Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

Mor, Adrian; Tankiewicz-Kwedlo, Anna; Krupa, Anna; Pawlak, Dariusz

doi:10.3390/cells10071603

Cited by 91 publications

(84 citation statements)

References 248 publications

(567 reference statements)

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“…The role of IDO2 in immune function is still being determined [ 4 ]. Kynurenine and its further breakdown products carry out important biological functions, including regulation of the immune response [ 5 , 6 ], involvement in oxidative stress [ 7 ], and dilating blood vessels during inflammation [ 8 ]. Some cancers increase KYN production, which promotes tumor growth [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the KYN pathway has received increasing attention concerning infectious disease as its connection to inflammation, the immune system, oxidative stress, and neurological conditions became apparent [ 7 , 18 , 19 ]. Evidence exists, that the KYN pathway is also involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Increased Kynurenine Indicates a Fatal Course of COVID-19

et al. 2021

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(1) Background: An inefficient immune response accompanied by an overwhelming inflammatory reaction is involved in severe courses of COVID-19. Kynurenine (KYN) has important immune-modulatory functions and may contribute to a failure in controlling SARS-CoV-2. The present study aims to explore biomarkers that hint at a fatal outcome of COVID-19 early on. (2) Methods: We established a cohort of 148 hospitalized COVID-19 patients for this study. Thirty-one patients died due to a severe COVID-19 course, and 117 recovered within 90 days. We built a biobank by collecting left-over material from these patients whenever blood arrived at the central laboratory of our University hospital for analysis of routine markers. The scientific laboratory analysis comprised KYN, Tryptophan (TRP), KYN/TRP ratio, ferritin, interleukin-6 (IL-6), C-reactive protein (CRP), creatinine, N-terminal pro-natriuretic peptide (NTproBNP), troponin T (TnT), fibrinogen, D-Dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin (AT), protein C, protein S, factor XIII, lupus aPTT, angiotensin-2, vitamin D metabolites, and telomeres in all COVID-19 patients. Basic clinical characteristics and anteceding diseases including cardiovascular, oncologic, renal, hypertension, pulmonary, metabolic (diabetes, obesity) were recorded in a database together with the laboratory data. (3) Results: At the time of diagnosis of SARS-CoV-2 infection those patients who deceased within 90 days afterwards due to COVID-19, had a significantly higher age, higher KYN, KYN/TRP ratio, ferritin, creatinine, and NTproBNP values than SARS-CoV-2 patients who survived COVID-19 along the same time span. In a Kaplan-Meier analysis the variables age, KYN, ferritin, D-Dimer, TnT, NTproBNP, and creatinine showed a significant influence on survival time. Gender, however, showed no influence. In a combined Cox regression analysis KYN had the highest hazard ratio (1.188, 95% CI: 1.071–1.319) followed by age (1.041, 95% CI: 1.011–1.073). In a ROC analysis, KYN values above the cut off limit of 4.82 nmol/l (as specified by Youden index) had a sensitivity of 82% (95% CI: 66–95%) and a specificity of 72% (95% CI: 65–82%) to predict COVID-19 related death within 90 days observation time. (4) Conclusions: Kynurenine is a promising blood biomarker to predict an increased risk of mortality in SARS-CoV-2 infected people already at the time of the first positive SARS-CoV-2 verification detected in these persons.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased Kynurenine Indicates a Fatal Course of COVID-19

et al. 2021

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“…They observed that the functional module for l -kyn synthesis was enriched in migraineurs. The higher l -kyn degradation module suggested an increased level of its catabolites, including neuroexcitatory QUIN and neuroinhibitory KYNA, both related to CNS diseases [ 164 ].…”

Section: Migraine and Functional Gi Disordersmentioning

confidence: 99%

“…They observed that the functional module for L-kyn synthesis was enriched in migraineurs. The higher L-kyn degradation module suggested an increased level of its catabolites, including neuroexcitatory QUIN and neuroinhibitory KYNA, both related to CNS diseases [164]. Some results showed that probiotic treatment resulted in a beneficial effect on the frequency and severity of migraine headache attacks (reviewed in [165]).…”

Section: Cvs Amentioning

confidence: 99%

Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders

Fila

Chojnacki

Pawłowska

et al. 2021

IJMS

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Migraine, the leading cause of disability in the population aged below 50, is associated with functional gastrointestinal (GI) disorders (FGIDs) such as functional nausea, cyclic vomiting syndrome, and irritable bowel syndrome (IBS). Conversely, changes in intestinal GI transit may cause diarrhea or constipation and are a component of the autonomic symptoms associated with pre- and post-dorsal phases of migraine attack. These mutual relationships provoke a question on a common trigger in migraine and FGIDs. The kynurenine (L-kyn) pathway (KP) is the major route for L-tryptophan (L-Trp) metabolism and transforms L-Trp into several neuroactive compounds. Changes in KP were reported in both migraine and FGIDs. Migraine was largely untreatable, but several drugs approved lately by the FDA, including monoclonal antibodies for calcitonin gene-related peptide (CGRP) and its receptor, create a hope for a breakthrough in migraine treatment. Derivatives of L-kyn were efficient in pain relief with a mechanism including CGRP inhibition. KP products are important ligands to the aryl hydrocarbon receptor (AhR), whose activation is implicated in the pathogenesis of GI and migraine. Toll-like receptors (TLRs) may play a role in migraine and IBS pathogeneses, and KP metabolites detected downstream of TLR activation may be an IBS marker. The TLR4 signaling was observed in initiating and maintaining migraine-like behavior through myeloid differentiation primary response gene 88 (MyD88) in the mouse. The aim of this review is to justify the view that KP modulation may provide common triggers for migraine and FGIDs with the involvement of TLR, AhR, and MyD88 activation.

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“…Previously, it was reported that this pathway is highly strongly associated with somatization disorder, a psychiatric disease accompanied by physiosomatic symptoms but not necessarily by fatigue [46]. The TRYCAT pathway acts as a redox-regulator and is one of the major antioxidant systems, although some TRYCATs have pro-oxidant and neurotoxic activities [47].…”

Section: Terms Over-represented In the Ioandns Multiomics Subnetworkmentioning

confidence: 99%

Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB and Wnt/Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis andChronic Fatigue Syndrome: A Review and New Hypothesis Based on Results of Network, Enrichment and Annotation Analyses

Maes¹,

Kubera²,

Kotańska³

2021

Preprint

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There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers. The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network. We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which we established in CFAS-D patients. PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks. MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA. The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease. Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

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Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

Cited by 91 publications

References 248 publications

Increased Kynurenine Indicates a Fatal Course of COVID-19

Increased Kynurenine Indicates a Fatal Course of COVID-19

Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders

Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB and Wnt/Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis andChronic Fatigue Syndrome: A Review and New Hypothesis Based on Results of Network, Enrichment and Annotation Analyses

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