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  • American Physiological Society  (2)
  • 1
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 299, No. 4 ( 2010-10), p. C791-C804
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2010
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    American Physiological Society ; 2011
    In:  Physiological Genomics Vol. 43, No. 22 ( 2011-11), p. 1255-1262
    In: Physiological Genomics, American Physiological Society, Vol. 43, No. 22 ( 2011-11), p. 1255-1262
    Abstract: Maternal lipoproteins have been studied extensively in human pregnancies, but little is known about the role of fetal lipoproteins. The vascularized human placenta interfaces between the mother and fetus to transfer nutrients for sustaining pregnancy. Unlike that of adults, fetal high-density lipoprotein (HDL), which is in contact with placental vessels, is characterized by a high proportion of apolipoprotein E (apoE). We hypothesize this unique composition of fetal HDL affects key functions of the growing fetal tissues. The aim was to identify genes regulated by apoE-HDL by incubating human placental endothelial cells (HPEC) with either fetal HDL or apoE-rich reconstituted HDL particles (apoE-rHDL). HPEC were exposed to 15 μg/ml fetal HDL, 15 μg/ml apoE-rHDL, or medium for 16 h, respectively. Microarray analysis determined genes regulated by fetal HDL and apoE. Characterization of HDL particles revealed a different hydrodynamic radius for apoE-rHDL (13.70 nm) compared with fetal HDL (18.11 nm). Stepwise gene clustering after microarray experiments identified 79 differentially expressed genes ( P 〈 0.05) when cells were exposed to HDL compared with controls. Among them 16 genes were downregulated, whereas five genes were upregulated by twofold, respectively. When HPEC were incubated with apoE-rHDL 18-fold more genes (1,417, 12% of transcripts) were regulated ( P 〈 0.05) in contrast to HDL. Thereof, 172 genes were downregulated and 376 genes upregulated (twofold). In the common subset of 38 genes regulated by both HDL particles, genes involved in cholesterol biosynthesis and cell protection prevailed. Strikingly, results suggest that HDL has the capability of regulating metallothioneins, which may have an effect on oxidative stress in HPEC.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 2031330-5
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