Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intraerythrocytic malaria parasites produce vast amounts of lactic acid through glycolysis. While the egress of lactate is very rapid, the mode of extrusion of H+ is not known. The possible involvement of a Na+/H+ antiport in the extrusion of protons across the plasma membrane of Plasmodium falciparum has been investigated by using the fluorescent pH probe 6-carboxyfluorescein. The resting cytosolic pH was 7.27 +/- 0.1 in ring stage parasites and 7.31 +/- 0.12 in trophozoites. Spontaneous acidification of parasite cytosol was observed in Na(+)-free medium and realkalinization occurred upon addition of Na+ to the medium in a concentration-dependent manner, with no apparent saturation. The rate of H(+)-efflux at the ring stage was higher than that at the trophozoite stage due to the larger surface/volume ratio of the young parasite stage. Na(+)-dependent H(+)-efflux was: 1) inhibited by the Na+/H+ inhibitors amiloride and 5-(N-ethyl-N-isopropyl) amiloride (EIPA), though at relatively high concentrations; 2) augmented with rising pH6 (pHi = 6.2, [Na+]o = 30 mM); and 3) decreased with increasing pHi (pHo = 7.4; [Na+]o = 30 mM). The pHi and the pHo dependencies of H(+)-efflux were almost identical at all parasite stages. Only at pHi > 7.6 efflux was totally obliterated. The target of this inhibitory effect is probably other than the antiport. Results indicate that H(+)-egress is mediated by a Na+/H+ antiport which is regulated by host and parasite pH and by the host cytosol sodium concentration. The proton transport capacity of the antiport can easily cope with all the protons of lactic acid produced by parasite's glycolysis.
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PMID:Kinetic characterization of Na+/H+ antiport of Plasmodium falciparum membrane. 838 9

O-Glycosylation is the major form of protein glycosylation in human erythrocytes infected with the asexual intraerythrocytic stage of the malaria parasite. Plasmodium falciparum. This study compares aspects of O-glycosylation in P. falciparum-infected and uninfected erythrocytes. Non-labeled and metabolically glucosamine-labeled O-glycans were obtained from the protein fraction of infected or uninfected erythrocytes by beta elimination. Additional label was introduced by reduction with sodium borohydride, or by the attachment of radioactive Gal to peripheral GlcNAc using galactosyltransferase. 2-4-times more labeled O-glycans were obtained from infected erythrocytes compared to the same number of uninfected ones, consistent with additional biosynthesis by the parasite. Our analysis of these O-glycans showed no significant qualitative divergence between the O-glycans of the infected and those of the uninfected red cell. According to preliminary alditol analyses, the O-glycans of P. falciparum-infected red cells do not contain GalNAc at their reducing terminus. Moreover, GalNAc was not synthesized by P. falciparum from either Glc, Gal, GlcN or GalN. At least one O-glycan found in P. falciparum-infected erythrocytes contains GlcNAc at its reducing terminus. Gel-filtration results had suggested the presence of O-GlcNAc on proteins in the infected erythrocyte. Probing with a synthetic pentapeptide, we could show that P. falciparum expresses its own O-GlcNAc transferase during intraerythrocytic development. Using this peptide, the enzyme was characterized to some degree. The localization and function of O-GlcNAc in P. falciparum remains to be elucidated.
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PMID:Studies on O-glycans of Plasmodium-falciparum-infected human erythrocytes. Evidence for O-GlcNAc and O-GlcNAc-transferase in malaria parasites. 840 96

The speed and stage specificity of antimalarial drug action on the metabolic activities of cultured Plasmodium falciparum were studied for chloroquine (CQ), quinine (QN), artemisinin (AR), and sodium artelinate (SA). CQ had the most rapid onset of action on [3H]hypoxanthine and [3H]isoleucine uptake, reaching 50% of its maximum effect in 1.8 hr compared with 3.5-7.4 hr for the other three drugs. In contrast there was a lag time of 1-4 hr before AR and SA had a measurable inhibitory effect, although after this delay antimalarial action was very rapid. Parasite glycolysis was relatively drug resistant; the inhibition of lactate production was < 60% of that for [3H]hypoxanthine and [3H]isoleucine uptake. The susceptibility of P. falciparum changed markedly as the parasite matured. Maximum drug effects occurred at the late ring and early trophozoite stage, which corresponds to the time at which the most rapid increases in synthetic and glycolytic activities occur. Mature schizonts and young rings were relatively unaffected by the antimalarial drugs. Young rings were particularly resistant to QN. Schizonts multiplied successfully in the presence of relatively high concentrations of all four drugs. The two artemisinin compounds had the broadest time window of action and may be particularly suitable for the treatment of severe malaria.
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PMID:Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. 846 1

Passive transfer of monoclonal antibodies (MAbs) against malaria circumsporozoite (CS) proteins protects animals against malaria. Active immunization with synthetic or recombinant peptides induces a level of polyclonal antibodies to sporozoites comparable to those found after passive immunization but does not provide comparable protection. In the Plasmodium yoelii system, synthetic or recombinant peptide-induced antibodies have never been shown to protect. The current studies were designed to determine whether immunogen structure (native protein versus synthetic peptide) or immunoglobulin G (IgG) subclass of antibodies was responsible for the absolute differences between protective, passively transferred MAbs and nonprotective, actively induced polyclonal antibodies. In this study we produced two MAbs, QGP-S1 (IgG1) and QGP-S2 (IgG2b), by immunization with a synthetic peptide based on the P. yoelii CS major repeat, (QGPGAP)4, conjugated to keyhole limpet hemocyanin. These MAbs were compared tp NYS1 (IgG3), an anti-CS protein MAb previously produced by immunization with irradiated P. yoelii sporozoites, which recognizes (QGP GAP)2. QGP-S1 and QGP-S2 passively transferred protection. However, when compared with NYS1, there was a hierarchy of protection, NYS1 > QGP-S1 > QGP-S2. There was no correlation between antibody level at challenge as determined by immunofluorescent antibody test against sporozoites or enzyme-linked immunosorbent assay against (QGPGAP)2 or apparent antibody avidity for (QGPGAP)2 by sodium thiocyanate elution assay. The data demonstrate that a synthetic peptide can induce protective antibodies and that a specific antibody subclass is not required for protection. Work to determine whether antibody affinity or fine specificity can explain the hierarchy of protection among the MAbs is under way.
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PMID:Monoclonal antibodies of three different immunoglobulin G isotypes produced by immunization with a synthetic peptide or native protein protect mice against challenge with Plasmodium yoelii sporozoites. 850 Aug 85

A novel difluorinated 3,3'-spirocyclopentane 1,2,4-trioxane ('Fenozan-50F') is a potent blood schizontocide against drug-sensitive and drug-resistant rodent malaria parasites. It also exerts some action against pre-erythrocytic schizogony, is a potent gametocytocide, and exerts a direct sporontocidal effect in infected mosquitoes. In the '4-day test' the ED90s are 6.8 and 6.0 mg/kg/day for four consecutive days by the subcutaneous and oral routes respectively against drug-sensitive Plasmodium berghei N, and 6.3 and 25 mg/kg against chloroquine-resistant P. yoelii NS in vivo. By the oral route against P. berghei N infection in mice, Fenozan-50F is about half as active as arteether but nearly three times as active as sodium artesunate. The activity of Fenozan-50F is retained against a wide spectrum of drug-resistant parasite lines, although those highly resistant to quinine or to artemisinin are less responsive at the ED90 level. At the ultrastructural level the compound, when administered to infected mice, causes marked changes in the membranes and ribosomes of trophozoites and young schizonts and of immature gametocytes, although few changes are apparent in mature gametocytes. Its toxicity appears to be very low when it is administered to mice by either the oral or subcutaneous route. Fenozan-50F is considered to be a good candidate for eventual use as a therapeutic agent for infection with polyresistant malaria in man.
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PMID:The chemotherapy of rodent malaria. L. The activities of some synthetic 1,2,4-trioxanes against chloroquine-sensitive and chloroquine-resistant parasites. Part 3: Observations on 'Fenozan-50F', a difluorinated 3,3'-spirocyclopentane 1,2,4-trioxane. 856 18

The water-soluble artemisinin analogue sodium beta-artelinate, a fast-acting blood schizontocide, was evaluated for gametocytocidal action against simian malaria Plasmodium cynomolgi B, and a single dose of the compound has been found to be an effective gametocytocide by both oral and intravenous routes. The compound was able to sterilize the circulating gametocytes in rhesus monkey, resulting in loss of mosquito infectivity and oocyst development in the Anopheles stephensi. However, no sporontocidal action has been observed with this compound.
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PMID:Sodium beta-artelinate--a new potential gametocytocide. 863 76

Renal function was assessed in 40 children during the acute illness and after recovery from falciparum malaria. Creatinine clearance was significantly lower during the acute illness than after recovery. Six of 18 children with impaired creatinine clearance (< 50 ml/min/1.73 m2) had evidence of acute tubular dysfunction. Hyponatraemia occurred in 12.5% during the acute phase. Fractional sodium excretion was raised in 27% during the acute illness and continuing sodium wastage occurred in 17% after recovery. Plasma potassium was significantly higher and fractional potassium excretion (FeK) significantly lower during the acute illness than after recovery. There was a positive correlation between FeNa and FeK both during and after recovery from the illness but they did not exactly mirror each other in every individual. Urine sodium:potassium ratios were similar during and after recovery from the illness and was related to FeNa. Fractional glucose excretion was zero. Mild proteinuria occurred in 40% during the acute illness but were not related to creatinine clearance, body temperature at presentation, or peripheral parasite density. Proteinuria was absent after recovery. Acute intrinsic renal impairment occurs during apparently 'uncomplicated' falciparum malaria in children.
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PMID:Renal function in acute falciparum malaria. 866 27

Crude extracts of Plasmodium falciparum schizont-infected erythrocytes (PfSE) induce polyclonal activation of peripheral blood T lymphocytes from naive (malaria unexposed) humans. We demonstrate that the active component of PfSE is membrane bound, soluble in sodium dodecyl sulphate (SDS) and partially heat stable, but distinct from the tumour necrosis factor (TNF)-inducing, exoantigen-like activity of schizont extracts. Malaria pigment induces little or no T-cell activation. The responding cells are predominately CD4+, CD45RO+, T-cell receptor (TCR) alpha beta+. Contrary to previous reports, expansion of the TCR gamma delta+ subset was observed in cells from only one of eight donors. Proliferating cells secrete interferon-gamma (IFN-gamma) and release large amounts of soluble interleukin-2R (sIL-2R) into the culture supernatant but produce no detectable interleukin-4 (IL-4), a phenotype typical of the T-helper (Th)1 subset of CD4+ T cells. We propose that these activated T cells may initiate the inflammatory response to malaria infection in non-immunes and may contribute to the pathology of the disease.
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PMID:Naive human alpha beta T cells respond to membrane-associated components of malaria-infected erythrocytes by proliferation and production of interferon-gamma. 877 59

The prevalence and likely cause of hyponatraemia in severe childhood malaria were investigated. One hundred and thirty two children, 47 of whom had cerebral malaria, were prospectively recruited and serial simple indices of fluid and electrolyte balance and renal function monitored during admission. In 55%, hyponatraemia (sodium < 135 mmol/l) was present on admission. Hyponatraemia was pronounced (sodium < or = 130 mmol/l) in 21%, and these children gained less weight during admission (mean weight gain 2.4% v 4.3%) than children with a normal sodium (135-145 mmol/l). Overall, 31% of survivors were at least moderately dehydrated on admission (5% weight gain by discharge). These children had higher plasma urea concentrations on admission (6.1 v 4.5 mmol/l) and were more acidotic (mean base excess -12.1 v -8.0) than children who were not dehydrated. There were changes in simple indices of renal function between admission and discharge in children who survived (creatinine 65.7 v 37.9 mumol/l and urea 5.5 v 1.9 mmol/l). The results suggest that dehydration is common in severe childhood malaria, that it may contribute to mild impairment in renal function, and that hyponatraemic children are less water depleted, showing appropriate rather than inappropriate secretion of antidiuretic hormone.
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PMID:Hyponatraemia and dehydration in severe malaria. 878 22

Glutathione peroxidase (GPx), a key enzyme involved in the detoxification of many peroxides, has been investigated in two malaria parasite species: P. yoelii in vivo (murine malaria) and P. falciparum in vitro (human malaria). We demonstrate the presence of an endogenous GPx activity in these two Plasmodia species. Enzymatic assays and the use of specific substrates and inhibitors allowed us to determine that the activity is selenium dependent. As this activity was shown to be lower in P. falciparum than in P. yoelii, and selenium levels were found to be low in culture medium and culture red blood cells, we hypothesized that a severe selenium deficiency could be responsible for this difference. After selenium supplementation, with either sodium selenite or selenocystine, we observed an increase in growth of P. falciparum only in with sodium selenite, whereas higher GPx activities were noted in parasites grown in media supplemented with both. An increase in GPx activities was also observed in parasites that had undergone an experimental oxidative stress with TBOOH. As the erythrocyte is unable to synthesize new proteins, these results provide further evidence for the existence of an endogenous parasitic selenium-dependent glutathione peroxidase.
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PMID:Increase in glutathione peroxidase activity in malaria parasite after selenium supplementation. 888 8


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