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1.
Mediators Inflamm ; 2021: 2911578, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621138

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), affecting multiple organ systems, including the respiratory tract and lungs. Several studies have reported that the tryptophan-kynurenine pathway is altered in COVID-19 patients. The tryptophan-kynurenine pathway plays a vital role in regulating inflammation, metabolism, immune responses, and musculoskeletal system biology. In this minireview, we surmise the effects of the kynurenine pathway in COVID-19 patients and how this pathway might impact muscle and bone biology.


Assuntos
Doenças Ósseas/etiologia , COVID-19/complicações , Cinurenina/metabolismo , Doenças Musculares/etiologia , SARS-CoV-2 , Triptofano/metabolismo , Animais , Humanos , Receptores de Hidrocarboneto Arílico/fisiologia , Transdução de Sinais/fisiologia
2.
Nat Commun ; 12(1): 5340, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504068

RESUMO

Free L-tryptophan (L-Trp) stalls ribosomes engaged in the synthesis of TnaC, a leader peptide controlling the expression of the Escherichia coli tryptophanase operon. Despite extensive characterization, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a TnaC variant (R23F) with greatly enhanced sensitivity for L-Trp. We show that the TnaC-ribosome complex captures a single L-Trp molecule to undergo termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. Importantly, the L-Trp binding site is not altered by the R23F mutation, suggesting that the relative rates of L-Trp binding and peptidyl-tRNA cleavage determine the tryptophan sensitivity of each variant. Thus, our study reveals a strategy whereby a nascent peptide assists the ribosome in detecting a small metabolite.


Assuntos
Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Iniciação Traducional da Cadeia Peptídica , Ribossomos/genética , Triptofano/química , Substituição de Aminoácidos , Sítios de Ligação , Microscopia Crioeletrônica , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Mutação , Óperon , Terminação Traducional da Cadeia Peptídica , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Aminoacil-RNA de Transferência/genética , Aminoacil-RNA de Transferência/metabolismo , Ribossomos/metabolismo , Ribossomos/ultraestrutura , Triptofano/metabolismo
3.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576297

RESUMO

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


Assuntos
Síndrome do Intestino Irritável/metabolismo , Cinurenina/metabolismo , Transtornos de Enxaqueca/metabolismo , Triptofano/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiologia , Síndrome do Intestino Irritável/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia
4.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360651

RESUMO

Cold Atmospheric Plasma (CAP) is an ionized gas near room temperature. Its anti-tumor effect can be transmitted either by direct treatment or mediated by a plasma-treated solution (PTS), such as treated standard cell culture medium, which contains different amino acids, inorganic salts, vitamins and other substances. Despite extensive research, the active components in PTS and its molecular or cellular mechanisms are not yet fully understood. The purpose of this study was the measurement of the reactive species in PTS and their effect on tumor cells using different plasma modes and treatment durations. The PTS analysis yielded mode- and dose-dependent differences in the production of reactive oxygen and nitrogen species (RONS), and in the decomposition and modification of the amino acids Tyrosine (Tyr) and Tryptophan (Trp). The Trp metabolites Formylkynurenine (FKyn) and Kynurenine (Kyn) were produced in PTS with the 4 kHz (oxygen) mode, inducing apoptosis in Mel Im melanoma cells. Nitrated derivatives of Trp and Tyr were formed in the 8 kHz (nitrogen) mode, elevating the p16 mRNA expression and senescence-associated ß-Galactosidase staining. In conclusion, the plasma mode has a strong impact on the composition of the active components in PTS and affects its anti-tumor mechanism. These findings are of decisive importance for the development of plasma devices and the effectiveness of tumor treatment.


Assuntos
Melanócitos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Gases em Plasma/farmacologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Triptofano/metabolismo , Tirosina/metabolismo , Apoptose , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Melanócitos/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Triptofano/química , Tirosina/química
5.
Neuropharmacology ; 198: 108766, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34454912

RESUMO

The coronavirus disease 2019 (Covid-19) pandemic intensified the already catastrophic drug overdose and substance use disorder (SUD) epidemic, signaling a syndemic as social isolation, economic and mental health distress, and disrupted treatment services disproportionally impacted this vulnerable population. Along with these social and societal factors, biological factors triggered by intense stress intertwined with incumbent overactivity of the immune system and the resulting inflammatory outcomes may impact the functional status of the central nervous system (CNS). We review the literature concerning SARS-CoV2 infiltration and infection in the CNS and the prospects of synergy between stress, inflammation, and kynurenine pathway function during illness and recovery from Covid-19. Taken together, inflammation and neuroimmune signaling, a consequence of Covid-19 infection, may dysregulate critical pathways and underlie maladaptive changes in the CNS, to exacerbate the development of neuropsychiatric symptoms and in the vulnerability to develop SUD. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.


Assuntos
COVID-19/epidemiologia , Uso Indevido de Medicamentos/estatística & dados numéricos , SARS-CoV-2 , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adaptação Psicológica , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Axônios/virologia , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/psicologia , Comorbidade , Suscetibilidade a Doenças , Células Endoteliais/virologia , Humanos , Imunidade Inata , Inflamação/etiologia , Cinurenina/metabolismo , Neurônios/virologia , Neurotransmissores/metabolismo , Mucosa Olfatória/virologia , Pandemias , SARS-CoV-2/fisiologia , Isolamento Social , Estresse Psicológico , Transtornos Relacionados ao Uso de Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Triptofano/metabolismo , Tropismo Viral
6.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230210

RESUMO

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.


Assuntos
COVID-19/imunologia , Ácido Cinurênico/imunologia , SARS-CoV-2 , Adulto , Idoso , COVID-19/sangue , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Ácido Cinurênico/sangue , Modelos Logísticos , Masculino , Redes e Vias Metabólicas/imunologia , Metabolômica , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/imunologia , Triptofano/metabolismo
7.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198750

RESUMO

Neurodegeneration is one of the driving forces behind the pathogenesis of multiple sclerosis (MS). Progression without activity, pathopsychological disturbances (cognitive impairment, depression, fatigue) and even optic neuropathy seems to be mainly routed in this mechanism. In this article, we aim to give a comprehensive review of the clinical aspects and symptomology, radiological and molecular markers and potential therapeutic targets of neurodegeneration in connection with MS. As the kynurenine pathway (KP) was evidenced to play an important role in the pathogenesis of other neurodegenerative conditions (even implied to have a causative role in some of these diseases) and more and more recent evidence suggest the same central role in the neurodegenerative processes of MS as well, we pay special attention to the KP. Metabolites of the pathway are researched as biomarkers of the disease and new, promising data arising from clinical evaluations show the possible therapeutic capability of KP metabolites as neuroprotective drugs in MS. Our conclusion is that the kynurenine pathway is a highly important route of research both for diagnostic and for therapeutic values and is expected to yield concrete results for everyday medicine in the future.


Assuntos
Biomarcadores/metabolismo , Cinurenina/metabolismo , Esclerose Múltipla/complicações , Doenças Neurodegenerativas/metabolismo , Animais , Progressão da Doença , Humanos , Terapia de Alvo Molecular , Esclerose Múltipla/metabolismo , Doenças Neurodegenerativas/etiologia , Transdução de Sinais , Triptofano/metabolismo
8.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207579

RESUMO

Biomanufacturing processes may be optimized by storing cell culture media at room temperature, but this is currently limited by their instability and change in color upon long-term storage. This study demonstrates that one of the critical contributing factors toward media browning is tryptophan. LC-MS technology was utilized to identify tryptophan degradation products, which are likely formed primarily from oxidation reactions. Several of the identified compounds were shown to contribute significantly to color in solutions but also to exhibit toxicity against CHO cells. A cell-culture-compatible antioxidant, a-ketoglutaric acid, was found to be an efficient cell culture media additive for stabilizing components against degradation, inhibiting the browning of media formulations, and decreasing ammonia production, thus providing a viable method for developing room-temperature stable cell culture media.


Assuntos
Meios de Cultura/química , Triptofano/metabolismo , Animais , Células CHO , Cricetulus , Oxirredução , Triptofano/análise
9.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199271

RESUMO

Nicotinamide mononucleotide (NMN) is a key intermediate in the nicotinamide adenine dinucleotide (NAD+) biosynthesis. Its supplementation has demonstrated beneficial effects on several diseases. The aim of this study was to characterize NMN deamidase (PncC) inactive mutants to use as possible molecular recognition elements (MREs) for an NMN-specific biosensor. Thermal stability assays and steady-state fluorescence spectroscopy measurements were used to study the binding of NMN and related metabolites (NaMN, Na, Nam, NR, NAD, NADP, and NaAD) to the PncC mutated variants. In particular, the S29A PncC and K61Q PncC variant forms were selected since they still preserve the ability to bind NMN in the micromolar range, but they are not able to catalyze the enzymatic reaction. While S29A PncC shows a similar affinity also for NaMN (the product of the PncC catalyzed reaction), K61Q PncC does not interact significantly with it. Thus, PncC K61Q mutant seems to be a promising candidate to use as specific probe for an NMN biosensor.


Assuntos
Amidoidrolases/genética , Técnicas Biossensoriais , Mutação/genética , Mononucleotídeo de Nicotinamida/metabolismo , Estabilidade Enzimática , Cinética , Mononucleotídeo de Nicotinamida/química , Multimerização Proteica , Espectrometria de Fluorescência , Temperatura , Triptofano/metabolismo
10.
BMC Plant Biol ; 21(1): 326, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229625

RESUMO

BACKGROUND: Glycolate oxidase (GLO) is not only a key enzyme in photorespiration but also a major engine for H2O2 production in plants. Catalase (CAT)-dependent H2O2 decomposition has been previously reported to be involved in the regulation of IAA biosynthesis. However, it is still not known which mechanism contributed to the H2O2 production in IAA regulation. RESULTS: In this study, we found that in glo mutants of rice, as H2O2 levels decreased IAA contents significantly increased, whereas high CO2 abolished the difference in H2O2 and IAA contents between glo mutants and WT. Further analyses showed that tryptophan (Trp, the precursor for IAA biosynthesis in the Trp-dependent biosynthetic pathway) also accumulated due to increased tryptophan synthetase ß (TSB) activity. Moreover, expression of the genes involved in Trp-dependent IAA biosynthesis and IBA to IAA conversion were correspondingly up-regulated, further implicating that both pathways contribute to IAA biosynthesis as mediated by the GLO-dependent production of H2O2. CONCLUSION: We investigated the function of GLO in IAA signaling in different levels from transcription, enzyme activities to metabolic levels. The results suggest that GLO-dependent H2O2 signaling, essentially via photorespiration, confers regulation over IAA biosynthesis in rice plants.


Assuntos
Oxirredutases do Álcool/metabolismo , Peróxido de Hidrogênio/metabolismo , Ácidos Indolacéticos/metabolismo , Oryza/enzimologia , Oxirredutases do Álcool/genética , Vias Biossintéticas/efeitos da radiação , Respiração Celular/efeitos da radiação , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Luz , Modelos Biológicos , Mutação/genética , Oryza/genética , Oryza/efeitos da radiação , Peroxissomos/metabolismo , Peroxissomos/efeitos da radiação , Fenótipo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Triptofano/metabolismo
11.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203517

RESUMO

Metabolites and enzymes involved in the kynurenine pathway (KP) are highly promising targets for cancer treatment, including gastrointestinal tract diseases. Thus, accurate quantification of these compounds in body fluids becomes increasingly important. The aim of this study was the development and validation of the UHPLC-ESI-MS/MS methods for targeted quantification of biologically important KP substrates (tryptophan and nicotinamide) and metabolites(kynurenines) in samples of serum and peritoneal fluid from gastric cancer patients. The serum samples were simply pretreated with trichloroacetic acid to precipitate proteins. The peritoneal fluid was purified by solid-phase extraction before analysis. Validation was carried out for both matrices independently. Analysis of the samples from gastric cancer patients showed different accumulations of tryptophan and its metabolites in different biofluids of the same patient. The protocols will be used for the evaluation of tryptophan and kynurenines in blood and peritoneal fluid to determine correlation with the clinicopathological status of gastric cancer or the disease's prognosis.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cinurenina/metabolismo , Neoplasias Gástricas/metabolismo , Espectrometria de Massas em Tandem/métodos , Líquido Ascítico/metabolismo , Humanos , Ácido Tricloroacético/metabolismo , Triptofano/metabolismo
12.
Nat Commun ; 12(1): 4447, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290243

RESUMO

Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1ß, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.


Assuntos
Aminas Biogênicas/farmacologia , Imunomodulação/efeitos dos fármacos , Cinurenina/análogos & derivados , Animais , Aminas Biogênicas/metabolismo , Aminas Biogênicas/uso terapêutico , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Células Endoteliais , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Inflamação , Interferon gama/farmacologia , Cinurenina/metabolismo , Cinurenina/farmacologia , Cinurenina/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Nefrite/tratamento farmacológico , Nefrite/imunologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Triptofano/metabolismo
13.
Int J Mol Sci ; 22(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205463

RESUMO

Violacein is a naturally occurring purple pigment, widely used in cosmetics and has potent antibacterial and antiviral properties. Violacein can be produced from tryptophan, consequently sufficient tryptophan biosynthesis is the key to violacein production. However, the complicated biosynthetic pathways and regulatory mechanisms often make the tryptophan overproduction challenging in Escherichia coli. In this study, we used the adaptive laboratory evolution (ALE) strategy to improve violacein production using galactose as a carbon source. During the ALE, a tryptophan-responsive biosensor was employed to provide selection pressure to enrich tryptophan-producing cells. From the biosensor-assisted ALE, we obtained an evolved population of cells capable of effectively catabolizing galactose to tryptophan and subsequently used the population to obtain the best violacein producer. In addition, whole-genome sequencing of the evolved strain identified point mutations beneficial to the overproduction. Overall, we demonstrated that the biosensor-assisted ALE strategy could be used to rapidly and selectively evolve the producers to yield high violacein production.


Assuntos
Evolução Biológica , Técnicas Biossensoriais , Galactose/metabolismo , Indóis/metabolismo , Engenharia Metabólica , Escherichia coli , Proteínas de Escherichia coli , Triptofano/metabolismo
14.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073081

RESUMO

We studied the effects of the addition of large neutral amino acids, such as tyrosine (Tyr) and tryptophan (Trp), in mice DBA/2J and tetrahybrid mice DBCB receiving a high-fat, high-carbohydrate diet (HFCD) for 65 days. The locomotor activity, anxiety, muscle tone, mass of internal organs, liver morphology, adipokines, cytokines, and biochemical indices of animals were assessed. The Tyr supplementation potentiated increased anxiety in EPM and contributed to a muscle tone increase, a decrease in the AST/ALT ratio, and an increase in protein anabolism in both mice strains. Tyr contributed to a decrease in liver fatty degeneration and ALT reduction only in DBCB that were sensitive to the development of obesity. The addition of Trp caused an increase in muscle tone and potentiated an increase in anxiety with age in animals of both genotypes. Trp had toxic effects on the livers of mice, which was manifested in increased fatty degeneration in DBCB, edema, and the appearance of micronuclei in DBA/2J. The main identified effects of Tyr on mice are considered in the light of its modulating effect on the dopamine neurotransmitter metabolism, while for the Trp supplement, effects were presumably associated with the synthesis of its toxic metabolites by representatives of the intestinal microflora.


Assuntos
Suplementos Nutricionais , Obesidade/metabolismo , Triptofano , Tirosina , Animais , Dieta Hiperlipídica/efeitos adversos , Dopamina/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Triptofano/administração & dosagem , Triptofano/metabolismo , Tirosina/administração & dosagem , Tirosina/metabolismo
15.
Toxins (Basel) ; 13(6)2021 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070838

RESUMO

This study investigated the impact of deoxynivalenol (DON) from naturally contaminated feed on pig growth, immune status, organ health, brain serotonin (5-Hydroxytryptamine, 5-HT) and behavior. Sixteen individually housed pigs (25.57 ± 0.98 kg, age 9 weeks) were randomly allotted to two dietary treatments: without DON (CON) or with 3.8 mg/kg of DON (MT). Pigs were pair-fed to eliminate differences in feed intake (equal tryptophan (Trp) intake). Pigs fed CON received a daily ration based on the ad libitum feed consumption of their MT pair-mate. Performance was determined over 21 days and blood collected for immunological and oxidative stress parameters. Behavior was recorded for 12 h on days 0, 7, 14 and 21. After 21 days, pigs were euthanized to collect tissues for immune parameters, gut morphology and brain serotonin levels. Overall, pigs fed MT had greater weight gain compared with CON. Immunological and oxidative stress parameters were unaffected, but pigs fed MT had reduced villus height, crypt depth and villus-to-crypt ratio in the jejunum. Pigs consuming MT had reduced concentration of 5-HT and increased 5-HT turnover in the hypothalamus. Mycotoxin-fed pigs spent more time lying and sitting, and less time standing and drinking. In conclusion, consumption of DON impacted gastrointestinal tract structure, altered behavior and changed Trp metabolism through increasing 5-HT turnover in hypothalamus.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Contaminação de Alimentos , Trato Gastrointestinal/efeitos dos fármacos , Tricotecenos/toxicidade , Triptofano/metabolismo , Zea mays/microbiologia , Ração Animal , Animais , Encéfalo/efeitos dos fármacos , Trato Gastrointestinal/imunologia , Masculino , Estresse Oxidativo , Condicionamento Físico Animal , Suínos
16.
Medicine (Baltimore) ; 100(23): e25313, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114978

RESUMO

ABSTRACT: Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials "Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant"-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.


Assuntos
Aprepitanto , Infecções por HIV , Transtornos do Humor , Neuroimunomodulação/efeitos dos fármacos , Ritonavir , Triptofano/metabolismo , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Aprepitanto/administração & dosagem , Aprepitanto/efeitos adversos , Contagem de Linfócito CD4/métodos , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/psicologia , Infecções por HIV/virologia , Humanos , Cinurenina/análise , Masculino , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/etiologia , Antagonistas dos Receptores de Neurocinina-1/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1/efeitos adversos , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Resultado do Tratamento
17.
Dokl Biochem Biophys ; 498(1): 170-176, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34189644

RESUMO

The spectral-kinetic characteristics of the fluorescence of the tryptophan molecule in an aqueous solution and in the composition of a protein (albumin) were studied in the temperature range from -170 to 25°C. To explain the observed changes in the spectra and the tryptophan fluorescence lifetime with temperature, a model of transitions between the excited and ground states involving a charge-transfer state was used, which takes into account the nonlinear nature of the dynamics of these transitions. In these processes, an important role is played by the interaction of tryptophan molecules with its microenvironment, as well as rearrangements in the system of hydrogen bonds of the water-protein matrix surrounding the tryptophan molecule.


Assuntos
Soroalbumina Bovina/química , Triptofano/química , Água/química , Animais , Bovinos , Fluorescência , Ligação de Hidrogênio , Cinética , Soroalbumina Bovina/metabolismo , Espectrometria de Fluorescência , Temperatura , Triptofano/metabolismo , Água/metabolismo
18.
Front Immunol ; 12: 658354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122415

RESUMO

The diverse and dynamic microbial community of the human gastrointestinal tract plays a vital role in health, with gut microbiota supporting the development and function of the gut immune barrier. Crosstalk between microbiota-gut epithelium and the gut immune system determine the individual health status, and any crosstalk disturbance may lead to chronic intestinal conditions, such as inflammatory bowel diseases (IBD) and celiac disease. Microbiota-derived metabolites are crucial mediators of host-microbial interactions. Some beneficially affect host physiology such as short-chain fatty acids (SCFAs) and secondary bile acids. Also, tryptophan catabolites determine immune responses, such as through binding to the aryl hydrocarbon receptor (AhR). AhR is abundantly present at mucosal surfaces and when activated enhances intestinal epithelial barrier function as well as regulatory immune responses. Exogenous diet-derived indoles (tryptophan) are a major source of endogenous AhR ligand precursors and together with SCFAs and secondary bile acids regulate inflammation by lowering stress in epithelium and gut immunity, and in IBD, AhR expression is downregulated together with tryptophan metabolites. Here, we present an overview of host microbiota-epithelium- gut immunity crosstalk and review how microbial-derived metabolites contribute to host immune homeostasis. Also, we discuss the therapeutic potential of bacterial catabolites for IBD and celiac disease and how essential dietary components such as dietary fibers and bacterial tryptophan catabolites may contribute to intestinal and systemic homeostasis.


Assuntos
Bactérias/metabolismo , Microbioma Gastrointestinal , Interações entre Hospedeiro e Microrganismos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Animais , Ácidos e Sais Biliares/metabolismo , Fibras na Dieta , Suscetibilidade a Doenças , Microbioma Gastrointestinal/imunologia , Homeostase , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Ligantes , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo
19.
Front Immunol ; 12: 653208, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149693

RESUMO

Tryptophan (Trp) is an essential amino acid primarily derived from the diet for use by the host for protein synthesis. The intestinal tract is lined with cells, both host and microbial, that uptake and metabolize Trp to also generate important signaling molecules. Serotonin (5-HT), kynurenine and its downstream metabolites, and to a lesser extent other neurotransmitters are generated by the host to signal onto host receptors and elicit physiological effects. 5-HT production by neurons in the CNS regulates sleep, mood, and appetite; 5-HT production in the intestinal tract by enterochromaffin cells regulates gastric motility and inflammation in the periphery. Kynurenine can signal onto the aryl hydrocarbon receptor (AHR) to elicit pleiotropic responses from several cell types including epithelial and immune cells, or can be further metabolized into bioactive molecules to influence neurodegenerative disease. There is a remarkable amount of cross-talk with the microbiome with regard to tryptophan metabolites as well. The gut microbiome can regulate the production of host tryptophan metabolites and can use dietary or recycled trp to generate bioactive metabolites themselves. Trp derivatives like indole are able to signal onto xenobiotic receptors, including AHR, to elicit tolerogenic effects. Here, we review studies that demonstrate that tryptophan represents a key intra-kingdom signaling molecule.


Assuntos
Microbioma Gastrointestinal/fisiologia , Interações entre Hospedeiro e Microrganismos/imunologia , Transdução de Sinais/imunologia , Triptofano/metabolismo , Animais , Humanos , Cinurenina/metabolismo , Redes e Vias Metabólicas/imunologia , Modelos Animais , Receptores de Hidrocarboneto Arílico/metabolismo , Serotonina/metabolismo
20.
Photochem Photobiol Sci ; 20(6): 733-746, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33977513

RESUMO

NewPHL is a recently discovered subgroup of ancestral DNA photolyases. Its domain architecture displays pronounced differences from that of canonical photolyases, in particular at the level of the characteristic electron transfer chain, which is limited to merely two tryptophans, instead of the "classical" three or four. Using transient absorption spectroscopy, we show that the dynamics of photoreduction of the oxidized FAD cofactor in the NewPHL begins similarly as that in canonical photolyases, i.e., with a sub-ps primary reduction of the excited FAD cofactor by an adjacent tryptophan, followed by migration of the electron hole towards the second tryptophan in the tens of ps regime. However, the resulting tryptophanyl radical then undergoes an unprecedentedly fast deprotonation in less than 100 ps in the NewPHL. In spite of the stabilization effect of this deprotonation, almost complete charge recombination follows in two phases of ~ 950 ps and ~ 50 ns. Such a rapid recombination of the radical pair implies that the first FAD photoreduction step, i.e., conversion of the fully oxidized to the semi-quinone state, should be rather difficult in vivo. We hence suggest that the flavin chromophore likely switches only between its semi-reduced and fully reduced form in NewPHL under physiological conditions.


Assuntos
Desoxirribodipirimidina Fotoliase/metabolismo , Termodinâmica , Desoxirribodipirimidina Fotoliase/química , Elétrons , Flavinas/química , Flavinas/metabolismo , Oxirredução , Processos Fotoquímicos , Triptofano/química , Triptofano/metabolismo
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