Evidence against resveratrol as a viable therapy for the rescue of defective ΔF508 CFTR.
Evidence against resveratrol as a viable therapy for the rescue of defective ΔF508 CFTR.
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DOI：
10.1016/j.bbagen.2015.08.020
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Bradbury NA
中科院分区：
文献类型：
--
作者：
Jai Y;Shah K;Bridges RJ;Bradbury NA
据报道，白藜芦醇是一种天然酚类化合物，可以挽救表达系统和原代上皮细胞中的突变ΔF508 CFTR。虽然这意味着对CF患者有治疗益处，但研究中使用的白藜芦醇浓度远远超过血浆中可达到的浓度。我们使用生理上可达到的白藜芦醇浓度，评估了白藜芦醇作为相关原代气道细胞CFTR校正剂的功效。表达wt或ΔF508 CFTR的细胞暴露于慢性或急性白藜芦醇中。监测CFTR mRNA和蛋白的表达。白藜芦醇对原代ΔF508人气道细胞的影响采用改良Ussing腔等效电流分析。与之前发表的异源表达系统的数据一致，高剂量白藜芦醇增加了CFTR的表达；然而，生理上相关的浓度没有影响。与异种表达系统相比，白藜芦醇不能增加原代气道细胞中突变体CFTR通道的活性。在某些细胞类型中，高浓度的白藜芦醇可以增加CFTR mRNA和蛋白，而表明钠转运的amyorde敏感电流升高，在CF气道细胞中也不受白藜芦醇影响。此外，急性白藜芦醇暴露可以刺激CFTR介导的氯化物分泌，可能是通过增加细胞cAMP水平。生理上可达到的水平的白藜芦醇对原代ΔF508气道细胞没有任何益处，无论是就阿米罗胺敏感电流还是CFTR电流而言。
Resveratrol, a natural phenolic compound, has been reported to rescue mutant ΔF508 CFTR in expression systems and primary epithelial cells. Although this implies a therapeutic benefit to patients with CF, investigations were performed using resveratrol concentrations greatly in excess of those achievable in plasma. We evaluated the efficacy of resveratrol as a CFTR corrector in relevant primary airway cells, using physiologically achievable resveratrol concentrations. Cells expressing wt or ΔF508 CFTR were exposed to chronic or acute resveratrol. CFTR mRNA and protein expression were monitored. The effects of resveratrol on primary ΔF508 human airway cells were evaluated by equivalent current analysis using modified Ussing chambers. Consistent with previously published data in heterologous expression systems, high doses of resveratrol increased CFTR expression; however physiologically relevant concentrations were without effect. In contrast to heterologous expression systems, resveratrol was unable to increase mutant CFTR channel activity in primary airway cells. Elevated amiloride-sensitive currents, indicative of sodium transport and characteristically elevated in CF airway cells, were also unaffected by resveratrol High concentrations of resveratrol can increase CFTR mRNA and protein in some cell types. In addition, acute resveratrol exposure can stimulate CFTR mediated chloride secretion, probably by increasing cellular cAMP levels. Resveratrol at physiologically achievable levels yielded no benefit in primary ΔF508 airway cells, either in terms of amiloride-sensitive currents of CFTR currents.