Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
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Concentrations and distribution of cadmium, chromium, copper, iron, lead, manganese and zinc in mosquito larval habitats in urban Kisumu and Malindi, Kenya and their effect on the presence of Anopheles gambiae, Aedes aegypti, Culex quinquefasciatus and Anopheles funestus larvae were investigated. Manganese and iron were the most prevalent heavy metals in water of larval habitats in urban Kisumu and Malindi, respectively. Iron was the most prevalent heavy metal in bottom sediments in larval habitats in both cities. The highest concentrations of all heavy metals, except cadmium and iron, were recorded in the poorly planned-well drained stratum in the two cities. All heavy metals were more concentrated in human-made than in natural larval habitats. Copper was positively associated with the presence of Ae. aegypti, and lead was associated with the presence of An. gambiae and Ae. aegypti in urban Kisumu. Absence of significant correlation between the other metals and mosquito species in both cities, despite relatively high concentrations, suggest that the local larval populations, including key malaria vectors have adapted to the detected levels of these metals.
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PMID:Heavy metals in mosquito larval habitats in urban Kisumu and Malindi, Kenya, and their impact. 1753 67

We reviewed interventions that affect maternal and child undernutrition and nutrition-related outcomes. These interventions included promotion of breastfeeding; strategies to promote complementary feeding, with or without provision of food supplements; micronutrient interventions; general supportive strategies to improve family and community nutrition; and reduction of disease burden (promotion of handwashing and strategies to reduce the burden of malaria in pregnancy). We showed that although strategies for breastfeeding promotion have a large effect on survival, their effect on stunting is small. In populations with sufficient food, education about complementary feeding increased height-for-age Z score by 0.25 (95% CI 0.01-0.49), whereas provision of food supplements (with or without education) in populations with insufficient food increased the height-for-age Z score by 0.41 (0.05-0.76). Management of severe acute malnutrition according to WHO guidelines reduced the case-fatality rate by 55% (risk ratio 0.45, 0.32-0.62), and recent studies suggest that newer commodities, such as ready-to-use therapeutic foods, can be used to manage severe acute malnutrition in community settings. Effective micronutrient interventions for pregnant women included supplementation with iron folate (which increased haemoglobin at term by 12 g/L, 2.93-21.07) and micronutrients (which reduced the risk of low birthweight at term by 16% (relative risk 0.84, 0.74-0.95). Recommended micronutrient interventions for children included strategies for supplementation of vitamin A (in the neonatal period and late infancy), preventive zinc supplements, iron supplements for children in areas where malaria is not endemic, and universal promotion of iodised salt. We used a cohort model to assess the potential effect of these interventions on mothers and children in the 36 countries that have 90% of children with stunted linear growth. The model showed that existing interventions that were designed to improve nutrition and prevent related disease could reduce stunting at 36 months by 36%; mortality between birth and 36 months by about 25%; and disability-adjusted life-years associated with stunting, severe wasting, intrauterine growth restriction, and micronutrient deficiencies by about 25%. To eliminate stunting in the longer term, these interventions should be supplemented by improvements in the underlying determinants of undernutrition, such as poverty, poor education, disease burden, and lack of women's empowerment.
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PMID:What works? Interventions for maternal and child undernutrition and survival. 1850 90

Enzymes involved in sexual differentiation and fertilization of the human malaria parasite Plasmodium falciparum represent potential targets for transmission blocking strategies. Parasite proteases are putatively involved in several steps during fertilization, but the types of proteases, their targets and modes of action remain hitherto unknown. We investigated the involvement of proteases in gametogenesis via exflagellation and immunofluorescence assays, using a variety of commercially available as well as newly designed protease inhibitors. The assays revealed a blockade of microgamete formation by the cysteine/serine protease inhibitors TLCK and TPCK. The serine protease inhibitor PMSF, the falcipain-targeting inhibitor RV112D, and the aspartic protease inhibitor EPNP also significantly decreased formation of microgametes. The metalloprotease inhibitor 1,10-phenanthroline, on the other hand, inhibited exflagellation by interfering with microgamete motility. Furthermore, EPNP reduced the activation of male and female gametocytes. Our data point to a major involvement of serine proteases and a non-thermolysin-like zinc metalloprotease in microgametocyte exflagellation.
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PMID:Effect of protease inhibitors on exflagellation in Plasmodium falciparum. 1824 65

Zinc is required for multiple cellular tasks, and especially the immune system depends on a sufficient availability of this essential trace element. During the last decades, many studies attempted to affect the outcome of various diseases by zinc supplementation. These efforts either aimed at supporting immunity by zinc administration or at correcting a loss of zinc secondary to the disease to restore the zinc-dependent functions of the immune system. This review aims to summarize the respective findings and to discuss possible molecular mechanisms by which zinc could influence viral, bacterial, and parasitic infections, autoimmune diseases, and the response to vaccination. Zinc supplementation in diseases such as diarrhea, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory infection, and leishmaniasis seems beneficial. In contrast, the results for the common cold and malaria are still not conclusive, and zinc was ineffective in most vaccination and rheumatoid arthritis studies. For AIDS and type 1 diabetes, zinc supplementation may even be a risk factor for increased mortality or deterioration of the glucose metabolism, respectively. In these cases, zinc supplementation should be used with care and limited to clearly zinc-deficient individuals.
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PMID:Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases. 1825 Sep 73

Developing effective, affordable, and sustainable delivery strategies for the isolated low-income populations that stand to gain the most from micronutrient interventions has proven difficult. We discuss our experience with implementation of zinc as treatment for diarrhea in children less than 5 y of age over the course of 3 operational research studies in rural Sikasso Region, Mali, West Africa. The initial formative research study highlighted how malaria affects perceptions of diarrhea and its causes and that malaria and diarrhea are not necessarily viewed as distinct conditions. The second-phase pilot introduction demonstrated that, in introducing zinc treatment in malaria-endemic regions, it is especially important that both community- and facility-level providers be trained to manage sick children presenting with multiple symptoms. The third-phase study on large-scale implementation detected that the experience with implementation of new treatments for malaria is distinct from that of diarrhea. To some extent zinc treatment is the solution to a problem that communities may not recognize at all. Interventions to improve case management of sick children must be integrated across diseases and nutritional problems at both the facility and community levels. Operational research can identify points where integration should occur and how it should be carried out. Programs targeting single diseases or single nutritional problems can have a variety of deleterious effects on health systems, no matter how well they are planned.
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PMID:Differential community response to introduction of zinc for childhood diarrhea and combination therapy for malaria in southern Mali. 1828 81

Diarrhoea was estimated to account for 18% of the estimated 10.6 million deaths of children aged less than five years annually in 2003. Two--Africa and South-East Asia--of the six regions of the World Health Organization accounted for approximately 40% and 31% of these deaths respectively, or almost three-quarters of the global annual deaths of children aged less than five years attributable to diarrhoea. Much of the effort to roll out low-osmolarity oral rehydration solution (ORS) and supplementation of zinc for the management of diarrhoea accordingly is being devoted to sub-Saharan Africa and to South and South-East Asia. A number of significant differences exist in diarrhoea-treatment behaviours and challenges of the public-health systems between Africa and Asia. The differences in rates of ORS use are the most common indicator of treatment of diarrhoea and vary dramatically by and within region and may significantly influence the roll-out strategy for zinc and low-osmolarity ORS. The prevalence of HIV/AIDS and the endemicity of malaria also differ greatly between regions; both the diseases consume the attention and financial commitment of public-health programmes in regions where rates are high. This paper examined how these differences could affect the context for the introduction of zinc and low-osmolarity ORS at various levels, including the process of policy dialogue with local decision-makers, questions to be addressed in formative research, implementation approaches, and strategies for behaviour-change communication and training of health workers.
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PMID:Effect of HIV/AIDS and malaria on the context for introduction of zinc treatment and low-osmolarity ORS for childhood diarrhoea. 1863 23

Zinc for the treatment of childhood diarrhoea was introduced in a pilot area in southern Mali to prepare for a cluster-randomized effectiveness study and to inform policies on how to best introduce and promote zinc at the community level. Dispersible zinc tablets in 14-tablet blister packs were provided through community health centres and drug kits managed by community health workers (CHWs) in two health zones in Bougouni district, Mali. Village meetings and individual counselling provided by CHWs and head nurses at health centres were the principal channels of communication. A combination of methods were employed to (a) detect problems in communication about the benefits of zinc and its mode of administration; (b) identify and resolve obstacles to implementation of zinc through existing health services; and (c) describe household-level constraints to the adoption of appropriate home-management practices for diarrhoea, including administration of both zinc and oral rehydration solution (ORS). Population-based household surveys with caretakers of children sick in the previous two weeks were carried out before and four months after the introduction of zinc supplementation. Household follow-up visits with children receiving zinc from the health centres and CHWs were conducted on day 3 and 14 after treatment for a subsample of children. A qualitative process evaluation also was conducted to investigate operational issues. Preliminary evidence from this study suggests that the introduction of zinc does not reduce the use of ORS and may reduce inappropriate antibiotic use for childhood diarrhoea. Financial access to treatments, management of concurrent diarrhoea and fever, and high use of unauthorized drug vendors were identified as factors affecting the effectiveness of the intervention in this setting. The introduction of zinc, if not appropriately integrated with other disease-control strategies, has the potential to decrease the appropriate presumptive treatment of childhood malaria in children with diarrhoea and fever in malaria-endemic areas.
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PMID:Operational issues and trends associated with the pilot introduction of zinc for childhood diarrhoea in Bougouni district, Mali. 1868 49

Malaria remains an important health problem in tropical countries like Brazil. Thrombocytopenia is the most common hematological disturbance seen in malarial infection. Oxidative stress (OS) has been implicated as a possible mediator of thrombocytopenia in patients with malaria. This study aimed to investigate the role of OS in the thrombocytopenia of Plasmodium vivax malaria through the measurement of oxidant and antioxidant biochemical markers in plasma and in isolated platelets. Eighty-six patients with P. vivax malaria were enrolled. Blood samples were analyzed for total antioxidant and oxidant status, albumin, total protein, uric acid, zinc, magnesium, bilirubin, total thiols, glutathione peroxidase (GPx), malondialdehyde (MDA), antibodies against mildly oxidized low-density lipoproteins (LDL-/nLDL ratio) and nitrite/nitrate levels in blood plasma and GPx and MDA in isolated platelets. Plasma MDA levels were higher in thrombocytopenic (TCP) (median 3.47; range 1.55-12.90 micromol/L) compared with the non-thrombocytopenic (NTCP) patients (median 2.57; range 1.95-8.60 micromol/L). Moreover, the LDL-/nLDL autoantibody ratio was lower in TCP (median 3.0; range 1.5-14.8) than in NTCP patients (median 4.0; range 1.9-35.5). Finally, GPx and MDA were higher in the platelets of TPC patients. These results suggest that oxidative damage of platelets might be important in the pathogenesis of thrombocytopenia found in P. vivax malaria as indicated by alterations of GPx and MDA.
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PMID:The role of platelet and plasma markers of antioxidant status and oxidative stress in thrombocytopenia among patients with vivax malaria. 1894 18

Histone acetyltransferase (HAT) is an enzyme required for chromatin remodeling and transcriptional activation. Sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) is an ATP coupled Ca(2+) ion pump involved in metabolic arrest. Both these enzymes are present in Plasmodia and have been selected as molecular targets for in silico studies of some new non-resistant antimalarial drugs like artemisinin, curcumin and diarylheptanoids along with some other inhibitors reported in literature. Ten top inhibitors have also been generated based on common pharmacophore from ZINC database. The HAT enzyme was modeled with the help of the Modeller software and the SERCA enzyme pdb file was obtained from the protein data bank. Ligbuilder was used for structure based drug designing, which generated a common pharmacophore of the ligands. Molegro was used to perform virtual screening of the hits from the pharmacophore based Zinc database search and known inhibitors of the enzymes from the literature survey. Curcumin shows good and optimal binding to both HAT and SERCA enzymes; therefore it might be a good inhibitor of these key enzymes in Plasmodium. Curcumin is reported to act synergistically with artemisinin which forms covalent adducts with the transmembrane proteins (SERCA enzyme) and inactivates them, thus inhibiting the activity of Plasmodium parasite. This combination has already been reported to be effective in malaria treatment. Some other diarylheptanoids besides curcumin showed better binding to both the enzymes. Therefore, a combination of artemisinin and diarylheptanoids can prove to be better combination for antimalarial therapy. Different formulations involving curcumin, artimisinin and diarylheptanoids may result in a more potent antimalarial drug.
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PMID:Computational screening of molecular targets in Plasmodium for novel non resistant anti-malarial drugs. 1925 45

The structures of recombinant histo-aspartic protease (HAP) from malaria-causing parasite Plasmodium falciparum as apoenzyme and in complex with two inhibitors, pepstatin A and KNI-10006, were solved at 2.5-, 3.3-, and 3.05-A resolutions, respectively. In the apoenzyme crystals, HAP forms a tight dimer not seen previously in any aspartic protease. The interactions between the monomers affect the conformation of two flexible loops, the functionally important "flap" (residues 70-83) and its structural equivalent in the C-terminal domain (residues 238-245), as well as the orientation of helix 225-235. The flap is found in an open conformation in the apoenzyme. Unexpectedly, the active site of the apoenzyme contains a zinc ion tightly bound to His32 and Asp215 from one monomer and to Glu278A from the other monomer, with the coordination of Zn resembling that seen in metalloproteases. The flap is closed in the structure of the pepstatin A complex, whereas it is open in the complex with KNI-10006. Although the binding mode of pepstatin A is significantly different from that in other pepsin-like aspartic proteases, its location in the active site makes unlikely the previously proposed hypothesis that HAP is a serine protease. The binding mode of KNI-10006 is unusual compared with the binding of other inhibitors from the KNI series to aspartic proteases. The novel features of the HAP active site could facilitate design of specific inhibitors used in the development of antimalarial drugs.
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PMID:Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum. 1928 84


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