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)

The homodimeric flavoenzyme glutathione reductase (GR) which catalyzes the reduction of glutathione disulfide is a cornerstone of the malaria parasite antioxidant defense and repair mechanisms. Here we report on the identification of the GR gene from Plasmodium falciparum. A 1.4-kb fragment of the gene was amplified by polymerase chain reaction (PCR). Using this PCR fragment as a probe a full length cDNA clone (2085 bp) was isolated from a P. falciparum gametocyte library. The deduced amino acid sequence of 541 residues shows an overall identity of 35% when compared to the human enzyme. Most amino acids of known function are identical. However, notable differences between human and parasite protein occur in the glutathione-binding pocket (for instance, Glu374 instead of the expected basic residue) and at the intersubunit contact area. These regions are of particular interest since they represent binding sites of known GR inhibitors. Consequently, parasite GR can serve as a target structure for the design of antimalarial drugs.
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PMID:Plasmodium falciparum glutathione reductase exhibits sequence similarities with the human host enzyme in the core structure but differs at the ligand-binding sites. 871 41

In this paper we report the isolation and the characterization of a gene encoding the antioxidant enzyme glutathione peroxidase from the human malaria parasite Plasmodium falciparum. This gene contains two introns of 208 and 168 bp and is present in a single copy on chromosome 13. The open reading frame encodes a protein with a predicted length of 205 amino acids, which possesses a potential cleavage site between residues 21 and 22 after a hydrophobic region with the characteristics of a signal sequence. Therefore, the mature protein is predicted to be 184 residues long with a molecular mass of 21404 Da. In comparison with other known glutathione peroxidases many amino acid residues implicated in catalysis are conserved in the malarial enzyme. Phylogenetic analysis indicates that the deduced protein sequence is more closely related to plant glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase. A 1.5-kb transcript was identified in asynchronous erythrocytic stages.
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PMID:Molecular characterization of the glutathione peroxidase gene of the human malaria parasite Plasmodium falciparum. 881 93

A 1-year longitudinal study of hyperendemic malaria was carried out at Tha-bye-wa village, Oktwin township, situated in the forested Bago mountain range in south-central Myanmar. Mosquito infectivity was assayed using specific, sporozoite enzyme-linked immunosorbent assays. Anopheles dirus was the predominant vector in the postmonsoon season (October); during the cool-dry season (January), both An. dirus and Anopheles minimus were vectors. Members of the Anopheles culicifacies complex were caught in the hot-dry season (April) but none was infective. The entomological inoculation rate was estimated to be at least 13.7 infective bites/person/year. Infective An. dirus were caught feeding on cattle as well as on humans. Three of the 4 positive An. dirus and both positive An. minimus were caught biting humans indoors in the second quarter of the night when most people were sleeping. This suggests that use of insecticide-impregnated bednets in this area could interrupt transmission.
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PMID:Hyperendemic malaria in a forested, hilly Myanmar village. 882 97

The ookinete is a motile form of the malaria parasite that travels from the midgut lumen of the mosquito, invades the epithelial cells and settles beneath the basal lamina. The events surrounding cessation of ookinete motility and its transformation into an oocyst are poorly understood, but interaction between components of the basal lamina and the parasite surface has been implicated. Here we report that interactions occur between basal lamina constituents and ookinete proteins and that these interactions inhibit motility and are likely to be involved in transformation to an oocyst. Plasmodium berghei ookinetes bound weakly to microtitre plate wells coated with fibronectin and much more strongly to wells coated with laminin and collagen IV. A 1:1 mixture of collagen and laminin significantly enhanced binding. Binding increased with time of incubation up to 10 h and different components showed different binding profiles with time. Two parasite molecules were shown to act as ligands for basal lamina components. Western blots demonstrated that the surface molecule Pbs21 bound strongly to laminin but not to collagen IV whereas a 215 kDa molecule (possibly PbCTRP) bound to both laminin and collagen IV. Furthermore up to 90% inhibition of binding of ookinetes to collagen IV/laminin combination occurred if parasites were pre-incubated with anti-Pbs21 monoclonal antibody 13.1. Some transformation of ookinetes to oocysts occurred in wells coated with laminin or laminin/collagen IV combinations but collagen IV alone did not trigger transformation. No binding or transformation occurred in uncoated wells. Our data support the suggestion that ookinete proteins Pbs21 and a 215 kDa protein may have multiple roles including interactions with midgut basal lamina components that cause binding, inhibit motility and trigger transformation.
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PMID:The role of Plasmodium berghei ookinete proteins in binding to basal lamina components and transformation into oocysts. 1179 26

In mosquitoes the melanotic encapsulation immune response is an important resistance mechanism against filarial worms and malaria parasites. The rate limiting substrate for melanin production is tyrosine that is hydroxylated by phenoloxidase (PO) to produce 3, 4-dihydroxyphenylalanine. The single pathway for endogenous production of tyrosine is by hydroxylation of phenylalanine by phenylalanine hydroxylase (PAH). In this study we describe a potential role for PAH in melanotic immune responses in the yellow fever mosquito, Aedes aegypti. A 1.6 kb A. aegypti PAH cDNA, encoding a 51 kDa protein, was isolated and subsequently expressed in an Escherichia coli expression system. In developing mosquitoes, PAH transcript is present in all stages and it is differentially expressed in adult tissues. Following an immune-challenge with Dirofilaria immitis microfilariae (mf) or bacteria, PAH transcript is up-regulated in hemocytes. Likewise, western analysis of hemocytes collected from immune-activated mosquitoes show an increase in gene product over control samples. Like PO, ultrastructure observations provide verification that PAH is located in oenocytoid and granulocyte hemocytes. Our results offer the first data that suggest PAH is used in mosquito melanin synthesis and defense responses.
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PMID:A potential role for phenylalanine hydroxylase in mosquito immune responses. 1260 19

A 1-year prospective community-based study of malaria during pregnancy was conducted in an area of seasonal and unstable malaria transmission in eastern Sudan. At a village antenatal clinic, 89 non-pregnant controls and 86 pregnant women were enrolled and followed every 2 weeks until 6 weeks after delivery. The incidence of Plasmodium falciparum infection was significantly higher among pregnant than control women (17.4% versus 5.6%) with no difference between primigravidae and multigravidae (22.2% versus 15.2%). There was no significant difference in the mean haemoglobin concentration between infected and uninfected mothers (9.1 +/- 1.3 versus 9.5 +/- 0.6 g/dL) but the mean birth weight of their babies was significantly lower (2.72 +/- 0.26 versus 2.95 +/- 0.05 kg) despite prompt case management of infected women.
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PMID:Plasmodium falciparum infection during pregnancy in an unstable transmission area in eastern Sudan. 1574 54

Spraying of agricultural crops with insecticides can select for resistance in nontarget insects and this may compromise the use of insecticides for the control of vector-borne diseases. The tolerance of the malaria vector, Anopheles arabiensis to deltamethrin was determined in a field population from a cotton-growing region of Northern Cameroon both prior to and midway through the 4-month period of insecticide application to the cotton crop. A 1.6-fold increase in the median knockdown time was observed. To determine whether this increased tolerance was associated with constitutively elevated levels of genes commonly associated with insecticide resistance, RNA was extracted from F1 progeny from family lines of field-caught mosquitoes and hybridized to the Anopheles gambiae detox chip. The experimental design avoided the confounding effects of colonization, and this study is the first to measure gene expression in the progeny of gravid, wild-caught mosquitoes. Several genes with antioxidant roles, including superoxide dismutases, a glutathione S-transferase and a thioredoxin-dependent peroxidase, and a cytochrome P450 showed elevated expression in mosquito families collected during the insecticide-spraying programme. These genes may constitute an important general defence mechanism against insecticides. Intriguingly, the levels of expression of these genes were strongly correlated suggesting a common regulatory mechanism.
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PMID:Pyrethroid tolerance is associated with elevated expression of antioxidants and agricultural practice in Anopheles arabiensis sampled from an area of cotton fields in Northern Cameroon. 1817 25

Plasmodium falciparum malaria and human immunodeficiency virus (HIV)-1 adversely interact in the context of pregnancy, however little is known regarding the influence of co-infection on the risk of congenital malaria. We aimed to determine the prevalence of placental and congenital malaria and impact of HIV co-infection on trans-placental malaria transmission in 157 parturient women and their infants by microscopy and by quantitative real-time polymerase chain reaction (PCR) in western Kenya. The prevalence of placental and cord blood infections were 17.2% and 0% by microscopy, and 33.1% and 10.8% by PCR. HIV co-infection was associated with a significant increase in placental parasite density (P < 0.05). Cord blood malaria prevalence was increased in co-infected women (odds ratio [OR] = 5.42; 95% confidence interval [CI] = 1.90-15.47) and correlated with placental parasite density (OR = 2.57; 95% CI = 1.80-3.67). A 1-log increase in placental monocyte count was associated with increased risk of congenital infection (P = 0.001) (OR = 48.15; 95% CI = 4.59-505.50). The HIV co-infected women have a significantly increased burden of placental malaria that increases the risk of congenital infection.
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PMID:Human immunodeficiency virus co-infection increases placental parasite density and transplacental malaria transmission in Western Kenya. 1914 49

Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria. Nitric oxide (NO) reduces endothelial expression of receptors/adhesion molecules used by pRBC to adhere to vascular endothelium, and reduces cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 showed vasorelaxation activity against rat aortic ring, which may be related with NO production. A series of a hydroxyl and a nitrogen-substituted derivatives and a dehydroxy derivative of 1 have been synthesized as having potent antimalarials against P. falciparum with vasodilator activity, which may reduce cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 exhibited a potent antimalarial activity and a high selectivity index in vitro, suggesting that the presence of a hydroxyl and a nitrogen atom without any substituents may be important to show antimalarial activity. Relative to cassiarin A, a methoxy derivative showed more potent vasorelaxant activity, although it did not show improvement for inhibition of P. falciparum in vitro. These cassiarin derivatives may be promising candidates as antimalarials with different mode of actions.
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PMID:Synthesis and structure-activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity. 1989 54

Thai adult males (N = 85) with acute Plasmodium vivax malaria and normal glucose-6-phosphate dehydrogenase screening were randomized to receive 30 mg or 60 mg primaquine daily for 7 days (N = 43 and 42, respectively). The regimens were well tolerated and all patients recovered fully. Median fever clearance (47 hours; range 4 to 130 hours), mean + or - SD parasite clearance times (87.7 + or - 25.3 hours), gametocyte clearance, and adverse effects were similar in the 2 groups. Two patients, 1 from each group, had a 30% reduction in hematocrit. The cumulative 28 day relapse rate (95% confidence interval) by Kaplan Meier survival analysis was 29% (16-49%) in the 30 mg group compared with 7% (2-24%) in the 60 mg group; P = 0.027. Comparison with previous data obtained at this same site suggests that the recurrences comprised approximately 17% recrudescences and 12% relapses in the 30 mg/day group compared with 3% recrudescences and 4% relapses in the 60 mg/day group. These data suggest that the dose-response relationships for primaquine's asexual stage and hypnozoitocidal activities in-vivo are different. A 1 week course of primaquine 60 mg daily is an effective treatment of vivax malaria in this region.
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PMID:A comparison of two short-course primaquine regimens for the treatment and radical cure of Plasmodium vivax malaria in Thailand. 2034 96


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