小檗碱通过调节PPARγ启动子甲基化对缺血再灌注脑损伤的作用

doi:10.5246/jcps.2018.03.018

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (3): 170-182.DOI: 10.5246/jcps.2018.03.018

小檗碱通过调节PPARγ启动子甲基化对缺血再灌注脑损伤的作用

庞雨浓¹, 梁英文¹, 王玉刚¹, 雷帆², 袁梽漪¹, 邢东明¹, 李俊³, 杜力军^1*

1. 清华大学生命科学学院药物药理实验室, 北京 100084
2. 清华大学药学院, 北京 100084
3. 江西中医药大学创新药物与高效节能降耗制药设备国家重点实验室, 江西南昌 330006

收稿日期:2017-12-14 修回日期:2018-02-28 出版日期:2018-03-31 发布日期:2018-03-04
通讯作者: Tel.: +86-010-62796270, E-mail: lijundu@mail.tsinghua.edu.cn
基金资助:
The National Natural Science Foundation of China (81374006, 90713043 and 81073092).

Effect of berberine against cerebral ischemia and reperfusion involving in the methylation of PPARγ promoter

Yunong Pang¹, Yinwen Liang¹, Yugang Wang¹, Fan Lei², Zhiyi Yuan¹, Dongming Xing¹, Jun Li³, Lijun Du^1*

1. Laboratory of Molecular Pharmacology and Pharmaceutical Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
2. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
3. State Key Laboratory of Innovative Drugs and Efficient Energy-saving Pharmaceutical Equipment, Jiangxi University of Chinese Medicine, Nancang 330006, China

Received:2017-12-14 Revised:2018-02-28 Online:2018-03-31 Published:2018-03-04
Contact: Tel.: +86-010-62796270, E-mail: lijundu@mail.tsinghua.edu.cn
Supported by:
The National Natural Science Foundation of China (81374006, 90713043 and 81073092).

摘要/Abstract

摘要：

脑缺血为高发的脑血管疾病, 且常给病人带来不可逆性伤害。作为传统的抗炎药物, 小檗碱(BBR)近年来显示出对脑缺血的防治作用, 但是其作用机制尚未完全清楚。为此, 我们从体内体外对其作用机制进行了研究。我们发现PPARγ是小檗碱的作用靶点之一: 小檗碱在缺血再灌损伤中可以上调PPARγ表达。抑制PPARγ可以减弱小檗碱对缺血再灌损伤神经细胞的保护作用。此外, 我们还发现脑缺血损伤过程中BBR可以降低DAN甲基化, 下调甲基化转移酶DNMT1和DNMT3a的表达。同时可以降低PPARγ启动区甲基化水平。上述结果提示, PPARγ是BBR的主要作用靶点之一。在脑缺血再灌注损伤中, BBR促进PPARγ表达的作用机制与其抑制启动子区的甲基化水平有关。

关键词: 小檗碱, 脑缺血再灌注, PPARγ, DNA甲基化, 神经元

Abstract:

Cerebral ischemia has higher incidence and causes irreversible damage to people. As a traditional drug for anti-inflammation, berberine (BBR) has recently been reported to have protective effect against cerebral ischemia. However, the mechanism has not been explored thoroughly. By employing in vivo and in vitro models for cerebral ischemia and reperfusion, we studied the mechanism of BBR against the ischemia-reperfusion. We found that BBR regulated the expression of peroxisome proliferator-activated receptor (PPARγ) in a specific way upon ischemia-reperfusion injury. BBR enhanced the PPARγ expression during cerebral ischemia-reperfusion. By inhibiting PPARγ activity uisng GW9662, a PPARγ inhibitor, we confirmed that BBR protected the mouse brain against the ischemia in a PPARγ-dependent mechanism. In addition, we found that BBR reduced the overall global methylation, declined the expressions of DNMT1 (DNA methyltransferases 1) and DNMT3a (DNA methyltransferases 3a) in the ischemia-reperfusion and reduced the methylation of PPARγ promoter region. Therefore, our data suggested that PPARγ was one of major targets of BBR, and such BBR-induced PPARγ expression during cerebral ischemia and reperfusion might be correlated to the reduced methylation of PPARγ promoter.

Key words: Berberine, Cerebral ischemia-reperfusion, PPARγ, DNA methylation, Neuron

中图分类号:

R962

Supporting:

庞雨浓, 梁英文, 王玉刚, 雷帆, 袁梽漪, 邢东明, 李俊, 杜力军. 小檗碱通过调节PPARγ启动子甲基化对缺血再灌注脑损伤的作用[J]. 中国药学(英文版), 2018, 27(3): 170-182.

Yunong Pang, Yinwen Liang, Yugang Wang, Fan Lei, Zhiyi Yuan, Dongming Xing, Jun Li, Lijun Du. Effect of berberine against cerebral ischemia and reperfusion involving in the methylation of PPARγ promoter[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(3): 170-182.

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小檗碱通过调节PPARγ启动子甲基化对缺血再灌注脑损伤的作用

Effect of berberine against cerebral ischemia and reperfusion involving in the methylation of PPARγ promoter

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