Pleiotropic role of PPARγ in intracerebral hemorrhage: an intricate system involving Nrf2, RXR, and NF-κB.
Pleiotropic role of PPARγ in intracerebral hemorrhage: an intricate system involving Nrf2, RXR, and NF-κB.
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DOI：
10.1111/cns.12350
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发表时间：
2015-04
影响因子：
5.5
通讯作者：
Aronowski J
中科院分区：
文献类型：
--
作者：
Zhao XR;Gonzales N;Aronowski J
脑出血（ICH）是一种涉及脑实质内血肿形成的卒中亚型，在西方社会占所有卒中的8-15%，在亚洲人群中占20-30%，并且一年死亡率大于50%。高死亡率和严重的发病率使ICH成为一个主要的公共卫生问题。只有少数循证靶向治疗用于ICH管理，干预措施主要集中在支持性治疗和合并症预防。即使在发作后存活的患者中，外渗的血液（包括血浆成分）和随后的血肿内溶血产物也会在脑实质内引发一系列不良事件，导致继发性脑损伤、水肿和严重的神经功能缺损或死亡。虽然人类的血肿在几个月内逐渐消退，但神经功能的完全恢复可能是缓慢的，而且往往是不完全的，使幸存者具有毁灭性的神经功能缺损。在过去的几年中，过氧化物酶体增殖物激活受体γ（PPARγ）转录因子及其激动剂不仅在调节葡萄糖和脂质代谢（这是其在2型糖尿病中的治疗作用的基础）中被认为是重要的参与者，而且最近被认为是抗炎、抗氧化调节和吞噬细胞介导的清除过程的工具多效性调节剂。PPARγ激动剂已成为脑卒中潜在的治疗靶点。使用PPARγ作为治疗靶点似乎对ICH的致病成分具有特别强的相容性。除了其直接的基因组效应，PPARγ可能与转录因子NF-κB相互作用，这可能是PPARγ抗炎作用的许多方面的基础。此外，PPARγ似乎调节Nrf 2的表达，Nrf 2是另一种转录因子，也是解毒和抗氧化调节的主要调节因子。最后，PPARγ和类维生素A X受体RXR的协同共刺激可能在PPARγ功能的治疗调节中发挥额外的作用。本文就过氧化物酶体增殖物激活受体γ在脑出血发病机制中的主要作用进行综述。
Intracerebral hemorrhage (ICH) is a subtype of stroke involving formation of hematoma within brain parenchyma, which accounts for 8–15% of all strokes in Western societies and 20–30% among Asian populations, and has a one-year mortality rate greater than 50%. The high mortality and severe morbidity make ICH a major public health problem. Only a few evidence-based targeted treatments are used for ICH management, and interventions focus primarily on supportive care and comorbidity prevention. Even in patients who survive the ictus, extravasated blood (including plasma components) and subsequent intra-hematoma hemolytic products trigger a series of adverse events within the brain parenchyma, leading to secondary brain injury, edema and severe neurological deficits or death. Although the hematoma in humans gradually resolves within months, full restoration of neurologic function can be slow and often incomplete, leaving survivors with devastating neurological deficits. During past years, peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor and its agonists received recognition as important players in regulating not only glucose and lipid metabolism (which underlies its therapeutic effect in type 2 diabetes mellitus), and more recently, as an instrumental pleiotropic regulator of anti-inflammation, anti-oxidative regulation, and phagocyte-mediated cleanup processes. PPARγ agonists have emerged as potential therapeutic target for stroke. The use of PPARγ as a therapeutic target appears to have particularly strong compatibility toward pathogenic components of ICH. In addition to its direct genomic effect, PPARγ may interact with transcription factor, NF-κB, which may underlie many aspects of the anti-inflammatory effect of PPARγ. Furthermore, PPARγ appears to regulate expression of Nrf2, another transcription factor and master regulator of detoxification and anti-oxidative regulation. Finally, the synergistic co-stimulation of PPARγ and retinoid X receptor, RXR, may play an additional role in the therapeutic modulation of PPARγ function. In this article, we outline the main components of the role of PPARγ in ICH pathogenesis.
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DOI：
10.1159/000346599
发表时间：
2013
期刊：
Cerebrovascular diseases (Basel, Switzerland)
影响因子：
--
作者：
Brouwers HB;Greenberg SM
通讯作者：
Greenberg SM
影响因子：
2.5
作者：
Dash PK;Zhao J;Orsi SA;Zhang M;Moore AN
通讯作者：
Moore AN
影响因子：
4.1
作者：
Belur, Praveen K.;Chang, Jason J.;Mack, William J.
通讯作者：
Mack, William J.
DOI：
10.1164/rccm.200907-1047oc
发表时间：
2010-07-01
影响因子：
24.7
作者：
Cho, Hye-Youn;Gladwell, Wesley;Kleeberger, Steven R.
通讯作者：
Kleeberger, Steven R.
影响因子：
4.1
作者：
Abdu, Emun;Hanley, Daniel F.;Newell, David W.
通讯作者：
Newell, David W.