Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.813
Filtrar
1.
Sci Rep ; 13(1): 1011, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653422

RESUMO

Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.


Assuntos
Cinurenina , Neoplasias Pulmonares , Humanos , Cinurenina/metabolismo , Triptofano/metabolismo , Estudos Transversais , Neopterina/metabolismo , NAD , Biomarcadores , Proteína C-Reativa/metabolismo , Inflamação , Interferon gama/metabolismo
2.
BMC Cancer ; 23(1): 62, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653774

RESUMO

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that converts tryptophan to kynurenine. IDO1 expression is found not only in tumor cells but also in immune cells and is associated with tumor proliferation and immune responses. IDO1 inhibitors and radiation may cooperatively suppress tumor proliferation through the alterations in the Wnt/ß-catenin pathway, cell cycle, and immune response. We investigated the antitumor effects of combination therapy of an IDO1 inhibitor, 1-methyl tryptophan (1-MT), and radiation on colorectal cancer. METHODS: In vitro experiments were conducted using human and murine colon cancer cell lines (HCT116, HT-29, and Colon26). Cell growth inhibition was assessed using a MTS assay and Clonogenic assay. Cells were cultured for 48 h with or without 500 µM 1-MT after exposure to radiation (4 Gy). Cell cycle effects and modulation of Wnt/ß-catenin pathway were evaluated using western blot analysis, flow cytometry, RT-PCR. Subcutaneous Colon26 tumors in BALB/c mice were treated by oral 1-MT (6 mg/mL) for 2 weeks and/or local radiation (10 Gy/10 fr). Bromodeoxyuridine (BrdU) incorporation in tumor cells and expression of differentiation markers of immune cells were evaluated using immunohistochemistry. RESULTS: 1-MT and a small interfering RNA against IDO1 suppressed proliferation of all cell lines, which was rescued by kynurenine. Clonogenic assay showed that administration of 1-MT improved radiosensitivity by suppressing the Wnt/ß-catenin pathway activated by radiation and enhancing cell cycle arrest induced by radiation. Combination therapy showed a further reduction in tumor burden compared with monotherapies or untreated control, inducing the highest numbers of intratumoral CD3 + and CD8 + T cells and the lowest numbers of Foxp3 + and BrdU-positive tumor cells. CONCLUSIONS: The combination of 1-MT and radiation suppressed colon cancer cells in vitro and in vivo via multiple mechanisms.


Assuntos
Neoplasias do Colo , Cinurenina , Humanos , Camundongos , Animais , Cinurenina/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , beta Catenina , Bromodesoxiuridina , Camundongos Endogâmicos C57BL , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/radioterapia , Células HT29
3.
BMC Psychiatry ; 23(1): 27, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631760

RESUMO

Previous studies reported significantly altered tryptophan catabolite concentrations in major depression. Thus, tryptophan catabolites were considered as potential biomarkers of depression and their modulators as potential targets for psychopharmacotherapy. However, the results were based mainly on studies with small sample sizes limiting their generalizability. Against this background, we investigated the relationship of peripheral tryptophan catabolites with depression in a population-based sample with n = 3,389 participants (with fasting status ≥ 8 h and C-reactive protein < 10 mg/L). N = 248 had clinically significant depression according to a PHQ-9 score of ≥ 10, n = 1,101 subjects had mild depressive symptoms with PHQ-9 scores between 5 and 9, and n = 2,040 had no depression. After multivariable adjustment, clinically significant depression was associated with lower kynurenine and kynurenic acid. Spearman correlation coefficients of the tryptophan catabolites with the severity of depression were very small (rho ≤ 0.080, p ≤ 0.015). None of the tryptophan catabolites could diagnostically separate depressed from not depressed persons. Concerning linear associations, kynurenine and kynurenic acid were associated only with the severity and the cognitive dimension of depression but not its somatic dimension. Tryptophan catabolites were not associated with persistence or recurrence of depression at the 5 year follow-up. The results replicated the association between kynurenine and kynurenic acid with depression. However, the associations were small raising doubts about their clinical utility. Findings underline the complexity of the relationships between depression and tryptophan catabolites. The search for subgroups of depression with a potentially higher impact of depression might be warranted.


Assuntos
Transtorno Depressivo Maior , Triptofano , Humanos , Cinurenina/metabolismo , Ácido Cinurênico/metabolismo , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/metabolismo , Proteína C-Reativa
4.
J Clin Invest ; 133(2)2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36647830

RESUMO

Tryptophan (Trp) metabolism plays a central role in sleep, mood, and immune system regulation. The kynurenine pathway (KP), which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO), which catalyze the conversion of Trp to kynurenine (Kyn), facilitates immune regulation and influences neurocognition. Notably, Kyn metabolites bind the N-methyl-d-aspartate receptor (NMDAR), essential for memory encoding, and in turn, cognition. Aberrant NMDAR activity through agonist binding influences excitability and cell death. In this issue of the JCI, Watne and authors demonstrate that KP pathway end products were elevated in the serum and the cerebrospinal fluid (CSF) of subjects with delirium. This observation provides insight regarding the basis of a variety of commonly observed clinical conditions including sundowning, abnormal sleep-wake cycles in hospitalized patients, neurodegenerative cognitive impairment, radiation-induced cognitive impairment, neurocognitive symptomatology related to COVID-19, and clinical outcomes observed in patients with CNS tumors, such as gliomas.


Assuntos
Delírio , Indolamina-Pirrol 2,3,-Dioxigenase , Cinurenina , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Cinurenina/metabolismo , Triptofano/metabolismo
5.
Nutrients ; 15(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36678127

RESUMO

Accumulating evidence suggests an association of the tryptophan-kynurenine (TRP-KYN) pathway with atherosclerosis and cardiovascular risk factors. In this cross-sectional analysis we investigated whether TRP-KYN pathway parameters are associated with 24 h blood pressure (BP) and other risk factors in patients with arterial hypertension from a tertiary care centre. In 490 participants, we found no significant and independent association of 24 h systolic and diastolic BP with parameters of the TRP-KYN pathway. However, linear regression analyses of HDL as dependent and TRP, KYN and quinolinic acid (QUIN) as explanatory variables adjusted for BMI and sex showed significant associations. These were found for KYN, BMI and sex (unstandardised beta coefficient -0.182, standard error 0.052, p < 0.001; -0.313 (0.078), p < 0.001; -0.180 (0.024), p < 0.001, respectively) as well as for QUIN, BMI and sex (-0.157 (0.038), p < 0.001; -0.321 (0.079), p < 0.001; -0.193 (0.024), p < 0.001, respectively). Smokers had significantly lower levels of KYN (2.36 µmol/L, IQR 2.01-2.98, versus 2.71 µmol/L, IQR 2.31-3.27, p < 0.001), QUIN (384 nmol/L, IQR 303-448, versus 451 nmol/L, IQR 369-575, p < 0.001) and KYN/TRP ratio (38.2, IQR 33.7-43.2, versus 43.1, IQR 37.5-50.9, p < 0.001) compared to non-smokers. We demonstrated that TRP/KYN pathway metabolites are associated with some cardiovascular risk factors, warranting further studies to elucidate the diagnostic and therapeutic potential of the TRP-KYN pathway for cardiovascular diseases.


Assuntos
Doenças Cardiovasculares , Hipertensão , Humanos , Triptofano/metabolismo , Cinurenina/metabolismo , Doenças Cardiovasculares/etiologia , Estudos Transversais , Fatores de Risco , Fatores de Risco de Doenças Cardíacas
6.
Nutrients ; 15(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36678277

RESUMO

BACKGROUND: The incidence of eating disorders (EDs), serious mental and physical conditions characterized by a disturbance in eating or eating-related behaviors, has increased steadily. The present study aims to develop insights into the pathophysiology of EDs, spanning over biochemical, epigenetic, psychopathological, and clinical data. In particular, we focused our attention on the relationship between (i) DNA methylation profiles at promoter-associated CpG sites of the SCL6A4 gene, (ii) serum kynurenine/tryptophan levels and ratio (Kyn/Trp), and (iii) psychopathological traits in a cohort of ED patients. Among these, 45 patients were affected by restricting anorexia nervosa (AN0), 21 by purging AN (AN1), 21 by bulimia (BN), 31 by binge eating disorders (BED), 23 by unspecified feeding or eating disorders (UFED), and finally 14 by other specified eating disorders (OSFED) were compared to 34 healthy controls (CTRs). RESULTS: Kyn level was higher in BED, UFED, and OSFED compared to CTRs (p ≤ 0.001). On the other hand, AN0, AN1, and BN patients showed significatively lower Kyn levels compared to the other three ED groups but were closed to CTRs. Trp was significantly higher in AN0, AN1, and BN in comparison to other ED groups. Moreover, AN1 and BN showed more relevant Trp levels than CTRs (p <0.001). BED patients showed a lower Trp as compared with CTRs (p ≤ 0.001). In addition, Kyn/Trp ratio was lower in the AN1 subtype but higher in BED, UFED, and OSFED patients than in CTRs (p ≤ 0.001). SCL6A4 DNA methylation level at CpG5 was lower in AN0 compared to BED (p = 0.021), and the CpG6 methylation was also significantly lower in AN0 in comparison to CTRs (p = 0.025). The mean methylation levels of the six CpGs analyzed were lower only in the AN0 subgroup compared to CTRs (p = 0.008). Relevant psychological trait EDI-3 subscales were correlated with biochemical and epigenetic data. CONCLUSIONS: These findings underline the complexity of psychological and pathophysiological components of EDs.


Assuntos
Anorexia Nervosa , Transtorno da Compulsão Alimentar , Bulimia Nervosa , Transtornos da Alimentação e da Ingestão de Alimentos , Humanos , Triptofano , Cinurenina , Metilação de DNA , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Bulimia Nervosa/epidemiologia , Transtorno da Compulsão Alimentar/psicologia , Anorexia Nervosa/psicologia , Proteínas da Membrana Plasmática de Transporte de Serotonina
7.
Curr Opin Nephrol Hypertens ; 32(2): 153-164, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36683540

RESUMO

PURPOSE OF REVIEW: Hypertensive disorders of pregnancy remain a highly morbid condition that affects both the mother and fetus, complicate approximately 10% of pregnancies worldwide, and contribute to immediate and long-term cardiovascular outcomes. There is still much to learn regarding pathogenesis and treatment goals. RECENT FINDINGS: There is updated information on the pathogenesis of preeclampsia and treatment thresholds for HTN in pregnancy. l-Kynurenine, a metabolite of the essential amino acid l-tryptophan, has been implicated in preeclampsia as decreased levels were found in a uninephrectomized pregnant mouse model of preeclampsia, where replacement of l-kynurenine rescued the preeclamptic state. Further, data from CHIPS (The Control of HTN in Pregnancy Study) and CHAP (Chronic HTN and Pregnancy) trials demonstrate not only the safety of lowering blood pressure to either a diastolic goal of 85 mmHg (CHIPS) or less than 160/105 mmHg (CHAP) without detriment to the fetus but the CHAPS trial has also shown a decrease in the rate of preeclampsia in the treatment group. SUMMARY: We will summarize the different types of hypertensive disorders in pregnancy, updates on the pathogenesis of preeclampsia, and appropriate HTN management based on the latest evidence in order to better care for mother and child.


Assuntos
Hipertensão , Pré-Eclâmpsia , Gravidez , Feminino , Animais , Camundongos , Humanos , Pré-Eclâmpsia/terapia , Cinurenina , Hipertensão/tratamento farmacológico , Feto
8.
Biochem Biophys Res Commun ; 643: 129-138, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36603530

RESUMO

There is an alarming increase in incidence of fatty liver disease worldwide. The fatty liver disease spectrum disease ranges from simple steatosis (NAFL) to steatohepatitis (NASH) which culminates in cirrhosis and cancer. Altered metabolism is a hallmark feature associated with fatty liver disease and palmitic acid is the most abundant saturated fatty acid, therefore, the aim of this study was to compare metabolic profiles altered in hepatocytes treated with palmitic acid and also the differentially expressed plasma metabolites in spectrum of nonalcoholic fatty liver. The metabolites were analyzed by liquid chromatography-mass spectrometry (LC-MS) platform. Hepatocyte cell lines PH5CH8 and HepG2 cells when treated with 400 µM dose of palmitic acid showed typical features of steatosis. Metabolomic analysis of lipid treated hepatocyte cell lines showed differential changes in phenylalanine and tyrosine pathways, fatty acid metabolism and bile acids. The key metabolites tryptophan, kynurenine and carnitine differed significantly between subjects with NAFL, NASH and those with cirrhosis. As the tryptophan-kynurenine axis is also involved in denovo synthesis of NAD+, we found significant alterations in the NAD+ related metabolites in both palmitic acid treated and also fatty liver disease with cirrhosis. The study underscores the importance of amino acid and NAD+supplementation as promising strategies in fatty liver disorder.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , NAD/metabolismo , Aminoácidos/metabolismo , Palmitatos/metabolismo , Cinurenina/metabolismo , Triptofano/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática/patologia , Ácido Palmítico/farmacologia , Ácido Palmítico/metabolismo , Fígado/metabolismo
9.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675130

RESUMO

Ozone (O3) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O3 also harms the brain; acute exposure to O3 has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O3 inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O3 exposure. In this study, our goals were to characterize neurobehavioral endpoints of O3 exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O3 behavioral effects. We evaluated O3-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O3, but not 2 or 1 ppm O3, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase (Ido1) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O3 and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O3 doses (1-3 ppm), suggesting that behavioral responses to O3 can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O3-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O3, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O3 exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O3, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.


Assuntos
Ozônio , Pneumonia , Feminino , Camundongos , Animais , Ozônio/toxicidade , Proteína Amiloide A Sérica/metabolismo , Cinurenina/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Fenótipo
10.
Artigo em Inglês | MEDLINE | ID: mdl-36372294

RESUMO

Previous studies have indicated that an imbalance in the kynurenine (KYN) pathway is an important pathophysiological mechanism of depression. Several studies have reported that an imbalance in the KYN pathway and its metabolites is associated with abnormalities in cerebral structure and function in depression, but the available evidence has been inconsistent. In this review, we systematically reviewed and integrated the findings concerning the associations between the KYN pathway and the brain in patients with major depressive disorder (MDD). A total of 22 neuroimaging studies were ultimately included in the present study. The neuroimaging modalities used in the studies included structural magnetic resonance imaging (MRI), diffusion tensor imaging, functional MRI, magnetic resonance spectroscopy, arterial spin labelling and positron emission tomography. The results revealed that an imbalance in the KYN pathway was associated with structural and functional abnormalities in several brain regions in patients with MDD. The brain regions most frequently associated with an imbalance in the KYN pathway were cortical regions (i.e., anterior cingulate cortex and orbitofrontal cortex), subcortical regions (i.e., striatum, thalamus and amygdala) and white matter fibres (i.e., inner capsule and left superior longitudinal tract). Our study provides robust evidence that cerebral abnormalities associated with the KYN pathway may be the underlying pathophysiological mechanisms of MDD. Future prospective studies are needed to further elucidate the causal relationships between the imbalanced KYN pathway and cerebral abnormalities in patients with MDD.


Assuntos
Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Cinurenina , Imagem de Tensor de Difusão , Neuroimagem , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética
11.
Fish Shellfish Immunol ; 132: 108485, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36521804

RESUMO

Tryptophan is mainly degraded through kynurenine pathway (KP) in vertebrates which is closely related to the nerve and depression, while the studies on immunity is still limited. This study aims to explore the functions of tryptophan in the innate immunity of primitive vertebrate lamprey. MTT (3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide) assay showed that tryptophan had no obvious effect on cell viability. Tryptophan was transported into leukocytes and degraded via the KP after tryptophan supplement. Tryptophan treatment (T1x and T2x) failed to alter the total antioxidant capacity regardless of stimulation and exposure time. Real-time quantitative PCR and western blotting results revealed that tryptophan was not only able to reduce the expression of pro-inflammatory factors Lj-TNF-α, Lj-IL1ß and Lj-NF-κB, but also to upregulate the expression of anti-inflammatory factor Lj-TGF-ß independent of stimulation and time. In addition, tryptophan can exert immune tolerance function by inhibiting TLR-MyD88 and promoting (Indoleamine 2, 3-Dioxygenase) IDO-kynurenine-AHR (aryl hydrocarbon receptor) pathways. This study provides a new understanding for tryptophan-kynurenine metabolism and mechanism of immune tolerance function in primitive vertebrate lamprey.


Assuntos
Cinurenina , Receptores de Hidrocarboneto Arílico , Animais , Cinurenina/metabolismo , Triptofano/farmacologia , Triptofano/metabolismo , Tolerância Imunológica , Vertebrados/metabolismo
12.
Cells ; 11(23)2022 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-36497053

RESUMO

Migraine is a complex neurovascular disorder, which causes intense socioeconomic problems worldwide. The pathophysiology of disease is enigmatic; accordingly, therapy is not sufficient. In recent years, migraine research focused on tryptophan, which is metabolized via two main pathways, the serotonin and kynurenine pathways, both of which produce neuroactive molecules that influence pain processing and stress response by disturbing neural and brain hypersensitivity and by interacting with molecules that control vascular and inflammatory actions. Serotonin has a role in trigeminal pain processing, and melatonin, which is another product of this pathway, also has a role in these processes. One of the end products of the kynurenine pathway is kynurenic acid (KYNA), which can decrease the overexpression of migraine-related neuropeptides in experimental conditions. However, the ability of KYNA to cross the blood-brain barrier is minimal, necessitating the development of synthetic analogs with potentially better pharmacokinetic properties to exploit its therapeutic potential. This review summarizes the main translational and clinical findings on tryptophan metabolism and certain neuropeptides, as well as therapeutic options that may be useful in the prevention and treatment of migraine.


Assuntos
Transtornos de Enxaqueca , Triptofano , Humanos , Triptofano/metabolismo , Serotonina/metabolismo , Cinurenina/metabolismo , Ácido Cinurênico , Redes e Vias Metabólicas , Dor
13.
Zh Nevrol Psikhiatr Im S S Korsakova ; 122(12): 138-142, 2022.
Artigo em Russo | MEDLINE | ID: mdl-36537644

RESUMO

OBJECTIVE: To develop a method for determining cinnabarinic acid (CA) and its immediate precursor 3-hydroxyanthranylic acid (3HAA) in blood plasma and to study their concentrations in patients with schizophrenia before and after treatment. MATERIAL AND METHODS: The study was carried out on a sample of 23 female patients with an attack-like progredient schizophrenia (F20.01). The levels of CA and 3HAA in blood plasma were measured using liquid chromatography with tandem mass spectrometry. RESULTS: We found an inverse statistically significant correlation of the sum of CA and 3HAA concentrations before treatment with the total PANSS score after treatment (R=-0.50; p<0.05). There was also an inverse correlation of the CA concentration of before treatment with the total PANSS score after treatment (R=-0.41, p=0.052), statistically significant at the trend level (0.05

Assuntos
Ácido 3-Hidroxiantranílico , Esquizofrenia , Humanos , Feminino , Prognóstico , Oxazinas , Cinurenina
14.
Kardiologiia ; 62(11): 40-48, 2022 Nov 30.
Artigo em Russo, Inglês | MEDLINE | ID: mdl-36521043

RESUMO

Aim    To compare serum concentrations of tryptophane (Trp) and its metabolites in subjects with no cardiovascular disease (CVD) and patients with СVD, including arterial hypertension (AH) and ischemic heart disease (IHD).Material and methods    This study included 131 participants; 58 participants (11 of them with documented peripheral atherosclerosis) were included into the AH group, 46 participants were included into the IHD group, and 27 participants with no signs of CVD were included into the control group. Plasma concentrations of Trp and its metabolites were measured by high-performance liquid chromatography in combination with a triple quadrupole analyzer.Results    Comparison of the three study groups revealed significant differences in concentrations of Trp (р=0.029), kynurenine (p<0.001), kynurenine/Trp ratio (p<0.001), quinolinic acid (р=0.007), kynurenic acid (р=0.003), serotonin (p<0.001), and 5­hydroxyindoleacetic acid (5­HIAA) (р=0.011). When the AH group was subdivided into subgroups without and with documented peripheral atherosclerosis, the intergroup differences remained for concentrations of kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, serotonin, and 5­HIAA. Also, correlations were found between concentrations of Trp metabolites and laboratory and instrumental data, primarily inflammatory markers. Conclusion    Analysis of serum concentrations of Trp and its metabolites in CVD patients showed increases in kynurenine, kynurenine/Trp ratio, quinolinic acid, kynurenic acid, and 5­HIAA along with decreases in concentrations of Trp and serotonin in the groups of AH, AH with documented peripheral atherosclerosis, and IHD.


Assuntos
Aterosclerose , Doença da Artéria Coronariana , Hipertensão , Humanos , Cinurenina/metabolismo , Triptofano/metabolismo , Ácido Cinurênico/metabolismo , Serotonina/metabolismo , Ácido Hidroxi-Indolacético , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Ácido Quinolínico , Hipertensão/complicações , Hipertensão/diagnóstico , Aterosclerose/complicações , Aterosclerose/diagnóstico
15.
Front Immunol ; 13: 1013784, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36426364

RESUMO

Background: Multiple sclerosis (MS) is a debilitating neurodegenerative disorder characterized by axonal damage, demyelination, and perivascular inflammatory lesions in the white matter of the central nervous system (CNS). Kynurenine pathway (KP), which is the major route of tryptophan (TRP) metabolism, generates a variety of neurotoxic as well as neuroprotective compounds, affecting MS pathology and the severity of impairments. Alterations in KP have been described not only in MS, but also in various psychiatric and neurodegenerative diseases. The purpose of this systematic review is to investigate the previously reported dysregulation of KP and differences in its metabolites and enzymes in patients with MS compared to healthy control subjects. Method: Electronic databases of PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science were searched to identify studies measuring concentrations of KP metabolites and enzymes in MS patients and control subjects. The following metabolites and enzymes implicated in the KP were investigated: TRP, kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUIN), picolinic acid (PIC), hydroxyindoleacetic acid (HIAA), indoleamine 2,3-dioxygenase (IDO), kynurenine aminotransferase (KAT), and their related ratios. Result: Ten studies were included in our systematic review. Our review demonstrates that IDO expression is reduced in the peripheral blood mononuclear cells (PBMCs) of MS patients compared to healthy controls. Also, increased levels of QUIN and QUIN/KYNA in the serum and cerebrospinal fluid (CSF) of MS patients is observed. Differences in levels of other metabolites and enzymes of KP are also reported in some of the reviewed studies, however there are discrepancies among the included reports. Conclusion: The results of this investigation suggest a possible connection between alterations in the levels of KP metabolite or enzymes and MS. QUIN levels in CSF were higher in MS patients than in healthy controls, suggesting that QUIN may be involved in the pathogenesis of MS. The data indicate that differences in the serum/blood or CSF levels of certain KP metabolites and enzymes could potentially be used to differentiate between MS patients and control subjects.


Assuntos
Cinurenina , Esclerose Múltipla , Humanos , Cinurenina/metabolismo , Triptofano/metabolismo , Leucócitos Mononucleares/metabolismo , Revisões Sistemáticas como Assunto , Ácido Quinolínico , Ácido Cinurênico/metabolismo
16.
Front Immunol ; 13: 950441, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405744

RESUMO

Objective: The occurrence of cardiovascular adverse events in the first year after ST-acute myocardial infarction (STEMI) remains high; therefore, identification of patients with poor prognosis is essential for early intervention. This study aimed to evaluate the prognostic value of metabolomics-based biomarkers in STEMI patients and explore their functional mechanisms. Methods: Metabolite profiling was performed using nuclear magnetic resonance. The plasma concentration of Kynurenine (Kyn) was measured using ultraperformance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Major adverse cardiac and cerebral events were assessed for 1 year. A functional metabolomics strategy was proposed for investigating the role of Kyn in both vitro and vivo models. Results: The adjusted hazard ratios in STEMI patients for Kyn in the 4th quartile 7.12(5.71-10.82) was significantly higher than that in the 3rd quartile 3.03(2.62-3.74), 2nd quartile 1.86(1.70-2.03), and 1st quartile 1.20(0.93-1.39).The incidence of MACCE was significantly different among Kyn quartiles and the highest incidence of MACCE was observed in the 4th quartile when compared with the 1st quartile (9.84% vs.2.85%, P<0.001).Immunofluorescence staining indicated that indoleamine-pyrrole 2,3-dioxygenase (IDO1) was located in the CD68 positive staining area of thrombi from STEMI patients and Kyn was induced in the early phase after myocardial infarction. Kyn could trigger inflammation and oxidative stress of macrophage cells by activation of the Sirt3-acSOD2/IL-1ß signaling pathway in vitro. Conclusions: Plasma Kyn levels were positively associated with the occurrence of STEMI. Kyn could induce macrophage cells inflammation and oxidative stress by activating the Sirt3-acSOD2/IL-1ß pathway following myocardial ischemia injury. Kyn could be a robust biomarker for STEMI prognosis and reduction of Kyn could be beneficial in STEMI patients.


Assuntos
Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Sirtuína 3 , Humanos , Cinurenina , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Prognóstico , Infarto do Miocárdio/complicações , Metabolômica , Biomarcadores , Inflamação/complicações
17.
Lupus Sci Med ; 9(1)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36384965

RESUMO

OBJECTIVE: Quinolinic acid (QA), a kynurenine (KYN)/tryptophan (TRP) pathway metabolite, is an N-methyl-D-aspartate receptor agonist that can produce excitotoxic neuron damage. Type I and II interferons (IFNs) stimulate the KYN/TRP pathway, producing elevated QA/kynurenic acid (KA), a potential neurotoxic imbalance that may contribute to SLE-mediated cognitive dysfunction. We determined whether peripheral blood interferon-stimulated gene (ISG) expression associates with elevated serum KYN:TRP and QA:KA ratios in SLE. METHODS: ISG expression (whole-blood RNA sequencing) and serum metabolite ratios (high-performance liquid chromatography) were measured in 72 subjects with SLE and 73 healthy controls (HCs). ISG were identified from published gene sets and individual IFN scores were derived to analyse associations with metabolite ratios, clinical parameters and neuropsychological assessments. SLE analyses were grouped by level of ISG expression ('IFN high', 'IFN low' and 'IFN similar to HC') and level of monocyte-associated gene expression (using CIBERSORTx). RESULTS: Serum KYN:TRP and QA:KA ratios were higher in SLE than in HC (p<0.01). 933 genes were differentially expressed ≥2-fold in SLE versus HC (p<0.05). 70 of the top 100 most highly variant genes were ISG. Approximately half of overexpressed genes that correlated with KYN:TRP and QA:KA ratios (p<0.05) were ISG. In 36 IFN-high subjects with SLE, IFN scores correlated with KYN:TRP ratios (p<0.01), but not with QA:KA ratios. Of these 36 subjects, 23 had high monocyte-associated gene expression, and in this subgroup, the IFN scores correlated with both KY:NTRP and QA:KA ratios (p<0.05). CONCLUSIONS: High ISG expression correlated with elevated KYN:TRP ratios in subjects with SLE, suggesting IFN-mediated KYN/TRP pathway activation, and with QA:KA ratios in a subset with high monocyte-associated gene expression, suggesting that KYN/TRP pathway activation may be particularly important in monocytes. These results need validation, which may aid in determining which patient subset may benefit from therapeutics directed at the IFN or KYN/TRP pathways to ameliorate a potentially neurotoxic QA/KA imbalance.


Assuntos
Disfunção Cognitiva , Lúpus Eritematoso Sistêmico , Humanos , Cinurenina/metabolismo , Triptofano/metabolismo , Interferons , Lúpus Eritematoso Sistêmico/complicações , Ácido Cinurênico/metabolismo , Ácido Quinolínico/metabolismo , Disfunção Cognitiva/etiologia
18.
J Chromatogr A ; 1685: 463602, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36371922

RESUMO

Tryptophan, an essential amino acid, and its metabolites are involved in many physiological processes including neuronal functions, immune system, and gut homeostasis. Alterations to tryptophan metabolism are associated with various pathologies such as neurologic, psychiatric disorders, inflammatory bowel diseases (IBD), metabolic disorders, and cancer. It is consequently critical to develop a reliable, quantitative method for the analysis of tryptophan and its downstream metabolites from the kynurenine, serotonin, and indoles pathways. An LC-MS/MS method was designed for the analysis of tryptophan and 20 of its metabolites, without derivatization and performed in a single run. This method was validated for both serum and stool. The comparisons between serum and plasma, collected with several differing anticoagulants, showed significant differences only for serotonin. References values were established in sera and stools from healthy donors. For stool samples, as a proof of concept, the developed method was applied to a healthy control group and an IBD patient group. Results showed significant differences in the concentrations of tryptophan, xanthurenic acid, kynurenic acid, indole-3-lactic acid, and picolinic acid. This method allowed an extensive analysis of the three tryptophan metabolic pathways in two compartments. Beyond the application to IBD patients, the clinical use of this method is wide-ranging and may be applied to other pathological conditions involving tryptophan metabolism, such as neurological, psychiatric, or auto-inflammatory pathologies.


Assuntos
Doenças Inflamatórias Intestinais , Triptofano , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Serotonina/metabolismo , Cinurenina
19.
Front Immunol ; 13: 1001956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389710

RESUMO

Many invasive micro-organisms produce 'quorum sensor' molecules which regulate colony expansion and may modulate host immune responses. We have examined the ability of Pseudomonas Quorum Sensor (PQS) to influence cytokine expression under conditions of inflammatory stress. The administration of PQS in vivo to mice with collagen-induced arthritis (CIA) increased the severity of disease. Blood and inflamed paws from treated mice had fewer regulatory T cells (Tregs) but normal numbers of Th17 cells. However, PQS (1µM) treatment of antigen-stimulated lymph node cells from collagen-immunised mice in vitro inhibited the differentiation of CD4+IFNγ+ cells, with less effect on CD4+IL-17+ cells and no change in CD4+FoxP3+Tregs. PQS also inhibited T cell activation by anti-CD3/anti-CD28 antibodies. PQS reduced murine macrophage polarisation and inhibited expression of IL1B and IL6 genes in murine macrophages and human THP-1 cells. In human monocyte-derived macrophages, IDO1 gene, protein and enzyme activity were all inhibited by exposure to PQS. TNF gene expression was inhibited in THP-1 cells but not murine macrophages, while LPS-induced TNF protein release was increased by high PQS concentrations. PQS is known to have iron scavenging activity and its suppression of cytokine release was abrogated by iron supplementation. Unexpectedly, PQS decreased the expression of indoleamine-2, 3-dioxygenase genes (IDO1 and IDO2), IDO1 protein expression and enzyme activity in mouse and human macrophages. This is consistent with evidence that IDO1 inhibition or deletion exacerbates arthritis, while kynurenine reduces its severity. It is suggested that the inhibition of IDO1 and cytokine expression may contribute to the quorum sensor and invasive actions of PQS.


Assuntos
Cinurenina , Pseudomonas , Humanos , Camundongos , Animais , Cinurenina/metabolismo , Pseudomonas aeruginosa , Ferro/metabolismo , Citocinas/metabolismo
20.
Proc Natl Acad Sci U S A ; 119(47): e2208886119, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36375056

RESUMO

Uterine leiomyoma is the most common tumor in women and causes severe morbidity in 15 to 30% of reproductive-age women. Epidemiological studies consistently indicate a correlation between leiomyoma development and exposure to endocrine-disrupting chemical phthalates, especially di-(2-ethylhexyl) phthalate (DEHP); however, the underlying mechanisms are unknown. Here, among the most commonly encountered phthalate metabolites, we found the strongest association between the urine levels of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), the principal DEHP metabolite, and the risk of uterine leiomyoma diagnosis (n = 712 patients). The treatment of primary leiomyoma and smooth muscle cells (n = 29) with various mixtures of phthalate metabolites, at concentrations equivalent to those detected in urine samples, significantly increased cell viability and decreased apoptosis. MEHHP had the strongest effects on both cell viability and apoptosis. MEHHP increased cellular tryptophan and kynurenine levels strikingly and induced the expression of the tryptophan transporters SLC7A5 and SLC7A8, as well as, tryptophan 2,3-dioxygenase (TDO2), the key enzyme catalyzing the conversion of tryptophan to kynurenine that is the endogenous ligand of aryl hydrocarbon receptor (AHR). MEHHP stimulated nuclear localization of AHR and up-regulated the expression of CYP1A1 and CYP1B1, two prototype targets of AHR. siRNA knockdown or pharmacological inhibition of SLC7A5/SLC7A8, TDO2, or AHR abolished MEHHP-mediated effects on leiomyoma cell survival. These findings indicate that MEHHP promotes leiomyoma cell survival by activating the tryptophan-kynurenine-AHR pathway. This study pinpoints MEHHP exposure as a high-risk factor for leiomyoma growth, uncovers a mechanism by which exposure to environmental phthalate impacts leiomyoma pathogenesis, and may lead to the development of novel druggable targets.


Assuntos
Dietilexilftalato , Poluentes Ambientais , Leiomioma , Ácidos Ftálicos , Humanos , Feminino , Dietilexilftalato/toxicidade , Dietilexilftalato/urina , Cinurenina , Triptofano , Sobrevivência Celular , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes , Exposição Ambiental/efeitos adversos , Leiomioma/induzido quimicamente , Leiomioma/urina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...