参考文献 (3)
Parkinson's disease (PD) is a neurodegenerative disorder that gets exacerbated by vascular injury. Neural stem cell-derived exosomes (NSC-Exos) display effective neuroprotective properties in PD models. Cell division control protein 42 (CDC42) is connected to angiogenesis, but its effects in PD remain undefined. This research aims to reveal the role of CDC42 in PD. First, we applied 1-methyl-4-phenylpyridinium (MPP + ) to induce the human cerebral microvascular endothelial cells (HCMECs) model and evaluated cell viability and ferroptosis. Then, we characterized NSC-Exos. Next, to appraise the effect of hypoxia-pretreated NSC-Exos (H-NSC-Exos) on the MPP + -induced cells model, we examined angiogenesis and ferroptosis in HCMECs. Moreover, we constructed the PD mice model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and tested the behavioral experiments and vascular injury of mice. Furthermore, we examined cellular ferroptosis and angiogenesis after knockdown of CDC42. Additionally, we investigated the interaction of CDC42 with Acyl-CoA synthetase long-chain family member 4 (ACSL4) and detected cellular ferroptosis and angiogenesis after overexpression of ACSL4. We found that H-NSC-Exos reversed the MPP + -induced decrease in HCMECs viability and migration, lowered lipid-reactive oxygen species (lipid-ROS) levels, suppressed ferroptosis, and facilitated angiogenesis. Moreover, H-NSC-Exos attenuated MPTP-induced PD development, vascular injury, and ferroptosis in mice. H-NSC-Exos with the knockdown of CDC42 reduced cell viability and angiogenesis and raised ferroptosis and lipid-ROS levels, which were reversed by ferrostatin-1 and liproxstatin-1. CDC42 interacted with ACSL4. Furthermore, overexpression of ACSL4 aggravated the above effects of H-NSC-Exos in which CDC42 was knocked down. Our study reveals that H-NSC-Exos-derived CDC42 inhibited ACSL4-related ferroptosis to alleviate vascular injury in PD mice models. CDC42 may serve as a potent therapeutic target for PD treatment.
Background:Chronic heart failure (CHF) is a serious cardiovascular condition. Vascular peroxidase 1 (VPO1) is associated with various cardiovascular diseases, yet its role in CHF remains unclear. This research aims to explore the involvement of VPO1 in CHF.Methods:CHF was induced in rats using adriamycin, and the expression levels of VPO1 and cylindromatosis (CYLD) were assessed. In parallel, the effects of VPO1 on programmed necrosis in H9c2 cells were evaluated through cell viability assays, lactate dehydrogenase (LDH) level measurements, and analysis of receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein (RIPK1/RIPK3/MLKL) pathway-related proteins. The impact of CYLD on RIPK1 protein stability and ubiquitination was also investigated, along with the interaction between VPO1 and CYLD. Additionally, cardiac structure and function were assessed using echocardiography, Hematoxylin-eosin (HE) staining, Masson staining, and measurements of myocardial injury-related factors, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), Aspartate aminotransferase (AST), LDH, and creatine kinase-myocardial band (CK-MB).Results:VPO1 expression was upregulated in CHF rats and in H9c2 cells treated with adriamycin. In cellular experiments, VPO1 knockdown improved cell viability, inhibited necrosis and the expression of proteins associated with the RIPK1/RIPK3/MLKL pathway. Mechanistically, VPO1 promoted cardiomyocyte programmed necrosis by interacting with the deubiquitinating enzyme CYLD, which enhanced RIPK1 ubiquitination and degradation, leading to activation of the RIPK1/RIPK3/MLKL signaling pathway. At animal level, overexpression of CYLD counteracted the cardiac failure, cardiac hypertrophy, myocardial injury, myocardial fibrosis, and tissue necrosis caused by VPO1 knockdown.Conclusions:VPO1 exacerbates cardiomyocyte programmed necrosis in CHF rats by upregulating CYLD, which activates the RIPK1/RIPK3/MLKL signaling pathway. Thus, VPO1 may represent a potential therapeutic target for CHF.
This study proposes to investigate the therapeutic efficacy and mechanism of combining tibial transverse transport (TTT) with platelet-rich plasma (PRP) for diabetic foot ulcer (DFU). The diabetic rabbit model was constructed with Streptozotocin, which was intervened with TTT and PRP. PRP injection combined with TTT significantly promoted vascularisation and enhanced CD31, VEGFA, and VEGFR2 expressions compared to traditional TTT. However, the VEGFR2 inhibitor suppressed these phenomena. In the in vitro injury model, PRP reversed the diminished human umbilical vein endothelial cells (HUVECs) function and vascularisation caused by high-glucose damage. Additionally, PRP reduced inflammation and oxidative stress (approximately 47% ROS level) and enhanced VEGFA and VEGFR2 expression in HUVECs. However, the knockdown of VEGFR2 reversed the effect of PRP. In conclusion, TTT combined with intraosseous flap injection of PRP sustained-release microspheres activated the VEGFA/VEGFR2 pathway to promote microcirculatory reconstruction in DFU. These findings may provide new potential therapeutic strategies for DFU.
