Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling
Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling
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DOI：
10.1152/ajpcell.00014.2010
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发表时间：
2010-10-01
影响因子：
5.5
通讯作者：
Ghoreschi, Kamran
中科院分区：
文献类型：
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作者：
Ghashghaeinia, Mehrdad;Bobbala, Diwakar;Ghoreschi, Kamran
[10] Ghashghaeinia M，Bobbala D，Wieder T，科卡S，Bruck J，Featurebacher B，Rocken M，Songier M，Lang F，Ghoreschi K.富马酸二甲酯靶向谷胱甘肽通过增强红细胞膜扰乱来预防实验性疟疾。美国生理学杂志细胞生理学299：C791-C804，2010年。首次发表于2010年7月14日; doi：10.1152/ajpcell.00014.2010。GSH水平和氧化应激之间的平衡对细胞存活至关重要。在疟原虫感染期间，红细胞的GSH水平显著降低。因此，我们研究了在体外和体内使用治疗确定剂量的富马酸二甲酯（DMF）靶向GSH对红细胞和疟原虫存活的影响。我们首先表明，暴露于DMF的未感染红细胞（RBC）发生典型的细胞凋亡或红细胞凋亡的变化，如细胞皱缩和细胞膜混乱与随后的磷脂酰丝氨酸（PS）暴露。DMF未诱导明显溶血。DMF引发的PS暴露由细胞内GSH耗竭介导，并被抗氧化剂N-乙酰-L-半胱氨酸逆转。DMF处理控制红细胞内DNA扩增和恶性疟原虫感染的红细胞的体外寄生虫血症。在体内，DMF处理对未感染小鼠的RBC计数或GSH水平无影响。与其对感染RBC的作用一致，DMF处理消除了寄生虫血症，并将感染伯氏疟原虫的小鼠的存活率从0%提高至60%。总之，DMF使红细胞对疟原虫感染对PS暴露的影响敏感，从而加速感染红细胞的清除。因此，DMF治疗有利地影响疟疾的临床病程。由于DMF靶向宿主细胞内的机制，因此不太可能产生病原体耐药性。
Ghashghaeinia M, Bobbala D, Wieder T, Koka S, Bruck J, Fehrenbacher B, Rocken M, Schaller M, Lang F, Ghoreschi K. Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling. Am J Physiol Cell Physiol 299: C791-C804, 2010. First published July 14, 2010; doi:10.1152/ajpcell.00014.2010.-The balance between GSH-levels and oxidative stress is critical for cell survival. The GSH-levels of erythrocytes are dramatically decreased during infection with Plasmodium spp. We therefore investigated the consequences of targeting GSH for erythrocyte and Plasmodium survival in vitro and in vivo using dimethylfumarate (DMF) at therapeutically established dosage. We first show that noninfected red blood cells (RBC) exposed to DMF undergo changes typical of apoptosis or eryptosis, such as cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine (PS) exposure. DMF did not induce appreciable hemolysis. DMF-triggered PS exposure was mediated by intracellular GSH depletion and reversed by the antioxidative N-acetyl-L-cysteine. DMF treatment controlled intraerythrocyte DNA amplification and in vitro parasitemia of Plasmodium falciparum-infected RBC. In vivo, DMF treatment had no effect on RBC count or GSH levels in noninfected mice. Consistent with its effects on infected RBC, DMF treatment abrogated parasitemia and enhanced the survival of mice infected with Plasmodium berghei from 0% to 60%. In conclusion, DMF sensitizes the erythrocytes to the effect of Plasmodium infection on PS exposure, thus accelerating the clearance of infected erythrocytes. Accordingly, DMF treatment favorably influences the clinical course of malaria. As DMF targets mechanisms within the host cell, it is not likely to generate resistance of the pathogen.