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Toxicokinetics of Arenobufagin and its Cardiotoxicity Mechanism Exploration Based on Lipidomics and Proteomics Approaches in Rats.

ABSTRACT: Arenobufagin (ArBu), one of the main active bufadienolides of toad venom with cardiotonic effect, analgesic effect, and outstanding anti-tumor potentiality, is also a potential cardiotoxic component. In the present study, the cardiac effect of ArBu and its underlying mechanism were explored by integrating data such as heart rates, toxicokinetics, myocardial enzyme and brain natriuretic peptide (BNP) activity, pathological sections, lipidomics and proteomics. Under different doses, the cardiac effects turned out to be different. The oral dose of 60 mg/kg of ArBu sped up the heart rate. However, 120 mg/kg ArBu mainly reduced the heart rate. Over time, they all returned to normal, consisting of the trend of ArBu concentration-time curve. High concentrations of myocardial enzymes and BNP indicated that ArBu inhibited or impaired the cardiac function of rats. Pathological sections of hearts also showed that ArBu caused myocardial fiber disorder and rupture, in which the high-dose group was more serious. At the same time, serum and heart tissue lipidomics were used to explore the changes in body lipid metabolism under different doses. The data indicated a larger difference in the high-dose ArBu group. There were likewise many significant differences in the proteomics of the heart. Furthermore, a multi-layered network was used to integrate the above information to explore the potential mechanism. Finally, 4 proteins that were shown to be significantly and differentially expressed were validated by targeted proteomics using parallel reaction monitoring (PRM) analysis. Our findings indicated that ArBu behaved as a bidirectional regulation of the heart. The potential mechanism of cardiac action was revealed with the increased dose, which provided a useful reference for the safety of clinical application of ArBu.

SUBMITTER: Zhao L

PROVIDER: S-EPMC8727535 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo explore the mechanism of edaravone in the treatment of oxidative stress in rats with cerebral infarction based on quantitative proteomics technology.MethodThe modified Zea Longa intracavitary suture blocking method was utilized to make rat CI model. After modeling, the rat was intragastrically given edaravone for 7 days, once a day. After the 7-day intervention, the total proteins of serum were extracted. After proteomics analysis, the differentially expressed proteins are analyzed by bioinformatics. Then chemoinformatics methods were used to explore the biomolecular network of edaravone intervention in CI.ResultThe neurological scores and pathological changes of rats were improved after the intervention of edaravone. Proteomics analysis showed that in the model/sham operation group, 90 proteins in comparison group were upregulated, and 26 proteins were downregulated. In the edaravone/model group, 21 proteins were upregulated, and 41 proteins were downregulated. Bioinformatics analysis and chemoinformatics analysis also show that edaravone is related to platelet activation and aggregation, oxidative stress, intercellular adhesion, glycolysis and gluconeogenesis, iron metabolism, hypoxia, inflammatory chemokines, their mediated signal transduction, and so on.ConclusionThe therapeutic mechanism of edaravone in the treatment of CI may involve platelet activation and aggregation, oxidative stress, intercellular adhesion, glycolysis and gluconeogenesis, iron metabolism, hypoxia, and so on. This study revealed the serum protein profile of edaravone in the treatment of cerebral infarction rats through serum TMT proteomics and discovered the relevant mechanism of edaravone regulating iron metabolism in cerebral infarction, which provides new ideas for the study of edaravone intervention in cerebral infarction and also provides reference information for future research on the mechanism of edaravone intervention in iron metabolism-related diseases.

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Toxicokinetics of Arenobufagin and its Cardiotoxicity Mechanism Exploration Based on Lipidomics and Proteomics Approaches in Rats.

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