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

Malaria is one of the most debilitating and life threatening diseases in tropical regions of the world. Over 500 million clinical cases occur, and 2-3 million people die of the disease each year. Because Plasmodium lacks genuine glutathione peroxidase and catalase, the two major antioxidant enzymes in the eukaryotic cell, malaria parasites are likely to utilize members of the peroxiredoxin (Prx) family as the principal enzymes to reduce peroxides, which increase in the parasite cell due to metabolism and parasitism during parasite development. In addition to its function of protecting macromolecules from H(2)O(2), Prx has also been reported to regulate H(2)O(2) as second messenger in transmission of redox signals, which mediate cell proliferation, differentiation, and apoptosis. In the malaria parasite, several lines of experimental data have suggested that the parasite uses Prxs as multifunctional molecules to adapt themselves to asexual and sexual development. In this review, we summarize the accumulated knowledge on the Prx family with respect to their functions in mammalian cells and their possible function(s) in malaria parasites.
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PMID:Peroxiredoxins in malaria parasites: parasitologic aspects. 1789 Jan 40

The involvement of reactive oxygen species (ROS) in mosquito immunity against bacteria and Plasmodium was investigated in the malaria vector Anopheles gambiae. Strains of An. gambiae with higher systemic levels of ROS survive a bacterial challenge better, whereas reduction of ROS by dietary administration of antioxidants significantly decreases survival, indicating that ROS are required to mount effective antibacterial responses. Expression of several ROS detoxification enzymes increases in the midgut and fat body after a blood meal. Furthermore, expression of several of these enzymes increases to even higher levels when mosquitoes are fed a Plasmodium berghei-infected meal, indicating that the oxidative stress after a blood meal is exacerbated by Plasmodium infection. Paradoxically, a complete lack of induction of catalase mRNA and lower catalase activity were observed in P. berghei-infected midguts. This suppression of midgut catalase expression is a specific response to ookinete midgut invasion and is expected to lead to higher local levels of hydrogen peroxide. Further reduction of catalase expression by double-stranded RNA-mediated gene silencing promoted parasite clearance by a lytic mechanism and reduced infection significantly. High mosquito mortality is often observed after P. berghei infection. Death appears to result in part from excess production of ROS, as mortality can be decreased by oral administration of uric acid, a strong antioxidant. We conclude that ROS modulate An. gambiae immunity and that the mosquito response to P. berghei involves a local reduction of detoxification of hydrogen peroxide in the midgut that contributes to limit Plasmodium infection through a lytic mechanism.
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PMID:Reactive oxygen species modulate Anopheles gambiae immunity against bacteria and Plasmodium. 1806 21

Cellular redox metabolism is considered to be involved in the pathophysiology of diseases caused by protozoal parasites such as Toxoplasma, Trypanosoma, Leishmania, and Plasmodia. Redox reactions furthermore are thought to play a major role in the action of and the resistance to some clinically used antiparasitic drugs. Interestingly, in malarial parasites, the antioxidant enzymes catalase and glutathione peroxidase are absent which indicates a crucial role of the thioredoxin system in redox control. Besides a glutathione peroxidase-like thioredoxin peroxidase and a glutathione S-transferase with slight peroxidase activity, Plasmodium falciparum (the causative agent of tropical malaria) possesses four classical peroxiredoxins: Two peroxiredoxins of the typical 2-Cys Prx class, one 1-Cys peroxiredoxin with homology to the atypical 2-Cys Prx class, and a peroxiredoxin of the 1-Cys Prx class have been identified and partially characterized In our article we give an introduction to redox-based drug development strategies against protozoal parasites and summarize the present knowledge on peroxiredoxin systems in Plasmodium.
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PMID:Peroxiredoxin systems of protozoal parasites. 1808 96

Artemether, artemether-lumefantrine, or coartem and halofantrine are alternative antimalarial drugs to chloroquine. Their efficacy and potential to delay drug resistance in falciparum malaria had led to their increased use. Although these drugs have proven to be well tolerated, there are adverse effects associated with them. This study was designed to examine the toxic potential of acute administration of these drugs in rats. Twenty-four rats were divided into four groups: group I (control) received distilled water; group II received artemether for 5 days with an initial dose of 3.2 g/kg body weight on day 1 and 1.6 mg/kg body weight on days 2-5; group III received coartem (27 mg/kg body weight/day) for 3 days, which was divided into two equal portions per day; and group IV received halofantrine (24 mg/kg body weight/day) in three equal portions. Administration of artemether, coartem and halofantrine caused significant decrease (P < 0.05) in reduced glutathione levels in the liver by 29%, 21% and 26%, respectively. In contrast, there were no significant differences (P > 0.05) in the kidney glutathione levels. Furthermore, artemether, coartem and halofantrine decreased the liver- and kidney-enzymatic antioxidant status of the animals. Precisely, artemether, coartem and halofantrine decreased liver superoxide dismutase and catalase activities by 45%, 50% and 57%; and 20%, 29% and 23%, respectively. While the kidney catalase activities were decreased by 41%, 28% and 30%, respectively, the drugs however did not produce significant effect (P > 0.05) on the kidney superoxide dismutase activities. In addition, artemether, coartem and halofantrine decreased the hepatic levels of glutathione S-transferase by 64%, 51% and 53%, respectively. Administration of artemether, coartem and halofantrine significantly increased (P < 0.05) liver and kidney lipid peroxidation levels by 67%, 50% and 81%; and 58%, 43% and 31%, respectively. This indicates that the liver is considerably more affected than the kidneys. Similarly, halofantrine treatment caused significant elevation (P < 0.05) in the levels of serum creatinine, aspartate and alanine aminotransferases and blood urea nitrogen by 73%, 66%, 61% and 63%, respectively. These data indicate that oral administration of artemether, coartem and halofantrine has adverse effects on both enzymic and non-enzymatic antioxidant status of the animals.
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PMID:Changes in antioxidant status and biochemical indices after acute administration of artemether, artemether-lumefantrine and halofantrine in rats. 1828 95

Catalase is a potent antioxidant, likely involved in post-blood meal homeostasis in mosquitoes. This enzyme breaks down H2O2, preventing the formation of the hydroxyl radical (HO*). Quiescins are newly classified sulfhydryl oxidases that bear a thioredoxin motif at the N-terminal and an ERV1-like portion at the C-terminal. These proteins have a major role in generating disulfides in intra- or extracellular environments, and thus participate in redox reactions. In the search for molecules to serve as targets for novel anti-mosquito strategies, we have silenced a catalase and a putative quiescin/sulfhydryl oxidase (QSOX), from the African malaria vector Anopheles gambiae, through RNA interference (RNAi) experiments. We observed that the survival of catalase- and QSOX-silenced insects was reduced over controls following blood digestion, most likely due to the compromised ability of mosquitoes to scavenge and/or prevent damage caused by blood meal-derived oxidative stress. The higher mortality effect was more accentuated in catalase-silenced mosquitoes, where catalase activity was reduced to low levels. Lipid peroxidation was higher in QSOX-silenced mosquitoes suggesting the involvement of this protein in redox homeostasis following a blood meal. This study points to the potential of molecules involved in antioxidant response and redox metabolism to serve as targets of novel anti-mosquito strategies and offers a screening methodology for finding targetable mosquito molecules.
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PMID:Silencing an Anopheles gambiae catalase and sulfhydryl oxidase increases mosquito mortality after a blood meal. 1845 89

Dapsone (DDS) is currently used in the treatment of leprosy, malaria and in infections with Pneumocystis jirovecii and Toxoplasma gondii in AIDS patients. Adverse effects of DDS involve methemoglobinemia and hemolysis and, to a lower extent, liver damage, though the mechanism is poorly characterized. We evaluated the effect of DDS administration to male and female rats (30 mg/kg body wt, twice a day, for 4 days) on liver oxidative stress through assessment of biliary output and liver content of reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, and expression/activities of the main antioxidant enzymes glutathione peroxidase, superoxide dismutase, catalase and glutathione S-transferase. The influence of DDS treatment on expression/activity of the main DDS phase-II-metabolizing system, UDP-glucuronosyltransferase (UGT), was additionally evaluated. The involvement of dapsone hydroxylamine (DDS-NHOH) generation in these processes was estimated by comparing the data in male and female rats since N-hydroxylation of DDS mainly occurs in males. Our studies revealed an increase in the GSSG/GSH biliary output ratio, a sensitive indicator of oxidative stress, and in lipid peroxidation, in male but not in female rats treated with DDS. The activity of all antioxidant enzymes was significantly impaired by DDS treatment also in male rats, whereas UGT activity was not affected in any sex. Taken together, the evidence indicates that DDS induces oxidative stress in rat liver and that N-hydroxylation of DDS was the likely mediator. Impairment in the activity of enzymatic antioxidant systems, also associated with DDS-NHOH formation, constituted a key aggravating factor.
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PMID:Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver. 1860 5

The bisquinoline drug dequalinium (DQ) has demonstrated remarkable activity against some infection diseases, including malaria. Oxidative stress represents a biochemical target for potential antimalarials. In this work, we have tested the ability of this compound to modify the oxidative status in Plasmodium berghei-infected erythrocytes. After hemolysis, activities of superoxide dismutase (SOD), catalase (CAT), glutathione cycle, and dehydrogenase enzymes were investigated. The activity of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGLD) in infected cells were diminished by this drug compared to controls (300% and 80% approximately, respectively), while glutathione peroxidase (GPx), glutathione transferase (GST), and glutathione levels were also lowered. As a compensatory response, we could appreciate an increase of SOD activity (20% approximately) in infected cells treated with DQ; however, catalase was not affected by the compound. Lipid peroxidation was also decreased by this drug, protecting the cells from the hemolysis caused by the infection. In conclusion, oxidative stress represents a biochemical event which is modulated by DQ, interfering with the antioxidant regular activities in P. berghei infection.
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PMID:Effect of dequalinium on the oxidative stress in Plasmodium berghei-infected erythrocytes. 1920 39

E-2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline (IQ) is a new quinoline derivative which has been reported as a haemoglobin degradation and ss-haematin formation inhibitor. The haemoglobin proteolysis induced by Plasmodium parasites represents a source of amino acids and haeme, leading to oxidative stress in infected cells. In this paper, we evaluated oxidative status in Plasmodium berghei-infected erythrocytes in the presence of IQ using chloroquine (CQ) as a control. After haemolysis, superoxide dismutase (SOD), catalase, glutathione cycle and NADPH + H+-dependent dehydrogenase enzyme activities were investigated. Lipid peroxidation was also assayed to evaluate lipid damage. The results showed that the overall activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were significantly diminished by IQ (by 53.5% and 100%, respectively). Glutathione peroxidase activity was also lowered (31%) in conjunction with a higher GSSG/GSH ratio. As a compensatory response, overall SOD activity increased and lipid peroxidation decreased, protecting the cells from the haemolysis caused by the infection. CQ shared most of the effects showed by IQ; however it was able to inhibit the activity of isocitrate dehydrogenase and glutathione-S-transferase. In conclusion, IQ could be a candidate for further studies in malaria research interfering with the oxidative status in Plasmodium berghei infection.
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PMID:Modification of oxidative status in Plasmodium berghei-infected erythrocytes by E-2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline compared to chloroquine. 1987 58

The malaria parasite, Plasmodium falciparum, develops within human erythrocytes, consuming host hemoglobin to support its own growth. Reactive oxygen species (superoxide and hydrogen peroxide) are by-products of hemoglobin digestion and are believed to exert significant oxidative stress on the parasite. We have characterized a cell permeant, far red fluorescent nucleic acid-binding dye, SYTO 61, that can be used to distinguish between uninfected and infected erythrocytes in a flow cytometric format. The spectral properties of SYTO 61 make it suitable for use in combination with the fluorescent reactive oxygen species reporter 5-(and-6)-chloromethyl-2',7'-dichlorodihydro-fluorescein diacetate acetyl ester. We have used this probe combination to measure oxidative stress in different stages of live P. falciparum. Low levels of the oxidized, fluorescent form of the reporter (2',7'-dichlorofluorescein, DCF) are detected in ring stage parasites; the DCF signal increases as the intraerythrocytic parasite matures into the trophozoite stage where active hemoglobin digestion occurs. Treatment of infected erythrocytes with the cysteine protease inhibitor, E-64, which inhibits hemoglobin digestion, decreases the DCF signal. We show that E-64 prevents schizont rupture but also causes delayed lethal effects when ring stage cultures are exposed to the drug. We also examined cultures of parasites in erythrocytes harboring 98% catalase inactivation and found no effect on growth and only a modest increase in DCF oxidation.
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PMID:Dual labeling with a far red probe permits analysis of growth and oxidative stress in P. falciparum-infected erythrocytes. 2009 70

Pyrimethamine is an antimalarial drug that has also been used successfully to treat autoimmune diseases such as lymphoproliferative syndrome. In this work, the effect of pyrimethamine (PYR) on the production of free radicals in malaria-infected mice was studied to better understand the drug's immunomodulatory properties. BALB/c and CBA/Ca mice were infected with Plasmodium yoelii 17XL. Seven days after infection, mice were treated with PYR or vehicle and sacrificed 24h later. Treatment with PYR increased superoxide dismutase and glutathione peroxidase activities in erythrocytes and the liver, augmented the levels of nitric oxide in the serum, and upregulated mRNA levels of superoxide dismutase, glutathione peroxidase, catalase, and iNOS in the spleen. In addition, PYR increased lipoperoxidation and protein carbonylation in infected mice. Our results indicate that P. yoelii 17XL reduces oxidative stress in infected cells, while PYR induces it, which is associated with increased parasite elimination. Thus, it is possible that oxidative stress generated by pyrimethamine is also involved in its immunomodulatory mechanism of action.
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PMID:Pyrimethamine induces oxidative stress in Plasmodium yoelii 17XL-infected mice: a novel immunomodulatory mechanism of action for an old antimalarial drug? 2019 82


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