Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.499
Filtrar
1.
Cancer Sci ; 112(3): 1038-1047, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33410234

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan-kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3-dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. In our analysis of RCC tissue samples, tissue Kyn levels were elevated in advanced-stage RCC and correlated well with TDO expression levels in RCC tumor cells. In patients with mRCC, TDO rather than IDO1 was expressed in RCC tumor cells, showing a strong association with Kyn expression. Furthermore, immunohistochemical staining of TDO was strongly associated with the staining intensity of forkhead box P3, as well as ICI therapy response and survival in patients with mRCC. Our study is the first to show that TDO expression in tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. Our findings suggest that strategies aimed at inhibiting TDO, rather than IDO1, in combination with ICI therapy may aid in the control of mRCC progression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Rim/patologia , Triptofano Oxigenase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , /uso terapêutico , Imuno-Histoquímica , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Rim/cirurgia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Cinurenina/análise , Cinurenina/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrectomia , Intervalo Livre de Progressão , Triptofano/metabolismo , Triptofano Oxigenase/análise , Triptofano Oxigenase/antagonistas & inibidores
2.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466562

RESUMO

Given the pharmacological properti es and the potential role of kynurenic acid (KYNA) in human physiology and the pleiotropic activity of the neurohormone melatonin (MEL) involved in physiological and immunological functions and as regulator of antioxidant enzymes, this study aimed at evaluating the capability of Saccharomyces cerevisiae EC1118 to release tryptophan derivatives (dTRPs) from the kynurenine (KYN) and melatonin pathways. The setting up of the spectroscopic and chromatographic conditions for the quantification of the dTRPs in LC-MS/MS system, the optimization of dTRPs' production in fermentative and whole-cell biotransformation approaches and the production of dTRPs in a soybean-based cultural medium naturally enriched in tryptophan, as a case of study, were included in the experimental plan. Variable amounts of dTRPs, with a prevalence of metabolites of the KYN pathway, were detected. The LC-MS/MS analysis showed that the compound synthesized at highest concentration is KYNA that reached 9.146 ± 0.585 mg/L in fermentation trials in a chemically defined medium at 400 mg/L TRP. Further experiments in a soybean-based medium confirm KYNA as the main dTRPs, whereas the other dTRPs reached very lower concentrations. While detectable quantities of melatonin were never observed, two MEL isomers were successfully measured in laboratory media.


Assuntos
Meios de Cultura/metabolismo , Saccharomyces cerevisiae/metabolismo , Soja/metabolismo , Triptofano/metabolismo , Cromatografia Líquida/métodos , Fermentação/fisiologia , Humanos , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Melatonina/metabolismo , Neurotransmissores/metabolismo , Transdução de Sinais/fisiologia , Espectrometria de Massas em Tandem/métodos
3.
J Med Chem ; 64(1): 797-811, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33369426

RESUMO

In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-ß-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD+ levels. In this study, an Food and Drug Administration (FDA)-approved drug, diflunisal, was found to competitively inhibit ACMSD. The complex structure of ACMSD with diflunisal revealed a previously unknown ligand-binding mode and was consistent with the results of inhibition assays, as well as a structure-activity relationship (SAR) study. Moreover, two synthesized diflunisal derivatives showed half-maximal inhibitory concentration (IC50) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 µM (22) and 3.10 ± 0.11 µM (20), respectively. The results suggest that diflunisal derivatives have the potential to modulate NAD+ levels. The ligand-binding mode revealed here provides a new direction for developing inhibitors of ACMSD.


Assuntos
Carboxiliases/metabolismo , Diflunisal/metabolismo , Inibidores Enzimáticos/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Vias Biossintéticas/efeitos dos fármacos , Carboxiliases/antagonistas & inibidores , Domínio Catalítico , Cristalografia por Raios X , Diflunisal/análogos & derivados , Diflunisal/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Cinurenina/metabolismo , Simulação de Acoplamento Molecular , NAD/metabolismo , Pseudomonas fluorescens/enzimologia , Relação Estrutura-Atividade , Triptofano/metabolismo
4.
Biosci Rep ; 40(10)2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33063092

RESUMO

COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is overexpressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and adenosine triphosphate (ATP), especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide (NAM), which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 (silent mating type information regulation 2 homologue 1) inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines and is effective against HIV infection. These properties qualify NAM for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Niacinamida/farmacologia , Pneumonia Viral/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Betacoronavirus/efeitos dos fármacos , Linhagem Celular , Infecções por Coronavirus/patologia , Citocinas/sangue , Humanos , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Pandemias , Pneumonia Viral/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo
5.
JCI Insight ; 5(14)2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32559180

RESUMO

BACKGROUNDReprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks.METHODSTo investigate metabolic effects of SARS-CoV-2 infection, we evaluated serum metabolites of patients with COVID-19 (n = 33; diagnosed by nucleic acid testing), as compared with COVID-19-negative controls (n = 16).RESULTSTargeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen).CONCLUSIONIn conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.FUNDINGBoettcher Foundation Webb-Waring Biomedical Research Award; National Institute of General and Medical Sciences, NIH; and National Heart, Lung, and Blood Institute, NIH.


Assuntos
Infecções por Coronavirus/metabolismo , Ácidos Graxos/metabolismo , Interleucina-6/metabolismo , Cinurenina/metabolismo , Estresse Oxidativo , Pneumonia Viral/metabolismo , Insuficiência Renal/metabolismo , Adulto , Idoso , Aminoácidos/metabolismo , Betacoronavirus , Glicemia/metabolismo , Estudos de Casos e Controles , Creatina/metabolismo , Creatinina/metabolismo , Cistina , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Masculino , Metaboloma , Metabolômica , Metionina/análogos & derivados , Pessoa de Meia-Idade , Pandemias , Poliaminas/metabolismo , Proteólise , Triptofano/metabolismo
6.
J Vis Exp ; (159)2020 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-32449703

RESUMO

The kynurenine pathway and the tryptophan catabolites called kynurenines have received increased attention for their involvement in immune regulation and cancer biology. An in vitro cell culture assay is often used to learn about the contribution of different tryptophan catabolites in a disease mechanism and for testing therapeutic strategies. Cell culture medium that is rich in secreted metabolites and signaling molecules reflects the status of tryptophan metabolism and other cellular events. New protocols for the reliable quantification of multiple kynurenines in the complex cell culture medium are desired to allow for a reliable and quick analysis of multiple samples. This can be accomplished with liquid chromatography coupled with mass spectrometry. This powerful technique is employed in many clinical and research laboratories for the quantification of metabolites and can be used for measuring kynurenines. Presented here is the use of liquid chromatography coupled with single quadrupole mass spectrometry (LC-SQ) for the simultaneous determination of four kynurenines, i.e., kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic, and xanthurenic acid in the medium collected from in vitro cultured cancer cells. SQ detector is simple to use and less expensive compared to other mass spectrometers. In the SQ-MS analysis, multiple ions from the sample are generated and separated according to their specific mass-to-charge ratio (m/z), followed by the detection using a Single Ion Monitoring (SIM) mode. This paper draws the attention on the advantages of the reported method and indicates some weak points. It is focused on critical elements of LC-SQ analysis including sample preparation along with chromatography and mass spectrometry analysis. The quality control, method calibration conditions and matrix effect issues are also discussed. We described a simple application of 3-nitrotyrosine as one analog standard for all target analytes. As confirmed by experiments with human ovary and breast cancer cells, the proposed LC-SQ method generates reliable results and can be further applied to other in vitro cellular models.


Assuntos
Cromatografia Líquida/métodos , Cinurenina/metabolismo , Espectrometria de Massas em Tandem/métodos , Técnicas de Cultura de Células , Meios de Cultura , Humanos
7.
Sci Rep ; 10(1): 6399, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286421

RESUMO

Amino acid metabolites in biofluids are associated with high body mass index (BMI) and cardiometabolic abnormalities. However, prospective investigations regarding these associations are few, particularly among young individuals. Moreover, little is presently known about the impact of long-term high BMI. Using data from the DOrtmund Nutritional and Anthropometric Longitudinally Designed study (111 males and 107 females), we prospectively investigated relations between repeatedly measured urinary levels of 33 metabolites and (1) previously identified long-term BMI trajectory groups from childhood into late adolescence and (2) cardiometabolic risk markers in late adolescence-young adulthood, in sex-specific linear mixed regression models. Males with long-term overweight had lower indole-3-acetic acid when compared to others. Further, methionine, isoleucine, tryptophan, xanthurenic acid, and indole-3-carboxaldehyde were negatively associated with C-reactive protein (CRP), but 5-hydroxyindole-3-acetic acid was positively associated with CRP. No associations were observed in females. Long-term overweight from childhood into late adolescence is associated with decreased urinary levels of gut bacteria-derived indole-3-acetic acid, and several urinary amino acids, including gut bacteria-derived indole-3-carboxaldehyde are associated with elevated CRP later on in life. Taken together, our data suggest that indole metabolites, and their gut bacteria producers play potentially important roles in overweight-related inflammation.


Assuntos
Aminoácidos/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/metabolismo , Indóis/metabolismo , Doenças Metabólicas/metabolismo , Metaboloma , Adolescente , Biomarcadores/metabolismo , Criança , Feminino , Humanos , Cinurenina/metabolismo , Modelos Lineares , Masculino , Análise Multivariada , Fatores de Risco
8.
Toxicology ; 438: 152458, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32289347

RESUMO

Kynurenine (Kyn) plays an important role as an immune check-point molecule and regulates various immune responses through its aryl hydrocarbon receptor (Ahr). Kyn is synthesized by indoleamine 2,3-dioxygenase (Ido) and tryptophan 2,3-dioxygenase (Tdo). Ido contributes approximately 90% of tryptophan catabolism. Although Kyn is increased in various liver disorders, the roles of Kyn in liver injury are complicated because Ido1, Ido2, and Tdo are activated in different cell types. In this study, the roles of Ido2 in carbon tetrachloride (CCl4; 1 ml/kg, i.p.)-induced acute liver injury were examined using Ido2 knockout mice and Ido2 inhibitor. After CCl4 treatment, the ratio of Kyn to tryptophan and levels of Kyn in the liver were increased, accompanied by activation of Ahr-mediated signaling, as revealed by increased nuclear Ahr and Cyp1a1 mRNA. Knockout of Ido2 (Ido2-/-) and treatment with Ido2 inhibitor 1-methyl-D-tryptophan (D-1MT; 100 mg/kg, i.p.) attenuated CCl4-induced liver injury, with decreased induction of Ahr-mediated signaling. Administration of D-Kyn (100 mg/kg, i.p.) to Ido2-/- mice canceled the effect of Ido2 deficiency and exacerbated acute liver damage by CCl4 treatment. In addition, liver fibrosis induced by repeated CCl4 administration was suppressed in Ido2-/- mice. In conclusion, the action of Ido2 and Kyn in the liver may prevent severe hepatocellular damage and liver fibrosis.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Cirrose Hepática Experimental/enzimologia , Fígado/enzimologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/deficiência , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais
9.
Exp Mol Pathol ; 114: 104415, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32165090

RESUMO

The kynurenine pathway (KP) has a principal role in the metabolism of tryptophan. This pathway is also involved in the pathogenesis of cancer. We evaluated expression of two rate limiting enzymes from this pathway (IDO1 and TDO2) as well as three long non-coding RNAs (lncRNAs) that have been predicted to alter expression of IDO1 (ITGB2-AS1, HCP5 and MIR155HG) in 82 breast cancer tissues and their adjacent non-cancerous tissues (ANCTs). While IDO1 expression levels were not significantly different between malignant tissues and ANCTs (expression ratio = 0.56, P = .21), TDO2 was significantly down-regulated in malignant tissues compared with ANCTs (Expression ratio = 0.001, P < .001). Among lncRNAs, expression of HCP5 was significantly lower in malignant tissues compared with ANCTs (Expression ratio = 0.17, P < .001). However, expression of ITGB2-AS1 was higher in malignant tissues compared with ANCTs (Expression ratio = 3.38, P = .01). Expressions of genes were not associated with any of clinical or demographic data of patients. However, there were trends towards association between IDO1 expression and tumor size as well as estrogen receptor (ER) status (P values 0.09 and 0.08 respectively). Significant pairwise correlations were found between expression levels of genes especially in ANCTs. Notably, TDO2 expression levels were correlated with expression of all other genes in ANCTs but none of them in tumor tissues. Based on the area under curve (AUC) values, HCP5 and TDO2 had "fair" diagnostic power (AUC values of 0.73 and 0.72). Notably, combination of HCP5, ITGB2-AS1 and TDO2 genes increased the diagnostic power to the level of "good". The current investigation underscores the role of KP in breast cancer and potentiates some genes within this pathway as diagnostic markers in breast cancer.


Assuntos
Neoplasias da Mama/genética , RNA Longo não Codificante/genética , Triptofano Oxigenase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indóis/metabolismo , Cinurenina/metabolismo , Redes e Vias Metabólicas/genética , MicroRNAs/genética , Pessoa de Meia-Idade , Triptofano/metabolismo
10.
Cancer Immunol Res ; 8(4): 451-464, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32127391

RESUMO

Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.


Assuntos
Neoplasias Colorretais/radioterapia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Interferons/farmacologia , Oximas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Sulfonamidas/farmacologia , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mucosa Intestinal/efeitos da radiação , Cinurenina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Protetores contra Radiação/farmacologia
11.
Anticancer Res ; 40(3): 1189-1200, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132016

RESUMO

The majority of patients receiving chemotherapy experience post-chemotherapy cognitive impairment, sometimes referred to as "chemo brain" or "chemo fog." The cognitive impairment associated with this syndrome can be severe, and can sometimes last for many years after therapy discontinuation. Despite extensive investigations, its etiology is unknown. We argue that chemo brain results from damage to tubulin within microtubules. This damage can occur directly from tubulin inhibitors such as taxanes, epothilones or vinca alkaloids. Other chemotherapies stimulate increased mitochondrial activity and biophoton release. This results in abnormal tryptophan metabolism and excess production of neurotoxic kynurenines, which, in turn, damage microtubules.


Assuntos
Encéfalo/metabolismo , Cinurenina/metabolismo , Tubulina (Proteína)/metabolismo , Humanos
12.
Gene ; 742: 144586, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32179171

RESUMO

Pycnoporus sanguineus, an edible mushroom, produces antimicrobial and antitumor bioactive compounds and pH- and thermo- stable laccases that have multiple potential biotechnological applications. Here we reported the complete genome of the species Pycnoporus sanguineus ACCC 51,180 by using the combination of Illumina HiSeq X Ten and the PacBio sequencing technology. The represented genome is 36.6 Mb composed of 59 scaffolds with 12,086 functionally annotated protein-coding genes. The genome of Pycnoporus sanguineus encodes at least 19 biosynthetic gene clusters for secondary metabolites, including a terpene cluster for biosynthesis of the antitumor clavaric acid. Seven laccases were identified, while 22 genes were found to be involved in the kynurenine pathway in which the intermediate metabolite 3-hydroxyanthranilic acid were catalyzed by laccases into cinnabarinic acid. This study represented the third genome of the genus Pycnoporus, and wound facilitate the exploration of useful sources from Pycnoporus sanguineus for future industrial applications.


Assuntos
Proteínas Fúngicas/genética , Genoma Fúngico/genética , Microbiologia Industrial/métodos , Lacase/genética , Pycnoporus/genética , Proteínas Fúngicas/metabolismo , Concentração de Íons de Hidrogênio , Cinurenina/metabolismo , Lacase/metabolismo , Engenharia Metabólica , Oxazinas/metabolismo , Estabilidade Proteica , Pycnoporus/enzimologia , Metabolismo Secundário/genética
13.
Am J Physiol Cell Physiol ; 318(6): C1078-C1082, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208988

RESUMO

Aryl hydrocarbon receptor (AhR), a highly conserved intracellular transcription factor, is activated by a plethora of ligands of both exogenous and endogenous nature. Besides activating xenobiotic-metabolizing enzymes, it is involved in the differentiation and development of hematopoietic, hepatic, nervous and immune systems. More and more data describe its role in the regulation of immune responses and in the onset and progression of inflammation. Particularly, established results view AhR as a downstream target of inflammatory molecules, since its transcription is regulated by the inflammatory cascade. Interleukin 6 (IL-6) has been described to sustain early stages of inflammation and to influence the expression of AhR either directly, following signal transducer and activator of transcription 3 (STAT3) activation, or in combination with other inflammatory mediators, e.g., transforming growth factor-ß (TGF-ß). In selected inflammatory milieus, once activated, AhR interacts with its targets including the IL-6 promoter, thus originating an autoinflammatory loop. This perspective review brings together evidence that, in some IL-6-driven pathways, AhR is a downstream target that amplifies the duration and extent of inflammation. Considering that many inflammatory mediators can also trigger the activities of AhR as biosensor and activator of xenobiotics metabolism, this issue is of pivotal importance. The individual susceptibly to some environmental ligands of AhR can be probably explained by considering the individual inflammatory state, which could additionally fuel the proinflammatory activity of AhR. Thus, AhR could be considered a transductor of a dynamic, bidirectional connection between internal and external environmental stimuli and the inflammatory response.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Interleucina-6/metabolismo , Cinurenina/metabolismo , Receptores de Hidrocarboneto Arílico/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
14.
Am J Physiol Cell Physiol ; 318(5): C818-C830, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208989

RESUMO

Tryptophan catabolism through the kynurenine pathway generates a variety of bioactive metabolites. Physical exercise can modulate kynurenine pathway metabolism in skeletal muscle and thus change the concentrations of select compounds in peripheral tissues and in the central nervous system. Here we review recent advances in our understanding of how exercise alters tryptophan-kynurenine metabolism in muscle and its subsequent local and distal effects. We propose that the effects of kynurenine pathway metabolites on skeletal muscle, adipose tissue, immune system, and the brain suggest that some of these compounds could qualify as exercise-induced myokines. Indeed, some of the more recently discovered biological activities for kynurenines include many of the best-known benefits of exercise: improved energy homeostasis, promotion of an anti-inflammatory environment, and neuroprotection. Finally, by considering the tissue expression of the different membrane and cytosolic receptors for kynurenines, we discuss known and potential biological activities for these tryptophan metabolites.


Assuntos
Sistema Nervoso Central/metabolismo , Cinurenina/metabolismo , Redes e Vias Metabólicas/fisiologia , Músculo Esquelético/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Sistema Nervoso Central/fisiologia , Exercício Físico/fisiologia , Homeostase/genética , Homeostase/fisiologia , Humanos , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiologia , Cinurenina/genética , Metabolismo/fisiologia , Músculo Esquelético/fisiologia , PPAR gama/genética , Triptofano/metabolismo
15.
Int J Mol Sci ; 21(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098023

RESUMO

In the pathology-oriented study of depression, inflammation hypothesis has received increasing attention for recent years. To mimic the depressive state caused by inflammation, rodents injected intraperitoneally with lipopolysaccharide (LPS) are usually used to stimulate an immune response. However, the dose of LPS that causes depressive-like behavior varies widely across many literatures. Previous study has uncovered the non-linearity in the dose-effect relationship for the depressive-like behavior induced by LPS administration, while the reason for this is still unclear. The present study aims to investigate the underlying mechanisms of this non-linear dose-dependent relationship. Four groups of mice were injected intraperitoneally with different doses of LPS (0, 0.32, 0.8, and 2 mg/kg). The tail suspension test was conducted to evaluate the depressive-like behavior within 23-25 h after the LPS administration. The neuroplasticity was assessed by the levels of related proteins, TrkB and PSD-95, and by the quantification of neurons using Nissl staining. The levels of the two metabolites of the kynurenine (KYN) pathway, 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA), in the brain were analyzed by LC-MS/MS. Activation of microglia and astrocytes in the brain were also determined by immunohistochemistry and western blotting, respectively. The results showed that, compared with the control group, the mice in the 0.8 mg/kg LPS-treated group exhibited a remarkable increase of immobility time in the tail suspension test. The neuroplasticity of mice in the 0.8 mg/kg LPS-treated group was also significantly reduced. The neurotoxic metabolite, 3-HK, was accumulated significantly in the hippocampus of the 0.8 mg/kg LPS-treated mice. Surprisingly, the 2 mg/kg LPS-treated mice did not exhibit a remarkable change of 3-HK but expressed increased KYNA significantly, which is neuroprotective. Furthermore, the activation of microglia and astrocytes, which were recognized as the primary source of 3-HK and KYNA, respectively, corresponded to the content of these two metabolites of the KYN pathway in each group. Consequently, it was speculated that the homeostasis of different glial cells could lead to a non-linear dose-dependent behavior by regulating the KYN pathway in the LPS-induced depressive-like mice.


Assuntos
Astrócitos/metabolismo , Depressão , Homeostase/efeitos dos fármacos , Cinurenina/metabolismo , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Animais , Astrócitos/patologia , Comportamento Animal/efeitos dos fármacos , Depressão/induzido quimicamente , Depressão/metabolismo , Depressão/patologia , Masculino , Camundongos , Microglia/patologia
16.
Sci Rep ; 10(1): 3184, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081969

RESUMO

The immature brain is especially vulnerable to lead (Pb2+) toxicity, which is considered an environmental neurotoxin. Pb2+ exposure during development compromises the cognitive and behavioral attributes which persist even later in adulthood, but the mechanisms involved in this effect are still unknown. On the other hand, the kynurenine pathway metabolites are modulators of different receptors and neurotransmitters related to cognition; specifically, high kynurenic acid levels has been involved with cognitive impairment, including deficits in spatial working memory and attention process. The aim of this study was to evaluate the relationship between the neurocognitive impairment induced by Pb2+ toxicity and the kynurenine pathway. The dams were divided in control group and Pb2+ group, which were given tap water or 500 ppm of lead acetate in drinking water ad libitum, respectively, from 0 to 23 postnatal day (PND). The poison was withdrawn, and tap water was given until 60 PND of the progeny. The locomotor activity in open field, redox environment, cellular function, kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) levels as well as kynurenine aminotransferase (KAT) and kynurenine monooxygenase (KMO) activities were evaluated at both 23 and 60 PND. Additionally, learning and memory through buried food location test and expression of KAT and KMO, and cellular damage were evaluated at 60 PND. Pb2+ group showed redox environment alterations, cellular dysfunction and KYNA and 3-HK levels increased. No changes were observed in KAT activity. KMO activity increased at 23 PND and decreased at 60 PND. No changes in KAT and KMO expression in control and Pb2+ group were observed, however the number of positive cells expressing KMO and KAT increased in relation to control, which correlated with the loss of neuronal population. Cognitive impairment was observed in Pb2+ group which was correlated with KYNA levels. These results suggest that the increase in KYNA levels could be a mechanism by which Pb2+ induces cognitive impairment in adult mice, hence the modulation of kynurenine pathway represents a potential target to improve behavioural alterations produced by this environmental toxin.


Assuntos
Disfunção Cognitiva/metabolismo , Cinurenina/metabolismo , Lactação , Chumbo/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Exposição Ambiental , Feminino , Lactação/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Longo Prazo/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Oxirredução
17.
Proc Natl Acad Sci U S A ; 117(7): 3848-3857, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32024760

RESUMO

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.


Assuntos
Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Regulação Alostérica , Sítio Alostérico , Animais , Biocatálise , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cinurenina/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos Knockout , Esclerose Múltipla/enzimologia , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Serotonina/análogos & derivados , Serotonina/química , Serotonina/metabolismo , Triptofano/metabolismo
18.
Sci Rep ; 10(1): 1961, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029791

RESUMO

Previous reports have shown that during chronic inflammation, the tryptophan (TRP)-kynurenine (KYN) pathway plays a pivotal role in the onset of depression. The aim of this study was to investigate the characteristics of the serum TRP-KYN pathway metabolite profile in high-risk subjects of major depressive disorder (HRMDD) defined by depression scores. The concentrations of TRP-KYN pathway metabolites {TRP, KYN, 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), kynurenic acid (KYNA) and anthranilic acid (AA)} were assessed in serum from HRMDD, chronic pain disorder patients and healthy controls. In serum from HRMDD, elevated levels of AA and decreased levels of TRP were observed, but the levels of other metabolites were not changed. Furthermore, the change in the AA2nd/AA1st ratio in subjects who progressed from a health. y state to a depressive state was correlated with an increase in the CES-D score. The level of IL-1 receptor antagonist (IL-1RA) was negatively correlated with that of AA. Interestingly, we confirmed AA as a possible biomarker for depression-related symptoms, since the metabolite profiles in the chronic pain disorder group and chronic unpredictable mild stress model mice were similar to those in the HRMDD. These results suggest that AA may be an effective marker for HRMDD.


Assuntos
Dor Crônica/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Estresse Psicológico/diagnóstico , ortoaminobenzoatos/sangue , Ácido 3-Hidroxiantranílico/análise , Ácido 3-Hidroxiantranílico/metabolismo , Adulto , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Dor Crônica/sangue , Dor Crônica/metabolismo , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/metabolismo , Modelos Animais de Doenças , Feminino , Voluntários Saudáveis , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Ácido Cinurênico/sangue , Ácido Cinurênico/metabolismo , Cinurenina/análogos & derivados , Cinurenina/sangue , Cinurenina/metabolismo , Masculino , Metaboloma , Camundongos , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estresse Psicológico/sangue , Estresse Psicológico/metabolismo , Triptofano/metabolismo , ortoaminobenzoatos/metabolismo
19.
Adv Exp Med Biol ; 1191: 155-167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002928

RESUMO

Anxiety disorders are a complex set of illnesses in which genetic factors, particularly stress, play a role in the etiopathogenesis. In recent years, inflammation and intestinal microbiota have also been included in this complex network of relationships. The functions associated with tryptophan catabolism and serotonin biosynthesis have long been associated with anxiety disorders. Tryptophan catabolism progresses toward the path of the kynurenine in the presence of stress and inflammation. The catabolism of kynurenine is a pathway in which many enzymes play a role and a large number of catabolites with neuroactive properties occur. The body's serotonin biosynthesis is primarily performed by enterochromaffin cells located in the intestines. A change in the intestinal microbiota composition (dysbiosis) directly affects the serotonin biosynthesis. Stress, unhealthy nutrition, and the use of antibiotics cause dysbiosis. In the light of this new perspective, the role of dysbiosis-induced inflammation and kynurenine pathway catabolites activated sequentially come into prominence in the etiopathogenesis of anxiety disorders.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Microbioma Gastrointestinal , Cinurenina/metabolismo , Disbiose/metabolismo , Disbiose/microbiologia , Humanos , Serotonina/biossíntese , Serotonina/metabolismo
20.
J Neuroinflammation ; 17(1): 56, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061259

RESUMO

BACKGROUND: In the last decade, there has been growing evidence that an interaction exists between inflammation and the kynurenine pathway in schizophrenia. Additionally, many authors found microglial activation in cases of schizophrenia due to inflammatory mechanisms related mostly to an increase of pro-inflammatory cytokines. In order to gain new insights into the pathophysiology of schizophrenia, it is important to incorporate the latest published evidence concerning inflammatory mechanisms and kynurenine metabolism. This systematic review aims to collect reliable recent findings within the last decade supporting such a theory. METHODS: A structured search of electronic databases was conducted for publications between 2008 and 2018 to identify eligible studies investigating patients with schizophrenia/psychosis and the relationship between inflammation and kynurenine pathway. Applicable studies were systematically scored using the NIH Quality Assessment Tools. Two researchers independently extracted data on diagnosis (psychosis/schizophrenia), inflammation, and kynurenine/tryptophan metabolites. RESULTS: Ten eligible articles were identified where seven studies assessed blood samples and three assessed cerebrospinal fluid in schizophrenic patients. Of these articles: Four investigated the relationship between immunoglobulins and the kynurenine pathway and found correlations between IgA-mediated responses and levels of tryptophan metabolites (i.e., kynurenine pathway).Five examined the correlation between cytokines and kynurenine metabolites where three showed a relationship between elevated IL-6, TNF-α concentrations, and the kynurenine pathway.Only one study discovered correlations between IL-8 and the kynurenine pathway.Two studies showed correlations with lower concentrations of IL-4 and the kynurenine pathway.Moreover, this systematic review did not find a significant correlation between CRP (n = 1 study), IFN-γ (n = 3 studies), and the kynurenine pathway in schizophrenia. INTERPRETATION: These results emphasize how different inflammatory markers can unbalance the tryptophan/kynurenine pathway in schizophrenia. Several tryptophan/kynurenine pathway metabolites are produced which can, in turn, underlie different psychotic and cognitive symptoms via neurotransmission modulation. However, due to heterogeneity and the shortage of eligible articles, they do not robustly converge to the same findings. Hence, we recommend further studies with larger sample sizes to elucidate the possible interactions between the various markers, their blood vs. CSF ratios, and their correlation with schizophrenia symptoms.


Assuntos
Inflamação/metabolismo , Cinurenina/metabolismo , Transtornos Psicóticos/metabolismo , Esquizofrenia/metabolismo , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...