Promoting Neuronal Tolerance of Diabetic Stress: Modulating Molecular Chaperones.
Promoting Neuronal Tolerance of Diabetic Stress: Modulating Molecular Chaperones.
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DOI：
10.1016/bs.irn.2016.03.001
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发表时间：
2016
影响因子：
--
通讯作者：
Dobrowsky RT
中科院分区：
文献类型：
--
作者：
Emery SM;Dobrowsky RT
糖尿病周围神经病变（DPN）的病因涉及一系列相互关联的代谢和血管损伤，最终导致感觉神经元变性。在寻求有效管理DPN的过程中，小分子抑制剂靶向了被认为是“糖尿病特异性”的蛋白质和途径以及在许多疾病状态下活性改变的其他蛋白质和途径。这些努力尚未产生任何显著的疗法，部分原因是这些靶点/途径对DPN进展的生化贡献在个体之间不具有时间和/或生化一致性的复杂问题。在复杂的慢性神经退行性疾病如DPN中，人们越来越认识到，有效的疾病管理可能不一定需要靶向被认为有助于疾病进展的途径或蛋白质。或者，它可能被证明是足够有益的，以间接增强内源性细胞保护途径的活性，以帮助神经元耐受和从葡萄糖毒性应激中恢复。在追求这一范式转变，我们已经表明，调节分子伴侣，如热休克蛋白70（Hsp 70）的活性和表达可能提供翻译潜力的有效医疗管理的无感觉DPN。大量证据支持调节Hsp 70在改善炎症、氧化应激和葡萄糖敏感性方面具有有益作用。鉴于新出现的潜力，调节热休克蛋白70管理DPN，目前的审查讨论的努力，以表征这种蛋白质的细胞保护作用和可能出现的好处和局限性，在药物开发的努力，利用其细胞保护活性。
The etiology of diabetic peripheral neuropathy (DPN) involves an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have targeted proteins and pathways regarded as “diabetes specific” as well as others whose activity are altered in numerous disease states. These efforts have not yielded any significant therapies, due in part to the complicating issue that the biochemical contribution of these targets/pathways to the progression of DPN does not occur with temporal and/or biochemical uniformity between individuals. In a complex, chronic neurodegenerative disease such as DPN, it is increasingly appreciated that effective disease management may not necessarily require targeting a pathway or protein considered to contribute to disease progression. Alternatively, it may prove sufficiently beneficial to pharmacologically enhance the activity of endogenous cytoprotective pathways to aid neuronal tolerance to and recovery from glucotoxic stress. In pursuing this paradigm shift, we have shown that modulating the activity and expression of molecular chaperones such as heat shock protein 70 (Hsp70) may provide translational potential for the effective medical management of insensate DPN. Considerable evidence supports that modulating Hsp70 has beneficial effects in improving inflammation, oxidative stress and glucose sensitivity. Given the emerging potential of modulating Hsp70 to manage DPN, the current review discusses efforts to characterize the cytoprotective effects of this protein and the benefits and limitations that may arise in drug development efforts that exploit its cytoprotective activity.