Ultrahigh-Performance Liquid Chromatography Tandem Mass Spectrometry with Electrospray Ionization Quantification of Tryptophan Metabolites and Markers of Gut Health in Serum and Plasma—Application to Clinical and Epidemiology Cohorts

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1. 1

   Lewis, M. R.; Pearce, J. T. M.; Spagou, K.; Green, M.; Dona, A. C.; Yuen, A. H. Y.; David, M.; Berry, D. J.; Chappell, K.; Horneffer-van der Sluis, V.; Shaw, R.; Lovestone, S.; Elliott, P.; Shockcor, J.; Lindon, J. C.; Cloarec, O.; Takats, Z.; Holmes, E.; Nicholson, J. K. Development and application of ultra-performance liquid chromatography-TOF MS for precision large scale urinary metabolic phenotyping. Anal. Chem. 2016, 88 (18), 9004– 9013,  DOI: 10.1021/acs.analchem.6b01481

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   1

   Development and Application of Ultra-Performance Liquid Chromatography-TOF MS for Precision Large Scale Urinary Metabolic Phenotyping

   Lewis, Matthew R.; Pearce, Jake T. M.; Spagou, Konstantina; Green, Martin; Dona, Anthony C.; Yuen, Ada H. Y.; David, Mark; Berry, David J.; Chappell, Katie; Horneffer-van der Sluis, Verena; Shaw, Rachel; Lovestone, Simon; Elliott, Paul; Shockcor, John; Lindon, John C.; Cloarec, Olivier; Takats, Zoltan; Holmes, Elaine; Nicholson, Jeremy K.

   Analytical Chemistry (Washington, DC, United States) (2016), 88 (18), 9004-9013CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

   To better understand the mol. mechanisms underpinning physiol. variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid samples. Hyphenated ultra-performance liq. chromatog. and mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. Yet, the seemingly inevitable need to analyze large studies in multiple anal. batches for UPLC-MS anal. poses a challenge to data quality which has been recognized in the field. Herein the authors describe in detail a fit-for-purpose UPLC-MS platform, method set, and sample anal. workflow, capable of sustained anal. on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed-phase chromatog. (RPC) and hydrophilic interaction liq. chromatog. (HILIC) together with high resoln. orthogonal acceleration time-of-flight mass spectrometry, exceptional measurement precision is exemplified with independent epidemiol. sample sets of ∼650 and 1000 participant samples. Evaluation of mol. ref. targets in repeated injections of pooled quality control (QC) samples distributed throughout each expt. demonstrates a mean retention time relative std. deviation of <0.3% across all assays in both studies and a mean peak area relative std. deviation of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extn. was performed followed by data filtration according to feature intensity response to QC sample diln. Anal. of the remaining features within the repeated QC sample measurements demonstrated median peak area relative std. deviation values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each expt. was acquired in a single continuous batch, instances of minor time-dependent intensity drift were obsd., highlighting the utility of data correction techniques despite reducing the dependency on them for generating high quality data. The platform and methodol. presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects. Details of the pipeline used to generate high quality raw data and mitigate the need for batch correction are provided.
2. 2

   Want, E. J.; Wilson, I. D.; Gika, H.; Theodoridis, G.; Plumb, R. S.; Shockcor, J.; Holmes, E.; Nicholson, J. K. Global metabolic profiling procedures for urine using UPLC–MS. Nat. Protoc. 2010, 5 (6), 1005– 1018,  DOI: 10.1038/nprot.2010.50

   Google Scholar

   There is no corresponding record for this reference.
3. 3

   Dunn, W. B.; Broadhurst, D.; Begley, P.; Zelena, E.; Francis-McIntyre, S.; Anderson, N.; Brown, M.; Knowles, J. D.; Halsall, A.; Haselden, J. N.; Nicholls, A. W.; Wilson, I. D.; Kell, D. B.; Goodacre, R. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat. Protoc. 2011, 6, 1060– 1083,  DOI: 10.1038/nprot.2011.335

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   3

   Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry

   Dunn, Warwick B.; Broadhurst, David; Begley, Paul; Zelena, Eva; Francis-McIntyre, Sue; Anderson, Nadine; Brown, Marie; Knowles, Joshau D.; Halsall, Antony; Haselden, John N.; Nicholls, Andrew W.; Wilson, Ian D.; Kell, Douglas B.; Goodacre, Royston

   Nature Protocols (2011), 6 (7), 1060-1083CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)

   Metab. has an essential role in biol. systems. Identification and quantitation of the compds. in the metabolome is defined as metabolic profiling, and it is applied to define metabolic changes related to genetic differences, environmental influences and disease or drug perturbations. Chromatog.-mass spectrometry (MS) platforms are frequently used to provide the sensitive and reproducible detection of hundreds to thousands of metabolites in a single biofluid or tissue sample. Here we describe the exptl. workflow for long-term and large-scale metabolomic studies involving thousands of human samples with data acquired for multiple anal. batches over many months and years. Protocols for serum- and plasma-based metabolic profiling applying gas chromatog.-MS (GC-MS) and ultraperformance liq. chromatog.-MS (UPLC-MS) are described. These include biofluid collection, sample prepn., data acquisition, data pre-processing and quality assurance. Methods for quality control-based robust LOESS signal correction to provide signal correction and integration of data from multiple anal. batches are also described.
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   Dunn, W. B.; Lin, W.; Broadhurst, D.; Begley, P.; Brown, M.; Zelena, E.; Vaughan, A. A.; Halsall, A.; Harding, N.; Knowles, J. D.; Francis-McIntyre, S.; Tseng, A.; Ellis, D. I.; O’Hagan, S.; Aarons, G.; Benjamin, B.; Chew-Graham, S.; Moseley, C.; Potter, P.; Winder, C. L.; Potts, C.; Thornton, P.; McWhirter, C.; Zubair, M.; Pan, M.; Burns, A.; Cruickshank, J. K.; Jayson, G. C.; Purandare, N.; Wu, F. C. W.; Finn, J. D.; Haselden, J. N.; Nicholls, A. W.; Wilson, I. D.; Goodacre, R.; Kell, D. B. Molecular phenotyping of a UK population: defining the human serum metabolome. Metabolomics 2015, 11, 9– 26,  DOI: 10.1007/s11306-014-0707-1

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   4

   Molecular phenotyping of a UK population: defining the human serum metabolome

   Dunn, Warwick B.; Lin, Wanchang; Broadhurst, David; Begley, Paul; Brown, Marie; Zelena, Eva; Vaughan, Andrew A.; Halsall, Antony; Harding, Nadine; Knowles, Joshua D.; Francis-McIntyre, Sue; Tseng, Andy; Ellis, David I.; O'Hagan, Steve; Aarons, Gill; Benjamin, Boben; Chew-Graham, Stephen; Moseley, Carly; Potter, Paula; Winder, Catherine L.; Potts, Catherine; Thornton, Paula; McWhirter, Catriona; Zubair, Mohammed; Pan, Martin; Burns, Alistair; Cruickshank, J. Kennedy; Jayson, Gordon C.; Purandare, Nitin; Wu, Frederick C. W.; Finn, Joe D.; Haselden, John N.; Nicholls, Andrew W.; Wilson, Ian D.; Goodacre, Royston; Kell, Douglas B.

   Metabolomics (2015), 11 (1), 9-26CODEN: METAHQ; ISSN:1573-3882. (Springer)

   Phenotyping of 1,200 'healthy' adults from the UK has been performed through the investigation of diverse classes of hydrophilic and lipophilic metabolites present in serum by applying a series of chromatog.-mass spectrometry platforms. These data were made robust to instrumental drift by numerical correction; this was prerequisite to allow detection of subtle metabolic differences. The variation in obsd. metabolite relative concns. between the 1,200 subjects ranged from less than 5 % to more than 200 %. Variations in metabolites could be related to differences in gender, age, BMI, blood pressure, and smoking. Investigations suggest that a sample size of 600 subjects is both necessary and sufficient for robust anal. of these data. Overall, this is a large scale and non-targeted chromatog. MS-based metabolomics study, using samples from over 1,000 individuals, to provide a comprehensive measurement of their serum metabolomes. This work provides an important baseline or ref. dataset for understanding the 'normal' relative concns. and variation in the human serum metabolome. These may be related to our increasing knowledge of the human metabolic network map. Information on the Husermet study is available at http://www.husermet.org/. Importantly, all of the data are made freely available at MetaboLights (http://www.ebi.ac.uk/metabolights/).
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   Murphy, R. A.; Moore, S.; Playdon, M.; Kritchevsky, S.; Newman, A. B.; Satterfield, S.; Ayonayon, H.; Clish, C.; Gerszten, R.; Harris, T. B. Metabolites associated with risk of developing mobility disability in the health, aging and body composition study. J. Gerontol., Ser. A 2019, 74 (1), 73– 80,  DOI: 10.1093/gerona/glx233

   Google Scholar

   There is no corresponding record for this reference.
6. 6

   Tzoulaki, I.; Ebbels, T. M. D.; Valdes, A.; Elliott, P.; Ioannidis, J. P. A. Design and analysis of metabolomics studies in epidemiologic research: A primer on -omic technologies. Am. J. Epidemiol. 2014, 180 (2), 129– 139,  DOI: 10.1093/aje/kwu143

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   6

   Design and analysis of metabolomics studies in epidemiologic research: a primer on -omic technologies

   Tzoulaki Ioanna; Ebbels Timothy M D; Valdes Ana; Elliott Paul; Ioannidis John P A

   American journal of epidemiology (2014), 180 (2), 129-39 ISSN:.

   Metabolomics is the field of "-omics" research concerned with the comprehensive characterization of the small low-molecular-weight metabolites in biological samples. In epidemiology, it represents an emerging technology and an unprecedented opportunity to measure environmental and other exposures with improved precision and far less measurement error than with standard epidemiologic methods. Advances in the application of metabolomics in large-scale epidemiologic research are now being realized through a combination of improved sample preparation and handling, automated laboratory and processing methods, and reduction in costs. The number of epidemiologic studies that use metabolic profiling is still limited, but it is fast gaining popularity in this area. In the present article, we present a roadmap for metabolomic analyses in epidemiologic studies and discuss the various challenges these data pose to large-scale studies. We discuss the steps of data preprocessing, univariate and multivariate data analysis, correction for multiplicity of comparisons with correlated data, and finally the steps of cross-validation and external validation. As data from metabolomic studies accumulate in epidemiology, there is a need for large-scale replication and synthesis of findings, increased availability of raw data, and a focus on good study design, all of which will highlight the potential clinical impact of metabolomics in this field.
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   Richard, D. M.; Dawes, M. A.; Mathias, C. W.; Acheson, A.; Hill-Kapturczak, N.; Dougherty, D. M. L-Tryptophan: basic metabolic functions, behavioral research and therapeutic indications. Int. J. Tryptophan Res. 2009, 2, 45– 60,  DOI: 10.4137/IJTR.S2129

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   7

   L-tryptophan: basic metabolic functions, behavioral research and therapeutic Indications

   Richard, Dawn M.; Dawes, Michael A.; Mathias, Charles W.; Acheson, Ashley; Hill-Kapturczak, Nathalie; Dougherty, Donald M.

   International Journal of Tryptophan Research (2009), 2 (), 45-60CODEN: IJTRBS; ISSN:1178-6469. (Libertas Academica)

   A review. An essential component of the human diet, L-tryptophan is crit. in a no. of metabolic functions and has been widely used in numerous research and clin. trials. This review provides a brief overview of the role of L-tryptophan in protein synthesis and a no. of other metabolic functions. With emphasis on L-tryptophan's role in synthesis of brain serotonin, details are provided on the research uses of L-tryptophan, particularly L-tryptophan depletion, and on clin. trials that have been conducted using L-tryptophan supplementation. The ability to change the rates of serotonin synthesis in the brain by manipulating concns. of serum tryptophan is the foundation of much research. As the sole precursor of serotonin, exptl. research has shown that L-tryptophan's role in brain serotonin synthesis is an important factor involved in mood, behavior, and cognition. Furthermore, clin. trials have provided some initial evidence of L-tryptophan's efficacy for treatment of psychiatric disorders, particularly when used in combination with other therapeutic agents.
8. 8

   Mándi, Y.; Vécsei, L. The kynurenine system and immunoregulation. J. Neural Transm. 2012, 119 (2), 197– 209,  DOI: 10.1007/s00702-011-0681-y

   Google Scholar

   There is no corresponding record for this reference.
9. 9

   Cervenka, I.; Agudelo, L. Z.; Ruas, J. L. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science 2017, 357, eaaf9794,  DOI: 10.1126/science.aaf9794

   Google Scholar

   There is no corresponding record for this reference.
10. 10

    Chen, Y.; Guillemin, G. J. Kynurenine pathway metabolites in humans: disease and healthy states. Int. J. Tryptophan Res. 2009, 2, IJTR.S2097,  DOI: 10.4137/IJTR.S2097

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    There is no corresponding record for this reference.
11. 11

    Li, Y.; Hu, N.; Yang, D.; Oxenkrug, G.; Yang, Q. Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism. FEBS J. 2017, 284 (6), 948– 966,  DOI: 10.1111/febs.14026

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    11

    Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism

    Li, Yang; Hu, Nan; Yang, Dan; Oxenkrug, Gregory; Yang, Qing

    FEBS Journal (2017), 284 (6), 948-966CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)

    Tryptophan is metabolized along the kynurenine and serotonin pathways, resulting in formation of kynurenine metabolites, neuroactive serotonin and melatonin. Each pathway is crit. for maintaining healthy homeostasis. However, the two pathways are extremely unequal in their ability to degrade tryptophan, and little is known about the mechanisms maintaining the balance between them. Here, we demonstrated that in PC12 cells, a change of expression of key genes of one pathway resulted in a change of expression of key genes of the other. Melatonin, the end product of the serotonin pathway, played an important role in tryptophan metab. by affecting both key enzymes of the two pathways. Melatonin treatment induced the expression of indole-2,3-dioxygenase 1 (IDO1) and enhanced the activity of the IDO1 promoter while decreasing the expression of arylalkylamine N-acetyl transferase. Melatonin treatment up-regulated the expression of forkhead box protein O1 (FoxO1) and enhanced the binding of FoxO1 to the IDO1 promoter. FoxO1 was shown to be a new regulator for IDO1 expression. Melatonin treatment decreased the phosphorylation of FoxO1 by extracellular signal-regulated kinases 1 and 2 and protein kinase B (Akt) and increased the phosphorylation of binding protein 14-3-3 by c-Jun N-terminal kinase (JNK), and thus the complex of FoxO1-14-3-3 in the cytoplasm was disassembled and FoxO1 was relocated to the nucleus to induce IDO1 expression. The JNK signaling pathway played an important role in melatonin-induced IDO1 up-regulation. In conclusion, this study suggests a link between melatonin, JNK, FoxO1 and IDO1 that acts as a potential balance regulator of tryptophan metab., and offers a new approach to treat diseases related to dysregulation of tryptophan metab.
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    Kennedy, P. J.; Cryan, J. F.; Dinan, T. G.; Clarke, G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology 2017, 112, 399– 412,  DOI: 10.1016/j.neuropharm.2016.07.002

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    12

    Kynurenine pathway metabolism and the microbiota-gut-brain axis

    Kennedy, P. J.; Cryan, J. F.; Dinan, T. G.; Clarke, G.

    Neuropharmacology (2017), 112 (Part_B), 399-412CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

    It has become increasingly clear that the gut microbiota influences not only gastrointestinal physiol. but also central nervous system (CNS) function by modulating signalling pathways of the microbiota-gut-brain axis. Understanding the neurobiol. mechanisms underpinning the influence exerted by the gut microbiota on brain function and behavior has become a key research priority. Microbial regulation of tryptophan metab. has become a focal point in this regard, with dual emphasis on the regulation of serotonin synthesis and the control of kynurenine pathway metab. Here, we focus in detail on the latter pathway and begin by outlining the structural and functional dynamics of the gut microbiota and the signalling pathways of the brain-gut axis. We summarise preclin. and clin. investigations demonstrating that the gut microbiota influences CNS physiol., anxiety, depression, social behavior, cognition and visceral pain. Pertinent studies are drawn from neurogastroenterol. demonstrating the importance of tryptophan and its metabolites in CNS and gastrointestinal function. We outline how kynurenine pathway metab. may be regulated by microbial control of neuroendocrine function and components of the immune system. Finally, preclin. evidence demonstrating direct and indirect mechanisms by which the gut microbiota can regulate tryptophan availability for kynurenine pathway metab., with downstream effects on CNS function, is reviewed. Targeting the gut microbiota represents a tractable target to modulate kynurenine pathway metab. Efforts to develop this approach will markedly increase our understanding of how the gut microbiota shapes brain and behavior and provide new insights towards successful translation of microbiota-gut-brain axis research from bench to bedside.
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    Wang, X.-D.; Notarangelo, F. M.; Wang, J.-Z.; Schwarcz, R. Kynurenic acid and 3-hydroxykynurenine production from D-kynurenine in mice. Brain Res. 2012, 1455, 1– 9,  DOI: 10.1016/j.brainres.2012.03.026

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    13

    Kynurenic acid and 3-hydroxykynurenine production from D-kynurenine in mice

    Wang, Xiao-Dan; Notarangelo, Francesca M.; Wang, Ji-Zuo; Schwarcz, Robert

    Brain Research (2012), 1455 (), 1-9CODEN: BRREAP; ISSN:0006-8993. (Elsevier B.V.)

    Kynurenic acid (KYNA), an antagonist of the α7 nicotinic acetylcholine receptor and the N-methyl-D-aspartate receptor, and 3-hydroxykynurenine (3-HK), a generator of reactive oxygen species, are neuroactive metabolites of the kynurenine pathway of tryptophan degrdn. In the mammalian brain as elsewhere, both compds. derive from a common bioprecursor, L-kynurenine (L-KYN). Recent studies in rats demonstrated that D-kynurenine (D-KYN), a metabolite of the bacterial amino acid D-tryptophan, can also function as a bioprecursor of brain KYNA. We now investigated the conversion of systemically administered D-KYN to KYNA in mice and also explored the possible prodn. of 3-HK in the same animals. Thirty min after an injection of D-KYN or L-KYN (30 mg/kg, i.p.), newly produced KYNA and 3-HK were recovered from plasma, liver, forebrain and cerebellum in all cases. Using a new chiral sepn. method, 3-HK produced from D-KYN was pos. identified as D-3-HK. L-KYN was the more effective precursor of KYNA in all tissues and also exceeded D-KYN as a precursor of brain 3-HK. In contrast, D-KYN was more potent as a precursor of 3-HK in the liver. The prodn. of both KYNA and 3-HK from D-KYN was rapid in all tissues, peaking at 15-30 min following a systemic injection of D-KYN. These results show that biosynthetic routes other than those classically ascribed to L-KYN can account for the synthesis of both KYNA and 3-HK in vivo. This new insight may be of significant physiol. or pathol. relevance.
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    Pierozan, P.; Biasibetti, H.; Schmitz, F.; Ávila, H.; Parisi, M. M.; Barbe-Tuana, F.; Wyse, A. T. S.; Pessoa-Pureur, R. Quinolinic acid neurotoxicity: Differential roles of astrocytes and microglia via FGF-2-mediated signaling in redox-linked cytoskeletal changes. Biochim. Biophys. Acta, Mol. Cell Res. 2016, 1863 (12), 3001– 3014,  DOI: 10.1016/j.bbamcr.2016.09.014

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    14

    Quinolinic acid neurotoxicity: Differential roles of astrocytes and microglia via FGF-2-mediated signaling in redox-linked cytoskeletal changes

    Pierozan, Paula; Biasibetti, Helena; Schmitz, Felipe; Avila, Helena; Parisi, Mariana M.; Barbe-Tuana, Florencia; Wyse, Angela T. S.; Pessoa-Pureur, Regina

    Biochimica et Biophysica Acta, Molecular Cell Research (2016), 1863 (12), 3001-3014CODEN: BBAMCO; ISSN:0167-4889. (Elsevier B.V.)

    QUIN is a glutamate agonist playing a role in the misregulation of the cytoskeleton, which is assocd. with neurodegeneration in rats. In this study, we focused on microglial activation, FGF2/Erk signaling, gap junctions (GJs), inflammatory parameters and redox imbalance acting on cytoskeletal dynamics of the in QUIN-treated neural cells of rat striatum. FGF-2/Erk signaling was not altered in QUIN-treated primary astrocytes or neurons, however cytoskeleton was disrupted. In co-cultured astrocytes and neurons, QUIN-activated FGF2/Erk signaling prevented the cytoskeleton from remodeling. In mixed cultures (astrocyte, neuron, microglia), QUIN-induced FGF-2 increased level failed to activate Erk and promoted cytoskeletal destabilization. The effects of QUIN in mixed cultures involved redox imbalance upstream of Erk activation. Decreased connexin 43 (Cx43) immunocontent and functional GJs, was also coincident with disruption of the cytoskeleton in primary astrocytes and mixed cultures. We postulate that in interacting astrocytes and neurons the cytoskeleton is preserved against the insult of QUIN by activation of FGF-2/Erk signaling and proper cell-cell interaction through GJs. In mixed cultures, the FGF-2/Erk signaling is blocked by the redox imbalance assocd. with microglial activation and disturbed cell communication, disrupting the cytoskeleton. Thus, QUIN signal activates differential mechanisms that could stabilize or destabilize the cytoskeleton of striatal astrocytes and neurons in culture, and glial cells play a pivotal role in these responses preserving or disrupting a combination of signaling pathways and cell-cell interactions. Taken together, our findings shed light into the complex role of the active interaction of astrocytes, neurons and microglia in the neurotoxicity of QUIN.
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    Guillemin, G. J. Quinolinic acid: neurotoxicity. FEBS J. 2012, 279 (8), 1355,  DOI: 10.1111/j.1742-4658.2012.08493.x

    Google Scholar

    There is no corresponding record for this reference.
16. 16

    Chatterjee, P.; Goozee, K.; Lim, C. K.; James, I.; Shen, K.; Jacobs, K. R.; Sohrabi, H. R.; Shah, T.; Asih, P. R.; Dave, P.; ManYan, C.; Taddei, K.; Lovejoy, D. B.; Chung, R.; Guillemin, G. J.; Martins, R. N. Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load: A pilot study. Sci. Rep. 2018, 8 (1), 8008,  DOI: 10.1038/s41598-018-25968-7

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    16

    Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load: A pilot study

    Chatterjee Pratishtha; Goozee Kathryn; Lim Chai K; Jacobs Kelly R; Sohrabi Hamid R; Shah Tejal; Dave Preeti; Lovejoy David B; Chung Roger; Guillemin Gilles J; Martins Ralph N; Chatterjee Pratishtha; Goozee Kathryn; Sohrabi Hamid R; Shah Tejal; Taddei Kevin; Martins Ralph N; Goozee Kathryn; Asih Prita R; Martins Ralph N; Goozee Kathryn; Dave Preeti; ManYan Candice; Goozee Kathryn; Sohrabi Hamid R; Martins Ralph N; Goozee Kathryn; Martins Ralph N; James Ian; Shen Kaikai; Sohrabi Hamid R; Shah Tejal; Taddei Kevin; Martins Ralph N; Asih Prita R

    Scientific reports (2018), 8 (1), 8008 ISSN:.

    The kynurenine pathway (KP) is dysregulated in neuroinflammatory diseases including Alzheimer's disease (AD), however has not been investigated in preclinical AD characterized by high neocortical amyloid-β load (NAL), prior to cognitive impairment. Serum KP metabolites were measured in the cognitively normal KARVIAH cohort. Participants, aged 65-90 y, were categorised into NAL+ (n = 35) and NAL- (n = 65) using a standard uptake value ratio cut-off = 1.35. Employing linear models adjusting for age and APOEε4, higher kynurenine and anthranilic acid (AA) in NAL+ versus NAL- participants were observed in females (kynurenine, p = 0.004; AA, p = 0.001) but not males (NALxGender, p = 0.001, 0.038, respectively). To evaluate the predictive potential of kynurenine or/and AA for NAL+ in females, logistic regressions with NAL+/- as outcome were carried out. After age and APOEε4 adjustment, kynurenine and AA were individually and jointly significant predictors (p = 0.007, 0.005, 0.0004, respectively). Areas under the receiver operating characteristic curves were 0.794 using age and APOEε4 as predictors, and 0.844, 0.866 and 0.871 when kynurenine, AA and both were added. Findings from the current study exhibit increased KP activation in NAL+ females and highlight the predictive potential of KP metabolites, AA and kynurenine, for NAL+. Additionally, the current study also provides insight into he influence of gender in AD pathogenesis.
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    Guillemin, G. J.; Rahman, A.; Ting, K. K.; Cullen, K.; Braidy, N.; Chung, R.; Wu, W.; Brew, B. J. Involvement of the kynurenine pathway in Alzheimer’s disease. Alzheimer's Dementia 2010, 6 (4), e21,  DOI: 10.1016/j.jalz.2010.08.063

    Google Scholar

    There is no corresponding record for this reference.
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    Gulaj, E.; Pawlak, K.; Bien, B.; Pawlak, D. Kynurenine and its metabolites in Alzheimer’s disease patients. Adv. Med. Sci. 2010, 55 (2), 204– 211,  DOI: 10.2478/v10039-010-0023-6

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    Kynurenine and its metabolites in Alzheimer's disease patients

    Gulaj, E.; Pawlak, K.; Bien, B.; Pawlak, D.

    Advances in Medical Sciences (2010), 55 (2), 204-211CODEN: AMSDCH; ISSN:1896-1126. (Medical University of Bialystok)

    Purpose: The kynurenine pathway (KP) is a major route of tryptophan metab. Several metabolites of this pathway are proposed to be involved in the pathogenesis of Alzheimer's disease. The aim of this study was to evaluate peripheral KP in patients with Alzheimer type dementia and a detailed anal. of correlation between kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), anthranilic acid (AA), quinolinic acid (QUIN) and degree of neuropsychol. changes in AD. The plasma concn. of tryptophan and its products degrdn. by kynurenine pathway were analyzed in 34 patients suffering from Alzheimer type dementia and 18 controls in similar age using high-performance liq. chromatog. technique. Results: In demented patients we found lower tryptophan and KYNA concns. There was a non-significant increase of KYN, 3-HK and AA levels, and a marked increase of QUIN in Alzheimer's disease group. We obsd. pos. correlations between cognitive function tests and plasma KYNA levels, and inversely correlations between these tests and QUIN levels in Alzheimer type dementia. Increased TRP degrdn. and simultaneous altered kynurenines levels were found in plasma of AD patients. It proves activation of peripheral kynurenine pathway in this type of dementia. The alterations of two main KYN metabolites: KYNA and QUIN seem to be assocd. with the impairment of the cognitive function in AD patients. This appears to offer novel therapeutic opportunities, with the development of new compds. as a promising perspective for brain neuroprotection.
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    Myint, A.-M.; Kim, Y. K.; Verkerk, R.; Scharpé, S.; Steinbusch, H.; Leonard, B. Kynurenine pathway in major depression: Evidence of impaired neuroprotection. J. Affective Disord. 2007, 98 (1), 143– 151,  DOI: 10.1016/j.jad.2006.07.013

    Google Scholar

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    Kynurenine pathway in major depression: evidence of impaired neuroprotection

    Myint, Aye-Mu; Kim, Yong Ku; Verkerk, Robert; Scharpe, Simon; Steinbusch, Harry; Leonard, Brian

    Journal of Affective Disorders (2007), 98 (1-2), 143-151CODEN: JADID7; ISSN:0165-0327. (Elsevier Ltd.)

    The neurodegeneration hypothesis proposed major depression as a consequence of the imbalance between neuroprotective and neurodegenerative metabolites in the kynurenine pathway. To test the hypothesis, plasma tryptophan and kynurenine pathway metabolites were studied in 58 patients with major depression and 189 normal controls. The mean tryptophan breakdown index was higher (p = 0.036), and mean kynurenic acid concn. and mean neuroprotective ratios were lower, in depressed patients (p = 0.003 and 0.003, resp.). In receiver operating characteristic anal., the kynurenic acid concns. and the neuroprotective ratio showed clear discrimination between depressed patients and controls with area under the curve 79% and 76.3% resp. The neuroprotective ratio did not change after treatment in those with repeated episodes of depression but it increased significantly (p = 0.044) in those with first episodes. The results suggested that the redn. in neuroprotective markers, which indicated an impaired neuroprotection, might play an important role in pathophysiol. of major depression.
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    Réus, G. Z.; Jansen, K.; Titus, S.; Carvalho, A. F.; Gabbay, V.; Quevedo, J. Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: evidences from animal and human studies. J. Psychiatr. Res. 2015, 68, 316– 328,  DOI: 10.1016/j.jpsychires.2015.05.007

    Google Scholar

    20

    Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies

    Reus Gislaine Z; Jansen Karen; Titus Stephanie; Carvalho Andre F; Gabbay Vilma; Quevedo Joao

    Journal of psychiatric research (2015), 68 (), 316-28 ISSN:.

    Treatment-resistant depression affects up to 20% of individuals suffering from major depressive disorder (MDD). The medications currently available to treat depression, including serotonin re-uptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), fail to produce adequate remission of depressive symptoms for a large number of patients. The monoamine hypothesis upon which these medications are predicated should be expanded and revised as research elucidates alternative mechanisms of depression and effective methods to treat the underlying pathologic consequences. Research into the role of tryptophan degradation and the kynurenine pathway in the setting of inflammation has brought new insight into potential etiologies of MDD. Further investigation into the connection between inflammatory mediators, tryptophan degradation, and MDD can provide many targets for novel antidepressant therapies. Thus, this review will highlight the role of the kynurenine pathway in the pathophysiology of depression, as well as a novel therapeutic target to classic and new modulators to treat depression based on findings from preclinical and clinical studies.
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    Ogyu, K.; Kubo, K.; Noda, Y.; Iwata, Y.; Tsugawa, S.; Omura, Y.; Wada, M.; Tarumi, R.; Plitman, E.; Moriguchi, S.; Miyazaki, T.; Uchida, H.; Graff-Guerrero, A.; Mimura, M.; Nakajima, S. Kynurenine pathway in depression: A systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2018, 90, 16– 25,  DOI: 10.1016/j.neubiorev.2018.03.023

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    Kynurenine pathway in depression: A systematic review and meta-analysis

    Ogyu, Kamiyu; Kubo, Kaoruhiko; Noda, Yoshihiro; Iwata, Yusuke; Tsugawa, Sakiko; Omura, Yuki; Wada, Masataka; Tarumi, Ryosuke; Plitman, Eric; Moriguchi, Sho; Miyazaki, Takahiro; Uchida, Hiroyuki; Graff-Guerrero, Ariel; Mimura, Masaru; Nakajima, Shinichiro

    Neuroscience & Biobehavioral Reviews (2018), 90 (), 16-25CODEN: NBREDE; ISSN:0149-7634. (Elsevier Ltd.)

    Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiol. of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-anal. about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examd. levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, resp. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were neg. assocd. with study SMDs for KYNA. In conclusion, this meta-anal. revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.
22. 22

    Erhardt, S.; Schwieler, L.; Imbeault, S.; Engberg, G. The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology 2017, 112, 297– 306,  DOI: 10.1016/j.neuropharm.2016.05.020

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    22

    The kynurenine pathway in schizophrenia and bipolar disorder

    Erhardt, Sophie; Schwieler, Lilly; Imbeault, Sophie; Engberg, Goeran

    Neuropharmacology (2017), 112 (Part_B), 297-306CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)

    The kynurenine pathway of tryptophan degrdn. generates several neuroactive compds. Of those, kynurenic acid is an N-methyl-D-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced prodn. of kynurenic acid, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the prodn. of kynurenic acid. One physiol. mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1β that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Exptl. studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, exptl. studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacol. strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia.
23. 23

    Kegel, M. E.; Bhat, M.; Skogh, E.; Samuelsson, M.; Lundberg, K.; Dahl, M.-L.; Sellgren, C.; Schwieler, L.; Engberg, G.; Schuppe-Koistinen, I.; Erhardt, S. Imbalanced Kynurenine Pathway in Schizophrenia. Int. J. Tryptophan Res. 2014, 7, IJTR.S16800,  DOI: 10.4137/IJTR.S16800

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    There is no corresponding record for this reference.
24. 24

    Demitrack, M. A.; Heyes, M. P.; Altemus, M.; Pigott, T. A.; Gold, P. W. Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: Relation to clinical and biochemical variable. Biol. Psychiatry 1995, 37 (8), 512– 520,  DOI: 10.1016/0006-3223(94)00173-Z

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    24

    Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variable

    Demitrack M A; Heyes M P; Altemus M; Pigott T A; Gold P W

    Biological psychiatry (1995), 37 (8), 512-20 ISSN:0006-3223.

    In brain, most L-tryptophan is metabolized to indoleamines, whereas in systemic tissues L-tryptophan is catabolized to kynurenine pathway metabolites. Among these latter compounds are: quinolinic acid, an N-methyl-D-aspartate receptor agonist; kynurenic acid, an antagonist of excitatory amino acid receptors that also reduces quinolinic acid-mediated neurotoxicity; and L-kynurenine, a possible convulsant. Because the metabolism of L-tryptophan through the kynurenine pathway is dependent upon adequate nutrition, we sought to determine whether the impaired nutrition characteristic of eating-disordered patients might be associated with specific disturbances in this metabolic pathway. Cerebrospinal fluid levels of L-tryptophan, quinolinic acid, kynurenic acid, L-kynurenine, and 5-hydroxyindoleacetic acid were measured in medication-free female patients meeting DSM-III-R criteria for either anorexia nervosa (n = 10) or normal-weight bulimia nervosa (n = 22), studied at varying stages of nutritional recovery. Eight healthy, normal-weight females served as a comparison group. Cerebrospinal fluid levels of kynurenic acid were significantly reduced in underweight anorectics, compared to normal females, but returned to normal values with restoration of normal body weight. Although cerebrospinal fluid quinolinic acid levels were not different from controls, the ratio of quinolinic acid to kynurenic acid was significantly increased during the underweight phase of anorexia nervosa. Furthermore, in the eating-disordered patients, kynurenic acid levels in cerebrospinal fluid correlated positively with percent-of-population average body weight.(ABSTRACT TRUNCATED AT 250 WORDS)
25. 25

    Berstad, A.; Raa, J.; Valeur, J. Tryptophan: ‘essential’ for the pathogenesis of irritable bowel syndrome?. Scand. J. Gastroenterol. 2014, 49 (12), 1493– 1498,  DOI: 10.3109/00365521.2014.936034

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    25

    Tryptophan: 'essential' for the pathogenesis of irritable bowel syndrome?

    Berstad Arnold; Raa Jan; Valeur Jorgen

    Scandinavian journal of gastroenterology (2014), 49 (12), 1493-8 ISSN:.

    There is no expanded citation for this reference.
26. 26

    Clarke, G.; McKernan, D. P.; Gaszner, G.; Quigley, E. M.; Cryan, J. F.; Dinan, T. G. A distinct profile of tryptophan metabolism along the kynurenine pathway downstream of toll-like receptor activation in irritable bowel syndrome. Front. Pharmacol. 2012, 3, 90,  DOI: 10.3389/fphar.2012.00090

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    26

    A distinct profile of tryptophan metabolism along the kynurenine pathway downstream of toll-like receptor activation in irritable bowel syndrome

    Clarke, Gerard; McKernan, Declan P.; Gaszner, Gabor; Quigley, Eamonn M.; Cryan, John F.; Dinan, Timothy G.

    Frontiers in Gastrointestinal Pharmacology (2012), 3 (May), 90CODEN: FGPRAL ISSN:. (Frontiers Media S.A.)

    Irritable bowel syndrome (IBS), a disorder of the brain-gut axis, is characterised by the absence of reliable biol. 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 prodn. of other neuroactive agents. We previously reported an increased degrdn. of tryptophan along this immunoresponsive pathway in IBS. Recently, altered cytokine prodn. 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 prodn. 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 h. Cell culture supernatants were then analyzed for both tryptophan and kynurenine concns., 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 prodn. 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 metab. 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 metab. along the kynurenine pathway can be controlled, a novel potential therapeutic strategy in this and other disorders.
27. 27

    Sofia, M. A.; Ciorba, M. A.; Meckel, K.; Lim, C. K.; Guillemin, G. J.; Weber, C. R.; Bissonnette, M.; Pekow, J. R. Tryptophan metabolism through the kynurenine pathway is associated with endoscopic inflammation in ulcerative colitis. Inflammatory Bowel Dis. 2018, 24 (7), 1471– 1480,  DOI: 10.1093/ibd/izy103

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    Tryptophan Metabolism through the Kynurenine Pathway is Associated with Endoscopic Inflammation in Ulcerative Colitis

    Sofia M Anthony; Meckel Katherine; Bissonnette Marc; Pekow Joel R; Ciorba Matthew A; Lim Chai K; Guillemin Gilles J; Weber Christopher R

    Inflammatory bowel diseases (2018), 24 (7), 1471-1480 ISSN:.

    Background and Aims: Mucosal appearance on endoscopy is an important indicator of inflammatory burden and determines prognosis in ulcerative colitis (UC). Inflammation induces tryptophan metabolism along the kynurenine pathway (KP) and yields immunologically relevant metabolites. We sought to examine whether changes in serum tryptophan metabolites and tissue expression of KP enzymes are associated with UC endoscopic and histologic disease severity. Methods: Serum and mucosal samples were prospectively obtained at colonoscopy in patients with UC. Mayo disease activity scores, demographics, smoking status, medications, and outcomes were collected. Serum tryptophan metabolites were analyzed using ultra-high performance liquid chromatography (uHPLC), and gas chromatography-mass spectrometry (GC-MS), and enzyme expression was determined by quantitative real-time polymerase chain reaction. Metabolite and enzyme levels were compared by endoscopic subscore, clinical disease activity, time to surgery, and hospitalization. Results: This study included 99 patients with Mayo endoscopic subscores 0-3. Kynurenic acid/tryptophan ratio (KYNA/T) and expression of indolamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase, kynurinase, and kynurenine monooxygenase correlated positively with endoscopic subscore. Adjusting for age of diagnosis, smoking status, disease extent, and medications yielded significant odds of endoscopic inflammation with increasing KYNA/T (OR 1.0015, P = 0.0186) and IDO1 expression (OR 1.0635, P = 0.0215). The highest tertile ratio of KYNA/T had shorter time to surgery (P = 0.009) and hospitalization (P = 0.01) than the lowest. Conclusions: Increasing KYNA/T is closely associated with endoscopic inflammation and predictive of disease outcomes in patients with UC. These findings identify this novel metabolic association and further support the role of the KP in regulating mucosal inflammation in UC. 10.1093/ibd/izy103_video1izy103.video15788135676001.
28. 28

    Nikolaus, S.; Schulte, B.; Al-Massad, N.; Thieme, F.; Schulte, D. M.; Bethge, J.; Rehman, A.; Tran, F.; Aden, K.; Häsler, R.; Moll, N.; Schütze, G.; Schwarz, M. J.; Waetzig, G. H.; Rosenstiel, P.; Krawczak, M.; Szymczak, S.; Schreiber, S. Increased tryptophan metabolism Is associated with activity of inflammatory bowel diseases. Gastroenterology 2017, 153 (6), 1504– 1516,  DOI: 10.1053/j.gastro.2017.08.028

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    28

    Increased Tryptophan Metabolism Is Associated With Activity of Inflammatory Bowel Diseases

    Nikolaus, Susanna; Schulte, Berenice; Al-Massad, Natalie; Thieme, Florian; Schulte, Dominik M.; Bethge, Johannes; Rehman, Ateequr; Tran, Florian; Aden, Konrad; Haesler, Robert; Moll, Natalie; Schuetze, Gregor; Schwarz, Markus J.; Waetzig, Georg H.; Rosenstiel, Philip; Krawczak, Michael; Szymczak, Silke; Schreiber, Stefan

    Gastroenterology (2017), 153 (6), 1504-1516.e2CODEN: GASTAB; ISSN:0016-5085. (Elsevier)

    Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their assocn. with clin. and serol. features. We studied 535 consecutive patients with IBD (211 with ulcerative colitis [UC], 234 with Crohn's disease [CD]; 236 male), enrolled in Germany from August 2013 through Apr. 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liq. chromatog. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by ELISA. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate assocns. between serum levels of tryptophan and compn. of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of mRNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients' disease activity scores, medications, lab. assessments, and clin. examns. during recruitment and follow-up visits. Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 × 10-6) with a stronger redn. in patients with CD (vs control; P = 1.1 × 10-10) than UC (vs control; P = 2.8 × 10-3). We found a neg. correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of mRNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of mRNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The compn. of the fecal microbiota assocd. with serum levels of tryptophan. Anal. of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concn. of interleukin 22 assocd. with disease activity in patients with IBD; there was an inverse assocn. between levels of interleukin 22 and serum levels of tryptophan. In an anal. of serum samples from more than 500 patients with IBD, we obsd. a neg. correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites-esp. of quinolinic acid-indicated a high activity of tryptophan degrdn. in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clin. studies are needed to det. whether modification of intestinal tryptophan pathways affects the severity of IBD.
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    Mole, D. J.; Webster, S. P.; Uings, I.; Zheng, X.; Binnie, M.; Wilson, K.; Hutchinson, J. P.; Mirguet, O.; Walker, A.; Beaufils, B.; Ancellin, N.; Trottet, L.; Bénéton, V.; Mowat, C. G.; Wilkinson, M.; Rowland, P.; Haslam, C.; McBride, A.; Homer, N. Z. M.; Baily, J. E.; Sharp, M. G. F.; Garden, O. J.; Hughes, J.; Howie, S. E. M.; Holmes, D. S.; Liddle, J.; Iredale, J. P. Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. Nat. Med. 2016, 22 (2), 202– 209,  DOI: 10.1038/nm.4020

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    Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

    Mole, Damian J.; Webster, Scott P.; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P.; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Beneton, Veronique; Mowat, Christopher G.; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie Z. M.; Baily, James E.; Sharp, Matthew G. F.; Garden, O. James; Hughes, Jeremy; Howie, Sarah E. M.; Holmes, Duncan S.; Liddle, John; Iredale, John P.

    Nature Medicine (New York, NY, United States) (2016), 22 (2), 202-209CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metab., is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochem. phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in exptl. AP-MODS. A medicinal chem. strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallog. at 3.2 Å resoln. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in crit. illness.
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    Jaworek, J.; Szklarczyk, J.; Jaworek, A. K.; Nawrot-Pora̧bka, K.; Leja-Szpak, A.; Bonior, J.; Kot, M. Protective effect of melatonin on acute pancreatitis. Int. J. Inflammation 2012, 2012, 173675,  DOI: 10.1155/2012/173675

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    Protective effect of melatonin on acute pancreatitis

    Jaworek Jolanta; Szklarczyk Joanna; Jaworek Andrzej K; Nawrot-PorAbka Katarzyna; Leja-Szpak Anna; Bonior Joanna; Kot Michalina

    International journal of inflammation (2012), 2012 (), 173675 ISSN:.

    Melatonin, a product of the pineal gland, is released from the gut mucosa in response to food ingestion. Specific receptors for melatonin have been detected in many gastrointestinal tissues including the pancreas. Melatonin as well as its precursor, L-tryptophan, attenuates the severity of acute pancreatitis and protects the pancreatic tissue from the damage caused by acute inflammation. The beneficial effect of melatonin on acute pancreatitis, which has been reported in many experimental studies and supported by clinical observations, is related to: (1) enhancement of antioxidant defense of the pancreatic tissue, through direct scavenging of toxic radical oxygen (ROS) and nitrogen (RNS) species, (2) preservation of the activity of antioxidant enzymes; such as superoxide dismutase (SOD), catalase (CAT), or glutathione peroxidase (GPx), (3) the decline of pro-inflammatory cytokine tumor necrosis α (TNFα) production, accompanied by stimulation of an anti-inflammatory IL-10, (4) improvement of pancreatic blood flow and decrease of neutrophil infiltration, (5) reduction of apoptosis and necrosis in the inflamed pancreatic tissue, (6) increased production of chaperon protein (HSP60), and (7) promotion of regenerative process in the pancreas. Conclusion. Endogenous melatonin produced from L-tryptophan could be one of the native mechanisms protecting the pancreas from acute damage and accelerating regeneration of this gland. The beneficial effects of melatonin shown in experimental studies suggest that melatonin ought to be employed in the clinical trials as a supportive therapy in acute pancreatitis and could be used in people at high risk for acute pancreatitis to prevent the development of pancreatic inflammation.
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    Kosek, M. N.; Mduma, E.; Kosek, P. S.; Lee, G. O.; Svensen, E.; Pan, W. K. Y.; Olortegui, M. P.; Bream, J. H.; Patil, C.; Asayag, C. R.; Sanchez, G. M.; Caulfield, L. E.; Gratz, J.; Yori, P. P. Plasma tryptophan and the kynurenine-tryptophan ratio are associated with the acquisition of statural growth deficits and oral vaccine underperformance in populations with environmental enteropathy. Am. J. Trop. Med. Hyg. 2016, 95 (4), 928– 937,  DOI: 10.4269/ajtmh.16-0037

    Google Scholar

    There is no corresponding record for this reference.
32. 32

    Mayneris-Perxachs, J.; Swann, J. R. Metabolic phenotyping of malnutrition during the first 1000 days of life. Eur. J. Nutr. 2018,  DOI: 10.1007/s00394-018-1679-0

    Google Scholar

    There is no corresponding record for this reference.
33. 33

    Mayneris-Perxachs, J.; Lima, A. A. M.; Guerrant, R. L.; Leite, Á. M.; Moura, A. F.; Lima, N. L.; Soares, A. M.; Havt, A.; Moore, S. R.; Pinkerton, R.; Swann, J. R. Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children. Sci. Rep. 2016, 6, 19780,  DOI: 10.1038/srep19780

    Google Scholar

    33

    Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children

    Mayneris-Perxachs, Jordi; Lima, Aldo A. M.; Guerrant, Richard L.; Leite, Alvaro M.; Moura, Alessandra F.; Lima, Noelia L.; Soares, Alberto M.; Havt, Alexandre; Moore, Sean R.; Pinkerton, Relana; Swann, Jonathan R.

    Scientific Reports (2016), 6 (), 19780CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

    Enteric infections, enteropathy and undernutrition in early childhood are preventable risk factors for child deaths, impaired neurodevelopment, and later life metabolic diseases. However, the mechanisms linking these exposures and outcomes remain to be elucidated, as do biomarkers for identifying children at risk. By examg. the urinary metabolic phenotypes of nourished and undernourished children participating in a case-control study in Semi-Arid Brazil, we identified key differences with potential relevance to mechanisms, biomarkers and outcomes. Undernutrition was found to perturb several biochem. pathways, including choline and tryptophan metab., while also increasing the proteolytic activity of the gut microbiome. Furthermore, a metabolic adaptation was obsd. in the undernourished children to reduce energy expenditure, reflected by increased N-methylnicotinamide and reduced β-aminoisobutyric acid excretion. Interestingly, accelerated catch-up growth was obsd. in those undernourished children displaying a more robust metabolic adaptation several months earlier. Hence, urinary N-methylnicotinamide and β-aminoisobutyric acid represent promising biomarkers for predicting short-term growth outcomes in undernourished children and for identifying children destined for further growth shortfalls. These findings have important implications for understanding contributors to long-term sequelae of early undernutrition, including cognitive, growth, and metabolic functions.
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    Crenn, P.; Messing, B.; Cynober, L. Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin. Nutr. 2008, 27 (3), 328– 339,  DOI: 10.1016/j.clnu.2008.02.005

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    34

    Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction

    Crenn, Pascal; Messing, Bernard; Cynober, Luc

    Clinical Nutrition (2008), 27 (3), 328-339CODEN: CLNUDP; ISSN:0261-5614. (Elsevier Ltd.)

    A review. In human, citrulline (plasma concn. about 40 μmol/L) is an amino acid involved in intermediary metab. and that is not incorporated in proteins. Circulating citrulline is mainly produced by enterocytes of the small bowel. For this reason plasma or serum citrulline concn. has been proposed as a biomarker of remnant small bowel mass and function. This article reviews this concept and its metabolic basis. Conditions in which there is a significantly reduced small bowel enterocyte mass and function and a plasma or serum citrulline were measured in adults and children. These studies included patients with a short bowel syndrome, villous atrophy states, Crohn's disease, during monitoring of digestive toxicity of chemotherapy and radiotherapy or follow-up of patients after small bowel transplantation. In all these situations, with more than 500 studied patients a decreased level of plasma citrulline correlated with the reduced enterocyte mass independently of nutritional and inflammatory status. A close correlation between small bowel remnant length and citrullinemia was found. In addn., diagnosis of intestinal failure was assessed through plasma citrulline levels in severe small bowel diseases in which there is a marked enterocyte mass redn. The threshold for establishing a diagnosis of intestinal failure is lower in villous atrophy disease (10 μmol/L) than in short bowel syndrome (20 μmol/L). Compromised renal function is an important factor when considering plasma citrulline levels as a marker of intestinal failure as this potentially can increase circulating citrulline values. Reduced plasma citrulline levels are an innovative quant. biomarker of significantly reduced enterocyte mass and function in different disease states in humans.
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    Baydar, T.; Yuksel, O.; Sahin, T. T.; Dikmen, K.; Girgin, G.; Sipahi, H.; Kurukahvecioglu, O.; Bostanci, H.; Sare, M. Neopterin as a prognostic biomarker in intensive care unit patients. J. Crit. Care 2009, 24 (3), 318– 321,  DOI: 10.1016/j.jcrc.2008.06.013

    Google Scholar

    35

    Neopterin as a prognostic biomarker in intensive care unit patients

    Baydar, Terken; Yuksel, Osman; Sahin, Tolga Tevfik; Dikmen, Kursat; Girgin, Gozde; Sipahi, Hande; Kurukahvecioglu, Osman; Bostanci, Hasan; Sare, Mustafa

    Journal of Critical Care (2009), 24 (3), 318-321CODEN: JCCAER; ISSN:0883-9441. (Elsevier Inc.)

    Purpose: The present study was undertaken to evaluate urinary neopterin in intensive care unit patients. Materials and Methods: Urinary neopterin levels were detd. in systemic inflammatory response syndrome (n = 10), sepsis (n = 18), septic shock (n = 9), and multiple organ dysfunction syndrome (n = 5). It was tested whether neopterin is a differential parameter among the patient groups. Furthermore, the results were also evaluated by comparing with a healthy control group (n = 30), and the relationship between neopterin and mortality or Acute Physiol. and Chronic Health Evaluation II scores were investigated. Results: Neopterin levels of the control group and patients were detected as 111 ± 11 and 3850 ± 1081 μmol/mol creatinine, resp. (P < .05). It was significantly increased in the sepsis and septic shock groups compared to the systemic inflammatory response syndrome group (P < .05). Neopterin levels were significantly higher in the patients with mortality and lower Acute Physiol. and Chronic Health Evaluation II scores. Conclusion: This study showed that monitoring of urinary neopterin profile can be used in intensive care units to show the degree and prognosis of the disease.
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    Melichar, B.; Spisarová, M.; Bartoušková, M.; Krčmová, L. K.; Javorská, L.; Študentová, H. Neopterin as a biomarker of immune response in cancer patients. Ann. Transl. Med. 2017, 5 (13), 280,  DOI: 10.21037/atm.2017.06.29

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    36

    Neopterin as a biomarker of immune response in cancer patients

    Melichar, Bohuslav; Spisarova, Martina; Bartouskova, Marie; Krcmova, Lenka Kujovska; Javorska, Lenka; Studentova, Hana

    Annals of Translational Medicine (2017), 5 (13), 280/1-280/12CODEN: ATMNDX; ISSN:2305-5847. (AME Publishing Co.)

    With the advent of immunotherapy the topic of biomarkers of immune response is of high interest. Along with the expression of programmed death ligand 1 (PD-L1) or tumor infiltrating lymphocytes (TIL), biomarkers of macrophage activation could be of interest. Neopterin is a biomarker of immune activation increased in different disorders assocd. with immune activation, including cancer. Neopterin synthesis is induced by interferon-γ that also induces indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing catabolism of tryptophan to kynurenine. Increased urinary or serum concns. of neopterin have been assocd. with poor prognosis across a spectrum of malignant disorders of different primary location. Neopterin concn. in peripheral blood as well as in the tumor microenvironment correlates with phenotypic and functional changes of lymphocytes, indicating immune dysfunction. Increased neopterin concns. are also accompanied by increased rate of conversion of tryptophan to kynurenine. Increasing neopterin concns. also accompany side effects of anticancer treatment and could predict subsequent complications. Although almost four decades have elapsed since the discovery of increased neopterin concns. in cancer patients, the full potential of neopterin as a biomarker in this setting has not been so far realized.
37. 37

    Wang, R.; Tang, A. Simultaneous determination of kynurenine and tryptophan in serum by high performance liquid chromatography. Chin. J. Chromatogr. 2006, 24 (2), 140– 143,  DOI: 10.1016/S1872-2059(06)60009-6

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    Simultaneous determination of kynurenine and tryptophan in serum by high performance liquid chromatography

    Wang Rui; Tang Aiguo

    Se pu = Chinese journal of chromatography (2006), 24 (2), 140-3 ISSN:1000-8713.

    A method was established for the simultaneous determination of kynurenine (Kyn) and tryptophan (Trp) in serum by high performance liquid chromatography-ultraviolet detection (HPLC-UV). It employed a Symmetry Shield RP-C18 column (150 mm x 3.9 mm i.d., 5 microm) and a mobile phase of 15 mmol/L sodium acetate-acetic acid solution containing 2.7% (v/v) acetonitrile (pH 3.6) at a flow rate of 1.0 mL/min. The ultraviolet detector was operated at 225 nm. Serum samples were first precipitated with a 5.0% perchloric acid solution, then centrifuged to remove protein residue and finally analyzed by HPLC. The retention time of Kyn was 3.5 min, the linear range of the method was from 0.098 to 49 micromol/L, and the detection limit was 0.02 micromol/L. The recoveries of Kyn were from 90.82% to 93.45%, the intraday and interday variations were 2.37% and 3.66%, respectively. The retention time of Trp was 8.1 min, the linear range of the method was from 4.9 to 490 micromol/L, and the detection limit was 0.20 micromol/L. The recoveries of Trp were from 95.51% to 98.67%, the intraday and interday variations were 1.50% and 2.65%, respectively. The method is simple, fast, accurate, and suitable for routine analysis.
38. 38

    Hu, L.-J.; Li, X.-F.; Hu, J.-Q.; Ni, X.-J.; Lu, H.-Y.; Wang, J.-J.; Huang, X.-N.; Lin, C.-X.; Shang, D.-W.; Wen, Y.-G. A simple HPLC–MS/MS method for determination of tryptophan, kynurenine and kynurenic acid in human serum and its potential for monitoring antidepressant therapy. J. Anal. Toxicol. 2017, 41 (1), 37– 44,  DOI: 10.1093/jat/bkw071

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    38

    A simple HPLC-MS/MS method for determination of tryptophan, kynurenine and kynurenic acid in human serum and its potential for monitoring antidepressant therapy

    Hu, Li-Jun; Li, Xiao-Fang; Hu, Jin-Qing; Ni, Xiao-Jia; Lu, Hao-Yang; Wang, Jia-Jia; Huang, Xiang-Ning; Lin, Chao-Xian; Shang, De-Wei; Wen, Yu-Guan

    Journal of Analytical Toxicology (2017), 41 (1), 37-44CODEN: JATOD3; ISSN:1945-2403. (Oxford University Press)

    The kynurenine pathway, in which tryptophan is metabolized to kynurenine and kynurenic acid, has been linked to depression. A rapid and highly reproducible liq.-chromatog.-tandem mass spectrometry (LC-MS/MS) method were established for detg. tryptophan, kynurenine and kynurenic acid in human serum. Biol. samples were pptd. with methanol before sepn. on an Agilent Eclipse XDB-C18. The stable-isotope-labeled internal stds. (kynurenine-13C415N and kynurenic acid-d5) were used for quantification. Detection was performed using multiple reaction monitoring in electrospray ionization mode at m/z 205.1→188.1 for tryptophan, m/z 209.1→146.1 for kynurenine, m/z 190.1→144.1 for kynurenic acid. Good linearity of analyte to internal std. peak area ratios was seen in the concn. range 1,000-50,000 ng/mL for tryptophan, 100-5,000 ng/mL for kynurenine and 1-60 ng/mL for kynurenic acid. Pooled drugfree human serum was purified using activated charcoal and the method was shown to be linear, with validation parameters within acceptable limits. The newly developed method was successfully used to det. concns. of tryptophan, kynurenine and kynurenic acid in serum from 26 healthy volunteers and 54 patients with depression. Concns. of tryptophan and kynurenine were lower in serum from depressed individuals than from healthy individuals.
39. 39

    Huang, Y.; Louie, A.; Yang, Q.; Massenkoff, N.; Xu, C.; Hunt, P. W.; Gee, W. A simple LC–MS/MS method for determination of kynurenine and tryptophan concentrations in human plasma from HIV-infected patients. Bioanalysis 2013, 5 (11), 1397– 1407,  DOI: 10.4155/bio.13.74

    Google Scholar

    39

    A simple LC-MS/MS method for determination of kynurenine and tryptophan concentrations in human plasma from HIV-infected patients

    Huang, Yong; Louie, Alexander; Yang, Qiyun; Massenkoff, Nicholas; Xu, Connie; Hunt, Peter W.; Gee, Winnie

    Bioanalysis (2013), 5 (11), 1397-1407CODEN: BIOAB4; ISSN:1757-6180. (Future Science Ltd.)

    Background: Indoleamine 2,3-dioxygenase, catalyzing tryptophan (Trp) metab. through the kynurenine (Kyn) metabolic pathway, plays important roles in immune suppression and the CNS. In this article, we report a simple, rapid and specific LC-MS/MS method for accurate detn. of Kyn and Trp concns. in human plasma from HIV-infected patients. Results: The human plasma sample (100 μl) was mixed with Kyn-d4 and Trp-d5 internal stds. and then pptd. with trifluoroacetic acid. The supernatant was directly analyzed by LC-MS/MS. The assay using surrogate matrix calibrators was validated for precision, accuracy, matrix effect, extn. efficiency and stability. Some assay validation issues for endogenous substance bioanal. using an LC-MS/MS method are discussed. Conclusion: A simple, specific and reproducible LC-MS/MS method has been developed and validated for measuring Kyn and Trp in human plasma samples.
40. 40

    Marcos, J.; Renau, N.; Valverde, O.; Aznar-Laín, G.; Gracia-Rubio, I.; Gonzalez-Sepulveda, M.; Pérez-Jurado, L. A.; Ventura, R.; Segura, J.; Pozo, O. J. Targeting tryptophan and tyrosine metabolism by liquid chromatography tandem mass spectrometry. J. Chromatogr. A 2016, 1434, 91– 101,  DOI: 10.1016/j.chroma.2016.01.023

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    40

    Targeting tryptophan and tyrosine metabolism by liquid chromatography tandem mass spectrometry

    Marcos, Josep; Renau, Nuria; Valverde, Olga; Aznar-Lain, Gemma; Gracia-Rubio, Irene; Gonzalez-Sepulveda, Marta; Perez-Jurado, Luis Alberto; Ventura, Rosa; Segura, Jordi; Pozo, Oscar J.

    Journal of Chromatography A (2016), 1434 (), 91-101CODEN: JCRAEY; ISSN:0021-9673. (Elsevier B.V.)

    An imbalance in tryptophan (Trp) and tyrosine (Tyr) metabolites is assocd. with neurol. and inflammatory disorders. The accurate and precise measurement of these compds. in biol. specimens is a powerful tool to understand the biochem. state in several diseases. A rapid, accurate and sensitive method based on liq. chromatog.-tandem mass spectrometry (LC-MS/MS) for the targeted anal. of the metab. of Trp and Tyr has been developed and validated. The method allows for the adequate quantification of Trp, Tyr and, eight Trp metabolites, three Tyr metabolites, together with four competitive large neutral amino acids. Serotonin, 5-hydroxyindoleacetic acid, kynurenine, kynurenic acid, dopamine, and homovanillic acid were among the targeted compds. Sample prepn., chromatog. sepn. and mass spectrometric detection were optimized in human urine, human plasma and mice prefrontal cortex exts. The method is linear (r > 0.98) in the range of endogenous concns. for all studied metabolites. In general, the limits of detection were suitable for the detection of the endogenous levels. Intra- and inter-assay precisions <25% and accuracies ranging from 80 to 120% were found for most of the analytes. The use of labeled internal stds. cor. the moderate matrix effect obsd. for some compds. The applicability of the method was confirmed by analyzing urine samples collected from 13 healthy volunteers and comparing the results with previously established normal ranges. In addn., urine samples from two patients and a heterozygous carrier of a family with disturbed monoamine metab. due to a loss of function mutation in the MAOA gene (X-linked) were analyzed and compared with samples from controls. All data together show the potential of the developed approach for targeted metabolomic studies.
41. 41

    Midttun, Ø; Hustad, S.; Ueland, P. M. Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom. 2009, 23 (9), 1371– 1379,  DOI: 10.1002/rcm.4013

    Google Scholar

    41

    Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry

    Midttun, Oeivind; Hustad, Steinar; Ueland, Per M.

    Rapid Communications in Mass Spectrometry (2009), 23 (9), 1371-1379CODEN: RCMSEF; ISSN:0951-4198. (John Wiley & Sons Ltd.)

    Vitamins B2 and B6 serve as cofactors in enzymic reactions involved in tryptophan and homocysteine metab. Plasma concns. of these vitamins and amino acids are related to smoking and inflammation, and correlate with other markers of immune activation. Large-scale studies of these relations have been hampered by lack of suitable anal. methods. The assay described includes riboflavin, five vitamin B6 forms (pyridoxal 5'-phosphate, pyridoxal, 4-pyridoxic acid, pyridoxine and pyridoxamine), tryptophan and six tryptophan metabolites (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid and 3-hydroxyanthranilic acid), cystathionine, neopterin and cotinine. Trichloroacetic acid contg. 13 isotope-labeled internal stds. was added to 60 μL of plasma, the mixt. was centrifuged, and the resulting supernatant used for anal. The analytes were sepd. within 5 min on a stable-bond C8 column by a gradient-type mobile phase contg. acetonitrile, heptafluorobutyric acid and high concn. (650 mmol/L) of acetic acid, and detected using electrospray ionization tandem mass spectrometry (ESI-MS/MS). The mobile phase ensured sufficient sepn. and high ionization efficiency of all analytes. Recoveries were 72-123% and within-day and between-day coeffs. of variance (CVs) were 2.5-9.5% and 5.4-16.9%, resp. Limits of detection ranged from 0.05 to 7 nmol/L. The method enables quantification of endogenous plasma concns. of 16 analytes related to B-vitamin status and inflammation, and may prove useful in large-scale epidemiol. studies.
42. 42

    Wang, W.; Zhuang, X.; Liu, W.; Dong, L.; Sun, H.; Du, G.; Ye, L. Determination of kynurnine and tryptophan, biomarkers of indoleamine 2,3-dioxygenase by LC–MS/MS in plasma and tumor. Bioanalysis 2018, 10 (16), 1335– 1344,  DOI: 10.4155/bio-2018-0041

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    There is no corresponding record for this reference.
43. 43

    Hényková, E.; Vránová, H. P.; Amakorová, P.; Pospíšil, T.; Žukauskaitė, A.; Vlčková, M.; Urbánek, L.; Novák, O.; Mareš, J.; Kaňovský, P.; Strnad, M. Stable isotope dilution ultra-high performance liquid chromatography–tandem mass spectrometry quantitative profiling of tryptophan-related neuroactive substances in human serum and cerebrospinal fluid. J. Chromatogr. A 2016, 1437, 145– 157,  DOI: 10.1016/j.chroma.2016.02.009

    Google Scholar

    There is no corresponding record for this reference.
44. 44

    Chen, G.-y.; Zhong, W.; Zhou, Z.; Zhang, Q. Simultaneous determination of tryptophan and its 31 catabolites in mouse tissues by polarity switching UHPLC-SRM-MS. Anal. Chim. Acta 2018, 1037, 200– 210,  DOI: 10.1016/j.aca.2018.02.026

    Google Scholar

    44

    Simultaneous determination of tryptophan and its 31 catabolites in mouse tissues by polarity switching UHPLC-SRM-MS

    Chen, Guan-yuan; Zhong, Wei; Zhou, Zhanxiang; Zhang, Qibin

    Analytica Chimica Acta (2018), 1037 (), 200-210CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)

    Tryptophan (TRP) and its catabolites have attracted a lot of attention because of their clin. significance to human health. Recently, microbiome-gut-brain axis has links to many diseases based on the imbalance of TRP catabolism. By using ultra-HPLC coupled to electrospray ionization triple quadrupole mass spectrometry, the authors present a rapid, robust and comprehensive method to det. 31 TRP catabolites covering three major pathways - kynurenic, serotonergic and bacterial degrdn. - within 5 min. Polarity switching was employed to analyze catabolites in both ionization modes simultaneously for greatly improved anal. throughput. The intra-day and inter-day precision were 0.5-15.8% and 1.5-16.7%, resp. Accuracy was 75.8-126.9%. The developed method was applied to study the tissue level of TRP catabolites in the liver, ileum, ileal contents, brain and plasma samples from 8 mice, and clear differences in the distribution of TRP catabolites were obsd. in different tissues. Ratios of key catabolites to TRP were used to evaluate the activities of specific enzyme and pathway in resp. tissues. This method has potential in high throughput anal. of TRP catabolites in biol. matrixes, which can facilitate understanding the influence of TRP catabolites on microbiome-gut-brain axis and on human health.
45. 45

    Chekmeneva, E.; dos Santos Correia, G.; Gómez-Romero, M.; Stamler, J.; Chan, Q.; Elliott, P.; Nicholson, J. K.; Holmes, E. Ultra-Performance liquid chromatography–high-resolution mass spectrometry and direct infusion–high-resolution mass spectrometry for combined exploratory and targeted metabolic profiling of human urine. J. Proteome Res. 2018, 17 (10), 3492– 3502,  DOI: 10.1021/acs.jproteome.8b00413

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    45

    Ultra-Performance Liquid Chromatography-High-Resolution Mass Spectrometry and Direct Infusion-High-Resolution Mass Spectrometry for Combined Exploratory and Targeted Metabolic Profiling of Human Urine

    Chekmeneva, Elena; dos Santos Correia, Goncalo; Gomez-Romero, Maria; Stamler, Jeremiah; Chan, Queenie; Elliott, Paul; Nicholson, Jeremy K.; Holmes, Elaine

    Journal of Proteome Research (2018), 17 (10), 3492-3502CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)

    The application of metabolic phenotyping to epidemiol. studies involving thousands of biofluid samples presents a challenge for the selection of anal. platforms that meet the requirements of high-throughput precision anal. and cost-effectiveness. Here direct infusion-nanoelectrospray (DI-nESI) was compared with an ultra-performance liq. chromatog. (UPLC)-high-resoln. mass spectrometry (HRMS) method for metabolic profiling of an exemplary set of 132 human urine samples from a large epidemiol. cohort. Both methods were developed and optimized to allow the simultaneous collection of high-resoln. urinary metabolic profiles and quant. data for a selected panel of 35 metabolites. The total run time for measuring the sample set in both polarities by UPLC-HRMS was 5 days compared with 9 h by DI-nESI-HRMS. To compare the classification ability of the two MS methods, the authors performed exploratory anal. of the full-scan HRMS profiles to detect sex-related differences in biochem. compn. Although metabolite identification is less specific in DI-nESI-HRMS, the significant features responsible for discrimination between sexes were mostly the same in both MS-based platforms. Using the quant. data, 10 metabolites have strong correlation (Pearson's r > 0.9 and Passing-Bablok regression slope of 0.8-1.3) and good agreement assessed by Bland-Altman plots between UPLC-HRMS and DI-nESI-HRMS and thus can be measured using a cheaper and less sample- and time-consuming method. A further twenty metabolites showed acceptable correlation between the two methods with only five metabolites showing weak correlation (Pearson's r < 0.4) and poor agreement due to the overestimation of the results by DI-nESI-HRMS.
46. 46

    FDA. Guidance for Industry Bioanalytical Method Validation. Biopharmaceutics; FDA: 2018; https://www.fda.gov/downloads/drugs/guidances/ucm070107.pdf (accessed February 14, 2019).

    Google Scholar

    There is no corresponding record for this reference.
47. 47

    Tiwari, G.; Tiwari, R. Bioanalytical method validation: An updated review. Pharm. Methods 2010, 1 (1), 25– 38,  DOI: 10.4103/2229-4708.72226

    Google Scholar

    47

    Bioanalytical method validation: An updated review

    Tiwari Gaurav; Tiwari Ruchi

    Pharmaceutical methods (2010), 1 (1), 25-38 ISSN:2229-4708.

    The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development, culminating in a marketing approval. The objective of this paper is to review the sample preparation of drug in biological matrix and to provide practical approaches for determining selectivity, specificity, limit of detection, lower limit of quantitation, linearity, range, accuracy, precision, recovery, stability, ruggedness, and robustness of liquid chromatographic methods to support pharmacokinetic (PK), toxicokinetic, bioavailability, and bioequivalence studies. Bioanalysis, employed for the quantitative determination of drugs and their metabolites in biological fluids, plays a significant role in the evaluation and interpretation of bioequivalence, PK, and toxicokinetic studies. Selective and sensitive analytical methods for quantitative evaluation of drugs and their metabolites are critical for the successful conduct of pre-clinical and/or biopharmaceutics and clinical pharmacology studies.
48. 48

    Gika, H. G.; Theodoridis, G. A.; Wingate, J. E.; Wilson, I. D. Within-day reproducibility of an HPLC–MS-based method for metabonomic analysis: Application to human urine. J. Proteome Res. 2007, 6 (8), 3291– 3303,  DOI: 10.1021/pr070183p

    Google Scholar

    48

    Within-Day Reproducibility of an HPLC-MS-Based Method for Metabonomic Analysis: Application to Human Urine

    Gika, Helen G.; Theodoridis, Georgios A.; Wingate, Julia E.; Wilson, Ian D.

    Journal of Proteome Research (2007), 6 (8), 3291-3303CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)

    Self-evidently, research in areas supporting "systems biol." such as genomics, proteomics, and metabonomics are critically dependent on the generation of sound anal. data. Metabolic phenotyping using LC-MS-based methods is currently at a relatively early stage of development, and approaches to ensure data quality are still developing. As part of studies on the application of LC-MS in metabonomics, the within-day reproducibility of LC-MS, with both pos. and neg. electrospray ionization (ESI), has been investigated using a std. "quality control" (QC) sample. The results showed that the first few injections on the system were not representative, and should be discarded, and that reproducibility was critically dependent on signal intensity. On the basis of these findings, an anal. protocol for the metabonomic anal. of human urine has been developed with proposed acceptance criteria based on a step-by-step assessment of the data. Short-term sample stability for human urine was also assessed. Samples were stable for at least 20 h at 4° in the autosampler while queuing for anal. Samples stored at either -20 or -80° for up to 1 mo were indistinguishable on subsequent LC-MS anal. Overall, by careful monitoring of the QC data, it is possible to demonstrate that the "within-day" reproducibility of LC-MS is sufficient to ensure data quality in global metabolic profiling applications.
49. 49

    Guo, X.; Lankmayr, E. Phospholipid-based matrix effects in LC–MS bioanalysis. Bioanalysis 2011, 3 (4), 349– 352,  DOI: 10.4155/bio.10.213

    Google Scholar

    There is no corresponding record for this reference.
50. 50

    Chiu, M. L.; Lawi, W.; Snyder, S. T.; Wong, P. K.; Liao, J. C.; Gau, V. Matrix effects - a challenge toward automation of molecular analysis. JALA 2010, 15 (3), 233– 242,  DOI: 10.1016/j.jala.2010.02.001

    Google Scholar

    50

    Matrix effects-a challenge toward automation of molecular analysis

    Chiu, May L.; Lawi, Walson; Snyder, Steven T.; Wong, Pak Kin; Liao, Joseph C.; Gau, Vincent

    JALA (2010), 15 (3), 233-242CODEN: JALLFO; ISSN:1535-5535. (Elsevier)

    A review. Many components in biol. matrixes influence the result of an anal., affecting assay sensitivity and reproducibility. Improved matrix management becomes crit. as requirements for higher assay sensitivity and increased process throughput become more demanding. There are several robotic lab. automation systems that are com. available, which serve to minimize matrix interference by performing purifn. and extn. protocols. However, there is an unmet need of inline matrix effect redn. solns. to reduce the processing time and cost for automated sample prepn. In microfluidics, effective matrix management is essential for developing fully integrated systems capable of meeting these requirements. This review surveys current biol. matrix management techniques for liq. chromatog.-tandem mass spectrometry (LC-MS/MS) methods and binding assays with a view toward building automatable processes. For some systems, simple sample-prepn. methods, such as diln. and protein pptn. (PPT), are sufficient, whereas other systems require labor-intensive methods, such as liq.-liq. extn. (LLE) and solid-phase extn. (SPE). To achieve high throughput, PPT, LLE, and SPE have been adopted to 96-well-plate format. Online SPE has also been coupled with LC-MS/MS to automate sample prepn. and anal. of urine, plasma, and serum matrixes. However, offline processing of whole blood is still required to obtain plasma and serum. The ultimate goal of implementing sample prepn. to reduce matrix effects within untreated sample is to achieve reproducibility and sensitivity required by the application; therefore, inline sample prepn. integrated with mol. anal. will be highly significant for lab. automation. Electrokinetic methods have the potential of handling whole-blood, urine, and saliva samples and can be incorporated into microfluidic systems for full automation. Optimization of anal. conditions and the use of appropriate stds. have likewise assisted in reducing or correcting matrix effects and will also be discussed.
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    Trufelli, H.; Palma, P.; Famiglini, G.; Cappiello, A. An overview of matrix effects in liquid chromatography–mass spectrometry. Mass Spectrom. Rev. 2011, 30 (3), 491– 509,  DOI: 10.1002/mas.20298

    Google Scholar

    51

    An overview of matrix effects in liquid chromatography-mass spectrometry

    Trufelli, Helga; Palma, Pierangela; Famiglini, Giorgio; Cappiello, Achille

    Mass Spectrometry Reviews (2011), 30 (3), 491-509CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)

    A review. Matrix-dependent signal suppression or enhancement represents a major drawback in quant. anal. with liq. chromatog. coupled to atm. pressure ionization mass spectrometry (LC-API-MS). Because matrix effects (ME) might exert a detrimental impact on important method parameters (limit of detection, limit of quantification, linearity, accuracy, and precision), they have to be tested and evaluated during validation procedure. This review gives a detailed description on when these phenomena might be expected, and how they can be evaluated. The major sources of ME are discussed and illustrated with examples from bioanal., pharmaceutical, environmental, and food anal. Because there is no universal soln. for ME, the main strategies to overcome these phenomena are described. Special emphasis is devoted to the sample-prepn. procedures as well as to the recent improvements on chromatog. and mass spectrometric conditions. An overview of the main calibration techniques to compensate for ME is also presented. All these solns. can be used alone or in combination to retrieve the performance of the LC-MS for a particular matrix-analyte combination. © 2010 Wiley Periodicals, Inc., Mass Spec Rev 30:491-509, 2011.
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    Thakare, R.; Chhonker, Y. S.; Gautam, N.; Alamoudi, J. A.; Alnouti, Y. Quantitative analysis of endogenous compounds. J. Pharm. Biomed. Anal. 2016, 128, 426– 437,  DOI: 10.1016/j.jpba.2016.06.017

    Google Scholar

    52

    Quantitative analysis of endogenous compounds

    Thakare, Rhishikesh; Chhonker, Yashpal S.; Gautam, Nagsen; Alamoudi, Jawaher Abdullah; Alnouti, Yazen

    Journal of Pharmaceutical and Biomedical Analysis (2016), 128 (), 426-437CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)

    A review. Accurate quant. anal. of endogenous analytes is essential for several clin. and non-clin. applications. LC-MS/MS is the technique of choice for quant. analyses. Abs. quantification by LC/MS requires prepg. std. curves in the same matrix as the study samples so that the matrix effect and the extn. efficiency for analytes are the same in both the std. and study samples. However, by definition, analyte-free biol. matrixes do not exist for endogenous compds. To address the lack of blank matrixes for the quantification of endogenous compds. by LC-MS/MS, four approaches are used including the std. addn., the background subtraction, the surrogate matrix, and the surrogate analyte methods. This review article presents an overview of these approaches, cites and summarizes their applications, and compares their advantages and disadvantages. In addn., in details, validation requirements and compatibility with FDA guidelines to ensure method reliability in quantifying endogenous compds. are discussed. The std. addn., background subtraction, and the surrogate analyte approaches allow the use of the same matrix for the calibration curve as the one to be analyzed in the test samples. However, in the surrogate matrix approach, various matrixes such as artificial, stripped, and neat matrixes were used as surrogate matrixes for the actual matrix of study samples. For the surrogate analyte approach, it is required to demonstrate similarity in matrix effect and recovery between surrogate and authentic endogenous analytes. Similarly, for the surrogate matrix approach, it is required to demonstrate similar matrix effect and extn. recovery in both the surrogate and original matrixes. All these methods represent indirect approaches to quantify endogenous compds. and regardless of what approach is followed, it has to be shown that none of the validation criteria have been compromised due to the indirect analyses.
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    Gray, N.; Zia, R.; King, A.; Patel, V. C.; Wendon, J.; McPhail, M. J. W.; Coen, M.; Plumb, R. S.; Wilson, I. D.; Nicholson, J. K. High-speed quantitative UPLC-MS analysis of multiple amines in human plasma and serum via precolumn derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate: Application to acetaminophen-induced liver failure. Anal. Chem. 2017, 89 (4), 2478– 2487,  DOI: 10.1021/acs.analchem.6b04623

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    53

    High-Speed Quantitative UPLC-MS Analysis of Multiple Amines in Human Plasma and Serum via Precolumn Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate: Application to Acetaminophen-Induced Liver Failure

    Gray, Nicola; Zia, Rabiya; King, Adam; Patel, Vishal C.; Wendon, Julia; McPhail, Mark J. W.; Coen, Muireann; Plumb, Robert S.; Wilson, Ian D.; Nicholson, Jeremy K.

    Analytical Chemistry (Washington, DC, United States) (2017), 89 (4), 2478-2487CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

    A targeted reversed-phase gradient UPLC-MS/MS assay has been developed for the quantification/monitoring of amino acids and amino-contg. compds. in human plasma and serum using pre-column derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQTag UltraTM). Derivatization of the target amino-contg. compds. reagent required minimal sample prepn. and resulted in analytes with excellent chromatog. and mass spectrometric properties. The resulting method, which requires only 10 μL of sample, provides the reproducible and robust sepn. of 66 analytes in 7.5 min, including baseline resoln. of isomers such as e.g. leucine and isoleucine. The assay has been validated for the quantification of 33 amino compds. (predominantly amino acids) over a concn. range from 2-20 and 800μM. Intra- and inter-day accuracy of between 0.05-15.6 and 0.78 -13.7% and precision between 0.91-16.9% and 2.12-15.9% were obtained. A further 33 biogenic amines can be monitored in samples for relative changes in concn. rather than quantification. Application of the assay to samples derived from healthy controls and patients suffering from acetaminophen (APAP, paracetamol) induced acute liver failure (ALF) showed significant differences in the amts. of arom. and branched chain amino acids between the groups as well as a no. of other analytes, including the novel observation of increased concns. of sarcosine in ALF patients. The properties of the developed assay, including short anal. time, make it suitable for high throughput targeted UPLC-ESI-MS/MS metabonomic anal. in clin. and epidemiol. environments.
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    Zhao, X.-E.; Zhu, S.; Yang, H.; You, J.; Song, F.; Liu, Z.; Liu, S. Simultaneous determination of amino acid and monoamine neurotransmitters in PC12 cells and rats models of Parkinson’s disease using a sensitizing derivatization reagent by UHPLC–MS/MS. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2015, 995–996, 15– 23,  DOI: 10.1016/j.jchromb.2015.05.017

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    54

    Simultaneous determination of amino acid and monoamine neurotransmitters in PC12 cells and rats models of Parkinson's disease using a sensitizing derivatization reagent by UHPLC-MS/MS

    Zhao, Xian-En; Zhu, Shuyun; Yang, Hongmei; You, Jinmao; Song, Fengrui; Liu, Zhiqiang; Liu, Shuying

    Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2015), 995-996 (), 15-23CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)

    Multi-analytes simultaneous monitoring of amino acid and monoamine neurotransmitters (NTs) has important scientific significance for their related pathol., physiol. and drug screening. In this work, in virtue of a mass spectrometry sensitizing reagent 10-ethyl-acridone-3-sulfonyl chloride (EASC) as derivatization reagent, an Ultra High Performance Liq. Chromatog.-Tandem Mass Spectrometry (UHPLC-MS/MS) method was developed and validated for simultaneous detn. of six amino acid NTs, two monoamine ones and its one metabolite. The simple and rapid derivatization reaction was innovatively combined with plasma prepn. by using EASC acetonitrile soln. as protein precipitant. This interesting combination brought the advantages of speediness, simpleness and high-throughput in a cost-effective way. Under the optimized conditions, LODs (0.004-3.80 nM) and LOQs (0.014-13.3 nM) of EASC derivatized-NTs were calcd. and found to be significantly lower than those of direct UHPLC-MS/MS detection about 11.5-275.0 and 14.4-371.4 times, resp. Moreover, EASC derivatization significantly improved chromatog. resoln. and matrix effect when compared with direct UPLC-MS/MS detection method without derivatization. Meanwhile, it also brought acceptable precision (3.0-13.0%, peak area CVs%), accuracy (86.4-112.9%), recovery (88.3-107.8%) and stability (3.8-8.5%, peak area CVs%) results. This method was successfully applied for the antiparkinsonian effect evaluation of levodopa and Ginsenoside Rg1 using PC12 cells and rats models by measuring multiple NTs. This provided a new method for the NTs related studies in the future.
55. 55

    Geisler, S.; Mayersbach, P.; Becker, K.; Schennach, H.; Fuchs, D.; Gostner, J. M. Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors. Pteridines 2015, 26, 31– 36,  DOI: 10.1515/pterid-2014-0015

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    55

    Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors

    Geisler, Simon; Mayersbach, Peter; Becker, Kathrin; Schennach, Harald; Fuchs, Dietmar; Gostner, Johanna M.

    Pteridines (2015), 26 (1), 31-36CODEN: PTRDEO; ISSN:0933-4807. (De Gruyter Open Ltd.)

    Formation of neopterin, a biomarker of the activated human immune system, is linked with tryptophan (TRP) and phenylalanine (PHE) metab. To obtain normal values, in this study, serum concns. of neopterin as well as of TRP, PHE and their resp. metabolites kynurenine (KYN) and tyrosine (TYR) were investigated in 100 successive blood donor serum specimens from the University Clinics of Innsbruck, Austria. In addn., nitrite concns. were detd. Donors had passed anamnestic examn. at entry and were therefore considered as healthy. The mean age of participants was 49±11.4 (mean±SD) years; 18% were older than 60 years. Both genders were included in the anal. Neopterin concns. measured by ELISA were 5.9±1.6 nmol/L (mean±SD). Levels of amino acids and metabolites were detd. by HPLC. Mean KYN and TRP concns. were 1.78±0.42 μmol/L and 67.4±10.2 μmol/L, resp. KYN to TRP ratio (KYN/TRP), an est. for the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase, was 26.7±6.2 μmol/mmol. Mean PHE and TYR concns. were 65.2±11.1 μmol/L and 90.6±22.9 μmol/L. PHE to TYR ratio (PHE/TYR), an est. for the activity of PHE-converting enzyme phenylalanine hydroxylase, was 0.75±0.14 μmol/μmol. Nitrite concns., estd. by Griess-Ilosvay reagent, were 44.9±32.0 μmol/L. Males were taller and heavier than females (both p<0.01), but body mass index did not differ. Males presented with significantly higher TRP and TYR concns. than females (both p<0.05). There existed significant correlations between neopterin and KYN (rs=0.368), KYN/TRP (rs=0.453), TYR (rs=-0.267; all p<0.01) and PHE/TYR (rs=0.236; p<0.05) concns. Data indicate that also in a population of healthy individuals an assocn. exists between "low-grade" immune activation as is indicated by slightly higher neopterin concns. and biochem. alterations in the amino acid metab. Although minor, such changes may interfere with psychoneuroimmunol. regulatory networks and thus be of clin. relevance.
56. 56

    Rescigno, A.; Sanjust, E.; Soddu, G.; Rinaldi, A. C.; Sollai, F.; Curreli, N.; Rinaldi, A. Effect of 3-hydroxyanthranilic acid on mushroom tyrosinase activity. Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol. 1998, 1384 (2), 268– 276,  DOI: 10.1016/S0167-4838(98)00018-1

    Google Scholar

    56

    Effect of 3-hydroxyanthranilic acid on mushroom tyrosinase activity

    Rescigno, Antonio; Sanjust, Enrico; Soddu, Giulia; Rinaldi, Andrea C.; Sollai, Francesca; Curreli, Nicoletta; Rinaldi, Augusto

    Biochimica et Biophysica Acta, Protein Structure and Molecular Enzymology (1998), 1384 (2), 268-276CODEN: BBAEDZ; ISSN:0167-4838. (Elsevier B.V.)

    Tyrosine is a copper-contg. protein which catalyzes the hydroxylation of monophenols and the oxidn. of diphenols to o-quinones. The monophenolase activity of tyrosinase is characterized by a typical lag time. In this paper the influence of 3-hydroxyanthranilic acid on monophenolase activity of tyrosinase is reported. 3-Hydroxyanthranilic acid reduced the lag time of tyrosinase when the enzyme acted on N-acetyl-L-tyrosine and on 4-tert-butylphenol. In the presence of 3-hydroxyanthranilic acid, the reaction product 4-tert-butyl-o-benzoquinone, derived from 4-tert-butylphenol oxidn., was formed at a higher rate than in its absence. The results reported in this paper indicate that 3-hydroxyanthranilic acid could affect the enzymic activity of mushroom tyrosinase, probably by acting as a diphenol substrate. A Km value of 0.78 mM was calcd. for 3-hydroxyanthranilic acid as substrate. When tyrosinase acted on 4-tert-butylphenol, Km for 3-hydroxyanthranilic acid as a cofactor was estd. to be 37.5 μM. No effect was obsd. on the diphenolase activity of the enzyme acting on 4-tert-butylcatechol in the presence of 3-hydroxyanthranilic acid.
57. 57

    Yen, G.-C.; Hsieh, C.-L. Antioxidant effects of dopamine and related compounds. Biosci., Biotechnol., Biochem. 1997, 61 (10), 1646– 1649,  DOI: 10.1271/bbb.61.1646

    Google Scholar

    There is no corresponding record for this reference.
58. 58

    Dykens, J. A.; Sullivan, S. G.; Stern, A. Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem. Pharmacol. 1987, 36 (2), 211– 217,  DOI: 10.1016/0006-2952(87)90691-5

    Google Scholar

    There is no corresponding record for this reference.
59. 59

    Darlington, L. G.; Forrest, C. M.; Mackay, G. M.; Smith, R. A.; Smith, A. J.; Stoy, N.; Stone, T. W. On the biological importance of the 3-hydroxyanthranilic acid: anthranilic acid ratio. Int. J. Tryptophan Res. 2010, 3, IJTR.S4282,  DOI: 10.4137/IJTR.S4282

    Google Scholar

    There is no corresponding record for this reference.
60. 60

    Xavier, R. J.; Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007, 448 (7152), 427– 434,  DOI: 10.1038/nature06005

    Google Scholar

    60

    Unraveling the pathogenesis of inflammatory bowel disease

    Xavier, R. J.; Podolsky, D. K.

    Nature (London, United Kingdom) (2007), 448 (7152), 427-434CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

    A review. Recently, substantial advances in the understanding of the mol. pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathol. of IBD.
61. 61

    Manichanh, C.; Borruel, N.; Casellas, F.; Guarner, F. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 2012, 9 (10), 599– 608,  DOI: 10.1038/nrgastro.2012.152

    Google Scholar

    61

    The gut microbiota in IBD

    Manichanh, Chaysavanh; Borruel, Natalia; Casellas, Francesc; Guarner, Francisco

    Nature Reviews Gastroenterology & Hepatology (2012), 9 (10), 599-608CODEN: NRGHA9; ISSN:1759-5045. (Nature Publishing Group)

    A review. IBD-ulcerative colitis and Crohn's disease-is emerging as a worldwide epidemic. An assocn. between the increased incidence of IBD and environmental factors linked to socioeconomic development has been persistently detected in different parts of the world. The lifestyle in developed countries might impair the natural patterns of microbial colonization of the human gut. The interaction of microbes with mucosal immune compartments in the gut seems to have a major role in priming and regulating immunity. In IBD, mucosal lesions are generated by an excessive or dysregulated immune response against commensal microbes in the gut. In individuals with a genetic susceptibility to IBD, abnormal microbial colonization of the gastrointestinal tract might be the origin of such dysregulation. Developments in gene-sequencing technologies, as well as increased availability of powerful bioinformatic tools, have enabled novel insights into the microbial compn. of the human gut microbiota and the effect of microbial communities on human physiol. and disease. Studies that used these technologies indicate that dysbiosis (i.e., abnormal microbiota compn.) and decreased complexity of the gut microbial ecosystem are common features in patients with Crohn's disease or ulcerative colitis. Whether such changes are a cause or a consequence of the disease remains to be elucidated.
62. 62

    Round, J. L.; Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 2009, 9, 313– 323,  DOI: 10.1038/nri2515

    Google Scholar

    62

    The gut microbiota shapes intestinal immune responses during health and disease

    Round, June L.; Mazmanian, Sarkis K.

    Nature Reviews Immunology (2009), 9 (5), 313-323CODEN: NRIABX; ISSN:1474-1733. (Nature Publishing Group)

    A review. Immunol. dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the mol. pathways that mediate host-symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.
63. 63

    Forrest, C. M.; Youd, P.; Kennedy, A.; Gould, S. R.; Darlington, L. G.; Stone, T. W. Purine, kynurenine, neopterin and lipid peroxidation levels in inflammatory bowel disease. J. Biomed. Sci. 2002, 9 (5), 436– 442,  DOI: 10.1159/000064554

    Google Scholar

    63

    Purine, Kynurenine, Neopterin and Lipid Peroxidation Levels in Inflammatory Bowel Disease

    Forrest, Caroline M.; Youd, Philippa; Kennedy, Alan; Gould, Stuart R.; Darlington, L. Gail; Stone, Trevor W.

    Journal of Biomedical Science (Basel, Switzerland) (2002), 9 (5), 436-442CODEN: JBCIEA; ISSN:1021-7770. (S. Karger AG)

    The kynurenine metabolites of tryptophan may be involved in the regulation of neuronal activity and thus gut motility and secretion. We have now performed a pilot study to measure serum concns. of purines and kynurenines in patients with mild inflammatory bowel disease, as well as in sex- and age-matched control subjects. For some analyses, the patients were subdivided into subgroups of those with Crohn's disease and those with ulcerative colitis. The analyses indicated an increased activity in one branch of the kynurenine pathway. While there was no demonstrable difference in neopterin levels in either of the patient groups compared with controls, indicating that the disorders were in an inactive quiescent phase, both groups showed significantly higher levels of lipid peroxidn. products. This suggests the presence of increased oxidative stress even during relative disease inactivity. The increased level of kynurenic acid may represent either a compensatory response to elevated activation of enteric neurons or a primary abnormality which induces a compensatory increase in gut activity. In either case, the data may indicate a role for kynurenine modulation of glutamate receptors in the symptoms of inflammatory bowel disease.
64. 64

    Badawy, A. A. B. Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects. Int. J. Tryptophan Res. 2017, 10, 1– 20,  DOI: 10.1177/1178646917691938

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    64

    Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects

    Badawy, Abdulla A-B.

    International Journal of Tryptophan Research (2017), 10 (), 1-20CODEN: IJTRBS; ISSN:1178-6469. (Libertas Academica Ltd.)

    Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degrdn. are reviewed. The KP accounts for ∼95% of dietary Trp degrdn., of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced NAD (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 "vitamin" nicotinic acid, and oxidized NAD. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunol., neurol., and neurodegenerative conditions to cancer.