Campo Giuseppe M, Avenoso Angela, Campo Salvatore, D'Ascola Angela, Traina Paola, Samà Dario, Calatroni Alberto
Department of Biochemical, Physiological and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, 98125 Messina, Italy.
J Appl Toxicol. 2008 May;28(4):509-17. doi: 10.1002/jat.1302.
Oxidative stress, inflammation and apoptosis play a critical role in the onset and progression of cellular damage. It was previously reported that hyaluronan (HA) and chondroitin-4-sulphate (C4S) were able to protect human skin fibroblasts from oxidative stress. This antioxidant activity is due to the chelation of transition metal ions. Nuclear factor kB (NF-kB), complexed with the inhibitory protein IkB alpha, is an ubiquitous response transcription factor involved in inflammatory reactions and acts by inducing cytokine expression, chemokines and cell adhesion molecules. Caspases are specific proteases responsible for the regulation and the execution of apoptotic cell death. The damage caused by free radicals may be amplified greatly by the activation of these factors. The study investigated whether the ability of these glycosaminoglycans (GAGs) to reduce oxidative damage in fibroblast cultures involves NF-kB and caspases modulation. The treatment of fibroblasts with both HA and C4S limited the cell damage induced by FeSO(4) plus ascorbate. An interesting aspect of this treatment was that these GAGs significantly inhibited NF-kB DNA binding, as confirmed by the normalization of IkB alpha protein, and reduced caspase activation at both mRNA and protein level. A possible explanation for these results, since lipid peroxidation intermediates may induce NF-kB and caspase activation, is that HA and C4S indirectly blocked NF-kB DNA binding and apoptosis by inhibiting reactive oxygen species (ROS) production. These data suggest that, during oxidative stress, HA and C4S may reduce cell damage by inhibiting NF-kB and apoptosis activation as well as protecting cells from free radical attack. According to these finding the use of HA and C4S could be positive both as tool to clarify the exact mechanism of GAGs/ROS interaction, and also as drug therapy to reduce oxidative stress during inflammation.
氧化应激、炎症和细胞凋亡在细胞损伤的发生和发展过程中起着关键作用。此前有报道称，透明质酸（HA）和硫酸软骨素-4（C4S）能够保护人类皮肤成纤维细胞免受氧化应激的影响。这种抗氧化活性归因于过渡金属离子的螯合作用。与抑制性蛋白IkBα结合的核因子kB（NF-kB）是一种普遍存在的反应转录因子，参与炎症反应，并通过诱导细胞因子表达、趋化因子和细胞黏附分子发挥作用。半胱天冬酶是负责调节和执行凋亡性细胞死亡的特异性蛋白酶。自由基造成的损伤可能会因这些因子的激活而大幅放大。该研究调查了这些糖胺聚糖（GAGs）减少成纤维细胞培养物中氧化损伤的能力是否涉及NF-kB和半胱天冬酶调节。用HA和C4S处理成纤维细胞可限制由硫酸亚铁（FeSO₄）加抗坏血酸诱导的细胞损伤。这种处理的一个有趣方面是，这些GAGs显著抑制了NF-kB与DNA的结合，IkBα蛋白的正常化证实了这一点，并且在mRNA和蛋白质水平上降低了半胱天冬酶的激活。由于脂质过氧化中间体可能诱导NF-kB和半胱天冬酶激活，这些结果的一个可能解释是，HA和C4S通过抑制活性氧（ROS）的产生间接阻断了NF-kB与DNA的结合以及细胞凋亡。这些数据表明，在氧化应激期间，HA和C4S可能通过抑制NF-kB和细胞凋亡激活以及保护细胞免受自由基攻击来减少细胞损伤。根据这些发现，HA和C4S的使用可能在作为阐明GAGs/ROS相互作用的确切机制的工具方面是积极的，并且在作为减少炎症期间氧化应激的药物治疗方面也是积极的。
