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)

Following invasion by the malaria parasite there appear in the parasitized erythrocyte new ("induced") permeation pathways that mediate the transport of a wide variety of small solutes. Although anion-selective, these pathways have a significant cation permeability and cause a substantial increase in the basal leak of cations into and out of the infected cell. In this study of human erythrocytes infected in vitro with Plasmodium falciparum it was shown that the transport of monovalent cations (Rb+ and choline), but not that of a nonelectrolyte (sorbitol) or a monovalent anion (lactate), via the malaria-induced pathways is strongly dependent on the nature of the anion in the suspending medium. Substitution of NO3- for Cl- resulted in a 4-6-fold increase in the unidirectional influx and efflux of Rb+, and a 2-3-fold increase in the influx of choline via the induced pathways. By contrast, replacement of Cl- with NO3- caused a slight (although not significant) decrease in the malaria-induced influx of sorbitol and lactate. Hemolysis experiments with a range of K+ salts revealed that the net influx of K+ into infected cells showed the same novel anion dependence as seen for the unidirectional flux of Rb+ and choline, with hemolysis occurring much faster in iso-osmotic KNO3 and KSCN solutions than in KCl, KBr, or KI solutions. Hemolysis in the corresponding Na+ salt solutions was very much slower, consistent with the induced pathways being selective for K+ over Na+, and raising the possibility that the efflux of cell K+ via these pathways may play a role in host cell volume regulation. A number of models that would account for the anion dependence of malaria-induced cation transport are considered.
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PMID:Novel anion dependence of induced cation transport in malaria-infected erythrocytes. 759 35

The production and function of nitric oxide during the early phase of blood-stage infection with Plasmodium chabaudi AS was analyzed using two inbred strains of mice that differ in the level of resistance to this parasite. Northern blot analysis of in vivo expression of inducible nitric oxide synthase (iNOS) revealed that early during infection resistant C57BL/6 mice, which clear the infection by 4 wk, have higher levels of iNOS mRNA in the spleen than susceptible A/J mice. In contrast, susceptible A/J mice have significantly increased levels of iNOS mRNA in the liver later in the course of infection just before death occurs. Splenic macrophages recovered from resistant C57BL/6 mice on day 7 postinfection express iNOS mRNA which is up-regulated following overnight stimulation of the cells with LPS. Furthermore, during the first week postinfection, splenic macrophages recovered from resistant hosts produce significantly higher levels of nitrite (NO2-) in vitro in response to LPS than similarly stimulated macrophages from susceptible A/J mice. Increased levels of nitrate (NO3-) were only detected in serum of resistant C57BL/6 mice at the time of peak parasitemia. Treatment with the iNOS inhibitor, aminoguanidine, reduced NO3- levels in serum of C57BL/6 mice and eliminated resistance of these hosts to P. chabaudi AS malaria without affecting parasitemia. These results demonstrate that the ability to produce high amounts of nitric oxide (NO) early during infection with blood-stage P. chabaudi AS correlates with resistance, but that NO may not be involved in parasite killing. Moreover, the tissue site of NO production, that is, spleen vs liver, appears to be critical and correlates with resistance vs susceptibility to P. chabaudi AS malaria, respectively.
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PMID:Nitric oxide expression in the spleen, but not in the liver, correlates with resistance to blood-stage malaria in mice. 759 44

The effects of IL-12 administration on the development of protective immunity to blood-stage Plasmodium chabaudi AS were analyzed. Treatment of susceptible A/J mice on the day of infection and for 5 days postinfection with various doses 0.025-0.3 microgram) of rIL-12 significantly decreased the peak parasitemia level, but only treatment with 0.1 microgram resulted in increased survival. Treatment of resistant B6 mice with 0.1 microgram of rIL-12 using the same regimen also significantly decreased the peak parasitemia level, but 40% of the animals died. Treatment of these mice with anti-IL-12 mAb resulted in a more severe course of infection, but survival was not significantly altered. The mechanism of IL-12-induced resistance was examined in A/J mice during infection. Compared with spleen cells from untreated mice, cells from IL-12-treated mice produced significantly higher levels of IFN-gamma spontaneously as well as in response to Con A or Ag stimulation on day 7 postinfection. Significantly higher levels of INF-gamma and TNF-alpha were found in the sera of IL-12-treated mice, which correlated with high levels of the nitric oxide (NO) metabolite, NO3-. Furthermore, CD4+T cell depletion was found to abrogate IL-12-induced resistance. Administration of neutralizing mAb against IFN-gamma or TNF-alpha to IL-12-treated mice showed that simultaneous depletion of both cytokines resulted in 100% mortality. The role of NO was investigated by administration of aminoguanidine, a selective inhibitor of cytokine-inducible nitric oxide synthase, to IL-12-treated mice. Significantly increased mortality was observed following treatment twice daily with 9 mg of aminoguanidine, but there was no effect on parasitemia. In conclusion, these results demonstrate that IL-12 regulates the development of resistance to P. chabaudi AS via a CD4+ Th1 response, which involves the cytokines IFN-gamma and TNF-alpha, and is in part NO dependent. Therefore, IL-12, given in the appropriate dose, may be useful in the induction of protective immunity to blood-state malaria.
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PMID:IL-12-induced protection against blood-stage Plasmodium chabaudi AS requires IFN-gamma and TNF-alpha and occurs via a nitric oxide-dependent mechanism. 765 Mar 84

Low K (LK) sheep red blood cells (SRBCs) serve as a model to study K-Cl cotransport which plays an important role in cellular dehydration in human erythrocytes homozygous for hemoglobin S. Cinchona bark derivatives, such as quinine (Q) and quinidine (QD), are effectively used in the treatment of malaria. In the present study, we investigated in LK SRBCs, the effect of various concentrations of Q and QD on Cl-dependent K efflux and Rb influx (K(Rb)-Cl flux), activated by either swelling in hyposmotic media, thiol alkylation with N-ethylmaleimide (NEM), or by cellular Mg (Mgi) removal through A23187 in the presence of external chelators. K efflux or Rb influx were determined in Cl and NO3 medium and K(Rb)-Cl flux was defined as the Cl-dependent (Cl minus NO3) component. K(Rb)-Cl flux stimulated by all three interventions was inhibited by both Q and QD in a dose-dependent manner. Maximum inhibition of K(Rb)-Cl flux occurred at Q and QD concentrations > or = 1 mM. The inhibitory effect of Q was manifested in Cl, but not in NO3, whereas QD reduced K and Rb fluxes both in Cl and NO3 media. The mean 50% inhibitory concentration (IC50) of Q and QD to inhibit K(Rb)-Cl flux varied between 0.23 and 2.24 mM. From determinations of the percentages of inhibition of the different components of K and Rb fluxes, we found that SRBCs possess a Cl-dependent QD-sensitive and a Cl-dependent QD-insensitive K efflux and Rb influx. These two components vary in magnitude depending on the manipulation and directional flux, but in average they are about 50% of the total Cl-dependent flux. This study raises the possibility that, in SRBCs, the Cl-dependent K(Rb) fluxes are heterogeneous.
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PMID:Quinine and quinidine inhibit and reveal heterogeneity of K-Cl cotransport in low K sheep erythrocytes. 788 11

We investigated whether gamma interferon (IFN-gamma; a Th1 cytokine), tumor necrosis factor alpha (TNF-alpha), and interleukin-4 (IL-4; a Th2 cytokine) modulate nitric oxide (NO) production in vivo during blood stage infection with Plasmodium chabaudi AS. Treatment of resistant C57BL/6 mice, which resolve infection with P. chabaudi AS and produce increased levels of IFN-gamma, TNF-alpha, and NO early during infection, with anti-IFN- gamma plus anti-TNF-alpha monoclonal antibodies (MAbs) resulted in a reduction of both splenic inducible NO synthase mRNA and serum NO3- levels by 50 and 100%, respectively. Treatment with the anti-TNF-alpha MAb alone reduced only serum NO3- levels by 35%, and treatment with the anti-IFN-gamma MAb alone had no effect on NO production by these mice during infection. Susceptible A/J mice, which succumb to infection with P. chabaudi AS and produce increased levels of IL-4 but low levels of IFN-gamma, TNF-alpha, and NO early during infection, were treated with an anti-IL-4 MAb. The latter treatment had no effect on NO production by this mouse strain during infection. In addition, our results also demonstrate that treatment of resistant C57BL/6 mice with anti-IFN-gamma plus anti-TNF-alpha MAbs affects, in addition to NO production, other traits of resistance to P. chabaudi AS malaria such as the peak level of parasitemia and the development of splenomegaly. Furthermore, the change in spleen weight was shown to be an IFN-gamma-independent effect of TNF-alpha. Treatment of susceptible A/J mice during infection with an anti IL-4 MAb had no effect on these markers of resistance. Thus, these results demonstrate that TNF-alpha and IFN-gamma are critical in the regulation of NO production and other traits of resistance during P. chabaudi AS malaria in C57BL/6 mice. These data also indicate that treatment with an anti-IL-4 antibody alone is not able to induce NO production or confer resistance to A/J mice against P. chabaudi AS malaria.
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PMID:In vivo regulation of nitric oxide production by tumor necrosis factor alpha and gamma interferon, but not by interleukin-4, during blood stage malaria in mice. 855 72

To determine whether iron chelation modulates nitric oxide (NO) formation and cell-mediated immune effector function in children with cerebral malaria, serum concentrations were measured of the stable end products of NO, nitrite and nitrate (NO2-/NO3-), interleukin (IL)-4, -6, and -10, and neopterin in 39 Zambian children enrolled in a placebo-controlled trial of desferrioxamine B and quinine therapy. Mean concentrations of NO2-/NO3- increased significantly over 3 days in children receiving desferrioxamine plus quinine but not in those given placebo and quinine. Neopterin levels declined significantly with placebo but not with desferrioxamine. IL-4 levels increased progressively in the placebo group and ultimately decreased in the desferrioxamine group, but the trends were not statistically significant. IL-6 and IL-10 levels were elevated initially and decreased significantly in both groups over 3 days. These data are consistent with the hypothesis that iron chelation therapy in children with cerebral malaria strengthens Th1-mediated immune effector function involving increased production of NO.
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PMID:Modulatory potential of iron chelation therapy on nitric oxide formation in cerebral malaria. 898 27

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

The effect of febrifugine, the main alkaloidal constituent of an antimalarial crude drug, Dichroa febrifuga Lour., on protective immunity in mice infected with erythrocytic stage Plasmodium berghei NK65 was investigated. Febrifugine was administered orally, at a dose of 1 mg/kg/day, to mice before and/or after they were infected intraperitoneally with 2 x 10(6) parasitized red blood cells. Then, mortality and the levels of parasitemia and plasma NO3- [a degradation product of nitric oxide (NO)] were monitored. Febrifugine significantly reduced the mortality and the level of parasitemia. The plasma NO3- concentration began to rise within 2 days after treatment with febrifugine and declined to normal in 2 days when the mice were treated orally with febrifugine once a day for 3 consecutive days before parasite infection. This antimalarial activity of febrifugine was reduced by both N(G)-monomethyl-L-arginine and aminoguanidine. These results indicate that the increased production of NO by febrifugine plays an important role in host defense against malaria infection in mice.
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PMID:Potentiation by febrifugine of host defense in mice against Plasmodium berghei NK65. 1053 50

Malaria, a disease accounting for more than one million deaths per year, is caused by intraerythrocytic growth of Plasmodia. Parasitemia may be blunted by suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and phosphatidylserine exposure. Triggers of eryptosis include lead nitrate (Pb(NO3)2). As shown here, Pb(NO3)2 (> or = 10 microM) increased phosphatidylserine exposure of Plasmodium falciparum-infected human erythrocytes, an effect significantly more marked than in noninfected cells. Pb(NO3)2 treatment accelerated the clearance of erythrocytes from circulating blood. Parasitemia in Plasmodium berghei-infected mice was significantly decreased and mouse survival significantly enhanced by 100 microM Pb(NO3)2 (20 ppm) in drinking water. The treatment significantly increased reticulocyte number but did not significantly decrease erythrocyte number in noninfected mice and in infected animals mainly triggered the disappearance of P. berghei harbouring erythrocytes. In conclusion, Pb(NO3)2 accelerates eryptosis and subsequent clearance of infected erythrocytes and thus favourably influences the course of malaria.
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PMID:Lead decreases parasitemia and enhances survival of Plasmodium berghei-infected mice. 1788 70