Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
4.7
4.6
Journals
Pharmaceuticals
Special Issues
Zebrafish as a Powerful Tool for Drug Discovery 2021
share announcement

Zebrafish as a Powerful Tool for Drug Discovery 2021

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 83805

Special Issue Editors

Prof. Dr. Yuhei Nishimura

E-Mail Website
Guest Editor
Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu 514-8507, Japan
Interests: pharmacology; toxicology; primary cilia; neurodevelopmental disorder; integrative omics approach; zebrafish
Special Issues, Collections and Topics in MDPI journals
Dr. Martin Distel

E-Mail Website
Guest Editor
St. Anna Kinderkrebsforschung e.V., CHILDREN'S CANCER RESEARCH INSTITUTE, Innovative Cancer Models, Zimmermannplatz 10, 1090 Vienna, Austria
Interests: cancer modeling in zebrafish; xenografts; compound screening

Special Issue Information

Dear Colleagues,

Our scientific and technological knowledge has grown tremendously. The number of drugs approved relative to the costs, however, has continuously decreased. Various approaches have emerged to increase the efficacy of research and development of new drugs. It has been widely recognized that zebrafish can be powerful tools in the drug discovery field, given advantages such as high fecundity, ease of drug administration, similarity to mammals in terms of structures and functions of various tissues, and suitability for the 3Rs (replacement, reduction, and refinement). The process of drug development consists of multiple steps, including the initial discovery of drugs that can be used as therapeutics, preclinical, and clinical validation of their efficacy and toxicity, and the review, approval, and post-marketing surveillance of drugs by regulatory authorities. Using genome-editing technologies, genetic abnormalities observed in human diseases can be mimicked in zebrafish to make a disease model. The phenotypes of the disease model zebrafish can be used to identify novel compounds and/or new indications for old drugs (i.e., drug repositioning) that ameliorate the abnormal phenotypes of the zebrafish disease models. The toxicity of compounds can also be assessed using zebrafish. The International Council for Harmonization has considered including developmental toxicity testing using zebrafish in their guidelines. Zebrafish can also be integrated to validate the efficacy and toxicities of compounds that are identified as novel therapeutics by other approaches, such as computational drug discovery using big data. In this Special Issue, we invite authors to contribute articles focusing on zebrafish as powerful tools for drug discovery. This research topic will maximize the knowledge of the usefulness of zebrafish in drug development, with hopes of increasing the efficiency of the process and identifying drugs that can be used to prevent and/or treat diseases for which effective medications are currently lacking.

Prof. Yuhei Nishimura
Dr. Martin Distel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • zebrafish
  • disease model
  • phenotype
  • drug repositioning
  • computational biology
  • toxicology

Related Special Issue

Published Papers (21 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

33 pages, 8193 KiB  
Article
Mapping Molecular Networks within Clitoria ternatea Linn. against LPS-Induced Neuroinflammation in Microglial Cells, with Molecular Docking and In Vivo Toxicity Assessment in Zebrafish
by Nurul Farah Adni Mat Zian, Puspanjali Swain, Siti Munirah Mohd Faudzi, Norzalina Zakaria, Wan Norhamidah Wan Ibrahim, Noraini Abu Bakar, Khozirah Shaari, Johnson Stanslas, Tae-Ik Choi and Cheol-Hee Kim
Pharmaceuticals 2022, 15(4), 467; https://doi.org/10.3390/ph15040467 - 12 Apr 2022
Cited by 2 | Viewed by 3327
Abstract
Clitoria ternatea Linn. (CT), or butterfly pea, is an Ayurvedic plant traditionally used as a brain tonic. Recently, it was reported to be of use in treating central nervous system (CNS) disorders, i.e., as an antistress treatment and antidepressant. In the present study, [...] Read more.
Clitoria ternatea Linn. (CT), or butterfly pea, is an Ayurvedic plant traditionally used as a brain tonic. Recently, it was reported to be of use in treating central nervous system (CNS) disorders, i.e., as an antistress treatment and antidepressant. In the present study, we report a detailed phytochemical profile of the ethyl acetate fraction of the flower of CT (CTF_EA) with significant neuroprotective and anti-neuroinflammatory properties in both LPS-activated BV-2 and SK-N-SH cells. Concurrently, the molecular network (MN) derived from the CTF_EA metabolome allows putative identification of flavonol 3-O-glycosides, hydrocinnamic acids, and primary metabolites. Molecular docking studies suggest that CTF_EA preferentially targets iNOS, resulting in a decrease in nitric oxide (NO). Furthermore, no toxic effects on normal embryonic development, blood vessel formation, and apoptosis are observed when CTF_EA is tested for in vivo toxicity in zebrafish models. The overall preliminary results suggest the anti-neuroinflammatory and neuroprotective effects of CT and provide scientific support for the efficacy of this medicinal plant at local and traditional levels. However, studies on the targeted isolation of bioactive metabolites, in-depth pharmacological efficacy, and safety in mammalian models are urgently needed to expand our understanding of this plant before it is developed into a promising therapeutic agent for brain-related diseases. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

13 pages, 1924 KiB  
Article
Generation of a Transgenic Zebrafish Line for In Vivo Assessment of Hepatic Apoptosis
by Aina Higuchi, Eri Wakai, Tomoko Tada, Junko Koiwa, Yuka Adachi, Takashi Shiromizu, Hidemasa Goto, Toshio Tanaka and Yuhei Nishimura
Pharmaceuticals 2021, 14(11), 1117; https://doi.org/10.3390/ph14111117 - 31 Oct 2021
Cited by 3 | Viewed by 2428
Abstract
Hepatic apoptosis is involved in a variety of pathophysiologic conditions in the liver, including hepatitis, steatosis, and drug-induced liver injury. The development of easy-to-perform and reliable in vivo assays would thus greatly enhance the efforts to understand liver diseases and identify associated genes [...] Read more.
Hepatic apoptosis is involved in a variety of pathophysiologic conditions in the liver, including hepatitis, steatosis, and drug-induced liver injury. The development of easy-to-perform and reliable in vivo assays would thus greatly enhance the efforts to understand liver diseases and identify associated genes and potential drugs. In this study, we developed a transgenic zebrafish line that was suitable for the assessment of caspase 3 activity in the liver by using in vivo fluorescence imaging. The larvae of transgenic zebrafish dominantly expressed Casper3GR in the liver under control of the promoter of the phosphoenolpyruvate carboxykinase 1 gene. Casper3GR is composed of two fluorescent proteins, tagGFP and tagRFP, which are connected via a peptide linker that can be cleaved by activated caspase 3. Under tagGFP excitation conditions in zebrafish that were exposed to the well-characterized hepatotoxicant isoniazid, we detected increased and decreased fluorescence associated with tagGFP and tagRFP, respectively. This result suggests that isoniazid activates caspase 3 in the zebrafish liver, which digests the linker between tagGFP and tagRFP, resulting in a reduction in the Förster resonance energy transfer to tagRFP upon tagGFP excitation. We also detected isoniazid-induced inhibition of caspase 3 activity in zebrafish that were treated with the hepatoprotectants ursodeoxycholic acid and obeticholic acid. The transgenic zebrafish that were developed in this study could be a powerful tool for identifying both hepatotoxic and hepatoprotective drugs, as well as for analyzing the effects of the genes of interest to hepatic apoptosis. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

18 pages, 6170 KiB  
Article
Exacerbation of Liver Tumor Metastasis in twist1a+/xmrk+ Double Transgenic Zebrafish following Lipopolysaccharide or Dextran Sulphate Sodium Exposure
by Jeng-Wei Lu, Yuxi Sun, Liang-In Lin, Dong Liu and Zhiyuan Gong
Pharmaceuticals 2021, 14(9), 867; https://doi.org/10.3390/ph14090867 - 28 Aug 2021
Cited by 4 | Viewed by 2566
Abstract
The poor prognosis for patients with hepatocellular carcinoma (HCC) is related directly to metastasis. The Twist1 gene encodes for a transcription factor essential to embryogenesis. It has also been shown to promote epithelial-to-mesenchymal transition (EMT), invasion, and metastasis; however, there is currently [...] Read more.
The poor prognosis for patients with hepatocellular carcinoma (HCC) is related directly to metastasis. The Twist1 gene encodes for a transcription factor essential to embryogenesis. It has also been shown to promote epithelial-to-mesenchymal transition (EMT), invasion, and metastasis; however, there is currently no in vivo evidence that Twist1 plays a role in the metastasis of liver tumors. Zebrafish are increasingly being used as an alternative cancer model. In the current study, an adult-stage zebrafish HCC model was used to examine the synergistic effects of twist1a and xmrk, a well characterized oncogene, during HCC metastasis. We also examined the effects of two inflammatory agents, lipopolysaccharides (LPS) and dextran sulfate sodium (DSS), on the hepatocyte-specific expression of transgenic twist1a and xmrk. The conditional overexpression of twist1a and xmrk was shown to promote liver tumor metastasis in zebrafish, resulting in increased apoptosis and cell proliferation as well as tumor maintenance and propagation independent of the inherent EMT-inducing activity of xmrk. Exposing twist1a+/xmrk+ transgenic zebrafish to LPS or DSS was shown to promote metastasis, indicating that the overexpression of twist1a and xmrk led to crosstalk between the signaling pathways involved in EMT. This study provides important evidence pertaining to the largely overlooked effects of signaling crosstalk between twist1a and xmrk in regulating HCC metastasis. Our results also suggest that the co-expression of twist1a/xmrk in conjunction with exposure to LPS or DSS enhances HCC metastasis, and provides a valuable in vivo platform by which to investigate tumor initiation and metastasis in the study of liver cancer. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

28 pages, 62795 KiB  
Article
Hypoglycemic Activity of Aqueous Extract of Latex from Hancornia speciosa Gomes: A Study in Zebrafish and In Silico
by Rosana Tomazi, Ângela Costa Figueira, Adriana Maciel Ferreira, Diego Quaresma Ferreira, Gisele Custódio de Souza, Wandson Braamcamp de Souza Pinheiro, José Rodrigues Pinheiro Neto, Geilson Alcantara da Silva, Henrique Barros de Lima, Lorane Izabel da Silva Hage-Melim, Arlindo César Matias Pereira, José Carlos Tavares Carvalho and Sheylla Susan Moreira da Silva de Almeida
Pharmaceuticals 2021, 14(9), 856; https://doi.org/10.3390/ph14090856 - 26 Aug 2021
Cited by 2 | Viewed by 3495
Abstract
Hancornia speciosa Gomes is a tree native to Brazil and has therapeutic potential for several diseases. Ethnopharmacological surveys have reported that the plant is used as a hypoglycemic agent and to lose weight. This study aimed to evaluate the effects of the aqueous [...] Read more.
Hancornia speciosa Gomes is a tree native to Brazil and has therapeutic potential for several diseases. Ethnopharmacological surveys have reported that the plant is used as a hypoglycemic agent and to lose weight. This study aimed to evaluate the effects of the aqueous extract from H. speciosa latex (LxHs) in a zebrafish model of diabetes. The extract was evaluated through high-performance thin-layer chromatography (HTPLC), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FT-IR). We then tested treatments with LxHs (500, 1000, and 1500 mg/kg) by assessing blood glucose levels in alloxan-induced diabetic animals, and metformin was used as a control. The toxicity was evaluated through histopathology of the pancreas and biochemical assessment of serum levels of AST, ALT, creatinine, and urea. The extract was also assessed for acute toxicity through several parameters in embryos and adult animals. Finally, we performed in silico analysis through the SEA server and docking using the software GOLD. The phytochemical study showed the compounds cornoside, dihydrocornoide, and 1-O-methyl-myoinositol (bornesitol). The treatment with all doses of LxHs significantly decreased alloxan-induced hyperglycemia without any significant histological or biochemical abnormalities. No significant frequency of teratogenesis was observed in the embryos exposed to the extract, and no significant behavioral changes or deaths were observed in adult animals. In silico, the results showed a potential interaction between inositol and enzymes involved in carbohydrates’ metabolism. Overall, the results show a hypoglycemic activity of the extract in vivo, with no apparent toxicity. The computational studies suggest this could be at least partially due to the presence of bornesitol, since inositols can interact with carbohydrates’ enzymes. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

15 pages, 3779 KiB  
Article
Characteristics of the New Insulin-Resistant Zebrafish Model
by Youn Hee Nam, Isabel Rodriguez, Sung Woo Shin, Ji Heon Shim, Na Woo Kim, Min Cheol Kim, Seo Yule Jeong, Wanlapa Nuankaew, Bin Na Hong, Hyunggun Kim and Tong Ho Kang
Pharmaceuticals 2021, 14(7), 642; https://doi.org/10.3390/ph14070642 - 4 Jul 2021
Cited by 7 | Viewed by 3762
Abstract
Insulin resistance, which occurs when insulin levels are sufficiently high over a prolonged period, causing the cells to fail to respond normally to the hormone. As a system for insulin resistance and diabetes drug development, insulin-resistant rodent models have been clearly established, but [...] Read more.
Insulin resistance, which occurs when insulin levels are sufficiently high over a prolonged period, causing the cells to fail to respond normally to the hormone. As a system for insulin resistance and diabetes drug development, insulin-resistant rodent models have been clearly established, but there is a limitation to high-throughput drug screening. Recently, zebrafish have been identified as an excellent system for drug discovery and identification of therapeutic targets, but studies on insulin resistance models have not been extensively performed. Therefore, we aimed to make a rapid insulin-resistant zebrafish model that complements the existing rodent models. To establish this model, zebrafish were treated with 10 μM insulin for 48 h. This model showed characteristics of insulin-resistant disease such as damaged pancreatic islets. Then we confirmed the recovery of the pancreatic islets after pioglitazone treatment. In addition, it was found that insulin-resistant drugs have as significant an effect in zebrafish as in humans, and these results proved the value of the zebrafish insulin resistance model for drug selection. In addition, RNA sequencing was performed to elucidate the mechanism involved. KEGG pathway enrichment analysis of differentially expressed genes showed that insulin resistance altered gene expression due to the MAPK signaling and calcium signaling pathways. This model demonstrates the utility of the zebrafish model for drug testing and drug discovery in insulin resistance and diabetes. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

26 pages, 8512 KiB  
Article
Probiotic Bacteria with High Alpha-Gal Content Protect Zebrafish against Mycobacteriosis
by Iván Pacheco, Sandra Díaz-Sánchez, Marinela Contreras, Margarita Villar, Alejandro Cabezas-Cruz, Christian Gortázar and José de la Fuente
Pharmaceuticals 2021, 14(7), 635; https://doi.org/10.3390/ph14070635 - 30 Jun 2021
Cited by 15 | Viewed by 4226
Abstract
Mycobacteriosis affects wild fish and aquaculture worldwide, and alternatives to antibiotics are needed for an effective and environmentally sound control of infectious diseases. Probiotics have shown beneficial effects on fish growth, nutrient metabolism, immune responses, disease prevention and control, and gut microbiota with [...] Read more.
Mycobacteriosis affects wild fish and aquaculture worldwide, and alternatives to antibiotics are needed for an effective and environmentally sound control of infectious diseases. Probiotics have shown beneficial effects on fish growth, nutrient metabolism, immune responses, disease prevention and control, and gut microbiota with higher water quality. However, the identification and characterization of the molecules and mechanisms associated with probiotics is a challenge that requires investigation. To address this challenge, herein we used the zebrafish model for the study of the efficacy and mechanisms of probiotic interventions against tuberculosis. First, bacteria from fish gut microbiota were identified with high content of the surface glycotope Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) that has been shown to induce protective immune responses. The results showed that probiotics of selected bacteria with high α-Gal content, namely Aeromonas veronii and Pseudomonas entomophila, were biosafe and effective for the control of Mycobacterium marinum. Protective mechanisms regulating immunity and metabolism activated in response to α-Gal and probiotics with high α-Gal content included modification of gut microbiota composition, B-cell maturation, anti-α-Gal antibodies-mediated control of mycobacteria, induced innate immune responses, beneficial effects on nutrient metabolism and reduced oxidative stress. These results support the potential of probiotics with high α-Gal content for the control of fish mycobacteriosis and suggested the possibility of exploring the development of combined probiotic treatments alone and in combination with α-Gal for the control of infectious diseases. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

17 pages, 5527 KiB  
Article
3,4-Difluorobenzocurcumin Inhibits Vegfc-Vegfr3-Erk Signalling to Block Developmental Lymphangiogenesis in Zebrafish
by Kazuhide S. Okuda, Mei Fong Ng, Nur Faizah Ruslan, Neil I. Bower, Dedrick Soon Seng Song, Huijun Chen, Sungmin Baek, Philip S. Crosier, Katarzyna Koltowska, Jonathan W. Astin, Pei Jean Tan, Benjamin M. Hogan and Vyomesh Patel
Pharmaceuticals 2021, 14(7), 614; https://doi.org/10.3390/ph14070614 - 26 Jun 2021
Cited by 4 | Viewed by 3480
Abstract
Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vasculature, plays critical roles in disease, including in cancer metastasis and chronic inflammation. Preclinical and recent clinical studies have now demonstrated therapeutic utility for several anti-lymphangiogenic agents, but optimal agents and efficacy in different [...] Read more.
Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vasculature, plays critical roles in disease, including in cancer metastasis and chronic inflammation. Preclinical and recent clinical studies have now demonstrated therapeutic utility for several anti-lymphangiogenic agents, but optimal agents and efficacy in different settings remain to be determined. We tested the anti-lymphangiogenic property of 3,4-Difluorobenzocurcumin (CDF), which has previously been implicated as an anti-cancer agent, using zebrafish embryos and cultured vascular endothelial cells. We used transgenic zebrafish labelling the lymphatic system and found that CDF potently inhibits lymphangiogenesis during embryonic development. We also found that the parent compound, Curcumin, does not inhibit lymphangiogenesis. CDF blocked lymphatic and venous sprouting, and lymphatic migration in the head and trunk of the embryo. Mechanistically, CDF impaired VEGFC-VEGFR3-ERK signalling in vitro and in vivo. In an in vivo pathological model of Vegfc-overexpression, treatment with CDF rescued endothelial cell hyperplasia. CDF did not inhibit the kinase activity of VEGFR3 yet displayed more prolonged activity in vivo than previously reported kinase inhibitors. These findings warrant further assessment of CDF and its mode of action as a candidate for use in metastasis and diseases of aberrant lymphangiogenesis. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

13 pages, 2616 KiB  
Article
Pharmacokinetics in Zebrafish Embryos (ZFE) Following Immersion and Intrayolk Administration: A Fluorescence-Based Analysis
by Marlly Guarin, Annelii Ny, Noémie De Croze, Jan Maes, Marc Léonard, Pieter Annaert and Peter A. M. de Witte
Pharmaceuticals 2021, 14(6), 576; https://doi.org/10.3390/ph14060576 - 16 Jun 2021
Cited by 6 | Viewed by 2723
Abstract
Zebrafish embryos (ZFE) have increasingly gained in popularity as a model to perform safety screenings of compounds. Although immersion of ZFE is the main route of exposure used, evidence shows that not all small molecules are equally absorbed, possibly resulting in false-negative readouts [...] Read more.
Zebrafish embryos (ZFE) have increasingly gained in popularity as a model to perform safety screenings of compounds. Although immersion of ZFE is the main route of exposure used, evidence shows that not all small molecules are equally absorbed, possibly resulting in false-negative readouts and incorrect conclusions. In this study, we compared the pharmacokinetics of seven fluorescent compounds with known physicochemical properties that were administered to two-cell stage embryos by immersion or by IY microinjection. Absorption and distribution of the dyes were followed at various timepoints up to 120 hpf by spatiotemporal fluorescence imaging. The concentration (10 µM) and dose (2 mg/kg) used were selected as quantities typically applied in preclinical experiments and zebrafish studies. The data show that in the case of a lipophilic compound (log D: 1.73) the immersion procedure resulted in an intrabody exposure which is similar or higher than that seen after the IY microinjection. In contrast, zero to low intrabody exposure was reached after immersion of the embryos with less lipophilic compounds. In the latter case IY microinjection, a technical procedure that can be easily automated, is highly recommended. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Graphical abstract

14 pages, 8541 KiB  
Article
Evaluation of Dexamethasone-Induced Osteoporosis In Vivo Using Zebrafish Scales
by Siripat Chaichit, Takuto Sato, Huiqing Yu, Yu-ki Tanaka, Yasumitsu Ogra, Takamasa Mizoguchi and Motoyuki Itoh
Pharmaceuticals 2021, 14(6), 536; https://doi.org/10.3390/ph14060536 - 3 Jun 2021
Cited by 8 | Viewed by 3652
Abstract
Glucocorticoid-induced osteoporosis (GIOP) is a major cause of secondary osteoporosis, and the pathogenic mechanisms of GIOP remain to be elucidated. Here, we show a rapid dexamethasone-induced osteoporosis animal model using zebrafish scales. Intraperitoneal injection of dexamethasone over a 5-day period suppressed the regeneration [...] Read more.
Glucocorticoid-induced osteoporosis (GIOP) is a major cause of secondary osteoporosis, and the pathogenic mechanisms of GIOP remain to be elucidated. Here, we show a rapid dexamethasone-induced osteoporosis animal model using zebrafish scales. Intraperitoneal injection of dexamethasone over a 5-day period suppressed the regeneration of scales. Furthermore, the circularity of the newly formed regenerated scales was also slightly reduced compared to that of the control group on day 5. The changes in bone-related enzymes, such as cathepsin K, tartrate-resistant acid phosphatase (TRAP) for bone resorption, and alkaline phosphatase (ALP) for bone formation, provide insight into the progression of bone diseases; therefore, we further developed a method to measure the activities of cathepsin K, TRAP, and ALP using zebrafish scales. We found that a lysis buffer with detergent at neutral pH under sonication efficiently helped extract these three enzymes with high activity levels. Interestingly, treatment with a dexamethasone injection produced considerably higher levels of cathepsin K activity and a lower Ca/P ratio than those in the control group, suggesting that dexamethasone increased osteoclast activity, with no significant changes in the activities of TRAP and ALP. Our GIOP model and enzyme assay method could help to design better treatments for GIOP. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

15 pages, 2149 KiB  
Article
Identification of Lactate as a Cardiac Protectant by Inhibiting Inflammation and Cardiac Hypertrophy Using a Zebrafish Acute Heart Failure Model
by Elijah R. Haege, Hui-Chi Huang and Cheng-chen Huang
Pharmaceuticals 2021, 14(3), 261; https://doi.org/10.3390/ph14030261 - 15 Mar 2021
Cited by 6 | Viewed by 2386
Abstract
Acute heart failure (AHF) commonly arises from decompensated chronic heart failure or sudden structural and functional breakdown causing a decrease in cardiac contractility and consequently fluid accumulation and systemic congestion. Current treatment for AHF aims at reducing fluid overload and improving hemodynamic which [...] Read more.
Acute heart failure (AHF) commonly arises from decompensated chronic heart failure or sudden structural and functional breakdown causing a decrease in cardiac contractility and consequently fluid accumulation and systemic congestion. Current treatment for AHF aims at reducing fluid overload and improving hemodynamic which results in quick symptom relief but still poor prognostic outcome. This study utilizes a zebrafish AHF model induced by aristolochic acid (AA) to look for natural products that could attenuate the progression of AHF. The project started off by testing nearly seventy herbal crude extracts. Two of the positive extracts were from Chinese water chestnuts and are further studied in this report. After several rounds of chromatographical chemical fractionation and biological tests, a near pure fraction, named A2-4-2-4, with several hydrophilic compounds was found to attenuate the AA-induced AHF. A2-4-2-4 appeared to inhibit inflammation and cardiac hypertrophy by reducing MAPK signaling activity. Chemical analyses revealed that the major compound in A2-4-2-4 is actually lactate. Pure sodium lactate showed attenuation of the AA-induced AHF and inflammation and cardiac hypertrophy suppression as well, suggesting that the AHF attenuation ability in A2-4-2-4 is attributable to lactate. Our studies identify lactate as a cardiac protectant and a new therapeutic agent for AHF. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

13 pages, 5487 KiB  
Article
Probing the Effects of the FGFR-Inhibitor Derazantinib on Vascular Development in Zebrafish Embryos
by Maria P. Kotini, Felix Bachmann, Jochen Spickermann, Paul M. McSheehy and Markus Affolter
Pharmaceuticals 2021, 14(1), 25; https://doi.org/10.3390/ph14010025 - 30 Dec 2020
Cited by 4 | Viewed by 2688
Abstract
Angiogenesis is a fundamental developmental process and a hallmark of cancer progression. Receptor tyrosine kinases (RTK) are targets for cancer therapy which may include their action as anti-angiogenic agents. Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors (FGFRs) 1–3 as [...] Read more.
Angiogenesis is a fundamental developmental process and a hallmark of cancer progression. Receptor tyrosine kinases (RTK) are targets for cancer therapy which may include their action as anti-angiogenic agents. Derazantinib (DZB) is an inhibitor of the fibroblast growth factor receptors (FGFRs) 1–3 as well as other kinase targets including vascular endothelial growth factor receptor 2 (VEGFR2), colony stimulating factor-1 receptor (CSF1R) and platelet-derived growth factor beta receptor (PDGFRbeta). This study aimed to investigate the effect of DZB on blood vessel morphogenesis and to compare its activity to known specific FGFR and VEGFR inhibitors. For this purpose, we used the developing vasculature in the zebrafish embryo as a model system for angiogenesis in vivo. We show that DZB interferes with multiple angiogenic processes that are linked to FGF and VEGF signalling, revealing a potential dual role for DZB as a potent anti-angiogenic treatment. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

13 pages, 1931 KiB  
Article
An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity
by Eri Wakai, Yuya Suzumura, Kenji Ikemura, Toshiro Mizuno, Masatoshi Watanabe, Kazuhiko Takeuchi and Yuhei Nishimura
Pharmaceuticals 2020, 13(12), 480; https://doi.org/10.3390/ph13120480 - 20 Dec 2020
Cited by 7 | Viewed by 3577
Abstract
Cisplatin is widely used to treat various types of cancers, but it is often limited by nephrotoxicity. Here, we employed an integrated in silico and in vivo approach to identify potential treatments for cisplatin-induced nephrotoxicity (CIN). Using publicly available mouse kidney and human [...] Read more.
Cisplatin is widely used to treat various types of cancers, but it is often limited by nephrotoxicity. Here, we employed an integrated in silico and in vivo approach to identify potential treatments for cisplatin-induced nephrotoxicity (CIN). Using publicly available mouse kidney and human kidney organoid transcriptome datasets, we first identified a 208-gene expression signature for CIN and then used the bioinformatics database Cmap and Lincs Unified Environment (CLUE) to identify drugs expected to counter the expression signature for CIN. We also searched the adverse event database, Food and Drug Administration. Adverse Event Reporting System (FAERS), to identify drugs that reduce the reporting odds ratio of developing cisplatin-induced acute kidney injury. Palonosetron, a serotonin type 3 receptor (5-hydroxytryptamine receptor 3 (5-HT3R)) antagonist, was identified by both CLUE and FAERS analyses. Notably, clinical data from 103 patients treated with cisplatin for head and neck cancer revealed that palonosetron was superior to ramosetron in suppressing cisplatin-induced increases in serum creatinine and blood urea nitrogen levels. Moreover, palonosetron significantly increased the survival rate of zebrafish exposed to cisplatin but not to other 5-HT3R antagonists. These results not only suggest that palonosetron can suppress CIN but also support the use of in silico and in vivo approaches in drug repositioning studies. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

17 pages, 4193 KiB  
Article
Cytochrome P450 Expression and Chemical Metabolic Activity before Full Liver Development in Zebrafish
by Tasuku Nawaji, Natsumi Yamashita, Haruka Umeda, Shuangyi Zhang, Naohiro Mizoguchi, Masanori Seki, Takio Kitazawa and Hiroki Teraoka
Pharmaceuticals 2020, 13(12), 456; https://doi.org/10.3390/ph13120456 - 11 Dec 2020
Cited by 21 | Viewed by 2945
Abstract
Zebrafish are used widely in biomedical, toxicological, and developmental research, but information on their xenobiotic metabolism is limited. Here, we characterized the expression of 14 xenobiotic cytochrome P450 (CYP) subtypes in whole embryos and larvae of zebrafish (4 to 144 h post-fertilization (hpf)) [...] Read more.
Zebrafish are used widely in biomedical, toxicological, and developmental research, but information on their xenobiotic metabolism is limited. Here, we characterized the expression of 14 xenobiotic cytochrome P450 (CYP) subtypes in whole embryos and larvae of zebrafish (4 to 144 h post-fertilization (hpf)) and the metabolic activities of several representative human CYP substrates. The 14 CYPs showed various changes in expression patterns during development. Many CYP transcripts abruptly increased at about 96 hpf, when the hepatic outgrowth progresses; however, the expression of some cyp1s (1b1, 1c1, 1c2, 1d1) and cyp2r1 peaked at 48 or 72 hpf, before full liver development. Whole-mount in situ hybridization revealed cyp2y3, 2r1, and 3a65 transcripts in larvae at 55 hpf after exposure to rifampicin, phenobarbital, or 2,3,7,8-tetrachlorodibenzo-p-dioxin from 30 hpf onward. Marked conversions of diclofenac to 4′-hydroxydiclofenac and 5-hydroxydiclofenac, and of caffeine to 1,7-dimethylxanthine, were detected as early as 24 or 50 hpf. The rate of metabolism to 4’-hydroxydiclofenac was more marked at 48 and 72 hpf than at 120 hpf, after the liver had become almost fully developed. These findings reveal the expression of various CYPs involved in chemical metabolism in developing zebrafish, even before full liver development. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Graphical abstract

19 pages, 3454 KiB  
Article
Rapid In Vivo Validation of HDAC Inhibitor-Based Treatments in Neuroblastoma Zebrafish Xenografts
by Jagoda K Wrobel, Sara Najafi, Simay Ayhan, Charlotte Gatzweiler, Damir Krunic, Johannes Ridinger, Till Milde, Frank Westermann, Heike Peterziel, Benjamin Meder, Martin Distel, Olaf Witt and Ina Oehme
Pharmaceuticals 2020, 13(11), 345; https://doi.org/10.3390/ph13110345 - 27 Oct 2020
Cited by 17 | Viewed by 3737
Abstract
The survival rate among children with relapsed neuroblastomas continues to be poor, and thus new therapeutic approaches identified by reliable preclinical drug testing models are urgently needed. Zebrafish are a powerful vertebrate model in preclinical cancer research. Here, we describe a zebrafish neuroblastoma [...] Read more.
The survival rate among children with relapsed neuroblastomas continues to be poor, and thus new therapeutic approaches identified by reliable preclinical drug testing models are urgently needed. Zebrafish are a powerful vertebrate model in preclinical cancer research. Here, we describe a zebrafish neuroblastoma yolk sac model to evaluate efficacy and toxicity of histone deacetylase (HDAC) inhibitor treatments. Larvae were engrafted with fluorescently labeled, genetically diverse, established cell lines and short-term cultures of patient-derived primary cells. Engrafted tumors progressed locally and disseminated remotely in an intact environment. Combination treatments involving the standard chemotherapy doxorubicin and HDAC inhibitors substantially reduced tumor volume, induced tumor cell death, and inhibited tumor cell dissemination to the tail region. Hence, this model allows for fast, cost-efficient, and reliable in vivo evaluation of toxicity and response of the primary and metastatic tumor sites to drug combinations. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

Review

Jump to: Research

19 pages, 887 KiB  
Review
Zebrafish as a Model System to Study the Mechanism of Cutaneous Wound Healing and Drug Discovery: Advantages and Challenges
by Ruth Naomi, Hasnah Bahari, Muhammad Dain Yazid, Hashim Embong and Fezah Othman
Pharmaceuticals 2021, 14(10), 1058; https://doi.org/10.3390/ph14101058 - 18 Oct 2021
Cited by 21 | Viewed by 4797
Abstract
In humans, cutaneous wounds may heal without scars during embryogenesis. However, in the adult phase, the similar wound may undergo a few events such as homeostasis, blood clotting, inflammation, vascularization, and the formation of granulation tissue, which may leave a scar at the [...] Read more.
In humans, cutaneous wounds may heal without scars during embryogenesis. However, in the adult phase, the similar wound may undergo a few events such as homeostasis, blood clotting, inflammation, vascularization, and the formation of granulation tissue, which may leave a scar at the injury site. In consideration of this, research evolves daily to improve the healing mechanism in which the wound may heal without scarring. In regard to this, zebrafish (Danio rerio) serves as an ideal model to study the underlying signaling mechanism of wound healing. This is an important factor in determining a relevant drug formulation for wound healing. This review scrutinizes the biology of zebrafish and how this favors the cutaneous wound healing relevant to the in vivo evidence. This review aimed to provide the current insights on drug discovery for cutaneous wound healing based on the zebrafish model. The advantages and challenges in utilizing the zebrafish model for cutaneous wound healing are discussed in this review. This review is expected to provide an idea to formulate an appropriate drug for cutaneous wound healing relevant to the underlying signaling mechanism. Therefore, this narrative review recapitulates current evidence from in vivo studies on the cutaneous wound healing mechanism, which favours the discovery of new drugs. This article concludes with the need for zebrafish as an investigation model for biomedical research in the future to ensure that drug repositions are well suited for human skin. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

16 pages, 982 KiB  
Review
Xenograft Zebrafish Models for the Development of Novel Anti-Hepatocellular Carcinoma Molecules
by Federica Tonon, Rossella Farra, Cristina Zennaro, Gabriele Pozzato, Nhung Truong, Salvatore Parisi, Flavio Rizzolio, Mario Grassi, Bruna Scaggiante, Fabrizio Zanconati, Deborah Bonazza, Gabriele Grassi and Barbara Dapas
Pharmaceuticals 2021, 14(8), 803; https://doi.org/10.3390/ph14080803 - 16 Aug 2021
Cited by 4 | Viewed by 2941
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of tumor and the second leading cause of tumor-related death worldwide. Liver cirrhosis is the most important predisposing factor for HCC. Available therapeutic approaches are not very effective, especially for advanced HCC, which is [...] Read more.
Hepatocellular carcinoma (HCC) is the sixth most common type of tumor and the second leading cause of tumor-related death worldwide. Liver cirrhosis is the most important predisposing factor for HCC. Available therapeutic approaches are not very effective, especially for advanced HCC, which is the most common form of the disease at diagnosis. New therapeutic strategies are therefore urgently needed. The use of animal models represents a relevant tool for preclinical screening of new molecules/strategies against HCC. However, several issues, including animal husbandry, limit the use of current models (rodent/pig). One animal model that has attracted the attention of the scientific community in the last 15 years is the zebrafish. This freshwater fish has several attractive features, such as short reproductive time, limited space and cost requirements for husbandry, body transparency and the fact that embryos do not show immune response to transplanted cells. To date, two different types of zebrafish models for HCC have been developed: the transgenic zebrafish and the zebrafish xenograft models. Since transgenic zebrafish models for HCC have been described elsewhere, in this review, we focus on the description of zebrafish xenograft models that have been used in the last five years to test new molecules/strategies against HCC. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Graphical abstract

19 pages, 1322 KiB  
Review
Zebrafish Model in Ophthalmology to Study Disease Mechanism and Drug Discovery
by Yiwen Hong and Yan Luo
Pharmaceuticals 2021, 14(8), 716; https://doi.org/10.3390/ph14080716 - 25 Jul 2021
Cited by 17 | Viewed by 5028
Abstract
Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish (Danio rerio) is an alternative vertebrate model as a useful tool [...] Read more.
Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish (Danio rerio) is an alternative vertebrate model as a useful tool for the mechanism elucidation and drug discovery of various eye disorders, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration, photoreceptor degeneration, etc. The genetic and embryonic accessibility of zebrafish in combination with a behavioral assessment of visual function has made it a very popular model in ophthalmology. Zebrafish has also been widely used in ocular drug discovery, such as the screening of new anti-angiogenic compounds or neuroprotective drugs, and the oculotoxicity test. In this review, we summarized the applications of zebrafish as the models of eye disorders to study disease mechanism and investigate novel drug treatments. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

18 pages, 1617 KiB  
Review
Zebrafish as a Model for Anticancer Nanomedicine Studies
by Hissa F. Al-Thani, Samar Shurbaji and Huseyin C. Yalcin
Pharmaceuticals 2021, 14(7), 625; https://doi.org/10.3390/ph14070625 - 28 Jun 2021
Cited by 8 | Viewed by 6001
Abstract
Nanomedicine is a new approach to fight against cancer by the development of anticancer nanoparticles (NPs) that are of high sensitivity, specificity, and targeting ability to detect cancer cells, such as the ability of Silica NPs in targeting epithelial cancer cells. However, these [...] Read more.
Nanomedicine is a new approach to fight against cancer by the development of anticancer nanoparticles (NPs) that are of high sensitivity, specificity, and targeting ability to detect cancer cells, such as the ability of Silica NPs in targeting epithelial cancer cells. However, these anticancer NPs require preclinical testing, and zebrafish is a useful animal model for preclinical studies of anticancer NPs. This model affords a large sample size, optical imaging, and easy genetic manipulation that aid in nanomedicine studies. This review summarizes the numerous advantages of the zebrafish animal model for such investigation, various techniques for inducing cancer in zebrafish, and discusses the methods to assess cancer development in the model and to test for the toxicity of the anticancer drugs and NPs. In addition, it summarizes the recent studies that used zebrafish as a model to test the efficacy of several different anticancer NPs in treating cancer. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

14 pages, 668 KiB  
Review
Zebrafish: An Attractive Model to Study Staphylococcus aureus Infection and Its Use as a Drug Discovery Tool
by Sari Rasheed, Franziska Fries, Rolf Müller and Jennifer Herrmann
Pharmaceuticals 2021, 14(6), 594; https://doi.org/10.3390/ph14060594 - 21 Jun 2021
Cited by 13 | Viewed by 5320
Abstract
Non-mammalian in vivo disease models are particularly popular in early drug discovery. Zebrafish (Danio rerio) is an attractive vertebrate model, the success of which is driven by several advantages, such as the optical transparency of larvae, the small and completely sequenced genome, [...] Read more.
Non-mammalian in vivo disease models are particularly popular in early drug discovery. Zebrafish (Danio rerio) is an attractive vertebrate model, the success of which is driven by several advantages, such as the optical transparency of larvae, the small and completely sequenced genome, the small size of embryos and larvae enabling high-throughput screening, and low costs. In this review, we highlight zebrafish models of Staphyloccoccus aureus infection, which are used in drug discovery and for studying disease pathogenesis and virulence. Further, these infection models are discussed in the context of other relevant zebrafish models for pharmacological and toxicological studies as part of early drug profiling. In addition, we examine key differences to commonly applied models of S. aureus infection based on invertebrate organisms, and we compare their frequency of use in academic research covering the period of January 2011 to January 2021. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Graphical abstract

26 pages, 2218 KiB  
Review
Zebrafish as a Screening Model to Study the Single and Joint Effects of Antibiotics
by Roxana Jijie, Gabriela Mihalache, Ioana-Miruna Balmus, Stefan-Adrian Strungaru, Emanuel Stefan Baltag, Alin Ciobica, Mircea Nicoara and Caterina Faggio
Pharmaceuticals 2021, 14(6), 578; https://doi.org/10.3390/ph14060578 - 17 Jun 2021
Cited by 28 | Viewed by 4765
Abstract
The overuse of antibiotics combined with the limitation of wastewater facilities has resulted in drug residue accumulation in the natural environment. Thus, in recent years, the presence of antibiotic residues in the environment has raised concerns over the potential harmful effects on ecosystems [...] Read more.
The overuse of antibiotics combined with the limitation of wastewater facilities has resulted in drug residue accumulation in the natural environment. Thus, in recent years, the presence of antibiotic residues in the environment has raised concerns over the potential harmful effects on ecosystems and human health. The in vivo studies represent an essential step to study the potential impact induced by pharmaceutical exposure. Due to the limitations of traditional vertebrate model systems, zebrafish (Danio rerio) has recently emerged as a promising animal model to study the toxic effects of drugs and their therapeutic efficacy. The present review summarizes the recent advances made on the toxicity of seven representative classes of antibiotics, namely aminoglycosides, β-lactams, macrolides, quinolones, sulfonamides, tetracyclines and polyether antibiotics, in zebrafish, as well as the combined effects of antibiotic mixtures, to date. Despite a significant amount of the literature describing the impact of single antibiotic exposure, little information exists on the effects of antibiotic mixtures using zebrafish as an animal model. Most of the research papers on this topic have focused on antibiotic toxicity in zebrafish across different developmental stages rather than on their efficacy assessment. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

20 pages, 2866 KiB  
Review
Zebrafish, an In Vivo Platform to Screen Drugs and Proteins for Biomedical Use
by Hung-Chieh Lee, Cheng-Yung Lin and Huai-Jen Tsai
Pharmaceuticals 2021, 14(6), 500; https://doi.org/10.3390/ph14060500 - 24 May 2021
Cited by 17 | Viewed by 7011
Abstract
The nearly simultaneous convergence of human genetics and advanced molecular technologies has led to an improved understanding of human diseases. At the same time, the demand for drug screening and gene function identification has also increased, albeit time- and labor-intensive. However, bridging the [...] Read more.
The nearly simultaneous convergence of human genetics and advanced molecular technologies has led to an improved understanding of human diseases. At the same time, the demand for drug screening and gene function identification has also increased, albeit time- and labor-intensive. However, bridging the gap between in vitro evidence from cell lines and in vivo evidence, the lower vertebrate zebrafish possesses many advantages over higher vertebrates, such as low maintenance, high fecundity, light-induced spawning, transparent embryos, short generation interval, rapid embryonic development, fully sequenced genome, and some phenotypes similar to human diseases. Such merits have popularized the zebrafish as a model system for biomedical and pharmaceutical studies, including drug screening. Here, we reviewed the various ways in which zebrafish serve as an in vivo platform to perform drug and protein screening in the fields of rare human diseases, social behavior and cancer studies. Since zebrafish mutations faithfully phenocopy many human disorders, many compounds identified from zebrafish screening systems have advanced to early clinical trials, such as those for Adenoid cystic carcinoma, Dravet syndrome and Diamond–Blackfan anemia. We also reviewed and described how zebrafish are used to carry out environmental pollutant detection and assessment of nanoparticle biosafety and QT prolongation. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-21
Back to TopTop