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1.
Aquat Toxicol ; 271: 106940, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38728927

RESUMO

Aminomethylphosphonic acid (AMPA) is the main metabolite in the degradation of glyphosate, a broad-spectrum herbicide, and it is more toxic and persistent in the environment than the glyphosate itself. Owing to their extensive use, both chemicals pose a serious risk to aquatic ecosystems. Here, we explored the genotoxicological and physiological effects of glyphosate, AMPA, and the mixed solution in the proportion 1:1 in Lymnaea stagnalis, a freshwater gastropod snail. To do this, adult individuals were exposed to increasing nominal concentrations (0.0125, 0.025, 0.050, 0.100, 0.250, 0.500 µg/mL) in all three treatments once a week for four weeks. The genotoxicological effects were estimated as genomic damage, as defined by the number of micronuclei and nuclear buds observed in hemocytes, while the physiological effects were estimated as the effects on somatic growth and egg production. Exposure to glyphosate, AMPA, and the mixed solution caused genomic damage, as measured in increased frequency of micronuclei and nuclear buds and in adverse effects on somatic growth and egg production. Our findings suggest the need for more research into the harmful and synergistic effects of glyphosate and AMPA and of pesticides and their metabolites in general.


Assuntos
Glicina , Glifosato , Herbicidas , Lymnaea , Organofosfonatos , Poluentes Químicos da Água , Animais , Glicina/análogos & derivados , Glicina/toxicidade , Lymnaea/efeitos dos fármacos , Lymnaea/genética , Poluentes Químicos da Água/toxicidade , Organofosfonatos/toxicidade , Herbicidas/toxicidade , Testes para Micronúcleos , Dano ao DNA/efeitos dos fármacos , Hemócitos/efeitos dos fármacos , Tetrazóis/toxicidade
2.
Chemosphere ; 358: 142219, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38704040

RESUMO

The worldwide used herbicide Glyphosate can interact with environmental variables, but there is limited information on the influence of environmental stressors on its toxicity. Environmental changes could modify glyphosate effects on non-target organisms, including parasites such as gordiids. The freshwater microscopic larvae of the gordiid Chordodes nobilii are sensitive to several pollutants and environmental variables, but their combined effect has not been evaluated yet. The aim of this study was to evaluate the impact of temperature, pH and exposure time on the toxicity of Glyphosate to C. nobilii larvae. A protocol was followed to evaluate the infectivity of larvae treated with factorial combinations of concentration (0 and 0.067 mg/L), exposure time (24 and 48 h), temperature (18, 23 and 28 °C), and pH (7, 8 and 9). The reference values were 23 °C, pH 8 and 48 h. The interaction effect on the infectivity of gordiid larvae was assessed post-exposure using Aedes aegyptii larvae as host. Results were evaluated using GLMM, which does not require data transformation. The modeling results revealed three highly significant triple interactions. Glyphosate toxicity varied depending on the combination of variables, with a decrease being observed after 24 h-exposure at pH 7 and 23 °C. Glyphosate and 28 °C combination led to slightly reduced infectivity compared to temperature alone. This study is the first to report the combined effects of glyphosate, temperature, pH and time on a freshwater animal. It demonstrates that a specific combination of factors determines the effect of glyphosate on a non-target organism. The potential use of C. nobilli as a bioindicator is discussed. In the context of global warming and considering that the behavioral manipulation of terrestrial hosts by gordiids can shape community structure and the energy flow through food webs, our results raise concerns about possible negative effects of climate change on host-parasite dynamics.


Assuntos
Glicina , Glifosato , Herbicidas , Larva , Temperatura , Glicina/análogos & derivados , Glicina/toxicidade , Animais , Herbicidas/toxicidade , Larva/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Concentração de Íons de Hidrogênio , Helmintos/efeitos dos fármacos , Helmintos/fisiologia , Aedes/efeitos dos fármacos , Parasitos/efeitos dos fármacos
3.
J Environ Manage ; 359: 121046, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38728981

RESUMO

The increasing concern over pesticide pollution in water bodies underscores the need for effective mitigation strategies to support the transition towards sustainable agriculture. This study assesses the effectiveness of landscape mitigation strategies, specifically vegetative buffer strips, in reducing glyphosate loads at the catchment scale under realistic conditions. Conducted over six years (2014-2019) in a small agricultural region in Belgium, our research involved the analysis of 732 water samples from two monitoring stations, differentiated by baseflow and event-driven sampling, and before (baseline) and after the implementation of mitigation measures. The results indicated a decline in both the number and intensity of point source losses over the years. Additionally, there was a general decrease in load intensity; however, the confluence of varying weather conditions (notably dry years during the mitigation period) and management practices (the introduction of buffer strips) posed challenges for a statistically robust evaluation of each contributing factor. A reduction of loads was measured when comparing mitigation with baseline, although this reduction is not statistically significant. Glyphosate loads during rainfall events correlated with a rainfall index and runoff ratio. Overall, focusing the mitigation strategy on runoff and erosion was a valid approach. Nevertheless, challenges remain, as evidenced by the continuous presence of glyphosate in baseflow conditions, highlighting the complex dynamics of pesticide transport. The study concludes that while progress has been made towards reducing pesticide pollution, the complexity of interacting factors necessitates further research. Future directions should focus on enhancing farmer engagement in mitigation programs and developing experiments with more intense data collection that help to assess underlying dynamics of pesticide pollution and the impact of mitigation strategies in more detail, contributing towards the goal of reducing pesticide pollution in water bodies.


Assuntos
Agricultura , Glifosato , Bélgica , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Glicina/análogos & derivados , Glicina/análise , Praguicidas/análise
4.
Nat Commun ; 15(1): 3797, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714656

RESUMO

Nucleoporins rich in phenylalanine/glycine (FG) residues form the permeability barrier within the nuclear pore complex and are implicated in several pathological cellular processes, including oncogenic fusion condensates. The self-association of FG-repeat proteins and interactions between FG-repeats play a critical role in these activities by forming hydrogel-like structures. Here we show that mutation of specific FG repeats of Nup98 can strongly decrease the protein's self-association capabilities. We further present a cryo-electron microscopy structure of a Nup98 peptide fibril with higher stability per residue compared with previous Nup98 fibril structures. The high-resolution structure reveals zipper-like hydrophobic patches which contain a GLFG motif and are less compatible for binding to nuclear transport receptors. The identified distinct molecular properties of different regions of the nucleoporin may contribute to spatial variations in the self-association of FG-repeats, potentially influencing transport processes through the nuclear pore.


Assuntos
Microscopia Crioeletrônica , Complexo de Proteínas Formadoras de Poros Nucleares , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/ultraestrutura , Humanos , Mutação , Poro Nuclear/metabolismo , Poro Nuclear/ultraestrutura , Poro Nuclear/química , Glicina/química , Glicina/metabolismo , Fenilalanina/química , Fenilalanina/metabolismo , Sequências Repetitivas de Aminoácidos , Ligação Proteica , Modelos Moleculares , Interações Hidrofóbicas e Hidrofílicas
5.
Zhonghua Xue Ye Xue Za Zhi ; 45(3): 264-270, 2024 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-38716598

RESUMO

Objective: To evaluate the efficacy and safety of roxadustat in patients with refractory non-severe aplastic anemia (NSAA) . Methods: The clinical data of patients with refractory NSAA who had been treated with roxadustat continuously for at least 3 months and followed up for more than 6 months at Peking Union Medical College Hospital from October 2020 to August 2022 were retrospectively collected. The demographic information, clinical data, treatment efficacy, adverse reactions, and outcomes were evaluated, and the factors influencing efficacy were analyzed. Results: A total of 41 patients were included. The male-to-female ratio was 16∶25, and the median age was 52 (18-84) years. The median duration of roxadustat treatment was 5 (3-20) months, and the median follow-up was 15 (6-26) months. Hematologic improvement-erythroid (HI-E) was 12.2%, 29.3%, 46.3%, 43.9%, and 30.3% at 1, 2, 3, 6, and 12 months, respectively. The rate of transfusion independence was 28.5%, 38.1%, and 33.3% at 3, 6, and 12 months, respectively. Hemoglobin returned to normal in some patients after treatment with roxadustat. The incidence of adverse events was 22%, all of which were grade Ⅰ-Ⅱ and recoverable. No factors that could affect HI-E were identified. By the end of follow-up, 45% of the patients relapsed, with a median time to relapse of 7 (3-12) months. No clonal evolution was observed, and one patient died. Conclusion: Roxadustat effectively improved anemia with good tolerance in patients with refractory NSAA.


Assuntos
Anemia Aplástica , Glicina , Isoquinolinas , Humanos , Masculino , Feminino , Anemia Aplástica/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Idoso , Adolescente , Isoquinolinas/uso terapêutico , Isoquinolinas/efeitos adversos , Glicina/análogos & derivados , Glicina/uso terapêutico , Glicina/efeitos adversos , Resultado do Tratamento , Idoso de 80 Anos ou mais , Adulto Jovem
6.
Zhonghua Xue Ye Xue Za Zhi ; 45(3): 290-293, 2024 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-38716602

RESUMO

Myelodysplastic syndromes is a heterogeneous group of myeloid neoplastic disorders originating from hematopoietic stem cells and manifesting as pathological bone marrow hematopoiesis and a high risk of transformation to acute myeloid leukemia. In low-risk patients, the therapeutic goal is to improve hematopoiesis and quality of life. Roxadustat is the world's first oral small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor, which, unlike conventional erythropoietin, corrects anemia through various mechanisms. In this study, we retrospectively analyzed the changes in anemia, iron metabolism, lipids and inflammatory indexes in patients with low-risk myelodysplastic syndromes to evaluate its therapeutic efficacy and safety, and to provide theoretical and practical data for the application of roxadustat in myelodysplastic syndromes.


Assuntos
Anemia , Isoquinolinas , Síndromes Mielodisplásicas , Humanos , Anemia/etiologia , Anemia/tratamento farmacológico , Glicina/análogos & derivados , Glicina/uso terapêutico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/uso terapêutico , Isoquinolinas/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Inibidores de Prolil-Hidrolase/uso terapêutico , Estudos Retrospectivos
7.
Anal Chim Acta ; 1308: 342647, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38740456

RESUMO

BACKGROUND: Presently, glyphosate (Gly) is the most extensively used herbicide globally, Nevertheless, its excessive usage has increased its accumulation in off-target locations, and aroused concerns for food and environmental safety. Commonly used detection methods, such as high-performance liquid chromatography and gas chromatography, have limitations due to expensive instruments, complex pre-processing steps, and inadequate sensitivity. Therefore, a facile, sensitive, and reliable Gly detection method should be developed. RESULTS: A photoelectrochemical (PEC) sensor consisting of a three-dimensional polymer phenylethnylcopper/nitrogen-doped graphene aerogel (PPhECu/3DNGA) electrode coupled with Fe3O4 NPs nanozyme was constructed for sensitive detection of Gly. The microscopic 3D network of electrodes offered fast transfer routes for photo-generated electrons and a large surface area for nanozyme loading, allowing high signal output and analytical sensitivity. Furthermore, the use of peroxidase-mimicking Fe3O4 NPs instead of natural enzyme improved the stability of the sensor against ambient temperature changes. Based on the inhibitory effect of Gly on the catalytic activity Fe3O4 NPs, the protocol achieved Gly detection in the range of 5 × 10-10 to 1 × 10-4 mol L-1. Additionally, feasibility of the detection was confirmed in real agricultural matrix including tea, maize seedlings, maize seeds and soil. SIGNIFICANCE: This work achieved facile, sensitive and reliable analysis towards Gly, and it was expected to inspire the design and utilization of 3D architectures in monitoring agricultural chemicals in food and environmental matrix.


Assuntos
Técnicas Eletroquímicas , Eletrodos , Glicina , Glifosato , Grafite , Nitrogênio , Processos Fotoquímicos , Grafite/química , Glicina/análogos & derivados , Glicina/química , Glicina/análise , Nitrogênio/química , Polímeros/química , Cobre/química , Géis/química , Herbicidas/análise , Limite de Detecção , Nanopartículas de Magnetita/química , Nanopartículas Magnéticas de Óxido de Ferro/química
8.
BMC Cancer ; 24(1): 622, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38778261

RESUMO

BACKGROUND: International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV. METHODS: A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios. RESULTS: Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty. CONCLUSIONS: At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Análise Custo-Benefício , Fluoruracila , Glicina , Isocitrato Desidrogenase , Leucovorina , Mutação , Piridinas , Humanos , Isocitrato Desidrogenase/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Piridinas/uso terapêutico , Piridinas/economia , Taiwan , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Fluoruracila/uso terapêutico , Fluoruracila/economia , Glicina/análogos & derivados , Glicina/uso terapêutico , Glicina/economia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/economia , Leucovorina/uso terapêutico , Leucovorina/economia , Masculino , Feminino , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/economia , Pessoa de Meia-Idade
9.
J Am Chem Soc ; 146(20): 13727-13732, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38728661

RESUMO

Although chemical methods for the selective derivatization of amino acid (AA) side chains in peptides and proteins are available, selective N-terminal labeling is challenging, especially for glycine, which has no side chain at the α-carbon position. We report here a double activation at glycine's α-methylene group that allows this AA to be differentiated from the other 19 AAs. A condensation reaction of dibenzoylmethane with glycine results in the formation of an imine, and subsequent tautomerization is followed by intramolecular cyclization, leading to the formation of a fluorescent pyrrole ring. Additionally, the approach exhibits compatibility with AAs possessing reactive side chains. Further, the method allows for selective pull-down assays of N-terminal glycine peptides from mixtures without prior knowledge of the N-terminal peptide distribution.


Assuntos
Corantes Fluorescentes , Glicina , Peptídeos , Glicina/química , Corantes Fluorescentes/química , Peptídeos/química , Estrutura Molecular
10.
J Am Chem Soc ; 146(20): 13754-13759, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38739748

RESUMO

a-Tertiary amino acids are essential components of drugs and agrochemicals, yet traditional syntheses are step-intensive and provide access to a limited range of structures with varying levels of enantioselectivity. Here, we report the α-alkylation of unprotected alanine and glycine by pyridinium salts using pyridoxal (PLP)-dependent threonine aldolases with a Rose Bengal photoredox catalyst. The strategy efficiently prepares various a-tertiary amino acids in a single chemical step as a single enantiomer. UV-vis spectroscopy studies reveal a ternary interaction between the pyridinium salt, protein, and photocatalyst, which we hypothesize is responsible for localizing radical formation to the active site. This method highlights the opportunity for combining photoredox catalysts with enzymes to reveal new catalytic functions for known enzymes.


Assuntos
Aminoácidos , Aminoácidos/química , Glicina Hidroximetiltransferase/metabolismo , Glicina Hidroximetiltransferase/química , Processos Fotoquímicos , Biocatálise , Catálise , Alquilação , Glicina/química , Glicina/análogos & derivados , Estereoisomerismo , Estrutura Molecular , Oxirredução
11.
Clin Transl Sci ; 17(5): e13829, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38769746

RESUMO

To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non-sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non-sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non-sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4-6), p = 0.008]. The serum levels of d-lactate (p = 0.033), intestinal fatty acid-binding protein (p = 0.005), interleukin-6 (p = 0.001), white blood cells (p = 0.007), C-reactive protein (p = 0.001), and procalcitonin (p < 0.001) of the sivelestat group were lower than those of the non-sivelestat group. The sivelestat group also demonstrated longer ICU-free days [18 (0-22) vs. 13 (0-17), p = 0.004] and ventilator-free days [22 (1-24) vs. 16 (1-19), p = 0.002] compared with the non-sivelestat group. In conclusion, sivelestat sodium administration appears to improve gastrointestinal dysfunction, mitigate dysregulated inflammation, and reduce disease severity in septic patients.


Assuntos
Gastroenteropatias , Glicina , Sepse , Sulfonamidas , Humanos , Sepse/tratamento farmacológico , Sepse/complicações , Sepse/sangue , Masculino , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Pessoa de Meia-Idade , Idoso , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Gastroenteropatias/tratamento farmacológico , Proteínas Secretadas Inibidoras de Proteinases , Biomarcadores/sangue , Resultado do Tratamento
12.
BMC Oral Health ; 24(1): 558, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38741081

RESUMO

BACKGROUND: We investigated the efficacy of two different cold atmospheric pressure jet plasma devices (CAP09 and CAPmed) and an air polishing device with glycine powder (AP) either applied as monotherapies or combined therapies (AP + CAP09; AP + CAPmed), in microbial biofilm removal from discs with anodised titanium surface. METHODS: Discs covered with 7-day-old microbial biofilm were treated either with CAP09, CAPmed, AP, AP + CAP09 or AP + CAPmed and compared with negative and positive controls. Biofilm removal was assessed with flourescence and electron microscopy immediately after treatment and after 5 days of reincubation of the treated discs. RESULTS: Treatment with CAP09 or CAPmed did not lead to an effective biofilm removal, whereas treatment with AP detached the complete biofilm, which however regrew to baseline magnitude after 5 days of reincubation. Both combination therapies (AP + CAP09 and AP + CAPmed) achieved a complete biofilm removal immediately after cleaning. However, biofilm regrew after 5 days on 50% of the discs treated with the combination therapy. CONCLUSION: AP treatment alone can remove gross biofilm immediately from anodised titanium surfaces. However, it did not impede regrowth after 5 days, because microorganisms were probably hidden in holes and troughs, from which they could regrow, and which were inaccessible to AP. The combination of AP and plasma treatment probably removed or inactivated microorganisms also from these hard to access spots. These results were independent of the choice of plasma device.


Assuntos
Biofilmes , Implantes Dentários , Gases em Plasma , Propriedades de Superfície , Titânio , Biofilmes/efeitos dos fármacos , Titânio/química , Implantes Dentários/microbiologia , Polimento Dentário/métodos , Glicina , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Varredura , Níquel
13.
Nature ; 629(8010): 98-104, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38693411

RESUMO

Photobiocatalysis-where light is used to expand the reactivity of an enzyme-has recently emerged as a powerful strategy to develop chemistries that are new to nature. These systems have shown potential in asymmetric radical reactions that have long eluded small-molecule catalysts1. So far, unnatural photobiocatalytic reactions are limited to overall reductive and redox-neutral processes2-9. Here we report photobiocatalytic asymmetric sp3-sp3 oxidative cross-coupling between organoboron reagents and amino acids. This reaction requires the cooperative use of engineered pyridoxal biocatalysts, photoredox catalysts and an oxidizing agent. We repurpose a family of pyridoxal-5'-phosphate-dependent enzymes, threonine aldolases10-12, for the α-C-H functionalization of glycine and α-branched amino acid substrates by a radical mechanism, giving rise to a range of α-tri- and tetrasubstituted non-canonical amino acids 13-15 possessing up to two contiguous stereocentres. Directed evolution of pyridoxal radical enzymes allowed primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents, to be coupled in an enantio- and diastereocontrolled fashion. Cooperative photoredox-pyridoxal biocatalysis provides a platform for sp3-sp3 oxidative coupling16, permitting the stereoselective, intermolecular free-radical transformations that are unknown to chemistry or biology.


Assuntos
Aminoácidos , Biocatálise , Acoplamento Oxidativo , Processos Fotoquímicos , Aminoácidos/biossíntese , Aminoácidos/química , Aminoácidos/metabolismo , Biocatálise/efeitos da radiação , Evolução Molecular Direcionada , Radicais Livres/química , Radicais Livres/metabolismo , Glicina/química , Glicina/metabolismo , Glicina Hidroximetiltransferase/metabolismo , Glicina Hidroximetiltransferase/química , Indicadores e Reagentes , Luz , Acoplamento Oxidativo/efeitos da radiação , Fosfato de Piridoxal/metabolismo , Estereoisomerismo , Aminoácidos de Cadeia Ramificada/química , Aminoácidos de Cadeia Ramificada/metabolismo
14.
Microb Cell Fact ; 23(1): 121, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38725068

RESUMO

BACKGROUND: Mycosporine-like amino acids (MAAs) are a class of strongly UV-absorbing compounds produced by cyanobacteria, algae and corals and are promising candidates for natural sunscreen components. Low MAA yields from natural sources, coupled with difficulties in culturing its native producers, have catalyzed synthetic biology-guided approaches to produce MAAs in tractable microbial hosts like Escherichia coli, Saccharomyces cerevisiae and Corynebacterium glutamicum. However, the MAA titres obtained in these hosts are still low, necessitating a thorough understanding of cellular factors regulating MAA production. RESULTS: To delineate factors that regulate MAA production, we constructed a shinorine (mycosporine-glycine-serine) producing yeast strain by expressing the four MAA biosynthetic enzymes from Nostoc punctiforme in Saccharomyces cerevisiae. We show that shinorine is produced from the pentose phosphate pathway intermediate sedoheptulose 7-phosphate (S7P), and not from the shikimate pathway intermediate 3-dehydroquinate (3DHQ) as previously suggested. Deletions of transaldolase (TAL1) and phosphofructokinase (PFK1/PFK2) genes boosted S7P/shinorine production via independent mechanisms. Unexpectedly, the enhanced S7P/shinorine production in the PFK mutants was not entirely due to increased flux towards the pentose phosphate pathway. We provide multiple lines of evidence in support of a reversed pathway between glycolysis and the non-oxidative pentose phosphate pathway (NOPPP) that boosts S7P/shinorine production in the phosphofructokinase mutant cells. CONCLUSION: Reversing the direction of flux between glycolysis and the NOPPP offers a novel metabolic engineering strategy in Saccharomyces cerevisiae.


Assuntos
Aminoácidos , Glicólise , Via de Pentose Fosfato , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Aminoácidos/metabolismo , Engenharia Metabólica/métodos , Nostoc/metabolismo , Nostoc/genética , Fosfatos Açúcares/metabolismo , Glicina/metabolismo , Glicina/análogos & derivados , Cicloexilaminas
15.
Mikrochim Acta ; 191(6): 319, 2024 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-38727763

RESUMO

The high-residual and bioaccumulation property of organophosphorus pesticides (OPs) creates enormous risks towards the ecological environment and human health, promoting the research for smart adsorbents and detection methods. Herein, 2D hemin-bridged MOF nanozyme (2D-ZHM) was fabricated and applied to the efficient removal and ultrasensitive dual-mode aptasensing of OPs. On the one hand, the prepared 2D-ZHM contained Zr-OH groups with high affinity for phosphate groups, endowing it with selective recognition and high adsorption capacity for OPs (285.7 mg g-1 for glyphosate). On the other hand, the enhanced peroxidase-mimicking biocatalytic property of 2D-ZHM allowed rapid H2O2-directed transformation of 3,3',5,5'-tetramethylbenzidine to oxidic product, producing detectable colorimetric or photothermal signals. Using aptamers of specific recognition capacity, the rapid quantification of two typical OPs, glyphosate and omethoate, was realized with remarkable sensitivity and selectivity. The limit of detections (LODs) of glyphosate were 0.004 nM and 0.02 nM for colorimetric and photothermal methods, respectively, and the LODs of omethoate were 0.005 nM and 0.04 nM for colorimetric and photothermal methods, respectively. The constructed dual-mode aptasensing platform exhibited outstanding performance for monitoring OPs in water and fruit samples. This work provides a novel pathway to develop MOF-based artificial peroxidase and integrated platform for pollutant removal and multi-mode aptasensing.


Assuntos
Glicina , Glifosato , Hemina , Limite de Detecção , Estruturas Metalorgânicas , Praguicidas , Praguicidas/análise , Praguicidas/química , Estruturas Metalorgânicas/química , Hemina/química , Glicina/análogos & derivados , Glicina/química , Glicina/análise , Colorimetria/métodos , Benzidinas/química , Adsorção , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , Peróxido de Hidrogênio/química , Dimetoato/análise , Dimetoato/química , Aptâmeros de Nucleotídeos/química , Compostos Organofosforados/análise , Compostos Organofosforados/química
16.
Sci Rep ; 14(1): 11566, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773199

RESUMO

There is a worrying scarcity of drug options for patients with severe COVID-19. Glycine possesses anti-inflammatory, cytoprotective, endothelium-protective, and platelet-antiaggregant properties, so its use in these patients seems promising. In this open label, controlled clinical trial, inpatients with severe COVID-19 requiring mechanical ventilation randomly received usual care (control group) or usual care plus 0.5 g/kg/day glycine by the enteral route (experimental group). Major outcomes included mortality, time to weaning from mechanical ventilation, total time on mechanical ventilation, and time from study recruitment to death. Secondary outcomes included laboratory tests and serum cytokines. Patients from experimental (n = 33) and control groups (n = 23) did not differ in basal characteristics. There were no differences in mortality (glycine group, 63.6% vs control group, 52.2%, p = 0.60) nor in any other major outcome. Glycine intake was associated with lower fibrinogen levels, either evaluated per week of follow-up (p < 0.05 at weeks 1, 2, and 4) or as weighted mean during the whole hospitalization (608.7 ± 17.7 mg/dl vs control 712.2 ± 25.0 mg/dl, p = 0.001), but did not modify any other laboratory test or cytokine concentration. In summary, in severe COVID-19 glycine was unable to modify major clinical outcomes, serum cytokines or most laboratory tests, but was associated with lower serum fibrinogen concentration.Registration: ClinicalTrials.gov NCT04443673, 23/06/2020.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Glicina , Respiração Artificial , Humanos , Masculino , Glicina/administração & dosagem , Glicina/uso terapêutico , Feminino , Pessoa de Meia-Idade , Projetos Piloto , Idoso , COVID-19/mortalidade , COVID-19/sangue , COVID-19/terapia , Resultado do Tratamento , SARS-CoV-2 , Fibrinogênio/análise , Fibrinogênio/metabolismo , Citocinas/sangue
17.
Sci Rep ; 14(1): 11567, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773223

RESUMO

The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02-1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Receptor para Produtos Finais de Glicação Avançada , Humanos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Predisposição Genética para Doença , Fatores de Risco , Alelos , Glicina/sangue , Doença das Coronárias/genética , Doença das Coronárias/sangue
18.
Cell Death Dis ; 15(5): 319, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710705

RESUMO

Argininosuccinate synthase (ASS1), a critical enzyme in the urea cycle, acts as a tumor suppressor in many cancers. To date, the anticancer mechanism of ASS1 has not been fully elucidated. Here, we found that phosphoglycerate dehydrogenase (PHGDH), a key rate-limiting enzyme in serine synthesis, is a pivotal protein that interacts with ASS1. Our results showed that ASS1 directly binds to PHGDH and promotes its ubiquitination-mediated degradation to inhibit serine synthesis, consequently suppressing tumorigenesis. Importantly, the tumor suppressive effects of ASS1 were strongly abrogated by PHGDH knockout. In addition, ASS1 knockout and knockdown partially rescued cell proliferation when serine and glycine were depleted, while the inhibitory effect of ASS1 overexpression on cell proliferation was restored by the addition of serine and glycine. These findings unveil a novel role of ASS1 and suggest that the ASS1/PHGDH serine synthesis pathway is a promising target for cancer therapy.


Assuntos
Argininossuccinato Sintase , Proliferação de Células , Fosfoglicerato Desidrogenase , Serina , Neoplasias de Mama Triplo Negativas , Fosfoglicerato Desidrogenase/metabolismo , Fosfoglicerato Desidrogenase/genética , Serina/metabolismo , Serina/biossíntese , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Animais , Argininossuccinato Sintase/metabolismo , Argininossuccinato Sintase/genética , Linhagem Celular Tumoral , Camundongos Nus , Ubiquitinação , Camundongos , Glicina/metabolismo
19.
Chemosphere ; 358: 142058, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38642777

RESUMO

Glyphosate (GLY) is a widely used broad-spectrum herbicide, and ivermectin (IVM) is a commonly used antiparasitic in livestock farming. Both substances can be found in water bodies from agricultural areas and can have negative impacts on ecosystems. The aim of this study was to evaluate the lethal and sublethal toxicity individually and in combination of a glyphosate-based herbicide (GBH) and an ivermectin commercial formulation (ICF). Groups of 10 larvae were exposed for 504 h, in triplicate to a concentration gradient of the commercial formulation of glyphosate and ivermectin, individually, and to a series of dilutions of a non-equitoxic mixture of both compounds based on environmental concentrations. Additionally, biomarkers of oxidative stress (catalase, glutathione S-transferase, and reduced glutathione) and neurotoxicity (acetylcholinesterase and butyrylcholinesterase) were evaluated at sublethal and environmental concentrations of ivermectin (0.00125 mg/L) and glyphosate (0.7 mg/L) individually and in mixture. The ICF (LC50-504h: 0.047 mg ai IVM/L) was more toxic to larvae than the GBH (LC50-504h: 24.73 mg ae GLY/L). In terms of lethality, exposure to the mixture was synergistic at all exposure times. Both compounds separately caused alterations in the biomarkers of oxidative stress and neurotoxicity. Regarding sublethal effects in organisms exposed to the mixture, potentiation was observed in acetylcholinesterase. The simultaneous exposure to both substances in water bodies can have synergistic and negative effects on aquatic organisms.


Assuntos
Glicina , Glifosato , Herbicidas , Ivermectina , Larva , Estresse Oxidativo , Poluentes Químicos da Água , Ivermectina/análogos & derivados , Ivermectina/toxicidade , Animais , Glicina/análogos & derivados , Glicina/toxicidade , Larva/efeitos dos fármacos , Herbicidas/toxicidade , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Sinergismo Farmacológico , Acetilcolinesterase/metabolismo , Praguicidas/toxicidade , Biomarcadores/metabolismo
20.
Int J Biol Macromol ; 267(Pt 1): 131407, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38582463

RESUMO

Succinate dehydrogenase (SDH) is an important inner mitochondrial membrane-bound enzyme involved in redox reactions during the tricarboxylic acid cycle. Therefore, a series of novel chitosan derivatives were designed and synthesized as potential microbicides targeting SDH and precisely characterized by FTIR, 1H NMR and SEM. Their antifungal and antibacterial activities were evaluated against Botrytis cinerea, Fusarium graminearum, Staphylococcus aureus and Escherichia coli. The bioassays revealed that these chitosan derivatives exerted significant antifungal effects, with four of the compounds achieving 100 % inhibition of Fusarium graminearum merely at a concentration of 0.5 mg/mL. Additionally, CSGDCH showed 79.34 % inhibition of Botrytis cinerea at a concentration of 0.1 mg/mL. In vitro antibacterial tests revealed that CSGDCH and CSGDBH have excellent Staphylococcus aureus and Escherichia coli inhibition with MICs of 0.0156 mg/mL and 0.03125 mg/mL, respectively. Molecular docking studies have been carried out to explore the binding energy and binding mode of chitosan and chitosan derivatives with SDH. The analyses indicated that chitosan derivatives targeted the active site of the SDH protein more precisely, disrupting its normal function and ultimately repressing the growth of microbial cells. Furthermore, the chitosan derivatives were also evaluated biologically for antioxidation, and all of these compounds had a greater degree of reducing power, superoxide radical, hydroxyl radical and DPPH-radical scavenging activity than chitosan. This research has the potential for the development of agricultural antimicrobial agents.


Assuntos
Antioxidantes , Quitosana , Inibidores Enzimáticos , Simulação de Acoplamento Molecular , Bases de Schiff , Succinato Desidrogenase , Quitosana/química , Quitosana/farmacologia , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo , Succinato Desidrogenase/química , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Glicina/química , Glicina/análogos & derivados , Glicina/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Staphylococcus aureus/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Escherichia coli/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/síntese química , Fusarium/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Técnicas de Química Sintética
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