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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently proposed a biochemical model of genetic resistance to falciparum malaria based on the role of oxidant stress (of parasitic origin) in inducing the irreversible oxidation of hemoglobin and its binding to the erythrocyte membrane (Destro-Bisol et al. 1996). To test the model, we analyzed the relationships between the polymorphisms at the hemoglobin beta chain (HBB) and red cell glutathione peroxidase (GPX1) loci in 18 populations that had been subjected to endemic malaria (Cameroon and Central African Republic). The erythrocytes of GPX1*2 heterozygotes should be more efficient in sheltering the cell membrane from irreversible oxidation and binding of hemoglobin caused by the oxidant stress exerted by Plasmodium falciparum. According to our model, the GPX1*2 allele has an epistatic effect on the HBB*A/*S genotype by lowering its protection against falciparum malaria. In turn, this should decrease the fitness of the HBB*A/*S-GPX1*2/*1 genotype. Our predictions were confirmed. In fact, we observed a clear trend toward a dissociation between the HBB*A/*S and GPX1*2/*1 genotypes in the overall data. To test alternative hypotheses, we also analyzed the genetic variation at 9 protein and 10 autosomal microsatellite loci at both the single- and the 2-locus level. We also discuss the possible relevance of an alternative biochemical pathway. The results further support the conclusions of our study because the dissociation between the GPX1*2/*1 and HBB*A/*S genotypes does not appear to be related either to a general decrease in heterozygosity or to an increased risk of sudden death in HBB*A/*S individuals.
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PMID:Testing a biochemical model of human genetic resistance to falciparum malaria by the analysis of variation at protein and microsatellite loci. 1038 Mar 69

To assess the extent of oxidative stress in erythrocytes of patients with acute Plasmodium falciparum malaria, erythrocyte thiobarbituric acid-reactive substance (ETBAR), and intracellular, membrane and extracellular antioxidants were estimated in 102 cases of P. falciparum malaria and 50 control subjects. The mean concentration of ETBAR was significantly higher (P < 0.001) and many of the antioxidants were significantly lower in patients than controls. Among the erythrocyte antioxidants, catalase, reduced glutathione (GSH) and tocopherol were significantly lower in the patients (P < 0.05, 0.001, 0.001, respectively). Erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were not reduced to a statistically significant level. Similarly, the plasma antioxidants ascorbate and albumin were significantly lower (P < 0.001) but not urate. ETBAR correlated inversely with erythrocyte GSH and tocopherol (P < 0.001), and plasma ascorbate and albumin (P < 0.001) but not with the erythrocyte enzymic antioxidants. However, on multiple regression analysis only tocopherol correlated strongly with ETBAR, followed by GSH and plasma ascorbate. ETBAR also correlated well with haemolytic indices such as haemoglobin, plasma unconjugated bilirubin and haptoglobin concentrations (P < 0.001, for all). On follow-up after 2 weeks, ETBAR and different antioxidants reached near control levels. These observations indicate an enhanced oxidative stress on erythrocytes in acute falciparum malaria that may contribute substantially to haemolysis and anaemia.
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PMID:Evidence for erythrocyte lipid peroxidation in acute falciparum malaria. 1049 92

A putative glutathione peroxidase gene (Swiss-Prot accession number Z 68200) of Plasmodium falciparum, the causative agent of tropical malaria, was expressed in Escherichia coli and purified to electrophoretic homogeneity. Like phospholipid hydroperoxide glutathione peroxidase of mammals, it proved to be monomeric. It was active with H(2)O(2) and organic hydroperoxides but, unlike phospholipid hydroperoxide glutathione peroxidase, not with phosphatidylcholine hydroperoxide. With glutathione peroxidases it shares the ping-pong mechanism with infinite V(max) and K(m) when analyzed with GSH as substrate. As a homologue with selenocysteine replaced by cysteine, its reactions with hydroperoxides and GSH are 3 orders of magnitude slower than those of the selenoperoxidases. Unexpectedly, the plasmodial enzyme proved to react faster with thioredoxins than with GSH and most efficiently with thioredoxin of P. falciparum (Swiss-Prot accession number 202664). It is therefore reclassified as thioredoxin peroxidase. With plasmodial thioredoxin, the enzyme also displays ping-pong kinetics, yet with a limiting K(m) of 10 microm and a k(1)' of 0.55 s(-)1. The apparent k(1)' for oxidation with cumene, t-butyl, and hydrogen peroxides are 2.0 x 10(4) m(-1) s(-1), 3.3 x 10(3) m(-1) s(-1), and 2.5 x 10(3) m (-1) s(-1), respectively. k(2)' for reduction by autologous thioredoxin is 5.4 x 10(4) m(-1) s(-1) (21.2 m(-1) s(-1) for GSH). The newly discovered enzymatic function of the plasmodial gene product suggests a reconsideration of its presumed role in parasitic antioxidant defense.
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PMID:The putative glutathione peroxidase gene of Plasmodium falciparum codes for a thioredoxin peroxidase. 1108 48

Oxidative stress and antioxidative capacity of platelets and the relationship with thrombocytopenia were determined in patients with vivax malaria and compared with those of healthy subjects. Whole blood thrombocyte count, platelet superoxide dismutase and glutathione peroxidase activities of patients with vivax malaria were lower and platelet lipid peroxidation levels were higher in patients than those of healthy subjects. There was an important negative correlation between whole blood thrombocyte count and platelet lipid peroxidation level. The antioxidative mechanisms of thrombocytes were insufficient in malaria patients and caused oxidative stress. The oxidative damage of thrombocytes might be important in the ethiopathogenesis of thrombocytopenia occurring in malaria.
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PMID:Oxidative stress of platelets and thrombocytopenia in patients with vivax malaria. 1144 Jul 37

Many lines of evidence reveal that artemisinin, an antimalarial containing endoperoxide, generates free radicals to kill malaria parasites. The present study re-evaluated the antioxidants of P. falciparum-infected erythrocytes in the absence and presence of 0.25, 0.5 and 1.0 ng/ml of dihydroartemisinin (DHA), the active metabolite of artemisinin. The ratio of reduced to oxidized glutathione (GSH/GSSG) and activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were determined. The data indicated that malaria infection induced oxidative stress in erythrocytes that resulted in a significant lower GSH in parasitized cells compared to the non-parasitized. DHA showed no effect on the antioxidant levels of non-parasitized erythrocytes treated under similar conditions as P. falciparum-infected erythrocytes. However, significantly lower GSH as well as catalase and GPx activities in parasitized cells were seen at drug concentrations of 0.5 and 1.0 ng/ml (p < 0.05). GSH is the most sensitive indicator of oxidative stress in malaria-infected erythrocytes both in the absence and in the presence of DHA. Parasite GPx might play a more important role than catalase in the elimination of peroxide. Parasite viabilities in the presence of DHA were analyzed simultaneously and were affected to a greater extent than the antioxidant levels. The present observation showed that although DHA killed malaria parasites by generating free radicals from the endoperoxide bridge causing the reduction of antioxidants, but the depletion of parasite antioxidants is not a prerequisite for the parasite death.
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PMID:Effect of dihydroartemisinin on the antioxidant capacity of P. falciparum-infected erythrocytes. 1511 82

Glutaredoxin-like proteins form a new subgroup of glutaredoxins with a serine replacing the second cysteine in the CxxC-motif of the active site. Yeast Grx5 is the only glutaredoxin-like protein studied biochemically so far. We identified and cloned three genes encoding glutaredoxin-like proteins from the malaria parasite Plasmodium falciparum (Pf Glp1, Pf Glp2, and Pf Glp3) containing a conserved cysteine in the CGFS-, CKFS-, and CKYS-motif, respectively. Here, we describe biochemical properties of Pf Glp1 and Pf Glp2. Cys 99, the only cysteine residue in Pf Glp1, has a pK(a) value as low as 5.5 and is able to mediate covalent homodimerization. Monomeric and dimeric Pf Glp1 react with GSSG and GSH, respectively. Pf Glp2 is monomeric and both of its cysteine residues can be glutathionylated. Molecular models reveal a thioredoxin fold for the putative C-terminal domain of Pf Glp1, Pf Glp2, and Pf Glp3, as well as conserved residues presumably required for glutathione binding. However, Pf Glp1 and Pf Glp2 neither possess activity in a classical glutaredoxin assay nor display activity as glutathione peroxidase or glutathione S-transferase. Mutation of Ser 102 in the CGFS-motif of Pf Glp1 to cysteine did not generate glutaredoxin activity either. We conclude that, despite their ability to react with glutathione, glutaredoxin-like proteins are a mechanistically and functionally heterogeneous group with only little similarities to canonical glutaredoxins.
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PMID:Plasmodium falciparum glutaredoxin-like proteins. 1584 45

Phagocyte-derived reactive oxygen species have been implicated in the clearance of malaria infections. We investigated the progression of five different strains of murine malaria in gp91(phox-/-) mice, which lack a functional NADPH oxidase and thus the ability to produce phagocyte-derived reactive oxygen species. We found that the absence of functional NADPH oxidase in the gene knockout mice had no effect on the parasitemia or total parasite burden in mice infected with either resolving (Plasmodium yoelii and Plasmodium chabaudi K562) or fatal (Plasmodium berghei ANKA, Plasmodium berghei K173 and Plasmodium vinckei vinckei) strains of malaria. This lack of effect was apparent in both primary and secondary infections with P. yoelii and P. chabaudi. There was also no difference in the presentation of clinical or pathological signs between the gp91(phox-/-) or wild-type strains of mice infected with malaria. Progression of P. berghei ANKA and P. berghei K173 infections was unchanged in glutathione peroxidase-1 gene knockout mice compared to their wild-type counterparts. The rates of parasitemia progression in gp91(phox-/-) mice and wild-type mice were not significantly different when they were treated with l-N(G)-methylarginine, an inhibitor of nitric oxide synthase. These results suggest that phagocyte-derived reactive oxygen species are not crucial for the clearance of malaria parasites, at least in murine models.
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PMID:Phagocyte-derived reactive oxygen species do not influence the progression of murine blood-stage malaria infections. 1604 Oct 8

The intraerythrocytic protozoan parasite Plasmodium falciparum is responsible for more than 500 million clinical cases of tropical malaria annually. Although exposed to high fluxes of reactive oxygen species, Plasmodium lacks the antioxidant enzymes catalase and glutathione peroxidase. Thus, the parasite depends on the antioxidant capacity of its host cell and its own peroxidases. These are fuelled by the thioredoxin system and are considered to represent the major defense line against peroxides. Five peroxidases that act in different compartments have been described in P. falciparum. They include two typical 2-Cys peroxiredoxins (Prx), a 1-Cys Prx, the so-called antioxidant protein (AOP), which is a further Prx acting on the basis of a 1-Cys mechanism, and a glutathione peroxidase-like thioredoxin peroxidase. Because of their central function in redox regulation and antioxidant defense, some of these proteins might represent highly interesting targets for structure-based drug development. In this article we summarize the present knowledge on the thioredoxin and peroxiredoxin metabolism in malaria parasitized red blood cells. We furthermore report novel data on the biochemical and kinetic characterization of different thioredoxins, of AOP, and of the classic 1-Cys peroxiredoxin of P. falciparum.
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PMID:Thioredoxin networks in the malarial parasite Plasmodium falciparum. 1691 Jul 70

Malaria is one of the most debilitating and life threatening diseases in tropical regions of the world. Over 500 million clinical cases occur, and 2-3 million people die of the disease each year. Because Plasmodium lacks genuine glutathione peroxidase and catalase, the two major antioxidant enzymes in the eukaryotic cell, malaria parasites are likely to utilize members of the peroxiredoxin (Prx) family as the principal enzymes to reduce peroxides, which increase in the parasite cell due to metabolism and parasitism during parasite development. In addition to its function of protecting macromolecules from H(2)O(2), Prx has also been reported to regulate H(2)O(2) as second messenger in transmission of redox signals, which mediate cell proliferation, differentiation, and apoptosis. In the malaria parasite, several lines of experimental data have suggested that the parasite uses Prxs as multifunctional molecules to adapt themselves to asexual and sexual development. In this review, we summarize the accumulated knowledge on the Prx family with respect to their functions in mammalian cells and their possible function(s) in malaria parasites.
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PMID:Peroxiredoxins in malaria parasites: parasitologic aspects. 1789 Jan 40

Cellular redox metabolism is considered to be involved in the pathophysiology of diseases caused by protozoal parasites such as Toxoplasma, Trypanosoma, Leishmania, and Plasmodia. Redox reactions furthermore are thought to play a major role in the action of and the resistance to some clinically used antiparasitic drugs. Interestingly, in malarial parasites, the antioxidant enzymes catalase and glutathione peroxidase are absent which indicates a crucial role of the thioredoxin system in redox control. Besides a glutathione peroxidase-like thioredoxin peroxidase and a glutathione S-transferase with slight peroxidase activity, Plasmodium falciparum (the causative agent of tropical malaria) possesses four classical peroxiredoxins: Two peroxiredoxins of the typical 2-Cys Prx class, one 1-Cys peroxiredoxin with homology to the atypical 2-Cys Prx class, and a peroxiredoxin of the 1-Cys Prx class have been identified and partially characterized In our article we give an introduction to redox-based drug development strategies against protozoal parasites and summarize the present knowledge on peroxiredoxin systems in Plasmodium.
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PMID:Peroxiredoxin systems of protozoal parasites. 1808 96


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