Imatinib­ and ponatinib­mediated cardiotoxicity in zebrafish embryos and H9c2 cardiomyoblasts.

Tyrosine kinase inhibitors (TKIs) offer targeted therapy for cancers but can cause severe cardiotoxicities. Determining their dose­dependent impact on cardiac function is required to optimize therapy and minimize adverse effects. The dose­dependent cardiotoxic effects of two TKIs, imatinib and ponatinib, were assessed in vitro using H9c2 cardiomyoblasts and in vivo using zebrafish embryos. In vitro, H9c2 cardiomyocyte viability, apoptosis, size, and surface area were evaluated to assess the impact on cellular health. In vivo, zebrafish embryos were analyzed for heart rate, blood flow velocity, and morphological malformations to determine functional and structural changes. Additionally, reverse transcription­quantitative PCR (RT­qPCR) was employed to measure the gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), established markers of cardiac injury. This comprehensive approach, utilizing both in vitro and in vivo models alongside functional and molecular analyses, provides a robust assessment of the potential cardiotoxic effects. TKI exposure decreased viability and surface area in H9c2 cells in a dose­dependent manner. Similarly, zebrafish embryos exposed to TKIs exhibited dose­dependent heart malformation. Both TKIs upregulated ANP and BNP expression, indicating heart injury. The present study demonstrated dose­dependent cardiotoxic effects of imatinib and ponatinib in H9c2 cells and zebrafish models. These findings emphasize the importance of tailoring TKI dosage to minimize cardiac risks while maintaining therapeutic efficacy. Future research should explore the underlying mechanisms and potential mitigation strategies of TKI­induced cardiotoxicities.

Zebrafish Model in Illuminating the Complexities of Post-Traumatic Stress Disorders: A Unique Research Tool.

Post-traumatic stress disorder (PTSD) is a debilitating psychological condition that may develop in certain individuals following exposure to life-threatening or traumatic events. Distressing symptoms, including flashbacks, are characterized by disrupted stress responses, fear, anxiety, avoidance tendencies, and disturbances in sleep patterns. The enduring effects of PTSD can profoundly impact personal and familial relationships, as well as social, medical, and financial stability. The prevalence of PTSD varies among different populations and is influenced by the nature of the traumatic event. Recently, zebrafish have emerged as a valuable model organism in studying various conditions and disorders. Zebrafish display robust behavioral patterns that can be effectively quantified using advanced video-tracking tools. Due to their relatively simple nervous system compared to humans, zebrafish are particularly well suited for behavioral investigations. These unique characteristics make zebrafish an appealing model for exploring the underlying molecular and genetic mechanisms that govern behavior, thus offering a powerful comparative platform for gaining deeper insights into PTSD. This review article aims to provide updates on the pathophysiology of PTSD and the genetic responses associated with psychological stress. Additionally, it highlights the significance of zebrafish behavior as a valuable tool for comprehending PTSD better. By leveraging zebrafish as a model organism, researchers can potentially uncover novel therapeutic interventions for the treatment of PTSD and contribute to a more comprehensive understanding of this complex condition.

The Role of p90 Ribosomal S6 Kinase (RSK) in Tyrosine Kinase Inhibitor (TKI)-Induced Cardiotoxicity.

Targeted therapy, such as tyrosine kinase inhibitors (TKIs), has been approved to manage various cancer types. However, TKI-induced cardiotoxicity is a limiting factor for their use. This issue has raised the need for investigating potential cardioprotective techniques to be combined with TKIs. Ribosomal S6-kinases (RSKs) are a downstream effector of the mitogen-activated-protein-kinase (MAPK) pathway; specific RSK isoforms, such as RSK1 and RSK2, have been expressed in cancer cells, in which they increase tumour proliferation. Selective targeting of those isoforms would result in tumour suppression. Moreover, activation of RSKs expressed in the heart has resulted in cardiac hypertrophy and arrhythmia; thus, inhibiting RSKs would result in cardio-protection. This review article presents an overview of the usefulness of RSK inhibitors that can be novel agents to be assessed in future research for their effect in reducing cancer proliferation, as well as protecting the heart from cardiotoxicity induced by TKIs.

Zebrafish (Danio rerio) as a Model for the Study of Developmental and Cardiovascular Toxicity of Electronic Cigarettes.

The increasing popularity of electronic cigarettes (e-cigarettes) as an alternative to conventional tobacco products has raised concerns regarding their potential adverse effects. The cardiovascular system undergoes intricate processes forming the heart and blood vessels during fetal development. However, the precise impact of e-cigarette smoke and aerosols on these delicate developmental processes remains elusive. Previous studies have revealed changes in gene expression patterns, disruptions in cellular signaling pathways, and increased oxidative stress resulting from e-cigarette exposure. These findings indicate the potential for e-cigarettes to cause developmental and cardiovascular harm. This comprehensive review article discusses various aspects of electronic cigarette use, emphasizing the relevance of cardiovascular studies in Zebrafish for understanding the risks to human health. It also highlights novel experimental approaches and technologies while addressing their inherent challenges and limitations.

Evaluation of Metal-Organic Framework MIL-89 nanoparticles toxicity on embryonic zebrafish development.

Metal-Organic Framework MIL-89 nanoparticles garnered remarkable attention for their widespread use in technological applications. However, the impact of these nanomaterials on human and environmental health is still limited, and concerns regarding the potential risk of exposure during manipulation is constantly rising. Therefore, the extensive use of nanomaterials in the medical field necessitates a comprehensive assessment of their safety and interaction with different tissues of the body system. In this study, we evaluated the systemic toxicity of nanoMIL-89 using Zebrafish embryos as a model system to determine the acute developmental effect. Zebrafish embryos were exposed to a range of nanoMIL-89 concentrations (1 - 300 µM) at 4 h post-fertilization (hpf) for up to 120 hpf. The viability and hatching rate were evaluated at 24-72 hpf, whereas the cardiac function was assessed at 72 and 96 hpf, and the neurodevelopment and hepatic steatosis at 120 hpf. Our study shows that nanoMIL-89 exerted no developmental toxicity on zebrafish embryos at low concentrations (1-10 µM). However, the hatching time and heart development were affected at high concentrations of nanoMIL-89 (> 30 µM). Our findings add novel information into the available data about the in vivo toxicity of nanoMIL-89 and demonstrate its innocuity and safe use in biological, environmental, and medical applications.

Cardiac function and blood flow hemodynamics assessment of zebrafish (Danio rerio) using high-speed video microscopy.

BACKGROUND: In the last few decades, zebrafish (Danio rerio) were introduced as a model organism to investigate human diseases including cardiovascular and neuronal disorders. In most zebrafish investigations, cardiac function and blood flow hemodynamics need to be assessed to study the effects of the interference on the cardiovascular system. For heart function assessment, most important parameters include heart rate, cardiac output, ejection fraction, fractional area change, and fractional shortening. METHODS: A 10 s high-speed video of beating heart and flowing blood within major vessels of zebrafish that are less than 5 days post fertilization (dpf) were recorded via a stereo microscope equipped with a high speed camera. The videos were analyzed using MicroZebraLab and image J software for the assessment of cardiac function. RESULTS: Using the technique described here, we were able to simply yet effectively assess cardiac function and blood flow dynamics of normal zebrafish embryos. We believe that the practical method presented here will help cardiac researchers using the zebrafish as a model to examine cardiac function by using tools that could be available in their laboratory.

Adaptation of a Mice Doppler Echocardiography Platform to Measure Cardiac Flow Velocities for Embryonic Chicken and Adult Zebrafish.

Ultrasonography is the most widely used imaging technique in cardiovascular medicine. In this technique, a piezoelectric crystal produces, sends, and receives high frequency ultrasound waves to the body to create an image of internal organs. It enables practical real time visualization in a non-invasive manner, making the modality especially useful to image dynamic cardiac structures. In the last few decades, echocardiography has been applied to in vivo cardiac disease models, mainly to rodents. While clinical echocardiography platforms can be used for relatively large animals such as pigs and rats, specialized systems are needed for smaller species. Theoretically, as the size of the imaged sample decreases, the frequency of the ultrasound transducer needed to image the sample increases. There are multiple modes of echocardiography imaging. In Doppler mode, erythrocytes blood flow velocities are measured from the frequency shift of the sent ultrasound waves compared to received echoes. Recorded data are then used to calculate cardiac function parameters such as cardiac output, as well as the hemodynamic shear stress levels in the heart and blood vessels. The multi-mode (i.e., b-mode, m-mode, Pulsed Doppler, Tissue Doppler, etc.) small animal ultrasound systems in the market can be used for most in vivo cardiac disease models including mice, embryonic chick and zebrafish. These systems are also associated with significant costs. Alternatively, there are more economical single-mode echocardiography platforms. However, these are originally built for mice studies and they need to be tested and evaluated for smaller experimental models. We recently adapted a mice Doppler echocardiography system to measure cardiac flow velocities for adult zebrafish and embryonic chicken. We successfully assessed cardiac function and hemodynamic shear stress for normal as well as for diseased embryonic chicken and zebrafish. In this paper, we will present our detailed protocols for Doppler flow measurements and further cardiac function analysis on these models using the setup. The protocols will involve detailed steps for animal stabilization, probe orientation for specific measurements, data acquisition, and data analysis. We believe this information will help cardiac researchers to establish similar echocardiography platforms in their labs in a practical and economical manner.

Ecotoxicological Assessment of Thermally- and Hydrogen-Reduced Graphene Oxide/TiO2 Photocatalytic Nanocomposites Using the Zebrafish Embryo Model.

Advanced oxidation processes (AOPs) have recently attracted great interest in water pollution management. Using the zebrafish embryo model, we investigated the environmental impacts of two thermally (RGOTi)- and hydrogen (H2RGOTi)-reduced graphene oxide/TiO2 semiconductor photocatalysts recently employed in AOPs. For this purpose, acutoxicity, cardiotoxicity, neurobehavioral toxicity, hematopoietic toxicity, and hatching rate were determinate. For the RGOTi, the no observed effect concentration (NOEC, mortality/teratogenicity score <20%) and the median lethal concentration (LC50) were <400 and 748.6 mg/L, respectively. H2RGOTi showed a NOEC similar to RGOTi. However, no significant mortality was detected at all concentrations used in the acutoxicity assay (up to1000 mg/L), thus indicating a hypothetical LC50 higher than 1000 mg/L. According to the Fish and Wildlife Service Acute Toxicity Rating Scale, RGOTi can be classified as "practically not toxic" and H2RGOTi as "relatively harmless". However, both nanocomposites should be used with caution at concentration higher than the NOEC (400 mg/L), in particular RGOTi, which significantly (i) caused pericardial and yolk sac edema; (ii) decreased the hatching rate, locomotion, and hematopoietic activities; and (iii) affected the heart rate. Indeed, the aforementioned teratogenic phenotypes were less devastating in H2RGOTi-treated embryos, suggesting that the hydrogen-reduced graphene oxide/TiO2 photocatalysts may be more ecofriendly than the thermally-reduced ones.

Using Zebrafish for Investigating the Molecular Mechanisms of Drug-Induced Cardiotoxicity.

Over the last decade, the zebrafish (Danio rerio) has emerged as a model organism for cardiovascular research. Zebrafish have several advantages over mammalian models. For instance, the experimental cost of using zebrafish is comparatively low; the embryos are transparent, develop externally, and have high fecundity making them suitable for large-scale genetic screening. More recently, zebrafish embryos have been used for the screening of a variety of toxic agents, particularly for cardiotoxicity testing. Zebrafish has been shown to exhibit physiological responses that are similar to mammals after exposure to medicinal drugs including xenobiotics, hormones, cancer drugs, and also environmental pollutants, including pesticides and heavy metals. In this review, we provided a summary for recent studies that have used zebrafish to investigate the molecular mechanisms of drug-induced cardiotoxicity. More specifically, we focused on the techniques that were exploited by us and others for cardiovascular toxicity assessment and described several microscopic imaging and analysis protocols that are being used for the estimation of a variety of cardiac hemodynamic parameters.

Protein arginine methyltransferase 5 (PRMT5) dysregulation in cancer.

Protein arginine methyltransferases (PRMTs) are known for their ability to catalyze methylation of specific arginine residues in a wide variety of cellular proteins, which are involved in a plethora of processes including signal transduction, transcription, and more recently DNA recombination. All members of the PRMT family can be grouped into three main classes depending on the type of methylation they catalyze. Type I PRMTs induce monomethylation and asymmetric dimethylation, while type II PRMTs catalyze monomethylation and symmetric dimethylation of specific arginine residues. In contrast, type III PRMTs carry out only monomethylation of arginine residues. In this review, we will focus on PRMT5, a type II PRMT essential for viability and normal development, which has been shown to be overexpressed in a wide variety of cancer cell types, owing it to the crucial role it plays in controlling key growth regulatory pathways. Furthermore, the role of PRMT5 in regulating expression and stability of key transcription factors that control normal stem cell function as well as cancer stem cell renewal will be discussed. We will review recent work that shows that through its ability to methylate various cellular proteins, PRMT5 functions as a master epigenetic regulator essential for growth and development, and we will highlight studies that have examined its dysregulation and the effects of its inhibition on cancer cell growth.