on function of human umbilical vein endothelial cells (HUVECs), were also determined. Twenty Trp-metabolites were detected. The levels of 9 Trp-metabolites including Kyn and ILA were higher (P < 0.05) in umbilical vein than maternal serum, whereas 2 (5-hydroxy-L-tryptophan and serotonin) were lower (P < 0.05) in umbilical vein compared to maternal serum. PE significantly (P < 0.05) elevated ILA levels in maternal and umbilical vein sera. Kyn dose-dependently decreased (P < 0.05) cell viability. Kyn and ILA dose- and time-dependently (P < 0.05) increased monolayer integrity in HUVECs. These data suggest that these Trp-metabolites are important in regulating endothelial function during pregnancy, and the elevated ILA in PE may antagonize increased endothelial permeability occurring in PE.
Topics: Female; Fetus; Human Umbilical Vein Endothelial Cells; Humans; Kynurenine; Pre-Eclampsia; Pregnancy; Tryptophan
PubMed: 34622427
DOI: 10.1007/s43032-021-00759-0 -
Oxidative Medicine and Cellular... 2018The placenta plays a vital role in fetal development during pregnancy. Dysfunction of the placenta can be caused by oxidative stress and can lead to abnormal fetal... (Review)
Review
The placenta plays a vital role in fetal development during pregnancy. Dysfunction of the placenta can be caused by oxidative stress and can lead to abnormal fetal development. Preventing oxidative stress of the placenta is thus an important measure to ensure positive birth outcomes. Research shows that tryptophan and its metabolites can efficiently clean free radicals (including the reactive oxygen species and activated chlorine). Consequently, tryptophan and its metabolites are suggested to act as potent antioxidants in the placenta. However, the mechanism of these antioxidant properties in the placenta is still unknown. In this review, we summarize research on the antioxidant properties of tryptophan, tryptophan metabolites, and metabolic enzymes. Two predicted mechanisms of tryptophan's antioxidant properties are discussed. (1) Tryptophan could activate the phosphorylation of p62 after the activation of mTORC1; phosphorylated p62 then uncouples the interaction between Nrf2 and Keap1, and activated Nrf2 enters the nucleus to induce expressions of antioxidant proteins, thus improving cellular antioxidation. (2) 3-Hydroxyanthranilic acid, a tryptophan kynurenine pathway metabolite, changes conformation of Keap1, inducing the dissociation of Nrf2 and Keap1, activating Nrf2 to enter the nucleus and induce expressions of antioxidant proteins (such as HO-1), thereby enhancing cellular antioxidant capacity. These mechanisms may enrich the theory of how to apply tryptophan as an antioxidant during pregnancy, providing technical support for its use in regulating the pregnancy's redox status and enriching our understanding of amino acids' nutritional value.
Topics: Antioxidants; Female; Humans; Placenta; Pregnancy; Tryptophan
PubMed: 30140360
DOI: 10.1155/2018/1054797 -
Frontiers in Bioscience (Scholar... Jan 2011L-Tryptophan is a nutritionally essential amino acid for monogastric animals and preweaning ruminants because it cannot be synthesized in the body. Besides serving as a... (Review)
Review
L-Tryptophan is a nutritionally essential amino acid for monogastric animals and preweaning ruminants because it cannot be synthesized in the body. Besides serving as a building block for proteins, tryptophan is a critical nutrient for the functions of nervous and immune systems. Over the past decades, much attention has been directed to study the role of tryptophan as a limiting amino acid in mammalian and avian nutrition. However, emerging evidence from recent studies shows that tryptophan and its metabolites (e.g., serotonin (5-hydroxytryptamine, 5-HT) and melatonin)) can regulate feed intake, reproduction, immunity, neurological function, and anti-stress responses. Additionally, tryptophan may modulate gene expression and nutrient metabolism to impact whole-body homeostasis in organisms. Thus, adequate intake of this amino acid from the diet is crucial for growth, development, and health of animals and humans.
Topics: Animal Nutritional Physiological Phenomena; Animals; Gene Expression Regulation; Homeostasis; Humans; Melatonin; Nervous System; Niacin; Nutritional Requirements; Serotonin; Tryptophan
PubMed: 21196377
DOI: 10.2741/s152