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 serum proteins supposed to be indicative of the nutritional status, albumin, prealbumin and transferrin, as well as the serum proteinase inhibitors alpha 1-protease inhibitor (alpha 1-antichymotrypsin (Ach) and alpha 2-macroglobulin (alpha 2M) were measured in 14 Thai males suffering from uncomplicated falciparum malaria on the day of admission and after treatment with mefloquin on the 2nd, 28th and 63rd day. The same serum proteins had been determined from 31 healthy Thai males. Upon admission albumin and prealbumin concentrations had been lower and Ach higher in malaria patients compared with healthy Thai males. A significantly higher alpha 1 PI value was observed on the day of admission compared with the 28th day of the malaria patients. Only on the day of admission and only for the patients was a statistically significant negative linear regression found for albumin and prealbumin with Ach and a positive correlation for prealbumin with alpha 2 M as well as for albumin and transferrin correlated with alpha 1 PI. In well-nourished malaria patients the synthesis of the "acute phase reactants", alpha 1 PI and Ach, might be enhanced and in a reverse relationship the synthesis of albumin, pre-albumin and transferrin depressed.
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PMID:Human serum proteins indicative for the nutritional status and serum proteinase inhibitors in uncomplicated falciparum malaria. 619 95

The human malaria parasite, Plasmodium falciparum, degrades nearly all its host cell hemoglobin during a short segment of its intraerythrocytic development. This massive catabolic process occurs in an acidic organelle, the digestive vacuole. Aspartic and cysteine proteases have been implicated in this pathway. We have isolated three vacuolar proteases that account for most of the globin-degrading activity of the digestive vacuole. One is the previously described aspartic hemoglobinase that initiates hemoglobin degradation. A second aspartic protease is capable of cleaving hemoglobin with an overlapping specificity, but seems to prefer acid-denatured globin. The third is a cysteine protease that does not recognize native hemoglobin but readily cleaves denatured globin. It is synergistic with the aspartic hemoglobinase, both by in vitro assay of hemoglobin degradation, and by isobologram analysis of protease inhibitor-treated parasites in culture. The cysteine protease is highly sensitive to chloroquine-heme complex, suggesting a possible mechanism of 4-aminoquinoline antimalarial action. The data suggest an ordered pathway of hemoglobin catabolism that presents an excellent target for chemotherapy.
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PMID:Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. 816 38

We performed a gene expression screen of the entire transcriptome of the major African malaria vector Anopheles gambiae for immune response genes in adult female mosquitoes, which is the developmental stage infected by malaria parasites. Mosquitoes were immune-stimulated for subtractive cloning by treatment with bacterial lipopolysaccharide, a potent and general elicitor of the innate immune response, and by injury. The screen yielded a highly enriched cDNA library in which more than half of the clones were immune responsive. In this paper, we describe 23 immune-regulated genes, including putative protease inhibitors, serine proteases, regulatory molecules, and a number of genes without known relatives. A molecule related to the protease inhibitor alpha-2-macroglobulin responded strongly to malaria parasite infection, but displayed little or no response to bacteria, whereas other genes exhibited the inverse pattern. These results indicate that the insect immune system discriminates between molecular signals specific to infection with bacteria and malaria parasites.
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PMID:Genes identified by an expression screen of the vector mosquito Anopheles gambiae display differential molecular immune response to malaria parasites and bacteria. 1100 29

We characterize a novel hemocyte-specific acute phase glycoprotein from the malaria vector, Anopheles gambiae. It shows substantial structural and functional similarities, including the highly conserved thioester motif, to both a central component of mammalian complement system, factor C3, and to a pan-protease inhibitor, alpha2-macroglobulin. Most importantly, this protein serves as a complement-like opsonin and promotes phagocytosis of some Gram-negative bacteria in a mosquito hemocyte-like cell line. Chemical inactivation by methylamine and depletion by double-stranded RNA knockout demonstrate that this function is dependent on the internal thioester bond. This evidence of a complement-like function in a protostome animal adds substantially to the accumulating evidence of a common ancestry of immune defenses in insects and vertebrates.
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PMID:Conserved role of a complement-like protein in phagocytosis revealed by dsRNA knockout in cultured cells of the mosquito, Anopheles gambiae. 1125 25

Malaria places an increasing burden on global public health resources. In the face of growing resistance of the malaria parasite to available antimalarial drugs, there is a need for new drugs and the identification of new chemotherapeutic targets. The malaria parasite has a complex life cycle which includes a number of obligate intracellular stages. Clinical malaria results from cyclic asexual replication of the blood-stage parasite in circulating erythrocytes of the human host. Erythrocyte entry and host cell rupture require the activity of parasite proteases, and these enzymes are, therefore, attractive targets for rational approaches to new drug development. Malarial proteases play a role in at least two distinct aspects of host cell invasion; modification of parasite proteins involved in host cell recognition and entry; and restructuring of the host cell itself, during and following invasion, and in order to allow parasite release from the host cell. This review details recent advances in the identification of these proteases, describes current understanding of their activation and functional role, and discusses their potential as targets for protease inhibitor-based drugs.
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PMID:Proteases involved in erythrocyte invasion by the malaria parasite: function and potential as chemotherapeutic targets. 1147 36

Erythrocytic malaria parasites degrade hemoglobin in an acidic food vacuole to acquire free amino acids and maintain parasite homeostasis. Hemoglobin hydrolysis appears to be a cooperative process requiring cysteine proteases (falcipains) and aspartic proteases (plasmepsins), but the specific roles of different enzymes in this process are unknown. We previously showed that falcipain-2 is a major trophozoite food vacuole cysteine protease. To characterize the specific role of falcipain-2, we disrupted the falcipain-2 gene and assessed the effect of this alteration. Falcipain-2-knockout trophozoites had markedly diminished cysteine protease activity and swollen, dark staining food vacuoles, consistent with a block in hemoglobin hydrolysis, as caused by cysteine protease inhibitors. However, more mature stages of knockout parasites were indistinguishable from wild-type parasites and developed normally. The knockout parasites had decreased and delayed expression of falcipain-2, which appeared to be directed by increased transcription of a second copy of the gene (falcipain-2'). Expression of other falcipains and plasmepsins was similar in wild-type and knockout parasites. Compared with wild-type, knockout parasites were about 3 times more sensitive to the cysteine protease inhibitors E-64 and leupeptin, and over 50-fold more sensitive to the aspartic protease inhibitor pepstatin. Our results assign a specific function for falcipain-2, the hydrolysis of hemoglobin in trophozoites. In addition, they highlight the cooperative action of cysteine and aspartic proteases in hemoglobin degradation by malaria parasites.
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PMID:Gene disruption confirms a critical role for the cysteine protease falcipain-2 in hemoglobin hydrolysis by Plasmodium falciparum. 1507 Jul 27

The plasmepsins are the aspartic proteases of malaria parasites. Treatment of aspartic protease inhibitor inhibits hemoglobin hydrolysis and blocks the parasite development in vitro suggesting that these proteases might be exploited their potentials as antimalarial drug targets. In this study, we determined the genetic variations of the aspartic proteases of Plasmodium vivax (PvPMs) of wild isolates. Two plasmepsins (PvPM4 and PvPM5) were cloned and sequenced from 20 P. vivax Korean isolates and two imported isolates. The sequences of the enzymes were highly conserved except a small number of amino acid substitutions did not modify key residues for the function or the structure of the enzymes. The high sequence conservations between the plasmepsins from the isolates support the notion that the enzymes could be reliable targets for new antimalarial chemotherapeutics.
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PMID:Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates. 1518 45

Organ failure in Plasmodium falciparum malaria is associated with neutrophil activation and endothelial damage. This study investigates whether neutrophil-induced endothelial damage involves apoptosis and whether it can be prevented by neutralization of neutrophil secretory products. Endothelial cells from human umbilical veins were coincubated with neutrophils from healthy donors and with sera from eight patients with P. falciparum malaria, three patients with P. vivax malaria, and three healthy controls. Endothelial apoptosis was demonstrated by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and annexin V staining. The rate of apoptosis of cells was markedly increased after incubation with patient serum compared to that with control serum. Apoptosis was most pronounced after incubation with sera from two patients with fatal cases of P. falciparum malaria, followed by sera of survivors with severe P. falciparum malaria and, finally, by sera of patients with mild P. falciparum and P. vivax malaria. Ascorbic acid, tocopherol, and ulinastatin reduced the apoptosis rate, but gabexate mesilate and pentoxifylline did not. Furthermore, in fatal P. falciparum malaria, apoptotic endothelial cells were identified in renal and pulmonary tissue by TUNEL staining. These findings show that apoptosis caused by neutrophil secretory products plays a major role in endothelial cell damage in malaria. The antioxidants ascorbic acid and tocopherol and the protease inhibitor ulinastatin can reduce malaria-associated endothelial apoptosis in vitro.
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PMID:Plasmodium falciparum Malaria: reduction of endothelial cell apoptosis in vitro. 1573 Oct 77

Bloodstage malaria parasites require proteolytic activity for key processes as invasion, hemoglobin degradation and merozoite escape from red blood cells (RBCs). We investigated by confocal microscopy the presence of cysteine-protease activity elicited by calcium stimulus in Plasmodium chabaudi and Plasmodium falciparum in free trophozoites or for the later parasite within RBC using fluorescence resonance energy transfer (FRET) peptides. Peptide probes access, to either free or intraerythrocytic parasites, was also tested by selecting a range of fluorescent peptides (653-3146 Da molecular mass) labeled with Abz or FITC. In the present work we show that Ca2+ stimulus elicited by treatment with either melatonin, thapsigargin, ionomicin or nigericin, promotes an increase of substrate hydrolysis, which was blocked by the specific cysteine-protease inhibitor E-64 and the intracellular Ca2+ chelator, BAPTA. When parasites were treated with cytoplasmic Ca2+ releasing compounds, a cysteine-protease was labeled in the parasite cytoplasm by the fluorescent specific irreversible inhibitor, Ethyl-Eps-Leu-Tyr-Cap-Lys(Abz)-NH2, where Ethyl-Eps is Ethyl-(2S,3S)-oxirane-2,3-dicarboxylate. In summary, we demonstrate that P. chabaudi and P. falciparum have a cytoplasmic dependent cysteine-protease activity elicited by Ca2+.
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PMID:Cysteine-protease activity elicited by Ca2+ stimulus in Plasmodium. 1581 28

Invasion of red blood cells by the malaria merozoite is an essential step in the life cycle of this obligate intracellular pathogen. The molecular details of invasion are only recently becoming understood, largely through studies in related apicomplexan parasites such as Toxoplasma. Protease activity is required for successful invasion to disengage interactions between parasite adhesins and host cell receptors. Shedding of at least two essential surface proteins from the merozoite is thought to occur continuously during invasion as the parasite moves into the nascent parasitophorous vacuole. This shedding is performed by way of juxtamembrane cleavage and is mediated by a sheddase, which probably belongs to the subtilisin-like superfamily. Recent revelations have shown that transmembrane adhesins that are secreted onto the Toxoplasma tachyzoite surface and capped to its posterior pole are shed by way of cleavage within their transmembrane domains. A family of intramembrane serine proteases called rhomboids have now been identified within Apicomplexa, and one Toxoplasma rhomboid has been localized to the posterior end of the parasite. This supports their role in capping proteolysis. Proteases involved in invasion constitute potential targets for the development of new protease inhibitor-based drugs.
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PMID:The role of malaria merozoite proteases in red blood cell invasion. 1601 57


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