Chong Zhao Zhong, Maiese Kenneth
Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine; Detroit, Michigan 48201, USA.
Curr Neurovasc Res. 2008 Aug;5(3):159-70. doi: 10.2174/156720208785425666.
Focus upon therapeutic strategies that intersect between pathways that govern cellular metabolism and cellular survival may offer the greatest impact for the treatment of a number of neurodegenerative and metabolic disorders, such as diabetes mellitus. In this regard, we investigated the role of a Drosophila nicotinamidase (DN) in mammalian SH-SY5Y neuronal cells during oxidative stress. We demonstrate that during free radical exposure to nitric oxide generators DN neuronal expression significantly increased cell survival and blocked cellular membrane injury. Furthermore, DN neuronal expression prevented both apoptotic late DNA degradation and early phosphatidylserine exposure that may serve to modulate inflammatory cell activation in vivo. Nicotinamidase activity that limited nicotinamide cellular concentrations appeared to be necessary for DN neuroprotection, since application of progressive nicotinamide concentrations could abrogate the benefits of DN expression during oxidative stress. Pathways that involved sirtuin activation and SIRT1 were suggested to be vital, at least in part, for DN to confer protection through a series of studies. First, application of resveratrol increased cell survival during oxidative stress either alone or in conjunction with the expression of DN to a similar degree, suggesting that DN may rely upon SIRT1 activation to foster neuronal protection. Second, the overexpression of either SIRT1 or DN in neurons prevented apoptotic injury specifically in neurons expressing these proteins during oxidative stress, advancing the premise that DN and SIRT1 may employ similar pathways for neuronal protection. Third, inhibition of sirtuin activity with sirtinol was detrimental to neuronal survival during oxidative stress and prevented neuronal protection during overexpression of DN or SIRT1, further supporting that SIRT1 activity may be necessary for DN neuroprotection during oxidative stress. Implementation of further work to elucidate the cellular mechanisms that govern nicotinamidase activity in mammalian cells may offer novel avenues for the treatment of disorders tied to oxidative stress and cellular metabolic dysfunction.
关注调控细胞代谢和细胞存活的信号通路之间交叉的治疗策略，可能对治疗多种神经退行性疾病和代谢紊乱（如糖尿病）产生最大影响。在这方面，我们研究了果蝇烟酰胺酶（DN）在氧化应激期间对哺乳动物SH-SY5Y神经元细胞的作用。我们证明，在自由基暴露于一氧化氮发生器期间，DN在神经元中的表达显著提高了细胞存活率并阻止了细胞膜损伤。此外，DN在神经元中的表达可防止凋亡晚期DNA降解和早期磷脂酰丝氨酸暴露，这可能有助于在体内调节炎症细胞激活。限制烟酰胺细胞浓度的烟酰胺酶活性似乎是DN神经保护所必需的，因为在氧化应激期间应用逐步增加的烟酰胺浓度可以消除DN表达的益处。通过一系列研究表明，涉及sirtuin激活和SIRT1的信号通路至少部分对于DN赋予保护作用至关重要。首先，白藜芦醇单独应用或与DN表达联合应用在氧化应激期间均能以相似程度提高细胞存活率，这表明DN可能依赖SIRT1激活来促进神经元保护。其次，在神经元中过表达SIRT1或DN可特异性防止在氧化应激期间表达这些蛋白质的神经元发生凋亡损伤，这进一步支持了DN和SIRT1可能采用相似的信号通路进行神经元保护的前提。第三，用sirtinol抑制sirtuin活性对氧化应激期间的神经元存活有害，并在DN或SIRT1过表达期间阻止神经元保护，进一步支持SIRT1活性可能是氧化应激期间DN神经保护所必需的。开展进一步工作以阐明哺乳动物细胞中调控烟酰胺酶活性的细胞机制，可能为治疗与氧化应激和细胞代谢功能障碍相关的疾病提供新途径。
