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)

Iron in food is classified as belonging to the haem pool, the nonhaem pool, and extraneous sources. Haem iron is derived from vegetable and animal sources with varying bioavailability. Hookworm infestation of the intestinal tract affects 450 million people in the tropics. Schistosoma mansoni caused blood loss in 7 Egyptian patients of 7.5- 25.9 ml/day which is equivalent to a daily loss of iron of .6-7.3 mg daily urinary loss of iron in 9 Egyptian patients. Trichuris trichiura infestation by whipworm is widespread in children with blood loss of 5 ml/day/worm. The etiology of anemia in children besides iron deficiency includes malaria, bacterial or viral infections, folate deficiency and sickle-cell disease. Severe infections cause profound iron-deficiency anemia in children in central American and Malaysia. Plasmodium falciparum malaria-induced anaemia in tropical Africa lowers the mean haemoglobin concentration in the population by 2 g/dI, causing profound anaemia in some. The increased risk of premature delivery, low birthweight, fetal abnormalities, and fetal death is directly related to the degree of maternal anemia. Perinatal mortality was reduced from 38 to 4% in treated anemic mothers. Mental performance was significantly lower in anemic school children and improved after they received iron. Supplements of iron, soy-protein, calcium, and vitamins given to villagers with widespread malnutrition, iron deficiency, and hookworm infestation in Colombia reduced enteric infections in children. Severe iron-deficiency anemia was treated in adults in northern Nigeria by daily in Ferastral 10 ml, which is equivalent to 500 mg of iron per day. Choloroquine, folic acid, rephenium hydroxynaphthoate, and tetrachlorethylene treat adults with severe iron deficiency from hookworm infestation in rural tropical Africa. Blood transfusion is indicated if the patient is dying of anaemia or is pregnant with a haemoglobin concentration 6 gm/dl. In South East Asia, mg per day prevented iron-deficiency anaemia in pregnancy. Field-trials on nutritional iron deficiency include an acidified milk formula plus ferrous sulphate for infants; biscuits with added bovine hemoglobin for children in Chile; sugar plus sodium ferric EDTA in Guatemala; salt with ferric orthophosphate and sodium acid sulphate in India; and Salt with ferrous sulphate plus sodium hexametaphosphate.
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PMID:Iron deficiency in the tropics. 704 57

Chloroquine-resistant (CQR) and -sensitive (CQS) Plasmodium berghei K173 strains possessed significant activities of heme oxygenase, biliverdin reductase and heme polymerase. Heme oxygenase and biliverdin reducatase activities of CQR were significantly higher (7-10 fold) as compared to that of CQS P. berghei, whereas heme polymerase showed a reverse trend (two-fold decrease). However, a 10-fold increase in heme, three-fold increase in ferriprotoporphyrin IX and a two-fold increase in hemozoin levels were noted in CQS as compared to CQR strains of P. berghei. This study suggests the importance of heme oxygenase and related components in the biochemical regulation of malaria parasites and in understanding the mechanism of the acquisition of chloroquine resistance.
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PMID:Heme oxygenase and related indices in chloroquine-resistant and -sensitive strains of Plasmodium berghei. 884 67

While studying the fate of heme generated during malaria infection, it was observed that mitochondrial preparations were highly enriched with heme compared to other subcellular particles. With this background, the present study aimed to determine the status of mitochondrial heme oxygenase and compare it with the microsomal enzyme. Mitochondrial and microsomal preparations were obtained from liver, spleen, kidney and brain of normal, inducer (cobalt chloride and hemin)-treated and Plasmodium berghei-infected Mastomys coucha. Heme oxygenase activity was determined by monitoring the formation of bilirubin. Biliverdin reductase activity was assayed by following the decrease in biliverdin content. Heme levels were measured by pyridine haemochromogen formation. Mitochondria from different tissues showed significant activity of heme oxygenase only after inducer (CoCl2 and hemin) treatment. In contrast, cerebral mitochondria did not show any enzyme activity. Hepatic, splenic and renal mitochondria of P. berghei-infected M. coucha showed noticeable heme oxygenase and biliverdin reductase activity. The response of hepatic mitochondrial heme oxygenase towards Triton X-100, trypsin, hydrogen peroxide, temperature, freezing and thawing and hemin was distinguishable from microsomal heme oxygenase. It is concluded that the mitochondria of different tissues from Mastomys display stress (biological and chemical)-induced activity of heme oxygenase. In addition, distinct differences between microsomal and mitochondrial heme oxygenase were observed.
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PMID:Mitochondrial heme oxygenase of Mastomys coucha. 893 Jan 30

Malaria parasite digests hemoglobin and utilizes the globin part for its nutritional requirements. Heme released as a byproduct of hemoglobin degradation is detoxified by polymerization into a crystalline, insoluble pigment, known as hemozoin. We have identified a novel reaction of depolymerization of hemozoin to heme. This reaction is initiated by the interaction of blood schizonticidal antimalarial drugs with the malarial hemozoin. The reaction has been confirmed, with the purified hemozoin as well as the lysate of the malaria parasite. Pigment breakdown was studied by infrared spectroscopy, thin-layer chromatography and spectrophotometric analysis. It was complete within 2 h of drug exposure, which explains the selective sensitivity of late stages (trophozoites and schizonts) of malarial parasites loaded with the hemozoin pigment to the toxic action of these drugs. It is suggested that the failure of the parasite heme detoxification system due to this reaction results in the accumulation of toxic heme, which alone, or complexed with the antimalarial leads to the death of malaria parasite.
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PMID:Depolymerization of malarial hemozoin: a novel reaction initiated by blood schizontocidal antimalarials. 903 2

The malaria parasite metabolizes haemoglobin and detoxifies the resulting haem by polymerizing it to form haemozoin (malaria pigment). A polymer identical to haemozoin, beta-haematin, can be obtained in vitro from haematin at acidic pH. Quinoline-containing anti-malarials (e.g. chloroquine) inhibit the formation of either polymer. Haem polymerization is an essential and unique pharmacological target. To identify molecules with haem polymerization inhibitory activity (HPIA) and quantify their potency, we developed a simple, inexpensive, quantitative in-vitro spectrophotometric microassay of haem polymerization. The assay uses 96-well U-bottomed polystyrene microplates and requires 24 h and a microplate reader. The relative amounts of polymerized and unpolymerized haematin are determined, based on solubility in DMSO, by measuring absorbance at 405 nm in the presence of test compounds as compared with untreated controls. The final product (a solid precipitate of polymerized haematin) was validated using infrared spectroscopy and the assay proved reproducible; in this assay, activity could be partly predicted based on the compound's chemical structure. Both water-soluble and water-insoluble compounds can be quantified by this method. Although the throughput of this assay is lower than that of radiometric methods, the assay is easier to set up and cheaper, and avoids the problems related to radioactive waste disposal.
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PMID:A microtitre-based method for measuring the haem polymerization inhibitory activity (HPIA) of antimalarial drugs. 970 May 28

We propose here a new and detailed model for the antimalarial action of chloroquine (CQ), based on the its ability to inhibit degradation of heme by glutathione. Heme, which is toxic to the malaria parasite, is formed when the intraerythrocytic malaria parasite ingests and digests inside its food vacuole its host cell cytosol, which consists mainly of hemoglobin. The parasite protects itself against the toxicity of heme by polymerizing some of it to insoluble hemozoin (HZ). We show here that in Plasmodium falciparum at the trophozoite stage only ca. 30% of the heme is converted into hemozoin. We suggest that nonpolymerized heme exits the food vacuole and is subsequently degraded by glutathione, as has been shown before for uninfected erythrocytes. Marginal amounts of free heme could be detected in the membrane fraction of infected cells but nowhere else. It is well established that CQ and amodiaquine (AQ) accumulate in the parasite's food vacuole and inhibit heme polymerization, thereby increasing its efflux out of the food vacuole. We found that these drugs competitively inhibit the degradation of heme by glutathione, thus allowing heme to accumulate in membranes. Incubation of intact infected cells with CQ and AQ results in a marked increase in membrane-associated heme in a dose- and time-dependent manner, and a relationship exists between membrane heme levels and the extent of parasite killing. Heme has been shown to disrupt the barrier properties of membranes and to upset ion homeostasis in CQ-treated malaria-infected cells. In agreement with the predictions of our model, increasing the cellular levels of glutathione leads to increased resistance to CQ, whereas decreasing them results in enhanced sensitivity to the drug. These results insinuate a novel mechanism of drug resistance.
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PMID:Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. 982 29

Proteolysis of hemoglobin provides an essential nutrient source for the malaria parasite Plasmodium falciparum during the intraerythrocytic stage of the parasite's lifecycle. Detoxification of the liberated heme occurs through a unique heme polymerization pathway, leading to the formation of hemozoin. Heme polymerization has been demonstrated in the presence of P. falciparum histidine-rich protein 2 (PfHRP2) [Sullivan, D. J., Gluzman, I. Y., and Goldberg, D. E. (1996) Science 271, 219-221]; however, the molecular role that PfHRP2 plays in this polymerization is currently unknown. PfHRP2 is a 30 kDa protein composed of several His-His-Ala-His-His-Ala-Ala-Asp repeats and is present in the parasite food vacuole, the site of hemoglobin degradation and heme polymerization. We found that, at pH 7.0, PfHRP2 forms a saturable complex with heme, with a PfHRP2 to heme stoichiometry of 1:50. Spectroscopic characterization of heme binding by electronic absorption, resonance Raman, and EPR has shown that bound hemes share remarkably similar heme environments as >95% of all bound hemes are six-coordinate, low-spin, and bis-histidyl ligated. The PfHRP2-ferric heme complex at pH 5.5 (pH of the food vacuole) has the same heme spin state and coordination as observed at pH 7.0; however, polymerization occurs as heme saturation is approached. Therefore, formation of a PfHRP2-heme complex appears to be a requisite step in the formation of hemozoin.
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PMID:Spectroscopic characterization of the heme-binding sites in Plasmodium falciparum histidine-rich protein 2. 1060 26

The heme oxygenase (HO) system was identified in the early 1970s as a distinct microsomal enzyme system that catalyzes formation of bile pigments (Maines and Kappas, 1974). Up to the early 1990s the system was considered only as a "molecular wrecking ball" (Lane, 1998) for degradation of the heme molecule and production of toxic waste products, CO and bile pigments. For those years, the HO system remained relatively unknown to the research community. In a rather short span of the past 10 years following the discovery of high levels of a second form of the enzyme, HO-2, in the brain, suggesting that "heme oxygenase in the brain has functions aside from heme degradation" (Sun et al., 1990); concomitant with finding that another toxic gas, NO, is a signal molecule for generation of cGMP (Ignarro et al., 1982), the system was propelled into main stream research. This propulsion was fueled by the realization of the multiple and diverse functions of heme degradation products. Heme oxygenase has now found relevance in all kinds of human pathophysiology ranging from stroke, cancer, multiple sclerosis, and malaria to transplantation and immune response. As it turns out, its potential benefits are mesmerizing investigators in diverse fields (Lane, 1998). The most recent findings with HO-2 being a hemoprotein and potentially an intracellular "sink" for NO (McCoubrey et al., 1997a; Ding et al., 1999), together with the discovery of the third form of the enzyme, HO-3 (McCoubrey et al., 1997b), are likely to insure the widespread interest in the enzyme system in the coming years. The present review is intended to highlight molecular properties of HO isozymes and their likely functions in the brain. Extended reviews of the system are found in Maines (1992, 1997).
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PMID:The heme oxygenase system and its functions in the brain. 1087 44

Malaria parasites digest haemoglobin and detoxify the free haem by its sequestration into an insoluble dark-brown pigment known as haemozoin (Hz). Until recently, this pigment could be found only in Plasmodium parasites. However, we have shown that Hz is also present in the midgut of the blood-sucking insect Rhodnius prolixus [Oliveira et al. (1999) Nature 400, 517-518]. Here we show that Hz synthesis in the midgut of this insect is promoted by a particulate fraction from intestine lumen. Haem aggregation activity is heat-labile and is inhibited in vitro by chloroquine (CLQ). Inhibition of Hz formation in vivo by feeding insects with CLQ leads to increased levels of haem in the haemolymph of the insect, which resulted in increased lipid peroxidation. Taken together, these results indicate that a factor capable of promoting Hz crystallisation is present in R. prolixus midgut and that this activity represents an important physiological defence of this insect against haem toxicity.
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PMID:Haemozoin formation in the midgut of the blood-sucking insect Rhodnius prolixus. 1089 17

Human cerebral malaria is a life threatening complication of Plasmodium falciparum infection. The cascades of signaling events resulting in tissue trauma, lesion formation, coma or resolution of lesions are only slowly becoming unraveled. Understanding the generation of local tissue protective cellular reactions might pave the way for generation of novel drugs limiting the formation of cerebral malaria lesions. Heme oxygenase-1 (HO-1) is an inducible enzyme degrading heme into the gaseous mediator carbon monoxide (CO) and biliverdin, a local antioxidant. Expression of HO-1 is considered a protective reaction against inflammatory and other insults to the brain. We have localized HO-1 to Durck's granulomas, typical lesions of advanced cerebral malaria. Here, activated monocytic cells and ramified microglia in direct vicinity to the lesions express HO-1. The striking association of HO-1 expression with areas of bleedings suggests that released hemoglobin and heme-- known inducers of HO-1--are mainly responsible for induction of monocytic HO-1 expression. HO-1 is expressed rather late to play a protective role in lesion formation and appears to have only a major role in Durck's granulomas. Further, generation of the gaseous mediator CO might contribute to the neurological derangements of advanced cerebral malaria.
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PMID:Heme oxygenase-1 in lesions of human cerebral malaria. 1119 43


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