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[Display omitted] • CQDs were non-toxic at low doses but harmful at higher concentrations to zebrafish. • The locomotor activity of zebrafish exposed to CQDs varies dose-dependently. • At high concentrations, CQDs cause morphological defects in zebrafish embryos. • In larvae, high CQD dosages result in dopamine decrease and organ damage. Fluorescent carbon dots have emerged as promising nanomaterials for various applications, including bioimaging, food safety detection and drug delivery. However, their potential impact on neurological systems, especially in-vivo models, remains a critical area of investigation. This review focuses on the neurological effects of carbon dots and carbon quantum dots on zebrafish, an established vertebrate model with a conserved central nervous system. Recent studies have demonstrated the efficient uptake and distribution of carbon dots in zebrafish tissues, with a particular affinity for neural tissues. The intricate neural architecture of zebrafish allows for the precise examination of behavioral changes and neurodevelopmental alterations induced by fluorescent carbon dots. Neurotoxicity assessments reveal both short-term and long-term effects, ranging from immediate behavioral alterations to subtle changes in neuronal morphology. The review discusses potential mechanisms underlying these effects highlights the need for standardized methodologies in assessing neurological outcomes and emphasizes the importance of ethical considerations in nanomaterial research. As the field of nanotechnology continues to advance, a comprehensive understanding of the impact of fluorescent carbon dots on neurological function in zebrafish is crucial for informing safe and sustainable applications in medicine and beyond. [ABSTRACT FROM AUTHOR]

A supplemented collagen peptide composition (SCPC) containing microbe-fermented collagen peptide, collagen tripeptide, elastin peptide, and sodium hyaluronate was investigated to determine its effects on skin aging, skin elasticity, and tissue regeneration in zebrafish. β-Galactosidase activity was inhibited, while telomerase activity was elevated, by exposure to 0.977 μL/mL of SCPC in an H 2 O 2 -induced aging zebrafish model, indicating that SCPC can delay cell senescence. Expression of the collagen I gene col1a1a was up-regulated by exposure to 62.5 μL/mL of SCPC, indicating that SCPC can improve skin elasticity. Regrowth of the injured caudal fin was enhanced by exposure to only 0.122 μL/mL of SCPC. These improvements to skin aging, elasticity, and tissue regeneration in zebrafish suggest that this SCPC has potential as a functional food with beneficial effects on skin health and aging resistance in humans. [Display omitted] • Zebrafish were used for building animal models. • Effects of the supplemented collagen peptide composition on the skin. • Inhibiting β-galactosidase activity and elevated telomerase activity. • Up-regulated the expression of collagen I gene col1a1a. • Enhanced the regrowth of injured caudal fin. [ABSTRACT FROM AUTHOR]

Based on recent single-cell transcriptomics and lineage tracing, sst1.1 + cell transdifferentiation and krt4 + cell differentiation have recently been recognized as the major sources of regeneration of insulin-producing cells in zebrafish. Large-scale in vivo small molecule screening has been successfully applied in zebrafish for the unbiased identification of chemicals promoting β-cell regeneration and glucose control. Multiple compounds have been validated to also promote β-cell proliferation, differentiation, or function in mammalian systems. Live imaging in zebrafish enables visualization of complex biological processes at the single-cell resolution in vivo (e.g., calcium flux in β-cells) as well as innervation and immune cell behaviors in the islet. Role of genes identified in human genetic data [e.g. genome-wide association studies (GWAS) and single-cell sequencing data] can be efficiently elucidated in zebrafish. The zebrafish has become an outstanding model for studying organ development and tissue regeneration, which is prominently leveraged for studies of pancreatic development, insulin-producing β-cells, and diabetes. Although studied for more than two decades, many aspects remain elusive and it has only recently been possible to investigate these due to technical advances in transcriptomics, chemical-genetics, genome editing, drug screening, and in vivo imaging. Here, we review recent findings on zebrafish pancreas development, β-cell regeneration, and how zebrafish can be used to provide novel insights into gene functions, disease mechanisms, and therapeutic targets in diabetes, inspiring further use of zebrafish for the development of novel therapies for diabetes. [ABSTRACT FROM AUTHOR]

• TMA+ exposure significantly inhibited the swimming activities of larval zebrafish. • Swimming path angle is the most sensitive endpoint in response to TMA+ exposure. • Neurobehavior endpoints of larvae were significantly related with oxidative stress. • The calculated 96 h-LC 50 of TMA+ was lower for zebrafish juveniles than larvae. • TMA+ evoked greater inhibitions on multi-biomarkers of juveniles than larvae. Tetramethylammonium hydroxide (TMAH) is an important compound that utilized and released by the rapidly expanding semiconductor industry, which could hardly be removed by the conventional wastewater treatment techniques. As a cholinergic agonist, the tetramethylammonium ion (TMA+) has been reported to induce toxicity to muscular and respiratory systems of mammals and human, however the toxicity on aquatic biota remains poorly known. We investigated the neurotoxic effects of TMA+ exposure on zebrafish, based on neurobehavior tests and a series of biomarkers. Significant inhibitions on the swimming distance of zebrafish larvae were observed when the exposure level exceeded 50 mg/L, and significant alterations on swimming path angles (straight and deflective movements) occurred even at 10 mg/L. The tested neurobehavioral endpoints of zebrafish larvae were significantly positively correlated with reactive oxygen species (ROS) and malondialdehyde (MDA), significantly negatively related with the activities of antioxidant enzymes, but not significantly correlated with the level of acetylcholinesterase (AChE). Such relationship indicates that the observed neurotoxic effects on swimming behavior of zebrafish larvae is mainly driven by oxidative stress, rather than the alterations of neurotransmitter. At the highest exposure concentration (200 mg/L), TMA+ evoked more severe toxicity on zebrafish juveniles, showing significantly stronger elevation on the MDA activity, and greater inhibitions on the activities of antioxidant enzymes and AChE, suggesting juveniles were more susceptible to TMA+ exposure than larval zebrafish. [Display omitted] [ABSTRACT FROM AUTHOR]

The prevalence of food allergies is on the rise, posing a significant challenge to public health. Rodents serve as the predominant animal model in food allergy research; yet, the application of rodent models proves to be a laborious and time-consuming endeavor. It is imperative to develop novel in vivo models. Ovalbumin (OVA) was administered as the allergen, following the recommended dosage used in other species. During the sensitization phase, a dosage of 0.25 mg per 10 tails per 1 L was administered twice daily, and during the challenge phase, the dosage was increased to 3 times the initial level. The study explored two dimensions of sensitization: the mode of exposure, which can be either continuous or intermittent, and the duration of exposure, which includes 3 days, 5 days, and 7 days. We examined midgut pathological changes, immunoglobulins contents, and mRNA expressions associated to T helper cells (Th) 2 cytokines following exposure. A significant 109.3 % increase in the number of eosinophils was observed in the midgut histopathology following intermittent 5-day OVA exposure, which emerged as the most effective model. OVA exposure increased concentrations of immunoglobulin M (IgM) (105.2 %), IgZ (312.1 %), and IgD (304.3 %) in this model. The mRNA expressions of Th2-related interleukin (IL)-4 and IL-13 were also elevated by 132.8 % and 421.0 %, respectively. The intermittent 5-day OVA exposure was suggested to be the best constructed zebrafish food allergy model, which may be a potential tool for research into food allergies. • Rodent food allergy models are laborious and tedious, novel models are needed. • The intermittent 5-day OVA exposure best simulates zebrafish food allergy model. • This work aims to enhance childhood health and promote sustainable aquaculture. [ABSTRACT FROM AUTHOR]

Eight novel clerodane diterpenoids (1 − 8) were isolated from the twigs of Casearia graveolens. Their structures were elucidated through comprehensive nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and electronic circular dichroism (ECD) analyses. In addition to structural determination, surface plasmon resonance (SPR) assays were conducted to investigate molecular interactions, revealing that compound 8 exhibited high affinity for vascular endothelial growth factor receptor 2 (VEGFR2), a key regulator of tumor angiogenesis. Subsequent in vivo experiments demonstrated that compound 8 effectively inhibited angiogenesis and displayed significant antitumor activity by suppressing tumor proliferation and metastasis in zebrafish xenograft models. These findings suggest that compound 8 holds promise as an anticancer lead compound targeting VEGFR-2 to obstruct tumor angiogenesis. [ABSTRACT FROM AUTHOR]

• Long-term exposure to neburon caused reproductive toxicity of male zebrafish. • Neburon exposure affected the reproductive behavior. • Neburon exposure affected sperm maturation and increased apoptosis in testes. • Neburon exposure disrupted hormone levels. Neburon is a phenylurea herbicide that is widely used worldwide, but its toxicity is poorly studied. In our previous study, we found that neburon has strong aryl hydrocarbon receptor (AhR) agonist activity, but whether it causes reproductive toxicity is not clear. In the present study, zebrafish were conducted as a model organism to evaluate whether environmental concentrations of neburon (0.1, 1 and 10 µg/L) induce reproductive disorder in males. After exposure to neburon for 150 days from embryo to adult, that the average spawning egg number in high concentration group was 106.40, which was significantly lower than 193.00 in control group. This result was mainly due to the abnormal male reproductive behavior caused by abnormal transcription of genes associated with reproductive behavior in the brain, such as secretogranin-2a. The proportions of spermatozoa in the medium and high concentration groups were 82.40% and 83.84%, respectively, which were significantly lower than 89.45% in control group. This result was mainly caused by hormonal disturbances and an increased proportion of apoptotic cells. The hormonal disruption was due to the significant changes in the transcription levels of key genes in the hypothalamus-pituitary-gonadal axis following neburon treatment. Neburon treatment also significantly activated the AhR signaling pathway, causing oxidative stress damage and eventually leading to a significant increase in apoptosis in the exposed group. Together, these data filled the currently more vacant profile of neburon toxicity and might provide information to assess the ecotoxicity of neburon on male reproduction at environmentally relevant concentrations. [Display omitted] [ABSTRACT FROM AUTHOR]

The serotonergic neurons in the raphe nucleus are implicated in various cognitive functions such as learning and emotion. In vertebrates, the raphe nucleus is divided into the dorsal raphe and the median raphe. In contrast to the abundance of knowledge on the functions of the dorsal raphe, the roles of the serotonergic neurons in the median raphe are relatively unknown. The studies using zebrafish revealed that the median raphe serotonergic neurons receive input from the two distinct pathways from the habenula and the IPN. The use of zebrafish may reveal the function of the Hb-IPN-median raphe pathway. To clarify the functions of the median raphe serotonergic neurons, it is necessary to distinguish them from those in the dorsal raphe. Most median raphe serotonergic neurons originate from rhombomere 2 in mice, and we generated the transgenic zebrafish which can label the serotonergic neurons derived from rhombomere 2. In this study, we found the serotonergic neurons derived from rhombomere 2 are localized in the median raphe and project axons to the rostral dorsal pallium in zebrafish. This study suggests that this transgenic system has the potential to specifically reveal the function and information processing of the Hb-IPN-raphe-telencephalon circuit in learning. • A new transgenic zebrafish labels 5HT neurons derived from rhombomere 2. • Most median raphe 5HT neurons are derived from rhombomere 2 in zebrafish. • Most median raphe 5HT neurons project to the rostral dorsal pallium. [ABSTRACT FROM AUTHOR]

Zebrafish are considered as model organisms in biological and medical research because of their high degree of homology with human genes. Automatic behavioral analysis of multiple zebrafish based on visual tracking is expected to improve research efficiency. However, vision-based multi-object tracking algorithms often suffer from data loss owing to mutual occlusion. In addition, simply tracking zebrafish as points is not sufficient-more detailed information, which is required for research on zebrafish behavior. In this paper, we propose Zebrafishtracker3D, which utilizes a skeleton stability strategy to reduce detection error caused by frequent overlapping of multiple zebrafish effectively and estimates zebrafish skeletons using head coordinates in the top view. Further, we transform the front- and top-view matching task into an optimization problem and propose a particle-matching method to perform 3D tracking. The robustness of the algorithm with respect to occlusion is estimated on the dataset comprising two and three zebrafish. Experimental results demonstrate that the proposed algorithm exhibits a multiple object tracking accuracy (MOTA) exceeding 90% in the top view and a 3D tracking matching accuracy exceeding 90% in the complex videos with frequent overlapping. It is noteworthy that each instance in the trace saves its skeleton. In addition, Zebrafishtracker3D is applied in the zebrafish courtship experiment, establishes the stability of the method in applications of life science, and proves that the data can be used for behavioral analysis. Zebrafishtracker3D is the first algorithm that realizes 3D skeleton tracking of multiple zebrafish simultaneously. • The first 3D multi-object zebrafish skeleton-level tracking method is proposed. • It can effectively solve the problem of data loss caused by cross occlusion. • A general method of bone spur removal based on morphology is proposed. • The algorithm has been successfully applied to life science experiments. [ABSTRACT FROM AUTHOR]

There has been growing emphasis on environmental pollutants, including heavy metals, pesticides, and nanoplastics, owing to the escalating significance of environmental pollution as a major global issue. Various toxicities induced by these compounds have been consistently reported, and many cell lines and animal models have been used in toxicity studies. Zebrafish are one of the most widely used animal models for verifying the toxic effects of environmental pollutants, owing to their many advantages. In this study, we provide brief guidelines for zebrafish maintenance and mating methods, toxicant treatments, survival measurements, and morphological abnormalities. [ABSTRACT FROM AUTHOR]

While the spatial distribution pattern of fish is increasingly used for toxicological test of chemicals or wastewater, no ideal parameter is available for quantitative assessment of spatial distribution, especially uneven distribution with multiple hotspots. Here, to develop a quantitative assessment parameter for spatial distribution, the zebrafish were exposed to ethanol, pentylenetetrazole (PTZ), paraquat dichloride (paraquat) and wastewater, followed by a behavioral test in a narrow tank. Behavioral data was acquired and analyzed by idTracker and MATLAB. By comparing the effects of all treatments on behavior parameters, we confirmed that the spatial distribution was more easily altered rather than general locomotor parameters, e.g. 0.7–70 mg/L PTZ and 5–20 mg/L paraquat being effective for altering spatial distribution but having little effects on general locomotor parameters. Based on the heatmap, i.e., the cumulative proportion of grids and that of frequency in grids, we calculated the behavioral Gini coefficient (G b) for quantitative assessment of fish spatial distribution. The Gini coefficient ranged from zero to 1, with larger values meaning poorer evenness of spatial distribution. Of note, G b showed smaller coefficient of variations (CV) with 3%-19% between replicate tanks in all treatments than the highest frequency (4%-79%), displaying well robustness. Especially, G b addressed the challenge of the complicated heatmap with multiple hotspots. Overall, the behavioral Gini coefficient we established is an ideal parameter to quantitatively assess spatial distribution of fish shoal, which is expected to be applied in toxicity testing for chemicals and wastewater and automatic quality monitoring for surface water and aquaculture water. [Display omitted] [ABSTRACT FROM AUTHOR]

Glial cells have a remarkable plasticity. Recent studies using zebrafish as a model highlight conserved cellular behavior in health and disease in the central nervous system (CNS) between zebrafish and humans. These findings inform our understanding of their function and how their dysregulation in pathogenesis can be determinant. [ABSTRACT FROM AUTHOR]

Mycobacterium marinum , a fish pathogen, was originally used to model natural host–pathogen interactions in zebrafish. Recent studies have shown that infections caused by a wide range of nontuberculous mycobacteria (NTM) can be studied in zebrafish. Zebrafish larvae and adults represent valuable host species that can be used to model important biological questions underlying NTM pathogenesis and host immunity. Many pathophysiological traits discovered in the zebrafish model accurately recapitulate NTM infections in humans. The incidence of infections due to nontuberculous mycobacteria (NTM) has increased rapidly in recent years, surpassing tuberculosis in developed countries. Due to inherent antimicrobial resistance, NTM infections are particularly difficult to treat with low cure rates. There is an urgent need to understand NTM pathogenesis and to develop novel therapeutic approaches for the treatment of NTM diseases. Zebrafish have emerged as an excellent animal model due to genetic amenability and optical transparency during embryonic development, allowing spatiotemporal visualization of host–pathogen interactions. Furthermore, adult zebrafish possess fully functional innate and adaptive immunity and recapitulate important pathophysiological hallmarks of mycobacterial infection. Here, we report recent breakthroughs in understanding the hallmarks of NTM infections using the zebrafish model. [ABSTRACT FROM AUTHOR]

Lipid conjugates have advanced the field of lipid-based nanomedicine by promoting active-targeting (ligand, peptide, antibody), stability (PEGylation), controlled release (lipoid prodrug), and probe-based tracking (fluorophore). Recent findings indicate lipid conjugates dissociating from nanomedicine upon encountering a biological environment. Yet, implications for (pre)clinical outcomes remain unclear. In this study, using the zebrafish model (Danio rerio), we investigated the fate of liposome-incorporated lipid fluorophore conjugates (LFCs) after intravenous (IV) administration. LFCs having a bilayer mismatch and relatively polar fluorophore revealed counter-predictive outcomes for Caelyx/Doxil (clearance vs. circulating) and AmBisome-like liposomes (scavenger endothelial cell vs. macrophage uptake). Findings on LFC (mis)match for Caelyx/Doxil-like liposomes were supported by translational intravital imaging studies in mice. Importantly, contradicting observations suggest to originate from LFC dissociation in vivo , which was investigated by Asymmetric Flow Field-Flow Fractionation (AF4) upon liposome-serum incubation in situ. Our data suggests that LFCs matching with the liposome bilayer composition – that did not dissociate upon serum incubation – revealed improved predictive outcomes for liposome biodistribution profiles. Altogether, this study highlights the critical importance of fatty acid tail length and headgroup moiety when selecting lipid conjugates for lipid-based nanomedicine. [Display omitted] [ABSTRACT FROM AUTHOR]

The Aesculus genus has several species, most notably Aesculus hippocastanum , with reported cytotoxic and venotonic effects. The angiogenic effect from A. hippocastanum is of interest given the current limitations of anti-angiogenic therapeutics. Aesculus glabra (Willdenow), known as the Ohio Buckeye Tree is a species native to North America with reported medicinal use by the Native Americans. Previous phytochemical studies have focused on the seed and leaf contents of the glabra species, with most of them reporting cytotoxic activity. In this study, we assessed preliminary anti-angiogenic activity and toxicity of isolated compounds from the bark of A. glabra utilizing a zebrafish (Danio rerio) model. Procyanidin A2 and epicatechin, two pure isolates, were tested using zebrafish and gave an anti-angiogenic response, suggesting an underlying mechanism involved in vascular development. [Display omitted] • The traditional use and therapeutic properties of the Aesculus genus are highlighted. • Aesculus glabra has been an understudied species in the Aesculus genus. • Research on A. glabra has not previously been focused on the bark. • Angiogenesis assessment of A. glabra isolates validate its therapeutic potential. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or β-methylamino- l -alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models. [Display omitted] • We characterise face and predictive validity of zebrafish models of sporadic ALS (sALS). • Phenotypes of sALS models include behavioural impairments and axonopathy. • BPA-induced sALS model shows altered metabolism and increased ER/redox stress. • ALS drug edaravone counteracts sALS phenotypes, modulating ER stress and metabolism. [ABSTRACT FROM AUTHOR]

Tributyltin (TBT), a common organotin environmental pollutant, may pose a threat to human development during critical early-life periods. We aimed to assess the neurodevelopmental intergenerational toxicity of early-life exposure to TBT and the protective effect of DNA methyl donor folic acid (FA). Specifically, after early-life exposure (1–21 days post-fertilization, dpf) to TBT (0, 1, 10 and 100 ng/L), zebrafish (Danio rerio) were cultured in clean medium until sexual maturity. The exposed females were mated with unexposed males to produce embryos (F1). The F1 generation were cultured (4–120 hours post-fertilization, hpf) with and without 1 mmol/L FA. The neurotoxic effects of early-life TBT exposure for zebrafish and their offspring (F1) were significantly enhanced anxiety and reduced aggression, decreased gene expression of DNA methyltransferase in the brain and increased serotonin levels in the body. Moreover, the intergenerational neurodevelopmental toxicity, as manifested in the F1 generation, was attenuated by FA supplementation. In summary, early-life TBT exposure led to intergenerational neurodevelopmental deficits in zebrafish, and DNA methyl donors had a protective effect on F1 neurodevelopment, which can inform the prevention and treatment of intergenerational neurotoxicity due to organotin pollutants. [Display omitted] [ABSTRACT FROM AUTHOR]

17β-Estradiol (E2) has been widely detected in natural water and treatment with E2 induces potential endocrine disrupting effects in fish. However, effects on fish fecundity and steroid system after treatment with environmentally relevant concentrations of E2 for the full sexual maturation cycle remain unclear. In this study, zebrafish were treatment with 0, 10 or 100 ng/L E2 from embryo to adult stage, and effects on gonadal development and differentiation, steroid hormone levels, transcription of genes associated with the hypothalamic-pituitary-gonadal-liver (HPG) axis in adults and fertilization rate of offspring were assessed. The results showed that treatment with E2 lead to increased number of feminization in zebrafish. In females, E2 decreased cumulative amount of spawning and inhibited the maturation of oocyte. In males, E2 inhibited the maturation and motility of sperm, as well as decreased the movement speed of sperm. These adverse effects on sperm might be responsible for the reduced fertilization observed in offspring. In addition, treatment with E2 changed the levels of steroid hormones in zebrafish gonad and altered the transcriptional levels of genes associated with HPG axis, which is responsible for the regulation of germ cells maturation and gonadal development in zebrafish. Overall, these results suggested that treatment with environmentally relevant concentrations of E2 for the full sexual maturity cycle resulted in adverse effects on reproduction in zebrafish. [Display omitted] [ABSTRACT FROM AUTHOR]

Ethanol exposure during pregnancy is an important problem and is the cause of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD). The etiology of FAS and FASD can be elucidated using animal models. Recently, a novel model, the zebrafish (Danio rerio), has garnered the interest of researchers. This study confirmed the negative influence of ethyl alcohol (0.5 %, 1.5 %, and 2.5 % v/v) on the development of zebrafish embryos. The observed malformations included pericardial and yolk sac edema, increased body curvature, tail edema, and a decreased embryo hatching rate. The differences in body length, body width, and heart rate were statistically significant. Due to the similarities in the quantity and function of ethanol biotransformation enzymes between zebrafish and mammals, this study investigated the nonoxidative metabolites of ethanol – ethyl glucuronide (EtG) and ethyl sulfate (EtS) – in zebrafish following ethanol exposure. This research confirmed that EtG and EtS concentrations can be measured in zebrafish embryos, and the levels of these metabolites appear to be associated with the ethyl alcohol concentration in the medium. • The toxic effect of ethanol on zebrafish embryos has been confirmed. • Non-oxidative metabolites have been observed following the exposure of embryos to ethanol. • EtG and EtS amount in zebrafish embryos seemed to be associated with ethanol concentration. [ABSTRACT FROM AUTHOR]

The Hippo signaling pathway regulates developmental organ growth, regeneration, and cell fate decisions. Although the role of the Hippo pathway, and its transcriptional effectors YAP and TAZ, has been well documented in many cell types and species, only recently have the roles for this pathway come to light in vascular development and disease. Experiments in mice, zebrafish, and in vitro have uncovered roles for the Hippo pathway, YAP, and TAZ in vasculogenesis, angiogenesis, and lymphangiogenesis. In addition, the Hippo pathway has been implicated in vascular cancers and cardiovascular diseases, thus identifying it as a potential therapeutic target for the treatment of these conditions. However, despite recent advances, Hippo's role in the vasculature is still underappreciated compared with its role in epithelial tissues. In this review, we appraise our current understanding of the Hippo pathway in blood and lymphatic vessel development and highlight the current knowledge gaps and opportunities for further research. Major roles for the Hippo signaling pathway and its transcriptional effectors YAP and TAZ have recently emerged in vascular development. In this review, Kobayashi et al. discuss how the pathway controls the formation of different vessel types, the major mechanisms at play, and emerging roles for Hippo signaling in vascular diseases. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae is one of the common pathogenic bacteria that can cause infections in hospitals and communities and can cause respiratory, urinary, and other multi-system infections. In recent years, the emergence of highly virulent and drug-resistant Klebsiella pneumoniae has greatly increased the difficulty of treatment for infection. Clinically, it is very important to accurately judge the virulence of isolated Klebsiella pneumoniae for treatment, but there is no better method to evaluate its virulence. In this study, zebrafish were used as a model organism, and the swimming distance was used as a detection index to identify clinically isolated Klebsiella pneumoniae. In this study, we selected two different strains of Klebsiella pneumoniae, i.e., NTUH-K2044 and ATCC BAA-1705, with known high and low virulence, respectively, to infect zebrafish juveniles and evaluated their behavioral ability according to different bacterial concentrations and different developmental times. It was found that highly virulent Klebsiella pneumoniae caused a significant decrease in the behavioral ability of zebrafish larvae, while low-virulence Klebsiella pneumoniae had relatively little effect. These results indicate that it is entirely feasible to assess the virulence of Klebsiella pneumoniae based on behavioral ability. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder is characterized by deficits in social communication and restricted or repetitive behaviors. Due to the extremely high genetic and phenotypic heterogeneity, it is critical to pinpoint the genetic factors for understanding the pathology of these disorders. We analyzed the exomes generated by the SPARK (Simons Powering Autism Research) project and performed a meta-analysis with previous data. We then generated 1 zebrafish knockout model and 3 mouse knockout models to examine the function of GIGYF1 in neurodevelopment and behavior. Finally, we performed whole tissue and single-nucleus transcriptome analysis to explore the molecular and cellular function of GIGYF1. GIGYF1 variants are significantly associated with various neurodevelopmental disorder phenotypes, including autism, global developmental delay, intellectual disability, and sleep disturbance. Loss of GIGYF1 causes similar behavioral effects in zebrafish and mice, including elevated levels of anxiety and reduced social engagement, which is reminiscent of the behavioral deficits in human patients carrying GIGYF1 variants. Moreover, excitatory neuron–specific Gigyf1 knockout mice recapitulate the increased repetitive behaviors and impaired social memory, suggesting a crucial role of Gigyf1 in excitatory neurons, which correlates with the observations in single-nucleus RNA sequencing. We also identified a series of downstream target genes of GIGYF1 that affect many aspects of the nervous system, especially synaptic transmission. De novo variants of GIGYF1 are associated with neurodevelopmental disorders, including autism spectrum disorder. GIGYF1 is involved in neurodevelopment and animal behavior, potentially through regulating hippocampal CA2 neuronal numbers and disturbing synaptic transmission. [ABSTRACT FROM AUTHOR]

While melanin plays a crucial role in shielding the skin from UV radiation, excessive production of melanin can lead to various skin-related disorders like melasma and solar lentigo. In this study, our focus was on exploring the potential of essential oil from Citrus reticulata blossom (EOB) as a potent anti-melanogenic agent. We subjected α-melanocyte-stimulating hormone (α-MSH)-stimulated B16-F10 cells and zebrafish embryos to EOB treatment to assess its effects. EOB demonstrated no cytotoxicity even at concentrations up to 500 μg/mL. Notably, EOB exhibited a significant dose-dependent inhibition of skin pigmentation in zebrafish. Additionally, in α-MSH-treated B16-F10 cells, EOB at concentrations of 62.5–500 μg/mL reduced intracellular tyrosinase activity and cellular melanin content. Furthermore, the expression levels of key transcription factors associated with melanogenic pathways—such as microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2)—decreased significantly in a dose-dependent manner upon EOB treatment in B16-F10 cells. The remarkable anti-melanogenic effects exhibited by EOB suggest its potential utility in the cosmetics industry. [Display omitted] • Anti-melanogenic effect of essential oil from Citrus Reticulate Blossom (EOB). • EOB were presumed to be due to the presence of β-caryophyllene, β-elemene, and p-cymene. • EOB could mediate melanogenic pathways by regulating the expression of MITF stimulated by α-MSH. • ECB reducing the melanin content and accumulation in zebrafish. • Anti-melanogenic effects of EOB can be useful in the cosmetic industry. [ABSTRACT FROM AUTHOR]

Social isolation has detrimental health effects, but the underlying mechanisms are unclear. Here, we investigated the impact of 2 weeks of isolation on behavior and gene expression in the central nervous system at different life stages of zebrafish. Results showed that socially deprived young adult zebrafish experienced increased anxiety, accompanied by changes in gene expression. Most gene expression patterns returned to normal within 24 hours of reintroduction to a social environment, except angptl4 , which was upregulated after reintroduction, suggesting an adaptive mechanism. Similarly, aging zebrafish displayed heightened anxiety and increased central nervous system expression of angptl4 during isolation, but effects were reversed upon reintroduction to a social group. The findings imply that angptl4 plays a homeostatic role in response to social isolation, which varies across the lifespan. The study emphasizes the importance of social interactions for psychological well-being and highlights the negative consequences of isolation, especially in older individuals. Further research may unravel how social isolation affects angptl4 expression and its developmental and aging effects. [Display omitted] [ABSTRACT FROM AUTHOR]

The first approved RNAi therapeutics, ONPATTRO, in 2017 moves the concept of RNA interference (RNAi) therapy from research to clinical reality, raising the hopes for the treatment of currently incurable diseases. However, RNAi therapeutics are still facing two main challenges—susceptibility to enzymatic degradation and low ability to escape from endo/lysosome into the cytoplasm. Therefore, we developed disulfide-based nanospheres (DBNPs) as universal vehicles to achieve efficient RNA delivery to address these problems. Notably, the DBNPs possess unique and desirable features, including improved resistance to nuclease degradation, direct cytoplasmic delivery through thiol-mediated cellular uptake, and cytosolic environment-responsive release, greatly enhancing the bioavailability of RNA therapeutics. Additionally, DBNPs are superior in terms of overcoming formidable physiological barriers, including vascular barriers and impermeable tumor tissues. Owning to these advantages, the DBNPs exhibit efficient gene silencing effect when delivering either small interfering RNA (siRNA) or microRNA in various cell lines and generate remarkable growth inhibition in the zebrafish and mouse model of pancreatic tumors as compared to traditional delivery vectors, such as PEI. Therefore, DBNPs have potential application prospect in RNAi therapy both in vitro and in vivo. RNA interference (RNAi) therapeutics could target and alter any disease-related mRNA translation, thus have great potential in clinical application. Delivery efficiency of RNA modalities into cell cytoplasm is the main problem that currently limit RNAi therapeutics to release their full potential. Most of the known delivery materials suffer from the endo/lysosomal entrapment and enzymatic degradation during endocytosis-dependent uptake, resulting unsatisfied efficiency of the cytoplasmic release. Here, we developed disulfide-based nanospheres could directly transfer RNA modalities into the cytoplasm and significantly enhance the delivery efficiency, thus holding great potential in RNAi therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Psychedelic use is rapidly growing in popularity for recreational and clinical purposes, but its potential risks for pregnant and breastfeeding women are currently unknown. The teratogenic potential of psychedelics was notably last considered in the 1970s and little attention has been given to this topic since the recent re-emergence of the field. Human case studies and previous animal studies provide mixed findings and we propose the zebrafish for the safety profiling of fetal psychedelic exposure. Practical simplicity, translational relevance, and established laboratory techniques make the zebrafish an effective animal model for fetal exposure studies Psychedelic drugs have experienced an unprecedented surge in recreational use within the past few years. Among recreational users, the risks of psychedelic use by pregnant and breastfeeding women are severely understudied and there is little information on the potential teratogenic effects of these drugs. We provide an overview of the previous data on psychedelic teratogenicity from rodent studies and human surveys, discuss their limitations, and propose the utility of the zebrafish as a potential effective model for investigating psychedelic teratogenicity. Recent years have validated the use of zebrafish in the study of fetal exposure and developmental biology; we highlight these properties of the zebrafish for its suitability in psychedelic toxicity research. [ABSTRACT FROM AUTHOR]

Various aspects of visual functioning, including motion perception, change with age. Yet, there is a lack of comprehensive understanding of age-related alterations at different stages of motion processing and in each motion system. To understand the effects of aging on second-order motion processing, we investigated optomotor responses (OMR) in younger and older wild-type (AB-strain) and acetylcholinesterase (ache sb55/+ ) mutant zebrafish. The mutant fish with decreased levels of acetylcholinesterase have been shown to have delayed age-related cognitive decline. Compared to previous results on first-order motion, we found distinct changes in OMR to second-order motion. The polarity of OMR was dependent on age, such that second-order stimulation led to mainly negative OMR in the younger group while older zebrafish had positive responses. Hence, these findings revealed an overall aging effect on the detection of second-order motion. Moreover, neither the genotype of zebrafish nor the spatial frequency of motion significantly changed the response magnitude. Our findings support the view that age-related changes in motion detection depend on the activated motion system. [ABSTRACT FROM AUTHOR]

• Phe affected hematopoietic organs and hematopoietic cells in peripheral blood. • Phe altered the primitive hematopoietic wave and definitive hematopoiesis. • Phe impaired the generation of differentiated progenies of HSCs. Phenanthrene (Phe) is one of the common polycyclic aromatic hydrocarbons in the environment, and recent studies show that it can cause cardiac developmental toxicity and immunotoxicity. However, it is still unknown whether it can affect the hematopoietic development in aquatic organisms. To address this question, zebrafish (Danio rerio) were chronically exposed to Phe at different concentrations. We found that Phe caused structural damage to the renal tubules in the kidney, induced malformed erythrocytes in peripheral blood, and decreased the proportion of myeloid cells in adult zebrafish, suggesting possible negative impacts that Phe posed to hematopoietic development. Then, using in situ hybridization technology, we found that Phe decreased the expression of primitive hematopoietic marker genes, specifically gata1 and pu.1 , accompanied by an obstruction of primitive erythrocyte circulation. Furthermore, Phe impaired definitive hematopoiesis, increased aberrations of the transient hematopoietic site (PBI), and reduced the generation of hematopoietic stem cells, ultimately influencing the number of erythrocytes and myeloid cells. The findings suggested that Phe could induce hematopoietic toxicity in zebrafish embryos and pose unknown ecological risks. [Display omitted] [ABSTRACT FROM AUTHOR]

• Chlorogenic acid, hyperocide, rutin and hyperforin were obtained in higher quantities. • Toxicity doses of SJW extracts used as nutritional supplements were determined. • SJW at doses of 10 µg/mL and below may be harmless to use as food supplement. • Caspase-3 expression was not observed in brain tissues of zebrafish larvae in SJW1-SJW3. Hypericum perforatum (St. John's wort) belongs to the Hypericaceae family and is one of the best known Hypericum species worldwide. It is a very popular and valuable medicinal plant widely distributed in Anatolia. Hypericum perforatum contains many bioactive components that play a role in activities has been used as a food supplement. The extracts are used within safe dose range that are harmless and effective for health. When the SJW1, SJW2 and SJW3 fractions of St. John's Wort extracts were exposed to zebrafish embryos and larvae at different concentrations (5, 10, 100, and 300 µg/mL), the survival rates at 96th hour were determined as 83.3, 27.5 and 2.5%, respectively. No significant changes were found in the malformation rates, and the larval emergence was found to be above 80% at 96th hour for all extracts. No caspase-3 expression was found at the 96th hour in the larvae. Similar secondary components of extracts were observed except quantitative differences. The use of samples in doses of 10 µg/mL and below as food supplement may be harmless, however, threshold dose values of H. perforatum extracts lower toxic doses may be due to the different amounts of secondary metabolites. [ABSTRACT FROM AUTHOR]

• Bone formation in vivo is reduced in both dominant and recessive OI zebrafish models Chi/+ and p3h1−/− , respectively. • Only the structural mutation in collagen type i of Chi/+ results in impaired osteoblasts differentiation and switch towards the adipocytic lineage, together with a more detrimental effect on the extracellular matrix. • Osteoclast number and activity are reduced during caudal fin regeneration in Chi/+ and associated with impaired precursors recruitment only in p3h1−/−. • 4-PBA chaperone activity rescues caudal fin regeneration ability only in the recessive p3h1−/− , pointing out the need for precision medicine approaches to properly treat each form of the disease. Osteogenesis imperfecta (OI) is a family of rare heritable skeletal disorders associated with dominant mutations in the collagen type I encoding genes and recessive defects in proteins involved in collagen type I synthesis and processing and in osteoblast differentiation and activity. Historically, it was believed that the OI bone phenotype was only caused by abnormal collagen type I fibrils in the extracellular matrix, but more recently it became clear that the altered bone cell homeostasis, due to mutant collagen retention, plays a relevant role in modulating disease severity in most of the OI forms and it is correlated to impaired bone cell differentiation. Despite in vitro evidence, in vivo data are missing. To better understand the physiopathology of OI, we used two zebrafish models: Chihuahua (Chi/+), carrying a dominant p.G736D substitution in the α1 chain of collagen type I, and the recessive p3h1−/− , lacking prolyl 3-hydroxylase (P3h1) enzyme. Both models share the delay of collagen type I folding, resulting in its overmodification and partial intracellular retention. The regeneration of the bony caudal fin of Chi/+ and p3h1−/− was employed to investigate the impact of abnormal collagen synthesis on bone cell differentiation. Reduced regenerative ability was evident in both models, but it was associated to impaired osteoblast differentiation and osteoblastogenesis/adipogenesis switch only in Chi/+. On the contrary, reduced osteoclast number and activity were found in both models during regeneration. The dominant OI model showed a more detrimental effect in the extracellular matrix organization. Interestingly, the chemical chaperone 4-phenylbutyrate (4-PBA), known to reduce cellular stress and increase collagen secretion, improved bone formation only in p3h1−/− by favoring caudal fin growth without affecting bone cell markers expression. Taken together, our in vivo data proved the negative impact of structurally abnormal collagen type I on bone formation but revealed a gene mutation-specific effect on bone cell differentiation and matrix organization in OI. These, together with the distinct ability to respond to the chaperone treatment, underline the need for precision medicine approaches to properly treat the disease. [ABSTRACT FROM AUTHOR]

A variant in the SLC4A3 anion exchanger has been identified as a novel cause of short QT syndrome (SQTS), but the clinical importance of SLC4A3 as a cause of SQTS or sudden cardiac death remains unknown. The purpose of this study was to investigate the prevalence of potential disease-causing variants in SQTS patients using gene panels including SLC4A3. In this multicenter study, genetic testing was performed in 34 index patients with SQTS. The pathogenicity of novel SLC4A3 variants was validated in a zebrafish embryo heart model. Potentially disease-causing variants were identified in 9 (26%) patients and were mainly (15%) located in SLC4A3 : 4 patients heterozygous for novel nonsynonymous SLC4A3 variants—p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His—and 1 patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2× in KCNQ1 , 1× in KCNJ2 , and CACNA1C each). SLC4A3 variant carriers (n = 5) had a similar heart rate but shorter QT and J point to T wave peak intervals than did noncarriers (n = 29). Knockdown of slc4a3 in zebrafish resulted in shortened heart rate–corrected QT intervals (calculated using the Bazett formula) that could be rescued by overexpression of the native human SLC4A3 -encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting pathogenicity of these variants. Dysfunction in slc4a3 /AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes. In about a quarter of patients with SQTS, a potentially disease-causing variant can be identified. Nonsynonymous variants in SLC4A3 represent the most common cause of SQTS, underscoring the importance of including SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death. [ABSTRACT FROM AUTHOR]

Premature ovarian failure (POF) is characterized as the ovarian dysfunction and defective oocyte development. In POF patients, ROS level is reported to be significantly higher than normal individuals. However, the involvement of oxidative stress in POF and the regulatory mechanisms underlying the antioxidative process in oocyte development remain largely unknown. Here, we discover that oxidation resistance 1a (Oxr1a), the ortholog of mammalian Oxr1, protects the oocytes of female zebrafish against oxidative stress and thus represses the POF phenotype. Oxr1a was widely expressed in oocytes at different developmental stages, of which the mRNA expression levels were significantly upregulated upon follicle activation and oocyte maturation. Oxr1a knockout exacerbated the POF phenotype, as evidenced by the decreased number and quality of oocytes. Moreover, the oocytes of oxr1a knockout zebrafish exhibited excessive ROS, increased mitochondrial DNA damage, reduced mitochondria, and abnormal morphology. Mechanistically, instead of decomposing ROS directly, Oxr1a participated in the process of oxidative stress through regulating the mRNA expression levels of the key antioxidant enzymes Cat and Sod1. Moreover, treatment with antioxidant N-Acetyl- l -cysteine attenuated the mitochondrial oxidative damage and improved the fertility of mutant females, indicating that Oxr1a may mediates the Sod1/Cat pathway to metabolize the intracellular ROS and avoid the mitochondrial oxidative damage, thus ensuring the normal development and maturation of oocytes. Taken together, these findings are useful for the elucidation of molecular mechanisms underlying the oxidative damage in oocytes and beneficial to the clinical therapeutics of POF. [Display omitted] • The oxr1a mutant presents a premature ovarian failure-like phenotype. • Zebrafish Oxr1a possesses no peroxidase activity. • Oxr1a regulates the antioxidative response through Cat and Sod1 during oocyte development. • AntiOxidants alleviate the phenotype of premature ovarian failure in the oxr1a mutant. [ABSTRACT FROM AUTHOR]

• Zebrafish makes a good experimental model for neuroscience research because of its size and optical transparency. • The easy correlation between zebrafish and other laboratory animals using neurobehavioural tests makes this model ideal. • Zebrafish can be made the most superior experimental model by bridging the gaps and limitations discussed. Zebrafish (Danio rerio) is currently in vogue as a prevalently used experimental model for studies concerning neurobehavioural disorders and associated fields. Since the 1960s, this model has succeeded in breaking most barriers faced in the hunt for an experimental model. From its appearance to its high parity with human beings genetically, this model renders itself as an advantageous experimental lab animal. Neurobehavioural disorders have always posed an arduous task in terms of their detection as well as in determining their exact etiology. They are still, in most cases, diseases of interest for inventing or discovering novel pharmacological interventions. Thus, the need for a harbinger experimental model for studying neurobehaviours is escalating. Ensuring the same model is used for studying several neuro-studies conserves the results from inter-species variations. For this, we need a model that satisfies all the pre-requisite conditions to be made the final choice of model for neurobehavioural studies. This review recapitulates the progress of zebrafish as an experimental model with its most up-to-the-minute advances in the area. Various tests, assays, and responses employed using zebrafish in screening neuroactive drugs have been tabulated effectively. The tools, techniques, protocols, and apparatuses that bolster zebrafish studies are discussed. The probable research that can be done using zebrafish has also been briefly outlined. The various breeding and maintenance methods employed, along with the information on various strains available and most commonly used, are also elaborated upon, supplementing Zebrafish's use in neuroscience. [ABSTRACT FROM AUTHOR]

Landfill leachate is an effluent characterized by a great heterogeneity in its composition, and may contain the most diverse types of organic and inorganic contaminants. Therefore, the leachate needs an efficient treatment before being released into the environment. For this, a lot of treatment processes are being developed and studied, such as simple distillation. To evaluate the efficiency of the treatment, the use of ecotoxicological assays with fish is a useful tool to determine the effects on the aquatic environment of the residual compounds present after the treatment. The aim of this study was to evaluate the efficiency of the simple distillation process in a landfill leachate. For this, in addition to the physical-chemical characterization, the presence of volatile organic compounds (VOC), metals, pharmaceuticals, hormones, and pesticides in the raw (RL) and distilled raw leachate (DRL) was evaluated. Finally, biochemical biomarkers were evaluated in Danio rerio fish exposed to different concentrations of RL and DRL. High concentrations of chemical (COD) and biochemical (BOD) demand for oxygen, nitrogen compounds, sulfates, and chlorides were detected, in addition to fatty acids, long-chain alkanes, alcohols and esters, heavy metals, and six pharmaceuticals. After the distillation process, most of these compounds were reduced by more than 90% and some were removed completely. The biomarkers showed greater changes in the groups exposed to LR and were influenced by the exposure concentration. Thus, the treatment of simple distillation of the leachate proved to be efficient because, in addition to reducing/removing the contaminants, it also reduced the toxicity in D. rerio. [Display omitted] • Landfill leachate contains pharmaceuticals, metals, and volatile organic compounds. • Simple distillation process is efficient in landfill leachate treatment. • Simple distillation treatment reduces toxicity in Danio rerio fish. [ABSTRACT FROM AUTHOR]

• Zebrafish feces had a high richness in a diversity of metabolites. • Fecal metabolites were closely associated with the endocrine system. • Aging led to a pronounced shift in fecal metabolome. • PFBS pollutant significantly disturbed the fecal metabolomics profile. • Young fecal transplantation alleviated the metabolic perturbation of PFBS. To protect the wellbeing of research animals, certain non-invasive measures are in increasing need to facilitate an early diagnosis of health and toxicity. In this study, feces specimen was collected from adult zebrafish to profile the metabolome fingerprint. Variability in fecal metabolite composition was also distinguished as a result of aging, perfluorobutanesulfonate (PFBS) toxicant, and fecal transplantation. The results showed that zebrafish feces was very rich in a diversity of metabolites that belonged to several major classes, including lipid, amino acid, carbohydrate, vitamin, steroid hormone, and neurotransmitter. Fecal metabolites had functional implications to multiple physiological activities, which were characterized by the enrichment of digestion, absorption, endocrine, and neurotransmission processes. The high richness and functional involvement of fecal metabolites pinpointed feces as an abundant source of diagnostic markers. By comparison between young and aged zebrafish, fundamental modifications of fecal metabolomes were caused by aging progression, centering on the neuroactive ligand-receptor interaction pathway. Exposure of aged zebrafish to PFBS pollutant also significantly disrupted the metabolomic structure in feces. Of special concern were the changes in fecal hormone intermediates after PFBS exposure, which was concordant with the in vivo endocrine disrupting effects of PFBS. Furthermore, it was intriguing that transplantation of young zebrafish feces efficiently mitigated the metabolic perturbation of PFBS in aged recipients, highlighting the health benefits of therapeutic strategies based on gut microbiota manipulation. In summary, the present study provides preliminary clues to evidence the non-invasive advantage of fecal metabolomics in the early diagnosis and prediction of physiology and toxicology. [Display omitted] [ABSTRACT FROM AUTHOR]

• TCBPA caused developmental neurotoxicity in zebrafish. • TCBPA caused developmental cardiovascular toxicity in zebrafish. • Focal adhesion, ECM-receptor interaction pathways were involved in the developmental toxicity of TCBPA. • TCBPA led to alterations in the arginine-related metabolic pathway. Tetrachlorobisphenol A (TCBPA), a widely used halogenated flame retardant, is frequently detected in environmental compartments and human samples. However, unknown developmental toxicity and mechanisms limit the entire understanding of its effects. In this study, zebrafish (Danio rerio) embryos were exposed to various concentrations of TCBPA while a combination of transcriptomics, behavioral and biochemical analyzes as well as metabolomics were applied to decipher its toxic effects and the potential mechanisms. We found that TCBPA could interfere with nervous and cardiovascular development through focal adhesion and extracellular matrix-receptor (ECM-receptor) interaction pathways through transcriptomic analysis. Behavioral and biochemical analysis results indicated abnormal swimming behavior of zebrafish larvae. Morphological observations revealed that TCBPA could cause the loss of head blood vessels. Metabolomic analysis showed that arginine-related metabolic pathways were one of the main pathways leading to TCBPA developmental toxicity. Our study demonstrated that by using omics, TCBPA was shown to have neurological and cardiovascular developmental toxicity and the underlying mechanisms were uncovered and major pathways identified. [Display omitted] [ABSTRACT FROM AUTHOR]

• Micro-sized PS accumulated in zebrafish and affected fish at sub-individual level. • Micro-sized PS caused disorders and diversity changes of gut microbiota in fish. • Micro-sized PS adsorbed chlorpyrifos and transferred it to zebrafish. • PS adsorbing chlorpyrifos caused greater impacts on zebrafish than its action alone. Microplastics often co-occur with a variety of organic contaminants in aquatic environment and pose combined risks to aquatic wildlife. Here, we investigated joint effects of micro-sized polystyrene (mPS, 5 µm) and an organophosphate pesticide chlorpyrifos on zebrafish, using multiple endpoints at both fish individual and gut microbiota levels. It was revealed that mPS ingested by zebrafish accumulated in gut and liver, and caused oxidative stress, hyperactive swimming performance and histological damages in fish, and induced disorders and diversity alterations of the gut microbial community. More importantly, mPS exhibited considerable adsorption capacity against chlorpyrifos, and those adsorbing chlorpyrifos presented greater effects on fish individuals but no different effects on gut microbiota compared to single mPS exposure. Together with body residues of chlorpyrifos in zebrafish, it was proposed that the joint effects between mPS and chlorpyrifos were attributed to the chlorpyrifos released from mPS within zebrafish. The present results provided a comprehensive understanding of joint effects of mPS and contaminants co-occurring in the environment and emphasized the importance of considering the adsorbed chemicals in toxicological studies of microplastics. [Display omitted] [ABSTRACT FROM AUTHOR]

Oxidative stress, which is a persistent state of elevated reactive oxygen species (ROS), is implicated in the pathogeneses of several diseases, making antioxidant-based therapeutics the aptest intervention. Nevertheless, the clinical failure of conventional low-molecular-weight (LMW) antioxidants in oxidative stress-related diseases to yield favorable therapeutic outcomes and an increased mortality rate attributable to their poor pharmacokinetic characteristics, necessitates the development of alternative therapeutics. In light of this, we designed and synthesized a new amphiphilic polymer functionalized with a clinically safe base polymer of poly(styrene-co-maleic anhydride) copolymer conjugated with the LMW pleiotropic antioxidant TEMPO (a potent antioxidant) and biocompatible poly(ethylene glycol) (TEMPO-installed PSMA-g-PEG), which self-assembles into nano-sized micelles (SMAPoTN) under physiological conditions. We investigated its safety and antioxidant ability using zebrafish models. Common LMW antioxidants, such as 4-hydroxy-TEMPO (TEMPOL), vitamin C, N-acetyl-L-cysteine, and edaravone exposure induced phenotypic distortions, a manifestation of developmental toxicity, and resulted in high lethality in zebrafish larvae. LMW TEMPOL also adversely affected embryo hatchability, induced arrhythmia and cardiac edema, and failed to protect against oxidative stress. In contrast, exposure of zebrafish embryos to SMAPoTN increased the hatchability, protected embryos against various inducers of oxidative stress, and did not induce any phenotypic alterations or discernible toxicity. Taken together, we conclude that SMAPoTN surpasses LMW TEMPOL in terms of the ability to protect zebrafish, attributable to efficient ROS scavenging without perturbing normal redox homeostasis. These results imply that SMAPoTN can be used as a therapeutic intervention against various oxidative stress-induced diseases. Failure of low molecular weight (LMW) antioxidants to improve therapeutic index in various oxidative stress-related pathogenesis, attributable to their poor pharmacokinetic characteristics, greatly limits their clinical translation. To overcome this limitation, we developed a self-assembling antioxidant nanoparticle (SMAPoTN) comprised of amphiphilic polymer; poly(styrene-co-maleic anhydride) conjugated with TEMPO as an antioxidant and biocompatible poly(ethylene glycol). Preliminary studies carried out in the in vivo models of zebrafish embryos confirmed that exposure of LMW antioxidant resulted in acute developmental toxicity, high lethality, and failure to rescue embryos against oxidative stress inducers. In contrast, SMAPoTN did not exert discernible toxicity and significantly improved their survival under oxidative stress. Our finding establishes antioxidant nanoparticles as more suitable therapeutic intervention for oxidative stress-induced diseases than LMW antioxidants. [Display omitted] [ABSTRACT FROM AUTHOR]

The study's primary goal was to enhance medicinal potential of piperine (PIP)-loaded zeolitic imidazolate frameworks-8 (PIP@ZIF-8) against doxorubicin (DOX)-induced cognitive impairments in zebrafish. Herein, PIP@ZIF-8 was synthesized via easy, economical and reproducible ultrasonication method followed by spray drying technology. ZIF-8's structural integrity has been confirmed by PXRD, and even after PIP was encapsulated, the structure of ZIF-8 remained unchanged. Pure ZIF-8 and PIP@ZIF-8 were subjected to TEM analysis, which revealed hexagonal morphology with a nanosize range. FTIR and UV–Visible spectroscopy studies confirmed the drug loading of ZIF-8. Studies on in vitro release revealed 71.48 ± 7.21% and 34.56 ± 5.35% PIP release from PIP@ZIF-8 and unformulated PIP, respectively in pH 7.4. The highest antioxidant scavenging results were obtained with vitamin C (73.77 ± 6.7%) at an intensity of 200 μg/ml, though it was 65.09 ± 2.5% and 57.99 ± 3.1% for PIP@ZIF-8 and PIP, respectively. In vivo studies on zebrafish showed that DOX administration remarkably impaired cognitive activity in T-Maze, and downregulated spatial memory and locomotor activity in the open field test. In addition, DOX administration caused a downregulation in GSH and SOD levels and increase in LPO, AChE and TNF-α levels compared to the vehicle group along with changes in brain histopathology. Further, PIP@ZIF-8 reversed the DOX-induced cognitive impairments by its antioxidant and neuroprotective properties. It can be concluded that PIP@ZIF-8 has a promising therapeutic potential against the chemotherapy-induced cognitive impairments in zebrafish. [Display omitted] • Novel piperine (PIP) loaded zeolitic imidazolate (ZIF-8) metal organic frameworks nanoparticles (PIP@ZIF-8) were prepared using ultrasonication method and dried by spray dryer. • PIP@ZIF-8 nanoparticles were characterized by FTIR, DSC, PXRD, DSC, FE-SEM, EDS and TEM techniques and result showed successful loading of the PIP into the pores of ZIF-8. Physicochemical characterization studies revealed the successful loading of PIP and formation of MOFs. • In vitro release studies demonstrated sustained release over 48 h at pH 7.4. • In vitro antioxidant activitydemonstrated dose dependent antioxidant activity. • Behavioural, biochemical, pro-inflammatory cytokine (TNF-α) and histopathological analysis studies displayed improved neuroprotection activity in chemobrain experimental zebrafish model [ABSTRACT FROM AUTHOR]

● TBP could be bioaccumulated differently in tested organs, liver>gonads>brain. ● TBP could also be transferred from parental generation to their progeny. ● TBP led to thyroid endocrine disruptions in both parental males and females. ● Transgenerational thyroid endocrine disruption occurred in unexposed offspring. Many environmental contaminants could be transmitted from parents and generate impairments to their progeny. The 2,4,6-tribromophenol (TBP), a novel brominated flame retardant which has been frequently detected in various organisms, was supposed to be bioaccumulated and intergenerational transmitted in human beings. Previous studies revealed that TBP could disrupt thyroid endocrine system in zebrafish larvae. However, there is no available data regarding the parental and transgenerational toxicity of this contaminant. Thus, in this study adult zebrafish were exposed to environmental contaminated levels of TBP for 60 days to investigate the parental and transgenerational impairments on thyroid endocrine system. Chemical analysis verified the bioaccumulation of TBP in tested organs of parents (concentration: liver>gonads>brain) and its transmission into eggs. For adults, increased thyroid hormones, disturbed transcriptions of related genes and histopathological changes in thyroid follicles indicate obvious thyroid endocrine disruptions. Transgenerational effects are indicated by the increased thyroid hormones both in eggs (maternal source) and in developed larvae (newly synthesized), as well as disrupted transcriptional profiles of key genes in HPT axis. The overall results suggest that the accumulated TBP could be transmitted from parent to offspring and generate thyroid endocrine disruptions in both generations. [Display omitted] [ABSTRACT FROM AUTHOR]

Compared with MR plain scanning, gadolinium (Gd)-enhanced MR scanning can provide more diagnostic information. Gadopentetate dimeglumine is generally used as an MR enhancement contrast agent in some countries. It is a member of linear Gd-based contrast agents (GBCAs) which are considered more likely to release free Gd ions (Gd3+) than macrocyclic GBCAs. Gd3+ is one of the most effective known calcium antagonists, and can compete with calcium ions (Ca2+) in Ca2+-related biological reactions. In this study, animal models of tissue regeneration were established by cutting the caudal fins of zebrafish, and the models were exposed with gadopentetate dimeglumine solution for different immersion times of 1, 3, and 5 min. Three GBCA exposures per week were performed in the first 3 weeks of the follow-up time. Morphological parameters such as regenerative area (RA), bone density, bone thickness and regenerative bone volume (RBV) were quantified using a camera and synchrotron radiation micro CT. RA decreased as total Gd intake increased in both the female group (ρ = −0.784, P < 0.0001) and the male group (ρ = −0.471, P = 0.011). The bone density of the regenerated bone increased after Gd exposure in the treated groups. The morphology of the regenerated bone from the treated groups became shorter and thicker. Our results showed that gadopentetate dimeglumine had osteogenic toxicity in zebrafish. • Gadopentetate dimeglumine released free Gd3+ from the chelating agent after use. • Gd3+ competed with Ca2+ in Ca2+-involved biological reactions. • The bone density of regenerative bone increased after Gd exposure in zebrafish. • The regenerated bone from the exposed zebrafish became shorter and thicker. [ABSTRACT FROM AUTHOR]

An enzyme-based fluorescent sensor was developed by adapting carbon dots derived from coffee waste to detect inhibitory neurotransmitters such as γ-aminobutyric acid (GABA). In this study, CDs were synthesized from biomass-derived coffee waste by the facile hydrothermal reaction (i.e., C-CDs). A C-CDs-based enzyme-based sensor was then developed using 3-aminophenyl boronic acid (APBA) and nicotinamide adenine dinucleotide phosphate (NADP+) cofactors (i.e., C-CANs). As a result of the addition of the GABase enzyme, the resulting blue-fluorescent C-CANs were effective in detecting GABA. This sensor is capable of sensing GABA in the range of 0–20 μM with a detection limit of 95.09 nM. A distinguished fluorescence quenching was observed in human neuroblastoma (SH-SY5Y) cells where probe (C-CANs-GABase) was able to detect GABA intracellularly. Zebrafish larvae were used to study the sensing potentials of the developed probe against GABA at different concentrations (10 and 20 μM). A validation study was conducted on real samples such as human serum, which showed high recovery values between 97 and 105.6%. [Display omitted] [ABSTRACT FROM AUTHOR]

• We tested how the social environment and cortisol exposure (acute/chronic) affect adult neurogenesis in zebrafish. • Cell proliferation is dependent on the valence of the social environment (positive > negative). • Cell proliferation is independent of either acute or chronic cortisol exposure. • Thus, there is a key role of the social environment in adult neurogenesis in zebrafish independently of cortisol modulation. In Mammals adult neurogenesis is influenced by environmental conditions, and the glucocorticoid hormones (GC) play a major role in this regulation. In contrast in fish, the study of the effects of cortisol on the regulation of environmental driven adult neurogenesis has produced conflicting results. While in some species elevated cortisol levels impair cell proliferation, in others, it promotes cell proliferation and differentiation. This lack of consistency may be explained by methodological differences across studies, namely in the stimuli and/or cortisol treatments used. Here, we tested the effects of the social environment on adult neurogenesis, considering a positive and a negative social context, and different durations of cortisol exposure. We hypothesise that there is an interaction between the valence of the social environment and cortisol, such that elevated acute cortisol experienced during social interactions only have a detrimental effect on neurogenesis in negative social contexts. Therefore, fish were exposed to a positive (conspecific shoal) or negative (predator) social experience, and the interaction between the valence of the social context and cortisol exposure (acute and chronic) was tested. Our results indicate that adult neurogenesis is modulated by the social environment, with the number of newly generated cells being dependent on the valence of the social information (positive > negative). These effects were independent of cortisol, either for acute or chronic exposure, highlighting the social environment as a key factor in the modulation of cell proliferation in the adult zebrafish brain, and rejecting a role for cortisol in this modulation. [ABSTRACT FROM AUTHOR]

• Netrin1 paralogs ntn1a and ntn1b are expressed in distinct patterns during the development of the zebrafish olfactory bulb. • Ntn1a, ntn1b, unc5b, and dcc are required for olfactory sensory neuron targeting. • Experiments using mutant lines replicate previously reported morpholino knockdown experiments. • Sample alignment shows distinct expression patterns of multiple guidance molecules in the olfactory bulb. • Multiple guidance pathways are utilized for olfactory neuron targeting in the olfactory bulb. Olfactory sensory neurons that express related odorant receptors specifically target large identifiable neuropils called protoglomeruli when they first reach the olfactory bulb in the zebrafish. This crude odorant receptor-related mapping is further refined as odorant receptor-specific glomeruli segregate from protoglomeruli later in development. Netrins are a prominent class of axon guidance molecules whose contribution to olfactory circuit formation is poorly studied. Morpholino knock down experiments have suggested that Netrin/Dcc signaling is involved in normal protoglomerular targeting. Here we extend these findings with more detailed characterization and modeling of netrin expression, and by examining protoglomerular targeting in mutant lines for netrin1a (ntn1a), netrin1b (ntn1b) , and their receptors unc5b , dcc , and neo1a. We confirm that ntn1a , ntn1b , and dcc are required for normal protoglomerular guidance of a subset of olfactory sensory neurons that are labeled with the Tg(or111-7 :IRES:Gal4) transgene. We also observe errors in the targeting of these axons in unc5b mutants, but not in neo1a mutants. Our findings are consistent with ntn1a and ntn 1b acting primarily as attractants for olfactory sensory neurons targeting the central zone protoglomerulus. [ABSTRACT FROM AUTHOR]

Photothermal therapy is a novel strategy for cancer treatment, which can kill tumor cells by converting light energy into heat energy through irradiating photothermal conversion materials with laser. As a common photothermal agent, gold nanorods (GNRs) have characteristics of high conversion efficiency and long circulation time in vivo. However, improving stability and reducing toxicity of GNRs remain a significant challenge. In this research, a simple and novel strategy for the synthesis of modified GNRs was proposed. The polysaccharide CL90 was obtained from lemon, which was modified to afford thiolated lemon polysaccharide (SH-CL90). SH-CL90 was used to prepare stable GNRs and give the composite GNRs-SH-CL90, which was found to have good stability in PBS solution and possess high photothermal conversion effects and photothermal stability. The biological experiments revealed that GNRs-SH-CL90 inhibited tumor cell proliferation under near-infrared light irradiation and could induce apoptosis significantly. Furthermore, in vivo experiments supported that GNRs-SH-CL90 could inhibit the proliferation and migration of tumor cells. All the experiments demonstrated that GNRs-SH-CL90 might be promising in the field of cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Low-molecular-weight chitosan (LMWCS) damaged cell membranes in zebrafish showed its possibility to release reporter proteins for detection. In this study, we developed a simple fluorometric-based assay for the evaluation of clinical antiangiogenic drugs using LMWCS and Tg(fli1:EGFP) transgenic zebrafish, which expressed green-fluorescence protein (GFP) in the endothelial cells of blood vessel. In vitro stable and transiently transfected cell lines was released luciferase and green fluorescent protein (GFP) for intensity evaluation upon LMWCS fluorometric-based assay. In vivo Tg(fli1:EGFP) transgenic zebrafish was also released GFP from endothelial cells of blood vessels and show an increase of fluorescent intensity upon LMWCS fluorometric-based assay. Treatment with the clinical antiangiogenic drug sorafenib and analyzed by LMWCS fluorometric-based assay showed significantly reduction of angiogenesis. Furthermore, treatment with 2 μM sorafenib showed a significant reduction in angiogenesis of the intersegmental vein (ISV) and dorsal longitudinal anastomotic vessels (DLAV) in Tg(fli1:EGFP) transgenic zebrafish. Fluorescence intensity reduction from 2 μM sorafenib was used as a factor in the LMWCS fluorescence-based assay for relative antiangiogenic evaluation. Relative angiogenesis evaluation of the clinical drugs axitinib, cabozantinib, and regorafenib showed a significant reduction. Collectively, this study provided a simple, convenient, and rapid LMWCS fluorometric-based assay for evaluating angiogenic drugs using transgenic zebrafish. • Low-molecular weight chitosan (LMWCS) damages cell membrane to release luciferase and green fluorescent protein (GFP). • LMWCS fluorometric assay show similar reduction of angiogenesis by sorafenib to microscope-based assay in Tg(fli1:EGFP) transgenic zebrafish. • Relative antiangiogenesis was used to analyze antiangiogenic effect of clinical drugs by comparing to the group treated with sorafenib. • LMWCS fluorometric assay could be used to evaluate antiangiogenic effect of clinical drugs. [ABSTRACT FROM AUTHOR]

Polyphyllin I (PPI) and polyphyllin II (PII) are the main active substances in the Paris polyphylla. However, liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated. In this work, we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner. The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders, which were alleviated by the cholesterol biosynthesis inhibitor lovastatin. Additionally, 3-hydroxy-3-methy-lglutaryl CoA reductase (HMGCR) and squalene epoxidase (SQLE), the two rate-limiting enzymes in the cholesterol synthesis, selected as the potential targets, were confirmed by the molecular docking, the overexpression, and knockdown of HMGCR or SQLE with siRNA. Finally, the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR. Collectively, these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways, thus disturbing the cholesterol biosynthesis pathway. The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future. [Display omitted] • PPI and PII could induced significant hepatotoxicity in vitro L02 and in vivo zebrafish. • Hepatotoxicity of PPI and PII were associated with the cholesterol synthesis pathway. • PPI intervention in SREBP2/HMGCR/SQLE/LSS pathway leads to hepatotoxicity. • The SQLE protein was the direct bind protein to PPI. [ABSTRACT FROM AUTHOR]

[Display omitted] • Exposure to morphine and cocaine induces changes in the transcriptome of zebrafish embryos. • Pathways related to lipid metabolism appear to be overrepresented for both treatments. • Other deregulated pathways are detoxification, response to chemicals and calcium signalling. • Morphine and cocaine modify global DNA methylation. Morphine and other opioid analgesics are the drugs of election to treat moderate-to-severe pain, and they elicit their actions by binding to the opioid receptors. Cocaine is a potent inhibitor of dopamine, serotonin, and noradrenaline reuptake, as it blocks DAT, the dopamine transporter, causing an increase in the local concentration of these neurotransmitters in the synaptic cleft. The molecular effects of these drugs have been studied in specific brain areas or nuclei, but the systemic effects in the whole organism have not been comprehensively analyzed. This study aims to analyze the transcriptomic changes elicited by morphine (10 uM) and cocaine (15 uM) in zebrafish embryos. An RNAseq assay was performed with tissues extracts from zebrafish embryos treated from 5 hpf (hours post fertilization) to 72 hpf, and the most representative deregulated genes were experimentally validated by qPCR. We have found changes in the expression of genes related to lipid metabolism, chemokine receptor ligands, visual system, hemoglobins, and metabolic detoxification pathways. Besides, morphine and cocaine modified the global DNA methylation pattern in zebrafish embryos, which would explain the changes in gene expression elicited by these two drugs of abuse. [ABSTRACT FROM AUTHOR]

• The inorganic arsenite and arsenate found in water as the most prevalent forms. • Excessive exposure to inorganic arsenate in drinking water causes a slew of health issues in human. • Hepatocytes are exposed to xenobiotics; they undergo morphological and structural damage. • Centella asiatica has the potential to reduce the cytotoxicity triggered by sodium arsenate in zebrafish. Arsenic contamination in drinking water is a major public health concern. It is classified as an environmental pollutant that necessitates immediate corrective action. Long-term arsenic exposure may cause hepatotoxicity. The current research focuses on the effectiveness of a methanolic extract of Centella asiatica against sodium arsenate-induced hepatotoxicity in Danio rerio (Zebrafish). Phytochemicals and bioactive compounds in C.asiatica extract were studied using standard procedure and GC-MS analysis. The extract was also assessed for antioxidant and antibacterial properties. The significant scavenging activity of oxygen-free radicals as well as the IC50 values was observed. Furthermore, the ability of C.asiatica (500 mg/g) leaf extract to alleviate hepatotoxicity in Zebrafish pretreated and post-treated with sodium arsenate (100g/l) was observed. In this work, phytochemical examination of C.asiatica leaf extract revealed the presence of bioactive substances such as alkaloids, flavonoids, terpenoids, glycosides, phenolics, proteins, and carbohydrates, which was validated by GC MS analysis of different percentage areas. Importantly, the methanolic extract of C.asiatica demonstrated strong antimicrobial and antioxidant activities. The plant extract, in particular, demonstrated its efficiency by alleviating the effects of arsenate in the liver of zebrafish (both pre-and post-treatment), as demonstrated by histological analysis. The results of histopathological research revealed that methanolic extract of C.asiatica had a considerable lowering effect on sodium arsenate-induced hepatocyte damage in zebrafish. As a result, the inhibitory action of Centella asiatica methanolic extract may be investigated to create effective candidates to fight arsenate toxicity. [ABSTRACT FROM AUTHOR]

Prodigiosin, a red bacterial pigment is a compound with promising therapeutic properties. Major hindrance in applying prodigiosin in pharmaceutics is the insolubility in water and lack of bioavailability. This study aims to optimize two different types of chitosan based delivery systems, microspheres and nanoparticles for prodigiosin derived from Serratia marcescens NITDPER1 through Taguchi method and determine toxicity perspectives. The results revealed 0.5 % chitosan, 1 % sodium-alginate and 5 % CaCl 2 optimum for microsphere and 0.1 % chitosan, 1.5 % TPP and 1.5 % acetic acid for nanoparticle with the entrapment efficiency and maximum release of 89.27 ± 1.2 % and 87.42 ± 1.9 % for microspheres and 96.36 ± 1.7 % and 91.58 ± 2.1 % for nanoparticles. Particle size was 93.03 ± 0.3 μm and 75.1 ± 1.4 nm for micro and nanoformulations. Kinetic parameters of release fitted best with Korsmeyer-Peppas model. Swelling index of microsphere and nanoparticles in pH 6.8 was 799 ± 7.1 % and 35.3 ± 2.1 % respectively. FESEM, FT-IR and XRD revealed spherical morphology, preservation of prodigiosin functional groups and amorphous nature of the formulations. Anticancer IC 50 values were (μg mL−1) 11.7 ± 1.2, 10.8 ± 1.4 and 9.4 ± 0.8 for free prodigiosin, microsphere and nanoparticles respectively. Toxicity studies on HEK-293 cell line, Daphnia magna and zebrafish model determined non-toxic nature of the bacterial prodigiosin and its formulations revealing suitability of animal system application. • Taguchi design was used to prepare two delivery systems for prodigiosin. • Microsphere and nanoparticles were of desired size and morphology. • Release kinetics unravelled best fit with the Korsmeyer-Peppas model. • The formulations were found non-toxic towards Daphnia magna and zebrafish. [ABSTRACT FROM AUTHOR]