MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons.
MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons.
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DOI：
10.1016/j.neuroscience.2013.10.027
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发表时间：
2014-01-03
期刊：
影响因子：
3.3
通讯作者：
Ray SK
中科院分区：
文献类型：
--
作者：
Chakrabarti M;Banik NL;Ray SK
运动神经元保护是脊髓损伤(SCI)治疗的重要目标。我们检测了神经保护性microRNAs(miR-206、miR-17、miR-21、miR-7-1和miR-106a)是否能增强雌激素受体激动剂1，3，5-三(4-羟基苯基)-4-丙基-1H-吡唑(PPT，ERα激动剂)、Way 200070(ERβ激动剂)和雌激素(Est，ERα和ERβ激动剂)在预防钙离子载体(CI)诱导的VSC4.1运动神经元凋亡中的作用。我们确定200 nM CI诱导了70%的细胞死亡。50 nM的PPT、100 nM的PPT和150 nM的EST分别在基因和蛋白水平诱导ERα、ERβ及其受体的过度表达。内质网激动剂可显著上调脑梗塞后VSC4.1运动神经元miR-206、miR-17和miR-7-1的表达。用miR-206、miR-17或miR-7-1模拟增强方式或EST抑制CI诱导的VSC4.1运动神经元的凋亡。过表达miR-7-1最大程度地增加了Way和EST下调促凋亡Bax和上调抗凋亡Bax-2的疗效。MiRDB检索表明，miR-7-1可抑制L型钙通道蛋白α1C(CPα1C)的表达。MIR-7-1过表达和途径或EST处理下调CPα1C，上调p-Akt以触发细胞生存信号。同样的治疗策略增加了钙/钙调蛋白依赖性蛋白激酶IIβ(CaMKIIβ)和磷酸化cAMP反应元件结合蛋白(p-CREB)的表达，从而促进了Bcl2的转录。全细胞膜电位和线粒体膜电位的研究表明，miR-7-1高度增强了EST，以保留CI损伤的VSC4.1运动神经元的功能。综上所述，我们的数据表明miR-7-1最显著地增强了EST的功能神经保护作用，这一治疗策略可以在未来用于减少脊髓损伤运动神经元的凋亡。
Protection of motoneurons is an important goal in the treatment of spinal cord injury (SCI). We tested whether neuroprotective microRNAs (miRs) like miR-206, miR-17, miR-21, miR-7-1, and miR-106a could enhance efficacy of estrogen receptor (ER) agonists such as 1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT, ERα agonist), Way200070 (WAY, ERβ agonist), and estrogen (EST, ERα and ERβ agonist) in preventing apoptosis in the calcium ionophore (CI) insulted VSC4.1 motoneurons. We determined that 200 nM CI induced 70% cell death. Treatment with 50 nM PPT, 100 nM WAY, and 150 nM EST induced overexpression of ERα, ERβ, and both receptors, respectively, at mRNA and protein levels. Treatment with ER agonists significantly upregulated miR-206, miR-17, and miR-7-1 in the CI insulted VSC4.1 motoneurons. Transfection with miR-206, miR-17, or miR-7-1 mimic potentiated WAY or EST to inhibit apoptosis in the CI insulted VSC4.1 motoneurons. Overexpression of miR-7-1 maximally increased efficacy of WAY and EST for down regulation of pro-apoptotic Bax and upregulation of anti-apoptotic Bcl-2. A search using miRDB indicated that miR-7-1 could inhibit expression of L-type Ca2+ channel protein alpha 1C (CPα1C). miR-7-1 overexpression and WAY or EST treatment down regulated CPα1C but upregulated p-Akt to trigger cell survival signaling. The same therapeutic strategy increased expression of the Ca2+/calmodulin-dependent protein kinase II beta (CaMKIIβ) and the phosphorylated cAMP response element binding protein (p-CREB) so as to promote Bcl-2 transcription. Whole cell membrane potential and mitochondrial membrane potential studies indicated that miR-7-1 highly potentiated EST to preserve functionality in the CI insulted VSC4.1 motoneurons. In conclusion, our data indicated that miR-7-1 most significantly potentiated efficacy of EST for functional neuroprotection and this therapeutic strategy could be used in the future to attenuate apoptosis of motoneurons in SCI.
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影响因子：
4.2
作者：
Gerstner, Bettina;Lee, Joan;DeSilva, Tara M.;Jensen, Frances E.;Volpe, Joseph J.;Rosenberg, Paul A.
通讯作者：
Rosenberg, Paul A.
影响因子：
2.4
作者：
MARTINA, M;KILIC, G;CHERUBINI, E
通讯作者：
CHERUBINI, E
影响因子：
10.3
作者：
Das A;McDowell M;Pava MJ;Smith JA;Reiter RJ;Woodward JJ;Varma AK;Ray SK;Banik NL
通讯作者：
Banik NL
影响因子：
13.8
作者：
KNOWLES, RG;MONCADA, S
通讯作者：
MONCADA, S
影响因子：
3.6
作者：
Behl, C;Skutella, T;Holsboer, F
通讯作者：
Holsboer, F