RESUMO
Bone and muscle are coupled through developmental, mechanical, paracrine, and autocrine signals. Genetic variants at the CPED1-WNT16 locus are dually associated with bone- and muscle-related traits. While Wnt16 is necessary for bone mass and strength, this fails to explain pleiotropy at this locus. Here, we show wnt16 is required for spine and muscle morphogenesis in zebrafish. In embryos, wnt16 is expressed in dermomyotome and developing notochord, and contributes to larval myotome morphology and notochord elongation. Later, wnt16 is expressed at the ventral midline of the notochord sheath, and contributes to spine mineralization and osteoblast recruitment. Morphological changes in wnt16 mutant larvae are mirrored in adults, indicating that wnt16 impacts bone and muscle morphology throughout the lifespan. Finally, we show that wnt16 is a gene of major effect on lean mass at the CPED1-WNT16 locus. Our findings indicate that Wnt16 is secreted in structures adjacent to developing bone (notochord) and muscle (dermomyotome) where it affects the morphogenesis of each tissue, thereby rendering wnt16 expression into dual effects on bone and muscle morphology. This work expands our understanding of wnt16 in musculoskeletal development and supports the potential for variants to act through WNT16 to influence bone and muscle via parallel morphogenetic processes.
Assuntos
Notocorda , Peixe-Zebra , Animais , Peixe-Zebra/genética , Coluna Vertebral , Músculos , Morfogênese/genética , Larva , Proteínas de Peixe-Zebra/genética , Proteínas Wnt/genéticaRESUMO
PURPOSE OF REVIEW: Chromosome region 7q31.31, also known as the CPED1-WNT16 locus, is robustly associated with BMD and fracture risk. The aim of the review is to highlight experimental studies examining the function of genes at the CPED1-WNT16 locus. RECENT FINDINGS: Genes that reside at the CPED1-WNT16 locus include WNT16, FAM3C, ING3, CPED1, and TSPAN12. Experimental studies in mice strongly support the notion that Wnt16 is necessary for bone mass and strength. In addition, roles for Fam3c and Ing3 in regulating bone morphology in vivo and/or osteoblast differentiation in vitro have been identified. Finally, a role for wnt16 in dually influencing bone and muscle morphogenesis in zebrafish has recently been discovered, which has brought forth new questions related to whether the influence of WNT16 in muscle may conspire with its influence in bone to alter BMD and fracture risk.
Assuntos
Fraturas Ósseas , Osteoporose , Animais , Camundongos , Densidade Óssea/genética , Fraturas Ósseas/genética , Osteoporose/genética , Proteínas Wnt/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
Obesity is a pandemic and a serious health problem in developed and undeveloped countries. Activation of estrogen receptor beta (ERß) has been shown to promote weight loss without modifying caloric intake, making it an attractive target for developing new drugs against obesity. This work aimed to predict new small molecules as potential ERß activators. A ligand-based virtual screening of the ZINC15, PubChem, and Molport databases by substructure and similarity was carried out using the three-dimensional organization of known ligands as a reference. A molecular docking screening of FDA-approved drugs was also conducted as a repositioning strategy. Finally, selected compounds were evaluated by molecular dynamic simulations. Compounds 1 (-24.27 ± 0.34 kcal/mol), 2 (-23.33 ± 0.3 kcal/mol), and 6 (-29.55 ± 0.51 kcal/mol) showed the best stability on the active site in complex with ERß with an RMSD < 3.3 Å. RMSF analysis showed that these compounds do not affect the fluctuation of the Cα of ERß nor the compactness according to the radius of gyration. Finally, an in silico evaluation of ADMET showed they are safe molecules. These results suggest that new ERß ligands could be promising molecules for obesity control.
Assuntos
Simulação de Dinâmica Molecular , Receptores de Estrogênio , Simulação de Acoplamento Molecular , Ligantes , Receptor beta de EstrogênioRESUMO
Neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), NT-4, and NT-5, are proteins involved in several important functions of the central nervous system. The activation of the signaling pathways of these neurotrophins, or even by their immature form, pro-neurotrophins, starts with their recognition by cellular receptors, such as tropomyosin receptor kinase (Trk) and 75 kD NT receptors (p75NTR). The Trk receptor is considered to have a high affinity for attachment to specific neurotrophins, while the p75NTR receptor has less affinity for attachment with neurotrophins. The correct functioning of these signaling pathways contributes to proper brain development, neuronal survival, and synaptic plasticity. Unbalanced levels of neurotrophins and pro-neurotrophins have been associated with neurological disorders, illustrating the importance of these molecules in the central nervous system. Furthermore, reports have indicated that viruses can alter the normal levels of neurotrophins by interfering with their signaling pathways. This work discusses the importance of neurotrophins in the central nervous system, their signaling pathways, and how viruses can affect them.
Assuntos
Transdução de Sinais , Viroses , Sistema Nervoso Central , Humanos , Plasticidade Neuronal , Receptores de Superfície Celular , Transdução de Sinais/fisiologiaRESUMO
Exopolysaccharides (EPS) production is a characteristic that has been widely described for many lactic acid bacteria (LAB) of different genera and species, but little is known about the relationship between the functional properties of the producing bacteria and EPS synthesis. Although many studies were addressed towards the application of EPS-producing LAB in the manufacture of several dairy products (fermented milk, cheese) due to their interesting technological properties (increased hardness, water holding capacity, viscosity, etc.), there are not many reports about the functional properties of the EPS extract itself, especially for the genus Lactobacillus. The aim of the present revision is to focus on the species Lactobacillus fermentum with reported functional properties, with particular emphasis on those strains capable of producing EPS, and try to establish if there is any linkage between this property and their functional/probiotic roles, considering the most recent bibliography.
Assuntos
Produtos Fermentados do Leite/microbiologia , Microbiologia de Alimentos , Limosilactobacillus fermentum/fisiologia , Polissacarídeos Bacterianos/biossíntese , Animais , Antibiose , Bactérias/patogenicidade , Fenômenos Fisiológicos Bacterianos , Fermentação , Fatores Imunológicos , Limosilactobacillus fermentum/química , Probióticos/metabolismoRESUMO
BACKGROUND: The elucidation of molecular pathways associated with adipogenesis has evidenced the relevance of estrogen and estrogen receptor beta (ERß). The positive effects of ERß ligands on adipogenesis, energy expenditure, lipolysis, food intake, and weight loss, make ERß an attractive target for obesity control. From ligand-based virtual screening, molecular docking, and molecular dynamic simulations, six new likely ERß ligands (C1 to C6) have been reported with potential for pharmacological obesity treatment. OBJECTIVE: In this study, the effect of molecules C1-C6 on adipogenesis using the murine 3T3-L1 cell line was evaluated. METHODS: Cell viability was assessed by MTT assays. Lipid accumulation and gene expression were investigated by ORO staining and real-time quantitative RT-PCR experiments, respectively. RESULTS: Cell viability was not significantly affected by C1-C6 at concentrations up to 10 µM. Interestingly, treatment with 10 µM of C1 (S-Dihydrodaidzein) and C2 (3-(1,3-benzoxazol-2-yl)- benzamide) for 72 h inhibited adipocyte differentiation; moreover, ORO staining evidenced a reduced intracellular lipid accumulation (40% at day 7). Consistently, mRNA expression of the adipogenic markers, PPARγ and C/EBPα, was reduced by 50% and 82%, respectively, in the case of C1, and by 83% and 59%, in the case of C2. CONCLUSION: Altogether, these results show the two new potential ß-estrogen receptor ligands, C1 and C2, to exhibit anti-adipogenic activity. They could further be used as lead structures for the development of more efficient drugs for obesity control.
Assuntos
Adipogenia , Benzamidas , Receptor beta de Estrogênio , Animais , Camundongos , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/síntese química , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Benzoxazóis/farmacologia , Benzoxazóis/química , Benzoxazóis/síntese química , Sobrevivência Celular/efeitos dos fármacos , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Isoflavonas/farmacologia , Isoflavonas/química , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Under optimized conditions, the lactic acid bacterium Lactobacillus fermentum Lf2 secretes up to 2 gL-1 of a mixture of polysaccharides into the fermentation medium when grown on sucrose. Earlier studies had shown that the mixture is biologically active and work was undertaken to characterise the polysaccharides. Preparative size exclusion chromatography was used to separate a high molecular mass ß-glucan (weight average mass of 1.23 × 106 gmol-1) from two medium molecular mass polysaccharides (weight average mass of 8.8 × 104 gmol-1). Under optimized growth conditions, the medium molecular mass polysaccharides accounted for more than 75% of the mixture by weight. Monomer, linkage analysis and NMR spectroscopy of the medium molecular mass polysaccharides, and material isolated after their Smith degradation, was used to identify the structure of the component polysaccharides. The mixture contains two novel polysaccharides. The first has a main chain of ß-1,6-linked galactofuranoses which is non-stoichiometrically 2-O-glucosylated. The degree of substitution at the 2-position, with α-D-Glcp, depends on the fermentation conditions; under optimized conditions greater than 80% 2-O-α-D-glucosylation was observed. The second polysaccharide is a heteroglycan with four monosaccharides in the repeat unit: residual signals in the NMR suggest that the sample also contains trace amounts (<3%) of cell wall polysaccharides.
Assuntos
Limosilactobacillus fermentum/crescimento & desenvolvimento , Polissacarídeos Bacterianos/química , beta-Glucanas/química , Sequência de Carboidratos , Fermentação , Limosilactobacillus fermentum/química , Peso MolecularRESUMO
Actinomyces spp have been increasingly associated with endodontic infections. However, the antimicrobial susceptibility of this genus has not been studied extensively. The objective of this study was to determine the susceptibility of oral isolates of Actinomyces naeslundii, Actinomyces gerencseriae, Actinomyces israelii, Actinomyces viscosus, and Actinomyces odontolyticus to amoxicillin, clindamycin, doxycycline, metronidazole, and moxifloxacin using in vitro assays. The minimum inhibitory concentration (MIC) of each bacterial isolate was determined by using E-test strips (AB Biodisk, Solna, Sweden). The MIC(90) was 0.19 microg/mL for amoxicillin, 0.25 microg/mL for doxycycline, 0.50 microg/mL for moxifloxacin, and 1.00 microg/mL for clindamycin. However, metronidazole was not active against any of the Actinomyces spp tested (MIC(90)>256 microg/mL).
Assuntos
Actinomyces/efeitos dos fármacos , Actinomicose/tratamento farmacológico , Anti-Infecciosos/uso terapêutico , Periodontite Periapical/microbiologia , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Compostos Aza/uso terapêutico , Clindamicina/uso terapêutico , Doxiciclina/uso terapêutico , Fluoroquinolonas , Humanos , Metronidazol/uso terapêutico , Moxifloxacina , Quinolinas/uso terapêuticoRESUMO
Avian infectious laryngotracheitis (ILT) is a worldwide infectious disease that causes important economic losses in the poultry industry. Although it is known that ILT virus (ILTV) is present in Argentina, there is no information about the circulating strains. With the aim to characterize them, seven different genomic regions (thymidine kinase, glycoproteins D, G, B, C, and J, and infected cell polypeptide 4) were partially sequenced and compared between field samples. The gJ sequence resulted to be the most informative segment, it allowed the differentiation among field sample strains, and also, between wild and vaccine viruses. Specific changes in selected nucleotidic positions led to the definition of five distinct haplotypes. Tests for detection of clustering were run to test the null hypothesis that ILTV haplotypes were randomly distributed in time in Argentina and in space in the most densely populated poultry region of this country, Entre Rios. From this study, it was possible to identify a 46 km radius cluster in which higher proportions of haplotypes 4 and 5 were observed, next to a provincial route in Entre Rios and a significant decline of haplotype 5 between 2009 and 2011. Results here provide an update on the molecular epidemiology of ILT in Argentina, including data on specific genome segments that may be used for rapid characterization of the virus in the field. Ultimately, results will contribute to the surveillance of ILT in the country.
RESUMO
Sex-specific pheromones are known to play an important role in butterfly courtship, and may influence both individual reproductive success and reproductive isolation between species. Extensive ecological, behavioural and genetic studies of Heliconius butterflies have made a substantial contribution to our understanding of speciation. Male pheromones, although long suspected to play an important role, have received relatively little attention in this genus. Here, we combine morphological, chemical and behavioural analyses of male pheromones in the Neotropical butterfly Heliconius melpomene. First, we identify putative androconia that are specialized brush-like scales that lie within the shiny grey region of the male hindwing. We then describe putative male sex pheromone compounds, which are largely confined to the androconial region of the hindwing of mature males, but are absent in immature males and females. Finally, behavioural choice experiments reveal that females of H. melpomene, H. erato and H. timareta strongly discriminate against conspecific males which have their androconial region experimentally blocked. As well as demonstrating the importance of chemical signalling for female mate choice in Heliconius butterflies, the results describe structures involved in release of the pheromone and a list of potential male sex pheromone compounds.