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)

Plasmodium falciparum-infected erythrocytes (pRBCs) adhere to the endothelium via receptors expressed on the surface of vascular endothelial cells (EC) and sequester in the microvasculature of several organs and block the blood circulation. The sequestration, which involves receptors, may be related to the severity of malaria. Here, we report that pRBCs bind to the membrane-bound form of Fractalkine/CX3CL1 (FKN), which is expressed on the surface of vascular EC in various organs. pRBCs adhered to FKN on the surface of FKN cDNA-transfected Chinese hamster ovary cells (CHO-FKN cells). Both the recombinant human FKN-chemokine domain (FKN-CD) and anti-FKN-CD antibody efficiently blocked adherence of pRBCs to CHO-FKN cells. Similar to binding between FKN and FKN receptor on blood mononuclear cells, two amino acid residues, Lys-7 and Arg-47 within FKN-CD, were critical for FKN-pRBC binding. Immunohistological analysis revealed the expression of FKN on EC at the site of sequestration in the brain of a patient with cerebral malaria. These results suggest that the membrane-bound form of FKN acts as a receptor for pRBCs, and this may contribute to furthering our present understanding of cytoadherence in the pathology of falciparum malaria.
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PMID:Binding of Plasmodium falciparum-infected erythrocytes to the membrane-bound form of Fractalkine/CX3CL1. 1466 93

Throughout the intraerythrocytic phase of its lifecycle the malaria parasite is separated from the extracellular medium by the plasma membrane of its host erythrocyte and by the parasitophorous vacuole in which the parasite is enclosed. The intracellular parasite itself has, at its surface, a plasma membrane, and has a variety of membrane-bound organelles which carry out a range of biochemical functions. Each of the various membranes of the infected cell have in them proteins that facilitate the movement of molecules and ions from one side of the membrane to the other. These 'channels' and 'transporters' play a central role in the physiology of the parasitised cell. From a clinical viewpoint they are of interest both as potential targets in their own right, and as potential drug targeting routes capable of mediating the entry of cytotoxic drugs into the appropriate compartment of the infected cell. In this review both of these aspects are considered.
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PMID:Channels and transporters as drug targets in the Plasmodium-infected erythrocyte. 1474 55

Bupleuri Radix (Chai-hu in Chinese and Saiko in Japanese) is one of the most important traditional Chinese crude drugs for treating hepatitis malaria and intermittent fever. B. kaoi is one of the Bupleurum spp. families locally found in Taiwan. The effects of saponin-enriched fraction (SEF) from Bupleurum Kaoi in human non-small cell lung cancer A549 cells were investigated in this study. An enhancement in Fas and its two forms of ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), was responsible for the apoptotic effect induced by SEF. Taken together, our study suggests that the activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of SEF in A549 cells.
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PMID:The antiproliferative activity of saponin-enriched fraction from Bupleurum Kaoi is through Fas-dependent apoptotic pathway in human non-small cell lung cancer A549 cells. 1525 50

High frequency of erythrocyte (red blood cell [RBC]) genetic disorders such as sickle cell trait, thalassemia trait, homozygous hemoglobin C (Hb-C), and glucose-6-phosphate dehydrogenase (G6PD) deficiency in regions with high incidence of Plasmodium falciparum malaria and case-control studies support the protective role of those conditions. Protection has been attributed to defective parasite growth or to enhanced removal of the parasitized RBCs. We suggested enhanced phagocytosis of rings, the early intraerythrocytic form of the parasite, as an alternative explanation for protection in G6PD deficiency. We show here that P falciparum developed similarly in normal RBCs and in sickle trait, beta- and alpha-thalassemia trait, and HbH RBCs. We also show that membrane-bound hemichromes, autologous immunoglobulin G (IgG) and complement C3c fragments, aggregated band 3, and phagocytosis by human monocytes were remarkably higher in rings developing in all mutant RBCs considered except alpha-thalassemia trait. Phagocytosis of ring-parasitized mutant RBCs was predominantly complement mediated and very similar to phagocytosis of senescent or damaged normal RBCs. Trophozoite-parasitized normal and mutant RBCs were phagocytosed similarly in all conditions examined. Enhanced phagocytosis of ring-parasitized mutant RBCs may represent the common mechanism for malaria protection in nonimmune individuals affected by widespread RBC mutations, while individuals with alpha-thalassemia trait are likely protected by a different mechanism.
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PMID:Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait. 1528 Feb 4

Band 3 modifications that normally occur during physiological red blood cell (RBC) senescence in humans, and occasionally in pathological conditions are described in the context of their role in enhancing RBC recognition and phagocytic removal. Band 3 modifications are mostly due to oxidative insults that gradually accumulate during the RBC lifespan or impact massively in a shorter time period in pathological conditions. The oxidative insults that impact on the RBC, the protective mechanisms that counteract those damages and the phenotypic modifications that accumulate during the RBC lifespan are described. It is shown how specific oxidative as well as non-oxidative band 3 modifications enhance RBC membrane affinity for normally circulating anti-band 3 antibodies, and how membrane-bound anti-band 3 antibodies bring about a limited complement activation and membrane deposition of complement C3 fragments. The partially covalent complexes between anti-band 3 antibodies and complement C3 fragments are very powerful opsonins readily recognized by the CR1 complement receptor on the phagocyte. Band 3 modifications typically encountered in old RBCs have crystallized to a number of band 3-centered models of RBC senescence. One of those band 3-centered models, the so-called 'band 3/complement RBC removal model' first put up by Lutz et al. is discussed in more detail. Finally, it is shown how the genetic deficiency of glucose-6-phosphate dehydrogenase (G6PD) plus fava bean consumption, and a widespread RBC parasitic disease, P. falciparum malaria, may lead to massive and rapid destruction of RBCs by a mechanism comparable to a dramatic, time-compressed enhancement of normal RBC senescence.
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PMID:Band 3/complement-mediated recognition and removal of normally senescent and pathological human erythrocytes. 1630 14

Type I signal peptidases are important membrane-bound serine proteases responsible for the cleavage of the signal peptide of the proteins. These enzymes are unique serine proteases that carry out catalysis using a serine/lysine catalytic dyad. In the present study, we report the isolation of type I signal peptidase from the malaria parasites Plasmodium falciparum, Plasmodium knowlesi, and Plasmodium yoelii and some characterization of type I signal peptidase of Plasmodium falciparum. We show that these enzymes are homologous to signal peptidases from various sources and also contain the conserved boxes present in other type I signal peptidases. The type I signal peptidase from P falciparum is an intron-less and a single-copy gene. The results also show that the enzyme from Plasmodium falciparum is subject to self-cleavage and it has been demonstrated to possess type I signal peptidase activity in E coli preprotein processing in vivo by complementation assay. This study will be helpful in understanding one of the important metabolic pathways "the secretory pathway" in the parasite and should make an important contribution in understanding the complex process of protein targeting in the parasite.
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PMID:Isolation and characterization of type I signal peptidase of different malaria parasites. 1648 63

The proliferation of the intraerythrocytic malaria parasite is dependent on the uptake from the blood plasma, and from the cytoplasm of the host cell, of a range of essential nutrients. These compounds are taken up into the parasitised cell via a combination of constitutively active endogenous host cell transporters and new parasite-induced permeability pathways. On entering the infected cell they are taken up by the intracellular parasite, across the parasitophorous vacuole and parasite plasma membranes, via a combination of channels and transporters, and/or via endocytosis. Once inside the parasite, nutrients are typically phosphorylated and thereby effectively trapped within the cell. The intraerythrocytic parasite has a range of subcellular membrane-bound organelles, each endowed with their own complement of transport proteins which mediate the uptake and efflux of metabolic substrates and byproducts. Proteins that mediate the uptake, intracellular trafficking and metabolism of essential nutrients in the Plasmodium-infected erythrocyte are potential antimalarial drug targets. Here we consider the nature of the pathways involved, focusing in particular on those that mediate the uptake of three important nutrients: glucose, the key energy-substrate for the parasite; pantothenate (vitamin B(5)), the precursor of the important enzyme cofactor, coenzyme A; and choline, the precursor of the phospholipid phosphatidylcholine.
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PMID:Targeting nutrient uptake mechanisms in Plasmodium. 1726 32

At the present time, adenylyl cyclases (ACs)--the enzymes, catalyzing the formation of second messenger cAMP, were found in yeasts and related fungi, amoeba Dictyostelium discoideum, flagellates, malaria plasmodium, ciliates. However, structural-functional organization of the ACs and molecular mechanisms of its regulation are different to great extent. The scores of structurally related ACs, one time penetrating the membrane and possessing the receptor function, were identified in flagellates. Three types of ACs, strongly differed in the topology, the domain organization and the sensitivity to regulatory molecules and physical factors, were found in amoeba D. discoideum. One of them (AC-A) is close to membrane-bound ACs of the mammals and can be regulated by extracellular cAMP. It was shown that the enzymes of the yeasts, lacking the transmembrane domains, formed the intermolecular complexes, which were stabilized by the interactions between leucine-rich repeat regions. The data presented in the review give evidence that the main molecular mechanisms of the functioning of vertebrate ACs were formed in unicellular organisms and fungi. At the same time the structure and functions of the ACs of the lower eukaryotes are strongly varied. It can be connected with the special features of life cycle of the lower eukaryotes and with the realization of different models of functioning and regulation of cAMP-dependent cascades at the earlier steps of evolution.
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PMID:[Structural-functional organization of the adenylyl cyclases in unicellular eukaryotes and molecular mechanisms of its regulation]. 1743 94

The human malaria parasite Plasmodium falciparum resides and multiplies within a membrane-bound vacuole in the cytosol of its host cell, the mature human erythrocyte. To enable the parasite to complete its intraerythrocytic life cycle, a large number of parasite proteins are synthesized and transported from the parasite to the infected cell. To gain access to the erythrocyte, parasite proteins must first cross the membrane of the parasitophorous vacuole (PVM), a process that is not well understood at the mechanistic level. Here, we review past and current literature on this topic, and make tentative predictions about the nature of the transport machinery required for transport of proteins across the PVM, and the molecular factors involved.
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PMID:Protein transport across the parasitophorous vacuole of Plasmodium falciparum: into the great wide open. 1794 5

The human malaria parasite Plasmodium falciparum exports a variety of its proteins through its endoplasmic reticulum (ER) based secretory pathway in order to survive in the host erythrocyte. Signal peptidases are membrane-bound endopeptidases and have an important role in the transport and maturation of these parasite proteins. Prokaryotic signal peptidases are indispensable enzymes required for the removal of N-terminal signal peptide from the secretory proteins. Eukaryotic signal peptidases exist as multimeric protein complex in the ER and the catalytic subunit of this complex catalyzes removal of the N-terminal signal peptide from preproteins. All the signal peptidases contain five regions of high-sequence similarity referred to as boxes A-E. Here we report characterization of the catalytic subunit of signal peptidase complex (SPC) from P. falciparum. This protein designated as PfSP21 shows homology with the similar subunit from other sources and contains all the conserved boxes A-E. PfSP21 is able to cleave the peptide substrate containing the signal peptidase cleavage site. PfSP21 is phosphorylated by protein kinase C and its enzyme activity was upregulated after this phosphorylation. Immunofluorescence assay studies revealed that PfSP21 is localized in the ER of P. falciparum. PfSP21 dsRNA specifically inhibits the growth of P. falciparum in culture and this inhibition is most likely due to the decrease in the amount of endogenous PfSP21 protein. These studies demonstrate the characterization of a functional subunit of SPC from P. falciparum and should make an important contribution in our better understanding of the complex process of protein translocation in the parasite.
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PMID:Plasmodium falciparum signal peptidase is regulated by phosphorylation and required for intra-erythrocytic growth. 1805 93


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