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Reductions in brain kynurenic acid levels, a neuroinhibitory metabolite, improve cognitive function in diverse organisms. Thus, modulation of kynurenic acid levels is thought to have therapeutic potential in a range of brain disorders. Here we report that the steroid 5-androstene 3ß, 17ß-diol (ADIOL) reduces kynurenic acid levels and promotes associative learning in Caenorhabditis elegans We identify the molecular mechanisms through which ADIOL links peripheral metabolic pathways to neural mechanisms of learning capacity. Moreover, we show that in aged animals, which normally experience rapid cognitive decline, ADIOL improves learning capacity. The molecular mechanisms that underlie the biosynthesis of ADIOL as well as those through which it promotes kynurenic acid reduction are conserved in mammals. Thus, rather than a minor intermediate in the production of sex steroids, ADIOL is an endogenous hormone that potently regulates learning capacity by causing reductions in neural kynurenic acid levels.
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Ácido Quinurénico , Esteroides , Animales , Ácido Quinurénico/farmacología , Hormonas , MamíferosRESUMEN
Nicotinamide adenine dinucleotide (NAD+) is a pivotal coenzyme, essential for cellular reactions, metabolism, and mitochondrial function. Depletion of kidney NAD+ levels and reduced de novo NAD+ synthesis through the tryptophan-kynurenine pathway are linked to acute kidney injury (AKI), whereas augmenting NAD+ shows promise in reducing AKI. We investigated de novo NAD+ biosynthesis using in vitro, ex vivo, and in vivo models to understand its role in AKI. Two-dimensional (2-D) cultures of human primary renal proximal tubule epithelial cells (RPTECs) and HK-2 cells showed limited de novo NAD+ synthesis, likely due to low pathway enzyme gene expression. Using three-dimensional (3-D) spheroid culture model improved the expression of tubular-specific markers and enzymes involved in de novo NAD+ synthesis. However, de novo NAD+ synthesis remained elusive in the 3-D spheroid culture, regardless of injury conditions. Further investigation revealed that 3-D cultured cells could not metabolize tryptophan (Trp) beyond kynurenine (KYN). Intriguingly, supplementation of 3-hydroxyanthranilic acid into RPTEC spheroids was readily incorporated into NAD+. In a human precision-cut kidney slice (PCKS) ex vivo model, de novo NAD+ synthesis was limited due to substantially downregulated kynurenine 3-monooxygenase (KMO), which is responsible for KYN to 3-hydroxykynurenine conversion. KMO overexpression in RPTEC 3-D spheroids successfully reinstated de novo NAD+ synthesis from Trp. In addition, in vivo study demonstrated that de novo NAD+ synthesis is intact in the kidney of the healthy adult mice. Our findings highlight disrupted tryptophan-kynurenine NAD+ synthesis in in vitro cellular models and an ex vivo kidney model, primarily attributed to KMO downregulation.NEW & NOTEWORTHY Nicotinamide adenine dinucleotide (NAD+) is essential in regulating mitochondrial function. Reduced NAD+ synthesis through the de novo pathway is associated with acute kidney injury (AKI). Our study reveals a disruption in de novo NAD+ synthesis in proximal tubular models, but not in vivo, attributed to downregulation of enzyme kynurenine 3-monooxygenase (KMO). These findings highlight a crucial role of KMO in governing de novo NAD+ biosynthesis within the kidney, shedding light on potential AKI interventions.
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Células Epiteliales , Túbulos Renales Proximales , Quinurenina 3-Monooxigenasa , NAD , Triptófano , Animales , Humanos , Ratones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/enzimología , Línea Celular , Células Cultivadas , Células Epiteliales/metabolismo , Túbulos Renales Proximales/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Quinurenina 3-Monooxigenasa/genética , Ratones Endogámicos C57BL , NAD/metabolismo , NAD/biosíntesis , Triptófano/metabolismoRESUMEN
A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.
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Chronic pain is a debilitating symptom with a significant negative impact on the quality of life and socioeconomic status, particularly among adults and the elderly. Major Depressive Disorder (MDD) stands out as one of the most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves as the primary route for tryptophan degradation and holds critical significance in various biological processes, including the regulation of neurotransmitters, immune responses, cancer development, metabolism, and inflammation. This review encompasses key research studies related to the kynurenine pathway in the context of headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, chronic fatigue syndrome, and MDD. Various metabolites produced in the kynurenine pathway, such as kynurenic acid and quinolinic acid, exhibit neuroprotective and neurotoxic effects, respectively. Recent studies have highlighted the significant involvement of kynurenine and its metabolites in the pathophysiology of pain. Moreover, pharmacological interventions targeting the regulation of the kynurenine pathway have shown therapeutic promise in pain management. Understanding the underlying mechanisms of this pathway presents an opportunity for developing personalized, innovative, and non-opioid approaches to pain treatment. Therefore, this narrative review explores the role of the kynurenine pathway in various chronic pain disorders and its association with depression and chronic pain.
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Dolor Crónico , Quinurenina , Quinurenina/metabolismo , Humanos , Dolor Crónico/metabolismo , Animales , Transducción de SeñalRESUMEN
BACKGROUND: The endocannabinoid (eCB) system and the serotonin (5-HT) are both implicated in the severity of the depression. 5-HT is synthesized from the amino acid tryptophan (Trp), which is also a precursor for kynurenine (Kyn) whose production is increased at the expense of 5-HT in depressed patients. No clinical studies have investigated the crosstalk between the eCB system and the Trp/5-HT/Kyn pathways. Here, we hypothesized that the eCB system is associated with an enhanced Kyn production in relation to the severity of depressive symptoms. METHODS: Eighty-two subjects (51 patients with a diagnosis of depressive disorder (DSM-5) and 31 healthy volunteers), were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Scale, and Global Clinical Impression. Serum concentrations of eCBs (N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)); structurally related fatty acyl compounds 2-oleoylglycerol (2-OG), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA); Trp, Kyn, Kyn/Trp ratio (an index of Trp degradation into Kyn) and 5-HT were also determined. RESULTS: Following a principal component analysis including the severity of depression, Kyn and the Kyn/Trp ratio appear to be directly associated with 2-AG, AEA, and PEA. Interestingly, these biomarkers also permitted to distinguish the population into two main clusters: one of individuals having mild/severe depressive symptoms and the other with an absence of depressive symptoms. Using parametric analysis, higher serum levels of 2-AG, Kyn, and the ratio Kyn/Trp and lower levels of Trp and 5-HT were found in individuals with mild/severe depressive symptoms than in those without depressive symptoms. While in asymptomatic people, PEA was directly associated to Trp, and OEA indirectly linked to 5-HT, in individuals with depressive symptoms, these correlations were lost, and instead, positive correlations between AEA and 2-AG, PEA and AEA, and PEA vs 2-AG and OEA concentrations were found. CONCLUSIONS: Parametric and non-parametric analyses suggest a possible association between eCBs, tryptophan/kynurenine biomarkers, and severity of depression, confirming a likely interplay among inflammation, stress, and depression. The enhanced relationships among the biomarkers of the 2-AG and AEA pathways and related lipids seen in individuals with depressive symptoms, but not in asymptomatics, suggest an altered metabolism of the eCB system in depression.
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Amidas , Etanolaminas , Quinurenina , Ácidos Palmíticos , Triptófano , Humanos , Triptófano/metabolismo , Quinurenina/metabolismo , Depresión/diagnóstico , Endocannabinoides , Serotonina , BiomarcadoresRESUMEN
Kynurenine pathway has a potential to convert L-tryptophan into multiple medicinal molecules. This study aims to explore the biosynthetic potential of kynurenine pathway for the efficient production of actinocin, an antitumor precursor selected as a proof-of-concept target molecule. Kynurenine pathway is first constructed in Escherichia coli by testing various combinations of biosynthetic genes from four different organisms. Metabolic engineering strategies are next performed to improve the production by inhibiting a competing pathway, and enhancing intracellular supply of a cofactor S-adenosyl-L-methionine, and ultimately to produce actinocin from glucose. Metabolome analysis further suggests additional gene overexpression targets, which finally leads to the actinocin titer of 719 mg/L. E. coli strain engineered to produce actinocin is further successfully utilized to produce 350 mg/L of kynurenic acid, a neuroprotectant, and 1401 mg/L of 3-hydroxyanthranilic acid, an antioxidant, also from glucose. These competitive production titers demonstrate the biosynthetic potential of kynurenine pathway as a source of multiple medicinal molecules. The approach undertaken in this study can be useful for the sustainable production of molecules derived from kynurenine pathway, which are otherwise chemically synthesized.
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Escherichia coli , Quinurenina , Oxazinas , Quinurenina/genética , Quinurenina/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Triptófano/genética , Triptófano/metabolismo , Glucosa/genética , Glucosa/metabolismo , Ingeniería Metabólica , Vías BiosintéticasRESUMEN
BACKGROUND: Perinatal depression (including antenatal-, postnatal-, and depression that spans both timepoints) is a prevalent disorder with high morbidity that affects both mother and child. Even though the full biological blueprints of perinatal depression remain incomplete, multiple studies indicate that, at least for antenatal depression, the disorder has an inflammatory component likely linked to a dysregulation of the enzymatic kynurenine pathway. The production of neuroactive metabolites in this pathway, including quinolinic acid (QUIN), is upregulated in the placenta due to the multiple immunological roles of the metabolites during pregnancy. Since neuroactive metabolites produced by the pathway also may affect mood by directly affecting glutamate neurotransmission, we sought to investigate whether the placental expression of kynurenine pathway enzymes controlling QUIN production was associated with both peripheral inflammation and depressive symptoms during pregnancy. METHODS: 68 placentas obtained at birth were analyzed using qPCR to determine the expression of kynurenine pathway enzymes. Cytokines and metabolites were quantified in plasma using high-sensitivity electroluminescence and ultra-performance liquid chromatography, respectively. Maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) throughout pregnancy and the post-partum. Associations between these factors were assessed using robust linear regression with ranked enzymes. RESULTS: Low placental quinolinate phosphoribosyl transferase (QPRT), the enzyme responsible for degrading QUIN, was associated with higher IL-6 and higher QUIN/kynurenic acid ratios at the 3rd trimester. Moreover, women with severe depressive symptoms in the 3rd trimester had significantly lower placental expression of both QPRT and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD); impaired activity of these two enzymes leads to QUIN accumulation. CONCLUSION: Overall, our data support that a compromised placental environment, featuring low expression of critical kynurenine pathway enzymes is associated with increased levels of plasma cytokines and the dysregulated kynurenine metabolite pattern observed in depressed women during pregnancy.
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Depresión , Inflamación , Quinurenina , Placenta , Ácido Quinolínico , Humanos , Femenino , Embarazo , Quinurenina/metabolismo , Quinurenina/sangre , Placenta/metabolismo , Adulto , Inflamación/metabolismo , Depresión/metabolismo , Ácido Quinolínico/metabolismo , Ácido Quinolínico/sangre , Citocinas/metabolismo , Complicaciones del Embarazo/metabolismo , Carboxiliasas/metabolismo , PentosiltransferasaRESUMEN
BACKGROUND AND AIMS: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI. MATERIAL AND METHODS: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up. RESULTS: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5Ì-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01). CONCLUSION: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531.
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Disfunción Cognitiva , Accidente Cerebrovascular , Anciano , Femenino , Humanos , Masculino , Biomarcadores , Disfunción Cognitiva/complicaciones , Estudios de Cohortes , Inflamación/complicaciones , Quinurenina/metabolismo , Neopterin , Estudios Prospectivos , Fosfato de Piridoxal , Accidente Cerebrovascular/complicaciones , Vitamina B 6/metabolismo , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
HIV infection compromises both the peripheral and central immune systems due to its pathogenic and neuropathogenic features. The mechanisms driving HIV-1 pathogenesis and neuropathogenesis involve a series of events, including metabolic dysregulation. Furthermore, HIV-subtype-specific variations, particularly alterations in the amino acid sequences of key viral proteins, are known to influence the severity of clinical outcomes in people living with HIV. However, the impact of amino acid sequence variations in specific viral proteins, such as Viral protein R (Vpr), on metabolites within the Tryptophan (Trp)-kynurenine (Kyn) pathway in people living with HIV remains unclear. Our research aimed to explore the relationship between variations in the Vpr amino acid sequence (specifically at positions 22, 41, 45, and 55, as these have been previously linked to neurocognitive function) and peripheral Trp-Kyn metabolites. Additionally, we sought to clarify the systems biology of Vpr sequence variation by examining the link between Trp-Kyn metabolism and peripheral inflammation, as a neuropathogenic mechanism. In this preliminary study, we analyzed a unique cohort of thirty-two (n = 32) South African cART naïve people living with HIV. We employed Sanger sequencing to ascertain blood-derived Vpr amino acid sequence variations and a targeted LC-MS/MS metabolomics platform to assess Trp-Kyn metabolites, such as Trp, Kyn, kynurenic acid (KA), and quinolinic acid (QUIN). Particle-enhanced turbidimetric assay and Enzyme-linked immunosorbent assays were used to measure immune markers, hsCRP, IL-6, suPAR, NGAL and sCD163. After applying Bonferroni corrections (p =.05/3) and adjusting for covariates (age and sex), only the Vpr G41 and A55 groups was nearing significance for higher levels of QUIN compared to the Vpr S41 and T55 groups, respectively (all p =.023). Multiple regression results revealed that Vpr amino acid variations at position 41 (adj R2 = 0.049, ß = 0.505; p =.023), and 55 (adj R2 = 0.126, ß = 0.444; p =.023) displayed significant associations with QUIN after adjusting for age and sex. Lastly, the higher QUIN levels observed in the Vpr G41 group were found to be correlated with suPAR (r =.588, p =.005). These results collectively underscore the importance of specific Vpr amino acid substitutions in influencing QUIN and inflammation (specifically suPAR levels), potentially contributing to our understanding of their roles in the pathogenesis and neuropathogenesis of HIV-1.
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Productos del Gen vpr , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , Triptófano/metabolismo , Quinurenina/metabolismo , VIH-1/genética , VIH-1/metabolismo , Secuencia de Aminoácidos , Infecciones por VIH/complicaciones , Cromatografía Liquida , Proyectos Piloto , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Espectrometría de Masas en Tándem , InflamaciónRESUMEN
BACKGROUND: L-Tryptophan (L-Trp), an essential amino acid, is the only amino acid whose level is regulated specifically by immune signals. Most proportions of Trp are catabolized via the kynurenine (Kyn) pathway (KP) which has evolved to align the food availability and environmental stimulation with the host pathophysiology and behavior. Especially, the KP plays an indispensable role in balancing the immune activation and tolerance in response to pathogens. SCOPE OF REVIEW: In this review, we elucidate the underlying immunological regulatory network of Trp and its KP-dependent catabolites in the pathophysiological conditions by participating in multiple signaling pathways. Furthermore, the KP-based regulatory roles, biomarkers, and therapeutic strategies in pathologically immune disorders are summarized covering from acute to chronic infection and inflammation. MAJOR CONCLUSIONS: The immunosuppressive effects dominate the functions of KP induced-Trp depletion and KP-produced metabolites during infection and inflammation. However, the extending minor branches from the KP are not confined to the immune tolerance, instead they go forward to various functions according to the specific condition. Nevertheless, persistent efforts should be made before the clinical use of KP-based strategies to monitor and cure infectious and inflammatory diseases.
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Biomarcadores , Inflamación , Quinurenina , Triptófano , Triptófano/metabolismo , Quinurenina/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/inmunología , Animales , Biomarcadores/metabolismo , Infecciones/inmunología , Infecciones/metabolismoRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the highly contagious respiratory disease Corona Virus Disease 2019 (COVID-19) that may lead to various neurological and psychological disorders that can be acute, lasting days to weeks or months and possibly longer. The latter is known as long-COVID or more recently post-acute sequelae of COVID (PASC). During acute COVID-19 infection, a strong inflammatory response, known as the cytokine storm, occurs in some patients. The levels of interferon-γ (IFN-γ), interferon-ß (IFN-ß), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are particularly increased. These cytokines are known to activate the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), catalysing the first step of tryptophan (Trp) catabolism through the kynurenine pathway (KP) leading to the production of several neurotoxic and immunosuppressive metabolites. There is already data showing elevation in KP metabolites both acutely and in PASC, especially regarding cognitive impairment. Thus, it is likely that KP involvement is significant in SARS-CoV-2 pathogenesis especially neurologically.
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OBJECTIVES: The stratification of individuals suffering from acute and post-acute SARS-CoV-2 infection remains a critical challenge. Notably, biomarkers able to specifically monitor viral progression, providing details about patient clinical status, are still not available. Herein, quantitative metabolomics is progressively recognized as a useful tool to describe the consequences of virus-host interactions considering also clinical metadata. METHODS: The present study characterized the urinary metabolic profile of 243 infected individuals by quantitative nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography mass spectrometry (LC-MS). Results were compared with a historical cohort of noninfected subjects. Moreover, we assessed the concentration of recently identified antiviral nucleosides and their association with other metabolites and clinical data. RESULTS: Urinary metabolomics can stratify patients into classes of disease severity, with a discrimination ability comparable to that of clinical biomarkers. Kynurenines showed the highest fold change in clinically-deteriorated patients and higher-risk subjects. Unique metabolite clusters were also generated based on age, sex, and body mass index (BMI). Changes in the concentration of antiviral nucleosides were associated with either other metabolites or clinical variables. Increased kynurenines and reduced trigonelline excretion indicated a disrupted nicotinamide adenine nucleotide (NAD+) and sirtuin 1 (SIRT1) pathway. CONCLUSIONS: Our results confirm the potential of urinary metabolomics for noninvasive diagnostic/prognostic screening and show that the antiviral nucleosides could represent novel biomarkers linking viral load, immune response, and metabolism. Moreover, we established for the first time a casual link between kynurenine accumulation and deranged NAD+/SIRT1, offering a novel mechanism through which SARS-CoV-2 manipulates host physiology.
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COVID-19 , Humanos , COVID-19/diagnóstico , Sirtuina 1 , NAD , SARS-CoV-2 , Metabolómica/métodos , Biomarcadores/orina , Antivirales , Prueba de COVID-19RESUMEN
Metabolites disruptions in tryptophan (TRP) and kynurenine pathway (KP) are believed to disturb neurotransmitter homeostasis and contribute to depressive symptoms. This study aims to investigate serum levels of KP metabolites in adolescent major depressive disorder (AMDD), and examine their relationship with depression severities. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze serum levels of TRP, kynurenic acid (KYNA), kynurenine (KYN), and 3-hydroxy-kynurenine (3-HK) in 143 AMDD participants and 98 healthy controls (HC). Clinical data, including Children's Depression Inventory (CDI) scores, were collected and analyzed using statistical methods, such as ANOVA, logistic regression, Receiver operating characteristic curve analysis and a significance level of p < 0.05 was used for all analyses. AMDD showed significantly decreased serum levels of KYNA (-25.5%), KYN (-14.2%), TRP (-11.0%) and the KYNA/KYN ratio (-11.9%) compared to HC (p < 0.01). Conversely, significant increases were observed in 3-HK levels (+50.4%), the 3-HK/KYNA ratio (+104.3%) and the 3-HK/KYN ratio (+93.0%) (p < 0.01). Logistic regression analysis identified increased level of 3-HK as a contributing factor to AMDD, while increased level of KYNA acted as a protective factor against AMDD. The 3-HK/KYNA ratio demonstrated an area under the curve (AUC) of 0.952. This study didn't explore AMDD's inflammatory status and its metabolites relationship explicitly. These findings indicate that metabolites of TRP and KP may play a crucial role in the pathogenesis of AMDD, emphasizing the potential of the 3-HK/KYNA ratio as a laboratory biomarker for early detection and diagnosis of AMDD.
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The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Resistencia a la Insulina , Quinurenina , Metformina , Metformina/farmacología , Metformina/uso terapéutico , Humanos , Quinurenina/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Animales , Transducción de Señal/efectos de los fármacosRESUMEN
In recent years, there has been a growing realization of intricate interactions between the nervous and immune systems, characterized by shared humoral factors and receptors. This interplay forms the basis of the neuroimmune system, the understanding of which will provide insights into the pathogenesis of neurological diseases, in which the involvement of the immune system has been overlooked. Kynurenine and its derivatives derived from tryptophan have long been implicated in the pathogenesis of various neurological diseases. Recent studies have revealed their close association not only with neurological disorders but also with sepsis-related deaths. This review provides an overview of the biochemistry of kynurenine and its derivatives, followed by a discussion of their role via the modulation of the neuroimmune system in various diseases.
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Quinurenina , Neuroinmunomodulación , Humanos , Quinurenina/metabolismo , Animales , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/inmunología , Triptófano/metabolismo , Triptófano/química , Sistema Inmunológico/metabolismo , Sistema Inmunológico/inmunología , Sepsis/inmunología , Sepsis/metabolismoRESUMEN
Persistent systemic chronic inflammatory conditions are linked with many pathologies, including cardiovascular diseases (CVDs), a leading cause of death across the globe. Among various risk factors, one of the new possible contributors to CVDs is the metabolism of essential amino acid tryptophan. Proinflammatory signals promote tryptophan metabolism via the kynurenine (KYN) pathway (KP), thereby resulting in the biosynthesis of several immunomodulatory metabolites whose biological effects are associated with the development of symptoms and progression of various inflammatory diseases. Some participants in the KP are agonists of aryl hydrocarbon receptor (AhR), a central player in a signaling pathway that, along with a regulatory influence on the metabolism of environmental xenobiotics, performs a key immunomodulatory function by triggering various cellular mechanisms with the participation of endogenous ligands to alleviate inflammation. An AhR ligand with moderate affinity is the central metabolite of the KP: KYN; one of the subsequent metabolites of KYN-kynurenic acid (KYNA)-is a more potent ligand of AhR. Understanding the role of AhR pathway-related metabolites of the KP that regulate inflammatory factors in cells of the cardiovascular system is interesting and important for achieving effective treatment of CVDs. The purpose of this review was to summarize the results of studies about the participation of the KP metabolite-KYNA-and of the AhR signaling pathway in the regulation of inflammation in pathological conditions of the heart and blood vessels and about the possible interaction of KYNA with AhR signaling in some CVDs.
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Enfermedades Cardiovasculares , Inflamación , Ácido Quinurénico , Receptores de Hidrocarburo de Aril , Transducción de Señal , Humanos , Receptores de Hidrocarburo de Aril/metabolismo , Enfermedades Cardiovasculares/metabolismo , Ácido Quinurénico/metabolismo , Inflamación/metabolismo , Animales , Quinurenina/metabolismo , Triptófano/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice BásicoRESUMEN
The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable metabolic illness caused by mutations of mitochondrial and nuclear DNA. Despite the intensive research, its diagnosis is usually difficult, and unfortunately, treating it challenges physicians. Metabolites of the kynurenine pathway are linked to many disorders, such as depression, schizophrenia, migraine, and also diseases associated with impaired mitochondrial function. The kynurenine pathway includes many substances, for instance kynurenic acid and quinolinic acid. In this review, we would like to show a possible link between the metabolites of the kynurenine pathway and mitochondrial stress in the context of intestinal flora. Furthermore, we summarize the possible markers of and future therapeutic options for the kynurenine pathway in excitotoxicity and mitochondrial oxidative stress.
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Microbioma Gastrointestinal , Enfermedades Mitocondriales , Enfermedades del Sistema Nervioso , Humanos , Quinurenina/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Ácido Quinolínico/metabolismo , Estrés OxidativoRESUMEN
Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc's inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences in KP activation among SSc patients and assess the impact of angiotensin-converting enzyme (ACE) inhibitors and estimated glomerular filtration rate (eGFR) on KP metabolite concentrations. We enrolled 48 SSc patients and 53 healthy controls, quantifying KP metabolites (tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA)) in serum via high-performance liquid chromatography. Separate multivariate analyses of covariance (MANCOVAs) for women and men were performed to ascertain mean differences between patients and healthy controls while correcting for age. For our secondary objective, we conducted a MANCOVA to explore disparities in ACE inhibitor users and non-users among patients, with BMI correction. Our findings revealed decreased TRP concentrations but increased KYNA/TRP ratio and KYN/TRP ratio in both male and female SSc patients compared to their respective controls. Unlike women, SSc males exhibited higher KYN concentrations and decreased KYNA/KYN ratio relative to their controls. Additionally, SSc patients using ACE inhibitors had higher serum KYNA levels than non-users. Notably, we established a significant correlation between eGFR and KYNA in SSc patients. These results indicate differential KP activation in male and female SSc patients, with males demonstrating heightened KP activation. While ACE inhibitors may influence the KP in SSc patients, further research is necessary to comprehensively understand their impact on symptoms and prognosis in the context of these KP alterations.
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Quinurenina , Esclerodermia Sistémica , Humanos , Femenino , Masculino , Triptófano , Inhibidores de la Enzima Convertidora de Angiotensina , Antivirales , Ácido QuinurénicoRESUMEN
As the kynurenine pathway's links to inflammation, the immune system, and neurological disorders became more apparent, it attracted more and more attention. It is the main pathway through which the liver breaks down Tryptophan and the initial step in the creation of nicotinamide adenine dinucleotide (NAD+) in mammals. Immune system activation and the buildup of potentially neurotoxic substances can result from the dysregulation or overactivation of this pathway. Therefore, it is not shocking that kynurenines have been linked to neurological conditions (Depression, Parkinson's, Alzheimer's, Huntington's Disease, Schizophrenia, and cognitive deficits) in relation to inflammation. Nevertheless, preclinical research has demonstrated that kynurenines are essential components of the behavioral analogs of depression and schizophrenia-like cognitive deficits in addition to mediators associated with neurological pathologies due to their neuromodulatory qualities. Neurodegenerative diseases have been extensively associated with neuroactive metabolites of the kynurenine pathway (KP) of tryptophan breakdown. In addition to being a necessary amino acid for protein synthesis, Tryptophan is also transformed into the important neurotransmitters tryptamine and serotonin in higher eukaryotes. In this article, a summary of the KP, its function in neurodegeneration, and the approaches being used currently to target the route therapeutically are discussed.
Asunto(s)
Trastornos del Conocimiento , Quinurenina , Animales , Triptófano , Aminoácidos , Inflamación , MamíferosRESUMEN
The gut-brain axis is increasingly understood to play a role in neuropsychiatric disorders. The probiotic bacterium Lactobacillus (L.) reuteri and products of tryptophan degradation, specifically the neuroactive kynurenine pathway (KP) metabolite kynurenic acid (KYNA), have received special attention in this context. We, therefore, assessed relevant features of KP metabolism, namely, the cellular uptake of the pivotal metabolite kynurenine and its conversion to its primary products KYNA, 3-hydroxykynurenine and anthranilic acid in L. reuteri by incubating the bacteria in Hank's Balanced Salt solution in vitro. Kynurenine readily entered the bacterial cells and was preferentially converted to KYNA, which was promptly released into the extracellular milieu. De novo production of KYNA increased linearly with increasing concentrations of kynurenine (up to 1 mM) and bacteria (107 to 109 CFU/mL) and with incubation time (1-3 h). KYNA neosynthesis was blocked by two selective inhibitors of mammalian kynurenine aminotransferase II (PF-048559989 and BFF-122). In contrast to mammals, however, kynurenine uptake was not influenced by other substrates of the mammalian large neutral amino acid transporter, and KYNA production was not affected by the presumed competitive enzyme substrates (glutamine and α-aminoadipate). Taken together, these results reveal substantive qualitative differences between bacterial and mammalian KP metabolism.