Existing antithrombotic drugs have side effects such as bleeding, and there is an urgent need to discover antithrombotic drugs with better efficacy and fewer side effects. In this study, a zebrafish thrombosis model was used to evaluate the antithrombotic activity and mechanism of Brevianamide F, a deep-sea natural product, with transcriptome sequencing analysis, RT-qPCR analysis, and molecular docking. The results revealed that Brevianamide F significantly attenuated the degree of platelet aggregation in the thrombus model zebrafish, leading to an increase in the number of circulating platelets, an augmentation in the return of blood to the heart, an elevated heart rate, and a significant restoration of caudal blood flow velocity. Transcriptome sequencing and RT-qPCR validation revealed that Brevianamide F may exert antithrombotic effects through the modulation of the MAPK signaling pathway and the coagulation cascade reaction. Molecular docking analysis further confirmed this result. This study provides a reference for the development of therapeutic drugs for thrombosis.

Hyperlipidemia and consequent endothelial inflammation, along with foam cell generation, promote the progression of atherosclerosis (AS). Here, we aimed to investigate the effects of 2-acetamidophenol (2-AAP), which was selected by zebrafish phenotypic screening, in alleviating AS by relieving hyperlipidemia and inhibiting foam cell formation, as well as the underlying mechanisms. In a zebrafish hyperlipidemia model, 2-AAP increased lipid-lowering efficacy; alleviated TC, TG, LDL-C, and MDA levels; elevated HDL-C and T-SOD levels; significantly improved intravascular macrophage aggregation; and improved blood flow. In an ox-LDL-induced RAW264.7 model, 2-AAP inhibited lipid phagocytosis in RAW264.7 cells; reduced the intracellular TC, TG, FC, and CE contents; and decreased the CE/TC ratio, thus slowing foam cell generation. In addition, 2-AAP alleviated intracellular ROS and ferrous ion accumulation in RAW264.7 cells, reduced the MDA content, and increased GPX4 viability. Furthermore, transcriptome analyses and gene expression validation showed 2-AAP treatment upregulates genes related to GSH synthesis and transport, such as gclc, gclm, gss, and gpx4a, and enhanced the expression levels of genes involved in the storage and transportation of iron ions, such as fpn1, fth, and g6pd, indicating that 2-AAP dramatically regulated the ferroptosis and glutathione metabolic pathways. Overall, our study demonstrated that 2-AAP demonstrated potential in AS by alleviating hyperlipidemia and attenuating the ferroptosis pathway and provided evidence supporting the future application of 2-AAP in AS treatment.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, yet effective agents for its prevention and therapy remain highly limited. Epicoccin A, a significant secondary metabolite from Exserohilum sp., demonstrates various biological activities; however, its neuroprotective effects have not been elucidated. Here, we investigated the therapeutic potential of epicoccin A for PD by evaluating its impact on neural phenotype, reactive oxygen species (ROS) generation, and locomotor activity in PD-like zebrafish. Transcriptomic analysis and molecular docking were conducted, with key gene expressions further verified using real-time qPCR. As a result, epicoccin A notably mitigated dopaminergic neuron loss, neural vasculature deficiency, nervous system injury, ROS accumulation, locomotor impairments, and abnormal expressions of hallmark genes associated with PD and oxidative stress. Underlying mechanism investigation indicated epicoccin A may alleviate PD-like symptoms by activating PINK1/Parkin-dependent mitophagy, as evidenced by the reversal of aberrant gene expressions related to the pink1/parkin pathway and its upstream mTOR/FoxO pathway following epicoccin A co-treatments. This finding was further confirmed by the robust interactions between epicoccin A and these mitophagy regulators. Our results suggest that epicoccin A relieves PD symptoms by activating pink1/parkin-dependent mitophagy and inhibiting excessive oxidative stress, highlighting its potential as a therapeutic approach for PD.

Sick sinus syndrome (SSS) is a term used for a variety of disorders defined by abnormal cardiac impulse formation and by abnormal propagation from the heart’s sinoatrial node. In this study, we present a case from a Chinese family in which two closely related individuals had the symptoms and electrocardiographic evidence of SSS. We hypothesized that multiple individuals affected by the disease in the family was an indication of its genetic predisposition, and thus performed high-throughput sequencing for the participants from the family to detect potential disease-associated variants. One of the potential variants that was identified was a KCNG2 gene variant (NC_000018.9: g.77624068_77624079del). Further bioinformatic analysis showed that the observed variant may be a pathogenic mutation. The results of protein-protein docking and whole cell patch-clamp measurements implied that the deletion variant in KCNG2 could affect its binding the KV2.1 protein, and finally affect the function of Kv channel, which is an important determinant in regulation of heartbeat. Therefore, we inferred that the variable KCNG2 gene may affect the function of Kv channel by changing the binding conformation of KCNG2 and KV2.1 proteins and then adversely affect propagation from the sinoatrial node and cardiac impulse formation by changing the action potential repolarization of heart cells. In summary, our findings suggested that the dominant KCNG2 deletion variant in the examined Chinese family with SSS may be a potential disease-associated variant.

Gentamicin is commonly used for effective treatment of severe Gram-negative bacterial infections. However, its use is being increasingly restricted owing to the ototoxic effects attributed to it. Gentamicin-induced ototoxicity is thought to be related with apoptosis induced by reactive oxygen species (ROS). In this study, we found a novel active peptide from Neptunea arthritica cumingii with otoprotective effects and no significant embryotoxic effects. The combined application of gentamicin and this novel active peptide helped sensory-hair cells to protect themselves from lethal ROS accumulation. This, in turn, reduced the expression of three genes (caspase-3, caspase-9, Bax), and thereby, the sensory-hair cell apoptosis promoted by ROS accumulation upon gentamicin administration. Our findings provided new insights into the prevention of gentamicin-induced hearing loss.

Auditory hair cell damage induced by aminoglycoside antibiotics (AmAn) leads to hearing loss, which has a serious effect on people’s mental and physical health. This ototoxicity is thought to be related with the excessive accumulation of reactive oxygen species (ROS) in hair cells. However, therapeutic agents that protect hair cells are limited. Marine peptides have been shown to have excellent potential applications in disease prevention and treatment. Therefore, this study investigated the protective effects of an active peptide from Neptunea arthritica cumingii against AmAn-induced hair cell damage using the model of hair cell damage zebrafish. We identified the number, ultrastructure, and function of hair cells using fluorescence probes and scanning electron microscopy. The uptake of AmAn, ROS level, mitochondrial permeability transition pore, and apoptosis in hair cells were also tested by fluorescence labeling and TUNEL assay. The molecular mechanism for hair cell protection exerted by the peptide was detected by a real-time quantitative PCR assay. The results indicated that the peptide suppressed the uptake of AmAn but did not damage the function of hair cells mediating hearing. It also prevented ROS accumulation, decreased the occurrence of apoptosis, and rescued the abnormal opening and expressions of mitochondrial permeability transition pore and genes related to antioxidants. The peptide may be an effective therapeutic agent for AmAn-induced ototoxicity. In the future, we plan to use mammalian models to further investigate the otoprotective effect of the peptide.