[_] 1: J Infect Dis 2001 May 1;183(9):1388-94
Regulatory interactions between iron and nitric oxide
metabolism for immune defense against Plasmodium falciparum
infection.
Fritsche G, Larcher C, Schennach H, Weiss G.
Department of Internal Medicine, University Hospital, Anichstr.
35, A-6020 Innsbruck, Austria.
Iron chelation therapy of Plasmodium falciparum infection
alleviates the clinical course of cerebral malaria in children.
This study assessed the underlying mechanisms of this therapy.
Cytokine stimulation of human (intestinal cell line DLD-1) or
murine cells (murine macrophage cell line RAW 264.7) resulted
in increased nitric oxide (NO) formation and decreased survival
of plasmodia within cocultured human erythrocytes. The addition
of desferrioxamine (DFO) before cytokine treatment increased
both NO formation and parasite killing but had no effect in the
presence of the inhibitor of NO formation,
L-N6-(1-iminoethyl)-lysine. Moreover, peroxynitrite, which is
formed after chemical reaction of NO with superoxide, appears
to be the principal effector molecule for macrophage-mediated
cytotoxicity toward P. falciparum, and interferon-gamma is a
major regulatory cytokine for this process. The effect of DFO
on the clearance of plasmodia appears to be due to enhanced
generation of NO, rather than to limitation of iron
availability to the parasite.
MeSH Terms:
+ Animal
+ Cells, Cultured
+ Coculture
+ Deferoxamine/therapeutic use*
+ Erythrocytes/parasitology
+ Erythrocytes/immunology
+ Human
+ Interferon Type II/immunology
+ Iron/metabolism*
+ Iron Chelating Agents/therapeutic use*
+ Lipopolysaccharides/immunology
+ Macrophages/parasitology
+ Macrophages/immunology
+ Malaria, Falciparum/immunology*
+ Malaria, Falciparum/drug therapy
+ Mice
+ Nitric Oxide/toxicity
+ Nitric Oxide/biosynthesis*
+ Plasmodium falciparum/metabolism
+ Plasmodium falciparum/immunology
+ Plasmodium falciparum/drug effects*
+ RNA, Messenger/analysis
+ Superoxide Dismutase/metabolism
+ Support, Non-U.S. Gov't
+ Tumor Cells, Cultured
Substances:
+ Superoxide Dismutase
+ Interferon Type II
+ Iron
+ Deferoxamine
+ Nitric Oxide
+ RNA, Messenger
+ Lipopolysaccharides
+ Iron Chelating Agents
PMID: 11294671 [PubMed - indexed for MEDLINE]
_________________________________________________________________
Subject: malaria
====================================
Principal Investigators
A. Shanzer, Dept. of Organic Chemistry
Z.I. Cabantchik, Dept. of Biological Chemistry, Hebrew University of
Jerusalem
LIPOPHILIC IRON CHELATORS, TREATMENT OF MALARIA, HEMOCHROMATOSIS AND IRON
LOADING CONDITIONS
Iron sequestering compounds are also known to arrest the
growth of malaria parasites including Plasmodium falciparum and are
used as antimalarial drugs.
==================================================
PARASITOLOGY ... Study Confirms Iron Supplements Increase Malaria
Parasite Development
________________________________________________________________
Study Confirms Iron Supplements Increase Malaria Parasite Development
Iron overload in mice increases the hepatic development of malaria
parasites.
The finding might explain why malaria was made worse in endemic
regions where iron supplementation was implemented, suggested J. Goma,
INSERM, Paris, France, and colleagues ("Iron Overload Increases
Hepatic Development of Plasmodium yoelii in Mice," Parasitology,
1996;112:165-168).
_________________________________________________________________
Subject: malaria/transferrin
Blood 1995 Jun 1;85(11):3297-301
Transferrin saturation and recovery from coma in cerebral malaria.
Gordeuk VR, Thuma PE, McLaren CE, Biemba G, Zulu S, Poltera AA, Askin JE,
Brittenham GM
Department of Medicine, George Washington University Medical Center,
Washington, DC 20037, USA.
To determine if the elevated transferrin saturations found in some
patients with severe malaria are associated with an adverse outcome in
cerebral malaria, we retrospectively measured baseline saturations in
stored serum samples from 81 Zambian children with strictly defined
cerebral malaria. The children had been treated with quinine,
sulfadox-ine-pyrimethamine, and intravenous infusions of either
placebo (n = 39) or the iron chelator, desferrioxamine B (n = 42), in
a previously reported trial (Gordeuk et al, N Engl J Med 327:1473,
1992). More than one-third of children in both the placebo- and iron
chelator-treated groups had transferrin saturations exceeding 43%,
which is 3 standard deviations above the expected mean for age. Among
children receiving quinine and placebo, those with elevated
transferrin saturations had a delayed estimated median time to recover
full consciousness (68.2 hours) compared with those with saturations <
or = 43% (25.4 hours; P = .006). The addition of iron chelation to
quinine therapy in children with high saturations appeared to hasten
recovery (P = .046). We conclude that increased transferrin
saturations may be associated with delayed recovery from coma during
standard therapy for cerebral malaria and that serum iron and total
iron binding capacity should be measured in future studies.
Publication Types:
* Clinical trial
* Randomized controlled trial
PMID: 7756663, UI: 95276267
_________________________________________________________________
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Subject: iron/parasites
FYI 5 April 2000 - Sapa
Seattle - US scientists report tests that show malaria parasites are
vulnerable to magnetism, raising hopes for an effective way to control
one of the world's worst killer diseases.
Bioengineer Henry Lai and his colleagues at Seattle's University of
Washington zapped plasmodium falciparum, the deadliest of the four
malaria parasite species, by simply exposing them to an oscillating
magnetic field.
Their theory is that microscopic iron particles the parasites absorb
with their human hosts' haemoglobin molecules attract the magnetic
bursts. Alternating magnetic fields shakes up these molecules,
utimately sending them into a deadly spin. Lai envisions future
treatment of malaria in something as simple as a lorry driven from
village to village. The emergence of drug-resistant malaria parasites,
spread by female anopheles mosquitoes, has made it increasingly
difficult to control the disease that kills 2,7 million people a year.
Lai believes it unlikely the parasites could develop resistance to
magnetism. - The end
======================================
Subject: malaria/chelator
Mol Biochem Parasitol 1999 Jun 25;101(1-2):43-59
Chelation of iron within the erythrocytic Plasmodium falciparum parasite by
iron chelators.
Loyevsky M, John C, Dickens B, Hu V, Miller JH, Gordeuk VR
Department of Medicine, The George Washington University Medical
Center, Washington, DC 20037, USA. loyevsky@gwis2.circ.gwu.edu
To examine the site of action of antimalarial iron chelators, iron
ligands were added to control erythrocytes and to erythrocytes
parasitized with Plasmodium falciparum, and the concentration of
intracellular labile iron was monitored with the fluorescent probe,
calcein. The fluorescence of calc (HOME) ein quenches upon binding iron and
increases upon releasing iron. The chelators included desferrioxamine
B, 2',2'-bipyridyl, and aminophenol II, a compound that is being newly
reported as having anti-plasmodial properties. Calcein-loaded
parasitized cells displayed fluorescence predominantly within the
cytosol of both rings and trophozoites. The addition of chelators to
both control and parasitized erythrocytes led to significant increases
of fluorescence (P < 0.001). Fluorescence was observed to increase
within the parasite itself after addition of iron chelators,
indicating that these agents bound labile iron within the plasmodium.
The relative increases of fluorescence after addition of chelators
were greater in control than parasitized erythrocytes (P < 0.05) as
were the estimated labile iron concentrations (P < or = 0.001). These
results suggest that (i) the anti-malarial action of iron chelators
might result from the ability to reach the infected cell's parasite
compartment and bind iron within the parasite cytosol, and (ii) the
labile iron pool of the host red cell may be either utilized or stored
during plasmodial growth.
PMID: 10413042, UI: 99339387
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