The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage.
The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage.
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松果体microRNA-325在调节新生儿缺氧缺血性脑损伤后昼夜节律中的作用
DOI：
10.4103/1673-5374.308101
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发表时间：
2021-10
影响因子：
6.1
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Sha N;Wang HW;Sun B;Gong M;Miao P;Jiang XL;Yang XF;Li M;Xu LX;Feng CX;Yang YY;Zhang J;Zhu WJ;Gao YY;Feng X;Ding X
昼夜节律紊乱是新生儿缺氧缺血性脑损伤（HIBD）的一种常见但常被忽视的后果。然而，其潜在的分子机制在很大程度上仍然未知。我们先前表明，在HIBD大鼠模型中，松果体中microRNA-325（miR-325）的上调是抑制Aanat的原因，Aanat是参与褪黑激素合成和昼夜节律调节的关键酶。为了更好地理解miR-325影响新生儿HIBD昼夜节律的机制，我们比较了2019年从苏州大学附属第一医院（独墅湖分支）招募的HIBD新生儿临床样本和健康新生儿样本。我们发现，循环miR-325水平与HIBD新生儿的睡眠和昼夜节律紊乱的严重程度呈正相关。此外，荧光素酶报告基因测定显示LIM同源框3（LHX 3）是miR-325的新下游靶点。此外，在miR-325敲低小鼠中，转录因子LHX 3在松果体中表现出miR-325依赖的昼夜节律表达模式。我们通过双层结扎左侧颈总动脉并将幼鼠暴露于低氧环境中2小时，建立了新生小鼠HIBD模型。Lhx 3 mRNA表达在这些小鼠中显著下调，并且在经历相同条件的miR-325敲除小鼠中部分获救。最后，我们发现HIBD动物的昼夜节律相关行为的改善依赖于miR-325和LHX 3。总之，我们的研究结果表明，miR-325-LHX 3轴负责调节昼夜节律，并为新生儿HIBD患者昼夜节律紊乱的潜在治疗靶点的鉴定提供了新的见解。本临床试验于2015年7月20日获得苏州大学附属儿童医院伦理委员会批准（批件号：2015028）。动物实验于2016年1月15日获得中国苏州大学医学院动物管理与使用委员会批准（批准号XD-2016-1）。
Circadian rhythm disorder is a common, but often neglected, consequence of neonatal hypoxic-ischemic brain damage (HIBD). However, the underlying molecular mechanisms remain largely unknown. We previously showed that, in a rat model of HIBD, up-regulation of microRNA-325 (miR-325) in the pineal gland is responsible for the suppression of Aanat, a key enzyme involved in melatonin synthesis and circadian rhythm regulation. To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD, we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University (Dushuhu Branch) in 2019. We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD. Furthermore, a luciferase reporter gene assay revealed that LIM homeobox 3 (LHX3) is a novel downstream target of miR-325. In addition, in miR-325 knock-down mice, the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland. We established a neonatal mouse model of HIBD by performing double-layer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours. Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions. Finally, we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3. Taken together, our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD. The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University (approval No. 2015028) on July 20, 2015. Animal experiments were approved by Animal Care and Use Committee, School of Medicine, Soochow University, China (approval No. XD-2016-1) on January 15, 2016.
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DOI：
10.1152/ajpregu.90463.2008
发表时间：
2009-03-01
影响因子：
2.8
作者：
Li, Jia-Da;Burton, Katherine J.;Zhou, Qun-Yong
通讯作者：
Zhou, Qun-Yong
影响因子：
10.5
作者：
Kim, Tae-Don;Woo, Kyung-Chul;Kim, Kyong-Tai
通讯作者：
Kim, Kyong-Tai
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：
5.1
作者：
Takenouchi, Toshiki;Rubens, Elayna O.;Perlman, Jeffrey M.
通讯作者：
Perlman, Jeffrey M.
影响因子：
64.5
作者：
Thaler, JP;Lee, SK;Pfaff, SL
通讯作者：
Pfaff, SL