More severe cases of the disease may involve neurological complications and encephalopathies characteristic of cerebral malaria Trampuz et al. Malaria prevention methods include mosquito eradication and use of medications able to target the parasite virulence Ramirez et al. The prevalence of malaria in endemic area presupposes the combination of several factors, including high human population density, high population density of Anopheles mosquitoes, and a high rate of transmission between humans and mosquitoes Martens and Hall, When any of these factors is reduced significantly, the parasite is expected to eventually disappear from the endemic regions as it occurred in North America, Europe and regions of the Middle East Shiff, There are a number of drugs available for malaria prevention in endemic areas.
Many of these drugs are also used in the treatment of the disease White, In cases where the parasite is still sensitive, chloroquine can be used. However, several species of Plasmodium are resistant to one or more drugs, so it is often necessary to resort to other drugs or combinations of drugs White, Among these are mefloquine, doxycycline or the combination of atovaquone and proguanil Gomes and Morrot, Ideally, drugs would be designed to act not only on prevention by acting directly on the parasite growth but also acting on the clinical symptoms by reducing disease severity.
In this regard, important considerations are given to targets of carbohydrate metabolism and glycoconjugate biosynthesis pathways. For instance, GPI anchors are abundantly expressed in the surface of Plasmodium spp. Previous work showed that glutamine analog DON reduced parasite growth in cultures of P. In the present study, we show that when administered to susceptible mouse models early in the onset of malaria blood-stage parasite infection, DON significantly decreased the levels of parasitemia thus reducing P. We demonstrated, for the first time, that the effect of DON in experimental malaria is due to inhibition of the aminotransferase activity of rate-limiting enzyme of the hexosamine biosynthetic pathway, GFPT.
Our findings demonstrated a requirement for GFPT activity for growth of erythrocytic forms of Plasmodium parasites.
In vitro culture of P. The inhibitory effect of DON was reverted upon exogenous addition of GlcN in infected erythrocytes, thus indicating a requirement for the UDP-GlcNAc downstream product of the hexosamine biosynthetic pathway in the parasite blood-stage cycle. In this line of evidence, coadministration of GlcN to DON treated mice reverts DON effect on mice survival, restoring high parasitemia and mortality of untreated mice. Moreover, our results indicate that the sensitivity of blood-stage forms of Plasmodium parasites to DON and GlcN, which reflects the importance of the parasite hexosamine biosynthetic pathway, is not restricted to dividing asexual forms, since our findings indicated that mice treated with DON presented significantly lower parasitemias of both asexual and gametocyte forms when compared with non-treated animals.
In this regard, it has been shown that in erythrocytes infected with P. Besides, studies have shown that gametocytes and gametes rely mainly on glycolysis but also display dependence on glutamine metabolism Srivastava et al.
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UDP-GlcNAc can be also obtained by the salvage pathway, perhaps due to the action of hexokinase that catalyzes the phosphorylation of glucosamine GlcN to GlcNP, which then enters the same route as the de novo pathway Sanz et al. Inhibition of P. GlcN specifically arrested the maturation of trophozoites, a stage at which the parasite synthesizes all of its GPI anchor pool, and had no effect during the parasite growth from rings to early trophozoites and from late trophozoites to schizonts and merozoites Naik et al.
Besides, addition of GlcNAc to P.
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Our findings demonstrating the blood-stage parasite dependence of the GFPT enzyme may indicate the use of the glutamine metabolism through the hexosamine biosynthetic pathway. The findings indicating that DON is able to act directly on the growth and differentiation of the blood forms of the Plasmodium parasites as well as attenuate the pathology of the host inflammatory responses emphasizing its importance in the design of new therapies against malaria. Drugs able to reduce the parasite blood-stage cycle, affecting the sexual stages of Plasmodium parasites should have an immediate impact on mosquito infection oocyst prevalence and intensity and the transmission intensity of vectors in the endemic areas of malaria Dyer and Day, In this regards, the therapeutic use of analogs of DON should provide a potential target for its use as transmission-blocking drugs against malaria.
All the authors have read and approved the final manuscript.
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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Belnoue, E. Bushkin, G.
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Trends Parasitol. Gomes, P. Therapeutic approaches blocking glycan synthesis as targeting strategy for malaria. Gordon, E. Targeting glutamine metabolism rescues mice from late-stage cerebral malaria. Howland, S. Activated brain endothelial cells cross-present malaria antigen.
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PLoS Pathog. Idro, R. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Jordan, K. Krishnegowda, G. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum : cell signaling receptors, glycosylphosphatidylinositol GPI structural requirement, and regulation of GPI activity. Lavazec, C. A nalysis of mutant Plasmodium berghei parasites lacking expression of multiple PbCCp genes. Macedo, C. Overlooked post-translational modifications of proteins in Plasmodium falciparum : N- and O-glycosylation — a review.
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Oswaldo Cruz , — Martens, P. Malaria on the move: human population movement and malaria transmission. Martins, Y. Naik, R. Glucosamine inhibits inositol acylation of the glycosylphosphatidylinositol anchors in intraerythrocytic Plasmodium falciparum. Plasmodium falciparum : the lethal effects of tunicamycin and mevastatin on the parasite are not mediated by the inhibition of N-linked oligosaccharide biosynthesis. Pinkus, L. Glutamine binding sites. Methods Enzymol. Plaimas, K. Computational and experimental analysis identified 6-diazooxonorleucine as a potential agent for treating infection by Plasmodium falciparum.
Polimeni, M. Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood-brain barrier integrity? Fluids Barriers CNS Ponnudurai, T. Synchronization of Plasmodium falciparum gametocytes using an automated suspension culture system. Parasitology 93 Pt 2 , — Queen, S. In vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism.
Agents Chemother. Ramirez, J.
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