In P falciparum cultured in CDM-C16alone, levels of transcripts

In P. falciparum cultured in CDM-C16alone, levels of transcripts of the putative mTOR inhibitor copper channel and the copper transporter were profoundly decreased, and those of the copper-transporting ATPase to a lesser extent (Figure  9) in KU55933 in vitro comparison with those in CDRPMI and GFSRPMI. The transcript level of the putative

COX17 was not significantly different among the media, similar to those of AP2-O and GCalpha, which served as controls for transcript levels of non-copper related proteins (Figure  9).These results may indicate that down-regulation of the putative copper channel, the copper transporter, and the copper-transporting ATPase affects copper pathways and trafficking, and eventually causes the perturbation EPZ-6438 order of copper homeostasis and growth arrest of the parasite. This implies also that the mono-unsaturated NEFA, C18:1, completely prevented the down-regulation of the gene expression observed with C16:0. Figure 9 Change in transcript levels. Putative copper channel (a), copper transporter (b), putative COX17 (c), copper-transporting ATPase (d), AP2-O (e), and GCalpha (f) of P. falciparum cultured for 28 h in CDM-C16alone, CDRPMI, and GFSRPMI were analyzed by qRT-PCR. Fold difference was calculated using ∆CT (2n: n = ∆CT); (*) indicates significant difference

versus CDRPMI and GFSRPMI and (**) versus CDRPMI. Discussion Copper ions are essential trace nutrients for all higher plants and animals at extremely low concentrations. They play an extensive role in living organisms, from microbes to plants and animals, by regulating the activities of several critical copper-binding proteins such as Histamine H2 receptor cytochrome c oxidase, Cu/Zn superoxide dismutase, dopamine β-hydroxylase, prion protein, tyrosinase, X-linked inhibitor of apoptosis protein,

lysyl oxidase, metallothionein, ceruloplasmin, and other proteins [12, 13]. Particularly in relation to microbes, copper ions are critical participants in the mitochondrial respiratory reaction and in energy generation, regulation of iron acquisition, oxygen transport, the cellular stress response, antioxidant defense, and several other important processes. The yeast Saccharomyces cerevisiae provides an accessible model for eukaryotic copper transport. Uptake of the Cu2+ ion by yeast cells is accompanied by reduction of Cu2+ to Cu1+ by a metalloreductase in the plasma membrane. Subsequent transport of the Cu1+ ion across the plasma membrane is carried out by a copper transporter (Ctr). Within the cell, Cu1+ ions are bound to the copper chaperones Atx1, Cox17, and CCS for specific delivery to the Golgi complex, mitochondria, and Cu/Zn superoxide dismutase, respectively [14]. Although there is no comprehensive understanding of copper metabolism and function in P. falciparum, the proteins involved in copper pathways and trafficking have been identified in Plasmodium spp.

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