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Although the concept of endocrine disruptors first appeared almost 30 years ago, the relatively recent involvement of these substances in the etiology of metabolic pathologies (obesity, diabetes, hepatic steatosis, etc.) has given rise to the concept of Metabolic Disrupting Chemicals (MDCs). Organs such as the liver and adipose tissue have been well studied in the context of metabolic disruption by these substances. The intestine, however, has been relatively unexplored despite its close link with these organs. In vivo models are useful for the study of the effects of MDCs in the intestine and, in addition, allow investigations into interactions with the rest of the organism. In the latter respect, the zebrafish is an animal model which is used increasingly for the characterization of endocrine disruptors and its use as a model for assessing effects on the intestine will, no doubt, expand. This review aims to highlight the importance of the intestine in metabolism and present the zebrafish as a relevant alternative model for investigating the effect of pollutants in the intestine by focusing, in particular, on cytochrome P450 3A (CYP3A), one of the major molecular players in endogenous and MDCs metabolism in the gut. [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]

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]

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]

Organisms have conversion systems for sulfate ion to take advantage of the chemical features. The use of biologically converted sulfonucleotides varies in an evolutionary manner, with the universal use being that of sulfonate donors. Sulfotransferases have the ability to transfer the sulfonate group of 3′-phosphoadenosine 5′-phosphosulfate to a variety of molecules. Cytosolic sulfotransferases (SULTs) play a role in the metabolism of low-molecular-weight compounds in response to the host organism's living environment. This review will address the diverse functions of the SULT in evolution, including recent findings. In addition to the diversity of vertebrate sulfotransferases, the molecular aspects and recent studies on bacterial and plant sulfotransferases are also addressed. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of the ethyl acetate fraction derived from Sargassum pallidum extract against particulate matter (PM)-induced oxidative stress and inflammation in HaCaT cells and zebrafish. Methods: HaCaT cells and zebrafish were used to evaluate the protective effects of the ethyl acetate fraction of Sargassum pallidum extract against PM-induced oxidative stress and inflammation. The production of nitric oxide (NO), intracellular ROS, prostaglandin E2 (PGE2), and pro-inflammatory cytokines, and the expression levels of COX-2, iNOS, and NF-κB were evaluated in PM-induced HaCaT cells. Furthermore, the levels of ROS, NO, and lipid peroxidation were assessed in the PM-exposed zebrafish model. Results: The ethyl acetate fraction of Sargassum pallidum extract significantly decreased the production of NO, intracellular ROS, and PGE2 in PM-induced HaCaT cells. In addition, the fraction markedly suppressed the levels of pro-inflammatory cytokines and inhibited the expression levels of COX-2, iNOS, and NF-κB. Furthermore, it displayed remarkable protective effects against PM-induced inflammatory response and oxidative stress, represented by the reduction of NO, ROS, and lipid peroxidation in zebrafish. Conclusions: The ethyl acetate fraction of Sargassum pallidum extract exhibits a protective effect against PM-induced oxidative stress and inflammation both in vitro and in vivo and has the potential as a candidate for the development of pharmaceutical and cosmeceutical products. [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]

From pre-historic era, all scientific discoveries have evolved around a concept – THINK BIG but for a change zebrafish as a model organism in research had managed to halt the entire medical community and made us realize that it's time to think small. From a barely imagined being in research few years ago to around 4,000 publications in just last year, zebrafish has definitely come a long way. Through these tiny fish, scientists have managed to find genes that caused human diseases and have also developed various specific models to know more about the pathology behind such diseases. This review will focus on zebrafish as a model organism from the time it was introduced to the most novel targets with particular emphasis on central nervous system (CNS) as it is rapidly evolving branch in zebrafish research these days. This review will try to shed light on the early stages of zebrafish as a model organism and will try to cover the journey of it developing as a successful model organism to map many diseases like diabetes, Alzheimer's and autism describing the rationale for using this specific model and briefly the techniques under each category and finally will summarize the pros and cons of the model with its expected future directions. [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]

OBJECTIVE: This study aimed to evaluate the anti-melanogenic activity of raspberry ketone glucoside (RKG) and further explore the specific molecular mechanisms by which RKG affects melanogenesis. MATERIALS AND METHODS: The B16F10 cells model, the mushroom tyrosinase model and the zebrafish model were used to assess the whitening activity of RKG. We subsequently identified possible pathways related to RKG inhibition of melanogenesis by RNA-seq analysis and qRT-PCR on the zebrafish model, and further explored the effects of key genes on the pathway on the melanogenic effect of RKG by using related pathway inhibitors and Tg [mpeg: EGFP] transgenic zebrafish line. RESULTS: RKG could noticeably inhibit melanogenesis in B16F10 cells in vitro and on zebrafish in vivo. The RNA-Seq analysis and the qRT-PCR in zebrafish embryos indicated that the inhibition of melanogenesis by RKG could be achieved by activating JAK1/STAT3 signal pathway and inhibiting the expression levels of the MITFa, TYR, TYRP1a genes directly associated with melanogenesis. The inhibitor tests revealed that the inhibitory effect of the RKG on melanogenesis was restored by the IL6, JAK1/2, and STAT3 inhibitors, specifically STAT3 inhibitor. We further examine the relationship between the JAK1/STAT3 signal pathway and the MITFa. The achieved results indicate that the RKG could activate the zebrafish macrophages via the JAK1, but the inhibition of macrophage activation by loganin did not affect the anti-pigmentation effect of the RKG. CONCLUSIONS: RKG showed remarkable whitening activity on both B16F10 cells in vitro and zebrafish model in vivo. Furthermore, RKG could inhibit melanogenesis by activating the IL6/JAK1/STAT3 pathway, inhibiting the transcriptional activity of MITFa, and its downstream expression levels of the TYR and TYRP1a genes. [ABSTRACT FROM AUTHOR]

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Upregulation of COX2 (cyclooxygenase 2) and prostaglandin E2 (PGE2) was linked to podocyte damage in GH. We explored the potential renoprotective effects of either separate or combined pharmacological blockade of EP2 (PGE2 receptor type 2) and EP4 (PGE2 receptor type 4) in GH. Methods: We conducted in vivo studies in a transgenic zebrafish model (Tg[fabp10a:gc-EGFP]) suitable for analysis of glomerular filtration barrier function and a genetic rat model with GH, albuminuria, and upregulation of PGE2. Similar pharmacological interventions and primary outcome analysis on albuminuria phenotype development were conducted in both model systems. Results: Stimulation of zebrafish embryos with PGE2 induced an albuminuria-like phenotype, thus mimicking the suggested PGE2 effects on glomerular filtration barrier dysfunction. Both separate and combined blockade of EP2 and EP4 reduced albuminuria phenotypes in zebrafish and rat models. A significant correlation between albuminuria and podocyte damage in electron microscopy imaging was identified in the rat model. Dual blockade of both receptors showed a pronounced synergistic suppression of albuminuria. Importantly, this occurred without changes in arterial blood pressure, glomerular filtration rate, or tissue oxygenation in magnetic resonance imaging, while RNA sequencing analysis implicated a potential role of circadian clock genes. Conclusions: Our findings confirm a role of PGE2 in the development of albuminuria in GH and support the renoprotective potential of combined pharmacological blockade of EP2 and EP4 receptors. These data support further translational research to explore this therapeutic option and a possible role of circadian clock genes. [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]

In vertebrates, nutritional tastants, such as amino acids and sugars, are recognized by G‐protein‐coupled receptors of the taste receptor type 1 (T1R) family. Previous studies have shown that fish T1Rs are functionally distinct from mammalian T1Rs in certain regards. Here, we report the existence of oral receptors with high sensitivity to amino acids in zebrafish and medaka fish. We describe the construction of multiple cell lines stably expressing functional T1Rs (from medaka fish or zebrafish) with a chimeric G‐protein (G16gust44) using the Flp‐In system. Through functional assays with these cell lines, medaka fish and zebrafish were confirmed to possess particular T1Rs highly sensitive to l‐proline, possibly reflecting the physiological importance of l‐proline in teleosts, in line with previous studies. [ABSTRACT FROM AUTHOR]

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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] • To study the mechanism of protocatechuic acid on osteoporosis in antioxidant stress environment. • Combined with network pharmacology, virtual and experimental verification, the core target of protocatechuic acid was determined. • According to GO and KEGG pathways, protocatechuic acid may play a role through HIF-1 signaling pathway. • The mechanism of protocatechuic acid in treating osteoporosis was expounded from two aspects: MC3T3-E1 cells cultured in vitro and zebrafish model in vivo. Protocatechuic acid (PCA), a naturally occurring polyphenol abundant in fruits, vegetables, and various plants, exhibits diverse biological activities. However, the mechanism of action of PCA in osteoporosis (OP) is unclear. This study aims to elucidate the anti-OP mechanisms of PCA through an integrated approach involving network pharmacology, virtual screening, and experimental validation. In this study, we found that PCA improved zebrafish skeletal development and promoted MC3T3-E1 cell proliferation, increasing ALP activity. In addition, PCA decreased the level of ROS and MDA, increased the level of SOD, GSH and NO, and mitigated the degree of oxidative stress. Concurrently, network pharmacological analysis indicated that PCA upregulated core target levels, activated the HIF-1 signaling pathway, ameliorated oxidative stress, and exerted an anti-OP effect by promoting bone formation. In conclusion, PCA may provide a new strategy in the prevention and treatment of OP. [ABSTRACT FROM AUTHOR]

Homosalate (HS) and octisalate (OS), which are used in sunscreen for the purpose of blocking ultraviolet rays, are frequently detected in water environment. Although effects on estrogens and androgens have been reported, studies on thyroid and growth hormone endocrine disruption are limited. In the present study, larval mortality was compared in wild-type and two knockout fish (thyroid hormone receptor alpha a knockout (thrαa-/-) and dre-miR-499 knockout (dre-miR-499-/-)) after 96 h of exposure to HS and OS (0, 0.003, 0.03, 0.3, 3, 30 and 300 µg/L). To investigate the mechanisms of thyroid and growth hormone endocrine disruption, we measured the levels of triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), growth hormone (GH), and insulin-like growth factor-1 (IGF-1), and the regulation of representative genes related to the hypothalamus-pituitary-thyroid (HPT) and GH/IGF axis in wild-type zebrafish exposed to target chemicals. The significantly lower larval survival rate of thrαa-/- and dre-miR-499-/- fish exposed to 300 μg/L of HS and OS suggest that thyroid hormone receptors and dre-miR-499 play a crucial role in the toxic effects of HS and OS. The finding of a significant increase in T3 and T4 in zebrafish larvae exposed to HS and OS supports a significant decrease in the crh gene. The reduction of GH and IGF-1 in fish exposed to HS and OS is well supported by the regulation of genes involved in the GH/IGF axis. Our observations suggest that exposure to HS and OS affects not only thyroid hormone receptors and their associated miRNAs, but also the feedback routes of HPT and GH/IGF axes, ultimately leading to growth reduction. [Display omitted] • Thrαa-/- and miR-499-/- can sensitively identify thyroid endocrine disruptors. • Body length reduced with increasing homosalate (HS) and octisalate (OS) exposure. • HS increased T3 and T4 contents, and decreased TSH, GH, and IGF-1 concentrations. • HS upregulated genes related to thyroid hormone synthesis (trαa, tpo, and nis). • OS increased T4 contents, while T3 and TSH were not statistically significant. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is predominantly prescribed for epilepsy, convulsions, and other psychiatric disorders. As an epigenetic regulator, it is also used to treat various forms of cancer. The clinical demand for the drug may pose an environmental hazard. Evidence indicates that VPA's significant therapeutic value comes at the cost of possible side toxic effects, as symptoms of birth defects have been confirmed in animal experiments using VPA. However, the effects of VPA during the development of the circulatory system remain unclear. In this study, zebrafish embryos were exposed to a series of concentrations of VPA between three hours post fertilization (hpf) and five days post fertilization (dpf). The results demonstrated time- and dose-dependent developmental delays in the zebrafish, including cardiovascular malformation and decreased movement and reaction time. Consistent with the in vivo results, exposure to VPA increased the levels of myocardial reactive oxygen species (ROS) and cell apoptosis through cardiac mitochondrial turnover disorders. The expression levels of genes related to cardiovascular development and antioxidant response were downregulated, while genes related to apoptosis pathways were upregulated. Overall, our toxicological studies of VPA exposure illustrate the damage to cardiovascular development, raising concerns about the hazard of VPA exposure in early pregnancy. Our study provides novel insights into the potential environmental risks of VPA. [Display omitted] • VPA is an environmental pollutant with potential developmental toxicity. • VPA has inhibitory effects on early cardiovascular development. • VPA-exposed toxicity on zebrafish is significantly dose- and time-dependent. • VPA causes cytotoxicity by affecting mitochondrial function and accumulating ROS. [ABSTRACT FROM AUTHOR]

• Exploring the anti-ALD effect of HSYA through an integrative pharmacology approach. • HSYA decreases lipid, ROS, inflammatory response and promotes ethanol catabolism. • HSYA reverses the abnormal gene expression caused by ethanol treatment. • HSYA is a promising natural product for prevention and treatment of ALD. Alcoholic liver disease (ALD) significantly contributes to global liver-related morbidity and mortality. Natural products play a crucial role in the prevention and treatment of ALD. Hydroxysafflor yellow A (HSYA), a unique and primary component of Safflower (Carthamus tinctorius l.), exhibits diverse pharmacological activities. However, the impact and mechanism of HSYA on ALD have not been fully elucidated. The purpose of this study was to employ an integrative pharmacology approach to assess the multi-targeted mechanism of HSYA against ALD. Network pharmacology and molecular docking techniques were used to analyze the potential therapeutic signaling pathways and targets of HSYA against ALD. An ALD model in zebrafish larvae was established. Larvae were pretreated with HSYA and then exposed to ethanol. Liver injury was measured by fluorescence expression analysis in the liver-specific transgenic zebrafish line Tg (fabp10a:DsRed) and liver tissue H&E staining. Liver steatosis was determined by whole-mount oil red O staining and TG level. Additionally, an ethanol-induced hepatocyte injury model was established in vitro to observe hepatocyte damage (cell viability, ALT level), lipid accumulation (oil red O staining, TC and TG), and oxidative stress (ROS, MDA, GPx and SOD) in HepG2 cells treated with or without HSYA. Finally, qRT-PCR combined with network pharmacology and molecular docking was employed to validate the effects of HSYA on targets. HSYA exhibited a significant, dose-dependent improvement in ethanol-induced liver injury in zebrafish larvae and HepG2 cells. Network pharmacology analysis revealed that HSYA may exert pharmacological effects against ALD through 341 potential targets. These targets are involved in various signaling pathways, including lipid metabolism and atherosclerosis, PI3K-Akt signaling pathway, MAPK signaling pathway, and ALD itself. Molecular docking studies displayed that HSYA had a strong binding affinity toward the domains of IL1B, IL6, TNF, PPARA, PPARG, HMGCR and ADH5. qRT-PCR assays demonstrated that HSYA effectively reversed the ethanol-induced aberrant gene expression of SREBF1, FASN, ACACA, CPT1A, PPARA, IL1B, IL6, TNFα, ADH5, and ALDH2 in vivo and in vitro. This study offers a comprehensive investigation into the anti-ALD mechanisms of HSYA using an integrative pharmacology approach. The potential targets of HSYA may be implicated in enhancing ethanol catabolism, reducing lipid accumulation, mitigating oxidative stress, and inhibiting inflammatory response. [Display omitted] [ABSTRACT FROM AUTHOR]

Although polyethylene terephthalate (PET) fibers are a representative form of plastic pollutants, studies on their toxicity are currently limited compared to other plastic types. Moreover, the effect of natural organic matter (NOM) on their toxicity has not been investigated. In this study, female and male adult zebrafish were exposed to synthesized PET fibers at concentrations of 0.1, 1, 10, and 100 mg/L in the presence and absence of 10 mg/L of NOM for 10 d. Bioaccumulation of PET fibers in zebrafish intestine, liver, and gills was identified and expression levels of reactive oxygen species (ROS) generation, sex hormones, and oxidative stress and sex hormone-related genes were measured. In addition, the developmental stages of gonadal cells were examined through histological analysis. We found that PET fibers bioaccumulated in the intestine and liver of zebrafish. ROS generation significantly increased at 100 mg/L of PET fibers, the expression of oxidative stress-related genes decreased in female and increased in male zebrafish. Exposure to 100 mg/L of PET fibers did not affect 17-beta estradiol, but significantly decreased the testosterone levels in male zebrafish. Sex hormone-related genes significantly decreased in both female and male zebrafish, except for androgen receptor in female zebrafish. However, these changes were exacerbated by the removal of NOM, suggesting a protective effect of NOM against PET fibers toxicity. We demonstrated that the accumulated PET fibers may lead to oxidative stress and sex hormone alteration, and disrupt the development of gonadal cells. Additionally, the NOM coating did not alter bioaccumulation considerably, but mitigated the adverse effects at the hormone level in PET fiber-exposed zebrafish. Thus, this study provides a basis for further research on the toxicity assessment of PET fibers and interactions between NOM and PET fiber-related toxicity. [Display omitted] ● PET fibers accumulated in the intestines and livers of zebrafish. ● PET fibers induced oxidative stress in adult zebrafish. ● PET fibers altered the testosterone level in male zebrafish. ● NOM has a protective effect on PET fiber-induced testosterone inhibition. [ABSTRACT FROM AUTHOR]

Aristolochic acid (AA) is renowned for engendering nephrotoxicity and teratogenicity. Previous literature has reported that AA treatment resulted in heart failure (HF) via inflammatory pathways. Yet, its implications in HF remain comparatively uncharted territory, particularly with respect to underlying mechanisms. In our study, the zebrafish model was employed to delineate the cardiotoxicity of AA exposure and the restorative capacity of a phytogenic alkaloid palmatine (PAL). PAL restored morphology and blood supply in AA-damaged hearts by o-dianisidine staining, fluorescence imaging, and Hematoxylin and Eosin staining. Furthermore, PAL attenuated the detrimental effects of AA on ATPase activity, implying myocardial energy metabolism recovery. PAL decreased the co-localization of neutrophils with cardiomyocytes, implying an attenuation of the inflammatory response induced by AA. A combination of network pharmacological analysis and qPCR validation shed light on the therapeutic mechanism of PAL against AA-induced heart failure via upregulation of the epidermal growth factor receptor (EGFR) signaling pathway. Subsequent evaluations using a transcriptological testing, inhibitor model, and molecular docking assay corroborated PAL as an IKBKB enzyme activator. The study underscores the possible exploitation of the EGFR pathway as a potential therapeutic target for PAL against AA-induced HF, thus furthering the continued investigation of the toxicology and advancement of protective pharmaceuticals for AA. [Display omitted] • Palmatine alleviated aristolochic acid-induced cardiotoxicity. • The epidermal growth factor receptor pathway played a critical role in the therapeutic efficacy of palmatine against heart failure. • Palmatine rescued IKBKB downregulation-induced heart failure. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid (PFOA), a perfluoroalkyl compound, is linked to congenital heart diseases, though its underlying mechanisms remain unclear. We hypothesized that PFOA induces cardiac defects through the inhibition of the Keap1/Nrf2 pathway, leading to oxidative damage in cardiomyocytes. In this study, zebrafish embryos exposed to PFOA showed significant cardiac malformations and dysfunction, characterized by excessive reactive oxygen species (ROS), malondialdehyde (MDA) production, decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities. Additionally, we observed dysregulation in the expression of key cardiac development genes (vmhc, gata4, nkx2.5, and sox9b). PFOA also reduced the expression of keap1, nrf2, and ho-1. After overexpression of Nrf2, levels of ROS and MDA decreased, while levels of SOD, CAT, and GSH-Px increased. Additionally, cardiomyocyte apoptosis and cardiac malformations were alleviated. These findings have suggested that PFOA induces oxidative stress through Keap1/Nrf2 pathway inhibition, ultimately leading to cardiac defects. • PFOA exposure significantly induces developmental toxicity in zebrafish embryo hearts. • PFOA exposure alters the expression of key genes involved in cardiac development. • PFOA exposure induces apoptosis in cardiomyocytes of zebrafish embryos. • PFOA mediates oxidative damage to zebrafish embryo hearts via the Keap1/Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Contamination of aquatic food webs with nanomaterials poses a significant ecological and human health challenge. Ingestion of nanomaterials alongside food disrupts digestion and impairs physiological processes, with potential consequences for organism fitness and survival. Complex interactions between nanomaterials and biota further exacerbate the issue, influencing life-history strategies and ecosystem dynamics. Accumulation of nanomaterials within autotrophic and detritus-based food webs raises concerns about biomagnification, especially for top-level consumers and seafood-dependent human populations. Understanding the extent and impact of nanomaterial contamination on aquatic biota is crucial for effective mitigation strategies. To address this challenge, we conducted a comprehensive study evaluating the bioaccumulation effects of graphene oxide (GO), a commonly used nanomaterial, within an aquatic food chain. Using a gnotobiotic freshwater microcosm, we investigated the effects of micro- and nano-scale GO sheets on key organisms: green algae (Chlorella vulgaris), brine shrimp (Artemia salina), and zebrafish (Danio rerio). Two feeding regimes, direct ingestion and trophic transfer, were employed to assess GO uptake and transfer within the food web. Direct exposure involved individual organisms being exposed to either nano- or micro-scale GO sheets, while trophic transfer involved a sequential exposure pathway: algae exposed to GO sheets, artemias feeding on the algae, and zebrafish consuming the artemias. Our study provides critical insights into nanomaterial contamination in aquatic ecosystems. Physicochemical properties of GO sheets, including ζ-potential and dispersion, were influenced by salt culture media, resulting in aggregation under salt conditions. Microscopic imaging confirmed the bioaccumulation of GO sheets within organisms, indicating prolonged exposure and potential long-term effects. Notably, biodistribution analysis in zebrafish demonstrated the penetration of nano-sized GO into the intestinal wall, signifying direct interaction with vital organs. Exposure to GO resulted in increased zebrafish mortality and impaired reproductive performance, particularly through trophic transfer. These findings emphasize the urgent need to address nanomaterial contamination in aquatic food webs to protect ecosystem components and human consumers. Our study highlights the importance of developing effective mitigation strategies to preserve the integrity of aquatic ecosystems, ensure resource sustainability, and safeguard human well-being. In conclusion, our study provides crucial insights into the impact of nanomaterial pollution on aquatic biota. By recognizing the challenges posed by nanomaterial contamination and implementing targeted interventions, we can mitigate the adverse effects, preserving the integrity of aquatic ecosystems and safeguarding human health. [Display omitted] • Bioaccumulation and toxicity potential of nano/micro GO dispersion on living organisms is evaluated. • In aquatic media, exposure to GO changes the reproductive capability of D. rerio. • Increasing the salt content of media shifts ξ-potential of GO to positive values. [ABSTRACT FROM AUTHOR]

Cyanobacteria are a group of photosynthetic bacteria and a rich secondary metabolites source. The Bank of Algae and Cyanobacteria of the Azores (BACA) culture collection holds a significant number of strains, including many novel genera and species. 56 strains from freshwater, brackish, and thermal habitats were selected, and grown under standard conditions. Biomass was extracted with methanol, and cytotoxicity was assessed on two carcinoma cell lines, HepG2 and HCT116. The reduction of lipids was tested in zebrafish larvae, and in a steatosis model with fatty acid overloaded human liver cells. The cyanobacterial metabolome was analyzed by HR-ESI-LC-MS/MS and compared using CompareMS2. High similarities were observed in strains of the same genus when isolated from similar habitats, clustering in concordance to the taxonomical order, while no relation could be observed between strains from different genera originated from the same habitat. The extracts of Cyanobium sp. BACA0019, Pseudocalidococcus azoricus BACA0433 and Pegethrix atlantica BACA0077 reduced neutral lipids >40 % in zebrafish at 25 μg/mL, while from Symphyonema sp. BACA0090 and Aliinostoc sp. BACA0355 induced mortality. Lipid reduction in the steatosis model was observed in many strains, with significant results varying from 50 % to 100 %. Several strains reduced cell viability with the strongest effects from Scytonematopsis sp. BACA0005 (HepG2, 59.8 % and HCT116, 68.1 %), Aliinostoc sp. BACA0035 (HepG2, 43.3 %, and HCT116, 59.4 %) and Aliinostoc sp. BACA0355 (HepG2, 46.2 %, and HCT116, 75.5 %). The feature-based molecular networking identified several cluster of mass peaks related to the observed bioactivities. Chlorophyll derivatives and glycerolipids from Cyanobium sp. BACA0019, Pseudocalidococcus azoricus BACA0433 and Pegethrix atlantica BACA0077 were correlated with the reduction of lipids in zebrafish larvae, while several oligopeptides and fatty amides of Symphyonema sp. BACA0090 and Aliinostoc sp. BACA0355 with toxicity. Many clusters associated to the bioactivities remained unidentified, which may represent novel compounds, highlighting the chemodiversity of the BACA culture collection. [Display omitted] [ABSTRACT FROM AUTHOR]

Ulva prolifera (U. prolifera), as the dominant species of green macro-algal bloom, caused great damage to marine aquaculture and economy. This study was carried out to find its industrial utilization ways by determination the structure characteristics and the immune enhancement effect of oligosaccharide fractions produced from this alga. The result indicated that oligosaccharide fraction of F3 showed the best immune enhancement activity via RAW 264.7 macrophages and zebrafish assays. Chemical and structural analysis indicated that F3 with 11.14%sulfate content was composed of rhamnose, xylose, and glucose in ratio of 77.11:16.33:6.56. NMR spectroscopy showed that F3 contained (1 → 4)-α- l -rhamnopyranose-3-SO 3 and α- l -rhamnopyranose-3-SO 3 -(1 → 4)-β-D-xylopyranose, with sulfate groups located at C-3 of rhamnopyranose. The results of immune effect in vitro demonstrated that F3 increased the production of nitric oxide (NO) and prostaglandin E2 (PGE 2) with up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. F3 also promoted the secretion of cytokines (TNF-α, IL-1β and IL-6) and activated the expression of mitogen-activated protein kinases (MAPK) and NF-κB signaling pathways. In vivo assay, F3 boosted the embryo survival rate and heart rate, as well as promoted the generation of NO and reactive oxygen species (ROS) in a dose-dependent manner. The novel structure and excellent activity in this study suggested that F3 could be the potential material for use as a natural immuno-enhancing agent in the biomedical and functional food industries. [Display omitted] • Oligosaccharides were purified from the green macro-algal bloom of Ulva prolifera. • Oligosaccharide fraction F3 was consisted of (1. → 4)-α- l -rhamnopyranose-3-SO 3 and α- l -rhamnopyranose-3-SO 3 -(1 → 4)-β-D-xylopyranose • F3 induced production of NO and PGE 2 with up-regulation iNOS and COX-2 expression in RAW 264.7 • F3 promoted secretion of cytokines and activated the expression of MAPK and NF-κB in RAW 264.7 • F3 increased generation of NO and ROS in a dose-dependent manner in zebrafish. [ABSTRACT FROM AUTHOR]

Musa basjoo Sieb polysaccharide (MBSP) is the active ingredient of Musa basjoo Sieb. The purpose of this study was to preliminarily characterize the structural properties of MBSP, and to explore its ameliorating effect LPS-induced macrophage RAW264.7 inflammation and its therapeutic effect on DSS-induced zebrafish colitis. The data indicated that the average molecular weight of MBSP was 393.4 kDa, which was an acidic heteropolysaccharide composed of seven monosaccharides. In the LPS-induced macrophage RAW264.7 inflammation model, we found that MBSP significantly reduced the level of inflammatory mediators (p < 0.001). The release of NO, IL-6, and TNF-α was reduced by 48.21%, 65.45%, and 86.49%, respectively. And MBSP modulated intracellular ROS levels. This might be related to the activation of NF-κB/MAPK signaling pathway by MBSP. Additionally, MBSP significantly improved the oxidative stress status of UC zebrafish. SOD, CAT, GSH-Px were increased by 50.58%, 39.07% and 65.86%, and MDA, MPO were decreased by 26.00% and 50.98%, respectively (p < 0.001). Meanwhile, MBSP was also found to be effective in improving UC by activating the TLR4/NF-κB/MAPK signaling pathway in vivo. In conclusion, the present study characterized the structural properties of MBSP from various aspects, confirmed the anti-inflammatory effect of MBSP in vitro , and further verified the in vivo anti-inflammatory activity of MBSP using UC zebrafish as an animal model. The results of this study provide a reference for the development and application of MBSP in the field of treating inflammatory diseases. [ABSTRACT FROM AUTHOR]

Toxicity of water accommodated fractions (WAF) from the oil spilled on the Brazilian coast at different stages of weathering were investigated using Danio rerio. Weathering stages included emulsified oil that reached the coast (OM) and oil collected 50 days later deposited on beach sand (OS) or adhered to shore rocks (OR). Parent and alkylated naphthalenes decreased whereas phenanthrenes increased from less weathered WAF-OM to more weathered WAF-OS and WAF-OR. More weathered WAF-OS and WAF-OR were more potent inducers of zebrafish developmental delay, suggesting that parent and alkylated phenanthrenes are involved. However, less weathered WAF-OM was a more potent inducer of failure in swim-bladder inflation than more weathered WAF-OS and WAF-OR, suggesting that parent and alkylated naphthalenes are involved. Decreases in heart rates and increased heart and skeletal deformities were observed in exposed larvae. Lowest observed effect concentrations for different developmental toxicity endpoints are within environmentally relevant polycyclic aromatic hydrocarbon concentrations. • Water accomodated fractions of spilled oil affected zebrafish development. • Weathering decreased parent and alkylated naphthalenes and increased phenanthrenes. • Weathering increased development delay during early zebrafish stages. • Weathering decreased failure in swim bladder inflation during early zebrafish stages. • Effect concentrations for developmental toxicity are environmentally relevant. [ABSTRACT FROM AUTHOR]

Mitochondrial proteostasis is critical for cellular function. The molecular chaperone HSP60 is essential for cell function and dysregulation of HSP60 expression has been implicated in cancer and diabetes. The few reported patients carrying HSP60 gene variants show neurodevelopmental delay and brain hypomyelination. Hsp60 interacts with more than 260 mitochondrial proteins but the mitochondrial proteins and functions affected by HSP60 deficiency are poorly characterized. We studied two model systems for HSP60 deficiency: (1) engineered HEK cells carrying an inducible dominant negative HSP60 mutant protein, (2) zebrafish HSP60 knockout larvae. Both systems were analyzed by RNASeq, proteomics, and targeted metabolomics, and several functional assays relevant for the respective model. In addition, skin fibroblasts from patients with disease-associated HSP60 variants were analyzed by proteomics. We show that HSP60 deficiency leads to a differentially downregulated mitochondrial matrix proteome, transcriptional activation of stress responses, and dysregulated cholesterol biosynthesis. This leads to lipid accumulation in zebrafish knockout larvae. Our data provide a compendium of the effects of HSP60 deficiency on the mitochondrial matrix proteome. We show that HSP60 is a master regulator and modulator of mitochondrial functions and metabolic pathways. HSP60 dysfunction also affects cellular metabolism and disrupts the integrated stress response. The effect on cholesterol synthesis explains the effect of HSP60 dysfunction on myelination observed in patients carrying genetic variants of HSP60. [Display omitted] • HSP60 deficiency disrupts the mitochondrial matrix proteome and activates stress responses. • Disrupted matrix proteome impairs catabolism causing acetyl-CoA shortage. • HSP60 deficiency dysregulates cytosolic cholesterol synthesis. • Dysregulated cholesterol synthesis links HSP60 deficiency to hypomyelination. [ABSTRACT FROM AUTHOR]

Prokineticin 2 (PK2) binds to prokineticin receptor 1 and prokineticin receptor 2 (PKR1 and PKR2, respectively), two G protein-coupled receptors (GPCRs) that can mediate multiple signalling pathways by promoting the elevation of intracellular calcium and cAMP levels, phosphorylation of Akt and activation of ERK and STAT3. This work aims to evidence the conservation of protein sequence and the mechanism of PK2 binding to PKR1 to use the zebrafish model for the identification of new drugs as targets of prokineticin receptors. To this end, we first demonstrated that the zebrafish genes pk2 and pkr1 are phylogenetically related to orthologous mammalian genes by constructing evolutionary trees and performing syntenic analyses. Subsequently, by comparing the amino acid sequences, we showed that the interaction sites with PK2 are conserved in the zPKR1. Using GST pull-down and cross-linking experiments, we demonstrated the crucial role of the N-terminal region of zPKR1 for binding to the PK2. Finally, by expressing zPKR1 in CHO cells, we demonstrated the ability of zPKR1 to induce the activation of ERK and STAT3. [ABSTRACT FROM AUTHOR]

• Verified the irrationality of traditional value orientation of bufonis venenum. • The key "toxicity and activity" bufadienolide Q-markers were screened and compared. • The correlation between toxicity and activity of bufonis venenum were identified. • Deacetylcinobufagin with low toxicity and strong activity was found and verified. Bufonis Venenum (BV) is a traditional animal-based Chinese medicine with therapeutic effects against cancer. However, its clinical use is significantly restricted due to associated cardiovascular risks. BV's value in China's market is typically assessed based on "content priority," focusing on indicator components. However, these components of BV possess both antitumor activity and toxicity, and the correlation between the antitumor activity and toxicity of BV has not yet been elucidated. This study employs an integrated multi-omics approach to identify bufadienolide Q-markers and explore the correlation between BV's antitumor activity and toxicity. The aim is to establish a more comprehensive method for BV's quality. Normal zebrafish and HepG2 xenograft zebrafish were chosen as activity and toxicity evaluation models. Ultra-high performance liquid chromatography (UHPLC) coupled with a linear ion trap orbitrap (LTQ-Orbitrap) mass spectrometry was used to quantify eight batches of BV and key "toxic and effective" components were screened out. Transcriptomic and metabolomic analyses were performed to elucidate the regulatory mechanisms underlying the antitumor activity and cardiovascular toxicity of the key components in BV. Eight key "toxic and effective" compounds were identified: resibufogenin, cinobufagin, arenobufagin, bufotalin, bufalin, gamabufotalin, desacetylcinobufagin, and telocinobufagin. The findings showed that bufalin and cinobufagin interfered with calcium homeostasis through CaV and CaSR, induced cardiotoxicity, and upregulated CASP9 to activate myocardial cell apoptosis. However, desacetylcinobufagin exhibited greater potential in terms of anti-tumor effects. Combining the results of untargeted and targeted metabolomics revealed that desacetylcinobufagin could have a callback effect on differential lipids and correct abnormal energy and amino acid metabolism caused by cancer, similar to cinobufagin and bufalin. Microscale thermophoresis (MST) ligand binding measurements also showed that the binding of desacetylcinobufagin to GPX4 has a more potent ability to induce ferroptosis in tumor cells compared to cinobufagin. An innovative evaluation method based on the zebrafish was developed to investigate the relationship between the toxicity and efficacy of BV. This study identified toxicity and activity Q-markers and explored the mechanism between the two effects of BV. The research data could offer valuable insights into the efficacy of BV. Additionally, desacetylcinobufagin, an active ingredient with low toxicity, was found to enhance the quality of BV. [Display omitted] [ABSTRACT FROM AUTHOR]

Hexafluoropropylene oxide dimer acid (HFPO-DA) and perfluoroethylcyclohexane sulfonate (PFECHS) are increasingly used as alternatives for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, their immunotoxicity and underlying molecular mechanisms remain poorly understood. Here, to assess immunotoxic effects, zebrafish embryos were exposed to environmentally relevant concentrations of PFOA, PFOS, HFPO-DA, and PFECHS for four days. Results revealed that all four per- and polyfluoroalkyl substances (PFAS) resulted in decreased heart rate and spontaneous movement, and induced oxidative stress in zebrafish larvae. Notably, HFPO-DA exhibited more severe oxidative stress than PFOA. Immune dysfunction was observed, characterized by elevated cytokine, complement factor, nitric oxide, and neutrophil content, along with a significant decrease in lysozyme content. Transcriptomic analysis revealed the activation of Toll-like receptor (TLR)/NOD-like receptor (NLR)/RIG-I-like receptor (RLR) and associated downstream genes, indicating their pivotal role in PFAS-induced immunomodulation. Molecular docking simulations demonstrated stable interactions between PFAS and key receptors (TLR2, NOD2 and RIG-I). Overall, HFPO-DA and PFECHS exhibited immunotoxic effects in zebrafish larvae similar to legacy PFAS, providing important information for understanding the toxic mode of action of these emerging alternatives. [Display omitted] • PFAS inhibited spontaneous movement and heart rate in embryos. • Legacy and alternative PFAS increased the number of neutrophils. • PFAS acts directly on TLR/NLR/RLR, leading to immune dysfunction in zebrafish. • Molecular docking revealed strong interactions between PFAS and key receptor. [ABSTRACT FROM AUTHOR]

Pyraclostrobin, a typical representative of strobilurin fungicides, is extensively used in agriculture to control fungi and is often detected in water bodies and food. However, the comprehensive toxicological molecular mechanism of pyraclostrobin requires further study. To assess the toxic effects and underlying mechanisms of pyraclostrobin on aquatic organisms, zebrafish embryos were exposed to pyraclostrobin (20, 40, and 60 μg/L) until 96 h post fertilization (hpf). These results indicated that exposure to pyraclostrobin induces morphological alterations, including spinal curvature, shortened body length, and smaller eyes. Furthermore, heart developmental malformations, such as pericardial edema and bradycardia, were observed. This indicated severe cardiotoxicity induced by pyraclostrobin in zebrafish embryos, which was confirmed by the dysregulation of genes related to heart development. Besides, our findings also demonstrated that pyraclostrobin enhanced the contents of reactive oxygen species (ROS) and malondialdehyde (MDA), up-regulated catalase (CAT) activity, but inhibited superoxide dismutase (SOD) activity. Subsequently, the NF-κb signaling pathway was further studied, and the results indicated that the up-regulation of tnf-α , tlr-4 , and myd88 activated the NF-κb signaling pathway and up-regulated the relative expression level of pro-inflammatory cytokines, such as cc - chemokine, ifn-γ, and cxcl - clc. Collectively, this study revealed that pyraclostrobin exposure induces developmental toxicity and cardiotoxicity, which may result from a combination of oxidative stress and inflammatory responses. These findings provide a basis for continued evaluation of the effects and ecological risks of pyraclostrobin on the early development of aquatic organisms. [Display omitted] • Pyraclostrobin significantly decreased survival rate and increased aberration rate. • Pyraclostrobin led to developmental toxicity and cardiotoxicity in zebrafish embryos. • Pyraclostrobin caused alterations in the antioxidant system, indicating oxidative stress. • Pyraclostrobin induced cell apoptosis and inflammation dysfunction. [ABSTRACT FROM AUTHOR]

Machine learning (ML) as a novel model-based approach has been used in studying aquatic toxicology in the environmental field. Zebrafish, as an ideal model organism in aquatic toxicology research, has been widely used to study the toxic effects of various pollutants. However, toxicity testing on organisms may cause significant harm, consume considerable time and resources, and raise ethical concerns. Therefore, ML is used in related research to reduce animal experiments and assist researchers in conducting toxicological research. Although ML techniques have matured in various fields, research on ML-based aquatic toxicology is still in its infancy due to the lack of comprehensive large-scale toxicity databases for environmental pollutants and model organisms. Therefore, to better understand the recent research progress of ML in studying the development, behavior, nerve, and genotoxicity of zebrafish, this review mainly focuses on using ML modeling to assess and predict the toxic effects of zebrafish exposure to different toxic chemicals. Meanwhile, the opportunities and challenges faced by ML in the field of toxicology were analyzed. Finally, suggestions and perspectives were proposed for the toxicity studies of ML on zebrafish in future applications. [Display omitted] • ML can be used to predict the developmental toxicity of zebrafish embryos. • ML can identify complex patterns in zebrafish behavior data. • ML can automate the extraction of relevant features from neurotoxicity datasets. • Studying genetic mutations through ML can better overcome uncertainties in biology. [ABSTRACT FROM AUTHOR]

The accumulation of the active pharmaceutical chemical in the environment usually results in environmental pollution to increase the risk to human health. Indomethacin is a non-steroidal anti-inflammatory drug that potentially causes systemic and developmental toxicity in various tissues. However, there have been few studies for its potential effects on cardiac development. In this study, we systematically determined the cardiotoxicity of acute indomethacin exposure in zebrafish at different concentrations with morphological, histological, and molecular levels. Specifically, the malformation and dysfunction of cardiac development, including pericardial oedema, abnormal heart rate, the larger distance between the venous sinus and bulbus arteriosus (SV-BA), enlargement of the pericardial area, and aberrant motor capability, were determined after indomethacin exposure. In addition, further investigation indicated that indomethacin exposure results in myocardial apoptosis in a dose-dependent manner in zebrafish at early developmental stage. Mechanistically, our results revealed that indomethacin exposure mainly regulates key cardiac development-related genes, especially genes related to the cardiac muscle contraction-related signaling pathway, in zebrafish embryos. Thus, our findings suggested that acute indomethacin exposure might cause cardiotoxicity by disturbing the cardiac muscle contraction-related signaling pathway and inducing myocardial apoptosis in zebrafish embryos. • Indomethacin potentially results in malformation and dysfunction of cardiac development in zebrafish embryos. • Indomethacin mainly regulates genes related to the cardiac muscle contraction-related signaling pathway in zebrafish embryos. • Indomethacin exposure induces myocardial apoptosis in a dose-dependent manner in zebrafish embryos. [ABSTRACT FROM AUTHOR]

Estrogens and estrogenic chemicals are endocrine-disrupting chemicals (EDCs). The potential toxicity of EDCs to humans and aquatic organisms has become increasingly concerning. However, at present, the potential toxic mechanisms of EDCs on neural and vascular development are still being fully investigated. During the study, we utilized zebrafish to assess the developmental neural and vascular toxicity of different estrogens. The results indicated that zebrafish treated with different estrogens, especially E2, exhibit developmental malformations, including increased mortality, decreased body length, decreased heart rate, aberrant swimming behavior, and increased developmental malformations, including spinal curvature (SC), yolk edema (YE) and pericaidial edema (PE), in a dose-dependent manner with 72 h-treated. Further morphological evaluation revealed that E2 exposure significantly induced motor neural abnormalities in zebrafish embryos. In addition, treated with these three estrogens also impaired the vascular development in the early stage of zebrafish embryos. Mechanistically, the identification of downstream factors revealed that several key neural and vascular development-related genes, including syn2a, gfap, gap43, shha, kdr, flt1 and flt4 , were transcriptionally downregulated after estrogen exposure in zebrafish, suggesting that estrogen exposure might cause neural and vascular toxicity by interfering the mRNA levels of genes relevant to neural and vascular development. [Display omitted] • The exposure of estrogen exhibits developmental toxicity on zebrafish embryos, especially 17β-estradiol. • Exposure to estrogens, impair vascular and neural development in zebrafish embryos. • Estrogen exposure causes toxicity by regulating the expression of some key neural and vascular development-related genes. [ABSTRACT FROM AUTHOR]

Pyridaben is a broad-spectrum, contact-killing acaricide that can be used to control a variety of harmful food and plant mites. Pyridaben displays cardiotoxicity and liver toxicity toward fish, but the effects on fish embryonic development have not been characterized. We exposed early zebrafish embryos to 20, 30, and 40 μg/L concentrations of pyridaben. The exposure caused developmental abnormalities, including delayed embryonic shield formation, yolk sac resorption, decreases in body length, reduced pigmentation, and delays in hatching. Pyridaben caused a significant increase in the transcription level of the endoderm marker foxa2 , but the transcription levels of the ectoderm development marker foxb1a and the mesoderm development marker snaila were not significantly altered. The transcription levels of the genes SOX17 in early embryos were significantly reduced. After exposure to pyridaben, catalase (CAT) activity and glutathione (GSH) content were increased, and cyclin D1 , that is involved in early embryonic development, was abnormally expressed. This study shows that pyridaben causes anomalous development in zebrafish embryos by interfering with the cell cycle order of early embryonic development and inducing excessive oxidative stress. Colivelin, an agonist of the STAT3 signaling pathway, acted as a salvage drug to restore the cell cycle order during embryonic development following exposure to pyridaben. Thus, the toxic effects may be caused by pyridaben's regulation of the STAT3 signaling pathway. • Pyridaben induced zebrafish larvae grow shorter and delayed early embryonic development. • Pyridaben reduced the number of mitotic nuclei at blastoshield stage. • Pyridaben exposure affects cell differentiation of early embryonic development. • Pyridaben affects early embryonic development in zebrafish through the STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Endocrine disrupting chemicals (EDCs) can disrupt normal endocrine function by interfering with the synthesis and release of hormones, causing adverse reactions to development, immunity, nerves, and reproduction. 4- tert -Butylphenol (4- t -BP) is disruptive to early zebrafish development, but its effects on zebrafish liver are unknown. In this study, the adverse effects of 4- t -BP on the liver were investigated using zebrafish as a model organism. 4- t -BP inhibited liver development in zebrafish embryos and induced liver damage in adult zebrafish. Even if F1 was not directly exposed to 4- t -BP, its growth and development were inhibited. 4- t -BP can lead to an increase in lipid accumulation, total cholesterol and triglycerides contents, and the activities of alanine transaminase and aspartate aminotransferase in zebrafish embryos and adult zebrafish livers, and also cause an acceleration of glucose metabolism in zebrafish embryos. In addition, qRT-PCR showed that 4- t -BP induced the changes in the expressions of liver development-, steroid and unsaturated fatty acid biosynthesis-, and glycerolipid and arachidonic acid metabolism-related genes in zebrafish embryos and inflammatory factors-, antioxidant enzymes- and lipid metabolism-related genes in adult zebrafish livers. Transcriptome sequencing of embryos showed that 4- t -BP altered the expressions of lipid metabolism pathways such as steroid and unsaturated fatty acid biosynthesis, glycerolipid, and arachidonic acid metabolism pathways. Therefore, 4- t -BP may be external stimuli that cause oxidative stress, inflammation, and lipid accumulation in zebrafish liver, resulting in tissue damage and dysfunction in zebrafish liver. [Display omitted] • 4-t-BP inhibits the liver development of juvenile zebrafish and causes liver damage. • 4-t-BP causes liver damage in adult zebrafish. • 4-t-BP inhibits F1 growth and development. • 4-t-BP induces lipid accumulation in zebrafish. • 4-t-BP disrupts lipid metabolism pathway in zebrafish. [ABSTRACT FROM AUTHOR]

Neonicotinoid insecticides specifically target insect subtypes of nicotinic acetylcholine receptors. Acetamiprid (ACE: C10H11ClN4), the neonicotinoid insecticide , is used to control crop insect pests worldwide. It is a nitrile, monochloropyridine, and carboxamidine that is highly soluble and accessible to waterways. There, it causes neurotoxic and oxidative perturbance to non-target organisms. The unionid mussel Chamabradia rubens is a common Northern River Nile suspension feeder. The current study aimed to assess ACE filtration from waters by C. rubens , and whether this biological power can reduce ACE effects on fish. Removal of ACE by C. rubens was assessed using LC-MS/MS. Zebrafish Danio rerio adults were exposed to different sublethal doses of ACE in the presence or absence of C. rubens in their aquaria. The results showed that mussels could remove significant ACE amounts from water, where it accumulated mostly in the digestive gland. The presence of C. rubens in zebrafish aquaria having ACE was accompanied by significant upregulation of antioxidant enzyme gene transcripts and total H 2 O 2 scavenging, in contrast to mussel-free ACE-exposed groups. Meanwhile, liver triglycerides rose 5-6-fold in response to ACE in the "Fish-Only" groups, indicating an ACE-induced hepatotoxicity. Also, Insulin-like growth factor 1 (igf1) and fish body mass increased more in "Fish + Mussel" groups than in the "Fish-Only" ones. In aggregate, these findings suggest that the Nile mussel could reduce the oxidative stress and metabolic changes induced in fish by ACE. This can contribute valuable environmental and economic benefits upon the use of this mussel as a biofilter. [Display omitted] • The neonicotinoid insecticide acetamiprid induces oxidative stress in zebrafish. • Nile clam Chambardia rubens removes significant amounts of acetamiprid in waters. • C. rubens in zebrafish aquaria alleviated acetamiprid-induced toxicity. • C. rubens was proven as a successful biofilter against acetamiprid adverse impacts. [ABSTRACT FROM AUTHOR]

Dexamethasone (DXMS), a synthetic glucocorticoid, is known for its pharmacological effects on anti-inflammation, stress response enhancement and immune suppression, and has been widely used to treat potential premature delivery and related diseases. However, emerging evidence has shown that prenatal DXMS exposure leads to increased susceptibility to multiple diseases. In the present study, we used zebrafish as a model to study the effects of embryonic DXMS exposure on liver development and disease. We discovered that embryonic DXMS exposure upregulated the levels of total cholesterol and triglycerides in the liver, increased the glycolysis process and ultimately caused hepatic steatosis in zebrafish larvae. Furthermore, DXMS exposure exacerbated hepatic steatosis in a zebrafish model of fatty liver disease. In addition, we showed that embryonic DXMS exposure worsened liver injury induced by paracetamol (N-acetyl-p-aminophenol, APAP), increased the infiltration of macrophages and neutrophils, and promoted the expression of inflammatory factors, leading to impeded liver regeneration. Taken together, our results provide new evidence that embryonic DXMS exposure exacerbates hepatic steatosis by activating glycolytic pathway, aggravates APAP-induced liver damage and impeded regeneration under a persistent inflammation, calling attention to DXMS administration during pregnancy with probable clinical implications for offspring. • Embryonic dexamethasone exposure promotes zebrafish hepatic steatosis by enhancing the glycolytic pathway. • Embryonic dexamethasone exposure exacerbates NAFLD in trappc11 deficient zebrafish by activating the UPR process. • Embryonic dexamethasone exposure impedes zebrafish liver regeneration by promoting inflammation. [ABSTRACT FROM AUTHOR]

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis due to excessive or long-term glucocorticoid administration, disturbing the homeostasis between bone formation and bone resorption. The bone biology of zebrafish shares a high degree of similarities with mammals. In terms of molecular level, genes and signaling pathways related to skeletogenesis are also highly correlated between zebrafish and humans. Therefore, zebrafish have been utilized to develop multiple GIOP models. Taking advantage of the transparency of zebrafish larvae, their skeletal development and bone mineralization can be readily visualized through in vivo staining without invasive experimental handlings. Moreover, the feasibility of using scales or fin rays to study bone remodeling makes adult zebrafish an ideal model for GIOP research. Here, we reviewed current zebrafish models for GIOP research, focused on the tools and methods established for examining bone homeostasis. As an in vivo, convenient, and robust model, zebrafish have an advantage in performing high-throughput drug screening and could be used to investigate the action mechanisms of therapeutic drugs. [ABSTRACT FROM AUTHOR]

Tollip is a multifunctional adaptor protein implicated in innate immunity, lysosomal trafficking/autophagy of protein aggregates and various signaling processes in mammalian models. To verify evolutionary conservation of these functions, we used CRISPR/Cas9 editing to construct a zebrafish line bearing a stable tollip knockout. In contrast to previously reported tollip morphants, Tollip-deficient fish display normal development until adulthood, are fertile, and have no apparent physiological defects. When challenged with lipopolysaccharide (LPS), inflammatory gene expression is unaffected. Moreover, Tollip deficiency does not aggravate swimming deficiency resulting from lysosomal dysfunction and proteotoxicity in a fish model of Gaucher disease. Thus, individual functions of Tollip may be organism-specific or manifest only upon certain conditions/challenges or disease backgrounds. [ABSTRACT FROM AUTHOR]

Dactylicapnos torulosa (D. torulosa) has been traditionally used as a therapeutic remedy. Here, a combined strategy using both phytochemical and biological approaches was conducted to discern the effective components of D. torulosa. Three new alkaloids, namely, (1 – 3), Torulosine A, 1-Methoxypseudoprotopine and 1,14-Dimethoxyprechilenine together with 33 (4 – 36) known compounds were isolated. The structures of the new compounds were fully established by extensive analysis of HR-ESI-MS NMR and CD spectroscopic data. These compounds were then screened using zebrafish bioassay methods for antithrombotic activities. Compounds 5 and 7 had the best antithrombotic effect with prevention rates of 100% at 50 μM, and Compounds 8 , 4 , 9 and 11 at 50 μM had prevention rates of 81.3%, 79.4%, 84.4% and 79.3%, respectively. The antithrombotic effect of compounds may be related to their inhibitory effect on platelet aggregation. The present study contributes to the diverse chemical and bioactivity data of the Dactylicapnos genus. [Display omitted] • Three new alkaloids (1 – 3) were isolated from Dactylicapnos torulosa. • Structural characterization data of 4 filled up a deficiency in the present literature. • Compounds 5 and 7 at 50 μM showed antithrombotic prevention rate of 100%. [ABSTRACT FROM AUTHOR]

In this study, the AILQSYSAGKTK (named AK-12) peptide, also known as AK-12, from the Synechococcus marine microalgae cell extract is examined to determine the mechanism by which tyrosinase inhibition takes place. According to the docking simulation, it is expected that the peptides bind and interact at the tyrosinase active site, with the potential to support the inhibition of tyrosinase. For testing, the required peptides were first synthesized, before the results revealed tyrosinase inhibitory activity for which the respective IC 50 values for mono- and di-phenolase activities were 489.71 ± 0.01 μM, and 765.57 ± 0.01 μM. The characteristics of the different competitive types were shown in a Lineweaver-Burk plot. For the treatment of B16F10 cells, peptide concentrations of 50–400 μM were selected, confirming the absence of cytotoxicity. When the peptide was introduced, both tyrosinase activity and the production of melanin were significantly inhibited. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was then used to assess the suppression of melanin synthesis in MITF (microphthalmia-associated transcription factor, TYR (tyrosinase), TRP-1 (tyrosinase-related protein-1) and TRP-2 (tyrosinase-related protein-2). An in vivo toxicity assay was also carried out to evaluate zebrafish embryo cell death, revealing that AK-12 did not significantly affect cell death, while strong anti-melanogenic activity was observed for the concentration of 50 μM. From these findings it could be concluded that the peptide in question may offer potential in future hyperpigmentation treatments. The hypothetical model illustrates the mechanisms underlying the anti-melanogenic effect mediated by AK-12. The images depict that AK-12 inhibits TYR by directly binding to the enzyme's active site, subsequently suppressing MITF, TYR, TRP-1, and TRP-2. MITF: microphthalmia-associated transcription factor, TYR: tyrosinase, TRP-1: tyrosinase-related protein-1, and TRP-2: tyrosinase-related protein-2. [Display omitted] • AK-12 peptide from Synechococcus marine microalgae inhibits tyrosinase. • B16F10 cell treatment with peptide confirms non-cytotoxicity and suppresses tyrosinase activity and melanin production. • qRT-PCR assesses melanin synthesis suppression in MITF, TYR, TRP-1, and TRP-2. • In vivo zebrafish embryo assay shows anti-melanogenic activity at 100 μM. • AK-12 peptide holds promise for future hyperpigmentation treatments. [ABSTRACT FROM AUTHOR]

• Qiangxinyin (QXY) formula protects against cardiac hypertrophy. • Psoralen, kaempferol and icaritin are active ingredients of QXY. • QXY regulates calcium flux in cardiomyocytes. • QXY inhibits isoproterenol (ISO)-induced mitochondrial dysfunction and cytoskeleton reorganization in cardiomyocytes. Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula Qiangxinyin (QXY) is effective for the treatment of heart failure while the underlying mechanism is not clear. This study aims to identify the active ingredients of QXY and explore its mechanisms protecting against cardiac hypertrophy. We found that QXY significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy and dysfunction in zebrafish. Eight compounds, including benzoylmesaconine (BMA), atractylenolide I (ATL I), icariin (ICA), quercitrin (QUE), psoralen (PRN), kaempferol (KMP), ferulic acid (FA) and protocatechuic acid (PCA) were identified from QXY. PRN, KMP and icaritin (ICT), an active pharmaceutical ingredient of ICA, prevented ISO-induced cardiac hypertrophy and dysfunction in zebrafish. In H9c2 cardiomyocyte treated with ISO, QXY significantly blocked the calcium influx, reduced intracellular lipid peroxidative product MDA, stimulated ATP production and increased mitochondrial membrane potential. QXY also inhibited ISO-induced cardiomyocyte hypertrophy and cytoskeleton reorganization. Mechanistically, QXY enhanced the phosphorylation of Smad family member 2 (SMAD2) and myosin phosphatase target subunit-1 (MYPT1), and suppressed the phosphorylation of myosin light chain (MLC). In conclusion, PRN, KMP and ICA are the main active ingredients of QXY that protect against ISO-induced cardiac hypertrophy and dysfunction largely via the blockage of calcium influx and inhibition of mitochondrial dysfunction as well as cytoskeleton reorganization. [Display omitted] [ABSTRACT FROM AUTHOR]

Myclobutanil (MYC) is a common triazole fungicide widely applied in agriculture. MYC extensively exists in the natural environment and can be detected in organisms. However, little is known about MYC-induced embryonic developmental damage. This study aimed to unravel the cardiotoxicity of MYC and the underlying mechanisms, as well as the cardioprotective effect of curcumin (CUR, an antioxidant polyphenol) using the zebrafish model. Here, zebrafish embryos were exposed to MYC at concentrations of 0, 0.5, 1 and 2 mg/L from 4 to 96 h post fertilization (hpf) and cardiac development was assessed. As results, MYC reduced the survival and hatching rate, body length and heart rate, but increased the malformation rate and spontaneous movement. MYC caused abnormal cardiac morphology and function in myl7:egfp transgenic zebrafish, and downregulated cardiac developmental genes. MYC promoted oxidative stress through excessive reactive oxygen species (ROS) accumulation and suppressed the activities of antioxidant enzymes, triggering cardiomyocytic apoptosis via upregulated expression of apoptosis-related genes. These adverse toxicities could be significantly ameliorated by the antioxidant properties of CUR, indicating that CUR rescued MYC-induced cardiotoxicity by inhibiting oxidative stress and apoptosis. Overall, our study revealed the potential mechanisms of oxidative stress and apoptosis in MYC-induced cardiotoxicity in zebrafish and identified the cardioprotection of CUR in this pathological process. [Display omitted] • MYC induces abnormal cardiac morphology and function in zebrafish. • MYC induces cardiotoxicity by initiating oxidative stress and apoptosis in zebrafish. • CUR attenuates MYC-induced cardiotoxicity by inhibiting oxidative stress and apoptosis. • CUR appears a novel therapeutic strategy for heart diseases. [ABSTRACT FROM AUTHOR]