Heat Shock Proteins Accelerate the Maturation of Brain Endothelial Cell Glucocorticoid Receptor in Focal Human Drug-Resistant Epilepsy.
Heat Shock Proteins Accelerate the Maturation of Brain Endothelial Cell Glucocorticoid Receptor in Focal Human Drug-Resistant Epilepsy.
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DOI：
10.1007/s12035-020-02043-9
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发表时间：
2020-11
影响因子：
5.1
通讯作者：
Ghosh C
中科院分区：
文献类型：
--
作者：
Hossain M;Williams S;Ferguson L;Bingaman W;Ghosh A;Najm IM;Ghosh C
癫痫的耐药性是临床治疗成功的主要挑战。糖皮质激素受体（GR）失调可以影响潜在的疾病发病机制。我们最近报道了在血脑屏障的局部药物生物转化被GR上调，GR控制药物代谢酶（例如，细胞色素P450，CYP）和外排药物转运蛋白（MDR 1）在人癫痫脑内皮细胞（EPI-EC）。在这里，我们建立了这种机制的影响上游GR和它的协会与热休克蛋白/辅分子伴侣（HSPs）在成熟过程中，差异影响人类癫痫（EPI）组织和脑内皮细胞。在EPI与NON-EPI脑区中发现GR、Hsp 90、Hsp 70、Hsp 40的过度表达。升高的神经血管GR表达和与Hsps的共定位在皮质发育不良的EPI区域是明显的，主要是在脑微毛细血管和神经元中。在EPI区域发现ATP酶活性的相应增加（*p < 0.05）。GR-Hsp 90/Hsp 70结合模式表明，更快的伴侣促进GR成熟，导致其在组织和EPI-EC中的过度激活，EPI-EC中的GR沉默减缓了这种GR-Hsp相互作用。在用GR调节剂/配体地塞米松、利福平或苯妥英治疗后，在EPI-EC中确定了显著加速的GR核转位。我们的研究结果表明，过表达的GR与Hsps共定位在EPI脑的神经血管系统中，通过Hsps增加GR成熟加速EPI GR机制，并且进一步地，EPI和NON-EPI GR-Hsp相互作用的这种变化随着癫痫患者癫痫发作的年龄而改变，共同影响癫痫脑内皮的病理生理学和药物调节。
Pharmacoresistance in epilepsy is a major challenge to successful clinical therapy. Glucocorticoid receptor (GR) dysregulation can affect the underlying disease pathogenesis. We recently reported that local drug biotransformation at the blood-brain barrier is upregulated by GR, which controls drug-metabolizing enzymes (e.g., cytochrome P450s, CYPs) and efflux drug transporters (MDR1) in human epileptic brain endothelial cells (EPI-ECs). Here we establish that this mechanism is influenced upstream by GR and its association with heat shock proteins/co-chaperones (Hsps) during maturation, which differentially affect human epileptic (EPI) tissue and brain endothelial cells. Overexpressed GR, Hsp90, Hsp70, Hsp40 were found in EPI vs. NON-EPI brain regions. Elevated neurovascular GR expression and co-localization with Hsps was evident in the EPI regions with cortical dysplasia, predominantly in the brain micro-capillaries and neurons. A corresponding increase in ATPase activity (*p < 0.05) was found in the EPI regions. The GR-Hsp90/Hsp70 binding patterns indicated a faster chaperone-promoted maturation of GR, leading to its overactivation in both the tissue and EPI-ECs derived from EPI/focal regions and GR silencing in EPI-ECs slowed such GR-Hsp interactions. Significantly accelerated GR nuclear translocation was determined in EPI-ECs following treatment with GR modulators/ligands dexamethasone, rifampicin or phenytoin. Our findings reveal that overexpressed GR co-localizes with Hsps in the neurovasculature of EPI brain, increased GR maturation by Hsps accelerates EPI GR machinery and further that this change in EPI and NON-EPI GR-Hsp interaction alters with the age of seizure-onset in epileptic patients, together affecting the pathophysiology and drug regulation in the epileptic brain endothelium.
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影响因子：
4.7
作者：
Furay, A. R.;Murphy, E. K.;Herman, J. P.
通讯作者：
Herman, J. P.
影响因子：
64.5
作者：
Kirschke E;Goswami D;Southworth D;Griffin PR;Agard DA
通讯作者：
Agard DA
影响因子：
5.6
作者：
Ghosh C;Gonzalez-Martinez J;Hossain M;Cucullo L;Fazio V;Janigro D;Marchi N
通讯作者：
Marchi N
CYP3A4 在人类癫痫脑中的细胞定位和功能意义。
影响因子：
5.6
作者：
Ghosh C;Marchi N;Desai NK;Puvenna V;Hossain M;Gonzalez-Martinez J;Alexopoulos AV;Janigro D
通讯作者：
Janigro D
影响因子：
5.3
作者：
Hawle, Patricija;Siepmann, Martin;Obermann, Wolfgang M. J.
通讯作者：
Obermann, Wolfgang M. J.