TP53-induced glycolysis and apoptosis regulator alleviates hypoxia/ischemia-induced microglial pyroptosis and ischemic brain damage.
TP53-induced glycolysis and apoptosis regulator alleviates hypoxia/ischemia-induced microglial pyroptosis and ischemic brain damage.
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TP53 诱导的糖酵解和凋亡调节剂可减轻缺氧/缺血引起的小胶质细胞焦亡和缺血性脑损伤。
DOI：
10.4103/1673-5374.300453
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发表时间：
2021-06
影响因子：
6.1
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Tan LL;Jiang XL;Xu LX;Li G;Feng CX;Ding X;Sun B;Qin ZH;Zhang ZB;Feng X;Li M
我们前期的研究表明TP 53诱导的糖酵解和凋亡调节因子（TIGAR）对脑缺血再灌注后神经元有保护作用。然而，TIGAR在新生儿缺氧缺血性脑损伤（HIBD）中的作用仍然未知。本研究采用永久性阻断大鼠左颈总动脉，缺氧2小时的方法建立7日龄SD大鼠HIBD模型。在HIBD诱导前6天，将含有TIGAR或gasdermin D的短发夹RNA（LV-sh_TIGAR或LV-sh_GSDMD）的慢病毒载体注射到左侧脑室和纹状体中。通过2小时氧/糖剥夺随后24小时复氧建立体外HIBD的高度侵袭性增殖永生化（HAPI）小胶质细胞模型。在体外HIBD诱导前三天，用LV-sh_TIGAR或LV-sh_GSDMD转染HAPI小胶质细胞。我们的研究结果表明，TIGAR表达增加新生大鼠大脑皮层HIBD后和HAPI小胶质细胞后氧/葡萄糖剥夺/复氧。慢病毒介导的TIGAR敲低在大鼠体内和体外明显加重缺氧/缺血后的焦亡和脑损伤。应用外源性烟酰胺腺嘌呤二核苷酸磷酸（NADPH）增加NADPH水平和谷胱甘肽/氧化型谷胱甘肽的比例，并降低活性氧水平在HAPI小胶质细胞后氧/葡萄糖剥夺/复氧。此外，外源性NADPH在体内和体外阻断了TIGAR敲低在新生儿HIBD中的作用。这些结果表明，TIGAR可以抑制小胶质细胞的焦凋亡，并在新生儿HIBD中发挥保护作用。本研究于2017年获得苏州大学动物伦理委员会批准（批准号：2017 LW 003）。
Our previous studies have demonstrated that TP53-induced glycolysis and apoptosis regulator (TIGAR) can protect neurons after cerebral ischemia/reperfusion. However, the role of TIGAR in neonatal hypoxic-ischemic brain damage (HIBD) remains unknown. In the present study, 7-day-old Sprague-Dawley rat models of HIBD were established by permanent occlusion of the left common carotid artery followed by 2-hour hypoxia. At 6 days before induction of HIBD, a lentiviral vector containing short hairpin RNA of either TIGAR or gasdermin D (LV-sh_TIGAR or LV-sh_GSDMD) was injected into the left lateral ventricle and striatum. Highly aggressively proliferating immortalized (HAPI) microglial cell models of in vitro HIBD were established by 2-hour oxygen/glucose deprivation followed by 24-hour reoxygenation. Three days before in vitro HIBD induction, HAPI microglial cells were transfected with LV-sh_TIGAR or LV-sh_GSDMD. Our results showed that TIGAR expression was increased in the neonatal rat cortex after HIBD and in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation. Lentivirus-mediated TIGAR knockdown in rats markedly worsened pyroptosis and brain damage after hypoxia/ischemia in vivo and in vitro. Application of exogenous nicotinamide adenine dinucleotide phosphate (NADPH) increased the NADPH level and the glutathione/oxidized glutathione ratio and decreased reactive oxygen species levels in HAPI microglial cells after oxygen/glucose deprivation/reoxygenation. Additionally, exogenous NADPH blocked the effects of TIGAR knockdown in neonatal HIBD in vivo and in vitro. These findings show that TIGAR can inhibit microglial pyroptosis and play a protective role in neonatal HIBD. The study was approved by the Animal Ethics Committee of Soochow University of China (approval No. 2017LW003) in 2017.
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影响因子：
16.6
作者：
Ito, Minako;Shichita, Takashi;Okada, Masahiro;Komine, Ritsuko;Noguchi, Yoshiko;Yoshimura, Akihiko;Morita, Rimpei
通讯作者：
Morita, Rimpei
DOI：
10.1073/pnas.1722041115
发表时间：
2018-06-26
影响因子：
11.1
作者：
McKenzie, Brienne A.;Mamik, Manmeet K.;Power, Christopher
通讯作者：
Power, Christopher
影响因子：
6.1
作者：
Jiang, Li-Jun;Xu, Zhen-Xing;Feng, Xing
通讯作者：
Feng, Xing
影响因子：
9.3
作者：
Liu W;Chen Y;Meng J;Wu M;Bi F;Chang C;Li H;Zhang L
通讯作者：
Zhang L
影响因子：
9.3
作者：
Iizumi T;Takahashi S;Mashima K;Minami K;Izawa Y;Abe T;Hishiki T;Suematsu M;Kajimura M;Suzuki N
通讯作者：
Suzuki N