Elevation of miR-146a Inhibits BTG2/BAX Expression to Ameliorate Postoperative Cognitive Dysfunction Following Probiotics (VSL#3) Treatment
Elevation of miR-146a Inhibits BTG2/BAX Expression to Ameliorate Postoperative Cognitive Dysfunction Following Probiotics (VSL#3) Treatment
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DOI：
10.1007/s12035-021-02330-z
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发表时间：
2021-03-16
影响因子：
5.1
通讯作者：
Xie, Min
中科院分区：
文献类型：
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作者：
Mao, Lei;Zeng, Qingcui;Xie, Min
据报告，肠道微生物组调节术后认知功能障碍（POCD），给予益生菌（VSLI #3）可有效缓解POCD。在本研究中，我们旨在确定VSLI #3在POCD中的潜在机制。在成年雄性C57 BL/6小鼠中构建POCD小鼠模型，然后用VSLI #3处理。VSL#3对POCD和由此产生的神经元凋亡发挥保护作用。发现POCD小鼠海马组织中miR-146 a的表达下调，而VSL#3可恢复其表达。进行了功能丧失和获得方法以确定microRNA（miR）-146 a、B细胞易位基因2（BTG 2）和Bcl-2相关X蛋白（Bax）在术后对认知功能和神经元凋亡的影响中的作用。测定脑组织中活性氧（ROS）、丙二醛（MDA）和超氧化物歧化酶（SOD）的水平，以确定脑组织中的氧化应激。双荧光素酶报告基因检测证实miR-146 a可靶向BTG 2并负调控其表达。BTG 2基因敲低可抑制神经元凋亡，缩短潜伏期，延长小鼠在目标象限的时间，并通过下调Bax表达减少氧化应激。最后，VSL#3处理上调miR-146 a的表达以阻断BTG 2/Bax轴，从而抑制神经元凋亡并降低POCD小鼠的氧化应激。总之，该研究表明，miR-146 a介导的BTG 2/Bax抑制有助于益生菌治疗对POCD的保护作用。
It has been reported that the gut microbiome modulates postoperative cognitive dysfunction (POCD), and that administration of probiotics (VSL#3) may effectively relieve POCD. In this study, we aimed to identify the underlying mechanism of VSL#3 in POCD. A mouse model of POCD was constructed in adult male C57BL/6 mice, which were then treated with VSL#3. VSL#3 exerted a protective role against POCD and resultant neuronal apoptosis. The expression of miR-146a was found to be downregulated in hippocampal tissues of POCD mice, while VSL#3 could restore its expression. Loss- and gain-function approaches were conducted to determine the roles of microRNA (miR)-146a, B-cell translocation gene 2 (BTG2), and Bcl-2-associated X protein (Bax) in post-operative effects on cognitive function and neuronal apoptosis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured to determine oxidative stress in brain tissue. The dual-luciferase reporter gene assay identified that miR-146a could target BTG2 and negatively regulate its expression. BTG2 knockdown suppressed neuronal apoptosis and contributed to shortened time of latency, prolonged time of mice spent in the target quadrant, and reduced oxidative stress through downregulating Bax expression. Finally, VSL#3 treatment upregulated the expression of miR-146a to block BTG2/Bax axis and consequently inhibited neuronal apoptosis and reduced oxidative stress in POCD mice. Taken together, the study suggested that miR-146a-mediated suppression of BTG2/Bax contributed to the protective role of probiotics treatment against POCD.