Dimethyl fumarate induces cardiac developmental toxicity in zebrafish via down-regulation of oxidative stress.

Dimethyl fumarate (DMF) is an immunosuppressant commonly used to treat multiple sclerosis and other autoimmune diseases. Despite known side effects such as lymphopenia, the effect of DMF on cardiac development remains unclear. To assess this, we used zebrafish to evaluate the cardiac developmental toxicity of DMF. Our study showed that DMF reduced the survival rate of zebrafish embryos, with those exposed to 1, 1.3, and 1.6 mg/L exhibiting heart rate reduction, shortened body length, delayed yolk sac absorption, pericardial edema, increased distance from sinus venous to bulbus arteriosus, and separation of cardiomyocytes and endocardial cells at 72 hpf. Heart development-related genes showed disorder, apoptosis-related genes were up-regulated, and the oxidative stress response was down-regulated. Treatment with cysteamine ameliorated the heart development defects. Our study demonstrates that DMF induces cardiac developmental toxicity in zebrafish, possibly by down-regulating oxidative stress responses. This study provides a certain research basis for further study of DMF-induced cardiac developmental toxicity, and provides some experimental evidence for future clinical application and study of DMF.

Apatinib induces zebrafish hepatotoxicity by inhibiting Wnt signaling and accumulation of oxidative stress.

Apatinib, a small-molecule VEGFR2-tyrosine kinase inhibitor, has shown potent anticancer activity in various clinical cancer treatments, but also different adverse reactions. Therefore, it is necessary to study its potential toxicity and working mechanism. We used zebrafish to investigate the effects of apatinib on the development of embryos. Zebrafish exposed to 2.5, 5, and 10 µM apatinib showed adverse effects such as decreased liver area, pericardial oedema, slow yolk absorption, bladder atrophy, and body length shortening. At the same time, it leads to abnormal liver tissue structure, liver function and related gene expression. Furthermore, after exposure to apatinib, oxidative stress levels were significantly elevated but liver developmental toxicity was effectively ameliorated with oxidative stress inhibitor treatment. Apatinib induces down-regulation of key target genes of Wnt signaling pathway in zebrafish, and it is found that Wnt activator can significantly rescue liver developmental defects. These results suggest that apatinib may induce zebrafish hepatotoxicity by inhibiting the Wnt signaling pathway and up-regulating oxidative stress, helping to strengthen our understanding of rational clinical application of apatinib.

Shikonin Inhibits Fin Regeneration in Zebrafish Larvae.

Shikonin is a naphthoquinone compound extracted from Chinese comfrey for treating cancer. However, there are few reports on its research on vertebrate tissue regeneration. Zebrafish is an ideal model for studying organ regeneration. In this study, we found that 3-dpf of zebrafish larvae exposed to shikonin at concentrations of 0.2, 0.3, and 0.4 mg/L showed increasingly inhibited regeneration of the tail fin. Immunohistochemical staining showed that shikonin exposure from 6 to 12 hpa increased the number of apoptotic cells in the caudal fin wound of larvae and decreased the number of proliferating cells. Shikonin exposure was found to up-regulate oxidative stress, increase ROS levels, and reduce neutrophil recruitment in the early stage of wound repair. Moreover, shikonin exposure caused disordered expression of fin regeneration blastemal-related genes. The use of astaxanthin to down-regulate oxidative stress was found to significantly reduce the inhibition of caudal fin regeneration. Mixed exposure of AMPK inhibitors or fullerenes (C60) with shikonin also showed the similar rescue effect. Collectively, our study showed that shikonin inhibited fin regeneration in zebrafish larvae by the upregulation of oxidative stress level and AMPK signaling pathway. This research provides valuable information on the mechanism of action of shikonin for its safe application.