Department of Biological Sciences, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia.
Department of Biochemistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India.
Int J Mol Sci. 2021 Apr 20;22(8):4259. doi: 10.3390/ijms22084259.
Doxorubicin increases endothelial permeability, hence increasing cardiomyocytes' exposure to doxorubicin (DOX) and exposing myocytes to more immediate damage. Reactive oxygen species are major effector molecules of doxorubicin's activity. Mangiferin (MGN) is a xanthone derivative that consists of C-glucosylxanthone with additional antioxidant properties. This particular study assessed the effects of MGN on DOX-induced cytotoxicity in human umbilical vein endothelial cells' (HUVECs') signaling networks. Mechanistically, MGN dramatically elevated Nrf2 expression at both the messenger RNA and protein levels through the upregulation of the PI3K/AKT pathway, leading to an increase in Nrf2-downstream genes. Cell apoptosis was assessed with a caspase-3 activity assay, transferase-mediated dUTP-fluorescein nick end labeling (TUNEL) staining was performed to assess DNA fragmentation, and protein expression was determined by Western blot analysis. DOX markedly increased the generation of reactive oxygen species, PARP, caspase-3, and TUNEL-positive cell numbers, but reduced the expression of Bcl-2 and antioxidants' intracellular concentrations. These were effectively antagonized with MGN (20 μM), which led to HUVECs being protected against DOX-induced apoptosis, partly through the PI3K/AKT-mediated NRF2/HO-1 signaling pathway, which could theoretically protect the vessels from severe DOX toxicity.
阿霉素增加血管内皮通透性，从而增加心肌细胞暴露于阿霉素（DOX）的机会，并使心肌细胞更容易受到直接损伤。活性氧是阿霉素活性的主要效应分子。芒果苷（MGN）是一种由 C-葡萄糖基黄烷酮组成的衍生物，具有额外的抗氧化特性。这项研究评估了 MGN 对人脐静脉内皮细胞（HUVECs）信号网络中 DOX 诱导的细胞毒性的影响。从机制上讲，MGN 通过上调 PI3K/AKT 途径，显著提高了 Nrf2 在信使 RNA 和蛋白质水平上的表达，导致 Nrf2 下游基因的增加。用 caspase-3 活性测定法评估细胞凋亡，用转谷氨酰胺酶介导的 dUTP-荧光素末端标记（TUNEL）染色法评估 DNA 片段化，并用 Western blot 分析测定蛋白质表达。DOX 显著增加活性氧、PARP、caspase-3 和 TUNEL 阳性细胞数量的产生，但降低了 Bcl-2 的表达和抗氧化剂的细胞内浓度。MGN（20 μM）有效地拮抗了这些作用，这导致 HUVEC 对 DOX 诱导的细胞凋亡具有保护作用，部分通过 PI3K/AKT 介导的 NRF2/HO-1 信号通路，这从理论上可以保护血管免受严重的 DOX 毒性。
