Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29.965
Filtrar
Mais filtros








Intervalo de ano de publicação
1.
J Ethnopharmacol ; 291: 115145, 2022 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-35219821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Shenling Baizhu San (SBS) is commonly employed to improve gastrointestinal dysfunction in patients with ulcerative colitis (UC) in China. SBS combined with mesalamine has been demonstrated to result in improve its curative effects without increasing any adverse reactions, but the underlying mechanism remains unclarified. AIM OF THE STUDY: Our study aimed to illuminate the potential therapeutic effects and mechanisms of SBS, which is a medicine complementary to mesalamine, in the treatment of UC. MATERIALS AND METHODS: A prospective cohort study was conducted to evaluate the efficacy of SBS as a complementary medicine to mesalamine for patients with UC (n = 48). The patients in the control group (n = 24) were given mesalamine alone, whereas those in the experimental group were administered mesalamine combined with SBS. The therapeutic outcome was assessed at 8 weeks. The structures of the gut microbiota (GMB) were characterized by 16S rRNA sequencing, and the microbial tryptophan metabolites were analyzed by UPLC-MS/MS to investigate the mechanism through which SBS achieves its effects. RESULTS: Our results showed that the combination of SBS and mesalamine could significantly improve the clinical signs of UC by achieving mucosal healing and relieving colon damage. Interestingly, the combination of SBS and mesalamine could alter the GMB structures and increase the microbial levels of tryptophan metabolites, including indole-3-propionic acid and indole-3-acetic acid. CONCLUSION: SBS combined with mesalamine is effective in improving the clinical and endoscopic outcomes of patients with UC. SBS, as a complementary therapy to conventional treatment, alleviates UC via the GMB-tryptophan metabolite axis.


Assuntos
Colite Ulcerativa , Terapias Complementares , Microbioma Gastrointestinal , Cromatografia Líquida , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Medicamentos de Ervas Chinesas , Humanos , Mesalamina/farmacologia , Mesalamina/uso terapêutico , Estudos Prospectivos , RNA Ribossômico 16S , Espectrometria de Massas em Tandem , Triptofano
2.
J Transl Med ; 20(1): 347, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918736

RESUMO

Cancer is one of the leading causes of death in both men and women worldwide. One of the main changes associated with cancer progression, metastasis, recurrence, and chemoresistance is the change in the tumor immune microenvironment, especially immunosuppression. Cancer immunosuppression appears in multiple forms, such as inhibition of immuno-stimulant cells with downregulation of immuno-stimulant mediators or through stimulation of immuno-suppressive cells with upregulation of immunosuppressive mediators. One of the most immunosuppressive mediators that approved potency in lung cancer progression is indoleamine 2,3-dioxygenase (IDO) and its metabolite kynurenine (Kyn). The current review tries to elucidate the role of IDO/Kyn on cancer proliferation, apoptosis, angiogenesis, oxidative stress, and cancer stemness. Besides, our review investigates the new therapeutic modalities that target IDO/Kyn pathway and thus as drug candidates for targeting lung cancer and drugs that potentiate IDO/Kyn pathway and thus can be cancer-promoting agents.


Assuntos
Cinurenina , Neoplasias Pulmonares , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Masculino , Triptofano/metabolismo , Microambiente Tumoral
3.
J Cell Mol Med ; 26(7): 1896-1904, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35934940

RESUMO

The pathophysiology of hypothermia during sepsis is unclear. Using genomic profiling of blood leukocytes, we aimed to determine if hypothermia is associated with a different gene expression profile compared to fever during sepsis. Patients with sepsis and either hypothermia or fever within 24 hours after ICU admission were included in the study (n = 168). Hypothermia was defined as body temperature below 36 °C. Fever was defined as body temperature equal to or above 38.3°C. We compared blood gene expression (whole-genome transcriptome in leukocytes) in hypothermic septic compared to febrile septic patients in an unmatched analysis and matched for APACHE IV score and the presence of shock. In total, 67 septic patients were hypothermic and 101 patients were febrile. Hypothermia was associated with a distinct gene expression profile in both unmatched and matched analyses. There were significant differences related to the up- and downregulation of canonical signalling pathways. In the matched analysis, the top upregulated gene was cold-inducible mRNA binding protein (CIRBP) which plays a role in cold-induced suppression of cell proliferation. In addition, we found three signalling pathways significantly upregulated in hypothermic patients compared to febrile patients; tryptophan degradation X, phenylalanine degradation IV and putrescine degradation III. In conclusion, there are distinct signalling pathways and genes associated with hypothermia, including tryptophan degradation and CIRBP expression, providing a possible link to the modulation of body temperature and early immunosuppression. Future studies may focus on the canonical signalling pathways presented in this paper to further investigate spontaneous hypothermia in sepsis.


Assuntos
Hipotermia , Sepse , Febre/genética , Humanos , Hipotermia/complicações , Hipotermia/genética , Proteínas de Ligação a RNA/metabolismo , Sepse/complicações , Sepse/genética , Transcriptoma/genética , Triptofano
4.
Front Immunol ; 13: 911381, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911670

RESUMO

Oxidative stress (OS) is a key factor regulating the systemic pathophysiological effects and one of the fundamental mechanisms associated with aging and fertility deterioration. Previous studies revealed that resveratrol (RV) exhibits a preventive effect against oxidative stress in the ovary. However, it remains unknown whether gut microbiota respond to resveratrol during an OS challenge. In Exp. 1, layers received intraperitoneal injection of tert-butyl hydroperoxide (tBHP) (0 or 800 µmol/kg BW) or received resveratrol diets (0 or 600 mg/kg) for 28 days. In Exp. 2, the role of intestinal microbiota on the effects of resveratrol on tBHP-induced oxidative stress was assessed through fecal microbiota transplantation (FMT). The OS challenge reduced the egg-laying rate and exhibited lower pre-hierarchical follicles and higher atretic follicles. Oral RV supplementation ameliorated the egg-laying rate reduction and gut microbiota dysbiosis. RV also reversed the tryptphan-kynurenine pathway, upregulated nuclear factor E2-related factor 2 (Nrf2) and silent information regulator 1(SIRT1) levels, and decreased the expression of forkhead box O1 (FoxO1) and P53. These findings indicated that the intestinal microbiota-related tryptophan-kynurenine pathway is involved in the resveratrol-induced amelioration of ovary oxidative stress induced by tBHP in the layer model, while SIRT1-P53/FoxO1 and Nrf2-ARE signaling pathway were involved in this process.


Assuntos
Microbiota , Sirtuína 1 , Animais , Feminino , Cinurenina/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Resveratrol/farmacologia , Sirtuína 1/metabolismo , Triptofano/metabolismo , Triptofano/farmacologia , Proteína Supressora de Tumor p53/metabolismo
5.
J Phys Chem B ; 126(31): 5793-5802, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35913127

RESUMO

We investigated d-amino acids as potential inhibitors targeting l-peptide toxins. Among the l- and d-amino acids tested, we found that d-tryptophan (d-Trp) acted as an inhibitor of melittin-induced hemolysis. We then evaluated various Trp derivatives and found that 5-chlorotryptamine (5CT) had the largest inhibitory effect on melittin. The indole ring, amino group, and steric hindrance of an inhibitor played important roles in the inhibition of melittin activity. Despite the small size and simple molecular structure of 5CT, its IC50 was approximately 13 µg/mL. Fluorescence quenching, circular dichroism measurements, and size-exclusion chromatography revealed that 5CT interacted with Trp19 in melittin and affected the formation of the melittin tetramer involved in hemolysis. Molecular dynamics simulation of melittin also indicated that the interaction of 5CT with Trp19 in melittin affected the formation of the tetramer.


Assuntos
Hemólise , Meliteno , Dicroísmo Circular , Humanos , Indóis , Meliteno/química , Meliteno/farmacologia , Triptofano/química
6.
BMC Psychiatry ; 22(1): 539, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941560

RESUMO

Over 50% of women experience mood disturbance in the postpartum period, with significant implications for maternal and infant health but identifying those at risk is not easily possible. The essential amino acid, tryptophan (TRP) through its neuroactive metabolites, has been implicated in the pathology of mood disorders. Thus, TRP levels tested in the peripartum period have been proposed as a potential biomarker for subsequent development of postpartum mood disturbances, in particular postpartum depression (PPD). A systematic review and meta-analysis following PROSPERO guidelines [CRD42021252462] was conducted on peer-reviewed, English language studies that measured blood levels of TRP during the postpartum period in women who were also evaluated for postpartum "blues" or PPD. Thirteen studies met the inclusion criteria, of which five studies contained sufficient data to conduct a meta-analysis. Low total TRP levels in postpartum days 1 to 5 were significantly associated with PPD (SMD: -5.39, 95%CI [-7.72, -3.05]). No significant association was found between free TRP levels in the postpartum period and PPD (SMD: -3.43, 95%CI [-7.76, 0.89]). Our findings confirm the necessity for more replicable designed studies regarding TRP and its relationship to postpartum depression. If there were greater clarity regarding TRP metabolism during pregnancy, then the next step would be to consider measuring total plasma TRP levels on postpartum days 1 to 5 to identify women at greater risk of developing PPD.


Assuntos
Depressão Pós-Parto , Transtornos Puerperais , Depressão Pós-Parto/diagnóstico , Feminino , Humanos , Transtornos do Humor/diagnóstico , Período Pós-Parto , Gravidez , Triptofano
7.
Water Res ; 221: 118789, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35785694

RESUMO

The negative effects of effluent organic matter (EfOM) on receiving aquatic environments and advanced treatment facilities pose significant concerns. However, the effective removal of EfOM is challenging due to its chemically complex nature and its refractory characteristics. In this study, two Fe(II)-assisted oxidation processes including UV/Fe(II)/H2O2 and UV/Fe(II)/persulfate (UV/Fe(II)/PS) were investigated to promote EfOM reduction. Fe(II) was essential for promoting EfOM degradation. The mineralization rate of EfOM increased from 7 to 29% with 2 mM Fe(II) addition in the UV/H2O2 process and to 23% with 0.8 mM Fe(II) addition in the UV/PS process. A preliminary experiment was conducted to obtain the optimal molar ratio of oxidant to Fe(II) for practical applications based on different indicators. The form of Fe(III) prevalent at different pH values strongly affected Fe(II)/Fe(III) cycling, thus determining the progress of EfOM degradation. A machine learning approach consisting of parallel factor analysis coupled with self-organizing maps (PARAFAC-SOM) was employed with fluorescence spectra to visualize the degradation behavior of EfOM in the different reaction systems. Four components (i.e., two humic-like substances, one fulvic acid, and one tryptophan-like substance) were eventually identified, and their reductions reached more than 62% during the Fe(II)-assisted oxidation processes. The degradation orders for each component in the different oxidation processes were initially evaluated by SOM analysis with Fmax percentage data. The degradation behavior of EfOM in the UV/Fe(II)/H2O2 and UV/Fe(II)/PS systems exhibited different trends based on the best matching unit map and component planes. The humic-like component was more refractory than the other three components in both oxidation processes. The microbial humic-like and high-molecular-weight fulvic acid substances showed higher reactivity with SO·4- than with ·OH, while the tryptophan-like substance was more reactive in the UV/Fe(II)/H2O2 system than in the UV/Fe(II)/PS system. The outcomes of this study provide new insights into the degradation behavior of EfOM, promoting the development of advanced wastewater treatments.


Assuntos
Águas Residuárias , Poluentes Químicos da Água , Análise Fatorial , Compostos Férricos , Compostos Ferrosos , Substâncias Húmicas/análise , Peróxido de Hidrogênio , Oxirredução , Triptofano , Águas Residuárias/química , Poluentes Químicos da Água/química
8.
Biomolecules ; 12(7)2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35883554

RESUMO

Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands.


Assuntos
Doenças Neurodegenerativas , Ácido Quinolínico , Citocinas , Humanos , Cinurenina/metabolismo , Doenças Neurodegenerativas/metabolismo , Ácido Quinolínico/metabolismo , Triptofano/metabolismo
9.
Phys Life Rev ; 42: 93-114, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35905538

RESUMO

Sunlight held the key to the origin of life on Earth. The earliest life forms, cyanobacteria, captured the sunlight to generate energy through photosynthesis. Life on Earth evolved in accordance with the circadian rhythms tied to sensitivity to sunlight patterns. A unique feature of cyanobacterial photosynthetic proteins and circadian rhythms' molecules, and later of nearly all photon-sensing molecules throughout evolution, is that the aromatic amino acid tryptophan (Trp) resides at the center of light-harvesting active sites. In this perspective, I review the literature and integrate evidence from different scientific fields to explore the role Trp plays in photon-sensing capabilities of living organisms through its resonance delocalization of π-electrons. The observations presented here are the product of apparently unrelated phenomena throughout evolution, but nevertheless share consistent patterns of photon-sensing by Trp-containing and Trp-derived molecules. I posit the unique capacity to transfer electrons during photosynthesis in the earliest life forms is conferred to Trp due to its aromaticity. I propose this ability evolved to assume more complex functions, serving as a host for mechanisms underlying mental aptitudes - a concept which provides a theoretical basis for defining the neural correlates of consciousness. The argument made here is that Trp aromaticity may have allowed for the inception of the mechanistic building blocks used to fabricate complexity in higher forms of life. More specifically, Trp aromatic non-locality may have acted as a catalyst for the emergence of consciousness by instigating long-range synchronization and stabilizing the large-scale coherence of neural networks, which mediate functional brain activity. The concepts proposed in this perspective provide a conceptual foundation that invites further interdisciplinary dialogue aimed at examining and defining the role of aromaticity (beyond Trp) in the emergence of life and consciousness.


Assuntos
Estado de Consciência , Cianobactérias , Cianobactérias/metabolismo , Redes Neurais de Computação , Fotossíntese , Proteínas , Triptofano/química , Triptofano/metabolismo
10.
Molecules ; 27(14)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35889347

RESUMO

Polyesters containing 2,4-dihydroxy-6-(2-hydroxypropyl)benzoate and 3-hydroxybutyrate moieties have been isolated from many fungal species. Talaromyces stipitatus was previously reported to produce a similar polyester, talapolyester G. The complete genome sequence and the development of bioinformatics tools have enabled the discovery of the biosynthetic potential of this microorganism. Here, a putative biosynthetic gene cluster (BGC) of the polyesters encoding a highly reducing polyketide synthase (HR-PKS) and nonreducing polyketide synthase (NR-PKS), a cytochrome P450 and a regulator, was identified. Although talapolyester G does not require an oxidative step for its biosynthesis, further investigation into the secondary metabolite production of T. stipitatus resulted in isolating two new metabolites called talarodioxadione and talarooxime, in addition to three known compounds, namely 6-hydroxymellein, 15G256α and transtorine that have never been reported from this organism. Interestingly, the biosynthesis of the cyclic polyester 15G256α requires hydroxylation of an inactive methyl group and thus could be a product of the identified gene cluster. The two compounds, talarooxime and transtorine, are probably the catabolic metabolites of tryptophan through the kynurenine pathway. Tryptophan metabolism exists in almost all organisms and has been of interest to many researchers. The biosynthesis of the new oxime is proposed to involve two subsequent N-hydroxylation of 2-aminoacetophenone.


Assuntos
Policetídeos , Talaromyces , Família Multigênica , Poliésteres , Policetídeo Sintases/metabolismo , Policetídeos/metabolismo , Talaromyces/genética , Talaromyces/metabolismo , Triptofano/genética
11.
Cells ; 11(15)2022 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-35892580

RESUMO

Amino acids and their metabolites are key regulators of immune responses, and plasma levels may change profoundly during acute disease states. Using targeted metabolomics, we evaluated concentration changes in plasma amino acids and related metabolites in community-acquired pneumonia (CAP, n = 29; compared against healthy controls, n = 33) from presentation to hospital through convalescence. We further aimed to identify biomarkers for acute CAP vs. the clinically potentially similar infection-triggered COPD exacerbation (n = 13). Amino acid metabolism was globally dysregulated in both CAP and COPD. Levels of most amino acids were markedly depressed in acute CAP, and total amino acid concentrations on admission were an accurate biomarker for the differentiation from COPD (AUC = 0.93), as were reduced asparagine and threonine levels (both AUC = 0.92). Reduced tryptophan and histidine levels constituted the most accurate biomarkers for acute CAP vs. controls (AUC = 0.96, 0.94). Only kynurenine, symmetric dimethyl arginine, and phenylalanine levels were increased in acute CAP, and the kynurenine/tryptophan ratio correlated best with clinical recovery and resolution of inflammation. Several amino acids did not reach normal levels by the 6-week follow-up. Glutamate levels were reduced on admission but rose during convalescence to 1.7-fold above levels measured in healthy control. Our data suggest that dysregulated amino acid metabolism in CAP partially persists through clinical recovery and that amino acid metabolism constitutes a source of promising biomarkers for CAP. In particular, total amino acids, asparagine, and threonine may constitute plasma biomarker candidates for the differentiation between CAP and infection-triggered COPD exacerbation and, perhaps, the detection of pneumonia in COPD.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Asparagina , Biomarcadores , Infecções Comunitárias Adquiridas/diagnóstico , Convalescença , Humanos , Cinurenina , Treonina , Triptofano
12.
Cells ; 11(15)2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35892593

RESUMO

Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. These metabolites play a critical role in maintaining the homeostasis of the gut and systematic immunity and also potentially affect the occurrence and development of diseases such as inflammatory bowel diseases, tumors, obesity and metabolic syndrome, diseases in the nervous system, infectious diseases, vascular inflammation and cardiovascular diseases and hepatic fibrosis. They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4+CD8αα+ regulatory cells, IL-10+ and/or IL-35+B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. These findings have important consequences in the immunotherapy against tumor and other immune-associated diseases. We will summarize here the recent advances in understanding the generation and regulation of tryptophan metabolites in the gut microbiota, the role of gut microbiota-derived tryptophan metabolites in different immune cells, the occurrence and development of diseases and immunotherapy against immune-associated diseases.


Assuntos
Microbioma Gastrointestinal , Microbioma Gastrointestinal/fisiologia , Homeostase , Imunidade Inata , Imunoterapia , Indóis , Cinurenina/metabolismo , Linfócitos/metabolismo , Triptofano/metabolismo
13.
Int J Mol Sci ; 23(14)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35887083

RESUMO

Gut bacteria are closely associated with the development of atopic dermatitis (AD) due to their immunoregulatory function. Indole derivatives, produced by gut bacteria metabolizing tryptophan, are ligands to activate the aryl hydrocarbon receptor (AHR), which plays a critical role in attenuating AD symptoms. Limosilactobacillus reuteri, a producer of indole derivatives, regulates mucosal immunity via activating the AHR signaling pathway. However, the effective substance and mechanism of L. reuteri in the amelioration of AD remain to be elucidated. In this research, we found that L. reuteri DYNDL22M62 significantly improved AD-like symptoms in mice by suppressing IgE levels and the expressions of thymic stromal lymphopoietin (TSLP), IL-4, and IL-5. L. reuteri DYNDL22M62 induced an increase in the production of indole lactic acid (ILA) and indole propionic acid (IPA) via targeted tryptophan metabolic analysis and the expression of AHR in mice. Furthermore, L. reuteri DYNDL22M62 increased the proportions of Romboutsia and Ruminococcaceae NK4A214 group, which were positively related to ILA, but decreased Dubosiella, which was negatively related to IPA. Collectively, L. reuteri DYNDL22M62 with the role of modulating gut bacteria and the production of indole derivatives may attenuate AD via activating AHR in mice.


Assuntos
Dermatite Atópica , Lactobacillus reuteri , Animais , Bactérias/metabolismo , Dermatite Atópica/metabolismo , Indóis/metabolismo , Indóis/farmacologia , Lactobacillus reuteri/metabolismo , Camundongos , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo
14.
Int J Mol Sci ; 23(14)2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35887324

RESUMO

Radiation-induced thrombocytopenia is a common and life-threatening side effect of ionizing radiation (IR) therapy. However, the underlying pathological mechanisms remain unclear. In the present study, irradiation was demonstrated to significantly reduce platelet levels, inhibit megakaryocyte differentiation, and promote the apoptosis of bone marrow (BM) cells. A metabolomics approach and a UHPLC-QTOF MS system were subsequently employed for the comprehensive analysis of serum metabolic profiles of normal and irradiated mice. A total of 66 metabolites were significantly altered, of which 56 were up-regulated and 10 were down-regulated in irradiated mice compared to normal mice on day 11 after irradiation. Pathway analysis revealed that disorders in glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, sphingolipid metabolism, inositol phosphate metabolism, and tryptophan metabolism were involved in radiation-induced thrombocytopenia. In addition, three important differential metabolites, namely L-tryptophan, LysoPC (17:0), and D-sphinganine, which were up-regulated in irradiated mice, significantly induced the apoptosis of K562 cells. L-tryptophan inhibited megakaryocyte differentiation of K562 cells. Finally, serum metabolomics was performed on day 30 (i.e., when the platelet levels in irradiated mice recovered to normal levels). The contents of L-tryptophan, LysoPC (17:0), and D-sphinganine in normal and irradiated mice did not significantly differ on day 30 after irradiation. In conclusion, radiation can cause metabolic disorders, which are highly correlated with the apoptosis of hematopoietic cells and inhibition of megakaryocyte differentiation, ultimately resulting in thrombocytopenia. Further, the metabolites, L-tryptophan, LysoPC (17:0), and D-sphinganine can serve as biomarkers for radiation-induced thrombocytopenia.


Assuntos
Trombocitopenia , Triptofano , Animais , Biomarcadores , Cromatografia Líquida de Alta Pressão/métodos , Metaboloma , Metabolômica/métodos , Camundongos , Trombocitopenia/etiologia
15.
BMC Infect Dis ; 22(1): 615, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840908

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both induce indoleamine-2,3-dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of this study was to systematically review and meta-analyze the status of the TRYCAT pathway, including the levels of TRP and kynurenine (KYN) and the activity of IDO, as measured by the ratio of KYN/TRP. METHODS: This systematic review searched PubMed, Google Scholar, and Web of Sciences and included 14 articles that compared TRP and tryptophan catabolites (TRYCATs) in COVID-19 patients versus non-COVID-19 controls, as well as severe/critical versus mild/moderate COVID-19. The analysis was done on a total of 1269 people, including 794 COVID-19 patients and 475 controls. RESULTS: The results show a significant (p < 0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD = 1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD = 1.123, 95% CI: 0.730; 1.516) and significantly lower TRP (SMD = - 1.002, 95%CI: - 1.738; - 0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD = 0.945, 95%CI: 0.629; 1.262) and KYN (SMD = 0.806, 95%CI: 0.462; 1.149) were also significantly (p < 0.0001) higher and TRP lower (SMD = - 0.909, 95% CI: - 1.569; - 0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in kynurenic acid (KA) and the KA/KYN ratio between COVID-19 patients and controls. CONCLUSIONS: Our results indicate increased activity of the IDO enzyme in COVID-19 and severe/critical patients. The TRYCAT pathway is implicated in the pathophysiology and progression of COVID-19 and may signal a worsening outcome of the disease.


Assuntos
COVID-19 , Cinurenina , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Triptofano/metabolismo
16.
BMC Cancer ; 22(1): 764, 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831824

RESUMO

The tumor microenvironment is a dynamic cellular milieu that interacts with cancer cells and promotes tumor progression and metastasis. However, the specific mechanisms by which the tumor microenvironment impacts cancer cells' behaviors remain poorly understood. In this study, enriched cancer-associated fibroblasts (CAFs) were observed in tumor tissues isolated from epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) resistant non-small cell lung cancer (NSCLC) patients. CAFs isolated from tumor tissues were capable of producing tryptophan metabolite kynurenine (Kyn), which significantly increased the proliferation and EGFR TKIs resistance of NSCLC cells. In this study, it was further observed that the activation of tryptophan 2,3-dioxygenase (TDO) in CAFs, resulted in the enhanced capability of tryptophan metabolism in them compared to normal fibroblasts. As a result, Kyn produced by CAFs facilitated the up-regulation of Aryl Hydrocarbon Receptor (AhR) signals in NSCLC, thereby resulting in the downstream ATK and ERK signaling pathways activation. Finally, inhibition of AhR signals efficiently prevented tumor growth and development of EGFR TKIs resistance, eventually improved the outcome of EGFR TKIs, and described a promising therapeutic strategy for NSCLC.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Hidrocarboneto Arílico , Triptofano , Microambiente Tumoral
17.
J Am Chem Soc ; 144(28): 12884-12892, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35796759

RESUMO

By combining UV transient absorption spectroscopy with sub-30-fs temporal resolution and CASPT2/MM calculations, we present a complete description of the primary photoinduced processes in solvated tryptophan. Our results shed new light on the role of the solvent in the relaxation dynamics of tryptophan. We unveil two consecutive coherent population transfer events involving the lowest two singlet excited states: a sub-50-fs nonadiabatic La → Lb transfer through a conical intersection and a subsequent 220 fs reverse Lb → La transfer due to solvent-assisted adiabatic stabilization of the La state. Vibrational fingerprints in the transient absorption spectra provide compelling evidence of a vibronic coherence established between the two excited states from the earliest times after photoexcitation and lasting until the back-transfer to La is complete. The demonstration of response to the environment as a driver of coherent population dynamics among the excited states of tryptophan closes the long debate on its solvent-assisted relaxation mechanisms and extends its application as a local probe of protein dynamics to the ultrafast time scales.


Assuntos
Triptofano , Vibração , Solventes/química
18.
Microb Cell Fact ; 21(1): 146, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35843946

RESUMO

BACKGROUND: Cyclic dipeptides are an important class of natural products owing to their structural diversity and biological activities. In fungi, the cyclo-ring system is formed through the condensation of two α-amino acids via non-ribosomal peptide synthetase (NRPS). However, there are few investigations on the functional identification of this enzyme. Additionally, information on how to increase the production of cyclic dipeptide molecules is relatively scarce. RESULTS: We isolated the Eurotium cristatum NWAFU-1 fungus from Jing-Wei Fu brick tea, whose fermentation metabolites contain echinulin-related cyclic dipeptide molecules. We cloned the cirC gene, encoding an NRPS, from E. Cristatum NWAFU-1 and transferred it into the heterologous host Aspergillus oryzae. This transformant produced a novel metabolite possessing an L-tryptophan-L-alanine cyclic dipeptide backbone (Cyclo-TA). Based on the results of heterologous expression and microsomal catalysis, CriC is the first NRPS characterized in fungi that catalyzes the formation of a cyclic dipeptide from L-tryptophan and L-alanine. After substrate feeding, the final yield reached 34 mg/L. In this study, we have characterized a novel NRPS and developed a new method for cyclic dipeptide production. CONCLUSIONS: In this study we successfully expressed the E. Cristatum NWAFU-1 criC gene in A. oryzae to efficiently produce cyclic dipeptide compounds. Our findings indicate that the A. oryzae heterologous expression system constitutes an efficient method for the biosynthesis of fungal Cyclic dipeptides.


Assuntos
Aspergillus oryzae , Alanina/metabolismo , Aspergillus oryzae/genética , Aspergillus oryzae/metabolismo , Dipeptídeos/metabolismo , Triptofano/metabolismo
19.
Front Immunol ; 13: 925558, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844615

RESUMO

Background: metabolic changes through SARS-CoV-2 infection has been reported but not fully comprehended. This metabolic dysregulation affects multiple organs during COVID-19 and its early detection can be used as a prognosis marker of severity. Therefore, we aimed to characterize metabolic and cytokine profile at COVID-19 onset and its relationship with disease severity to identify metabolic profiles predicting disease progression. Material and Methods: we performed a retrospective cross-sectional study in 123 COVID-19 patients which were stratified as asymptomatic/mild, moderate and severe according to the highest COVID-19 severity status, and a group of healthy controls. We performed an untargeted plasma metabolic profiling (gas chromatography and capillary electrophoresis-mass spectrometry (GC and CE-MS)) and cytokine evaluation. Results: After data filtering and identification we observed 105 metabolites dysregulated (66 GC-MS and 40 CE-MS) which shown different expression patterns for each COVID-19 severity status. These metabolites belonged to different metabolic pathways including amino acid, energy, and nitrogen metabolism among others. Severity-specific metabolic dysregulation was observed, as an increased transformation of L-tryptophan into L-kynurenine. Thus, metabolic profiling at hospital admission differentiate between severe and moderate patients in the later phase of worse evolution. Several plasma pro-inflammatory biomarkers showed significant correlation with deregulated metabolites, specially with L-kynurenine and L-tryptophan. Finally, we describe a strong sex-related dysregulation of metabolites, cytokines and chemokines between severe and moderate patients. In conclusion, metabolic profiling of COVID-19 patients at disease onset is a powerful tool to unravel the SARS-CoV-2 molecular pathogenesis. Conclusions: This technique makes it possible to identify metabolic phenoconversion that predicts disease progression and explains the pronounced pathogenesis differences between sexes.


Assuntos
COVID-19 , Estudos Transversais , Citocinas , Progressão da Doença , Feminino , Humanos , Cinurenina , Masculino , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Triptofano/metabolismo
20.
Front Immunol ; 13: 908015, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35903106

RESUMO

With the increased demand for safe and sustainable alternatives to growth promoting antibiotics in the livestock industry, oregano essential oils (OEO) and Lactobacillus reuteri (LR) have been examined as alternatives to antibiotics for growth promotion and to improve animal health and performance. However, the mechanism underlying the OEO and LR mediation of sheep growth remains unknown. In this study, 16S rRNA gene sequencing and untargeted metabolomics were used to determine the role of the gut microbiota in the growth improvements observed. The potential modulating roles of intestinal microbial metabolites of OEO and LR to intestinal health were systematically explored as well. It was observed that both OEO and LR had greater average daily gain (ADG) and lower F/G ratio. Furthermore, OEO also appeared to have produced a greater amylase enzyme activity and mucin gene expression in the jejunal mucosa. It was also observed that OEO reduced serum IL-2 and TNF-ß as well as mRNA levels of NF-κB p65, toll-like receptor-4 (TLR-4), and IL-6 in the jejunal mucosa. Moreover, dietary OEO supplementation increased the abundances of Ruminococcus, Bifidobacterium and Enterococcus, while the relative abundances of Succiniclasticum, Marvinbryantia and Streptococcus were enriched in LR group. Spearman's correlation analysis revealed that the abundances of Bifidobacterium, Ruminococcus and Enterococcus were positively correlated with the mRNA expression of mucins. Moreover, the relative abundance of Enterococcus was positively correlated with amylase activity. Metabolomics analysis indicated that OEO and LR increased the levels of indole acetaldehyde and indole-3-acetic acid through the tryptophan metabolism pathway. It was observed that LR also decreased the inflammatory metabolites including tryptamine and 5-hydroxyindole-3-acetic acid. Collectively, these results suggested that OEO exerted a beneficial effect on growth performance and the mucosal barrier, affected tryptophan metabolism and improved the intestinal microbiota of sheep.


Assuntos
Microbioma Gastrointestinal , Lactobacillus reuteri , Óleos Voláteis , Origanum , Amilases , Ração Animal/análise , Animais , Antibacterianos , Óleos Voláteis/farmacologia , RNA Mensageiro , RNA Ribossômico 16S/genética , Ovinos , Triptofano
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA