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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidant stress is associated with the generation of reactive oxygen species that are responsible for the damage of a variety of cellular components. The prevention of such biological damage can be achieved by dismutation of superoxide to H2O2 which in turn is removed by catalase and GSH peroxidase. However, redox-active iron released during the development of plasmodia in the erythrocyte can mediate the conversion of H2O2 to hydroxyl radical which is more reactive. The roles of SOD and the nitroxide SOD mimic 4-OH,2,2,6,6,tetramethyl piperidine-N-oxyl (Tempol) were examined in P. falciparum grown in vitro. Both compounds did not prevent the interference with growth inflicted by various inducers of oxidant stress. Moreover, Tempol inhibited parasite growth, in agreement with previous experiments depicting accelerated mortality in SOD overexpressing mouse model of malaria. Probably, effective defense against ROS requires balanced increments in antioxidant enzymes and is not necessarily improved by an increase in the activity of one enzyme.
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PMID:The role of superoxide dismutation in malaria parasites. 1044 98

Reactive Oxygen species play an important role in pathology during malaria infection. The status of hepatic oxidative stress and antioxidant defence indices was studied during Plasmodium yoelii nigeriensis (P. y. nigeriensis) infection in mice and arteether treatment of P. y. nigeriensis infected mice. P. y. nigeriensis infection caused a significant increase in hepatic xanthine oxidase, rate of lipid peroxidation, reduced glutathione (GSH) and glutathione reductase with progressive rise in parasitemia. This was accompanied by a significant decrease in hepatic superoxide dismutase (SOD) and catalase with increase in parasitemia. Arteether treatment (10 mg/kg body weight of mice) of infected mice from day 2 of post infection resulted in complete clearance of parasitemia on day 4 of post infection which was accompanied by restoration of all the oxidative stress and antioxidant defence indices to normal levels.
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PMID:Studies on hepatic oxidative stress and antioxidant defence systems during arteether treatment of Plasmodium yoelii nigeriensis infected mice. 1044 17

To assess the extent of oxidative stress in erythrocytes of patients with acute Plasmodium falciparum malaria, erythrocyte thiobarbituric acid-reactive substance (ETBAR), and intracellular, membrane and extracellular antioxidants were estimated in 102 cases of P. falciparum malaria and 50 control subjects. The mean concentration of ETBAR was significantly higher (P < 0.001) and many of the antioxidants were significantly lower in patients than controls. Among the erythrocyte antioxidants, catalase, reduced glutathione (GSH) and tocopherol were significantly lower in the patients (P < 0.05, 0.001, 0.001, respectively). Erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were not reduced to a statistically significant level. Similarly, the plasma antioxidants ascorbate and albumin were significantly lower (P < 0.001) but not urate. ETBAR correlated inversely with erythrocyte GSH and tocopherol (P < 0.001), and plasma ascorbate and albumin (P < 0.001) but not with the erythrocyte enzymic antioxidants. However, on multiple regression analysis only tocopherol correlated strongly with ETBAR, followed by GSH and plasma ascorbate. ETBAR also correlated well with haemolytic indices such as haemoglobin, plasma unconjugated bilirubin and haptoglobin concentrations (P < 0.001, for all). On follow-up after 2 weeks, ETBAR and different antioxidants reached near control levels. These observations indicate an enhanced oxidative stress on erythrocytes in acute falciparum malaria that may contribute substantially to haemolysis and anaemia.
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PMID:Evidence for erythrocyte lipid peroxidation in acute falciparum malaria. 1049 92

Hemozoin (malaria pigment), a polymer of hematin (ferri-protoporphyrin IX) derived from hemoglobin ingested by intraerythrocytic plasmodia, modulates cytokine production by phagocytes. Mouse peritoneal macrophages (PM) fed with synthetic beta-hematin (BH), structurally identical to native hemozoin, no longer produce tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) in response to lipopolysaccharide (LPS). Impairment of NO synthesis is due to inhibition of inducible nitric oxide synthase (iNOS) production. BH-mediated inhibition of PM functions cannot be ascribed to iron release from BH because neither prevention by iron chelators nor down-regulation of iron-regulatory protein activity was detected. Inhibition appears to be related to pigment-induced oxidative stress because (a) thiol compounds partially restored PM functions, (b) heme oxygenase (HO-1) and catalase mRNA levels were up-regulated, and (c) free radicals production increased in BH-treated cells. The antioxidant defenses of the cells determine the response to BH: microglia cells, which show a lower extent of induction of HO-1 and catalase mRNAs and lower accumulation of oxygen radicals, are less sensitive to the inhibitory effect of BH on cytokine production. Results indicate that BH is resistant to degradation by HO-1 and that heme-iron mediated oxidative stress may contribute to malaria-induced immunosuppression. This study may help correlate the different clinical manifestations of malaria, ranging from uncomplicated to severe disease, with dysregulation of phagocyte functions and promote better therapeutic strategies to counteract the effects of hemozoin accumulation.
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PMID:Macrophage preconditioning with synthetic malaria pigment reduces cytokine production via heme iron-dependent oxidative stress. 1114 Jun 91

Many lines of evidence reveal that artemisinin, an antimalarial containing endoperoxide, generates free radicals to kill malaria parasites. The present study re-evaluated the antioxidants of P. falciparum-infected erythrocytes in the absence and presence of 0.25, 0.5 and 1.0 ng/ml of dihydroartemisinin (DHA), the active metabolite of artemisinin. The ratio of reduced to oxidized glutathione (GSH/GSSG) and activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were determined. The data indicated that malaria infection induced oxidative stress in erythrocytes that resulted in a significant lower GSH in parasitized cells compared to the non-parasitized. DHA showed no effect on the antioxidant levels of non-parasitized erythrocytes treated under similar conditions as P. falciparum-infected erythrocytes. However, significantly lower GSH as well as catalase and GPx activities in parasitized cells were seen at drug concentrations of 0.5 and 1.0 ng/ml (p < 0.05). GSH is the most sensitive indicator of oxidative stress in malaria-infected erythrocytes both in the absence and in the presence of DHA. Parasite GPx might play a more important role than catalase in the elimination of peroxide. Parasite viabilities in the presence of DHA were analyzed simultaneously and were affected to a greater extent than the antioxidant levels. The present observation showed that although DHA killed malaria parasites by generating free radicals from the endoperoxide bridge causing the reduction of antioxidants, but the depletion of parasite antioxidants is not a prerequisite for the parasite death.
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PMID:Effect of dihydroartemisinin on the antioxidant capacity of P. falciparum-infected erythrocytes. 1511 82

The malaria parasite Plasmodium falciparum is highly adapted to cope with the oxidative stress to which it is exposed during the erythrocytic stages of its life cycle. This includes the defence against oxidative insults arising from the parasite's metabolism of haemoglobin which results in the formation of reactive oxygen species and the release of toxic ferriprotoporphyrin IX. Central to the parasite's defences are superoxide dismutases and thioredoxin-dependent peroxidases; however, they lack catalase and glutathione peroxidases. The vital importance of the thioredoxin redox cycle (comprising NADPH, thioredoxin reductase and thioredoxin) is emphasized by the confirmation that thioredoxin reductase is essential for the survival of intraerythrocytic P. falciparum. The parasites also contain a fully functional glutathione redox system and the low-molecular-weight thiol glutathione is not only an important intracellular thiol redox buffer but also a cofactor for several redox active enzymes such as glutathione S-transferase and glutaredoxin. Recent findings have shown that in addition to these cytosolic redox systems the parasite also has an important mitochondrial antioxidant defence system and it is suggested that lipoic acid plays a pivotal part in defending the organelle from oxidative damage.
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PMID:Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. 1538 10

In addition to their well-known anti-malarial activity, artemisinin and its derivatives (1,2,4-trioxanes) possess potent activity against tumor cells in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. These genes are from classes with different biological function; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Anti-oxidant stress genes (thioredoxin, catalase, gamma-glutamyl-cysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines over-expressing genes that confer resistance to established anti-tumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that this drug has a different target and is not subject to multidrug resistance. The Plasmodium translationally controlled tumor protein (TCTP) represents a known target protein of artemisinin and its derivatives in the malaria parasite. The microarray-based mRNA expression of human TCTP correlated with sensitivity to artesunate in tumor cells, suggesting that human TCTP contributes to response of tumor cells to the drug. The multi-factorial nature of cellular response to artemisinin and its derivatives may be beneficial to treat otherwise drug-resistant tumors and may explain why resistance development has not been observed in either cancer or malaria.
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PMID:Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. 1587 3

The intraerythrocytic protozoan parasite Plasmodium falciparum is responsible for more than 500 million clinical cases of tropical malaria annually. Although exposed to high fluxes of reactive oxygen species, Plasmodium lacks the antioxidant enzymes catalase and glutathione peroxidase. Thus, the parasite depends on the antioxidant capacity of its host cell and its own peroxidases. These are fuelled by the thioredoxin system and are considered to represent the major defense line against peroxides. Five peroxidases that act in different compartments have been described in P. falciparum. They include two typical 2-Cys peroxiredoxins (Prx), a 1-Cys Prx, the so-called antioxidant protein (AOP), which is a further Prx acting on the basis of a 1-Cys mechanism, and a glutathione peroxidase-like thioredoxin peroxidase. Because of their central function in redox regulation and antioxidant defense, some of these proteins might represent highly interesting targets for structure-based drug development. In this article we summarize the present knowledge on the thioredoxin and peroxiredoxin metabolism in malaria parasitized red blood cells. We furthermore report novel data on the biochemical and kinetic characterization of different thioredoxins, of AOP, and of the classic 1-Cys peroxiredoxin of P. falciparum.
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PMID:Thioredoxin networks in the malarial parasite Plasmodium falciparum. 1691 Jul 70

Elevated plasma levels of xanthine oxidase and liver function parameters have been associated with inflammatory events in several human diseases. While xanthine oxidase provides in vitro protection against malaria, its pathophysiological functions in vivo and interactions with liver function parameters remain unclear. This study examined the interactions and plasma levels of xanthine oxidase (XO) and uric acid (UA), catalase (CAT) and liver function parameters GOT, GPT and bilirubin in asymptomatic (n=20), uncomplicated (n=32), and severe (n=18) falciparum malaria children aged 3-13 years. Compared to age-matched control (n=16), significant (p<0.05) elevation in xanthine oxidase by 100-550%, uric acid by 15.4-153.8%, GOT and GPT by 22.1-102.2%, and total bilirubin by 2.3-86% according to parasitaemia (geometric mean parasite density (GMPD)=850-87100 parasites/microL) was observed in the malarial children. Further comparison with control revealed higher CAT level (16.2+/-0.5 vs 14.6+/-0.4 U/L; p<0.05) lacking significant (p>0.05) correlation with XO, but lower CAT level (13.4-5.4 U/L) with improved correlations (r=-0.53 to -0.91; p<0.05) with XO among the asymptomatic and symptomatic malaria children studied. 75% of control, 45% of asymptomatic, 21.9% of uncomplicated, and none of severe malaria children had Hb level>11.0 g/dL. Multivariate analyses further revealed significant (p<0.05) correlations between liver function parameters and xanthine oxidase (r=0.57-0.64) only in the severe malaria group. We conclude that elevated levels of XO and liver enzymes are biochemical features of Plasmodium falciparum parasitaemia in Nigerian children, with both parameters interacting differently to modulate the catalase response in asymptomatic and symptomatic falciparum malaria.
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PMID:Levels and interactions of plasma xanthine oxidase, catalase and liver function parameters in Nigerian children with Plasmodium falciparum infection. 1720 84

The mosquito Anopheles gambiae is a primary vector of Plasmodium parasites in Africa. The effect of aging on reproductive output in A. gambiae females from three strains that differ in their ability to melanize Plasmodium and in their systemic levels of hydrogen peroxide (H2O2), a reactive oxygen species (ROS), was analyzed. The number of eggs oviposited after the first blood meal decreases with age in all strains; however, this decline was much more pronounced in the G3 (unselected) and R (refractory to Plasmodium infection) strains than in the S (highly susceptible to Plasmodium) strain. Reduction of ROS levels in G3 and R females by administration of antioxidants reversed this age-related decline in fecundity. The S and G3 strains were fixed for two functionally different catalase alleles that differ at the second amino acid position (Ser2Trp). Biochemical analysis of recombinant proteins revealed that the Trp isoform has lower specific activity and higher Km than the Ser isoform, indicating that the former is a less efficient enzyme. The Trp-for-Ser substitution appears to destabilize the functional tetrameric form of the enzyme. Both alleles are present in the R strain, and Ser/Ser females had significantly higher fecundity than Trp/Trp females. Finally, a systemic reduction in catalase activity by dsRNA-mediated knockdown significantly reduced the reproductive output of mosquito females, indicating that catalase plays a central role in protecting the oocyte and early embryo from ROS damage.
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PMID:Reactive oxygen species detoxification by catalase is a major determinant of fecundity in the mosquito Anopheles gambiae. 1728 4


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