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Abstract：
BACKGROUND: Doxorubicin (DOX) is a first-line chemotherapeutic drug for various malignancies that causes cardiotoxicity. Plant-derived exosome-like nanovesicles (P-ELNs) are growing as novel therapeutic agents. Here, we investigated the protective effects in DOX cardiotoxicity of ELNs from Momordica charantia L. (MC-ELNs), a medicinal plant with antioxidant activity.
RESULTS: We isolated MC-ELNs using ultracentrifugation and characterized them with canonical mammalian extracellular vesicles features. In vivo studies proved that MC-ELNs ameliorated DOX cardiotoxicity with enhanced cardiac function and myocardial structure. In vitro assays revealed that MC-ELNs promoted cell survival, diminished reactive oxygen species, and protected mitochondrial integrity in DOX-treated H9c2 cells. We found that DOX treatment decreased the protein level of p62 through ubiquitin-dependent degradation pathway in H9c2 and NRVM cells. However, MC-ELNs suppressed DOX-induced p62 ubiquitination degradation, and the recovered p62 bound with Keap1 promoting Nrf2 nuclear translocation and the expressions of downstream gene HO-1. Furthermore, both the knockdown of Nrf2 and the inhibition of p62-Keap1 interaction abrogated the cardioprotective effect of MC-ELNs.
CONCLUSIONS: Our findings demonstrated the therapeutic beneficials of MC-ELNs via increasing p62 protein stability, shedding light on preventive approaches for DOX cardiotoxicity.
RESULTS: We isolated MC-ELNs using ultracentrifugation and characterized them with canonical mammalian extracellular vesicles features. In vivo studies proved that MC-ELNs ameliorated DOX cardiotoxicity with enhanced cardiac function and myocardial structure. In vitro assays revealed that MC-ELNs promoted cell survival, diminished reactive oxygen species, and protected mitochondrial integrity in DOX-treated H9c2 cells. We found that DOX treatment decreased the protein level of p62 through ubiquitin-dependent degradation pathway in H9c2 and NRVM cells. However, MC-ELNs suppressed DOX-induced p62 ubiquitination degradation, and the recovered p62 bound with Keap1 promoting Nrf2 nuclear translocation and the expressions of downstream gene HO-1. Furthermore, both the knockdown of Nrf2 and the inhibition of p62-Keap1 interaction abrogated the cardioprotective effect of MC-ELNs.
CONCLUSIONS: Our findings demonstrated the therapeutic beneficials of MC-ELNs via increasing p62 protein stability, shedding light on preventive approaches for DOX cardiotoxicity.
摘要：
背景：阿霉素（DOX）是导致心脏毒性的各种恶性肿瘤的一线化疗药物。植物来源的外泌体样纳米囊泡(P-ELN)正在成长为新型治疗剂。这里,我们研究了苦瓜ELN（MC-ELN）对DOX心脏毒性的保护作用，具有抗氧化活性的药用植物。
结果：我们使用超速离心分离MC-ELN，并用典型的哺乳动物细胞外囊泡特征对其进行表征。体内研究证明，MC-ELN改善了DOX心脏毒性，增强了心脏功能和心肌结构。体外实验表明MC-ELN促进细胞存活，减少活性氧，并在DOX处理的H9c2细胞中保护线粒体完整性。我们发现DOX处理通过泛素依赖性降解途径降低了H9c2和NRVM细胞中p62的蛋白水平。然而,MC-ELN抑制DOX诱导的p62泛素化降解，回收的p62与Keap1结合，促进Nrf2核易位和下游基因HO-1的表达。此外，Nrf2的敲低和p62-Keap1相互作用的抑制都消除了MC-ELN的心脏保护作用。
结论：我们的发现证明了MC-ELNs通过增加p62蛋白稳定性的治疗益处，探讨DOX心脏毒性的预防方法。
结果：我们使用超速离心分离MC-ELN，并用典型的哺乳动物细胞外囊泡特征对其进行表征。体内研究证明，MC-ELN改善了DOX心脏毒性，增强了心脏功能和心肌结构。体外实验表明MC-ELN促进细胞存活，减少活性氧，并在DOX处理的H9c2细胞中保护线粒体完整性。我们发现DOX处理通过泛素依赖性降解途径降低了H9c2和NRVM细胞中p62的蛋白水平。然而,MC-ELN抑制DOX诱导的p62泛素化降解，回收的p62与Keap1结合，促进Nrf2核易位和下游基因HO-1的表达。此外，Nrf2的敲低和p62-Keap1相互作用的抑制都消除了MC-ELN的心脏保护作用。
结论：我们的发现证明了MC-ELNs通过增加p62蛋白稳定性的治疗益处，探讨DOX心脏毒性的预防方法。
