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

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

Cerebral malaria claims more than 1 million lives per year. We report that heme oxygenase-1 (HO-1, encoded by Hmox1) prevents the development of experimental cerebral malaria (ECM). BALB/c mice infected with Plasmodium berghei ANKA upregulated HO-1 expression and activity and did not develop ECM. Deletion of Hmox1 and inhibition of HO activity increased ECM incidence to 83% and 78%, respectively. HO-1 upregulation was lower in infected C57BL/6 compared to BALB/c mice, and all infected C57BL/6 mice developed ECM (100% incidence). Pharmacological induction of HO-1 and exposure to the end-product of HO-1 activity, carbon monoxide (CO), reduced ECM incidence in C57BL/6 mice to 10% and 0%, respectively. Whereas neither HO-1 nor CO affected parasitemia, both prevented blood-brain barrier (BBB) disruption, brain microvasculature congestion and neuroinflammation, including CD8(+) T-cell brain sequestration. These effects were mediated by the binding of CO to hemoglobin, preventing hemoglobin oxidation and the generation of free heme, a molecule that triggers ECM pathogenesis.
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PMID:Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. 1755 29

The clinically silent Plasmodium liver stage is an obligatory step in the establishment of malaria infection and disease. We report here that expression of heme oxygenase-1 (HO-1, encoded by Hmox1) is upregulated in the liver following infection by Plasmodium berghei and Plasmodium yoelii sporozoites. HO-1 overexpression in the liver leads to a proportional increase in parasite liver load, and treatment of mice with carbon monoxide and with biliverdin, each an enzymatic product of HO-1, also increases parasite liver load. Conversely, mice lacking Hmox1 completely resolve the infection. In the absence of HO-1, the levels of inflammatory cytokines involved in the control of liver infection are increased. These findings suggest that, while stimulating inflammation, the liver stage of Plasmodium also induces HO-1 expression, which modulates the host inflammatory response, protecting the infected hepatocytes and promoting the liver stage of infection.
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PMID:Heme oxygenase-1 is an anti-inflammatory host factor that promotes murine plasmodium liver infection. 1847 53

Malaria, the disease caused by Plasmodium infection, is endemic to poverty in so-called underdeveloped countries. Plasmodium falciparum, the main infectious Plasmodium species in sub-Saharan countries, can trigger the development of severe malaria, including cerebral malaria, a neurological syndrome that claims the lives of more than one million children (<5 years old) per year. Attempts to eradicate Plasmodium infection, and in particular its lethal outcomes, have so far been unsuccessful. Using well-established rodent models of malaria infection, we found that survival of a Plasmodium-infected host is strictly dependent on the host's ability to up-regulate the expression of heme oxygenase-1 (HO-1 encoded by the gene Hmox1). HO-1 is a stress-responsive enzyme that catabolizes free heme into biliverdin, via a reaction that releases Fe and generates the gas carbon monoxide (CO). Generation of CO through heme catabolism by HO-1 prevents the onset of cerebral malaria. The protective effect of CO is mediated via its binding to cell-free hemoglobin (Hb) released from infected red blood cells during the blood stage of Plasmodium infection. Binding of CO to cell-free Hb prevents heme release and thus generation of free heme, which we found to play a central role in the pathogenesis of cerebral malaria. We will address hereby how defense mechanisms that prevent the deleterious effects of free heme, including the expression of HO-1, impact on the pathologic outcome of Plasmodium infection and how these may be used therapeutically to suppress its lethal outcomes.
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PMID:A central role for free heme in the pathogenesis of severe malaria: the missing link? 1864 63

Infection by Plasmodium, the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Under inflammatory conditions, cell-free hemoglobin can be oxidized, releasing its heme prosthetic groups and producing deleterious free heme. Here we demonstrate that survival of a Plasmodium-infected host relies strictly on its ability to prevent the cytotoxic effects of free heme via the expression of the heme-catabolyzing enzyme heme oxygenase-1 (HO-1; encoded by the Hmox1 gene). When infected with Plasmodium chabaudi chabaudi (Pcc), wild-type (Hmox1(+/+)) BALB/c mice resolved infection and restored homeostasis thereafter (0% lethality). In contrast, HO-1 deficient (Hmox1(-/-)) BALB/c mice developed a lethal form of hepatic failure (100% lethality), similar to the one occurring in Pcc-infected DBA/2 mice (75% lethality). Expression of HO-1 suppresses the pro-oxidant effects of free heme, preventing it from sensitizing hepatocytes to undergo TNF-mediated programmed cell death by apoptosis. This cytoprotective effect, which inhibits the development of hepatic failure in Pcc-infected mice without interfering with pathogen burden, is mimicked by pharmacological antioxidants such as N-acetylcysteine (NAC). When administered therapeutically, i.e., after Pcc infection, NAC suppressed the development of hepatic failure in Pcc-infected DBA/2 mice (0% lethality), without interfering with pathogen burden. In conclusion, we describe a mechanism of host defense against Plasmodium infection, based on tissue cytoprotection against free heme and limiting disease severity irrespectively of parasite burden.
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PMID:Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. 1980 9

Malaria affects thousands of people around the world representing a critical issue regarding health policies in tropical countries. Similarly, also haemolytic diseases such as sickle cell disease and thalassemias are a concern in different parts of the globe. It is well established that haemolytic diseases, such as sickle cell disease (SCD) and thalassemias, represent a resistance factor to malaria, which explains the high frequencies of such genetic variants in malaria endemic areas. In this context, it has been shown that the rate limiting enzyme heme oxygenase I (HO-1), responsible for the catabolism of the free heme in the body, is an important resistance factor in malaria and is also important in the physiopathology of haemolytic diseases. Here, we suggest that allelic variants of HO-1, which display significant differences in terms of protein expression, have been selected in endemic malaria areas since the HO-1 enzyme can enhance the protection against malaria conferred by haemolytic diseases This protection apply mainly in what concerns protection against severe malaria forms. Therefore, HO-1 genotyping would be fundamental to determine resistance of a given individual to lethal forms of malaria as well as to common clinical complications typical to haemolytic diseases and would be helpful in the establishment of public health politics.
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PMID:HO-1 polymorphism as a genetic determinant behind the malaria resistance afforded by haemolytic disorders. 2010 3

MP from the RES are responsible for the clearance of senescent RBC. Although the frequency of senescent RBC is low under steady-state conditions, it increases dramatically during hemolytic disorders, resulting in enhanced erythrophagocytosis. As erythrophagocytosis has been involved in MP dysfunction and as certain hemolytic disorders associate to MP apoptosis, a possible link between erythrophagocytosis and the viability of phagocytes was investigated herein. To mimic hemolytic disorders, two distinct in vitro models, artificially oxidized RBC and DSRBC, were chosen to study the erythrophagocytosis impact on the viability of J774A.1 MP. Although CRBC were weakly phagocytosed and did not affect MP viability significantly, erythrophagocytosis of oxidized RBC and DSRBC was robust and resulted in a sharp decrease of MP viability via apoptosis. Under these conditions, Hb-derived HE was shown to be involved in the induction of apoptosis. Moreover, oxidized RBC, DSRBC, and HE generated ROS species, which were responsible for the apoptosis of MP. Furthermore, HO-1, strongly induced in response to treatment with oxidized RBC, DSRBC, or HE, was shown to protect MP partially against apoptosis, suggesting that robust erythro-phagocytosis may exceed the detoxification capabilities of MP. Taken together, these results suggest that enhanced erythrophagocytosis associated to hemolytic disorders leads to MP apoptosis in vitro and may have critical implications for the control of malaria infection and for the exacerbated susceptibility to bacterial infections during hemolytic disorders.
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PMID:Robust erythrophagocytosis leads to macrophage apoptosis via a hemin-mediated redox imbalance: role in hemolytic disorders. 2088 48

Malaria associated-acute kidney injury (AKI) is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. However, the causes that lead to a framework of malaria-associated AKI are still poorly characterized. Some clinical studies speculate that oxidative stress products, a characteristic of Plasmodium infection, as well as proinflammatory response induced by the parasite are involved in its pathophysiology. Therefore, we aimed to investigate the development of malaria-associated AKI during infection by P. berghei ANKA, with special attention to the role played by the inflammatory response and the involvement of oxidative stress. For that, we took advantage of an experimental model of severe malaria that showed significant changes in the renal pathophysiology to investigate the role of malaria infection in the renal microvascular permeability and tissue injury. Therefore, BALB/c mice were infected with P. berghei ANKA. To assess renal function, creatinine, blood urea nitrogen, and ratio of proteinuria and creatininuria were evaluated. The products of oxidative stress, as well as cytokine profile were quantified in plasma and renal tissue. The change of renal microvascular permeability, tissue hypoxia and cellular apoptosis were also evaluated. Parasite infection resulted in renal dysfunction. Furthermore, we observed increased expression of adhesion molecule, proinflammatory cytokines and products of oxidative stress, associated with a decrease mRNA expression of HO-1 in kidney tissue of infected mice. The measurement of lipoprotein oxidizability also showed a significant increase in plasma of infected animals. Together, our findings support the idea that products of oxidative stress, as well as the immune response against the parasite are crucial to changes in kidney architecture and microvascular endothelial permeability of BALB/c mice infected with P. berghei ANKA.
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PMID:Oxidative stress and modification of renal vascular permeability are associated with acute kidney injury during P. berghei ANKA infection. 2295 50

Heme, in the presence of hydrogen peroxide, can act as a peroxidase. Intravascular hemolysis results in a massive release of heme into the plasma in several pathophysiological conditions such as hemolytic anemia, malaria, and sickle cell disease. Heme is known to induce heme oxygenase-1(HO-1) expression, and the extent of induction depends on the ratio of albumin to heme in plasma. HO-1 degrades heme and ultimately generates the antioxidant bilirubin. Heme also causes oxidative stress in cells, but whether it causes protein-radical formation has not yet been studied. In the literature, two purposes for the degradation of heme by HO-1 are discussed. One is the production of the antioxidant bilirubin and the other is the prevention of heme-dependent adverse effects. Here we have investigated heme-induced protein-radical formation, which might have pathophysiological consequences, and have used immuno-spin trapping to establish the formation of heme-induced protein radicals in two systems: human serum albumin (HSA)/H2O2 and human plasma/H2O2.We found that excess heme catalyzed the formation of HSA radicals in the presence of hydrogen peroxide. When heme and hydrogen peroxide were added to human plasma, heme was found to oxidize proteins, primarily and predominantly HSA; however, when HSA-depleted plasma was used, heme triggered the oxidation of several other proteins, including transferrin. Thus, HSA in plasma protected other proteins from heme/H2O2-induced oxidation. The antioxidants ascorbate and uric acid significantly attenuated protein-radical formation induced by heme/H2O2; however, bilirubin did not confer significant protection. Based on these findings, we conclude that heme is degraded by HO-1 because it is a catalyst of protein-radical formation and not merely to produce the relatively inefficient antioxidant bilirubin.
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PMID:Immuno-spin trapping of heme-induced protein radicals: Implications for heme oxygenase-1 induction and heme degradation. 2362 3

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.
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PMID:Biochemical and immunological mechanisms by which sickle cell trait protects against malaria. 2402 76


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