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1.
Sci Rep ; 12(1): 15617, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114337

RESUMO

Dysregulation of the kynurenine pathway (KP) is implicated in many human diseases and disorders, from immunological, metabolic, neurodegenerative, and neuropsychiatric conditions to cancer, and represents an appealing target for new therapeutic approaches. In this intricate scenario, invertebrates, like Lymnaea stagnalis (LS), provide a flexible tool to unravel the complexity of the KP. Starting from the available LS genome and transcriptome, we identified putative transcripts of all KP enzymes containing an ORF; each predicted protein possessed a high degree of sequence conservation to known orthologues of other invertebrate and vertebrate model organisms. Sequences were confirmed by qualitative PCR and sequencing. At the same time, the qRT-PCR analysis revealed that Lym IDO-like, Lym TDO-like, Lym AFMID-like, Lym KMO-like, Lym AADAT-like, Lym KYAT I/III-like, Lym KYNU-like, Lym HAAO-like, and Lym ACMSD-like showed widespread tissue expression. Then, tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxy-kynurenine, xanthurenic acid, picolinic acid, and quinolinic acid were identified in the hemolymph of LS by UHPLC-Q exactive mass spectrometer. Our study provides the most thorough characterization to date of the KP in an invertebrate model, supporting the value of LS for future functional studies of this pathway at the cellular, synaptic, and behavioral levels.


Assuntos
Cinurenina , Lymnaea , Animais , Humanos , Ácido Cinurênico , Ácido Quinolínico , Triptofano
2.
Int J Mol Sci ; 23(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077360

RESUMO

In recent decades, neuropsychiatric disorders such as major depressive disorder, schizophrenia, bipolar, etc., have become a global health concern, causing various detrimental influences on patients. Tryptophan is an important amino acid that plays an indisputable role in several physiological processes, including neuronal function and immunity. Tryptophan's metabolism process in the human body occurs using different pathways, including the kynurenine and serotonin pathways. Furthermore, other biologically active components, such as serotonin, melatonin, and niacin, are by-products of Tryptophan pathways. Current evidence suggests that a functional imbalance in the synthesis of Tryptophan metabolites causes the appearance of pathophysiologic mechanisms that leads to various neuropsychiatric diseases. This review summarizes the pharmacological influences of tryptophan and its metabolites on the development of neuropsychiatric disorders. In addition, tryptophan and its metabolites quantification following the neurotransmitters precursor are highlighted. Eventually, the efficiency of various biomarkers such as inflammatory, protein, electrophysiological, genetic, and proteomic biomarkers in the diagnosis/treatment of neuropsychiatric disorders was discussed to understand the biomarker application in the detection/treatment of various diseases.


Assuntos
Transtorno Depressivo Maior , Triptofano , Humanos , Cinurenina/metabolismo , Proteômica , Serotonina/metabolismo , Triptofano/metabolismo
3.
J Pharmacol Sci ; 150(2): 49-55, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36055751

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has been associated with high mortality worldwide. Owing to its complicated pathophysiology, diagnostic and prognostic biomarkers for effective patient management remain scarce. We analyzed kynurenine, tryptophan, and serotonin levels in the serum of patients with COVID-19 via liquid chromatography/mass spectrometry analysis. Serum serotonin levels were decreased in patients with more severe COVID-19, along with increased kynurenine and decreased tryptophan concentrations. Patients with moderate disease who subsequently worsened showed significantly lower serotonin concentrations compared with those who did not experience severe disease. Serum serotonin levels may represent a valuable biomarker for COVID-19 severity and prognosis.


Assuntos
COVID-19 , Cinurenina , Biomarcadores , Cromatografia Líquida , Humanos , Espectrometria de Massas , Prognóstico , Serotonina , Triptofano
4.
Dis Markers ; 2022: 5447017, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118672

RESUMO

Background: Tryptophan 2,3-dioxygenase (TDO) encoded by TDO2, a rate-limiting enzyme in the kynurenine pathway, catabolizes tryptophan to kynurenine, evades immune surveillance, and promotes tumor growth. Although accumulating evidence suggests a crucial role of TDO2 during tumor formation and development, systematic evaluation of TDO2 across human cancers has rarely been reported. Methods: To shed more light on the role of TDO2 in human cancer, we explored the expression profiles of TDO2 and identified its prognostic value in pancancer analysis through TCGA, CCLE, and GTEx databases. We further utilized TCGA data to evaluate the association between TDO2 and tumor immunological features, such as mismatch repair (MMR), tumor immune infiltration, immune checkpoint-related genes, tumor mutational burden (TMB), microsatellite instability (MSI), and DNA methyltransferase (DNMT). Results: TDO2 exhibited different expression levels in various cancer cell lines. Frequently, TDO2 was detected to be highly expressed in the majority of cancers. In addition, high TDO2 expression was correlated with an unfavorable prognosis for patients in KIRP, LGG, TGCT, and UVM. Moreover, high TDO2 expression level positively correlated with higher immune infiltration, especially dendritic cells. Additionally, there is a close relationship between TDO2 and immune checkpoint-related gene markers, such as LAIR1, CD276, NRP1, CD80, and CD86. Finally, correlation analysis has demonstrated a high-correlation between TDO2 and TMB, MSI, MMR, and DNMT of multiple cancer types. Conclusion: Therefore, our results suggest that TDO2 can function as a potential prognostic biomarker due to its role in tumor immunity regulation.


Assuntos
Neoplasias , Triptofano Oxigenase , Antígenos B7/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , DNA , Humanos , Imunoterapia , Cinurenina/genética , Cinurenina/metabolismo , Metiltransferases/genética , Instabilidade de Microssatélites , Neoplasias/genética , Neoplasias/terapia , Prognóstico , Triptofano/genética , Triptofano/metabolismo , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo
5.
Front Immunol ; 13: 953115, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119020

RESUMO

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called "kynurenine (Kyn) pathway", which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.


Assuntos
Neoplasias do Endométrio , Cinurenina , Biomarcadores , Neoplasias do Endométrio/terapia , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Triptofano/metabolismo
6.
BMC Neurol ; 22(1): 356, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127656

RESUMO

BACKGROUND: The etiological and pathophysiological factors of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) are currently not well understood. These disorders disrupt some cognitive abilities. Identifying biomarkers for these disorders is a cornerstone to their proper management. Kynurenine (KYN) and oxidative stress markers have been reported to influence some cognitive abilities. Therefore, the aim was to measure the level of KYN and some oxidative stress indicators in children with LD with and without ADHD and to investigate their correlations with the abilities of children with LD. METHODS: The study included 154 participants who were divided into 3 groups: one for children who have LD (N = 69); another for children with LD and ADHD (N = 31); and a group for neurotypical (NT) children (N = 54). IQ testing, reading, writing, and other ability performance evaluation was performed for children with LD. Measuring plasma levels of KYN, malondialdehyde, glutathione peroxidase, and superoxide dismutase by enzyme-linked immunosorbent assay was performed for all participants. RESULTS: Some IQ measures and learning skills differed between the first two groups. The biochemical measures differed between children with LD (with and without ADHD) and NT children (p < 0.001). However, the biochemical measures did not show a significant statistical difference between the first two groups. KYN and glutathione peroxidase levels were correlated with one-minute writing and at-risk quotient, respectively (p = 0.03;0.04). KYN and malondialdehyde showed the highest sensitivity and specificity values. CONCLUSION: These biochemical measures could be involved or have a role in the abilities' performance of children with specific learning disorder.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Deficiências da Aprendizagem , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Criança , Glutationa Peroxidase , Humanos , Cinurenina , Deficiências da Aprendizagem/diagnóstico , Malondialdeído , Estresse Oxidativo , Superóxido Dismutase
7.
Biochem J ; 479(17): 1807-1824, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-35997090

RESUMO

IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift with regard to IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson's disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.


Assuntos
Neoplasias Pancreáticas , Receptores de Hidrocarboneto Arílico , Animais , Carbidopa/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase , Janus Quinases/metabolismo , Cinurenina/metabolismo , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Triptofano/metabolismo
8.
Biochim Biophys Acta Mol Basis Dis ; 1868(11): 166509, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35914653

RESUMO

Type 2 diabetes is associated with an inflammatory phenotype in the pancreatic islets. We previously demonstrated that proinflammatory cytokines potently activate the tryptophan/kynurenine pathway (TKP) in INS-1 cells and in normal rat islets. Here we examined: (1) the TKP enzymes expression in the diabetic GK islets; (2) the TKP enzymes expression profiles in the GK islets before and after the onset of diabetes; (3) The glucose-stimulated insulin secretion (GSIS) in vitro in GK islets after KMO knockdown using specific morpholino-oligonucleotides against KMO or KMO blockade using the specific inhibitor Ro618048; (4) The glucose tolerance and GSIS after acute in vivo exposure to Ro618048 in GK rats. We report a remarkable induction of the kmo gene in GK islets and in human islets exposed to proinflammatory conditions. It occurred prominently in beta cells. The increased expression and activity of KMO reflected an acquired adaptation. Both KMO knockdown and specific inhibitor Ro618048 enhanced GSIS in vitro in GK islets. Moreover, acute administration of Ro618048 in vivo improved glucose tolerance, GSIS and basal blood glucose levels in GK rats. These results demonstrate that targeting islet TKP is able to correct defective GSIS. KMO inhibition could represent a potential therapeutic strategy for type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animais , Glicemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/metabolismo , Morfolinos , Ratos , Ratos Wistar , Triptofano/metabolismo
9.
Immun Inflamm Dis ; 10(9): e690, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36039641

RESUMO

INTRODUCTION: Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive tryptophan-depleting enzyme expressed in nasopharyngeal carcinoma (NPC) tissue. However, IDO has not been reported in the peripheral blood of NPC patients. The aim of this study was to analyze, IDO1 and IDO2 messenger RNA (mRNA) expression, the kynurenine (Kyn) and tryptophan (Trp) plasma levels, their clinical values and their relationship with cytokine levels in NPC. METHODS: We evaluated IDO1 and IDO2 mRNA expression in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR, plasma Trp and Kyn levels by HPLC, and cytokine levels by ELISA in 75 NPC patients and 51 healthy controls. RESULTS: Compared to controls, IDO1 mRNA expression was significantly upregulated and IDO2 mRNA expression was significantly downregulated in PBMC of patients. Also compared to controls, plasma Kyn levels and Kyn/Trp ratio were significantly higher in patients. At the time of diagnosis, the plasma Kyn/Trp ratio was associated with advanced cancer status and was an independent prognostic factor for worse disease-specific survival. According to cancer stages, IDO1 mRNA expression was positively correlated with plasma Kyn/Trp ratio in patients with earlier stages (I-II-III) but negatively correlated in patients with the late-stage cancer (IV). Tumor necrosis factor-α, interleukin (IL)-6 and IL-10 levels were significantly higher in patients compared to controls. Moreover, and despite treatment, patients simultaneously carrying high plasma Kyn/Trp ratio and high plasma IL-6 and IL-10 levels at diagnosis died approximately 1 year after first diagnosis. CONCLUSION: Measuring blood IDO mRNA expression and Kyn/Trp ratio at diagnosis could be a potential marker to evaluate NPC progression and predict survival outcome.


Assuntos
Cinurenina , Neoplasias Nasofaríngeas , Citocinas/genética , Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interleucina-10/genética , Interleucina-6/genética , Cinurenina/metabolismo , Leucócitos Mononucleares/metabolismo , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , RNA Mensageiro/genética , Triptofano/metabolismo
10.
Exp Physiol ; 107(9): 1029-1036, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35912981

RESUMO

NEW FINDINGS: What is the central question in this study? Promoting muscle health with regular aerobic exercise can improve mental health through a kynurenine metabolic pathway: do conditions of muscle disease such as muscular dystrophy negatively influence this pathway? What is the main finding and its importance? The DBA/2J mdx model of Duchenne muscular dystrophy exhibits altered kynurenine metabolism with less kynurenic acid and peroxisome proliferator-activated receptor-γ coactivator 1-α and higher levels of tumour necrosis factor α mRNA - results associated with anxiety-like behaviour. ABSTRACT: Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. However, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviours in approximately 25% of patients with Duchenne muscular dystrophy (DMD), possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of DMD. Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating kynurenic acid (KYNA) and lower KYNA:KYN ratio compared with their respective wild-type (WT) controls. While both C57 and D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of the arena during a novel object recognition test, this effect was more prominent in D2 mdx mice. Correlational analysis detected a significant negative association between KYNA:KYN levels and time spent in corners in D2 mice, but not C57 mice. In extensor digitorum longus muscles from D2 mdx mice, but not C57 mdx mice, we found lowered protein levels of peroxisome proliferator-activated receptor-γ coactivator 1-α and kynurenine amino transferase-1 enzyme when compared with WT. Furthermore, D2 mdx quadriceps muscles had the highest level of tumour necrosis factor α expression, which is suggestive of enhanced inflammation. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health.


Assuntos
Distrofia Muscular de Duchenne , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Ácido Cinurênico/metabolismo , Ácido Cinurênico/farmacologia , Cinurenina/metabolismo , Cinurenina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
J Reprod Immunol ; 153: 103692, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35970080

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are key enzymes for tryptophan degradation, regulating immune tolerance during pregnancy. The intrauterine renin-angiotensin system is also involved in the progression of a healthy pregnancy. Angiotensin(1-7) maintains the integrity of fetal membranes via counteracting the pro-inflammatory actions of Angiotensin II. No data are available on placental Angiotensin(1-7) co-expression with TDO. We aimed to characterize TDO mRNA expression and its localization in different areas of the placenta of physiological pregnancies delivered at term; its co-expression with Angiotensin(1-7) and its correlation with the plasma kynurenine/tryptophan (Kyn/Trp) ratio was investigated. This prospective observational study included a nonconsecutive series of 20 singleton uncomplicated pregnancies delivered vaginally. TDO mRNA was expressed in both maternal and fetal sides of the placentas and TDO protein also in the villi and it was co-expressed with IDO1 in almost half of the placental cells at these sites. The percentage of TDO+ and IDO1+ cells appeared to be influenced by maternal pre-gestational smoking and newborn weight. A strong correlation was found between the percentage of TDO+ and IDO1+ cells in the villi. TDO+ cells also expressed Angiotensin(1-7), with a higher percentage on the fetal side and in the villi compared to the maternal one. Kyn/Trp plasma ratio was not correlated with IDO and TDO expression nor with the patient's characteristics. Collectively, our data indicate that TDO is detectable in placental tissue and is co-expressed with IDO and with Angiotensin(1-7)+ on the fetal side and in the villi.


Assuntos
Cinurenina , Triptofano Oxigenase , Angiotensina I , Angiotensina II , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Recém-Nascido , Cinurenina/metabolismo , Fragmentos de Peptídeos , Placenta/metabolismo , Gravidez , RNA Mensageiro , Triptofano/metabolismo , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo
12.
Cells ; 11(16)2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-36010680

RESUMO

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it accounts for about half of the cases of acute kidney injury (AKI). Although sepsis is the most frequent cause of AKI in critically ill patients, its pathophysiological mechanisms are not well understood. Sepsis has the ability to modulate the function of cells belonging to the innate immune system. Increased activity of indoleamine 2,3-dioxygenase 1 (IDO1) and production of kynurenines are the major metabolic pathways utilized by innate immunity cells to maintain immunological tolerance. The activation of the kynurenine pathway (KP) plays a dual role in sepsis-in the early stage, the induction of IDO1 elicits strong proinflammatory effects that may lead to tissue damage and septic shock. Afterwards, depletion of tryptophan and production of kynurenines contribute to the development of immunosuppression that may cause the inability to overpower opportunistic infections. The presented review provides available data on the various interdependencies between elements of innate immunity and sepsis-induced AKI (SAKI) with particular emphasis on the immunomodulatory significance of KP in the above processes. We believe that KP activation may be one of the crucial, though underestimated, components of a deregulated host response to infection during SAKI.


Assuntos
Injúria Renal Aguda , Sepse , Injúria Renal Aguda/etiologia , Humanos , Imunidade Inata , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Sepse/complicações
13.
Cells ; 11(16)2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-36010683

RESUMO

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.


Assuntos
Cinurenina , Doenças Mitocondriais , Animais , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Humanos , Cinurenina/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Triptofano/metabolismo
14.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36012419

RESUMO

(1) Background: Tryptophan metabolism is known to be one of the important mechanisms used by cancer to evade immune surveillance. Altered tryptophan metabolism was studied in patients with pigmented malignant melanoma confirmed histologically by the anatomic stage grouping for cutaneous melanoma using clinical staging on the basis of the Breslow thickness of the melanoma, the degree of spread to regional lymph nodes, and by the presence of distant metastasis. (2) Methods: Urinary tryptophan metabolites were detected by RP-HPLC method. (3) Results: In the present work, we provided evidence of altered metabolism of all tryptophan pathways in melanoma patients. (4) Conclusions: Knowledge of the shifted serotonin pathway toward DHICA formation and kynurenine pathway shifted toward NAD+ production could serve in the early detection of the disease and the initiation of early treatment of malignant melanoma.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Indóis , Cinurenina/metabolismo , Serotonina/metabolismo , Triptofano/metabolismo
15.
Front Immunol ; 13: 906815, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36032151

RESUMO

Objective: High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T-cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes. Materials and methods: Systemic IDO1 activity was calculated by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. The dynamic change of IDO1 activity was followed in 24 patients by measuring the Kyn : Trp ratio before, during, and after RT administration. Results: In 24 patients with dynamic tracking of plasma IDO1 activity, there were no significant alterations observed among the three time points (Friedman test, p = 0.13). The changing pattern of the Kyn : Trp ratio was divided into four groups: decreased consistently during RT, first increased, then decreased, increased consistently, first decreased then increased. Patients whose Kyn : Trp ratio kept decreasing or first increased then decreased were defined as the good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p = 0.04; p = 0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than the bad-change group (p = 0.01, HR = 0.22). In 113 stage III NSCLC patients with pre-radiation Kyn : Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p = 0.079). Conclusion: Favorable change in IDO1 activity during RT was associated with superior OS, PFS, and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quimiorradioterapia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase , Cinurenina , Triptofano
16.
Nutrients ; 14(16)2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-36014759

RESUMO

BACKGROUND: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD) patients without specific treatment. Aryl hydrocarbon receptor (AhR) activation is associated with better outcomes in intestinal inflammation. Development of novel therapies targeting fibrogenic pathways is required and we aimed to screen dietary AhR ligands for their anti-fibrotic properties in TGF-ß1-stimulated human colonic fibroblast cells. METHODS: The study was conducted using TGF-ß1-stimulated CCD-18Co, a human colonic fibroblast cell line in response to increased concentrations of dietary ligands of AhR such as FICZ, ITE, L-kynurenine and curcumin. Fibrosis markers such as α-SMA, COL1A1, COL3A1 and CTGF were assessed. AhR and ANRT RNA were evaluated. RESULTS: TGF-ß1 at 10 ng/mL significantly induced mRNA levels for ECM-associated proteins such as CTGF, COL1A1 and COL3A1 in CCD-18Co cells. FICZ from 10 to 1000 nM, L-kynurenine from 0.1 to 10 µM, ITE from 1 to 100 µM or curcumin from 5 to 20 µM had no significant effect on fibrosis markers in TGF-ß1-induced CCD-18Co. CONCLUSIONS: Our data highlight that none of the tested dietary AhR ligands had an effect on fibrosis markers in TGF-ß1-stimulated human colonic fibroblast cells in our experimental conditions. Further studies are now required to identify novel potential targets in intestinal fibrosis.


Assuntos
Curcumina , Fator de Crescimento Transformador beta1 , Curcumina/metabolismo , Curcumina/farmacologia , Fibroblastos , Fibrose , Humanos , Cinurenina/metabolismo , Cinurenina/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
17.
Nutrients ; 14(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36014776

RESUMO

L-tryptophan (Trp) contributes to regulating bilateral communication of the gut-brain axis. It undergoes three major metabolic pathways, which lead to formation of kynurenine, serotonin (5-HT), and indole derivatives (under the control of the microbiota). Metabolites from the principal Trp pathway, kynurenic acid and quinolinic acid, exhibit neuroprotective activity, while picolinic acid exhibits antioxidant activity, and 5-HT modulates appetite, sleep cycle, and pain. Abnormality in Trp plays crucial roles in diseases, including depression, colitis, ulcer, and gut microbiota-related dysfunctions. To address these diseases, the use of natural products could be a favorable alternative because they are a rich source of compounds that can modulate the activity of Trp and combat various diseases through modulating different signaling pathways, including the gut microbiota, kynurenine pathway, and serotonin pathway. Alterations in the signaling cascade pathways via different phytochemicals may help us explore the deep relationships of the gut-brain axis to study neuroprotection. This review highlights the roles of natural products and their metabolites targeting Trp in different diseases. Additionally, the role of Trp metabolites in the regulation of neuroprotective and gastroprotective activities is discussed. This study compiles the literature on novel, potent neuroprotective agents and their action mechanisms in the gut-brain axis and proposes prospective future studies to identify more pharmaceuticals based on signaling pathways targeting Trp.


Assuntos
Produtos Biológicos , Fármacos Neuroprotetores , Eixo Encéfalo-Intestino , Depressão , Cinurenina/metabolismo , Serotonina/metabolismo , Triptofano/metabolismo
18.
Food Funct ; 13(18): 9513-9522, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-35993820

RESUMO

Depression is highly prevalent in patients suffering from chronic inflammatory diseases. Dysregulated neuroinflammation and concomitant-activated microglia play a pivotal role in the pathogenesis of depression. As one of the biologically functional phytochemicals in soybeans, soy isoflavones (SI) have been reported to exhibit anti-inflammatory, antioxidant, estrogen-like and neuroprotective activities. However, there is no research on how SI administration affects the depressive-like behavior induced by neuroinflammation. Therefore, this study was conducted to evaluate the antidepressant-like action of SI in acute lipopolysaccharide (LPS)-treated mice and to explore its underlying mechanisms. An open field test, a sucrose preference experiment, a tail suspension test and a forced swimming task were conducted to assess the influence of SI on the depressive-like behavior induced by LPS injection. Then, the levels of the pro-inflammation cytokines, tryptophan (Trp) metabolism in the cortex and hippocampus, and the synaptic plasticity-related signal pathway in the hippocampus, which are involved in the pathophysiology of depression, were examined. The results showed that SI administration remarkably alleviated LPS-induced depressive-like behavior as indicated by the increased sucrose preference index and the decreased immobility time both in the tail suspension test and the forced swimming task. SI significantly suppressed neuroinflammation in the hippocampus of LPS mice, as indicated by a decrease in the levels of interleukin (IL)-1ß, IL-10, tumor necrosis factor (TNF-α) and suppression of the signal pathway of TLR4/NF-κB. Additionally, SI administration regulated tryptophan (Trp) metabolism by increasing 5-hydroxytryptamine (5-HT) levels, inhibiting the release of kynurenine (KYN) in the cortex and hippocampus, and elevating the expressions of synaptic plasticity-related protein markers such as postsynaptic density-95 (PSD-95) and synaptophysin (SYN). The current study demonstrated that soy isoflavones could reverse LPS-induced depressive-like behavior by suppressing neuroinflammation, normalizing the Trp metabolism, up-regulating the expressions of synaptic plasticity-related proteins, and inhibiting the TLR4/NF-κB pathway activation in the hippocampus of mice, exerting their antidepressant-like action.


Assuntos
Isoflavonas , Lipopolissacarídeos , Animais , Anti-Inflamatórios , Antidepressivos/farmacologia , Antioxidantes , Citocinas/metabolismo , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/metabolismo , Estrogênios , Interleucina-10 , Isoflavonas/farmacologia , Cinurenina/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Doenças Neuroinflamatórias , Plasticidade Neuronal , Serotonina , Sacarose , Sinaptofisina , Receptor 4 Toll-Like/genética , Triptofano/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Biosci Trends ; 16(4): 249-256, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36002303

RESUMO

By far, no revolutionary breakthrough in the treatment of Parkinson's disease (PD) was found. It is indeed a knotty problem to select a satisfactory strategy for treating some patients with advanced stage PD. Development of novel therapeutic targets against PD has been an urgent task faced by global PD researchers. Targets in the tryptophan-kynurenine pathway (KP) were then considered. Metabolites in the KP are liposoluble. Some neurotoxic metabolites, including 3-hydroxykynurenine and its downstream 3-hydroxyanthranilic acid and quinolinic acid, are mainly produced peripherally. They can easily cross the blood-brain barrier (BBB) and exert their neurotoxic effects in the central neuron system (CNS), which is considered as a potential pathophysiological mechanism of neurodegenerative diseases. Hence, agents against the targets in the KP have two characteristics: (1) being independent from the dopaminergic system and (2) being seldom affected by the BBB. Inspiringly, one agent, namely, the inhibitor of indoleamine 2,3-dioxygenase 1, has been currently reported to present satisfactory efficacy comparable to levodopa, implying that the KP might be a potential novel target for PD. This review collected and summarized the updated information regarding the association of the KP with PD, which is helpful for understanding the clinical value of the KP in the PD scenario.


Assuntos
Cinurenina , Doença de Parkinson , Ácido 3-Hidroxiantranílico , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Levodopa , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Ácido Quinolínico/metabolismo , Triptofano/metabolismo
20.
Int J Mol Sci ; 23(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35955633

RESUMO

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways.


Assuntos
Cinurenina , Serotonina , Depressão/metabolismo , Humanos , Cinurenina/metabolismo , Redes e Vias Metabólicas , Serotonina/metabolismo , Triptofano/metabolismo
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