Dipsacoside B Exerts a Beneficial Effect on Brain Injury in the Ischemic Stroke Rat through Inhibition of Mitochondrial E3 Ubiquitin Ligase 1

Abstract

Background: Upregulation of mitochondrial E3 ubiquitin ligase 1 (Mul1) contributes to brain injury in ischemic stroke due to disturbance of mitochondrial dynamics, and bioinformatics analysis predicts that Mul1 is a potential target of Dipsacoside B. Objective: The aim of the study was to explore whether Dipsacoside B can exert a beneficial effect on brain injury in the ischemic stroke rat via targeting Mul1. Methods: The SD rat brains or PC12 cells were subjected to 2 h-ischemia or 8 h-hypoxia plus 24 h-reperfusion or 24 h-reoxygenation to establish the ischemic stroke rat model in vivo or in vitro, which were treated with Dipsacoside B at different dosages. The brain or PC12 cell injury, relevant protein levels and mitochondrial functions were measured by methods of biochemistry, flow cytometry or Western blot. Results: The neurological dysfunction and brain injury (such as infarction and apoptosis) observed in the ischemic stroke rats were accompanied by increases in Mul1 and dynamin-related protein 1 (Drp1) levels along with decreases in mitofusin 2 (Mfn2) level and ATP production. These effects were attenuated by Dipsacoside B. Consistently, cell injury (necroptosis and apoptosis) occurred in the PC12 cells exposed to hypoxia concomitant with the upregulation of Mul1 and Drp1 along with downregulation of Mfn2 and mitochondrial functions (such as increases in reactive oxygen species production and mitochondrial fission and decreases in mitochondrial membrane potential and ATP production).These phenomena were reversed in the presence of Dipsacoside B. Conclusion: Dipsacoside B can protect the rat brain against ischemic injury via inhibition of Mul1 due to the improvement of mitochondrial function.

Dipsacoside B Inhibits the Migration and Proliferation of VSMCs and Blunts Neointimal Formation by Upregulating PTEN Expression

“…Nevertheless, it has not been reported that triterpenoid saponins inhibit the phenotype transformation of VSMC in VR via PTEN. Dipsacoside B (DB), triterpenoid saponins, is an herb monomer extracted from Chinese medicine-Dipsacusasper or Lonicera macranthoides [21]. However, the pharmacological effects of DB are rarely reported.…”

“…However, the pharmacological effects of DB are rarely reported. Recent studies have demonstrated that DB exerts beneficial effects on brain ischemic injury via the inhibition of mitochondrial E3 ubiquitin ligase 1 [21], suggesting the therapeutic potential of DB in VR-related diseases. Our previous study [22] has demonstrated that DB suppresses the proliferation of VSMCs by downregulating TOP2α, but whether DB exert its role by interfering VSMCs' phenotype switch and its interaction with PTEN needs to be further elucidated.…”