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1.
Sci Rep ; 10(1): 16824, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033346

RESUMO

The biological mechanisms involved in SARS-CoV-2 infection are only partially understood. Thus we explored the plasma metabolome of patients infected with SARS-CoV-2 to search for diagnostic and/or prognostic biomarkers and to improve the knowledge of metabolic disturbance in this infection. We analyzed the plasma metabolome of 55 patients infected with SARS-CoV-2 and 45 controls by LC-HRMS at the time of viral diagnosis (D0). We first evaluated the ability to predict the diagnosis from the metabotype at D0 in an independent population. Next, we assessed the feasibility of predicting the disease evolution at the 7th and 15th day. Plasma metabolome allowed us to generate a discriminant multivariate model to predict the diagnosis of SARS-CoV-2 in an independent population (accuracy > 74%, sensitivity, specificity > 75%). We identified the role of the cytosine and tryptophan-nicotinamide pathways in this discrimination. However, metabolomic exploration modestly explained the disease evolution. Here, we present the first metabolomic study in SARS-CoV-2 patients which showed a high reliable prediction of early diagnosis. We have highlighted the role of the tryptophan-nicotinamide pathway clearly linked to inflammatory signals and microbiota, and the involvement of cytosine, previously described as a coordinator of cell metabolism in SARS-CoV-2. These findings could open new therapeutic perspectives as indirect targets.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Citosina/sangue , Metaboloma , Metabolômica/métodos , Niacinamida/sangue , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Triptofano/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Diagnóstico Precoce , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença
2.
Arch Osteoporos ; 15(1): 167, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33083938

RESUMO

Tryptophan metabolites influence bone. We aimed to investigate the relationship between dietary tryptophan and bone health in a population-based sample of men and women. Following adjustment for age, dietary tryptophan was not associated with bone quantity or quality, suggesting a non-critical role of superfluous tryptophan on the skeleton. PURPOSE: Tryptophan metabolites, such as serotonin, influence bone. We sought to determine the relationship between dietary intake of tryptophan and bone health in a population-based study of men and women. METHODS: Participants (1033 women and 900 men, aged 20-98 years) enrolled in the Geelong Osteoporosis Study (GOS) were investigated. Dietary information was collected using a validated questionnaire. Tryptophan levels were calculated (mg/day) in accordance with Food Standards Australia and New Zealand and dichotomised according to the median. Bone mineral density (BMD; g/cm2) was measured at the spine (postero-anterior projection) and total hip using dual-energy X-ray absorptiometry. Stiffness index (SI), broadband ultrasound attenuation (BUA) and speed of sound (SOS) were derived from quantitative heel ultrasound. Linear regression models were used to test associations between dietary tryptophan and bone health, after adjustment for potential confounders. RESULTS: Tryptophan intakes ranged from 112 to 3796 mg/day (median 1035) in men and 115-2869 mg/day (median 885) in women. In men older than 45 years and women, a high tryptophan intake was associated with greater hip BMD compared to participants with a low tryptophan intake (p = 0.002 and p = 0.04, respectively); however, these relationships were attenuated by age (all p > 0.05). Participants with high tryptophan intake had greater BUA and SI compared to participants with low tryptophan intake (men; BUA, p = 0.02 and SI, p = 0.02, and women; BUA, p = 0.03 and SI, p = 0.08), yet also attenuated by age (all p > 0.05). CONCLUSION: No association was found between tryptophan intake and bone health in this population, which suggests a non-critical role of superfluous tryptophan consumption on the skeleton.


Assuntos
Densidade Óssea , Calcanhar/diagnóstico por imagem , Vigilância da População/métodos , Triptofano/administração & dosagem , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Inquéritos e Questionários , Triptofano/sangue , Ultrassonografia , Adulto Jovem
3.
PLoS One ; 15(7): e0236357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687509

RESUMO

Adult growth hormone deficiency (GHD) is being increasingly recognized to cause premature mortality exacerbated by oxidative stress. A case-control observational study has been performed with the primary objective of evaluating new parameters of oxidative stress and macromolecular damage in adult GHD subjects: serum nitrotryptophan; Total Antioxidant Capacity expressed as LAG time; urinary hexanoil-lysine; urinary dityrosine and urinary 8-OH-deoxyguanosine. GHD was diagnosed using Growth Hormone-Releasing Hormone 50µg iv+arginine 0,5 g/Kg test, with a peak GH response <9 µg /L when BMI was <30 kg/m2 or <4 µg/L when BMI was >30 kg/m2. Patients affected by adult GHD were divided into three groups, total GHD (n = 26), partial GHD (n = 25), and controls (n = 29). Total Antioxidant Capacity, metabolic and hormonal parameters have been determined in separate plasma samples; nitrotryptophan in serum samples; hexanoil-lysine, dityrosine, 8-OH-deoxyguanosine in urine samples. Assessment of hexanoil-lysine exhibited a trend to increase in comparing total GHD vs partial and controls, although not significant. Values of 8-OH-deoxyguanosine did not significantly differ among the three groups. Significant lower levels of dityrosine in partial GHD vs total and controls were found. No significant difference in nitrotriptophan serum levels was found, while significantly greater values of Total Antioxidant Capacity were showed in total and partial GHD vs controls. Thus, our result confirm that oxidative stress is increased both in partial and total adult GHD. The lack of compensation by antioxidants in total GHD may be connected to the complications associated to this rare disorder.


Assuntos
Antioxidantes/análise , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/metabolismo , Síndrome Metabólica/metabolismo , Estresse Oxidativo/fisiologia , 8-Hidroxi-2'-Desoxiguanosina/urina , Adulto , Malformação de Arnold-Chiari/sangue , Malformação de Arnold-Chiari/complicações , Malformação de Arnold-Chiari/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Síndrome da Sela Vazia/sangue , Síndrome da Sela Vazia/complicações , Síndrome da Sela Vazia/metabolismo , Feminino , Humanos , Hipopituitarismo/sangue , Hipopituitarismo/etiologia , Hipopituitarismo/urina , Peroxidação de Lipídeos , Lisina/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Síndrome Metabólica/urina , Pessoa de Meia-Idade , Triptofano/análogos & derivados , Triptofano/sangue , Tirosina/análogos & derivados , Tirosina/urina
4.
Medicine (Baltimore) ; 99(19): e19906, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384433

RESUMO

Septic shock is associated with a strong inflammatory response that induces vasodilation and vascular hyporeactivity. We investigated the role for tryptophan-pathway catabolites of proinflammatory cytokines in septic shock.We prospectively included 30 patients with very recent-onset septic shock and 30 healthy volunteers. The following were assayed once in the controls and on days 1, 2, 3, 7, and 14 in each patient: plasma free and total tryptophan, platelet and plasma serotonin, total blood serotonin, urinary serotonin, plasma and urinary 5-hydroxyindolacetic acid, plasma kynurenine, monoamine oxidase activity, and total indole amine 2,3-dioxygenase activity. Organ-system failure and mortality were recorded.Compared with the healthy controls, the patients with septic shock had 2-fold to 3-fold lower total tryptophan levels throughout the 14-day study period. Platelet serotonin was substantially lower, while monoamine oxidase activity and 5-hydroxyindolacetic acid were markedly higher in the patients than in the controls, consistent with the known conversion of tryptophan to serotonin, which is then promptly and largely degraded to 5-hydroxyindolacetic acid. Plasma kynurenine was moderately increased and indole amine 2,3-dioxygenase activity markedly increased in the patients versus the volunteers, reflecting conversion of tryptophan to kynurenine. Changes over time in tryptophan metabolites were not associated with survival in the patients but were associated with the Sequential Organ Failure Assessment score and hemodynamic variables including hypotension and norepinephrine requirements.Our results demonstrate major tryptophan pathway alterations in septic shock. Marked alterations were found compared with healthy volunteers, and tryptophan metabolite levels were associated with organ failure and hemodynamic alterations. Tryptophan metabolite levels were not associated with surviving septic shock, although this result might be ascribable to the small sample size.Trial registration: ClinicalTrials.gov; No: NCT00684736; URL: www.clinicaltrials.gov.


Assuntos
Choque Séptico/sangue , Choque Séptico/mortalidade , Triptofano/sangue , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Ácido Hidroxi-Indolacético/sangue , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Cinurenina/sangue , Masculino , Pessoa de Meia-Idade , Monoaminoxidase/sangue , Escores de Disfunção Orgânica , Estudos Prospectivos , Serotonina/sangue , Taxa de Sobrevida
5.
BMC Cardiovasc Disord ; 20(1): 178, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32299366

RESUMO

BACKGROUND: Heart failure is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT) with approximately one-third of non-response rate. Thus far, there is no specific biomarker to predict the response to CRT in patients with heart failure. In this study, we assessed the role of the blood metabolomic profile in predicting the response to CRT. METHODS: A total of 105 dilated cardiomyopathy patients with severe heart failure who received CRT were included in our two-stage study. Baseline blood samples were collected prior to CRT implantation. The response to CRT was defined according to echocardiographic criteria. Metabolomic profiling of serum samples was carried out using ultrahigh performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. RESULTS: Seventeen metabolites showed significant differences in their levels between responders and non-responders, and these metabolites were primarily involved in six pathways, including linoleic acid metabolism, Valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, citrate cycle, tryptophan metabolism, and sphingolipid metabolism. A combination of isoleucine, tryptophan, and linoleic acid was identified as an ideal metabolite panel to distinguish responders from non-responders in the discovery set (n = 51 with an AUC of 0.981), and it was confirmed in the validation set (n = 54 with an AUC of 0.929). CONCLUSIONS: Mass spectrometry based serum metabolomics approach provided larger coverage of metabolome which can help distinguish CRT responders from non-responders. A combination of isoleucine, tryptophan, and linoleic acid may associate with significant prognostic values for CRT.


Assuntos
Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/terapia , Isoleucina/sangue , Ácido Linoleico/sangue , Metabolômica , Triptofano/sangue , Idoso , Biomarcadores/sangue , Terapia de Ressincronização Cardíaca/efeitos adversos , Cromatografia Líquida de Alta Pressão , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Resultado do Tratamento
6.
Exerc Immunol Rev ; 26: 24-42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32139353

RESUMO

INTRODUCTION: The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise. METHODS: 24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes. RESULTS: The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session. CONCLUSIONS: In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations.


Assuntos
Treino Aeróbico , Cinurenina/sangue , Leucócitos Mononucleares/imunologia , Treinamento de Resistência , Adulto , Estudos Cross-Over , Exercício Físico , Humanos , Hidrocortisona/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interleucina-6/imunologia , Ácido Cinurênico/sangue , Leucócitos Mononucleares/enzimologia , Masculino , Ácido Quinolínico/sangue , Transaminases/imunologia , Triptofano/sangue
7.
Med Sci Sports Exerc ; 52(6): 1394-1403, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31895298

RESUMO

INTRODUCTION: Protein ingestion and the ensuing hyperaminoacidemia stimulates skeletal muscle protein synthesis in the postexercise period. This response facilitates muscle remodeling, which is important during intensified training. The aim of this study was to determine whether supplementation with α-lactalbumin (LA), with high leucine and tryptophan contents, would improve responses to short periods of intensified aerobic training compared with supplementation with an isonitrogenous quantity of collagen peptides (CP). METHODS: Endurance-trained participants (5 male, 6 female, 24 ± 4 yr, V˙O2 = 53.2 ± 9.1 mL·kg·min, peak power output = 320 ± 48 W; means ± SD) consumed a controlled diet (1.0 g·kg·d protein) and refrained from habitual training for 11 d while taking part in this double-blind randomized, crossover trial. The two intervention phases, which consisted of brief intensified training (4 × 4-min cycling intervals at 70% of peak power output on 3 consecutive days) combined with the ingestion of LA or CP supplements after exercise (20 g) and before sleep (40 g), were separated by 4 d of washout without protein supplementation (i.e., the control phase). In response to each phase, myofibrillar (MyoPS), sarcoplasmic protein synthesis (SarcPS) rates (via H2O ingestion) and parameters of sleep quality were measured. RESULTS: LA ingestion increased plasma leucine (P < 0.001) and tryptophan concentrations (P < 0.001) relative to CP. Intensified training increased MyoPS and SarcPS above the washout phase in LA- and CP-supplemented phases (P < 0.01), with increases being 13% ± 5% and 5% ± 7% greater with LA than CP for MyoPS (P < 0.01) and SarcPS, respectively (P < 0.01). CONCLUSIONS: Despite an isonitrogenous diet, protein synthesis was enhanced to a greater extent when trained participants consumed LA compared with CP during intensified aerobic training, suggesting that protein quality is an important consideration for endurance-trained athletes aiming to augment adaption to exercise training.


Assuntos
Colágeno/administração & dosagem , Suplementos Nutricionais , Exercício Físico/fisiologia , Lactalbumina/administração & dosagem , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Humano/fisiologia , Disponibilidade Biológica , Feminino , Humanos , Leucina/administração & dosagem , Leucina/sangue , Masculino , Miofibrilas/metabolismo , Retículo Sarcoplasmático/metabolismo , Sono/fisiologia , Triptofano/administração & dosagem , Triptofano/sangue , Adulto Jovem
8.
Int J Infect Dis ; 91: 162-168, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31821895

RESUMO

OBJECTIVES: During dengue fever, a pronounced gamma-interferon immune response produces neopterin and promotes tryptophan degradation by the enzyme indoleamine-2,3-dioxygenase 1 (IDO-1). Activated IDO-1 is indicated by an increased kynurenine to tryptophan ratio (Kyn/Trp) in patients. METHODS: Plasma levels of neopterin, kynurenine, and tryptophan were measured in 72 hospitalized dengue virus (DENV) patients and 100 healthy individuals. Plasma levels of neopterin, kynurenine, and tryptophan were also measured prospectively in a second cohort of 13 DENV patients; on the day of hospitalization, on day 2-3 at discharge, and 7-10 days after discharge. DENV RNA positivity was determined by qualitative and quantitative methodologies. RESULTS: DENV RNA-positive patients presented significantly higher levels of neopterin (mean 36.5nmol/l) and Kyn/Trp ratios (mean 102µmol/mmol) compared to DENV RNA-negative individuals. A significant correlation between neopterin levels and Kyn/Trp ratios was observed in both DENV RNA-positive (Spearman's rho=0.37, p< 0.01) and DENV RNA-negative (Spearman's rho=0.89, p<0.001) patients. Kyn/Trp ratios were negatively correlated with platelet counts (Spearman's rho=-0.43, p<0.01) and positively correlated with liver enzymes: AST (Spearman's rho=0.68, p<0.01) and ALT (Spearman's rho=0.51, p<0.05). In addition, the follow-up data presented a significant decrease in neopterin levels and Kyn/Trp ratios within 10 days after hospital entry. CONCLUSIONS: Neopterin levels and Kyn/Trp ratios were significantly increased in DENV patients and subsequently decreased after recovery.


Assuntos
Dengue/sangue , Cinurenina/sangue , Neopterina/sangue , Triptofano/sangue , Adolescente , Adulto , Criança , Dengue/virologia , Vírus da Dengue/genética , Vírus da Dengue/isolamento & purificação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Adulto Jovem
9.
Artigo em Inglês | MEDLINE | ID: mdl-31676443

RESUMO

Dysregulation of the tryptophan (Trp)-NAD+ pathway has been related to several pathological conditions, and the metabolites in this pathway are known to influence mitochondrial respiration and redox status. The aim of this project was to investigate if stimulation of beta-oxidation and mitochondrial proliferation by the mitochondrial-targeted compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA) would influence metabolites of the Trp-Kyn-NAD+ pathway. We wished to investigate how carnitine depletion by meldonium-treatment influenced these metabolites. After dietary treatment of male Wistar rats with 1-triple TTA for three weeks, increased hepatic mitochondrial- and peroxisomal fatty acid oxidation resulted. The plasma content of total carnitines decreased compared to control animals, whereas hepatic genes involved in CoA biosynthesis were upregulated by 1-triple TTA treatment. The plasma Trp level and individual metabolites in the kynurenine pathway were increased by 1-triple TTA, associated with decreased hepatic gene expression of indoleamine2,3-dioxygenase. 1-triple TTA treatment increased conversion of Trp to nicotinamide (Nam) as the plasma content of quinolinic acid, Nam and N1-methylnicotinamide (mNam) increased, accompanied with suppression of hepatic gene expression of α-amino-α-carboxymuconate-ε-semialdehyde decarboxylase. A positive correlation between mitochondrial fatty acid oxidation and Trp-derivatives was found. Almost identical results were obtained by 1-triple TTA in the presence of meldonium, which alone exerted minor effects. Moreover, the plasma Kyn:Trp ratio (KTR) correlated negatively to mitochondrial function. Whether increased flux through the Trp-NAD+ pathway increased redox status and lowered inflammation locally and systemically should be considered.


Assuntos
Cinurenina/metabolismo , Fígado/metabolismo , Mitocôndrias/metabolismo , Niacinamida/metabolismo , Triptofano/metabolismo , Animais , Carnitina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Cinurenina/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Metilidrazinas/farmacologia , Mitocôndrias/efeitos dos fármacos , NAD/metabolismo , Niacinamida/sangue , Oxirredução/efeitos dos fármacos , Peroxissomos/efeitos dos fármacos , Peroxissomos/metabolismo , Ratos , Triptofano/sangue
10.
Talanta ; 206: 120245, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514823

RESUMO

A novel L-tryptophan (L-Trp) electrochemical sensor is fabricated, which is based on the molecularly imprinted copolymer (MIP) of dual -functional monomers and ionic liquid (i.e. 1-butyl-3-methylimidazolium hexafluorophosphate) functionalized multi-walled carbon nanotubes (MWCNTs@IL). The MWCNTs@IL is prepared via ion exchange, while the MIP is synthesized by using L-Trp as template, styrene and 4-vinylbenzoic acid as functional monomers, Triton X-100 as emulsifier, 1, 2-divinylbenzene as cross-linking reagent and K2S2O8 as initiator. Prior to copolymerization the functional monomer 4-vinylbenzoic acid is combined with the template molecule by forming amide bond. The template molecule is eluted by hydrolysis, and rebound by electrostatic, hydrogen-bond and π-π interaction. To construct L-Trp sensor a little of Nafion is introduced to enhance the stability and to promote rebinding. The resulting sensor Nafion-MIP-MWCNTs@IL/GCE shows a wide linear range (8 nM-26 µM) and a low detection limit (6 nM). It is successfully applied to the determination of L-Trp in oral liquid and human serum samples.


Assuntos
Técnicas Eletroquímicas/métodos , Polímeros/química , Triptofano/sangue , Técnicas Eletroquímicas/instrumentação , Eletrodos , Polímeros de Fluorcarboneto/química , História Medieval , Humanos , Imidazóis/química , Limite de Detecção , Impressão Molecular/métodos , Nanotubos de Carbono/química , Polimerização , Polímeros/síntese química , Reprodutibilidade dos Testes , Estereoisomerismo , Estireno/química , Estirenos/química , Triptofano/química
11.
Int J Cancer ; 146(9): 2394-2405, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/sangue , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Inflamação/complicações , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/etiologia , Adulto , Idoso , Carcinoma de Células Grandes/sangue , Carcinoma de Células Grandes/etiologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/imunologia , Cinurenina/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Prognóstico , Estudos Prospectivos , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/etiologia , Triptofano/sangue
12.
Int J Biol Macromol ; 142: 693-704, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31739063

RESUMO

The present study aimed to evaluate effect of Ganoderma atrum polysaccharide (PSG) on acute lung injury (ALI) rats and its mechanisms. Results showed that PSG exhibited protective effects against ALI by maintaining pulmonary histology, reducing levels of pro-inflammatory cytokines and NO both in serum and lung tissue. Moreover, this study further evaluated the metabolic effects of PSG based on UPLC-Triple-TOF/MS metabolomics analysis in rats. Compared with control group, LysoPC (18:2), LPA (18:1), taurocholic acid, L-histidine, and L-tryptophan were identified as metabolic biomarkers in serum of ALI group. Furthermore, biological pathways analysis demonstrated that histidine metabolism, nitrogen metabolism, tryptophan and part glycerophospholipids metabolism were notably modified by PSG treatment in ALI rats. Additionally, improved gut microbial metabolite short-chain fatty acids were found after intake of PSG in ALI rat. Altogether, PSG could control ALI-induced aberrant inflammation and its mechanisms were linked to inhibit release of pro-inflammatory mediators and reverse metabolic pathway disturbances.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/química , Ganoderma/química , Polissacarídeos/química , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Histidina/sangue , Histidina/metabolismo , Lisofosfatidilcolinas/sangue , Lisofosfatidilcolinas/metabolismo , Lisofosfolipídeos/sangue , Lisofosfolipídeos/metabolismo , Masculino , Metabolômica , Polissacarídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Espectrometria de Massas em Tandem , Ácido Taurocólico/sangue , Ácido Taurocólico/metabolismo , Triptofano/sangue , Triptofano/metabolismo
13.
Chirality ; 32(2): 215-222, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31747471

RESUMO

Tryptophan is a key amino acid related to metabolomics in gastric cancer. To date, methods were developed only for the assay of l-tryptophan, the role of d-tryptophan being not yet established. Therefore, four stochastic sensors based on different graphene materials modified with ß-cyclodextrins, 2,2-diphenyl-1-picrylhydrazyl, and protoporphyrin IX were designed and used for enantioanalysis of tryptophan in whole blood samples. High sensitivities, and reliabilities were recorded when the stochastic sensors were used for the enantioanalysis of tryptophan in whole blood samples. The paper opened a new chapter in early detection of gastric cancer, based on establishing the role of d-tryptophan in metabolomics, and in early diagnosis of gastric cancer.


Assuntos
Análise Química do Sangue/métodos , Detecção Precoce de Câncer , Neoplasias Gástricas/diagnóstico , Triptofano/sangue , Triptofano/química , Grafite/química , Humanos , Nitrogênio/química , Estereoisomerismo , Processos Estocásticos , Neoplasias Gástricas/sangue
14.
Clin Cancer Res ; 26(1): 282-289, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31471311

RESUMO

PURPOSE: We recently reported that indoleamine 2, 3-dioxygenase (IDO) activity is significantly correlated with more distant metastasis and worse survival. The present study examined whether radiotherapy (RT) dose fractionation correlates with IDO-mediated immune activity in patients with early-stage NSCLC.Methods: Patients with newly diagnosed stage I-II NSCLC treated with either conventionally fractionated 3-dimensional conformal radiotherapy (3DCRT) or stereotactic body radiotherapy (SBRT) were analyzed. Levels of two key molecules associated with the IDO immune checkpoint, serum kynurenine and the kynurenine:tryptophan ratio (K:T ratio), were measured at pre-RT, during-RT, and 3-month post-RT. The relationship between disease control outcomes [overall survival (OS), progression free survival, and local/regional/distant failure rates] and absolute levels of these markers, as well as dynamic changes in their levels during RT, was studied. RESULTS: Fifty-six patients (SBRT = 28, 3DCRT = 28) with early-stage NSCLC were studied. In all patients, higher kynurenine post-RT was significantly associated with worse OS ([HR, 1.25; 95% confidence interval (CI), 1.01-1.55; P = 0.044). No statistically significant differences in absolute kynurenine levels or the K:T ratio were observed in patients treated with 3DCRT or SBRT at any of the three time points. However, the absolute kynurenine levels rose significantly more post-RT in the 3DCRT patients with a median increase 0.721 ng/mL, compared to that of SBRT patients (0.115 ng/mL); P = 0.022. CONCLUSIONS: This study validated that elevated IDO activity correlated with worse survival outcomes in patients with early-stage NSCLC treated with definitive RT. Hypofractionated SBRT may have less immunosuppressive effect than 3DCRT, as measured by IDO.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Pulmonares/mortalidade , Radiocirurgia/métodos , Radioterapia Conformacional/métodos , Idoso , Biomarcadores Tumorais/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Fracionamento da Dose de Radiação , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Cinurenina/sangue , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Masculino , Estadiamento de Neoplasias , Taxa de Sobrevida , Triptofano/sangue
15.
mBio ; 10(6)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848275

RESUMO

Multiple cellular metabolic pathways are altered by HIV-1 infection, with an impact on immune activation, inflammation, and acquisition of non-AIDS comorbid diseases. The dysfunction of tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the underlying mechanism remains unknown. In this study, we demonstrated that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is activated by Trp metabolites to promote HIV-1 infection and reactivation. AHR directly binds to the HIV-1 5' long terminal repeat (5'-LTR) at the molecular level to activate viral transcription and infection, and AHR activation by Trp metabolites increases its nuclear translocation and association with the HIV 5'-LTR; moreover, the binding of AHR with HIV-1 Tat facilitates the recruitment of positive transcription factors to viral promoters. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.IMPORTANCE Cellular metabolic pathways that are altered by HIV-1 infection may accelerate disease progression. Dysfunction in tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the mechanism responsible was not known. This study demonstrates that Trp metabolites augment the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, to promote HIV-1 infection and transcription. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.


Assuntos
Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Triptofano/metabolismo , Ativação Viral , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Regulação Viral da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Repetição Terminal Longa de HIV/genética , Humanos , Modelos Biológicos , Ativação Transcricional , Triptofano/sangue , Carga Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana
16.
J Sports Sci Med ; 18(4): 669-673, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31827351

RESUMO

Regular physical activity and exercise interventions are suspected to have anti-inflammatory effects depending on exercise modality, thereby potentially reducing the risk and progress of several chronic diseases. Alterations in the kynurenine pathway may represent a link between inflammatory responses following acute exercise and chronic anti-inflammatory properties, such as increased levels of regulatory T-cells (Treg). Here, we hypothesize that acute exercise activates the kynurenine pathway and physical fitness is associated with proportions of circulating anti-inflammatory Treg in older healthy women. Nineteen older healthy female participants (55 years (SD: ± 5.6)) completed a cardiopulmonary incremental exercise test (CPET) with spirometry on a bicycle ergometer until exhaustion with maximum oxygen uptake (VO2max) as outcome. Blood samples were taken before (T0) and one minute after (T1) the CPET. Levels of tryptophan, serotonin and kynurenine were determined by enzyme-linked immunosorbent assays. Flow cytometry was used to identify proportions of T-cell subsets. Both, kynurenine (p = 0.003, d = 0.40) and the kynurenine/tryptophan ratio (p = 0.034, d = 0.48) increased significantly after acute exercise. Moreover, participants` VO2max was strongly correlated with Treg levels (p < 0.001, r = 0.689). This is the first study indicating a kynurenine pathway activation following acute exercise in older healthy women. The observed correlation between Treg levels and VO2max emphasizes a potential link between short-term upregulated kynurenine levels and longer-term anti-inflammatory properties of exercise. Future research is needed to clarify to what extend acute exercise-induced activations of the kynurenine pathway contribute to Treg differentiation.


Assuntos
Exercício Físico/fisiologia , Cinurenina/sangue , Linfócitos T Reguladores/metabolismo , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Diferenciação Celular , Feminino , Humanos , Consumo de Oxigênio/fisiologia , Resistência Física/fisiologia , Aptidão Física/fisiologia , Projetos Piloto , Serotonina/sangue , Linfócitos T Reguladores/imunologia , Triptofano/sangue
17.
Sci Rep ; 9(1): 16842, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727978

RESUMO

The lack of effective treatments and a high rate of relapse in cocaine addiction constitute a major health problem. The present study was conducted to examine the expression of tryptophan-derived metabolites in the context of cocaine addiction and psychiatric comorbidity, which is common in addicted subjects. Abstinent patients with cocaine use disorder (CUD) and control subjects were recruited for a cross-sectional study. Participants were assessed with a semi-structured diagnostic interview (PRISM) based on DSM-IV-TR for substance and mental disorders. Plasma concentrations of tryptophan metabolites and their association with relevant CUD-related variables and psychiatric comorbidity were explored. We observed decreased plasma kynurenic acid concentrations in the cocaine group, however no associations between CUD-related variables and tryptophan-derived metabolites were found. In contrast, 5-HT concentrations were increased in CUD-patients and the diagnosis of different psychiatric disorders in the cocaine group was related to higher plasma 5-HT concentrations compared with non-comorbid patients. Therefore, while changes in plasma kynurenic acid concentrations appear to be directly associated with lifetime CUD, changes in 5-HT concentrations are associated with psychiatric comorbidity. These results emphasize the need to find potential biomarkers for a better stratification of cocaine-addicted patients in order to develop therapeutic approaches to prevent cocaine relapse.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/psicologia , Transtornos Mentais/metabolismo , Serotonina/sangue , Triptofano/química , Adulto , Estudos de Casos e Controles , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Comorbidade , Estudos Transversais , Feminino , Humanos , Ácido Cinurênico/sangue , Masculino , Transtornos Mentais/sangue , Triptofano/sangue
18.
BMC Nephrol ; 20(1): 412, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729973

RESUMO

BACKGROUND: Inflammaging is a persistent, low-grade, sterile, nonresolving inflammatory state, associated with the senescence of the immune system. Such condition downregulates both innate and adaptive immune responses during chronic disorders as type II diabetes, cancer and hemodialysis, accounting for their susceptibility to infections, malignancy and resistance to vaccination. Aim of this study was to investigate hemodialysis inflammaging, by evaluating changes of several hemodialysis treatments on indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation. METHODS: We conducted a randomized controlled observational crossover trial. Eighteen hemodialysis patients were treated with 3 different hemodialysis procedures respectively: 1) Low-flux bicarbonate hemodialysis, 2) Low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, and 3) Hemodialfitration. The control group consisted of 14 hospital staff healthy volunteers. Blood samples were collected from all 18 hemodialysis patients just after the long interdialytic interval, at the end of each hemodialysis treatment period. RESULTS: Hemodialysis kynurenine and kynurenine/L - tryptophan blood ratio levels were significantly higher, when compared to the control group, indicating an increased indoleamine 2,3-dioxygenase-1 activity in hemodialysis patients. At the end of the low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers period, L - tryptophan serum levels remained unchanged vs both low-flux bicarbonate hemodialysis and hemodialfitration. Kynurenine levels instead decreased, resulting in a significant reduction of kynurenine/L - tryptophan blood ratio and indoleamine 2,3-dioxygenase-1 activity, when matched to both low-flux bicarbonate hemodialysis and HDF respectively. Serum nitric oxide control group levels, were significantly lower when compared to all hemodialysis patient groups. Interestingly, low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers nitric oxide serum levels from venous line blood samples taken 60 min after starting the hemodialysis session were significantly lower vs serum taken simultaneously from the arterial blood line. CONCLUSIONS: The treatment with more biocompatible hemodialysis procedure as low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, reduced indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation when compared to both low-flux bicarbonate hemodialysis and hemodialfitration. These data suggest that low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers lowering hemodialysis inflammaging, could be associated to changes of proinflammatory signalling a regulated molecular level. TRIAL REGISTRATION: NCT Number: NCT02981992; Other Study ID Numbers: 20100014090. First submitted: November 26, 2016. First posted: December 5, 2016. Last Update Posted: December 5, 2016.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Membranas Artificiais , Óxido Nítrico/biossíntese , Diálise Renal/métodos , Vitamina E/administração & dosagem , Vitaminas/administração & dosagem , Bicarbonatos , Proteína C-Reativa/análise , Estudos Cross-Over , Regulação para Baixo , Feminino , Hemodiafiltração , Humanos , Inflamação/sangue , Inflamação/etiologia , Inflamação/prevenção & controle , Cinurenina/sangue , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Diálise Renal/efeitos adversos , Triptofano/sangue
19.
BMJ Open ; 9(10): e025336, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666259

RESUMO

OBJECTIVES: We investigated the association of specific serum amino acids (AAs) with the odds of arsenic-induced skin lesions (AISL) and their ability to distinguish patients with AISL from people chronically exposed to arsenic. DESIGN: Case-control study. SETTING: Three arsenic-exposed villages in Wuyuan County, Hetao Plain, Inner Mongolia, China were evaluated. PARTICIPANTS: Among the 450 residents aged 18-79 years, who were chronically exposed to arsenic via drinking water, 56 were diagnosed as having AISL (defined as cases). Another 56 participants without AISL, matched by gender and age (±1 year) from the same population, were examined as controls. MAIN OUTCOME MEASURES AND METHODS: AA levels were determined by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics analysis. Potential confounding variables were identified via a standardised questionnaire and clinical examination. Multivariable conditional logistic regression model and receiver operating characteristic curve analyses were performed to investigate the relationship between specific AAs and AISL. RESULTS: Tryptophan and phenylalanine levels were negatively associated with AISL (p<0.05). Compared with that in the first quartile, the adjusted OR of AISL in the second, third and fourth quartiles were decreased by 44%, 88% and 79% for tryptophan and 30%, 80% and 80% for phenylalanine, respectively. The combination of these two higher-level AAs showed the lowest OR for AISL (OR=0.08; 95% CI 0.02 to 0.25; p<0.001). Furthermore, both AAs showed a moderate ability to distinguish patients with AISL from the control, with the area under the curve (AUC; 95% CI) as 0.67 (0.57 to 0.77) for tryptophan and 0.70 (0.60 to 0.80) for phenylalanine (p<0.05). The combined pattern with AUC (95% CI) was 0.72 (0.62 to 0.81), showing a sensitivity of 76.79% and specificity of 58.93% (p<0.001). CONCLUSIONS: Specific AAs may be linked to AISL and play important roles in early AISL identification. TRIAL REGISTRATION NUMBER: NCT02235948.


Assuntos
Intoxicação por Arsênico/complicações , Água Potável/efeitos adversos , Fenilalanina/sangue , Dermatopatias/induzido quimicamente , Triptofano/sangue , Adulto , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/urina , Estudos de Casos e Controles , China , Cromatografia Líquida de Alta Pressão , Água Potável/análise , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Inquéritos e Questionários
20.
Biomol Concepts ; 10(1): 209-225, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31734647

RESUMO

In schizophrenia, a single latent trait underlies psychosis, hostility, excitation, mannerism, negative (PHEMN) symptoms, formal thought disorders (FTD) and psychomotor retardation (PMR). Schizophrenia is accompanied by a breakdown of gut and blood-brain-barrier (BBB) pathways, increased tryptophan catabolite (TRYCAT) levels, bacterial translocation, and lowered natural IgM and paraoxonase (PON)1 activity. The aim of this study was to examine the factor structure of schizophrenia symptom domains and the biomarker correlates of these factors. We recruited 80 patients with schizophrenia and 40 healthy subjects and assessed the IgA/IgM responses to paracellular/transcellular (PARA/TRANS) ratios, IgA responses to TRYCATs, natural IgM to malondialdehyde and Gram-negative bacteria, and PON1 enzymatic activity. Direct Hierarchical Exploratory Factor Analysis showed a bifactorial oblique model with a) a general factor which loaded highly on all symptom domains, named overall severity of schizophrenia ("OSOS"); and b) a single-group factor (SGF) loading on negative symptoms and PMR. We found that 40% of the variance in OSOS score was explained by IgA/IgM to PARA/TRANS ratio, male sex and education while 36.9% of the variance in SGF score was explained by IgA to PARA/TRANS, IgM to Gram-negative bacteria, female sex (positively associated) and IgM to MDA, and PON1 activity (negatively associated). Schizophrenia phenomenology comprises two biologically-validated dimensions, namely a general OSOS dimension and a single-group negative symptom dimension, which are associated with a breakdown of gut/BBB barriers, increased bacterial translocation and lowered protection against oxidation, inflammation and bacterial infections through lowered PON1 and natural IgM.


Assuntos
Neurotoxinas/imunologia , Esquizofrenia/genética , Esquizofrenia/imunologia , Adulto , Biomarcadores/sangue , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Neurotoxinas/sangue , Esquizofrenia/sangue , Índice de Gravidade de Doença , Triptofano/sangue , Triptofano/imunologia , Triptofano/metabolismo
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