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

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

Carbon dioxide (CO2) is essential for the growth of intraerythrocytic malaria parasites to synthesize pyrimidine through CO2 fixation and to regulate intracellular pH. CO2 transport across the plasma membrane of erythrocytes is facilitated by carbonic anhydrase (CA). With the use of electron microscopy and CA-specific Hansson's stain, CA is found also in all the intraerythrocytic stages of Plasmodium falciparum. When CA inhibitors, including acetazolamide, potassium iodide, and sodium deoxycholate, were added to continuous culture of P. falciparum, they, particularly sodium deoxycholate, produced a marked reduction in parasitemia. These results explain the biochemical basis of some of the clinical conditions associated with malaria and strongly suggest that CA inhibitors have potential as a new class of antimalarials.
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PMID:The pivotal role of carbonic anhydrase in malaria infection. 948 77

One major quantitative trait locus controls melanization of both malaria ookinetes and Sephadex CM beads in a refractory strain of the mosquito, Anopheles gambiae. Hemolymph transferred from a nonmelanizing, Plasmodium-susceptible strain (4arr) to a melanizing, Plasmodium-refractory strain (L35) caused a reduction in the melanization of CM beads. In addition, when beads were first incubated in vivo in susceptible mosquitoes and then recovered, washed, and transferred to refractory mosquitoes, a strong reduction in melanization was observed. No changes in melanization were observed when beads or hemolymph were transferred in the opposite direction or within a strain. Incubation of beads in vitro in refractory or susceptible hemolymph resulted in a reduction of melanization when these beads were subsequently transferred to refractory mosquitoes. This reduction was significantly stronger when susceptible hemolymph was used as the incubating medium. Protection from melanization was observed after 3-, 6-, and 24-h incubations of beads in susceptible mosquitoes with longer incubations resulting in greater protection. Treatment of protected beads with 1 M NaOH resulted in the loss of the protection but treatment with 1% sodium dodecyl sulfate (SDS), 1% SDS/DTT/boiling, or 1 M NaOAc (pH 8.9) did not. These results show that a melanization-preventing factor covalently binds to the surface of CM beads in susceptible mosquitoes and can subsequently prevent melanization in refractory mosquitoes.
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PMID:A factor preventing melanization of sephadex CM C-25 beads in Plasmodium-susceptible and refractory anopheles gambiae. 970 28

The urban area of Dakar, Senegal, contains > 5,000 market-garden wells that provide permanent sites for mosquito larvae, in particular Anopheles arabiensis Patton, the major vector of malaria. A study of the bioecology of mosquito larvae was conducted over 1 yr with a monthly visit to 48 of these wells. Overall, 9,589 larvae were collected of which 80.1% were Culicinae and 11.9% Anophelinae. Larvae from stages III and IV (n = 853) were identified to 10 species. An. arabiensis represented 86% of the anophelines collected and An. ziemanni Grunberg 14%. The most common Culicinae species included Aedeomyia africana Neveu-Lemaire, Culex quinquefasciatus Say, and Mimomyia splendens Theobald. Maximum anopheline abundance was observed at the end of the dry season in June, whereas maximum Culicinae abundance was observed at the end of the rainy season in September. Most wells (67%) did not harbor any An. arabiensis larvae and in the remaining 33% the larval abundance was low, averaging 0.54 larvae in stages III-IV per tray sample. To identify factors that determine the abundance of larvae in these wells, a co-inertia (multivariate) analysis was carried out to account for physicochemical variables (depth, turbidity, temperature, pH, conductivity, Na+, Cl-, HCO3-, CO3--, and NO3- concentrations) and biological variables (abundance of mosquito species, predators [e.g., fish, Dytiscidae, Notonectidae, odonates], molluscs [Bulinus and Biomphalaria], and surface plants [water lettuce, Lemna, and filamentous algae]). The co-inertia analysis indicated that the abundance of An. arabiensis was associated with Cx. quinquefasciatus and Cx. decens for the physiochemical data but was not associated with other mosquito species for floro-faunistic data. The conditions associated with abundant An. arabiensis were warm temperature (28-30 degrees C), clear and not too deep water (< 0.5 m), elevated concentrations of HCO3- and CO3--, low concentrations of NO3- and NaCl, low populations of larvivorous fish and invertebrate predators (notably odonates), the presence of water lettuce, and an absence of Lemna. These results indicate that many contributing factors influence the ecology of the immature stages of An. arabiensis.
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PMID:Ecology of larval mosquitoes, with special reference to Anopheles arabiensis (Diptera: Culcidae) in market-garden wells in urban Dakar, Senegal. 983 85

In experiments carried out in mice, hamsters, guinea pigs and rabbits both dihydroartemisinin and artesunate showed contragestational effect. In mice and rabbits they caused embryo absorption whereas in hamsters and guinea pigs they induced abortion. The contragestational ED50 of dihydroartemisinin given sc on d 7 of pregnancy in mice and d 5 of pregnancy in hamsters were 32.8(27.7-38.9) mg.kg-1 and 6.1(5.6-6.7) mg.kg-1 respectively. The ED50 of this drug given im on d 18 of pregnancy in guinea pigs was 18.3(13.9-24.2) mg.kg-1. Dihydroartemisinin also showed mid-pregnancy terminating effect in hamsters. The contragestational ED50 of artesunate given sc on d 5 of pregnancy in hamsters and the ED50 of sodium artesunate given sc on d 5-8 of pregnancy in hamsters were 12.2(10.3-14.4) mg.kg-1 and 1.0(0.9-1.2) mg.kg-1 daily respectively. Results of light microscopic examination revealed that dihydroartemisinin was selectively toxic to embryo sac. At dose levels sufficient to induce embryo sac necrosis, dihydroartemisinin did not injure the uterus and ovary of the maternal animals. On the ground of the foregoing observations we consider that dihydroartemisinin, artesunate and their analogous drugs should not be used to treat malaria in pregnant women and there is the possibility to exploit intentional abortion agents from artemisinin derivatives.
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PMID:[Contragestational effects of dihydroartemisinin and artesunate]. 986 30

During the course of its development in the mosquito and transmission to a new vertebrate host, the malaria parasite must interact with the mosquito midgut and invade the gut epithelium. To investigate how the parasite recognizes the midgut before invasion, we have developed an in vitro adhesion assay based on combining fluorescently labelled ookinetes with isolated midgut epithelia from blood-fed mosquitoes. Using this assay, we found that Plasmodium gallinaceum ookinetes readily adhered to midguts of Aedes aegypti, mimicking the natural recognition of the epithelium by the parasite. This interaction is specific: the ookinetes preferentially adhered to the lumen (microvillar) side of the gut epithelium and did not bind to other mosquito tissues. Conversely, the binding was not due to a non-specific adhesive property of the midguts, because a variety of other cell types, including untransformed P. gallinaceum zygotes or macrogametes, did not show similar binding to the midguts. High concentrations of glycosylated (fetuin, orosomucoid, ovalbumin) or non-glycosylated (bovine serum albumin) proteins, added as non-specific competitors, failed to compete with the ookinetes in binding assays. We also found that the adhesion of ookinetes to the midgut surface is necessary for sporogonic development of the parasite in the mosquito. Antibodies and other reagents that blocked adhesion in vitro also reduced oocyst formation when these reagents were combined with mature ookinetes and fed to mosquitoes. Chemical modification of the midguts with sodium periodate at pH 5.5 destroyed adhesion, indicating that the ookinete binds to a carbohydrate ligand on the surface of the midgut. The ligand is sensitive to periodate concentrations of less than 1 mmol l-1, suggesting that it may contain sialic-acid-like sugars. Furthermore, free N-acetylneuraminic acid competed with the ookinetes in binding aasays, while other monosaccharides had no effect. However, in agreement with the current belief that adult insects do not contain sialic acids, we were unable to detect any sialic acids in mosquito midguts using the most sensitive HPLC-based fluorometric assay currently available. We postulate that a specific carbohydrate group is used by the ookinete to recognize the midgut epithelium and to attach to its surface. This is the first receptor-ligand interaction demonstrated for the ookinete stage of a malaria parasite. Further characterization of the midgut ligand and its parasite counterpart may lead to novel strategies of blocking oocyst development in the mosquito.
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PMID:Plasmodium gallinaceum ookinetes adhere specifically to the midgut epithelium of Aedes aegypti by interaction with a carbohydrate ligand. 992 52

Asexual stages of Plasmodium falciparum cause severe malaria and are dependent upon host glucose for energy. We have identified a glucose transporter of P. falciparum (PfHT1) and studied its function and expression during parasite development in vitro. PfHT1 is a saturable, sodium-independent, and stereospecific transporter, which is inhibited by cytochalasin B, and has a relatively high affinity for glucose (Km = 0.48 mM) when expressed in Xenopus laevis oocytes. Competition experiments with glucose analogues show that hydroxyl groups at positions C-3 and C-4 are important for ligand binding. mRNA levels for PfHT1, assessed by the quantitative technique of tandem competitive polymerase chain reaction, are highest during the small ring stages of infection and lowest in gametocytes. Confocal immunofluorescence microscopy localizes PfHT1 to the region of the parasite plasma membrane and not to host structures. These findings have implications for development of new drug targets in malaria as well as for understanding of the pathophysiology of severe infection. When hypoglycemia complicates malaria, modeling studies suggest that the high affinity of PfHT1 is likely to increase the relative proportion of glucose taken up by parasites and thereby worsen the clinical condition.
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PMID:Intraerythrocytic Plasmodium falciparum expresses a high affinity facilitative hexose transporter. 1006 89

The ionophore properties of cationomycin and monensin were studied on human erythrocytes by measuring Na+ influx by 23Na NMR and concomitant K+ efflux by potentiometry in the presence of increasing amounts of serum. Both ion currents (Na+ or K+) decreased linearly with the reciprocal of serum amount. The serum effects on ion currents were stronger with cationomycin than with monensin. Assuming this decreased transport activity was due to drug binding to serum proteins, a partition coefficient between the protein and the membrane phase was determined for each ionophore by using a novel model. This partition coefficient is about 30 times higher for cationomycin than for monensin; the same result was obtained with purified human serum albumin, indicating that albumin may be the major ionophore binding protein of serum. In parallel, we also measured IC50 for 50% in vitro growth inhibition of Plasmodium falciparum, the agent of malaria. In the presence of increasing serum concentrations, the antimalarial activity was decreased for both ionophores. Serum effect was less severe for monensin than for cationomycin, in agreement with the weaker interaction of monensin with proteins as shown from the partition coefficient values. A correlation was established between the ion transport currents (sodium and potassium) and the IC50 measured on P. falciparum in the presence of the various concentrations of serum. The relative value of the ion transport currents (expressed as percentage of control in absence of serum) can be indicative of the ionophore unbound fraction in the medium.
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PMID:Cationomycin and monensin partition between serum proteins and erythrocyte membrane: consequences for Na+ and K+ transport and antimalarial activities. 1006 60

To establish the effects of chloroquine on kidney function we monitored renal parameters in age and sex matched control subjects and patients who presented with acute transient fever. The patients were immediately treated with chloroquine diphosphate in the recommended dosage. Blood samples for creatinine, urea, Na+ and K+ determinations were collected before treatment (Day 0), on the 3rd day of treatment (Day 3) and two days after the last dose of chloroquine (Day 5). 24 h urine collections were collected for five consecutive days from the second day of treatment. Spot urine samples showed the absence of blood cells, bilirubin, glucose, protein and ketones. Examination of thick blood smears over three days did not reveal any forms of malaria parasites. Urinary tract infection in the patients was also excluded. Therefore, these patients were a suitable group to assess the effects of chloroquine on renal function. The blood pressure in females and males decreased significantly after two days of chloroquine treatment compared with Day 0. The plasma concentration of creatinine in females and females was increased by chloroquine 2 days after the last dose by comparison with the Day 0 (females, 66 +/- 2 mumol/L versus 83 +/- 2 mumol/L n = 20, p < 0.01 and males, 78 +/- 6 mumol/L versus 81 +/- 9 mumol/L, n = 20, p < 0.01). This was paralleled by a reduction in urinary creatinine excretion during the same period (females 15 +/- 1 mg/kg body weight/24 h versus 12 +/- 1 mg/kg body weight/24 h and males 23 +/- 3 mg/kg/24 h versus 18 +/- 2 mg/kg/24 h, p < 0.01 in both instances). Urinary urea excretion in females was reduced from 290 +/- 6 mumol/kg/24 h to 215 +/- 5 mumol/kg/24 h 2 days after treatment. The results of the study suggest that the effects of chloroquine in patients with acute transient fever include lowered urinary urea and creatinine excretion.
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PMID:Chloroquine influences renal function in rural Zimbabweans with acute transient fever. 1008 79

The introduction of reactive thiol groups in recombinant human tumor necrosis factor (TNF) alpha (rhTNF-alpha) by the reagent succinimidyl-S-acetylthioacetate resulted in the formation of a chemically stabilized rhTNF-alpha trimer (rhTNFalpha-AT; as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis). rhTNFalpha-AT showed a substantially enhanced protective efficacy against the development of experimental murine cerebral malaria (ECM) after intravenous injection compared to the protective efficacy of nonmodified rhTNF-alpha. Administration of thiolated rhTNF-alpha with protected thiol groups (rhTNFalpha-ATA; no stabilized trimers in vitro) exhibited the same protective efficacy against ECM, while in vitro bioactivity was reduced. Parasitemia was significantly suppressed in rhTNF-treated mice that were protected against ECM but not in treated mice that developed ECM. Protection against ECM was not related to increased concentrations in plasma of soluble TNF receptor 1 and 2 directly after injection or at the moment of development of ECM in nontreated mice. The results indicate that thiolation of rhTNF-alpha leads to the formation of stable trimers with increased potential in vivo.
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PMID:Thiolated recombinant human tumor necrosis factor-alpha protects against Plasmodium berghei K173-induced experimental cerebral malaria in mice. 1022 10


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