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Fishing for Health: Zebrafish Models of Human Disease

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (1 April 2022) | Viewed by 33397

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Special Issue Editors

Dr. Kinga Gawel

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Guest Editor

Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 8b Jaczewskiego Str., 20-090 Lublin, Poland
Interests: epilepsy; neuropharmacology; zebrafish; behavioral neuroscience; genetic models; screening; deep phenotyping
Special Issues, Collections and Topics in MDPI journals

Dr. Wietske van der Ent

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Guest Editor

Centre for Molecular Medicine, University of Oslo, Oslo, Norway
Interests: neurodevelopmental disorders; pediatric cancer; transgenic animal model development; imaging technologies; high-throughput technologies

Dr. Tomasz K. Prajsnar

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Guest Editor

Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
Interests: infectious and inflammatory diseases; bacterial infection; host–pathogen interactions; autophagic response to intracellular pathogens

Special Issue Information

Dear Colleagues,

Zebrafish is now a highly recognized model in biomedical research and for numerous human diseases. This small fish possesses multiple advantages which make it an excellent alternative and complementary system to rodents. Among those advantages, rapid external development, transparent embryos and larvae, as well as high number of offspring from one mating pair should be highlighted. Thus, zebrafish has been shown to be a very useful model organism in, for example, toxicologic and pharmacological assessment using high-throughput screening platforms. Additionally, the zebrafish genome has been sequenced and ca. 80% of genes represent a human orthologue. The growing number of genetic tools allows for very quick and efficient modeling of different diseases with a genetic origin. Moreover, zebrafish and human immune systems are highly similar which, together with the optical transparency of larval zebrafish, has made zebrafish a successful model of immune-related diseases which can be visualized in real time.

Here, in this Special Issue of Cells on “Fishing for Health: Zebrafish Models if Human Disease”, we invite colleagues from different fields ((neuro)developmental disorders, infectious and inflammatory disease, cancer, pharmacology, toxicology, etc.) working with zebrafish to submit novel research articles or reviews with zebrafish as a model of interest. This special issue is prepared with the support of The Polish Zebrafish Society (http://www.zebrafish.org.pl).

Dr. Kinga Gawel
Dr. Wietske van der Ent
Dr. Tomasz K. Prajsnar
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. Cells is an international peer-reviewed open access semimonthly 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 2700 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
toxicology
pharmacology
disease models
screening
host–pathogen interactions
infectious and inflammatory diseases

Published Papers (10 papers)

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Research

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15 pages, 4301 KiB

Open AccessArticle

A Zebrafish/Drosophila Dual System Model for Investigating Human Microcephaly

by Slawomir Bartoszewski, Mateusz Dawidziuk, Natalia Kasica, Roma Durak, Marta Jurek, Aleksandra Podwysocka, Dorothy Lys Guilbride, Piotr Podlasz, Cecilia Lanny Winata and Pawel Gawlinski

Cells 2022, 11(17), 2727; https://doi.org/10.3390/cells11172727 - 01 Sep 2022

Viewed by 1958

Abstract

Microcephaly presents in neurodevelopmental disorders with multiple aetiologies, including bi-allelic mutation in TUBGCP2, a component of the biologically fundamental and conserved microtubule-nucleation complex, γ-TuRC. Elucidating underlying principles driving microcephaly requires clear phenotype recapitulation and assay reproducibility, areas where go-to experimental models fall short. We present an alternative simple vertebrate/invertebrate dual system to investigate fundamental TUBGCP2-related processes driving human microcephaly and associated developmental traits. We show that antisense morpholino knockdown (KD) of the Danio rerio homolog, tubgcp2, recapitulates human TUBGCP2-associated microcephaly. Co-injection of wild type mRNA pre-empts microcephaly in 55% of KD zebrafish larvae, confirming causality. Body shortening observed in morphants is also rescued. Mitotic marker (pH3) staining further reveals aberrantly accumulated dividing brain cells in microcephalic tubgcp2 KD morphants, indicating that tubgcp2 depletion disrupts normal mitosis and/or proliferation in zebrafish neural progenitor brain cells. Drosophila melanogaster double knockouts (KO) for TUBGCP2 homologs Grip84/cg7716 also develop microcephalic brains with general microsomia. Exacerbated Grip84/cg7716-linked developmental aberration versus single mutations strongly suggests interactive or coinciding gene functions. We infer that tubgcp2 and Grip84/cg7716 affect brain size similarly to TUBGCP2 and recapitulate both microcephaly and microcephaly-associated developmental impact, validating the zebrafish/fly research model for human microcephaly. Given the conserved cross-phyla homolog function, the data also strongly support mitotic and/or proliferative disruption linked to aberrant microtubule nucleation in progenitor brain cells as key mechanistic defects for human microcephaly. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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18 pages, 3442 KiB

Open AccessArticle

Assessment of the Preventive Effect of L-carnitine on Post-statin Muscle Damage in a Zebrafish Model

by Joanna Niedbalska-Tarnowska, Katarzyna Ochenkowska, Marta Migocka-Patrzałek and Magda Dubińska-Magiera

Cells 2022, 11(8), 1297; https://doi.org/10.3390/cells11081297 - 11 Apr 2022

Cited by 3 | Viewed by 2351

Abstract

Statins, such as lovastatin, are lipid-lowering drugs (LLDs) that have been used to treat hypercholesterolaemia, defined as abnormally elevated cholesterol levels in the patient’s blood. Although statins are considered relatively safe and well tolerated, recipients may suffer from adverse effects, including post-statin myopathies. Many studies have shown that supplementation with various compounds may be beneficial for the prevention or treatment of side effects in patients undergoing statin therapy. In our study, we investigated whether L-carnitine administered to zebrafish larvae treated with lovastatin alleviates post-statin muscle damage. We found that exposure of zebrafish larvae to lovastatin caused skeletal muscle disruption observed as a reduction of birefringence, changes in muscle ultrastructure, and an increase in atrogin-1. Lovastatin also affected heart performance and swimming behaviour of larvae. Our data indicated that the muscle-protective effect of L-carnitine is partial. Some observed myotoxic effects, such as disruption of skeletal muscle and increase in atrogin-1 expression, heart contraction could be rescued by the addition of L-carnitine. Others, such as slowed heart rate and reduced locomotion, could not be mitigated by L-carnitine supplementation. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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15 pages, 2093 KiB

Open AccessArticle

The Inhibitory Effect of Selected D₂ Dopaminergic Receptor Agonists on VEGF-Dependent Neovascularization in Zebrafish Larvae: Potential New Therapy in Ophthalmic Diseases

by Natalia Kasica, Anna Święch, Katarzyna Saładziak, Jerzy Mackiewicz and Maciej Osęka

Cells 2022, 11(7), 1202; https://doi.org/10.3390/cells11071202 - 02 Apr 2022

Cited by 7 | Viewed by 2277

Abstract

Pathological angiogenesis is correlated with many ophthalmic diseases. The most common are exudative age-related macular degeneration and proliferative diabetic retinopathy. The current treatment for these diseases is based on regularly administered anti-VEGF antibodies injections. In the study, we investigated selected D₂ dopaminergic receptor agonists, namely bromocriptine, cabergoline and pergolide, on hypoxia-induced neovascularization. We used the zebrafish laboratory model, specifically three-day post fertilization (dpf) Tg(fli-1: EGFP) zebrafish larvae. To induce abnormal angiogenesis of hyaloid-retinal vessels (HRVs) and intersegmental vessels (ISVs), the larvae were treated with cobalt chloride (II) (CoCl₂) (a hypoxia-inducing agent) from 24 h post fertilization. The inhibitory role of D₂ dopaminergic receptor agonists was investigated using confocal microscopy and qPCR. Additionally, the results were compared to those obtained in the group treated with CoCl₂ followed by bevacizumab, the well-known antiangiogenic agent. Confocal microscopy analyses revealed severe deformation of vessels in the CoCl₂ treated group, while co-incubation with bromocriptine, cabergoline, pergolide and bevacizumab, respectively, significantly inhibited abnormalities of angiogenesis. The qPCR analyses supported the protective role of the chosen dopaminergic agonists by demonstrating their influence on CoCl₂-derived upregulation of vegfaa expression. The present results suggest that the D₂ receptor agonists can be considered as a new direction in research for antiangiogenic therapy. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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15 pages, 5411 KiB

Open AccessArticle

The Anti-Tumoral Potential of Phosphonate Analog of Sulforaphane in Zebrafish Xenograft Model

by Magdalena Rudzinska-Radecka, Łukasz Janczewski, Anna Gajda, Marlena Godlewska, Malgorzata Chmielewska-Krzesinska, Krzysztof Wasowicz and Piotr Podlasz

Cells 2021, 10(11), 3219; https://doi.org/10.3390/cells10113219 - 18 Nov 2021

Cited by 7 | Viewed by 2920

Abstract

Isothiocyanates (ITCs) show strong activity against numerous human tumors. Five structurally diverse ITCs were tested in vivo using the zebrafish embryos 6 and 48 h post-fertilization (hpf). The survival rate, hatching time, and gross morphological changes were assessed 24, 48, and 72 h after treatment with all compounds in various doses (1–10 µM). As a result, we selected a phosphonate analog of sulforaphane (P-ITC; 1–3 µM) as a non-toxic treatment for zebrafish embryos, both 6 and 48 hpf. Furthermore, the in vivo anti-cancerogenic studies with selected 3 µM P-ITC were performed using a set of cell lines derived from the brain (U87), cervical (HeLa), and breast (MDA-MB-231) tumors. For the experiment, cells were labeled using red fluorescence dye Dil (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindocarbocyanine, 10 μg/mL) and injected into the hindbrain ventricle, yolk sac region and Cuvier duct of zebrafish embryos. The tumor size measurement after 48 h of treatment demonstrated the significant inhibition of cancer cell growth in all tested cases by P-ITC compared to the non-treated controls. Our studies provided evidence for P-ITC anti-cancerogenic properties with versatile activity against different cancer types. Additionally, P-ITC demonstrated the safety of use in the living organism at various stages of embryogenesis. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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Graphical abstract

18 pages, 4349 KiB

Open AccessArticle

FDA-Approved Drug Screening for Compounds That Facilitate Hematopoietic Stem and Progenitor Cells (HSPCs) Expansion in Zebrafish

by Zhi Feng, Chenyu Lin, Limei Tu, Ming Su, Chunyu Song, Shengnan Liu, Michael Edbert Suryanto, Chung-Der Hsiao and Li Li

Cells 2021, 10(8), 2149; https://doi.org/10.3390/cells10082149 - 20 Aug 2021

Viewed by 2789

Abstract

Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs’ administration caused HSPCs diminishment and 118 drugs’ treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1^−/− mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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22 pages, 2249 KiB

Open AccessArticle

The Role of Galanin during Bacterial Infection in Larval Zebrafish

by Natalia Nowik, Tomasz K. Prajsnar, Anna Przyborowska, Krzysztof Rakus, Waldemar Sienkiewicz, Herman P. Spaink and Piotr Podlasz

Cells 2021, 10(8), 2011; https://doi.org/10.3390/cells10082011 - 06 Aug 2021

Cited by 3 | Viewed by 2555

Abstract

Galanin is a peptide that is conserved among different species and plays various roles in an organism, although its entire role is not completely understood. For many years, galanin has been linked mainly with the neurotransmission in the nervous system; however, recent reports underline its role in immunity. Zebrafish (Danio rerio) is an intensively developing animal model to study infectious diseases. In this study, we used larval zebrafish to determine the role of galanin in bacterial infection. We showed that knockout of galanin in zebrafish leads to a higher bacterial burden and mortality during Mycobacterium marinum and Staphylococcus aureus infection, whereas administration of a galanin analogue, NAX 5055, improves the ability of fish to control the infection caused by both pathogens. Moreover, the transcriptomics data revealed that a lower number of genes were regulated in response to mycobacterial infection in gal−/− mutants compared with their gal+/+ wild-type counterparts. We also found that galanin deficiency led to significant changes in immune-related pathways, mostly connected with cytokine and chemokine functions. The results show that galanin acts not only as a neurotransmitter but is also involved in immune response to bacterial infections, demonstrating the complexity of the neuroendocrine system and its possible connection with immunity. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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19 pages, 2521 KiB

Open AccessArticle

Antidepressant Screening Demonstrated Non-Monotonic Responses to Amitriptyline, Amoxapine and Sertraline in Locomotor Activity Assay in Larval Zebrafish

by Michael Edbert Suryanto, Gilbert Audira, Boontida Uapipatanakul, Akhlaq Hussain, Ferry Saputra, Petrus Siregar, Kelvin H.-C. Chen and Chung-Der Hsiao

Cells 2021, 10(4), 738; https://doi.org/10.3390/cells10040738 - 26 Mar 2021

Cited by 15 | Viewed by 4356

Abstract

Antidepressants are well-known drugs to treat depression and major depressive disorder for humans. However, the misuse and abuse of antidepressants keep increasing with several side effects reported. The aim of this study was to assess the potential adverse effects of 18 antidepressants by monitoring zebrafish larval locomotor activity performance based on the total distance traveled, burst movement count, and total rotation count at four dark-light intercalated phases. In general, zebrafish larvae displayed sedative effects after antidepressant exposure by showing a significant reduction in all of the locomotor activity-related endpoints. However, three antidepressants i.e., amitriptyline, amoxapine, and sertraline were able to trigger a significantly high locomotor activity in zebrafish larvae during the light cycle. These differences might be due to the pharmacologic differences among the antidepressants. In addition, since each antidepressant possesses a different dosage range from the other, overdoses of these antidepressants might also be the causes of these differences. Furthermore, based on these results, a further study was conducted to observe the effect of these three antidepressants in lower concentrations. From the results, biphasic effects in terms of zebrafish larval locomotor activity were demonstrated by these drugs. Even though further studies are still required to validate the mechanism, these findings indicate that these antidepressants might share a common mechanism responsible for their effects on zebrafish larval locomotor activity although there were some differences in potency of these effects. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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16 pages, 6034 KiB

Open AccessArticle

P-Glycoprotein Inhibitor Tariquidar Plays an Important Regulatory Role in Pigmentation in Larval Zebrafish

by Natalia Kasica, Piotr Jakubowski and Jerzy Kaleczyc

Cells 2021, 10(3), 690; https://doi.org/10.3390/cells10030690 - 20 Mar 2021

Cited by 3 | Viewed by 2480

Abstract

Zebrafish has emerged as a powerful model in studies dealing with pigment development and pathobiology of pigment diseases. Due to its conserved pigment pattern with established genetic background, the zebrafish is used for screening of active compounds influencing melanophore, iridophore, and xanthophore development and differentiation. In our study, zebrafish embryos and larvae were used to investigate the influence of third-generation noncompetitive P-glycoprotein inhibitor, tariquidar (TQR), on pigmentation, including phenotype effects and changes in gene expression of chosen chromatophore differentiation markers. Five-day exposure to increasing TQR concentrations (1 µM, 10 µM, and 50 µM) resulted in a dose-dependent augmentation of the area covered with melanophores but a reduction in the area covered by iridophores. The observations were performed in three distinct regions—the eye, dorsal head, and tail. Moreover, TQR enhanced melanophore renewal after depigmentation caused by 0.2 mM 1-phenyl-2-thiourea (PTU) treatment. qPCR analysis performed in 56-h post-fertilization (hpf) embryos demonstrated differential expression patterns of genes related to pigment development and differentiation. The most substantial findings include those indicating that TQR had no significant influence on leukocyte tyrosine kinase, GTP cyclohydrolase 2, tyrosinase-related protein 1, and forkhead box D3, however, markedly upregulated tyrosinase, dopachrome tautomerase and melanocyte inducing transcription factor, and downregulated purine nucleoside phosphorylase 4a. The present study suggests that TQR is an agent with multidirectional properties toward pigment cell formation and distribution in the zebrafish larvae and therefore points to the involvement of P-glycoprotein in this process. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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Review

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19 pages, 1887 KiB

Open AccessReview

Oxidative Stress and AKT-Associated Angiogenesis in a Zebrafish Model and Its Potential Application for Withanolides

by Jen-Yang Tang, Yuan-Bin Cheng, Ya-Ting Chuang, Kun-Han Yang, Fang-Rong Chang, Wangta Liu and Hsueh-Wei Chang

Cells 2022, 11(6), 961; https://doi.org/10.3390/cells11060961 - 11 Mar 2022

Cited by 8 | Viewed by 3246

Abstract

Oxidative stress and the AKT serine/threonine kinase (AKT) signaling pathway are essential regulators in cellular migration, metastasis, and angiogenesis. More than 300 withanolides were discovered from the plant family Solanaceae, exhibiting diverse functions. Notably, the relationship between oxidative stress, AKT signaling, and angiogenesis in withanolide treatments lacks comprehensive understanding. Here, we summarize connecting evidence related to oxidative stress, AKT signaling, and angiogenesis in the zebrafish model. A convenient vertebrate model monitored the in vivo effects of developmental and tumor xenograft angiogenesis using zebrafish embryos. The oxidative stress and AKT-signaling-modulating abilities of withanolides were highlighted in cancer treatments, which indicated that further assessments of their angiogenesis-modulating potential are necessary in the future. Moreover, targeting AKT for inhibiting AKT and its AKT signaling shows the potential for anti-migration and anti-angiogenesis purposes for future application to withanolides. This particularly holds for investigating the anti-angiogenetic effects mediated by the oxidative stress and AKT signaling pathways in withanolide-based cancer therapy in the future. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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16 pages, 2868 KiB

Open AccessReview

Muscle Glycogen Phosphorylase and Its Functional Partners in Health and Disease

by Marta Migocka-Patrzałek and Magdalena Elias

Cells 2021, 10(4), 883; https://doi.org/10.3390/cells10040883 - 13 Apr 2021

Cited by 27 | Viewed by 6437

Abstract

Glycogen phosphorylase (PG) is a key enzyme taking part in the first step of glycogenolysis. Muscle glycogen phosphorylase (PYGM) differs from other PG isoforms in expression pattern and biochemical properties. The main role of PYGM is providing sufficient energy for muscle contraction. However, it is expressed in tissues other than muscle, such as the brain, lymphoid tissues, and blood. PYGM is important not only in glycogen metabolism, but also in such diverse processes as the insulin and glucagon signaling pathway, insulin resistance, necroptosis, immune response, and phototransduction. PYGM is implicated in several pathological states, such as muscle glycogen phosphorylase deficiency (McArdle disease), schizophrenia, and cancer. Here we attempt to analyze the available data regarding the protein partners of PYGM to shed light on its possible interactions and functions. We also underline the potential for zebrafish to become a convenient and applicable model to study PYGM functions, especially because of its unique features that can complement data obtained from other approaches. Full article

(This article belongs to the Special Issue Fishing for Health: Zebrafish Models of Human Disease)

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