Search results for "Hip"
showing 10 items of 9327 documents
Effects of Pimozide Derivatives on pSTAT5 in K562 Cells
2017
STAT5 is a transcription factor, a member of the STAT family of signaling proteins. STAT5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), in which this protein is found constitutively activated as a consequence of BCR-ABL expression. The neuroleptic drug pimozide was recently reported to act as an inhibitor of STAT5 phosphorylation and is capable of inducing apoptosis in CML cells in vitro. Our research group has synthesized simple derivatives of pimozide with cytotoxic activity and that are able to decrease the levels of phosphorylated STAT5. In this work we continued the search for novel STAT5 inhibitors, synthesizing compounds in which the benzoimidazol…
Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives
2018
A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-b-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced 62% HSD1 inhibition at 5 mM and, furthermore, three of them produced 68% inhibition at 1 mM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-b-hydroxysteroid dehydrogenase 2 – a requirement for lowe…
Do Brincar do Bebê ao Brincar da Criança: Um Estudo sobre o Processo de Subjetivação da Criança Autista
2018
RESUMO O brincar primitivo do bebê poderia nos revelar traços precoces de uma provável organização autística em curso na criança pequena? Em que medida o investimento do bebê face aos objetos do mundo externo e do ambiente poderia ser associado a suas primeiras experiências com o objeto materno? Tais questões são levantadas neste artigo, cujo principal objetivo é abordar o processo de subjetivação da criança autista a partir da correlação entre o brincar primitivo do bebê e o brincar simbólico da criança. Por meio de um estudo longitudinal de bebês com risco de autismo, constatou-se que, desde uma idade precoce, é possível detectar particularidades na maneira como eles investem e interagem …
Pre-imaginal conditioning alters adult sex pheromone response in Drosophila
2018
https://peerj.com/articles/5585/#supplemental-information; International audience; Pheromones are chemical signals that induce innate responses in individuals of the same species that may vary with physiological and developmental state. In Drosophila melanogaster, the most intensively studied pheromone is 11-cis-vaccenyl acetate (cVA), which is synthezised in the male ejaculatory bulb and is transferred to the female during copulation. Among other effects, cVA inhibits male courtship of mated females. We found that male courtship inhibition depends on the amount of cVA and this effect is reduced in male flies derived from eggs covered with low to zero levels of cVA. This effect is not obser…
SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
2017
AbstractBiogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we…
MECP2 impairs neuronal structure by regulating KIBRA
2016
Using a Drosophila model of MECP2 gain-of-function, we identified memory associated KIBRA as a target of MECP2 in regulating dendritic growth. We found that expression of human MECP2 increased kibra expression in Drosophila, and targeted RNAi knockdown of kibra in identified neurons fully rescued dendritic defects as induced by MECP2 gain-of-function. Validation in mouse confirmed that Kibra is similarly regulated by Mecp2 in a mammalian system. We found that Mecp2 gain-of-function in cultured mouse cortical neurons caused dendritic impairments and increased Kibra levels. Accordingly, Mecp2 loss-of-function in vivo led to decreased Kibra levels in hippocampus, cortex, and cerebellum. Togeth…
Astrocytic Ephrin-B1 Controls Synapse Formation in the Hippocampus During Learning and Memory
2020
Astrocytes play a fundamental role in synapse formation, pruning, and plasticity, which are associated with learning and memory. However, the role of astrocytes in learning and memory is still largely unknown. Our previous study showed that astrocyte-specific ephrin-B1 knock-out (KO) enhanced but ephrin-B1 overexpression (OE) in hippocampal astrocytes impaired contextual memory recall following fear conditioning. The goal of this study was to understand the mechanism by which astrocytic ephrin-B1 influences learning; specifically, learning-induced remodeling of synapses and dendritic spines in CA1 hippocampus using fear-conditioning paradigm. While we found a higher dendritic spine density …
Nitric oxide/cGMP signaling via guanylyl cyclase isoform 1 modulates glutamate and GABA release in somatosensory cortex of mice
2017
Abstract In hippocampus, two guanylyl cyclases (NO-GC1 and NO-GC2) are involved in the transduction of the effects of nitric oxide (NO) on synaptic transmission. However, the respective roles of the NO-GC isoforms on synaptic transmission are less clear in other regions of the brain. In the present study, we used knock-out mice deficient for the NO-GC1 isoform (NO-GC1 KO) to analyze its role in the glutamatergic and GABAergic neurotransmission at pyramidal neurons in layers II/III of somatosensory cortex. NO-GC1 KO slices revealed reduced frequencies of miniature excitatory- and inhibitory-postsynaptic currents, increased paired-pulse ratios and decreased input–output curves of evoked signa…
Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors
2018
Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM−1 μM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activi…
Identification and structural characterization of LytU, a unique peptidoglycan endopeptidase from the lysostaphin family
2017
AbstractWe introduce LytU, a short member of the lysostaphin family of zinc-dependent pentaglycine endopeptidases. It is a potential antimicrobial agent for S. aureus infections and its gene transcription is highly upregulated upon antibiotic treatments along with other genes involved in cell wall synthesis. We found this enzyme to be responsible for the opening of the cell wall peptidoglycan layer during cell divisions in S. aureus. LytU is anchored in the plasma membrane with the active part residing in the periplasmic space. It has a unique Ile/Lys insertion at position 151 that resides in the catalytic site-neighbouring loop and is vital for the enzymatic activity but not affecting the …