Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 136
Filtrar
Mais filtros

País/Região como assunto
Intervalo de ano de publicação
1.
Nucleic Acids Res ; 2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39417423

RESUMO

PIF1 is a conserved helicase and G4 DNA binding and unwinding enzyme, with roles in genome stability. Human PIF1 (hPIF1) is poorly understood, but its functions can become critical for tumour cell survival during oncogene-driven replication stress. Here we report the discovery, via an X-ray crystallographic fragment screen (XChem), of hPIF1 DNA binding and unwinding inhibitors. A structure was obtained with a 4-phenylthiazol-2-amine fragment bound in a pocket between helicase domains 2A and 2B, with additional contacts to Valine 258 from domain 1A. The compound makes specific interactions, notably through Leucine 548 and Alanine 551, that constrain conformational adjustments between domains 2A and 2B, previously linked to ATP hydrolysis and DNA unwinding. We next synthesized a range of related compounds and characterized their effects on hPIF1 DNA-binding and helicase activity in vitro, expanding the structure activity relationship (SAR) around the initial hit. A systematic analysis of clinical cancer databases is also presented here, supporting the notion that hPIF1 upregulation may represent a specific cancer cell vulnerability. The research demonstrates that hPIF1 is a tractable target through 4-phenylthiazol-2-amine derivatives as inhibitors of its helicase action, setting a foundation for creation of a novel class of anti-cancer therapeutics.

2.
Nucleic Acids Res ; 51(10): 5255-5270, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37115000

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to evade the immune system. NendoU is a promising target for the development of new antiviral drugs. However, the complexity of the enzyme's structure and kinetics, along with the broad range of recognition sequences and lack of structural complexes, hampers the development of inhibitors. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of manganese on enzymatic activity. Through combining cryo-electron microscopy at different pHs, X-ray crystallography and biochemical and structural analysis, we showed that NendoU can shift between open and closed forms, which probably correspond to active and inactive states, respectively. We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. Overall, our findings provide insights into the complex structure and function of NendoU and offer new opportunities for the development of inhibitors.


Assuntos
SARS-CoV-2 , Humanos , Regulação Alostérica , Sequência de Aminoácidos , COVID-19 , Microscopia Crioeletrônica , Endorribonucleases/metabolismo , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/química
3.
J Toxicol Environ Health A ; 85(7): 276-290, 2022 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-34789080

RESUMO

Brazilian plant biodiversity is a rich alternative source of bioactive compounds since plant-derived extracts and/or their secondary metabolites exhibit potential properties to treat several diseases. In this context, Licania rigida Benth (Chrysobalanaceae Family), a large evergreen tree distributed in Brazilian semi-arid regions, deserves attention for its widespread use in popular medicine, although its biological properties are still poorly studied. The aim of this study was to examine (1) acute and sub-chronic oral toxicity at 2000 mg/kg dose; (2) in vitro cytotoxicity at 0.1; 1; 10; 100 or 1000 µg/ml; (3) in vivo mutagenicity at 5, 10 or 20 mg/ml, and (4) potential antioxidant protective effect of L. rigida aqueous leaf extract of (AELr). No marked apparent toxic and genotoxic effects were observed using in vitro and in vivo assays after in vitro treatment of Chinese hamster ovary cell line (CHO-K1) with AELr or in vivo exposure of Wistar rats and Drosophila melanogaster to different extract concentrations. Concerning the antioxidant effect, the extract exhibited a protective effect by decreasing lipid peroxidation as determined by malondialdehyde levels. No significant changes were observed for glutathione (GSH) levels and activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Data demonstrate the beneficial potential of AELr to be employed for therapeutic purposes. However, further studies are required to validate the pharmacological application of this plant extract to develop as a phytotherapeutic formulation.


Assuntos
Chrysobalanaceae/química , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Animais , Brasil , Células CHO , Cricetulus , Drosophila melanogaster , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Plantas Medicinais/toxicidade , Ratos Wistar
4.
Biochem J ; 478(19): 3655-3670, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34529035

RESUMO

Several Schistosoma species cause Schistosomiasis, an endemic disease in 78 countries that is ranked second amongst the parasitic diseases in terms of its socioeconomic impact and human health importance. The drug recommended for treatment by the WHO is praziquantel (PZQ), but there are concerns associated with PZQ, such as the lack of information about its exact mechanism of action, its high price, its effectiveness - which is limited to the parasite's adult form - and reports of resistance. The parasites lack the de novo purine pathway, rendering them dependent on the purine salvage pathway or host purine bases for nucleotide synthesis. Thus, the Schistosoma purine salvage pathway is an attractive target for the development of necessary and selective new drugs. In this study, the purine nucleotide phosphorylase II (PNP2), a new isoform of PNP1, was submitted to a high-throughput fragment-based hit discovery using a crystallographic screening strategy. PNP2 was crystallized and crystals were soaked with 827 fragments, a subset of the Maybridge 1000 library. X-ray diffraction data was collected and structures were solved. Out of 827-screened fragments we have obtained a total of 19 fragments that show binding to PNP2. Fourteen of these fragments bind to the active site of PNP2, while five were observed in three other sites. Here we present the first fragment screening against PNP2.


Assuntos
Descoberta de Drogas/métodos , Purina-Núcleosídeo Fosforilase/química , Purina-Núcleosídeo Fosforilase/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismo , Schistosoma mansoni/enzimologia , Tiazóis/metabolismo , Animais , Domínio Catalítico , Cristalização , Cristalografia por Raios X/métodos , Dimetil Sulfóxido/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Moleculares , Conformação Proteica em alfa-Hélice , Purina-Núcleosídeo Fosforilase/genética , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia
5.
J Struct Biol ; 207(1): 67-73, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009756

RESUMO

Septins are GTP-binding proteins that will often spontaneously assemble into filaments. In some species, particularly budding yeast, it is well known that these are capable of associating with membranes in order to fulfill their cellular role as a component of the cytoskeleton. Different from other human septins, SEPT7 appears to be unique in that it is an essential component of all hetero-oligomeric complexes described to date. As a step towards understanding the molecular basis of filament assembly, here we present two high-resolution structures of the SEPT7 GTPase domain complexed with GDP. One of these reveals a previously unreported coordination for the magnesium ion involving four water molecules and only a tenuous connection to the protein. The higher resolution structures provide unambiguous insight into the interactions at the G-interface where a structural motif based on an antiparallel ß-bridge allows for the rationalization of why some septins show nucleotide-dependent ß-strand slippage and others do not.


Assuntos
Proteínas de Ciclo Celular/química , Proteínas de Ligação ao GTP/química , Septinas/química , Sítios de Ligação , Cristalografia por Raios X , GTP Fosfo-Hidrolases/metabolismo , Guanosina Difosfato/metabolismo , Humanos , Manganês/química , Conformação Proteica em Folha beta , Domínios Proteicos , Água/química
6.
J Biol Chem ; 293(7): 2534-2545, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29237730

RESUMO

Nicotinic acetylcholine receptors (nAChRs) belong to the family of pentameric ligand-gated ion channels and mediate fast excitatory transmission in the central and peripheral nervous systems. Among the different existing receptor subtypes, the homomeric α7 nAChR has attracted considerable attention because of its possible implication in several neurological and psychiatric disorders, including cognitive decline associated with Alzheimer's disease or schizophrenia. Allosteric modulators of ligand-gated ion channels are of particular interest as therapeutic agents, as they modulate receptor activity without affecting normal fluctuations of synaptic neurotransmitter release. Here, we used X-ray crystallography and surface plasmon resonance spectroscopy of α7-acetylcholine-binding protein (AChBP), a humanized chimera of a snail AChBP, which has 71% sequence similarity with the extracellular ligand-binding domain of the human α7 nAChR, to investigate the structural determinants of allosteric modulation. We extended previous observations that an allosteric site located in the vestibule of the receptor offers an attractive target for receptor modulation. We introduced seven additional humanizing mutations in the vestibule-located binding site of AChBP to improve its suitability as a model for studying allosteric binding. Using a fragment-based screening approach, we uncovered an allosteric binding site located near the ß8-ß9 loop, which critically contributes to coupling ligand binding to channel opening in human α7 nAChR. This work expands our understanding of the topology of allosteric binding sites in AChBP and, by extrapolation, in the human α7 nAChR as determined by electrophysiology measurements. Our insights pave the way for drug design strategies targeting nAChRs involved in ion channel-mediated disorders.


Assuntos
Acetilcolina/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/química , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Acetilcolina/química , Regulação Alostérica , Sítio Alostérico , Animais , Cristalografia por Raios X , Humanos , Modelos Moleculares , Domínios Proteicos , Receptores Nicotínicos/química , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Caramujos , Receptor Nicotínico de Acetilcolina alfa7/genética
7.
J Biol Chem ; 292(38): 15598-15610, 2017 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-28726643

RESUMO

One central goal in molecular evolution is to pinpoint the mechanisms and evolutionary forces that cause an enzyme to change its substrate specificity; however, these processes remain largely unexplored. Using the glycolytic ADP-dependent kinases of archaea, including the orders Thermococcales, Methanosarcinales, and Methanococcales, as a model and employing an approach involving paleoenzymology, evolutionary statistics, and protein structural analysis, we could track changes in substrate specificity during ADP-dependent kinase evolution along with the structural determinants of these changes. To do so, we studied five key resurrected ancestral enzymes as well as their extant counterparts. We found that a major shift in function from a bifunctional ancestor that could phosphorylate either glucose or fructose 6-phosphate (fructose-6-P) as a substrate to a fructose 6-P-specific enzyme was started by a single amino acid substitution resulting in negative selection with a ground-state mode against glucose and a subsequent 1,600-fold change in specificity of the ancestral protein. This change rendered the residual phosphorylation of glucose a promiscuous and physiologically irrelevant activity, highlighting how promiscuity may be an evolutionary vestige of ancestral enzyme activities, which have been eliminated over time. We also could reconstruct the evolutionary history of substrate utilization by using an evolutionary model of discrete binary characters, indicating that substrate uses can be discretely lost or acquired during enzyme evolution. These findings exemplify how negative selection and subtle enzyme changes can lead to major evolutionary shifts in function, which can subsequently generate important adaptive advantages, for example, in improving glycolytic efficiency in Thermococcales.


Assuntos
Complexos de ATP Sintetase/metabolismo , Evolução Molecular , Complexos de ATP Sintetase/química , Complexos de ATP Sintetase/genética , Sequência de Aminoácidos , Euryarchaeota/enzimologia , Frutosefosfatos/metabolismo , Glucose/metabolismo , Cinética , Modelos Moleculares , Mutação , Filogenia , Conformação Proteica , Especificidade por Substrato
8.
J Biol Chem ; 292(26): 10899-10911, 2017 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-28476887

RESUMO

Septins are filament-forming GTP-binding proteins involved in many essential cellular events related to cytoskeletal dynamics and maintenance. Septins can self-assemble into heterocomplexes, which polymerize into highly organized, cell membrane-interacting filaments. The number of septin genes varies among organisms, and although their structure and function have been thoroughly studied in opisthokonts (including animals and fungi), no structural studies have been reported for other organisms. This makes the single septin from Chlamydomonas (CrSEPT) a particularly attractive model for investigating whether functional homopolymeric septin filaments also exist. CrSEPT was detected at the base of the flagella in Chlamydomonas, suggesting that CrSEPT is involved in the formation of a membrane-diffusion barrier. Using transmission electron microscopy, we observed that recombinant CrSEPT forms long filaments with dimensions comparable with those of the canonical structure described for opisthokonts. The GTP-binding domain of CrSEPT purified as a nucleotide-free monomer that hydrolyzes GTP and readily binds its analog guanosine 5'-3-O-(thio)triphosphate. We also found that upon nucleotide binding, CrSEPT formed dimers that were stabilized by an interface involving the ligand (G-interface). Across this interface, one monomer supplied a catalytic arginine to the opposing subunit, greatly accelerating the rate of GTP hydrolysis. This is the first report of an arginine finger observed in a septin and suggests that CrSEPT may act as its own GTP-activating protein. The finger is conserved in all algal septin sequences, suggesting a possible correlation between the ability to form homopolymeric filaments and the accelerated rate of hydrolysis that it provides.


Assuntos
Chlamydomonas reinhardtii/química , Complexos Multiproteicos/química , Proteínas de Plantas/química , Multimerização Proteica , Septinas/química , Chlamydomonas reinhardtii/enzimologia , Chlamydomonas reinhardtii/genética , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Complexos Multiproteicos/ultraestrutura , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Septinas/genética , Septinas/metabolismo
9.
Biochim Biophys Acta ; 1864(12): 1658-1666, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27567706

RESUMO

Citrus canker, caused by bacteria Xanthomonas citri subsp. citri, can affect all economically important varieties of citrus. Studying Xanthomonas genes related to the invasive capacity may improve the knowledge on how this works and ultimately use the information to avoid the disease. Some annotated genes from Xanthomonas citri subsp. citri published genome are addressed to an interesting class of genes named "pathogenicity, virulence and adaptation". One of them is xanA, which encodes a predicted phosphoglucomutase. Phosphoglucomutases are ubiquitous enzymes among the living kingdoms that play roles in carbohydrate metabolism, catalyzing the reversible conversion of 1- to 6-phosphoglucose. In Xanthomonas, phosphoglucomutase activity is required to synthesize precursors of the pathogenesis-related polysaccharide xanthan. In this work, a characterization of this gene product is presented by structural and functional studies. Molecular cloning was used for heterologous expression and deletion of xanA. A Michaelis-Menten kinetics model was obtained using the recombinant protein. The protein structure was also determined by X-ray diffraction on the recombinant enzyme substrate-free, bound to glucose-1,6-biphosphate and to glucose-1-phosphate. Deletion of xanA was done with a suicide plasmid construct and the obtained mutant was tested for pathogenic capacity. This study is the first describing the properties of the Xanthomonas citri subsp. citri phosphoglucomutase.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Fosfoglucomutase/química , Fosfoglucomutase/metabolismo , Xanthomonas/enzimologia , Proteínas de Bactérias/genética , Domínio Catalítico , Citrus/microbiologia , Clonagem Molecular , Cristalografia por Raios X , Genes Bacterianos , Cinética , Modelos Moleculares , Mutação , Fosfoglucomutase/genética , Doenças das Plantas/microbiologia , Polissacarídeos Bacterianos/biossíntese , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Virulência/genética , Xanthomonas/genética , Xanthomonas/patogenicidade
10.
J Biol Chem ; 289(11): 7799-811, 2014 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-24464615

RESUMO

Septins are filament-forming GTP-binding proteins involved in important cellular events, such as cytokinesis, barrier formation, and membrane remodeling. Here, we present two crystal structures of the GTPase domain of a Schistosoma mansoni septin (SmSEPT10), one bound to GDP and the other to GTP. The structures have been solved at an unprecedented resolution for septins (1.93 and 2.1 Å, respectively), which has allowed for unambiguous structural assignment of regions previously poorly defined. Consequently, we provide a reliable model for functional interpretation and a solid foundation for future structural studies. Upon comparing the two complexes, we observe for the first time the phenomenon of a strand slippage in septins. Such slippage generates a front-back communication mechanism between the G and NC interfaces. These data provide a novel mechanistic framework for the influence of nucleotide binding to the GTPase domain, opening new possibilities for the study of the dynamics of septin filaments.


Assuntos
Schistosoma mansoni/química , Septinas/química , Animais , Sítios de Ligação , Calorimetria , Catálise , Membrana Celular/metabolismo , Cristalografia por Raios X , Escherichia coli/metabolismo , GTP Fosfo-Hidrolases/química , Guanosina Difosfato/química , Guanosina Trifosfato/química , Hidrólise , Magnésio/química , Espectroscopia de Ressonância Magnética , Nucleotídeos/química , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Termodinâmica , Água/química
11.
Acta Crystallogr D Biol Crystallogr ; 71(Pt 6): 1257-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26057666

RESUMO

The sequences of all seven polypeptide chains from the giant haemoglobin of the free-living earthworm Glossoscolex paulistus (HbGp) are reported together with the three-dimensional structure of the 3.6 MDa complex which they form. The refinement of the full particle, which has been solved at 3.2 Å resolution, the highest resolution reported to date for a hexagonal bilayer haemoglobin composed of 12 protomers, is reported. This has allowed a more detailed description of the contacts between subunits which are essential for particle stability. Interpretation of features in the electron-density maps suggests the presence of metal-binding sites (probably Zn(2+) and Ca(2+)) and glycosylation sites, some of which have not been reported previously. The former appear to be important for the integrity of the particle. The crystal structure of the isolated d chain (d-HbGp) at 2.1 Å resolution shows different interchain contacts between d monomers compared with those observed in the full particle. Instead of forming trimers, as seen in the complex, the isolated d chains associate to form dimers across a crystallographic twofold axis. These observations eliminate the possibility that trimers form spontaneously in solution as intermediates during the formation of the dodecameric globin cap and contribute to understanding of the possible ways in which the particle self-assembles.


Assuntos
Hemoglobinas/química , Oligoquetos/química , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , Dados de Sequência Molecular , Conformação Proteica , Homologia de Sequência de Aminoácidos
12.
J Am Coll Nutr ; 34(4): 290-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25759961

RESUMO

OBJECTIVE: Because most publications on growth and development deal with children with zinc deficiency, we decided to study the effects of this micronutrient on the secretion of growth hormone (GH), insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), osteocalcin (OCN), and alkaline phosphatase (ALP) in healthy and eutrophic children. This study is original because the methodology was unique. METHODS: Forty schoolchildren participated in the study, 17 females and 23 males, aged 8 and 9 years. The study was carried out during a 3-month period. It was characterized as a triple-blind randomized controlled trial. The children were divided in a control group (20 schoolchildren using 10% sorbitol) and experimental group (20 schoolchildren using zinc). All were submitted to oral zinc supplementation (10 mg Zn/day) and venous zinc administration (0.06537 mg Zn/kg of body weight). Blood samples were collected at 0, 60, 120, 180, and 210 min. All schoolchildren were also submitted to anthropometric, clinical, and dietetic assessments as well as biochemistry analyses. RESULTS: Oral zinc supplementation in the experimental group (1) stimulated an increase in the consumption of protein and fat (p = 0.0007, p < 0.0001, p < 0.0001, respectively), (2) increased basal serum zinc (p < 0.0001), (3) increased plasma ALP (p = 0.0270), and (4) showed a positive correlation for IGF1, IGFBP3, and OCN, comparing before and after oral zinc supplementation (p = 0.0011, p < 0.0001, p < 0.0446, respectively). During zinc administration, plasma IGF1 and IGFBP3 increased significantly in the experimental group (p = 0.0468, p < 0.0001, respectively). Plasma GH increased in the experimental group but without statistical difference comparing before and after oral zinc supplementation. CONCLUSIONS: Zinc supplementation stimulated an increase in the consumption of some macronutrients and basal serum zinc and improved plasma alkaline phosphatase levels. Zinc administration increased hormones of the GH-IGF1 system.


Assuntos
Fosfatase Alcalina/sangue , Suplementos Nutricionais , Hormônio do Crescimento Humano/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Osteocalcina/sangue , Zinco/farmacologia , Criança , Feminino , Voluntários Saudáveis , Humanos , Masculino , Valores de Referência , Oligoelementos/farmacologia , Zinco/sangue
13.
Ann Nutr Metab ; 65(4): 272-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25376908

RESUMO

BACKGROUND/AIMS: Berardinelli-Seip syndrome (BSS) is a recessive autosomal genetic disorder characterized by the near loss of adipose tissue with disturbance in lipid metabolism. METHODS: Biochemical and hormonal parameters and Pro12Ala, Pvull, Avall, Sstl and ADIPOQ polymorphisms in 22 patients with BSS were analyzed and examined for a possible association with lipid profiles. RESULTS: Parental consanguinity, insulin resistance and diabetes mellitus were observed in 63.6, 81.8 and 59.1% of patients, respectively. All individuals presented high triglyceride levels, and 68.1% of patients showed high cholesterol levels. The Pro/Pro genotype of the Pro12Ala polymorphism of the PPARγ2 gene was found in 86.3% of patients; the Ala/Ala variant was not observed in any patient. The PvuII polymorphism of the LPL gene showed a frequency of 50% for the P1P2 variant. The AvaII polymorphism of the LDLR gene showed a similar frequency of 40.9% for both CT and TT variants. The S1S1 genotype of the Sstl polymorphism of the APOC3 gene had a frequency of 86.3%. The CC allele of the ADIPOQ polymorphism of the adiponectin gene was found in 54.6% of patients. CONCLUSIONS: No association was found between lipid parameters and the relevant Pvull, Avall and Sstl polymorphisms. However, we did observe an association of the Pro12Ala and ADIPOQ polymorphisms with higher lipid levels, suggesting a close relationship between these factors.


Assuntos
Adiponectina/genética , Predisposição Genética para Doença , Lipodistrofia Generalizada Congênita/genética , PPAR gama/genética , Adulto , Brasil , Colesterol/sangue , Feminino , Humanos , Lipodistrofia Generalizada Congênita/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , População Branca
14.
PLoS One ; 19(8): e0307617, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39186716

RESUMO

INTRODUCTION: The thyroid cancer has the ninth larger incidence of cancer in the world. Investigations related to the exposure to metals have become important due to the sensibility of the thyroid gland to them. Studies reveal that carcinogenic progressions are associated to the deficiency of the essential trace elements. In this context, the zinc is highlighted, essential for the metabolism of the thyroidal hormone and has a potential relation with the pathogenesis of the thyroid cancer. The objective of this systematic review and meta-analysis is to evaluate the low serum zinc as a risk factor for thyroid cancer in adults. METHODS AND ANALYSIS: PubMed/MEDLINE, Scopus, Embase and LILACS databases will be searched for observational studies investigating the low serum zinc as a risk factor for thyroid cancer in adults. No language or publication period restrictions will be imposed. The primary outcome will be that the low serum zinc is a risk factor for thyroid cancer. Three independent reviewers will select the studies and extract data from the original publications. The risk-of-bias will be assessed by using the Newcastle-Ottawa Quality Assessment Scale (NOS). Data synthesis will be performed using the R software (V.4.3.1) and to assess heterogeneity, we will compute the I2 statistic and the results will be based on either random-effects or fixed-effects models, depending on the heterogeneity. The Grading of Recommendations, Development, and Evaluation (GRADE) system will be used to evaluate the reliability and quality of evidence. PROSPERO REGISTRATION NUMBER: International Prospective Register of Systematic Reviews (PROSPERO) CRD42023463747.


Assuntos
Neoplasias da Glândula Tireoide , Zinco , Humanos , Metanálise como Assunto , Fatores de Risco , Revisões Sistemáticas como Assunto , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/epidemiologia , Zinco/sangue
15.
J Nutr Metab ; 2024: 5522139, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39328357

RESUMO

Background: The study hypothesized that zinc supplementation would increase or preserve lean body mass in Duchenne muscular dystrophy (DMD) patients. Therefore, we aimed to evaluate the body composition of DMD patients before and after zinc supplementation. Materials and Methods: The study is a clinical trial comprising 21 boys diagnosed with DMD. Dietary intake parameters were evaluated before zinc supplementation. Serum zinc levels, anthropometry, and body composition were measured in three moments, four months apart. The patients received 5, 10, or 15 mg of zinc bis-glycine supplementation according to age as an oral solution daily for four months. The sample was distributed into two groups according to serum zinc status: zinc deficiency (G1) or adequate zinc (G2). Results: There was a significant difference in lean body mass between the groups: zinc deficiency (G1) or adequate zinc (G2), at three times (p=0.041, 0.016, and 0.009, respectively). After oral zinc supplementation, serum zinc levels were not different between groups. We did not observe differences when associating the parameters between times and groups. Conclusion: Zinc supplementation was able to maintain lean body mass and fat mass in patients with DMD with previous deficiencies. Therefore, it is necessary to have a prior screening of serum zinc levels to observe changes after supplementation.

16.
Nutrients ; 16(19)2024 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-39408270

RESUMO

Zinc plays a crucial role in cell structure and functionality. Neurodegenerative Duchenne muscular dystrophy (DMD) alters muscle membrane structure, leading to a loss of muscle mass and strength. The objective of this study was to evaluate the changes in phase angle (PA) and bioelectrical impedance vector analysis (BIVA) results in patients with DMD after oral zinc supplementation. This clinical trial included 33 boys aged 5.6 to 24.5 years diagnosed with DMD. They were divided into three groups according to age (G1, G2, and G3) and supplemented with oral zinc. The mean serum zinc concentration was 74 µg/dL, and 29% of patients had concentrations below the reference value. The baseline values (mean (standard deviation)) of the bioelectrical impedance parameters PA, resistance (R), and reactance (Xc) were 2.59° (0.84°), 924.36 (212.31) Ω, and 39.64 (8.41) Ω, respectively. An increase in R and a decrease in PA and lean mass proportional to age were observed, along with a negative correlation (r = -0.614; p < 0.001) between age and PA. The average cell mass in G1 was greater than that in G3 (p = 0.012). There were no significant differences in serum zinc levels or bioelectrical impedance parameters before and after zinc supplementation. We conclude that this population is at risk of zinc deficiency and the proposed dosage of zinc supplementation was not sufficient to alter serum zinc levels, PA and BIVA results.


Assuntos
Suplementos Nutricionais , Impedância Elétrica , Distrofia Muscular de Duchenne , Zinco , Humanos , Distrofia Muscular de Duchenne/tratamento farmacológico , Zinco/administração & dosagem , Zinco/sangue , Zinco/deficiência , Masculino , Adolescente , Criança , Adulto Jovem , Pré-Escolar , Composição Corporal/efeitos dos fármacos , Administração Oral , Músculo Esquelético/efeitos dos fármacos
17.
Sci Rep ; 14(1): 1582, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38238498

RESUMO

Schistosomiasis is caused by parasites of the genus Schistosoma, which infect more than 200 million people. Praziquantel (PZQ) has been the main drug for controlling schistosomiasis for over four decades, but despite that it is ineffective against juvenile worms and size and taste issues with its pharmaceutical forms impose challenges for treating school-aged children. It is also important to note that PZQ resistant strains can be generated in laboratory conditions and observed in the field, hence its extensive use in mass drug administration programs raises concerns about resistance, highlighting the need to search for new schistosomicidal drugs. Schistosomes survival relies on the redox enzyme thioredoxin glutathione reductase (TGR), a validated target for the development of new anti-schistosomal drugs. Here we report a high-throughput fragment screening campaign of 768 compounds against S. mansoni TGR (SmTGR) using X-ray crystallography. We observed 49 binding events involving 35 distinct molecular fragments which were found to be distributed across 16 binding sites. Most sites are described for the first time within SmTGR, a noteworthy exception being the "doorstop pocket" near the NADPH binding site. We have compared results from hotspots and pocket druggability analysis of SmTGR with the experimental binding sites found in this work, with our results indicating only limited coincidence between experimental and computational results. Finally, we discuss that binding sites at the doorstop/NADPH binding site and in the SmTGR dimer interface, should be prioritized for developing SmTGR inhibitors as new antischistosomal drugs.


Assuntos
Complexos Multienzimáticos , NADH NADPH Oxirredutases , Esquistossomose mansoni , Esquistossomose , Animais , Criança , Humanos , Schistosoma mansoni , Cristalografia por Raios X , NADP/metabolismo , Esquistossomose/tratamento farmacológico , Sítios de Ligação , Esquistossomose mansoni/parasitologia
18.
Clin Nutr ESPEN ; 61: 393-398, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38777460

RESUMO

BACKGROUND & AIMS: Duchenne muscular dystrophy (DMD) involves muscle fragility, sarcolemma instability, and chronic inflammation. This study aims to identify the inflammatory profile of DMD patients and evaluate associations between clinical and nutritional variables. METHODS: We performed a cross-sectional study nested in a cohort to obtain sociodemographics, illness time, use of medications, and supplement data through interviews and the patient's medical records. Then, we assessed the relationships between illness time, cytokine levels, and nutritional status. RESULTS: Forty-four male participants, aged 4.3-24.2 years, were evaluated. Concerning nutritional status, 18 participants were eutrophic. The fat mass increased and the lean mass decreased from the beginning of the first signs of DMD. Cytokines levels in DMD patients, even under corticosteroids therapy, are higher than values described in the literature on healthy subjects. The regression models demonstrated that illness time and BMI/A z-scores are associated with higher values of interleukin-6. CONCLUSIONS: A persistent inflammatory profile was observed in the patients evaluated. The data suggest that maintaining adequate nutritional status and body composition is important for determining the inflammation presented by individuals with DMD.


Assuntos
Composição Corporal , Inflamação , Distrofia Muscular de Duchenne , Estado Nutricional , Humanos , Distrofia Muscular de Duchenne/complicações , Masculino , Estudos Transversais , Adolescente , Criança , Adulto Jovem , Pré-Escolar , Citocinas/sangue , Índice de Massa Corporal , Interleucina-6/sangue
20.
Acta Crystallogr D Biol Crystallogr ; 69(Pt 5): 920-3, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23633603

RESUMO

Crystal dehydration is a post-crystallization technique that can potentially improve the diffraction of macromolecular crystals. There are currently several ways of undertaking this process; however, dehydration experiments are often limited in their throughput and require prior manipulation of the samples. In the present study, a novel method is proposed that uses in situ plate screening to assess the effect of dehydration by combining the throughput of 96-well crystallization plates with direct X-ray feedback on crystal diffraction quality.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/química , Cristalização/instrumentação , Cristalização/métodos , Cristalografia por Raios X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA