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

We studied the differential effect of tryptophan-N-formylated gramicidin on uninfected and Plasmodium falciparum-infected erythrocytes. Trp-N-formylated gramicidin induces a much faster leakage of K+ from infected cells than from uninfected cell whereas, and at an even lower concentration, gramicidin A' causes a rapid K+ leakage from both uninfected and infected cells. We also studied the effect of Trp-N-formylated gramicidin and gramicidin A' incorporated in liposomes on the growth of Plasmodium falciparum in an in vitro culture. Incorporation of Trp-N-formylated gramicidin in the membranes of so-called 'stealth' vesicles strongly decreases the concentration needed to induce 50% inhibition of parasite growth. Moreover, no decrease in the K+ content of uninfected cells was observed when cells were exposed to liposome-incorporated Trp-N-formylated gramicidin at a concentration which causes full inhibition of parasite growth. These observations strongly suggest that Trp-N-formylated gramicidin incorporated in 'stealth' vesicles ends up specifically in the infected cell, thereby inhibiting the growth of the growth of the malaria parasite.
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PMID:Growth inhibition of Plasmodium falciparum in in vitro cultures by selective action of tryptophan-N-formylated gramicidin incorporated in lipid vesicles. 170 2

Zymosan-activated and non-activated human polymorphonuclear neutrophils (PMN) were added to in-vitro cultures of the human malaria parasite Plasmodium falciparum in microtitre wells. Microscopic counting of parasites in Giemsa-stained smears showed that at a PMN:RBC ratio of 1:150, the same as occurs in human malaria, parasites in wells with zymosan-activated neutrophils were suppressed 65%. Determination of parasite nucleic acid synthesis by 3H-hypoxanthine incorporation showed that in wells with PMN:RBC ratio of 1:150 parasite viability was only 22% of control. Various oxygen scavengers were tested for ability to reverse the effects of activated neutrophils on parasite development. Superoxide dismutase (20 mg/ml) and catalase (50 mg/ml) had no effect; tryptophan protected the parasites to a moderate degree while histidine alleviated suppression of parasite development to the greatest extent. This suggests that singlet oxygen is the most effective neutrophil product in killing or suppressing the growth of parasites. We also observed that non-activated neutrophils were activated by parasites and/or their products resulting in killing of newly-released parasites.
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PMID:Evidence for a neutrophil-mediated protective response in malaria. 328 Nov 2

Cultured Plasmodium falciparum was retarded in intraerythrocytic development by serum from malaria-immune adults, by human TB serum, and by rabbit tumor necrosis serum. Neither the potency nor efficacy of any of these sera was altered by a variety of antioxidants or oxygen-free radial scavengers, including ascorbate, alpha-tocopherol, BHT, cystine or cysteine, glutathione, histidine, phenylalanine, tryptophan, tyrosine, superoxide dismutase, catalase (or combination of the two enzymes), or by reducing the ambient O2 tension to 1%. It is thus unlikely that the antiparasitic activity of these inhibitory sera can be attributed to oxidative mechanisms.
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PMID:Antioxidants do not prevent the in vitro induction of Plasmodium falciparum crisis forms by human malaria-immune, TB or rabbit TNF serum. 352 84

Fluorescence histochemical methods for the demonstration of specific residues in peptides and proteins are reviewed: Formaldehyde-ozone for NH2-terminal tryptophan, formaldehyde-HCl for tryptophan regardless of position in the peptide, OPT for NH2-terminal histidine, formaldehyde-fluorescamine for "protected" amino groups, nitroso-naphthol for tyrosine, and phenanthrenequinone for arginine residues. The methods are potent in demonstrating granule-stored material in peptide hormone-producing cells. Also quinacrine, the fluorescent anti-malaria agent, binds to granular components, as yet unidentified, in several endocrine cell types. In many cases the fluorescence histochemical methods seem to demonstrate peptides and proteins distinct from the known hormones.
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PMID:Fluorescence histochemical methods for the study of peptide hormone-producing cells. 629 61

In order to get a better understanding in the mechanism by which tryptophan-N-formylated gramicidin (NFG) and gramicidin kill the malaria parasite Plasmodium falciparum in vitro, we studied the capacity of these peptides to change the potassium, as well as the sodium, composition of normal human erythrocytes, and their ability to cause cell lysis. It is shown that both peptides are able to induce potassium leakage from, and sodium flux into, erythrocytes in such a manner that it is most likely that they are able to form cation channels in the membrane of these cells. For both peptides, potassium efflux proceeds at a faster rate than sodium influx, but this difference is greater for NFG than for gramicidin. This explains the observation that gramicidin is more lytic than NFG is, even when comparing concentrations that show the same antimalarial activity. The finding that gramicidin is approximately 10 times more active than NFG in causing potassium efflux from normal erythrocytes, as well as in killing the malaria parasite, supports the hypothesis that peptide-induced parasite death is related to their capacity to induce potassium leakage from infected erythrocytes. Finally, the observation that erythrocytes are able to restore their normal ion contents after losing more than 50% of their potassium content by incubation with NFG or gramicidin, suggests that, in vivo, and upon treatment with drug concentrations that cause full inhibition of parasite growth, these cells would not be irreversibly damaged by action of the drugs.
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PMID:Effects of gramicidin and tryptophan-N-formylated gramicidin on the sodium and potassium content of human erythrocytes. 911 61

The effect of tryptophan-N-formylated gramicidin (NFG) on the growth of Plasmodium berghei in mice was tested in three different experiments. NFG was shown to be capable of inhibiting the growth of the parasite in a dose-dependent way, although its action did not result in elimination of the parasite and was only temporary, preventing mice from early death, presumably due to cerebral malaria, but not from fatal generalized malaria. Intriguingly, a similar observation was made with two other drugs, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, an inhibitor of viral and eukaryotic DNA polymerases, and the presumed topoisomerase II inhibitor, a bisquaternary quinolinium salt. A rise in the level of parasitemia after 8 days, despite continued treatment, was not due to parasite-induced reticulocytosis, as demonstrated in experiments in which this condition was induced artificially. NFG was added in the form of lipid vesicles in which the peptide had been incorporated. The inhibitory action of NFG was not modulated by the lipid composition of the vesicles. Control experiments did not demonstrate any toxicity of NFG when it was administered in lipid vesicles. The main observation is that NFG is able to inhibit the growth of a malaria parasite in vivo at concentrations that are well tolerated by the host.
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PMID:Effect of tryptophan-N-formylated gramicidin on growth of Plasmodium berghei in mice. 925 60

The pathogenesis of human cerebral malaria (CM) remains unresolved. In the most widely used murine model of CM, the presence of T lymphocytes and/or interferon (IFN)-gamma is a prerequisite. IFN-gamma is the key inducer of indoleamine 2,3-dioxygenase (IDO), which is the catalyst of the first, and rate-limiting, step in the metabolism of tryptophan (Trp) along the kynurenine (Kyn) pathway. Quinolinic acid (QA), a product of this pathway, is a neuro-excitotoxin, like glutamic acid (Glu) and aspartic acid (Asp). Kynurenic acid (KA), also produced from the Kyn pathway, antagonizes the neuro-excitotoxic effects of QA, Glu, and Asp. We therefore examined the possible roles of IDO, metabolites of the Kyn pathway, Glu, and Asp in the pathogenesis of fatal murine CM. Plasmodium berghei ANKA infection was studied on days 6 and 7 post-inoculation (p.i.), at which time the mice exhibited cerebral symptoms such as convulsions, ataxia, coma, and a positive Wooly/White sign and died within 24 hours. A model for noncerebral malaria (NCM), P. berghei K173 infection, was also studied on days 6 and 7 and 13 to 17 p.i. to examine whether any changes were a general response to malaria infection. Biochemical analyses were done by high-pressure liquid chromatography and gas chromatography/mass spectrometry/mass spectrometry (GC/MS/MS). IDO activity was low or absent in the brains of uninfected mice and NCM mice (days 6 and 7 p.i.) and was induced strongly in the brains of fatal murine CM mice (days 6 and 7 p.i.) and NCM animals (days 13 to 17 p.i.). This induction was inhibited greatly by administration of dexamethasone, a treatment that also prevented CM symptoms and death. Furthermore, IDO induction was absent in IFN-gamma gene knockout mice, which were also resistant to CM. Brain concentrations of Kyn, 3-hydroxykynurenine, and the neuro-excitotoxin QA were significantly increased in both CM mice on days 6 and 7 p.i. and NCM mice on days 13 to 17 p.i., whereas an increase in the ratio of brain QA to KA occurred only in the CM mice at the time they were exhibiting cerebral symptoms. Brain concentrations of Glu and Asp were significantly decreased in CM and NCM mice (days 13 to 17 p.i.). The results imply that neuro-excitation induced by QA may contribute to the convulsions and neuro-excitatory signs observed in CM.
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PMID:Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and noncerebral malaria. 946 88

Plasmodium falciparum glutathione reductase (PfGR) has emerged as a drug target against tropical malaria. Here we report the expression of PfGR in Escherichia coli SG5(DE3) and isolation procedures for this protein. Recombinant PfGR does not differ from the authentic enzyme in its enzymic properties, the turnover number being 9900 min(-1). The dimeric flavoenzyme exhibits redox-dependent absorption spectra; the single tryptophan residue (per 57.2 kDa subunit) is strongly fluorescent. PfGR can be inhibited by the antimalarial drug methylene blue at therapeutic concentrations; the Ki for non-competitive inhibition is 6.4 microM. The sensitivity to methylene blue is observed also at high ionic strength so that, by analogy to human GR, analysis of crystalline enzyme-drug complexes can be envisaged.
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PMID:Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. 949 6

Malaria is transmitted from vertebrate host to mosquito vector by mature sexual blood-living stages called gametocytes. Within seconds of ingestion into the mosquito bloodmeal, gametocytes undergo gametogenesis. Induction requires the simultaneous exposure to at least two stimuli in vitro: a drop in bloodmeal temperature to 5 degrees C below that of the vertebrate host, and a rise in pH from 7.4 to 8.0-8.2. In vivo the mosquito bloodmeal has a pH of between 7.5 and 7.6. It is thought that in vivo the second inducer is an unknown mosquito-derived gametocyte-activating factor. Here we show that this factor is xanthurenic acid. We also show that low concentrations of xanthurenic acid can act together with pH to induce gametogenesis in vitro. Structurally related compounds are at least ninefold less effective at inducing gametogenesis in vitro. In Drosophila mutants with lesions in the kynurenine pathway of tryptophan metabolism (of which xanthurenic acid is a side product), no alternative active compound was detected in crude insect homogenates. These data could form the basis of the rational development of new methods of interrupting the transmission of malaria using drugs or new refractory mosquito genotypes to block parasite gametogenesis.
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PMID:Identification of xanthurenic acid as the putative inducer of malaria development in the mosquito. 952 15

A small, heat stable chromophore extracted from mosquitoes has recently been implicated as the signal that induces mating of Plasmodium, the malaria parasite. We have used high resolution electrospray mass spectrometry to determine that this gamete activation factor (GAF) has a m/z = 205.0450, suggesting a molecular species composition of C10H7NO4. Xanthurenic acid (XA), a product of tryptophan catabolism, was determined to have an elemental composition, ultraviolet absorbance maxima, and mass spectrum consistent with those characteristics of GAF. XA activated gametogenesis of Plasmodium gallinaceum and P. falciparum in vitro at concentrations lower than 0.5 microM in saline buffered to pH 7.4. A structural analog of XA, kynurenic acid (C10H6NO3), also activated gametogenesis but only at higher concentrations and with less effect. We propose that XA is GAF. This is the first evidence that XA has induction activity.
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PMID:Xanthurenic acid induces gametogenesis in Plasmodium, the malaria parasite. 957 40


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