UMLS:C0024530 - FACTA Search

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

The glutathione status of Plasmodium vinckei parasitized erythrocytes of mice was determined in correlation to the intraerythrocytic stage of maturation of the parasite. The different stages of blood schizogony were separated by discontinuous Dextran-density-centrifugation. The changes of protein content, glutathione concentration (reduced/oxidized and bound/free glutathione) and in the specific activities of the following enzymes: gamma-glutamyl-cysteine-synthetase (GC-synthetase), glutathione-reductase (GR), glucose-6-phosphate dehydrogenase (Gl-DH), glutathione-peroxydase (G-POD) and catalase were investigated in dependence of the intraerythrocytic stage of development. The following changes of the investigated metabolic parameters were observed during the schizogony: - the protein content decreased to about one half, - the glutathione concentration increased about 10-fold, while the relations reduced/oxidized and free/bound glutathione remained constant, - Gl-DH activity appeared and increased steeply, - the specific activities of GC-synthetase and of GR increased more than 2-fold, while G-POD remained almost constant, - and the activities of G-6-PDH and catalase showed a significant, strong decrease to about 25% of the original values. It is tried to relate the observed changes to the growing parasite or to the host cell. The significance of the results for the metabolism of malaria parasites and for a possible adaptation to the mosquito by a GSH mediated protection of the malaria parasite against an enzymatic defence-reaction of the mosquito, is discussed.
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PMID:[Glutathionestatus of Plasmodium vinckei parasitized erythrocytes in correlation to the intraerythrocytic development of the parasite (author's transl)]. 121 29

The interaction of certain metabolites of the 8-aminoquinoline antimalarial primaquine with both normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes and with haemoglobin preparations was studied in an attempt to elucidate the mechanisms of methaemoglobin formation and haemolytic anaemia associated with the use of primaquine. Studies using erythrocytes revealed that oxidation of haemoglobin and reduced glutathione (GSH) was due to the metabolites rather than the parent drug. Incubation of free haemoglobin with 5-hydroxylated metabolites of primaquine also led to oxidation of oxyhaemoglobin and GSH. Oxidation of GSH also occurred in the absence of oxyhaemoglobin. The results suggest a dual mechanism for these oxidative effects, involving autoxidation of the 5-hydroxy-8-aminoquinolines and their coupled oxidation with oxyhaemoglobin. The initial products of these processes would be drug metabolite free radicals, superoxide radical anions, hydrogen peroxide and methaemoglobin. Further free radical reactions would lead to oxidation of GSH, more haemoglobin and probably other cellular constituents. NADPH had no effect on the oxidative effects of the primaquine metabolites in these experiments. In the G6PD-deficient erythrocyte, the oxidation of haemoglobin and GSH leads to Heinz body formation and eventually to haemolysis, the mechanisms of which are as yet unclear. The possible role of oxygen free radicals in the mode of action of 8-aminoquinolines against the malaria parasite is also briefly discussed.
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PMID:Studies on the mechanisms of oxidation in the erythrocyte by metabolites of primaquine. 283 99

BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] and its less toxic derivative HeCNU [1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea] are clinically-used antitumour drugs. In erythrocytes BCNU is a highly specific inhibitor of the enzyme glutathione reductase [H. Frischer and T. Ahmad, J. Lab. clin. Med. 89, 1080 (1977)]. When treating erythrocytes in vitro, 50% enzyme inhibition was obtained with 1 microM BCNU or 3 microM HeCNU within 2 hr. The two drugs were used for preparing red cell populations with various levels of glutathione reductase activity; complete inhibition (greater than or equal to 98%) was only achieved when the medium contained glucose as a source of reducing equivalents. The erythrocytes were then tested in drug-free media as host cells for the malaria parasite Plasmodium falciparum. In the range of 0-300 mU/ml cells, there was a correlation between glutathione reductase activity and parasite growth; erythrocytes with an activity of less than 20 mU/ml did not serve as host cells for P. falciparum at all although these erythrocytes were viable. When the culture medium was supplemented with 20 mM glutathione (GSH), parasite growth was normal irrespective of the glutathione reductase level in the erythrocytes. This is consistent with the finding that poisoning glutathione reductase led to a 10-fold decrease of the cytosolic GSH level. Our results corroborate the concept that intraerythrocytic inhibition of glutathione reductase mimicks the biochemistry of drug-sensitive glucose-6-phosphate dehydrogenase deficiency (favism), an inherited condition which confers protection from malaria.
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PMID:Glutathione reductase-deficient erythrocytes as host cells of malarial parasites. 327 13

The existence of haemolytic anaemia in malaria indicates disturbances in red cell stability due to physical as well as metabolic stress attributable to the malarial parasite. As erythrocytic reduced glutathione (GSH) is involved in maintaining the integrity of red cells, the status of erythrocytic GSH was studied in 40 patients infected with Plasmodium vivax before and after therapy with chloroquine. 40 normal subjects, age- and sex-matched, were studied as controls. The level of erythrocytic GSH of malaria patients during infection and before therapy was significantly lower in comparison with controls (P less than 0.0005). Instability of GSH was recorded in 17 of 40 patients, while none of the controls showed such a defect. There was a progressive decrease in GSH level and stability of the host red cells with increasing parasitaemia. Normal values were obtained following therapy and cure of malaria indicating that the changes in GSH level and stability are induced by P. vivax. Alterations in the GSH metabolism may represent one of the factors contributing to the severity of anaemia in malaria due to P. vivax infection.
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PMID:Reduction in erythrocytic GSH level and stability in Plasmodium vivax malaria. 332 36

Riboflavin deficiency suppresses parasitic growth in malaria. Three possible mechanisms have been proposed previously to explain the survival advantage of riboflavin-deficient hosts: a) enhanced fragility of red blood cells (RBC), b) decreased formation of reticulocytes and/or c) decreased concentrations of reduced glutathione (GSH) and ATP. The validity of these proposed mechanisms was tested by investigating whether riboflavin deficiency alters the hemolytic response to three stimuli: hydrogen peroxide (H2O2), a hypotonic medium or ferriprotoporphyrin IX (FP). Reticulocyte counts and concentrations of ATP and GSH were also determined. The percentage of hemolysis induced by H2O2 or FP was significantly less in riboflavin-deficient than in control animals. By contrast, hemolytic response to a hypotonic medium was enhanced during riboflavin deficiency. Despite diminished activity of glutathione reductase and normal glutathione peroxidase activity during riboflavin deficiency, the erythrocyte concentration of GSH was increased over that in control animals. Concentrations of ATP and hemoglobin in erythrocytes as well as the reticulocyte count were unaltered during riboflavin deficiency. Thus, diminished malarial parasitemia in riboflavin-deficient animals occurs despite greater resistance of RBC to either H2O2- or FP-induced hemolysis, and in the presence of a normal reticulocyte count and erythrocytes ATP concentration. Results of this study raise the possibility that Plasmodium parasites have greater requirements for flavin coenzymes, GSH or ATP than those of host erythrocytes, which may explain the apparent protection of the riboflavin-deficient host from malaria.
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PMID:Riboflavin deficiency and glutathione metabolism in rats: possible mechanisms underlying altered responses to hemolytic stimuli. 341 22

The need to investigate further the phenomenon of sulfone-induced haemolysis is becoming greater as the use of sulfones may increase, particularly for malaria therapy in areas where Plasmodium falciparum is found to be resistant to chloroquine. The authors report on studies of the haemolytic effects of diaphenylsulfone (DDS) administered orally, in doses ranging from 25 mg to 300 mg daily for 21 days, to normal healthy men and to healthy Negro men with deficiency of glucose-6-phosphate dehydrogenase (G-6-PD). The latter proved more susceptible to diaphenylsulfone-induced haemolysis than did normal men. There was a direct relationship between the dose of diaphenylsulfone and the extent of haemolysis in both groups of men studied. Comparison of the haemolytic effects of diaphenylsulfone with those of the antimalarial drug primaquine revealed that, on a dose for weight basis, diaphenylsulfone is more haemolytic than primaquine in normal persons and less so in G-6-PD-deficient persons. A marked decrease in the content of reduced glutathione (GSH) in red cells, comparable to the changes in levels of erythrocytic GSH known to occur during primaquine-induced haemolysis, occurred just before and early during the acute haemolytic episode that resulted from administration of diaphenylsulfone to G-6-PD-deficient subjects; in contrast, levels of erythrocytic GSH increased early during the course of diaphenylsulfone-induced haemolysis in normal men.
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PMID:The haemolytic effects of diaphenylsulfone (DDS) in normal subjects and in those with glucose-6-phosphate-dehydrogenase deficiency. 529 1

Thiol status and growth in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes. Experimental Parasitology 57, 239-247. The relationship of the thiol status of the human erythrocyte to the in vitro growth of Plasmodium falciparum in normal and in glucose-6-phosphate dehydrogenase (G6PD)-deficient red cells was investigated. Pretreatment with the thiol-oxidizing agent diamide led to inhibition of growth of P. falciparum in G6PD-deficient cells, but did not affect parasite growth in normal cells. Diamide-treated normal erythrocytes quickly regenerated intracellular glutathione (GSH) and regained normal membrane thiol status, whereas G6PD-deficient cells did not. Parasite invasion and intracellular development were affected under conditions in which intracellular GSH was oxidized to glutathione disulfide and membrane intrachain and interchain disulfides were produced. An altered thiol status in the G6PD-deficient erythrocytes could underlie the selective advantage of G6PD deficiency in the presence of malaria.
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PMID:Plasmodium falciparum: thiol status and growth in normal and glucose-6-phosphate dehydrogenase deficient human erythrocytes. 637 52

The role of oxidative stress resulting from production of reactive oxygen species and/or from suppression of the cellular antioxidant capacity in parasitic infections is shortly reviewed. The experimental part of the paper deals with the glutathione (GSH)--glutathione reductase (GR) system, a cornerstone of intracellular antioxidant defence mechanisms. For studying this system in parasitic diseases such as malaria new or modified methods are required. Total glutathione comprising GSH and glutathione disulphide (GSSG) in blood samples was assayed as follows. One volume of blood (> or = 10 microliters) is mixed with two volumes of 5% sulphosalicylic acid; after centrifugation (5 min, 10000 g), 10 microliters of supernatant is taken for spectrophotometric analysis using the 5,5'-dithiobis(2-nitrobenzoate) (DTNB)-glutathione recycling assay. When compared with the original method, the procedure reported here is more sensitive, less time-consuming, avoids unfavourable pH-values and leads to a sample which when frozen is stable for months. In a pilot study, the method was applied to 14 patients suffering from malaria caused by Plasmodium falciparum. The concentrations of erythrocyte glutathione were significantly decreased in the patients (1.42 +/- 0.47 mM, mean +/- SD) when compared to age- and sex-matched controls (2.11 +/- 0.45 mM, P < 0.01). The findings are contrasted with P. falciparum cultures in vitro where glutathione levels are known to be elevated. Based on the characteristics of GR a concept of determining the redox state of single cells is introduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Redox processes in malaria and other parasitic diseases. Determination of intracellular glutathione. 786 69

Malaria-infected red blood cells are under a substantial oxidative stress. Glutathione metabolism may play an important role in antioxidant defense in these cells, as it does in other eukaryotes. In this work, we have determined the levels of reduced and oxidized glutathione (GSH and GSSG, respectively) and their distributions in the parasite, and in the host-cell compartments of human erythrocytes infected with the malaria parasite Plasmodium falciparum. In intact trophozoite-infected erythrocytes, [GSH] is low and [GSSG] is high, compared with the levels in normal erythrocytes. Normal erythrocytes and the parasite compartment display high GSH/GSSG ratios of 321.6 and 284.5, respectively, indicating adequate antioxidant defense. This ratio drops to 26.7 in the host-cell compartment, indicating a forceful oxidant challenge, the low ratios resulting from an increase in GSSG and a decline in GSH concentrations. On the other hand, the concentrations of GSH and GSSG in the parasite compartment remain physiological and comparable to their concentrations in normal red blood cells. This results from de novo glutathione synthesis and its recycling, assisted by the intensive activity of the hexose monophosphate shunt in the parasite. A large efflux of GSSG from infected cells has been observed, its rate being similar from free parasites and from intact infected cells. This result suggests that de novo synthesis by the parasite is the dominating process in infected cells. GSSG efflux from the intact infected cell is more than 60-fold higher than the rate observed in normal erythrocytes, and is mediated by permeability pathways that the parasite induces in the erythrocyte's membrane. The main route for GSSG efflux through the cytoplasmic membrane of the parasite seems to be due to a specific transport system and occurs against a concentration gradient. Gamma-glutamylcysteine [Glu(-Cys)] and GSH can penetrate through the pathways from the extracellular space into the host cytosol, but not into that of the parasite. This implies that the parasite membrane is impermeable to these peptides, and that the host cannot supply GSH to the parasite as suggested previously. Exogenous Glu(-Cys) is not converted into GSH in the host cell, arguing that GSH synthetase may not be functional. Compartment analysis of Mg2+ in infected erythrocytes revealed that the host compartment exhibits a low concentration of Mg2+ (0.5 mM) in comparison with the parasite compartment (4 mM) and the normal erythrocytes (1.5-3 mM). The drop in [Mg2+] results in cessation of Glu(-Cys) synthesis, and hence of GSH synthesis in the host-cell compartment. The decrease in [Mg2+] can affect other Mg2+-ATP-dependent functions, such as Na+ and Ca2+ active efflux. The present investigation confirms that the host-cell compartment is oxidatively distressed, whereas the parasite is efficiently equipped with anti-oxidant means that protect the parasite from the oxidative injury. The parasite has a huge capacity for de novo synthesis of GSH and for the reduction of GSSG. Part of the GSSG that is actively extruded from the parasite is reduced to GSH in the host cell whose own GSH synthesis is crippled.
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PMID:The malaria parasite supplies glutathione to its host cell--investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodium falciparum. 946 Dec 89

Riboflavin deficiency interferes with the growth and multiplication of malaria parasites as well as the host response to malaria. The objective of the present work was to determine the effects of riboflavin deficiency on erythrocyte glutathione peroxidase (EC 1.11.1.9; GPx) and superoxide dismutase (EC 1.15.1.1; SOD) in rats infected with Plasmodium berghei malaria. Riboflavin in its co-enzyme form, FAD, is required by glutathione reductase (EC 1.6.4.1) to regenerate GSH and GSH is an important cellular antioxidant both in its own right and also as a substrate for the enzyme GPx. Weanling rats were deprived of riboflavin for 8 weeks before intraperitoneal injection of 1 x 10(6) P. berghei parasites. Control animals were weight-matched to the respective riboflavin-deficient group. At 10 d post-infection, parasite counts were higher in the weight-matched control group than the riboflavin-deficient group (P = 0.004). GPx activity was higher in erythrocytes of rats parasitized with P. berghei than comparable non-infected rats regardless of riboflavin status (P < 0.05). As mature erythrocytes do not synthesize new protein, the higher GPx activities were probably due to the presence of the parasite protein. In erythrocytes from riboflavin-deficient rats, GPx activity tended to be lower than in those rats fed on diets adequate in riboflavin (weight-matched controls) whether parasitized or not, but the difference was not significant. Neither riboflavin deficiency nor malaria had any effect on erythrocyte SOD activity. It was concluded that riboflavin deficiency has no marked effect on erythrocyte GPx or SOD activity in the rat.
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PMID:Glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities in riboflavin-deficient rats infected with Plasmodium berghei malaria. 957 9

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