Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nine non-immune patients with imported falciparum malaria were examined for signs of diffuse intravascular coagulation (DIC). Although all had thrombocytopenia initially and some later had a decline in plasma fibrinogen concentrations, DIC was never detected, even in severely affected patients with coma and kidney damage. None of the patients were given heparin and all recovered without residual symptoms. Heparin administration should probably be considered only when clear-cut DIC, which possibly never occurs in falciparum malaria, has been demonstrated.
 ...
PMID:Haemostatic defect in non-immune patients with falciparum malaria: no evidence of diffuse intravascular coagulation. 35 86

Rosetting, i.e. the spontaneous binding of uninfected to malaria infected erythrocytes and endothelial cytoadherence may hinder the blood flow and lead to severe Plasmodium falciparum malaria. Falciparum isolates obtained from unconscious patients all form rosettes and/or express a significantly higher mean rosetting rate than isolates from patients with uncomplicated malaria. Furthermore, sera of patients with cerebral malaria are devoid of anti-rosetting activity while sera from patients with mild disease carry high levels of anti-rosetting antibodies. The presence of anti-rosetting antibodies also seems important for the efficient interaction of rosetting infected rbc and leukocytes. Two parasite derived rosetting ligands of Mr 22K and Mr 28K named "rosettins", have been found on the surface of rosetting infected erythrocytes. CD36 has in at least some strains of parasites been found to function as a rosetting receptor on the uninfected erythrocyte. Heparin disrupts rosettes of P. falciparum in vitro and inhibits the sequestration of rosetting cells ex vivo. In conclusion, rosetting seems a crucial factor in the development of cerebral malaria and treatment of patients with anti-rosetting substances might become an effective adjunct in the treatment of severe malaria.
 ...
PMID:Molecular mechanisms and biological importance of Plasmodium falciparum erythrocyte rosetting. 128 15

Heparin and various heparin fractions were separated according to differences in molecular weight or affinity for antithrombin III and used for the inhibition of Plasmodium falciparum merozoite invasion of red blood cells in vitro. No variation in sensitivity to heparin was found among the four strains of P. falciparum tested; all required approximately 5 micrograms/ml (0.5 U/ml) of heparin for 50% inhibition of invasion. The most efficient fraction of heparin was the one with low affinity for antithrombin III. Its 50% inhibition concentration was 1 microgram/ml, indicating that it was more efficient than unfractionated heparin and other heparin fractions. The effect of heparin was reversible, since washing of heparin-treated cultures containing mainly schizonts showed no inhibition of merozoite invasion. The results suggest that a heparin fraction with no anticoagulant effect might be useful in the treatment of patients with falciparum malaria.
 ...
PMID:Effect of different fractions of heparin on Plasmodium falciparum merozoite invasion of red blood cells in vitro. 159 53

We have studied the ability of heparin to disrupt spontaneous rosettes formed between Plasmodium falciparum-infected and uninfected red blood cells, which has been proposed to have importance in the pathogenesis of cerebral malaria. Substantial variation in this activity was found among six laboratory stains of P. falciparum. Rosettes formed by three of these strains were highly sensitive to heparin (50% disruption at 0.5-25 micrograms/ml; 1 microgram/ml corresponds to 0.15 IU/ml). The rosettes formed by two other strains showed a much lower sensitivity (50% disruption at 700-2,500 micrograms/ml), while the rosettes formed by another strain were almost completely resistant to heparin (20% disruption at 6,500 micrograms/ml). The ability of heparin (65 or 650 micrograms/ml) to disrupt rosettes formed by 54 fresh Gambian isolates of P. falciparum also varied. Rosettes of 27 (50%) of the 54 isolates were disrupted to a significant degree (greater than or equal to 15%), while rosettes of the other 27 isolates remained unaffected at the concentrations tested. Heparin was fractionated by molecular weight and/or affinity for antithrombin III. We found that its property of rosette disruption was associated, to some extent, with size (high molecular weight) but not with its anticoagulant potential (affinity for antithrombin III). A heparin fraction with low affinity for antithrombin III and one with combined high molecular weight and low affinity for antithrombin III were as effective at disrupting rosettes as standard heparin, while a chemically modified (N-acetylated) high molecular weight-heparin fraction, similarly devoid of anticoagulant activity, lacked strong anti-rosette potential.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Disruption of Plasmodium falciparum erythrocyte rosettes by standard heparin and heparin devoid of anticoagulant activity. 159 54

Eleven of 43 nonimmune patients with falciparum malaria had one or several organ complications: cerebral malaria, acute respiratory failure, acute renal failure, secondary infection, autoimmune haemolysis, spontaneous spleen rupture, and acute pancreatitis. Parasitaemia was 0.1 to 60%. Initial antiparasitic therapy with quinine given parenterally resulted in rapid regression of parasitaemia. An additional schizonticide agent was given depending on parasitic resistance. Supportive therapy comprised intensive-care monitoring including fluid and electrolyte balance and, if necessary, early haemodialysis and (or) endotracheal intubation with PEEP breathing. In one patient with excessive parasitaemia exchange transfusion was performed. Heparin was given only in proven disseminated intravascular coagulation, corticosteroids only in persistent autoimmune haemolysis. All patients survived without suffering permanent defects. Retrospective analysis shows that, apart from rapid specific therapy, supportive treatment of the individual organ complications determines course and prognosis of complicated falciparum malaria.
 ...
PMID:[Complicated malaria tropica: specific and supportive therapy in the imported diseases]. 351 46

The asexual erythrocytic stage of Plasmodium falciparum was grown in culture in the presence or absence of glycoconjugate polyanions of varying structure, size and substitutions. Heparin, dextran sulfate, fucoidan and pentosan polysulfate had antimalarial IC50 values between one and 11 microg ml(-1). Constituent heparin disaccharides were ineffective against the malaria parasite and desulfation from either the O- or N-substitution sites of heparin or reduction of the uronic acid carboxyl group neutralized the antimalarial response to varying degrees. Immobilization of heparin onto agarose beads still permitted antimalarial activity suggesting that parasite uptake of the glycoconjugate is not required for inhibition. Accordingly, it is concluded that invasion of free parasites into the erythrocytes was inhibited rather than parasite maturation within the red cell. Merozoite surface antigen-1 was apparently prevented from binding to human erythrocytes in the presence of highly sulfated polyanions and, in a dose-dependent fashion, heparin.
 ...
PMID:Saccharide anions as inhibitors of the malaria parasite. 924 45

Glycosaminoglycans such as heparin, heparan sulphate and dermatan sulphate, are distributed widely in the human body. Several glycosaminoglycans form part of the extracellular matrix and heparan sulphate is expressed on all eukaryotic surfaces. The identification of specific binding to different glycosaminoglycan molecules by bacteria (e.g., Helicobacter pylori, Bordetella pertussis and Chlamydia trachomatis), viruses (e.g., herpes simplex and dengue virus), and protozoa (e.g., Plasmodium and Leishmania), is therefore of great interest. Expression of glycosaminoglycan-binding proteins depends on growth and culture conditions in bacteria, and differs in various phases of parasite development. Glycosaminoglycan-binding microbial proteins may mediate adhesion of microbes to eukaryotic cells, which may be a primary mechanism in mucosal infections, and are also involved in secondary effects such as adhesion to cerebral endothelia in cerebral malaria or to synovial membranes in arthritis caused by Borrelia burgdorferi. It has been suggested that they may enhance intracellular survival in macrophages. Microbial binding of heparin may interfere with heparin-dependent growth factors. Whether or not glycosaminoglycan-binding proteins mediate invasion of epithelial cells is a matter of controversy. Heparin and other glycosaminoglycans may have potential uses as therapeutic agents in microbial infections and could form part of future vaccines against such infections.
 ...
PMID:Glycosaminoglycan-binding microbial proteins in tissue adhesion and invasion: key events in microbial pathogenicity. 1033 89

Various pathogenic bacteria, viruses, and protozoan bind to glycosaminoglycan-based receptors on host cells and initiate an infection. Sporozoites of Plasmodium predominantly express circumsporozoite (CS) protein on their surface, which binds to heparan sulfate proteoglycans on liver cell surface that subsequently leads to malaria. Here we show that the interaction of free heparin with this parasite ligand has the potential to be a critical component of invasion. CS protein of P. falciparum contains four cysteines at positions 361, 365, 396, and 401. In this study, all four cysteine residues were mutagenized to alanine both individually and in different combinations. Conversion of cysteine 396 to alanine (protein CS3) led to a 10-fold increase in the binding activity of the protein to HepG2 cells. Replacement of cysteines at positions 361, 365, and 401 either alone or in different combinations led to a near total loss of binding. Surprisingly, activity in these inactive mutants could be effectively restored in the presence of submolar concentrations of heparin. Heparin also up-regulated binding of CS3 at submolar concentrations with respect to the protein but down-regulated binding when present in excess. Given the significantly different concentrations of heparin in different organs of the host and the in vitro results described here one can consider in vivo ramifications of this phenomenon for pathogen targeting of specific organs and for the functional effects of antigenic variation on receptor ligand interaction.
 ...
PMID:Role of cysteines in Plasmodium falciparum circumsporozoite protein: interactions with heparin can rejuvenate inactive protein mutants. 1089 Sep 3

Circumsporozoite (CS) protein is a predominant surface antigen of malaria sporozoites, the infective form of the parasite, and has been used for making anti-malaria vaccines. For the first time we have examined the interaction of CS protein with various glycosaminoglycans in real time using surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Heparin was the best binder among the glycosaminoglycans tested and bound to CS protein with nanomolar affinity. Using purified and structurally defined small heparin oligosaccharides, we identified a decasaccharide to be the minimum sized CS protein-binding sequence. In an indirect competition assay, this decasaccharide blocked the CS protein interaction with HepG2 cells with an ID(50) of less than 60 nM. The decasaccharide has a structure commonly found in hepatic heparan sulfate, and the same sequence has recently been shown to bind specifically to apolipoprotein E. Examination of porcine liver heparan sulfate in this indirect competition assay showed that it and heparin were the only glycosaminoglycans that could effectively block CS protein interaction with HepG2 cells in culture. These data support the hypothesis that the invasion of liver cells by the parasite shares a common mechanism with the hepatic uptake of lipoprotein remnants from the blood.
 ...
PMID:Direct measurement of the interactions of glycosaminoglycans and a heparin decasaccharide with the malaria circumsporozoite protein. 1156 May

Circumsporozoite protein (CSP) coats the malarial sporozoite and functions to target the liver for infection, which is the first step to developing malaria. An important tissue ligand for CSP is the glycosaminoglycan heparan sulfate (HS) found on the surface of hepatocytes and in the basement membrane of the space of Disse. To better understand this efficient targeting process, we set out to identify and characterize the HS binding site(s) of CSP. We synthesized a series of peptides corresponding to five regions of Plasmodium falciparum CSP containing basic residues, a common requirement of HS binding sites, and screened them for heparin and HS binding activity. Only one of these peptides (Pf 2), which contains a motif we have named region I-plus, demonstrated both high affinity heparin/HS binding activity and the ability to block the binding of recombinant CSP to heparin-Sepharose 4B. Analysis by isothermal titration calorimetry revealed that region I-plus has a binding constant of K(d) = 5.0 microm and a stoichiometry of n = 7.8 binding sites/heparin chain. Heparin binding was dependent on the amino acid sequence of region I-plus, and the binding sites on heparin/HS are contained within a decasaccharide. Furthermore, HS oligosaccharides rich in sulfate and iduronic acid content (heparin-like) are required for efficient binding. Because liver HS is exceptionally high in both these components relative to the HS of other organs, the HS structural requirements for efficient region I-plus/HS binding are consistent with this peptide sequence functioning to target sporozoites to the liver for attachment to hepatocytes. Finally, the region I-plus heparin/HS binding site was also discovered for two other species that infect humans, Plasmodium malariae and Plasmodium vivax, further supporting the existence of a HS binding domain in the N-terminal portion of CSP.
 ...
PMID:A binding site for highly sulfated heparan sulfate is identified in the N terminus of the circumsporozoite protein: significance for malarial sporozoite attachment to hepatocytes. 1500 56


1 2 Next >>