Gonçalves A C, Cortesão E, Oliveiros B, Alves V, Espadana A I, Rito L, Magalhães E, Lobão M J, Pereira A, Nascimento Costa J M, Mota-Vieira L, Sarmento-Ribeiro A B
Laboratory of Oncobiology and Hematology, FMUC - Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
Free Radic Res. 2015;49(9):1081-94. doi: 10.3109/10715762.2015.1035268. Epub 2015 May 25.
The imbalance between reactive oxygen species (ROS) production and their elimination by antioxidants leads to oxidative stress. Depending on their concentration, ROS can trigger apoptosis or stimulate cell proliferation. We hypothesized that oxidative stress and mitochondrial dysfunction may participate not only in apoptosis detected in some myelodysplastic syndrome (MDS) patients, but also in increasing proliferation in other patients. We investigated the involvement of oxidative stress and mitochondrial dysfunction in MDS pathogenesis, as well as assessed their diagnostic and prognostic values. Intracellular peroxides, superoxide, superoxide/peroxides ratio, reduced glutathione (GSH), and mitochondrial membrane potential (Δψ(mit)) levels were analyzed in bone marrow cells from 27 MDS patients and 12 controls, by flow cytometry. We observed that all bone marrow cell types from MDS patients had increased intracellular peroxide levels and decreased GSH content, compared with control cells. Moreover, oxidative stress levels were MDS subtype- and risk group-dependent. Low-risk patients had the highest ROS levels, which can be related with their high apoptosis; and intermediate-2-risk patients had high Δψ(mit) that may be associated with their proliferative potential. GSH levels were negatively correlated with transfusion dependency, and peroxide levels were positively correlated with serum ferritin level. GSH content proved to be an accurate parameter to discriminate patients from controls. Finally, patients with high ROS or low GSH levels, as well as high superoxide/peroxides ratio had lower overall survival. Our results suggest that oxidative stress and mitochondrial dysfunction are involved in MDS development, and that oxidative stress parameters may constitute novel diagnosis and/or prognosis biomarkers for MDS.
活性氧（ROS）生成与抗氧化剂对其清除之间的失衡会导致氧化应激。根据其浓度，ROS可引发细胞凋亡或刺激细胞增殖。我们推测氧化应激和线粒体功能障碍不仅可能参与某些骨髓增生异常综合征（MDS）患者中检测到的细胞凋亡，还可能参与其他患者的增殖增加。我们研究了氧化应激和线粒体功能障碍在MDS发病机制中的作用，并评估了它们的诊断和预后价值。通过流式细胞术分析了27例MDS患者和12例对照的骨髓细胞中的细胞内过氧化物、超氧化物、超氧化物/过氧化物比值、还原型谷胱甘肽（GSH）和线粒体膜电位（Δψ(mit)）水平。我们观察到，与对照细胞相比，MDS患者的所有骨髓细胞类型的细胞内过氧化物水平均升高，GSH含量降低。此外，氧化应激水平取决于MDS亚型和风险组。低风险患者的ROS水平最高，这可能与其高凋亡率有关；中-2风险患者的Δψ(mit)较高，这可能与其增殖潜力有关。GSH水平与输血依赖性呈负相关，过氧化物水平与血清铁蛋白水平呈正相关。GSH含量被证明是区分患者与对照的准确参数。最后，ROS水平高或GSH水平低以及超氧化物/过氧化物比值高的患者总生存率较低。我们的结果表明，氧化应激和线粒体功能障碍参与了MDS的发展，并且氧化应激参数可能构成MDS的新型诊断和/或预后生物标志物。
