Resveratrol Preconditioning Induces Genomic and Metabolic Adaptations within the Long-Term Window of Cerebral Ischemic Tolerance Leading to Bioenergetic Efficiency.
Resveratrol Preconditioning Induces Genomic and Metabolic Adaptations within the Long-Term Window of Cerebral Ischemic Tolerance Leading to Bioenergetic Efficiency.
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白藜芦醇预处理在脑缺血性耐受性的长期窗口内诱导基因组和代谢适应，从而导致生物能效率。
DOI：
10.1007/s12035-018-1380-6
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发表时间：
2019-06
影响因子：
5.1
通讯作者：
Perez-Pinzon MA
中科院分区：
文献类型：
--
作者：
Khoury N;Xu J;Stegelmann SD;Jackson CW;Koronowski KB;Dave KR;Young JI;Perez-Pinzon MA
迄今为止，临床上脑缺血后给予的神经保护剂未能促进显着恢复。因此，许多努力转向预防方法，如预处理作为替代治疗策略。我们的实验室已经揭示了一种新的长期窗口脑缺血耐受介导的白藜芦醇预处理（RPC），持续两周的小鼠。为了鉴定其介质，我们在RPC后两周对小鼠皮层进行了RNA-seq实验，结果显示了136个差异表达的基因。大多数基因（116/136）在RPC上下调，并聚集到涉及转录、突触信号传导和神经传递的生物学过程中。这些过程中的下调让人想起代谢抑制，冬眠动物通过下调能量消耗途径来适应严重的缺血状态。因此，为了评估代谢，我们使用神经元-星形胶质细胞共培养模型，并测量RPC后长期窗口的细胞呼吸率。值得注意的是，我们观察到RPC后糖酵解和线粒体呼吸效率的增加。我们还观察到参与丙酮酸摄取、TCA循环和氧化磷酸化的基因表达增加，所有这些都表明对能量产生途径的依赖增加。然后，我们揭示了这些核和线粒体适应，减少了对能量消耗途径的依赖，增加了对能量产生途径的依赖，通过乙酰辅酶A代谢在表观遗传学上偶联，并最终增加了基线ATP水平。这种ATP的增加将使大脑，一个高度代谢的器官，能够忍受由脑缺血引起的长时间的能量剥夺。
Neuroprotective agents administered post cerebral ischemia have failed so far in the clinic to promote significant recovery. Thus, numerous efforts were redirected towards prophylactic approaches such as preconditioning as an alternative therapeutic strategy. Our lab has revealed a novel long-term window of cerebral ischemic tolerance mediated by resveratrol preconditioning (RPC) that lasts for two weeks in mice. To identify its mediators, we conducted an RNA-seq experiment on the cortex of mice two weeks post RPC, which revealed 136 differentially expressed genes. The majority of genes (116/136) were downregulated upon RPC and clustered into biological processes involved in transcription, synaptic signaling, and neurotransmission. The downregulation in these processes was reminiscent of metabolic depression, an adaptation used by hibernating animals to survive severe ischemic states by downregulating energy-consuming pathways. Thus to assess metabolism, we used a neuronal-astrocytic co-culture model and measured the cellular respiration rate at the long-term window post RPC. Remarkably, we observed an increase in glycolysis and mitochondrial respiration efficiency upon RPC. We also observed an increase in the expression of genes involved in pyruvate uptake, TCA cycle, and oxidative phosphorylation, all of which indicated an increased reliance on energy-producing pathways. We then revealed that these nuclear and mitochondrial adaptations, which reduce the reliance on energy-consuming pathways and increase the reliance on energy-producing pathways, are epigenetically coupled through acetyl-CoA metabolism and ultimately increase baseline ATP levels. This increase in ATP would then allow the brain, a highly metabolic organ, to endure prolonged durations of energy deprivation caused by cerebral ischemia.
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影响因子：
3.3
作者：
Della-Morte, D.;Dave, K. R.;Defazio, R. A.;Bao, Y. C.;Raval, A. P.;Perez-Pinzon, M. A.
通讯作者：
Perez-Pinzon, M. A.
影响因子：
16.1
作者：
Busija, David W.;Gaspar, Tamas;Domoki, Ferenc;Katakam, Prasad V.;Bari, Ferenc
通讯作者：
Bari, Ferenc
影响因子：
29
作者：
Arroyo JD;Jourdain AA;Calvo SE;Ballarano CA;Doench JG;Root DE;Mootha VK
通讯作者：
Mootha VK
影响因子：
3.4
作者：
Huang, Tao;Gao, Dakuan;Fei, Zhou
通讯作者：
Fei, Zhou
影响因子：
3
作者：
Beher, Dirk;Wu, John;Wang, Minghan
通讯作者：
Wang, Minghan