Search results for "BRAF"
showing 10 items of 253 documents
Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties
2010
Abstract Artemisinins are plant products with a wide range of medicinal applications. Most prominently, artesunate is a well tolerated and effective drug for treating malaria, but is also active against several protozoal and schistosomal infections, and additionally exhibits anti-angiogenic, anti-tumorigenic and anti-viral properties. The array of activities of the artemisinins, and the recent emergence of malaria resistance to artesunate, prompted us to synthesize and evaluate several novel artemisinin-like derivatives. Sixteen distinct derivatives were therefore synthesized and the in vitro cytotoxic effects of each were tested with different cell lines. The in vivo anti-angiogenic proper…
Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors.
2018
Many new drugs have appeared in last years in the oncological treatment scenario. Each drug carries an important set of adverse events, not less, cardiovascular adverse events. This aspect is even more important considering the increasing use of combination therapies with two drugs, or three drugs as in some ongoing clinical trials. Besides it represents a growing problem for Cardiologists, that face it in every day clinical practice and that will face it probably more and more in the coming years. This work reviews the mechanism of action of BRAF-inhibitors and MEK-inhibitors used together, the pathophysiological mechanisms that lead to cardiovascular toxicity. Particularly, it focuses on …
The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds.
2021
ABSTRACT With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening campaigns is a major obstacle in drug discovery. Moreover, in vivo testing using conventional animal TB models, such as mice, is time consuming and costly, and represents a major bottleneck in lead compound discovery and development. Here, we report the use of the zebrafish embryo TB model for evaluating the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently id…
EGFL7 ligates αvβ3 integrin to enhance vessel formation
2013
Angiogenesis, defined as blood vessel formation from a preexisting vasculature, is governed by multiple signal cascades including integrin receptors, in particular integrin αVβ3. Here we identify the endothelial cell (EC)-secreted factor epidermal growth factor-like protein 7 (EGFL7) as a novel specific ligand of integrin αVβ3, thus providing mechanistic insight into its proangiogenic actions in vitro and in vivo. Specifically, EGFL7 attaches to the extracellular matrix and by its interaction with integrin αVβ3 increases the motility of EC, which allows EC to move on a sticky underground during vessel remodeling. We provide evidence that the deregulation of EGFL7 in zebrafish embryos leads …
Early asymmetric cues triggering the dorsal/ventral gene regulatory network of the sea urchin embryo
2014
Dorsal/ventral (DV) patterning of the sea urchin embryo relies on a ventrally-localized organizer expressing Nodal, a pivotal regulator of the DV gene regulatory network. However, the inceptive mechanisms imposing the symmetry-breaking are incompletely understood. In Paracentrotus lividus, the Hbox12 homeodomain-containing repressor is expressed by prospective dorsal cells, spatially facing and preceding the onset of nodal transcription. We report that Hbox12 misexpression provokes DV abnormalities, attenuating nodal and nodal-dependent transcription. Reciprocally, impairing hbox12 function disrupts DV polarity by allowing ectopic expression of nodal. Clonal loss-of-function, inflicted by b…
Bioconcentration, metabolism and toxicity of substituted anilines in the zebrafish (Brachydanio rerio).
1991
The LC50 (96 h) values and the bioconcentration factors (BCF) for nine anilines (aniline; 2-, 3-, 4-chloroaniline; 2-, 3-, 4-nitroaniline; 2,4- and 3,4-dichloroaniline) in the zebrafish (Brachydanio rerio) were determined. Biotransformation products of anilines in the zebrafish were analyzed by HPLC. The aim of the investigations was to find relationships between accumulation/elimination/metabolism and toxicity on the one hand and between chemical structure and biotransformation on the other. We found a good correlation of log BCF and of log Pow with log LC50. This concurs with the assumption that the internal dose determines the toxicological effect. All anilines investigated, with the exc…
The role of the transcription factor hsf1 in zebrafish erythropoiesis
2020
Heat shock proteins (HSPs) are reported to play an important role in erythropoiesis. The expression of HSP genes is mainly controlled by Heat shock factor 1 (HSF1), a highly conserved transcription factor. So far, a detailed understanding of the function of HSF1 in erythropoiesis remains uncharacterized. This study has employed zebrafish as a relevant model to investigate the role of Hsf1 during embryonic erythropoiesis. We established hsf1-disrupted zebrafish lines using the CRISPR/Cas9 technology and performed phenotypic analyses throughout embryogenesis. We found that Hsf1 deficient embryos had a decreased number of primitive erythrocytes, while erythrocyte number in adults was unchanged…
Stress reactivity elicits a tissue-specific reduction in telomere length in aging zebrafish (Danio rerio)
2020
ABSTRACTTelomere length reflects cellular ageing. Increased telomere shortening in leukocytes is associated with a range of neurodegenerative and cardiovascular diseases, the onset and progression of which may be mediated by behavioural traits such as anxiety and stress reactivity. However, the effects of the hypothalamus-pituitary-adrenal axis stress response are shown to be tissue specific. As such, leukocyte telomere length may not give an accurate measure of the relationship between stress-reactivity and telomere length in disease relevant tissues. To test the hypothesis that stress-reactivity contributes to age-related telomere shortening in a tissue specific manner, we examined the co…
The Influence of Infective Dose on the Virulence of a Generalist Pathogen in Rainbow Trout (Oncorhynchus mykiss) and Zebra Fish (Danio rerio)
2015
Pathogen density and genetic diversity fluctuate in the outside-host environment during and between epidemics, affecting disease emergence and the severity and probability of infections. Although the importance of these factors for pathogen virulence and infection probability has been acknowledged, their interactive effects are not well understood. We studied how an infective dose in an environmentally transmitted opportunistic fish pathogen, Flavobacterium columnare, affects its virulence both in rainbow trout, which are frequently infected at fish farms, and in zebra fish, a host that is not naturally infected by F. columnare. We used previously isolated strains of confirmed high and low …
Comparative analysis of zebrafish nos2a and nos2b genes
2008
Abstract Nitric oxide synthase (NOS) produces nitric oxide (NO) from arginine. Three NOS isoforms have been identified in mammals, namely a neuronal (NOS1), an inducible (NOS2) and an endothelial (NOS3) enzyme. In zebrafish genome, one nos1 gene and two nos2 genes (nos2a and nos2b) were observed. We cloned zebrafish nos2a cDNA and compared nos2a and nos2b sequences, expression and inducibility. When analyzed by reverse transcription-PCR, the expression of nos2a remained very low during initial development, then increased at 96 hpf, while nos2b was expressed from 6 hpf and subsequently remained stable. Expression of nos2a is detected in the head, eye and gut regions by WISH experiments perfo…