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)

Merozoites are the invasive stage of the malaria parasite, which are released from infected erythrocytes to invade other erythrocytes. Antibody to surface antigens on merozoites may prevent invasion by agglutinating merozoites as they are released from infected erythrocytes or by blocking receptors before contact of merozoites with the host erythrocyte. Monoclonal antibodies were produced to a 140,000-m.w. protein on the merozoite surface. The protein was synthesized by the mature intraerythrocytic parasite, the schizont, as a 143,000-m.w. protein and had a m.w. of 140,000 on the surface of free merozoites. The monoclonal antibodies were shown to bind to the surface of merozoites by immune electron microscopy. Ascitic fluid containing four of 11 anti-140,000 monoclonal antibodies partially blocked invasion of erythrocytes by merozoites released from schizont-infected cells. The low invasion rate was always associated with a high frequency of multiply infected erythrocytes (two or more rings per erythrocyte). Monoclonal antibodies purified by (NH4)2SO4 precipitation and diethylaminoethyl column fractionation also blocked invasion and caused multiple invasion of individual erythrocytes. The monoclonal antibodies, incubated with free merozoites, did not block invasion, indicating that the antibodies did not bind to merozoite receptors for erythrocytes. We propose that the reduced rate of invasion and the multiple invasion of erythrocytes, the characteristic of these monoclonal antibodies, was caused by weak agglutination of merozoites as they were released from infected erythrocytes.
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PMID:Monoclonal antibodies to a 140,000-m.w. protein on Plasmodium knowlesi merozoites inhibit their invasion of rhesus erythrocytes. 669 Jun 7

The protective immunity conferred by subcutaneous injection of outbred CD-1 mice with a killed Plasmodium yoelii (YM strain) vaccine was strongly potentiated by saponin. By adjusting the dose of antigen, the number of immunizations and the number of living parasites in the challenge infection, conditions were defined where antigen alone was non-protective but 100% protection was obtained by the addition of saponin. Inbred BALB/c, CBA/CA and C57 B1 mice were much less responsive than the CD-1 mice. The following adjuvants were compared with saponin: mineral oil emulsions (Freund's incomplete and complete adjuvants); A1(OH)3(Alhydrogel); bacteria and synthetic bacterial derivatives (Bordetella pertussis, Corynebacterium parvum and muramyl dipeptide); surface active materials (digitonin, vitamin A, Arquad 18, dimethyldioctadecyl ammonium bromide, and the polyene antibiotics, Nystatin and Amphotericin B). None of these adjuvants were as effective as saponin, although FCA, A1(OH)3 and C. parvum augmented immunity considerably. The possible reasons for the efficacy of saponin as an adjuvant for protozoal vaccines are discussed. The P. yoelli/mouse system provides a sensitive and rapid screening assay for comparison of potential adjuvants suitable for use with a malaria vaccine.
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PMID:A comparison of saponin with other adjuvants for the potentiation of protective immunity by a killed Plasmodium yoelii vaccine in the mouse. 714 65

We describe a simple dose-response approach to assess the affinity distribution of polyclonal antibodies. The proportion of antigen-specific antibodies dissociated by increasing concentrations of the mild chaotropic agent ammonium thiocyanate (NH4SCN) was measured by enzyme immunoassay, and the distribution of tolerances to this agent was presented in a histogram form. Such 'tolerance distribution', which is analogous to that described in classical dose-response bioassays, is proposed as a representation of the actual antibody affinity distribution. To test this approach, we assessed affinity maturation patterns of anti-Plasmodium falciparum IgG antibodies in paired sera obtained from 22 malaria patients during the acute infection and convalescence. We obtained patterns of antibody affinity distributions consistent with those previously described in immunization experiments with the aid of more complex laboratory and computational approaches. Therefore, we suggest the thiocyanate elution technique as an alternative method for rapid assessment of affinity distributions of polyclonal antibodies elicited against complex antigens, readily applicable to large number of serum samples.
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PMID:The assessment of antibody affinity distribution by thiocyanate elution: a simple dose-response approach. 749 89

A number of lipophilic nitrogenous bases, designed to act as membrane-active, catalytic proton transfer agents, were tested for their ability to neutralize the acidity of lysosomes, a model for other acidic intracellular vesicles involved in drug sorting. The most successful of these, an imidazole 1, caused a 1.7 unit rise in lysosomal pH of RAW cells at 100 microM, compared to a 0.2 and 1.4 unit rise for ammonium chloride at 100 microM and 10 mM, respectively. Compound 1 also exhibited potent reversal of doxorubicin (DOX) resistance in the HCT116-VM46 cell line by a factor of 14 over the sensitive strain, and superior to that of widely used verapamil (VRP) by a factor of 1.75 at 20 microM. It also has antiviral properties, and potential applications in other lysosome-related areas such as immunotoxin potentiation and the control of bacterial toxins, immune response, prion replication, malaria and intralysosomal microorganisms.
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PMID:Reversal of doxorubicin resistance and catalytic neutralization of lysosomes by a lipophilic imidazole. 815 64

Iron overload in BALB/c mice by treatment with ferric ammonium citrate promotes the hepatic development of Plasmodium yoelii in vivo and in vitro. This was the result of increased penetration of the parasite into hepatocytes since no effect was observed on parasite transformation or maturation. These results could explain why in endemic regions iron supplementation led, in certain studies, to an increase in clinical episodes of malaria and in the prevalence of malaria infection.
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PMID:Iron overload increases hepatic development of Plasmodium yoelii in mice. 885 55

TNF, a potent immunoregulatory cytokine, is associated with inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and cerebral malaria when produced in excess. Antimalarial agents such as chloroquine and hydroxychloroquine have been used to treat some rheumatic diseases. Chloroquine was reported to inhibit production of TNF, although the underlying mechanism is poorly understood. In RAW 264.7 cells stimulated with LPS, addition of chloroquine at nontoxic concentrations did not inhibit induction of TNF mRNA and NF-kappaB activity. In the same cells, synthesis and steady state level of 26-kDa pro-TNF were also not significantly reduced by addition of chloroquine, while only small amount of 17-kDa mature TNF was detected in the medium. A pulse-chase experiment of pro-TNF produced in chloroquine-treated cells showed significant inhibition of processing of prohormone. Hydroxychloroquine showed similar inhibitory effect, whereas other lysosomal inhibitors such as ammonium chloride and methylamine had no effect on the production of TNF. Our results suggest that chloroquine inhibits production of TNF at the step of processing of membrane-bound pro-TNF to make soluble mature protein in a lysosome-independent manner.
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PMID:Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated RAW 264.7 macrophages. 914 7

A series of 80 compounds, primary, secondary, and tertiary amines and quaternary ammonium and bisammonium salts, most of them synthesized as potential choline or ethanolamine analogs, were tested against the in vitro growth of Plasmodium falciparum, the human malaria parasite. They were active over the 10(-3)-10(-8) M concentration range. A structure-activity relationship study was carried out using autocorrelation vectors as structural descriptors, and multidimensional analysis. Principal component analysis, ascending hierarchical classification, and stepwise discriminant analysis showed that both the size and shape of the molecule were essential for antimalarial potency, making the lipophilicity and electronegativity distribution in the molecular space essential. Using the autocorrelogram describing the molecular shape and the electronegativity distribution on the molecular graph, 98% of the molecules were correctly classified either as poorly active or active with only three explanatory variables. The most active compounds were quaternary ammoniums salts whose nitrogen atom had only one long lipophilic chain of 11 or 12 methylene groups (E5, E6, E10, E13, E20, E21, E22, E23, F4, F8), or the bisammoniums whose polar heads were linked by linear alkyl chains of 10 to 12 carbon atoms (G4, G23). The hydroxyethyl group of choline was not very beneficial, whereas the charge and substitutions of nitrogen (aimed at increasing lipophilicity) were essential for optimal interactions. A crude topographic model of the ligand (choline) binding site was thus drawn up.
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PMID:Antimalarial activity of molecules interfering with Plasmodium falciparum phospholipid metabolism. Structure-activity relationship analysis. 935 23

Prenylated proteins have been shown to function in important cellular regulatory processes including signal transduction. The enzymes involved in protein prenylation, farnesyl transferase and geranylgeranyl transferase, have been recent targets for development of cancer chemotherapeutics. We have initiated a systematic study of protein prenyl transferases of the malaria parasite, Plasmodium falciparum, to determine whether these enzymes can be developed as targets for antimalarial chemotherapy. We report here the identification of protein farnesyl transferase and protein geranylgeranyl transferase-I in the malaria parasite, P. falciparum. The farnesyl transferase has been partially purified from the cytosolic fraction through ammonium sulfate precipitation and Mono-Q chromatography. Farnesyl and geranylgeranyl transferase-I activities are present at all stages of P. falciparum intraerythrocytic development with maximum specific activity in the ring stage. Geranylgeranyl transferase-I specific activity is two times that of farnesyl transferase in the ring stage. Peptidomimetics and prenyl analogues of protein farnesyl transferase substrates were tested as in vitro inhibitors of partially purified P. falciparum prenyl transferase and of malaria parasite growth. The peptidomimetics were significantly more potent inhibitors than lipid substrate analogues of both the activity of Mono-Q purified enzyme and parasite growth in intraerythrocytic cultures. Exposure of the parasite to the peptidomimetic L-745,631 also showed significant inhibition of morphological development beyond the trophozoite stage. These studies suggest the potential of designing or identifying differential inhibitors of P. falciparum and mammalian prenyl transferases as an approach to novel malaria therapy.
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PMID:Protein prenyl transferase activities of Plasmodium falciparum. 974 68

The human malaria parasite, Plasmodium falciparum, induces in the plasma membrane of its host red blood cell new permeation pathways (NPP) that allow the influx of a variety of low molecular weight solutes. In this study we have demonstrated that the NPP confer upon the parasitised erythrocyte a substantial permeability to a range of monovalent organic (quaternary ammonium) cations, the largest having an estimated minimum cross-sectional diameter of 11-12 A. The rate of permeation of these cations showed a marked dependence on the nature of the anion present, increasing with the lyotropicity of the anion. There was no clear relationship between the permeation rate and either the size or the hydrophobicity of these solutes. However, the data were consistent with the rate of permeation being influenced by a combination of these two factors, with the pathways showing a marked preference for the relatively small and hydrophobic phenyltrimethylammonium ion over larger or less hydrophobic solutes. Large quaternary ammonium cations inhibited flux via the NPP, as did long-chain n-alkanols. For both classes of compound the inhibitory potency increased with the size and hydrophobicity of the solute. This study extends the range of solutes known to permeate the NPP of malaria-infected erythrocytes as well as providing some insight into the factors governing the rate of permeation.
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PMID:Increased permeability of the malaria-infected erythrocyte to organic cations. 1063 Dec 97

A simple, rapid, and accurate high-pressure liquid chromatographic method with fluorescence detection is described for the measurement of tafenoquine (TQ) (also known as WR 238605) from human plasma and venous and capillary blood. Tafenoquine was measured in plasma and venous blood following protein precipitation. Chromatographic separation was achieved using a Waters S5P Spherisorb phenyl analytical cartridge (150 mm x 4.6 mm I.D., 5 microm particle size) (Waters, Milford, MA, USA) and a mobile phase of 22 mM ammonium acetate, pH 4:acetonitrile (45:55, vol/vol). The flow rate was 1.5 mL/min and the retention times were approximately 3.5 min for WR VIIIAc (internal standard) and approximately 7.8 min for TQ. The interday and intraday coefficients of variation of TQ over a concentration range of 20-1000 ng/mL in plasma were < or =8.4% and in venous blood were < or =9.6%. The mean percent difference between added concentration and obtained concentration was 7.3% in plasma and 8.5% in venous blood over the corresponding concentration range. The limit of quantitation for both fluids was 10 ng/mL. Tafenoquine concentrations were comparable between capillary and venous blood with no significant difference between measurement in both biological fluids. The clinical application of the method was demonstrated by measuring plasma and whole blood concentrations of TQ from participants in a chemosuppression trial of the drug against malaria infections in Thailand.
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PMID:Measurement of tafenoquine (WR 238605) in human plasma and venous and capillary blood by high-pressure liquid chromatography. 1077 31


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