Breviscapine protects against pathological cardiac hypertrophy by targeting FOXO3a-mitofusin-1 mediated mitochondrial fusion.

Forkhead box O3a (FOXO3a)-mediated mitochondrial dysfunction plays a pivotal effect on cardiac hypertrophy and heart failure (HF). However, the role and underlying mechanisms of FOXO3a, regulated by breviscapine (BRE), on mitochondrial function in HF therapy remain unclear. This study reveals that BRE-induced nuclear translocation of FOXO3a facilitates mitofusin-1 (MFN-1)-dependent mitochondrial fusion in cardiac hypertrophy and HF. BRE effectively promotes cardiac function and ameliorates cardiac remodeling in pressure overload-induced mice. In addition, BRE mitigates phenylephrine (PE)-induced cardiac hypertrophy in cardiomyocytes and fibrosis remodeling in fibroblasts by inhibiting ROS production and promoting mitochondrial fusion, respectively. Transcriptomics analysis underscores the close association between the FOXO pathway and the protective effect of BRE against HF, with FOXO3a emerging as a potential target of BRE. BRE potentiates the nuclear translocation of FOXO3a by attenuating its phosphorylation, other than its acetylation in cardiac hypertrophy. Mechanistically, over-expression of FOXO3a significantly inhibits cardiac hypertrophy and mitochondrial injury by promoting MFN-1-mediated mitochondrial fusion. Furthermore, BRE demonstrates its ability to substantially curb cardiac hypertrophy, reduce mitochondrial ROS production, and enhance MFN-1-mediated mitochondrial fusion through a FOXO3a-dependent mechanism. In conclusion, nuclear FOXO3a translocation induced by BRE presents a successful therapeutic avenue for addressing cardiac hypertrophy and HF through promoting MFN-1-dependent mitochondrial fusion.

A mass defect filtering combined background subtraction strategy for rapid screening and identification of metabolites in rat plasma after oral administration of Yindan Xinnaotong soft capsule.

The absorbed prototypes and metabolites of traditional Chinese medicines (TCMs) serves an important part in pharmacological action and clinical effects. However, the comprehensive characterization of which is facing actual or possible rigorous challenges due to the lack of data mining methods and the complexity of metabolite samples. Yindan Xinnaotong soft capsule (YDXNT), a typical traditional Chinese medicine prescription consisting of extracts from 8 herbal medicines, is widely used for the treatment of angina pectoris and ischemic stroke in the clinic. This study established a systematic data mining strategy based on ultra-high performance liquid chromatography tandem quadrupole-time-of-fight mass spectrometry (UHPLC-Q-TOF MS) for comprehensive metabolite profiling of YDXNT in rat plasma after oral administration. The multi-level feature ion filtration strategy was primarily conducted through the full scan MS data of plasma samples. All potential metabolites were rapidly fileted out from the endogenous background interference based on the background subtract and the chemical type specifically mass defect filter (MDF) windows including flavonoids, ginkgolides, phenolic acids, saponins, and tanshinones. As the MDF windows of certain types were overlapped, the screened-out potential metabolites were deeply characterized and identified according to their retention times (RT), integrating neutral loss filtering (NLF), diagnostic fragment ions filtering (DFIF), and further confirmed by reference standards. Thus, a total of 122 compounds, consisting of 29 prototype components (16 confirmed with reference standards) and 93 metabolites had been identified. This study provides a rapid and robust metabolite profiling method for researching complicated traditional Chinese medicine prescriptions.

A sensitive LC-MS/MS method-based pharmacokinetic study of fifteen active ingredients of Yindan Xinnaotong soft capsule in rats and its potential mechanism in the treatment of cardiovascular diseases.

Yindan Xinnaotong soft capsule (YDXNT) is a commonly used Chinese herbal preparation for the clinical treatment of coronary disease. However, there is a lack of pharmacokinetic studies on YDXNT, and its active ingredients and their mechanism in the treatment of cardiovascular diseases (CVD) are still unclear. In this study, 15 absorbed ingredients in rat plasma after oral administration of YDXNT were quickly identified based on liquid chromatography tandem quadrupole time-of-flight mass spectrometry (LC-QTOF MS), and then a sensitive and accurate quantitative method based on ultra-high performance liquid chromatography tandem triple quadrupole mass spectrometry (UHPLC-QQQ MS) was established and validated for simultaneous determination of the 15 ingredients of YDXNT in rat plasma, which was then applied to the pharmacokinetic study. Different types of compounds showed various pharmacokinetic characteristics, for instance, ginkgolides with higher maximum plasma concentration (Cmax), flavonoids presenting concentration-time curve with double peaks, phenolic acids with shorter time to reach maximum plasma concentration (Tmax), saponins with long elimination half-life (t1/2) and tanshinones showing fluctuant plasma concentration. Then the measured analytes were regarded as effective compounds and their potential targets and mechanism of action were predicted by constructing and analyzing the compound-target network of YDXNT and CVD. Those potential active compounds of YDXNT interacted with targets such as MAPK1 and MAPK8, and molecular docking showed that the binding free energies of 12 ingredients with MAPK1 were less than -5.0 kcal/mol, indicating that YDXNT intervened in the MAPK signaling pathway to display its therapeutic effect on CVD.