■绞股蓝(Thunb。)牧野,一种著名的食用和药用植物,具有抗衰老特性,用于治疗与糖尿病相关的疾病,代谢综合征,和心血管疾病。绞股蓝皂苷(GYP)是绞股蓝的主要成分。越来越多的证据表明GYP在保持线粒体稳态和预防心力衰竭(HF)方面是有效的。本研究旨在揭示GYP与线粒体调控相关的心脏保护机制。
■使用网络药理学方法获得并筛选了GYP中的生物活性成分和治疗HF的潜在靶标,其次是药物-疾病目标预测和富集分析。GYPs在心脏保护中的药理作用,线粒体功能,线粒体质量控制,进一步研究了阿霉素(Dox)刺激的H9c2心肌细胞的潜在机制。
■总共鉴定了88种GYP的生物活性化合物及其各自的71种药物-疾病靶标。中心目标覆盖了MAPK,EGFR,PI3KCA,还有Mcl-1.富集分析显示,这些途径主要含有PI3K/Akt,MAPK,和福克斯信号,以及钙调节,蛋白质磷酸化,凋亡,和线粒体自噬过程。在Dox刺激的H9c2大鼠心肌细胞中,用GYP预处理增加细胞活力,增强细胞ATP含量,恢复的基础耗氧率(OCR),改善线粒体膜电位(MMP)。此外,GYP改善了PINK1/parkin介导的线粒体自噬,而不影响线粒体裂变/融合蛋白和自噬LC3水平。机械上,PI3K的磷酸化,Akt,GSK-3β,通过GYP处理,Mcl-1的蛋白水平上调。
■我们的研究结果表明,GYP通过挽救有缺陷的线粒体自噬发挥心脏保护作用,和PI3K/Akt/GSK-3β/Mcl-1信号可能参与该过程。
UNASSIGNED: Gynostemma pentaphyllum (Thunb.) Makino, a well-known edible and medicinal plant, has anti-aging properties and is used to treataging-associated conditions such as diabetes, metabolic syndrome, and cardiovascular diseases. Gypenosides (GYPs) are the primary constituents of G. pentaphyllum. Increasing evidence indicates that GYPs are effective at preserving mitochondrial homeostasis and preventing heart failure (HF). This study aimed to uncover the cardioprotective mechanisms of GYPs related to mitochondrial regulation.
UNASSIGNED: The bioactive components in GYPs and the potential targets in treating HF were obtained and screened using the network pharmacology approach, followed by drug-disease target prediction and enrichment analyses. The pharmacological effects of GYPs in cardioprotection, mitochondrial function, mitochondrial quality control, and underlying mechanisms were further investigated in Doxorubicin (Dox)-stimulated H9c2 cardiomyocytes.
UNASSIGNED: A total of 88 bioactive compounds of GYPs and their respective 71 drug-disease targets were identified. The hub targets covered MAPK, EGFR, PI3KCA, and Mcl-1. Enrichment analysis revealed that the pathways primarily contained PI3K/Akt, MAPK, and FoxO signalings, as well as calcium regulation, protein phosphorylation, apoptosis, and mitophagy process. In Dox-stimulated H9c2 rat cardiomyocytes, pretreatment with GYPs increased cell viability, enhanced cellular ATP content, restored basal oxygen consumption rate (OCR), and improved mitochondrial membrane potential (MMP). Furthermore, GYPs improved PINK1/parkin-mediated mitophagy without influencing mitochondrial fission/fusion proteins and the autophagic LC3 levels. Mechanistically, the phosphorylation of PI3K, Akt, GSK-3β, and the protein level of Mcl-1 was upregulated by GYP treatment.
UNASSIGNED: Our findings reveal that GYPs exert cardioprotective effects by rescuing the defective mitophagy, and PI3K/Akt/GSK-3β/Mcl-1 signaling is potentially involved in this process.