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Zebrafish drug screen

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https://www.readbyqxmd.com/read/28208716/cell-imaging-counting-as-a-novel-ex-vivo-approach-for-investigating-drug-induced-hepatotoxicity-in-zebrafish-larvae
#1
Xuan-Bac Nguyen, Stanislav Kislyuk, Duc-Hung Pham, Angela Kecskés, Jan Maes, Deirdre Cabooter, Pieter Annaert, Peter De Witte, Annelii Ny
Drug-induced liver injury (DILI) is the most common reason for failures during the drug development process and for safety-related withdrawal of drugs from the pharmaceutical market. Therefore, having tools and techniques that can detect hepatotoxic properties in drug candidates at an early discovery stage is highly desirable. In this study, cell imaging counting was used to measure in a fast, straightforward, and unbiased way the effect of paracetamol and tetracycline, (compounds known to cause hepatotoxicity in humans) on the amount of DsRed-labeled hepatocytes recovered by protease digestion from Tg(fabp10a:DsRed) transgenic zebrafish...
February 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28181494/microenvironment-derived-factors-driving-metastatic-plasticity-in-melanoma
#2
Isabella S Kim, Silja Heilmann, Emily R Kansler, Yan Zhang, Milena Zimmer, Kajan Ratnakumar, Robert L Bowman, Theresa Simon-Vermot, Myles Fennell, Ralph Garippa, Liang Lu, William Lee, Travis Hollmann, Joao B Xavier, Richard M White
Cellular plasticity is a state in which cancer cells exist along a reversible phenotypic spectrum, and underlies key traits such as drug resistance and metastasis. Melanoma plasticity is linked to phenotype switching, where the microenvironment induces switches between invasive/MITF(LO) versus proliferative/MITF(HI) states. Since MITF also induces pigmentation, we hypothesize that macrometastatic success should be favoured by microenvironments that induce a MITF(HI)/differentiated/proliferative state. Zebrafish imaging demonstrates that after extravasation, melanoma cells become pigmented and enact a gene expression program of melanocyte differentiation...
February 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28168859/zebrafish-screens-for-new-colitis-treatments-a-bottom-up-approach
#3
Jou A Lee, Stephen A Renshaw
Many factors interact in the development and progression of inflammatory bowel disease. This complexity demands a combination of methods to disentangle the pathology of this disease. As reported by Oehlers et al. in this issue, the zebrafish drug screen is one simple approach that could enable the elucidation of the pathways involved in IBD and ultimately the discovery of new therapeutics.
February 2017: FEBS Journal
https://www.readbyqxmd.com/read/28154320/screening-for-chemical-suppressors-of-the-wnt-%C3%AE-catenin-signaling-pathway
#4
Naoyuki Nishiya
 Aberrant activation of Wnt/β-catenin canonical signaling is observed in multiple malignant tumors, and is recognized as an attractive therapeutic target for molecular targeted drugs. This signaling pathway is also involved in maintaining pluripotency in adult stem cells. Therefore, lowering potential stem cell toxicity is a key factor for the development of a Wnt/β-catenin signaling inhibitor. Here, we show Wnt/β-catenin pathway inhibitors with low toxicity, identified through phenotype-based screening using zebrafish embryos...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28153846/miconazole-protects-blood-vessels-from-matrix-metalloproteinase-9-dependent-rupture-and-hemorrhage
#5
Ran Yang, Yunpei Zhang, Dandan Huang, Xiao Luo, Liangren Zhang, Xiaojun Zhu, Xiaolin Zhang, Zhenming Liu, Jingyan Han, Jing-Wei Xiong
Hemorrhagic stroke accounts for 10-15% of all strokes and is strongly associated with mortality and morbidity worldwide, but its prevention and therapeutic interventions remain a major challenge. Here, we report the identification of miconazole as a hemorrhagic suppressor by a small-molecule screen in zebrafish. We found that a hypomorphic mutant fn40a, one of known β-pix mutant alleles in zebrafish, had the major symptoms of brain hemorrhage, vessel rupture, and inflammation as those in hemorrhagic stroke patients...
February 2, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28137236/the-use-of-the-zebrafish-model-to-aid-in-drug-discovery-and-target-validation
#6
Prusothman Yoganantharjah, Yann Gibert
The zebrafish is fast becoming a leading and prominent model organism used by researchers for developmental biology, and research in modeling human diseases in zebrafish is being undertaken at a fast pace. Many therapeutic areas, including oncology and cardiovascular diseases to name a few all have zebrafish models based on known disease mechanisms that are translatable to modes of action in humans. Many novel assays have been and are continuing to be developed to study human disease in zebrafish. Prominent methods to identify novel drug targets within the organism include, chemical mutagenesis, insertional mutagenesis and high throughput small molecule screens...
January 30, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28129855/a-zebrafish-xenograft-model-for-studying-human-cancer-stem-cells-in-distant-metastasis-and-therapy-response
#7
L Chen, A Groenewoud, C Tulotta, E Zoni, M Kruithof-de Julio, G van der Horst, G van der Pluijm, B Ewa Snaar-Jagalska
Lethal and incurable bone metastasis is one of the main causes of death in multiple types of cancer. A small subpopulation of cancer stem/progenitor-like cells (CSCs), also known as tumor-initiating cells from heterogenetic cancer is considered to mediate bone metastasis. Although over the past decades numerous studies have been performed in different types of cancer, it is still difficult to track small numbers of CSCs during the onset of metastasis. With use of noninvasive high-resolution imaging, transparent zebrafish embryos can be employed to dynamically visualize cancer progression and reciprocal interaction with stroma in a living organism...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28129853/analysis-of-myelinated-axon-formation-in-zebrafish
#8
M D'Rozario, K R Monk, S C Petersen
Myelin is a lipid-rich sheath formed by the spiral wrapping of specialized glial cells around axon segments. Myelinating glia allow for rapid transmission of nerve impulses and metabolic support of axons, and the absence of or disruption to myelin results in debilitating motor, cognitive, and emotional deficits in humans. Because myelin is a jawed vertebrate innovation, zebrafish are one of the simplest vertebrate model systems to study the genetics and development of myelinating glia. The morphogenetic cellular movements and genetic program that drive myelination are conserved between zebrafish and mammals, and myelin develops rapidly in zebrafish larvae, within 3-5days postfertilization...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28123103/embryonic-exposure-to-the-environmental-neurotoxin-bmaa-negatively-impacts-early-neuronal-development-and-progression-of-neurodegeneration-in-the-sod1-g93r-zebrafish-model-of-amyotrophic-lateral-sclerosis
#9
Samantha Powers, Samantha Kwok, Emily Lovejoy, Tom Lavin, Roger Sher
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive paralysis and death within 2-5 years after diagnosis. Sporadic cases (SALS) comprise ∼90% of cases with the remaining 10% familial (FALS) caused by mutations in ∼27 genes. The vast heterogeneity seen in age and location of disease onset, rate of progression, and duration of disease have been linked with genetic and environmental influences in both SALS and FALS cases. Increased ALS incidence clusters in Guam, southern France, and Maryland have been linked with exposure to Beta-methylamino-L-alanine (BMAA), a non-proteinogenic amino acid produced by cyanobacteria, dinoflaggelates, and diatoms...
January 25, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28121224/a-new-probe-to-measure-autophagic-flux-in-vitro-and-in-vivo
#10
Hideaki Morishita, Takeshi Kaizuka, Yutaro Hama, Noboru Mizushima
Macroautophagy is a catabolic process that delivers cytoplasmic components via the autophagosome to lysosomes for degradation. Measuring autophagic activity is critical to dissect molecular mechanisms and functions of autophagy but remains challenging due to the lack of a definitive method. We have recently developed a new fluorescent probe, GFP-LC3-RFP-LC3ΔG, to assess autophagic flux. Upon intracellular expression, the probe is cleaved by ATG4 family proteases into equimolar amounts of GFP-LC3 and RFP-LC3ΔG...
January 25, 2017: Autophagy
https://www.readbyqxmd.com/read/28118493/anticonvulsant-effect-of-sodium-cyclamate-and-propylparaben-on-ptz-induced-seizures-in-zebrafish
#11
Antonella Pisera-Fuster, Sofía Otero, Alan Talevi, Luis Bruno-Blanch, Ramón Bernabeu
Screening for novel anticonvulsant drugs requires appropriate animal seizure models. Zebrafish provide small, accessible and cost-efficient preclinical models applicable to high-throughput small molecule screening. Based in previous results in rodents, we have here examined the effects of artificial sweetener sodium cyclamate and antimicrobial agent sodium propylparaben on a model of PTZ-induced seizures in zebrafish. Sodium cyclamate reduced the bursts of hyperactivity, the spasms, increased the latency to spasms and the latency to seizure, while propylparaben increased the latency to spasms...
January 24, 2017: Synapse
https://www.readbyqxmd.com/read/28117738/in-vitro-biotransformation-of-two-human-cyp3a-probe-substrates-and-their-inhibition-during-early-zebrafish-development
#12
Evy Verbueken, Derek Alsop, Moayad A Saad, Casper Pype, Els M Van Peer, Christophe R Casteleyn, Chris J Van Ginneken, Joanna Wilson, Steven J Van Cruchten
At present, the zebrafish embryo is increasingly used as an alternative animal model to screen for developmental toxicity after exposure to xenobiotics. Since zebrafish embryos depend on their own drug-metabolizing capacity, knowledge of their intrinsic biotransformation is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this in vitro study was to assess the activity of cytochrome P450 (CYP)-a group of drug-metabolizing enzymes-in microsomes from whole zebrafish embryos (ZEM) of 5, 24, 48, 72, 96 and 120 h post-fertilization (hpf) by means of a mammalian CYP substrate, i...
January 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28104252/novel-zebrafish-eae-model-a-quick-in-vivo-screen-for-multiple-sclerosis
#13
Pushkar Kulkarni, Swapna Yellanki, Raghavender Medishetti, Dharmarajan Sriram, Uday Saxena, Perumal Yogeeswari
INTRODUCTION: Pre-clinical drug discovery for multiple sclerosis (MS) is a labor intensive activity to perform in rodent models. This is owing to the long duration of disease induction and observation of treatment effects in an experimental autoimmune encephalomyelitis (EAE) model. We propose a novel adult zebrafish based model which offers a quick and simple protocol that can used to screen candidates as a step between in vitro experiments and rodent studies. The experiments conducted for this manuscript were to standardize a suitable model of EAE in adult zebrafish and validate it using known modulators...
January 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/28073790/clemizole-and-modulators-of-serotonin-signalling-suppress-seizures-in-dravet-syndrome
#14
Aliesha Griffin, Kyla R Hamling, Kelly Knupp, SoonGweon Hong, Luke P Lee, Scott C Baraban
Dravet syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics...
January 10, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28069987/transgenic-zebrafish-reporter-lines-as-alternative-in-vivo-organ-toxicity-models
#15
Kar Lai Poon, Xingang Wang, Serene Gp Lee, Ashley S Ng, Wei Huang Goh, Zhonghua Zhao, Muthafar Al-Haddawi, Haishan Wang, Sinnakaruppan Mathavan, Phillip W Ingham, Claudia Mcginnis, Tom J Carney
Organ toxicity, particularly liver toxicity, remains one of the major reasons for termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would therefore find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults...
January 9, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28058624/zebrafish-phenotypic-screen-identifies-novel-notch-antagonists
#16
Vithya Velaithan, Kazuhide Shaun Okuda, Mei Fong Ng, Norazwana Samat, Sze Wei Leong, Siti Munirah Mohd Faudzi, Faridah Abas, Khozirah Shaari, Sok Ching Cheong, Pei Jean Tan, Vyomesh Patel
Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors...
January 5, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28053068/alternative-models-of-developmental-and-reproductive-toxicity-in-pharmaceutical-risk-assessment-and-the-3rs
#17
Kimberly C Brannen, Robert E Chapin, Abigail C Jacobs, Maia L Green
In the pharmaceutical industry, preclinical developmental and reproductive toxicity studies are conducted in laboratory animals in order to predict and prevent adverse effects of drugs on human reproductive health and development. However, these studies require a relatively large number of animals and are usually conducted late in the drug development process. Early, simple, and inexpensive screening assays could facilitate smarter decisions, reductions in animal use, and development of safe drugs. The current state and future needs for alternative models of developmental and reproductive toxicity are reviewed here...
December 2016: ILAR Journal
https://www.readbyqxmd.com/read/28053067/drug-discovery-in-fish-flies-and-worms
#18
Kevin Strange
Nonmammalian model organisms such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish Danio rerio provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. An interdisciplinary approach that strategically combines the study of nonmammalian and mammalian animal models with diverse experimental tools has and will continue to provide deep molecular and genetic understanding of human disease and will significantly enhance the discovery and application of new therapies to treat those diseases...
December 2016: ILAR Journal
https://www.readbyqxmd.com/read/28035003/a-quininib-analogue-and-cysteinyl-leukotreine-receptor-antagonist-inhibits-vegf-independent-angiogenesis-and-exerts-an-additive-anti-angiogenic-response-with-bevacizumab
#19
Clare T Butler, Alison L Reynolds, Miriam Tosetto, Eugene T Dillon, Patrick Guiry, Gerard Cagney, Jacintha O'Sullivan, Breand Aacuten N Kennedy
Excess blood vessel growth contributes to the pathology of metastatic cancers and age-related retinopathies. Despite development of improved treatments, these conditions are associated with high economic costs and drug resistance. Bevacizumab (Avastin®), a monoclonal antibody against vascular endothelial growth factor (VEGF) is used clinically to treat certain types of metastatic cancers. Unfortunately, many patients do not respond or inevitably become resistant to bevacizumab, highlighting the need for more effective anti-angiogenic drugs with novel mechanisms of action...
December 29, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28025085/modelling-viral-infections-using-zebrafish-innate-immune-response-and-antiviral-research
#20
REVIEW
Mónica Varela, Antonio Figueras, Beatriz Novoa
Zebrafish possess a highly developed immune system that is remarkably similar to the human one. Therefore, it is expected that the majority of the signalling pathways and molecules involved in the immune response of mammals exist and behave similarly in fish. The innate antiviral response depends on the recognition of viral components by host cells. Pattern recognition receptors initiate antimicrobial defence mechanisms via several well-conserved signalling pathways. In this paper, we review current knowledge of the antiviral innate immune response in zebrafish by considering the main molecules that have been characterized and the infection models used for the in vivo study of the antiviral innate immune response...
December 23, 2016: Antiviral Research
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