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21 pages, 3828 KiB

Open AccessArticle

Behavioral Effects of Developmental Exposure to JWH-018 in Wild-Type and Disrupted in Schizophrenia 1 (disc1) Mutant Zebrafish

by Judit García-González, Bruno de Quadros, William Havelange, Alistair J. Brock and Caroline H. Brennan

Biomolecules 2021, 11(2), 319; https://doi.org/10.3390/biom11020319 - 19 Feb 2021

Cited by 11 | Viewed by 4085

Abstract

Synthetic cannabinoids can cause acute adverse psychological effects, but the potential impact when exposure happens before birth is unknown. Use of synthetic cannabinoids during pregnancy may affect fetal brain development, and such effects could be moderated by the genetic makeup of an individual. [...] Read more.

Synthetic cannabinoids can cause acute adverse psychological effects, but the potential impact when exposure happens before birth is unknown. Use of synthetic cannabinoids during pregnancy may affect fetal brain development, and such effects could be moderated by the genetic makeup of an individual. Disrupted in schizophrenia 1 (DISC1) is a gene with important roles in neurodevelopment that has been associated with psychiatric disorders in pedigree analyses. Using zebrafish as a model, we investigated (1) the behavioral impact of developmental exposure to 3 μM 1-pentyl-3-(1-naphthoyl)-indole (JWH-018; a common psychoactive synthetic cannabinoid) and (2) whether disc1 moderates the effects of JWH-018. As altered anxiety responses are seen in several psychiatric disorders, we focused on zebrafish anxiety-like behavior. Zebrafish embryos were exposed to JWH-018 from one to six days post-fertilization. Anxiety-like behavior was assessed using forced light/dark and acoustic startle assays in larvae and novel tank diving in adults. Compared to controls, both acutely and developmentally exposed zebrafish larvae had impaired locomotion during the forced light/dark test, but anxiety levels and response to startle stimuli were unaltered. Adult zebrafish developmentally exposed to JWH-018 spent less time on the bottom of the tank, suggesting decreased anxiety. Loss-of-function in disc1 increased anxiety-like behavior in the tank diving assay but did not alter sensitivity to JWH-018. Results suggest developmental exposure to JWH-018 has a long-term behavioral impact in zebrafish, which is not moderated by disc1. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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20 pages, 3904 KiB

Open AccessArticle

Pharmacological Manipulation of Early Zebrafish Skeletal Development Shows an Important Role for Smad9 in Control of Skeletal Progenitor Populations

by Georgina L. K. McDonald, Mengdi Wang, Chrissy L. Hammond and Dylan J. M. Bergen

Biomolecules 2021, 11(2), 277; https://doi.org/10.3390/biom11020277 - 13 Feb 2021

Cited by 4 | Viewed by 3529

Abstract

Osteoporosis and other conditions associated with low bone density or quality are highly prevalent, are increasing as the population ages and with increased glucocorticoid use to treat conditions with elevated inflammation. There is an unmet need for therapeutics which can target skeletal precursors [...] Read more.

Osteoporosis and other conditions associated with low bone density or quality are highly prevalent, are increasing as the population ages and with increased glucocorticoid use to treat conditions with elevated inflammation. There is an unmet need for therapeutics which can target skeletal precursors to induce osteoblast differentiation and osteogenesis. Genes associated with high bone mass represent interesting targets for manipulation, as they could offer ways to increase bone density. A damaging mutation in SMAD9 has recently been associated with high bone mass. Here we show that Smad9 labels groups of osteochondral precursor cells, which are not labelled by the other Regulatory Smads: Smad1 or Smad5. We show that Smad9⁺ cells are proliferative, and that the Smad9⁺ pocket expands following osteoblast ablation which induced osteoblast regeneration. We further show that treatment with retinoic acid, prednisolone, and dorsomorphin all alter Smad9 expression, consistent with the effects of these drugs on the skeletal system. Taken together these results demonstrate that Smad9⁺ cells represent an undifferentiated osteochondral precursor population, which can be manipulated by commonly used skeletal drugs. We conclude that Smad9 represents a target for future osteoanabolic therapies. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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21 pages, 6630 KiB

Open AccessArticle

Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis

by Ozgun Ozalp, Ozge Cark, Yagmur Azbazdar, Betul Haykir, Gokhan Cucun, Ismail Kucukaylak, Gozde Alkan-Yesilyurt, Erdinc Sezgin and Gunes Ozhan

Biomolecules 2021, 11(1), 100; https://doi.org/10.3390/biom11010100 - 14 Jan 2021

Cited by 6 | Viewed by 4776

Abstract

Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases [...] Read more.

Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75^NTR), as a negative regulator of Wnt/β-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/β-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/β-catenin signaling during development. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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12 pages, 1530 KiB

Open AccessArticle

Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae

by Andrea Messina, Alessandra Boiti, Valeria Anna Sovrano and Paola Sgadò

Biomolecules 2020, 10(10), 1364; https://doi.org/10.3390/biom10101364 - 24 Sep 2020

Cited by 6 | Viewed by 2292

Abstract

Autism spectrum disorders (ASDs) comprise a genetically heterogeneous group of conditions characterized by a multifaceted range of impairments and multifactorial etiology. Epidemiological studies have identified valproic acid (VPA), an anticonvulsant used to treat epilepsy, as an environmental factor for ASDs. Based on these [...] Read more.

Autism spectrum disorders (ASDs) comprise a genetically heterogeneous group of conditions characterized by a multifaceted range of impairments and multifactorial etiology. Epidemiological studies have identified valproic acid (VPA), an anticonvulsant used to treat epilepsy, as an environmental factor for ASDs. Based on these observations, studies using embryonic exposure to VPA have been conducted in many vertebrate species to model ASD. The zebrafish is emerging as a popular model in biomedical research to study the molecular pathways involved in nervous system disorders. VPA exposure in zebrafish larvae has been shown to produce a plethora of effects on social, motor and anxiety behavior, and several genetic pathways altered by VPA have been described. However, the doses and regimen of administration reported in the literature are very heterogenous, creating contradictory results and posing serious limits to the interpretation of VPA action on neurodevelopment. To shed light on the toxic effect of VPA, we tested micromolar concentrations of VPA, using exposure for 24 and 48 h in two different zebrafish strains. Our results show that micromolar doses of VPA mildly affect embryo survival but are sufficient to induce molecular alterations in neurodevelopmental genes previously shown to be influenced by VPA, with substantial differences between strains. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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24 pages, 4259 KiB

Open AccessArticle

Validation of a Novel Zebrafish Model of Dengue Virus (DENV-3) Pathology Using the Pentaherbal Medicine Denguenil Vati

by Acharya Balkrishna, Siva Kumar Solleti, Sudeep Verma and Anurag Varshney

Biomolecules 2020, 10(7), 971; https://doi.org/10.3390/biom10070971 - 28 Jun 2020

Cited by 9 | Viewed by 12081

Abstract

Dengue is a devastating viral fever of humans, caused by dengue virus. Using a novel zebrafish model of dengue pathology, we validated the potential anti-dengue therapeutic properties of pentaherbal medicine, Denguenil Vati. At two different time points (at 7 and 14 days post [...] Read more.

Dengue is a devastating viral fever of humans, caused by dengue virus. Using a novel zebrafish model of dengue pathology, we validated the potential anti-dengue therapeutic properties of pentaherbal medicine, Denguenil Vati. At two different time points (at 7 and 14 days post infection with dengue virus), we tested three translational doses (5.8 μg/kg, 28 μg/kg, and 140 μg/kg). Dose- and time-dependent inhibition of the viral copy numbers was identified upon Denguenil Vati treatment. Hepatocyte necrosis, liver inflammation, and red blood cell (RBC) infiltration into the liver were significantly inhibited upon Denguenil treatment. Treatment with Denguenil Vati significantly recovered the virus-induced decreases in total platelet numbers and total RBC count, and concomitantly increasing hematocrit percentage, in a dose- and time-dependent manner. Conversely, virus-induced white blood cell (WBC) counts were significantly normalized. Virus-induced hemorrhage was completely abrogated by Denguenil after 14 days, at all the doses tested. Gene expression analysis identified a significant decrease in disease-induced endothelial apoptotic marker Angiopoetin2 (Ang-2) and pro-inflammatory chemokine marker CCL3 upon Denguenil treatment. Presence of gallic acid, ellagic acid, palmetin, and berberine molecules in the Denguenil formulation was detected by HPLC. Taken together, our results exhibit the potential therapeutic properties of Denguenil Vati in ameliorating pathological features of dengue. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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21 pages, 3488 KiB

Open AccessArticle

Application of Zebrafish Model in the Suppression of Drug-Induced Cardiac Hypertrophy by Traditional Indian Medicine Yogendra Ras

by Acharya Balkrishna, Yashika Rustagi, Kunal Bhattacharya and Anurag Varshney

Biomolecules 2020, 10(4), 600; https://doi.org/10.3390/biom10040600 - 13 Apr 2020

Cited by 9 | Viewed by 9131

Abstract

Zebrafish is an elegant vertebrate employed to model the pathological etiologies of human maladies such as cardiac diseases. Persistent physiological stresses can induce abnormalities in heart functions such as cardiac hypertrophy (CH), which can lead to morbidity and mortality. In the present study, [...] Read more.

Zebrafish is an elegant vertebrate employed to model the pathological etiologies of human maladies such as cardiac diseases. Persistent physiological stresses can induce abnormalities in heart functions such as cardiac hypertrophy (CH), which can lead to morbidity and mortality. In the present study, using zebrafish as a study model, efficacy of the traditional Indian Ayurveda medicine “Yogendra Ras” (YDR) was validated in ameliorating drug-induced cardiac hypertrophy. YDR was prepared using traditionally described methods and composed of nano- and micron-sized metal particles. Elemental composition analysis of YDR showed the presence of mainly Au, Sn, and Hg. Cardiac hypertrophy was induced in the zebrafish following a pretreatment with erythromycin (ERY), and the onset and reconciliation of disease by YDR were determined using a treadmill electrocardiogram, heart anatomy analysis, C-reactive protein release, and platelet aggregation time-analysis. YDR treatment of CH-induced zebrafish showed comparable results with the Standard-of-care drug, verapamil, tested in parallel. Under in-vitro conditions, treatment of isoproterenol (ISP)-stimulated murine cardiomyocytes (H9C2) with YDR resulted in the suppression of drug-stimulated biomarkers of oxidative stress: COX-2, NOX-2, NOX-4, ANF, troponin-I, -T, and cardiolipin. Taken together, zebrafish showed a strong disposition as a model for studying the efficacy of Ayurvedic medicines towards drug-induced cardiopathies. YDR provided strong evidence for its capability in modulating drug-induced CH through the restoration of redox homeostasis and exhibited potential as a viable complementary therapy. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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Review

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18 pages, 2234 KiB

Open AccessFeature PaperReview

Zebrafish Tools for Deciphering Habenular Network-Linked Mental Disorders

by Anja Bühler and Matthias Carl

Biomolecules 2021, 11(2), 324; https://doi.org/10.3390/biom11020324 - 20 Feb 2021

Cited by 9 | Viewed by 4291

Abstract

The prevalence of patients suffering from mental disorders is substantially increasing in recent years and represents a major burden to society. The underlying causes and neuronal circuits affected are complex and difficult to unravel. Frequent disorders such as depression, schizophrenia, autism, and bipolar [...] Read more.

The prevalence of patients suffering from mental disorders is substantially increasing in recent years and represents a major burden to society. The underlying causes and neuronal circuits affected are complex and difficult to unravel. Frequent disorders such as depression, schizophrenia, autism, and bipolar disorder share links to the habenular neural circuit. This conserved neurotransmitter system relays cognitive information between different brain areas steering behaviors ranging from fear and anxiety to reward, sleep, and social behaviors. Advances in the field using the zebrafish model organism have uncovered major genetic mechanisms underlying the formation of the habenular neural circuit. Some of the identified genes involved in regulating Wnt/beta-catenin signaling have previously been suggested as risk genes of human mental disorders. Hence, these studies on habenular genetics contribute to a better understanding of brain diseases. We are here summarizing how the gained knowledge on the mechanisms underlying habenular neural circuit development can be used to introduce defined manipulations into the system to study the functional behavioral consequences. We further give an overview of existing behavior assays to address phenotypes related to mental disorders and critically discuss the power but also the limits of the zebrafish model for identifying suitable targets to develop therapies. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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32 pages, 1229 KiB

Open AccessReview

Zebrafish Models of Photoreceptor Dysfunction and Degeneration

by Nicole C. L. Noel, Ian M. MacDonald and W. Ted Allison

Biomolecules 2021, 11(1), 78; https://doi.org/10.3390/biom11010078 - 09 Jan 2021

Cited by 20 | Viewed by 5007

Abstract

Zebrafish are an instrumental system for the generation of photoreceptor degeneration models, which can be utilized to determine underlying causes of photoreceptor dysfunction and death, and for the analysis of potential therapeutic compounds, as well as the characterization of regenerative responses. We review [...] Read more.

Zebrafish are an instrumental system for the generation of photoreceptor degeneration models, which can be utilized to determine underlying causes of photoreceptor dysfunction and death, and for the analysis of potential therapeutic compounds, as well as the characterization of regenerative responses. We review the wealth of information from existing zebrafish models of photoreceptor disease, specifically as they relate to currently accepted taxonomic classes of human rod and cone disease. We also highlight that rich, detailed information can be derived from studying photoreceptor development, structure, and function, including behavioural assessments and in vivo imaging of zebrafish. Zebrafish models are available for a diversity of photoreceptor diseases, including cone dystrophies, which are challenging to recapitulate in nocturnal mammalian systems. Newly discovered models of photoreceptor disease and drusenoid deposit formation may not only provide important insights into pathogenesis of disease, but also potential therapeutic approaches. Zebrafish have already shown their use in providing pre-clinical data prior to testing genetic therapies in clinical trials, such as antisense oligonucleotide therapy for Usher syndrome. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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24 pages, 2946 KiB

Open AccessReview

A Great Catch for Investigating Inborn Errors of Metabolism—Insights Obtained from Zebrafish

by Maximilian Breuer and Shunmoogum A. Patten

Biomolecules 2020, 10(9), 1352; https://doi.org/10.3390/biom10091352 - 22 Sep 2020

Cited by 9 | Viewed by 7011

Abstract

Inborn errors of metabolism cause abnormal synthesis, recycling, or breakdown of amino acids, neurotransmitters, and other various metabolites. This aberrant homeostasis commonly causes the accumulation of toxic compounds or depletion of vital metabolites, which has detrimental consequences for the patients. Efficient and rapid [...] Read more.

Inborn errors of metabolism cause abnormal synthesis, recycling, or breakdown of amino acids, neurotransmitters, and other various metabolites. This aberrant homeostasis commonly causes the accumulation of toxic compounds or depletion of vital metabolites, which has detrimental consequences for the patients. Efficient and rapid intervention is often key to survival. Therefore, it requires useful animal models to understand the pathomechanisms and identify promising therapeutic drug targets. Zebrafish are an effective tool to investigate developmental mechanisms and understanding the pathophysiology of disorders. In the past decades, zebrafish have proven their efficiency for studying genetic disorders owing to the high degree of conservation between human and zebrafish genes. Subsequently, several rare inherited metabolic disorders have been successfully investigated in zebrafish revealing underlying mechanisms and identifying novel therapeutic targets, including methylmalonic acidemia, Gaucher’s disease, maple urine disorder, hyperammonemia, TRAPPC11-CDGs, and others. This review summarizes the recent impact zebrafish have made in the field of inborn errors of metabolism. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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