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Fish as Simple Models for Human Disease and Drug Screen

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 33044

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Prof. Dr. Chung-Der Hsiao

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Guest Editor

Epidermal Stem Cell Lab, Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li 320314, Taiwan
Interests: deep learning; image analysis; aquatic animal physiology and toxicology; new tool invention
Special Issues, Collections and Topics in MDPI journals

Dr. Jung-Ren Chen

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Co-Guest Editor

Department of Biological Science & Technology College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
Interests: drug screen; zebrafish disease model; bone development and disease; toxicology; multiple omics; cardiovascular function

Special Issue Information

Dear Colleagues,

Traditionally, rodents were used as a typical small animal model for human diseases. However, due to the animal 3R (replacement, reduction, and refinement) principles, lower vertebrate alternatives or non-vertebrate models have been proposed. For lower vertebrate animal models, zebrafish and other teleost, such as medaka and annual fish, have been recognized as excellent models for studying human diseases in several different fields, including aging, obesity, bone disease, cancer, and neurobehavioral disorders. This Special Issue of Biomolecules will particularly welcome researchers who use fish as a model to address problems relating to human diseases. Disease models generated by mutant screening, genome editing or transgenesis that recapitulate human diseases are especially welcome. Research on small molecule drugs or chemicals that can induce disease-like symptoms is also highly appreciated. In addition, novel tools or methodology capable of performing physiological assessment in fish are also suitable for publication in this Special Issue. This Special Issue of the Biomolecules journal invites researchers and clinicians around the world to submit their results or reviews within the field of “Fish as Simple Models for Human Disease and Drug Screen”.

Prof. Chung-Der Hsiao
Dr. Jung-Ren Chen
Guest Editors

Manuscript Submission Information

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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. Biomolecules 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 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

genome editing
CRISPR/Cas9
TALEN
transgenics
disease model
behavior
neurodegenerative disease
tissue regeneration
apoptosis
wound healing
obesity
cardiovascular dysfunction
heart disease
arrythmia
cancer
aging
depression
anxiety
behavioral abnormality
locomotor alteration
high-throughput/high-content drug screen
zebrafish
medaka
annual fish/killifish

Published Papers (10 papers)

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Research

12 pages, 2101 KiB

Open AccessArticle

Mcm5 Represses Endodermal Migration through Cxcr4a-itgb1b Cascade Instead of Cell Cycle Control

by Yu Zhang, Jiamin Xia, Min Liu, Bingyu Chen, Min Yang, Xiaoping Yu, Yu Ou, Shurong Li, Xindong Liu, Yi Feng, Bingyin Su and Sizhou Huang

Biomolecules 2022, 12(2), 286; https://doi.org/10.3390/biom12020286 - 10 Feb 2022

Cited by 1 | Viewed by 2122

Abstract

Minichromosome maintenance protein 5 (MCM5) is a critical cell cycle regulator; its role in DNA replication is well known, but whether it is involved in the regulation of organogenesis in a cell cycle-independent way, is far from clear. In this study, we found that a loss of mcm5 function resulted in a mildly smaller liver, but that mcm5 overexpression led to liver bifida. Further, the data showed that mcm5 overexpression delayed endodermal migration in the ventral–dorsal axis and induced the liver bifida. Cell cycle analysis showed that a loss of mcm5 function, but not overexpression, resulted in cell cycle delay and increased cell apoptosis during gastrulation, implying that liver bifida was not the result of a cell cycle defect. In terms of its mechanism, our data proves that mcm5 represses the expression of cxcr4a, which sequentially causes a decrease in the expression of itgb1b during gastrulation. The downregulation of the cxcr4a-itgb1b cascade leads to an endodermal migration delay during gastrulation, as well as to the subsequent liver bifida during liver morphogenesis. In conclusion, our results suggest that in a cell cycle-independent way, mcm5 works as a gene expression regulator, either partially and directly, or indirectly repressing the expression of cxcr4a and the downstream gene itgb1b, to coordinate endodermal migration during gastrulation and liver location during liver organogenesis. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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10 pages, 1482 KiB

Open AccessCommunication

A Brief Analysis of Proteomic Profile Changes during Zebrafish Regeneration

by Zulvikar Syambani Ulhaq and William Ka Fai Tse

Biomolecules 2022, 12(1), 35; https://doi.org/10.3390/biom12010035 - 27 Dec 2021

Cited by 1 | Viewed by 2598

Abstract

Unlike mammals, zebrafish are capable to regenerate many of their organs, however, the response of tissue damage varies across tissues. Understanding the molecular mechanism behind the robust regenerative capacity in a model organism may help to identify and develop novel treatment strategies for mammals (including humans). Hence, we systematically analyzed the current literature on the proteome profile collected from different regenerated zebrafish tissues. Our analyses underlining that several proteins and protein families responsible as a component of cytoskeleton and structure, protein synthesis and degradation, cell cycle control, and energy metabolism were frequently identified. Moreover, target proteins responsible for the initiation of the regeneration process, such as inflammation and immune response were less frequently detected. This highlights the limitation of previous proteomic analysis and suggested a more sensitive modern proteomics analysis is needed to unfold the mechanism. This brief report provides a list of target proteins with predicted functions that could be useful for further biological studies. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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21 pages, 7014 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

An OpenCV-Based Approach for Automated Cardiac Rhythm Measurement in Zebrafish from Video Datasets

by Ali Farhan, Kevin Adi Kurnia, Ferry Saputra, Kelvin H.-C. Chen, Jong-Chin Huang, Marri Jmelou M. Roldan, Yu-Heng Lai and Chung-Der Hsiao

Biomolecules 2021, 11(10), 1476; https://doi.org/10.3390/biom11101476 - 07 Oct 2021

Cited by 9 | Viewed by 4037

Abstract

Cardiac arrhythmia has been defined as one of the abnormal heart rhythm symptoms, which is a common problem dealt with by cardiologists. Zebrafish were established as a powerful animal model with a transparent body that enables optical observation to analyze cardiac morphology and cardiac rhythm regularity. Currently, research has observed heart-related parameters in zebrafish, which used different approaches, such as starting from the use of fluorescent transgenic zebrafish, different software, and different observation methods. In this study, we developed an innovative approach by using the OpenCV library to measure zebrafish larvae heart rate and rhythm. The program is designed in Python, with the feature of multiprocessing for simultaneous region-of-interest (ROI) detection, covering both the atrium and ventricle regions in the video, and was designed to be simple and user-friendly, having utility even for users who are unfamiliar with Python. Results were validated with our previously published method using ImageJ, which observes pixel changes. In summary, the results showed good consistency in heart rate-related parameters. In addition, the established method in this study also can be widely applied to other invertebrates (like Daphnia) for cardiac rhythm measurement. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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14 pages, 5895 KiB

Open AccessArticle

Establishment of a Drug Screening Model for Cardiac Complications of Acute Renal Failure

by Shuyi Liao, Wenmin Yang, Ting Yu, Lu Dai, Xiaoliang Liu, Jiangping Zhang, Jinghong Zhao and Chi Liu

Biomolecules 2021, 11(9), 1370; https://doi.org/10.3390/biom11091370 - 16 Sep 2021

Cited by 3 | Viewed by 2489

Abstract

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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16 pages, 7201 KiB

Open AccessFeature PaperArticle

TCMacro: A Simple and Robust ImageJ-Based Method for Automated Measurement of Tail Coiling Activity in Zebrafish

by Kevin Adi Kurnia, Fiorency Santoso, Bonifasius Putera Sampurna, Gilbert Audira, Jong-Chin Huang, Kelvin H.-C. Chen and Chung-Der Hsiao

Biomolecules 2021, 11(8), 1133; https://doi.org/10.3390/biom11081133 - 01 Aug 2021

Cited by 3 | Viewed by 3184

Abstract

Tail coiling is a reflection response in fish embryos that can be used as a model for neurotoxic analysis. The previous method to analyze fish tail coiling is largely based on third-party software. In this study, we aim to develop a simple and cost-effective method called TCMacro by using ImageJ macro to reduce the operational complexity. The basic principle of the current method is based on the dynamic change of pixel intensity in the region of interest (ROI). When the fish tail is moving, the average intensity is increasing. In time when the fish freeze, the peak of mean intensity is maintaining at a relatively low level. By using the optimized macro settings and excel VBA scripts, all the tail coiling measurement processes can be archived with few operation steps with high precision. Three major endpoints of tail coiling counts, tail coiling duration and tail coiling intervals can be obtained in batch. To validate this established method, we tested the potential neurotoxic activity of Tricaine (methanesulfonate, MS-222) and psychoactive compound of caffeine. Zebrafish embryos after Tricaine exposure displayed significantly less tail coiling activity in a dose-dependent manner, and were comparable to manual counting through the Wilcoxon test and Pearson correlation double validation. Zebrafish embryos after caffeine exposure displayed significantly high tail coiling activity. In conclusion, the TCMacro method presented in this study provides a simple and robust method that is able to measure the relative tail coiling activities in zebrafish embryos in a high-throughput manner. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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12 pages, 4195 KiB

Open AccessArticle

Effects of Diethylstilbestrol on Zebrafish Gonad Development and Endocrine Disruption Mechanism

by Xuan Liu, Xianyi Xie and Hongling Liu

Biomolecules 2021, 11(7), 941; https://doi.org/10.3390/biom11070941 - 25 Jun 2021

Cited by 2 | Viewed by 2502

Abstract

Environmental estrogen is a substance that functions as an endocrine hormone in organisms and can cause endocrine system disruption. A typical environmental estrogen, diethylstilbestrol (DES), can affect normal sexual function and organism development. However, even though the effects of different exposure stages of DES on the endocrine system and gonadal development of zebrafish juveniles are unknown, sex determination is strongly influenced by endocrine-disrupting chemicals (EDCs). From 10–90 days post fertilization (dpf), juvenile zebrafish were exposed to DES (100 and 1000 ng/L) in three different stages (initial development stage (IDS), 10–25 dpf; gonadal differentiation stage (GDS), 25–45 dpf and gonadal maturity stage (GMS), 45–60 dpf). Compared with that of IDS and GMS, the growth indicators (body length, body weight, and others) decreased significantly at GDS, and the proportion of zebrafish females exposed to 100 ng/L DES was significantly higher (by 59.65%) than that of the control; in addition, the zebrafish were biased towards female differentiation. The GDS is a critical period for sex differentiation. Our results show that exposure to environmental estrogen during the critical gonadal differentiation period not only affects the development of zebrafish, but also affects the population development. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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20 pages, 4342 KiB

Open AccessArticle

Innate Immune Response to Fasting and Refeeding in the Zebrafish Kidney

by Zongzhen Liao, Dihang Lin, Jirong Jia, Ran Cai, Yang Yu and Wensheng Li

Biomolecules 2021, 11(6), 825; https://doi.org/10.3390/biom11060825 - 01 Jun 2021

Cited by 11 | Viewed by 3527

Abstract

Animals acquire nutrients and energy through feeding to achieve a balance between growth and organismal health. When there is a change in nutrient acquisition, the state of growth changes and may also cause changes in the intrinsic immune system. Compensatory growth (CG), a specific growth phenomenon, involves the question of whether changes in growth can be accompanied by changes in innate immunity. The zebrafish (Danio rerio), a well-known fish model organism, can serve as a suitable model. In this study, the zebrafish underwent 3 weeks of fasting and refeeding for 3 to 7 day periods. It was found that CG could be achieved in zebrafish. Zebrafish susceptibility to Streptococcus agalactiae increased after starvation. In addition, the amount of melano-macrophage centers increased after fasting and the proportion of injured tubules increased after refeeding for 3 and 5 days, respectively. Furthermore, the kidneys of zebrafish suffering from starvation were under oxidative stress, and the activity of several antioxidant enzymes increased after starvation, including catalase, glutathione peroxidases and superoxide dismutase. Innate immune parameters were influenced by starvation. Additionally, the activity of alkaline phosphatase and lysozyme increased after starvation. The mRNA expression of immune-related genes like il-1β was elevated to a different extent after fasting with or without lipopolysaccharides (LPS) challenge. This study showed that the function of the innate immune system in zebrafish could be influenced by nutrition status. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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20 pages, 4223 KiB

Open AccessArticle

Zebrafish mafbb Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients

by Yujie Han, Weihao Shao, Dan Zhong, Cui Ma, Xiaona Wei, Abrar Ahmed, Tingting Yu, Wei Jing and Lili Jing

Biomolecules 2021, 11(3), 480; https://doi.org/10.3390/biom11030480 - 23 Mar 2021

Cited by 8 | Viewed by 2988

Abstract

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia with osteolysis at the carpal and tarsal bones. Heterozygous missense mutations in the transcription factor MAFB are found in patients with MCTO. MAFB is reported to negatively regulate osteoclastogenesis in vitro. However, the in vivo function of MAFB and its relation to MCTO remains unknown. In this study, we generated zebrafish MAFB homolog mafbb mutant utilizing CRISPR/Cas9 technology. Mafbb deficient zebrafish demonstrated enhanced osteoclast cell differentiation and abnormal cartilage and bone development resembling MCTO patients. It is known that osteoclasts are hematopoietic cells derived from macrophages. Loss of mafbb caused selective expansion of definitive macrophages and myeloid cells, supporting that mafbb restricts myeloid differentiation in vivo. We also demonstrate that MAFB MCTO mutations failed to rescue the defective osteoclastogenesis in mafbb^−/− embryos, but did not affect osteoclast cells in wild type embryos. The mechanism of MCTO mutations is likely haploinsufficiency. Zebrafish mafbb mutant provides a useful model to study the function of MAFB in osteoclastogenesis and the related MCTO disease. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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16 pages, 3366 KiB

Open AccessArticle

Generation and Application of the Zebrafish heg1 Mutant as a Cardiovascular Disease Model

by Shuxian Lu, Mengyan Hu, Zhihao Wang, Hongkai Liu, Yao Kou, Zhaojie Lyu and Jing Tian

Biomolecules 2020, 10(11), 1542; https://doi.org/10.3390/biom10111542 - 12 Nov 2020

Cited by 22 | Viewed by 3952

Abstract

Cardiovascular disease (CVD) is the leading cause of global mortality, which has caused a huge burden on the quality of human life. Therefore, experimental animal models of CVD have become essential tools for analyzing the pathogenesis, developing drug screening, and testing potential therapeutic strategies. In recent decades, zebrafish has entered the field of CVD as an important model organism. HEG1, a heart development protein with EGF like domains 1, plays important roles in the development of vertebrate cardiovascular system. Loss of HEG1 will affect the stabilization of vascular endothelial cell connection and eventually lead to dilated cardiomyopathy (DCM). Here, we generated a heg1-specific knockout zebrafish line using CRISPR/Cas9 technology. Zebrafish heg1 mutant demonstrated severe cardiovascular malformations, including atrial ventricular enlargement, heart rate slowing, venous thrombosis and slow blood flow, which were similar to human heart failure and thrombosis phenotype. In addition, the expression of zebrafish cardiac and vascular markers was abnormal in heg1 mutants. In order to apply zebrafish heg1 mutant in cardiovascular drug screening, four Traditional Chinese Medicine (TCM) herbs and three Chinese herbal monomers were used to treat heg1 mutant. The pericardial area, the distance between sinus venosus and bulbus arteriosus (SV-BA), heart rate, red blood cells (RBCs) accumulation in posterior cardinal vein (PCV), and blood circulation in the tail vein were measured to evaluate the therapeutic effects of those drugs on DCM and thrombosis. Here, a new zebrafish model of DCM and thrombosis was established, which was verified to be suitable for drug screening of cardiovascular diseases. It provided an alternative method for traditional in vitro screening, and produced potential clinical related drugs in a rapid and cost-effective way. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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17 pages, 2307 KiB

Open AccessArticle

Suppression of Inflammation Delays Hair Cell Regeneration and Functional Recovery Following Lateral Line Damage in Zebrafish Larvae

by Ru Zhang, Xiaopeng Liu, Yajuan Li, Ming Wang, Lin Chen and Bing Hu

Biomolecules 2020, 10(10), 1451; https://doi.org/10.3390/biom10101451 - 16 Oct 2020

Cited by 5 | Viewed by 3146

Abstract

Cochlear hair cells in human beings cannot regenerate after loss; however, those in fish and other lower species can. Recently, the role of inflammation in hair cell regeneration has been attracting the attention of scientists. In the present study, we investigated how suppression of inflammatory factors affects hair cell regeneration and the functional recovery of regenerated hair cells in zebrafish. We killed hair cells in the lateral line of zebrafish larvae with CuSO₄ to induce an inflammatory response and coapplied BRS-28, an anti-inflammatory agent to suppress the inflammation. The recovery of the hair cell number and rheotaxis was slower when CuSO₄ and BRS-28 were coapplied than when CuSO₄ was applied alone. The recovery of hair cell count lagged behind that of the calcium imaging signal during the regeneration. The calcium imaging signal in the neuromasts in the inflammation-inhibited group was weaker than that in the noninflammation-inhibited group at the early stage of regeneration, although it returned to normal at the late stage. Our study demonstrates that suppressing inflammation by BRS-28 delays hair cell regeneration and functional recovery when hair cells are damaged. We suspect that BRS-28 inhibits pro-inflammatory factors and thereby reduces the migration of macrophages to delay the regeneration of hair cells. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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