Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways.
Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways.
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DOI：
10.2174/156720208785425666
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发表时间：
2008-08
影响因子：
2.1
通讯作者：
Maiese K
中科院分区：
文献类型：
--
作者：
Chong ZZ;Maiese K
专注于控制细胞代谢和细胞存活的途径之间交叉的治疗策略可能对治疗许多神经退行性和代谢性疾病（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）在哺乳动物SH-SY 5 Y神经元细胞在氧化应激过程中的作用。我们证明，在自由基暴露于一氧化氮发生器DN神经元的表达显着增加细胞的存活率和阻断细胞膜损伤。此外，DN神经元的表达阻止了凋亡晚期DNA降解和早期磷脂酰丝氨酸暴露，这可能有助于调节体内炎性细胞活化。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，因为应用渐进的烟酰胺浓度可以消除氧化应激期间DN表达的益处。通过一系列的研究表明，参与sirtuin激活和SIRT 1的途径对DN提供保护至关重要，至少部分如此。首先，白藜芦醇的应用在氧化应激期间单独或与DN的表达一起增加细胞存活到相似的程度，这表明DN可能依赖于SIRT 1激活来促进神经元保护。第二，神经元中SIRT 1或DN的过表达防止了在氧化应激期间表达这些蛋白质的神经元中的凋亡损伤，推进了DN和SIRT 1可能采用类似途径进行神经元保护的前提。第三，抑制sirtuin活性与sirtinol是有害的氧化应激过程中的神经元存活，并防止在DN或SIRT 1过表达的神经元保护，进一步支持SIRT 1活性可能是必要的DN神经保护在氧化应激。进一步研究哺乳动物细胞中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的途径。
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.
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影响因子：
3.8
作者：
Feng, YZ;Paul, IA;LeBlanc, MH
通讯作者：
LeBlanc, MH
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA
影响因子：
4.8
作者：
Chong, Zhao Zhong;Li, Faqi;Maiese, Kenneth
通讯作者：
Maiese, Kenneth
影响因子：
37.8
作者：
Chong, ZZ;Kang, JQ;Maiese, K
通讯作者：
Maiese, K
影响因子：
4.8
作者：
Bitterman, KJ;Anderson, RM;Sinclair, DA
通讯作者：
Sinclair, DA