Development of molecular pharmacological strategies against oxidant stress-induced steroid resistance

1.暴露于氧化应激的细胞中类固醇敏感性降低：使用绿色荧光蛋白标记的受体和报告基因测定，证实了氧化应激导致的糖皮质激素依赖性受体核输入和转录激活受损。在另一项研究中，发现雌激素依赖性转录激活的雌激素受体-a也受到氧化应激的损害。因此，氧化应激损害类固醇依赖的基因转录。热休克蛋白（HSPs）在类固醇敏感性中的作用：在细胞氧化应激模型中，引入HSPs成员HSC 70，恢复类固醇敏感性。在内毒素诱导的血管通透性变化的体内模型中，热应激诱导的HSP 70阻止了随后的小鼠皮肤中内毒素诱导的微血管通透性变化。这些结果表明，通过分子药理学手段诱导HSPs的表达，可以保护氧化应激诱导的细胞类固醇抵抗.病理生理条件下自由基产生的机制和抗氧化药物的应用：作为进行性肾脏疾病细胞损伤的机制，一些尿毒症毒素，有机酸，新发现的氧化应激诱导肾近端小管损伤后，由细胞重吸收的载体药物摄取。一些抗氧化药物被发现具有清除一氧化氮的能力。这种作用可能会改变药物在一氧化氮和氧源性自由基共存的特定病理生理条件下的药理作用。

1. Reduced steroid sensitivity in cells exposed to oxidant stress : Using green fluorescent protein-tagged receptor and reporter gene assays, impaired glucocorticoid-dependent nuclear import of receptor and transcriptional activation by oxidant stress was demonstrated. In a separate study, estrogen-dependent transcriptional activation by estrogen receptor-a was found to be also impaired by oxidant stress. Thus, oxidant stress impairs steroid-dependent gene transcription.2. Role of heat shock proteins (HSPs) in steroid sensitivity : In the model of cellular oxidant stress, an introduction of a member of HSPs, HSC70, restored steroid sensitivity. In vivo model of endotoxin-induced vascular permeability change, induction of HSP70 by heat stress prevented subsequent endotoxin-induced microvascular permeability change in mouse skin. These results indicated molecular pharmacological manipulation to induce HSPs may protect cellular steroid resistance induced by oxidant stress.3. Mechanisms of free radical production in pathophysiological conditions and applications of antioxidant drugs : As a mechanism of cellular injury in progressive renal disease, some uremic toxins, organic acids, were newly found to induce renal proximal tubular injury by oxidant stress after reabsorbed by the cells vial transporter-medicated uptake. Some antioxidant drugs were found to have nitric oxide scavenging ability. Such effect may modify the pharmacological effect of the drug in specific paphophysiological conditions where nitric oxide and oxygen-derived free radicals co-exist.