Antimalarial effect in vitro and lack of modulating effect of desipramine and imipramine

Based on previous studies in vitro of the modulating effect of desipramine on chloroquine-resistance of Plasmodium falciparum, the effect of desipramine and imipramine on freshly isolated resistant Brazilian strains of the parasite was investigated. Both drugs in therapeutic doses showed an unexpected antimalarial effect in vitro in duplicate tests (IC50=44.26 and 46.53 mu g/L for desipramine, and 83.93 and 41.26 mu g/L for imipramine), but no reversal of resistance when added to cultures together with chloroquine.

Sequence, evolution and ligand binding properties of mammalian Duffy antigen/receptor for chemokines

The Duffy antigen/receptor for chemokine, DARC, acts as a widely expressed promiscuous chemokine receptor and as the erythrocyte receptor for Plasmodium vivax. To gain insight into the evolution and structure/function relations of DARC, we analyzed the binding of anti-human Fy monoclonal antibodies (mAbs) and human chemokines to red blood cells (RBCs) from 11 nonhuman primates and two nonprimate mammals, and we elucidated the structures of the DARC genes from gorilla, gibbon, baboon, marmoset, tamarin, night monkey and cattle. CXCL-8 and CCL-5 chemokine binding analysis indicated that the promiscuous binding profile characteristic of DARC is conserved across species. Among three mAbs that detected the Fy6 epitope by flow cytometric analysis of human and chimpanzee RBCs, only one reacted with night monkey and squirrel monkey. Only chimpanzee RBCs bound a significant amount of the anti-Fy3 mAb. Fy3 was also poorly detected on RBCs from gorilla, baboon and rhesus monkey, but not from new world monkeys. Alignment of DARC homologous sequences allowed us to construct a phylogenetic tree in which all branchings were in accordance with current knowledge of primate phylogeny. Although DARC was expected to be under strong internal and external selection pressure, in order to maintain chemokine binding and avoid Plasmodium vivax binding, respectively, our present study did not provide arguments in favor of a selection pressure on the extracellular domains involved in ligand specificity. The amino acid variability of DARC-like polypeptides was found to be well correlated with the hydrophylicity indexes, with the highest divergence on the amino-terminal extracellular domain. Analysis of the deduced amino acid sequences highlighted the conservation of some amino acid residues, which should prove to be critical for the structural and functional properties of DARC.

Hemoglobin and HFE gene polymorphisms in Brazilian populations in regions endemic for malaria

Our objective was to determine how the distribution of red blood cell diseases is related to malaria occurrence in north Brazil, a region endemic for malaria. We evaluated the incidence of two mutations in the HFE gene, H63D and C282Y, in two study groups: a control blood donor group, with no indication of malaria infection, and a group constituted of malaria patients of four states of the Amazonian region. The hemoglobin polymorphisms were obtained by HPLC and classical laboratory methodologies, and the two mutations in the HFE gene were assayed by PCR-RFLP. We found a high frequency of alpha thalassemia, but there were no significant differences between blood donors and malaria patients. There were also no significant differences in the frequencies of HbA(2); however, the frequency of HbF was significantly different in individuals with malaria from Para and Rondonia. The mean number of reticulocytes was significantly reduced in the blood donors from the northern region, suggesting an adaptive strategy of these populations to parasitic attack by Plasmodium. Most individuals were heterozygous for the H63D allele of the HFE gene in both study groups. In the blood donors group, the greatest frequency of the H63D allele was found in Caucasians of all the states. In the malaria patients group in Rondonia, there was a high frequency of the H63D allele among the non-Caucasians. In the other states, and in the malaria patients group, the H63D allele was the most frequent among the Caucasians. Based on our results, we suggest that the maintenance of polymorphism of the mutations in the gene HFE can be explained by selective factors other than malaria, or it is due to simple allelic oscillation and by the constant gene flow among the populations in Brazil.

On the study of the dynamical aspects of parasitemia in the blood cycle of malaria

Malaria is an important cause of morbidity and mortality worldwide. One striking aspect regarding malaria is the fact that individuals living in endemic areas do not develop immunity against the parasite, falling ill whenever they are exposed tothe parasite. The understanding of why immunity is not developed in the usual way against Plasmodium is crucial to the improvement of treatment and prevention. In this work, we study some aspects of the dynamics of the blood cycle of malaria using both modelling and data analysis of observed case-histories described by parasitemia time series. By comparing our simulations with experimental results we have shown that the different behaviour observed among patients may be associated to differences in the efficiency of the immune system to control the infection. © EDP Sciences/Societa Italiana di Fisica/Springer-Verlag 2007.

Aspectos estruturais da membrana eritrocitária

This article describes the structures and functions of the erythrocyte membrane and its importance in transfusional medicine. The erythrocyte membrane is one of the best known membranes in terms of structure, function and genetic disorders. As any other plasma membrane, it mediates transport functions. It also provides the erythrocytes with their resilience and deformability. According to the International Society of Blood Transfusion (ISBT), more than 500 antigens are expressed in the erythrocyte membrane, and around 270 are involved in transfusion reaction cases and hemolytic diseases of the fetus and newborn. In the ISBT classification, the high frequency series is represented by antigens in more than 99% of population (high prevalence antigen). In transfusion, the absence of these antigens determines severe problems as for example, one woman without the P antigen suffered 6 repetitive miscarriages due to placental insufficiency, which was caused by an antibody formed against the absent P antigen. Some important erythrocyte membrane proteins are described here including Band 3, Glycophorins and spectrin. The most abundant integral membrane protein is Band 3 and its main function is to mediate exchange of chloride and bicarbonate anions across the plasma membrane. The second most abundant integral membrane protein in the human erythrocyte is sialoglycoprotein glycophorin A (GPA). With its high sialic acid content, GPA is the main contributor to the net negative cell-surface charge and is thus critical for minimizing cell-cell interactions and preventing red cell aggregation. Glycophorin C (GPC) is the receptor for PfEBP-2 (baebl, EBA-140), the newly identified erythrocyte binding ligand of Plasmodium falciparum. The ternary complex of spectrin, actin and 4.1R defines the nodes of the erythrocyte membrane skeletal network, and is inseparable from membrane stability when under mechanical stress. This erythrocyte membrane review is important for a better understanding of transfusion reactions, where the antibody formation against high prevalence antigens makes compatible transfusions difficult. The study of antigen diversity and biochemical characterization of different proteins will contribute to healthcare, as well as diagnosis, development of technology such as monoclonal antibody production and the therapeutic conduct of many diseases.

Frequency of the HFE C282Y and H63D polymorphisms in Brazilian malaria patients and blood donors from the Amazon region

Malaria is an endemic parasitosis and its causitive agent, Plasmodium, has a metabolism linked to iron supply. HFE is a gene with the polymorphisms C282Y and H63D, which are associated with a progressive iron accumulation in the organism leading to a disease called hereditary hemochromatosis. The aim of the present study was to determine the allelic and genotypic frequencies of the HFE gene polymorphisms in malaria patients and blood donors from the Brazilian Amazon region. We screened 400 blood donors and 400 malaria patients for the HFE C282Y and H63D polymorphisms from four states of the Brazilian Amazon region by polymerase chain reaction and restriction fragment length polymorphism analysis. We did not find any C282Y homozygous individuals, and the only five heterozygous individuals detected were from Pará State. The most frequent genotype in the North region of Brazil was the H63D heterozygote, in both study groups. Our results contribute to the concept that the Brazilian Amazon region should not be regarded as a single entity in South America. These polymorphisms did not influence the symptoms of malaria in the population studied, as neither severe signs nor high parasitemia were observed. Therefore, different hereditary hemochromatosis diagnostic and control measures must be developed and applied within its diverse locations. Investigations are currently being carried out in our laboratory in order to determine the importance of the coexistence of hereditary hemochromatosis in patients affected by parasitic diseases, such as malaria. ©FUNPEC-RP.

Biodiversity Can Help Prevent Malaria Outbreaks in Tropical Forests

Background: Plasmodium vivax is a widely distributed, neglected parasite that can cause malaria and death in tropical areas. It is associated with an estimated 80-300 million cases of malaria worldwide. Brazilian tropical rain forests encompass host- and vector-rich communities, in which two hypothetical mechanisms could play a role in the dynamics of malaria transmission. The first mechanism is the dilution effect caused by presence of wild warm-blooded animals, which can act as dead-end hosts to Plasmodium parasites. The second is diffuse mosquito vector competition, in which vector and non-vector mosquito species compete for blood feeding upon a defensive host. Considering that the World Health Organization Malaria Eradication Research Agenda calls for novel strategies to eliminate malaria transmission locally, we used mathematical modeling to assess those two mechanisms in a pristine tropical rain forest, where the primary vector is present but malaria is absent. Methodology/Principal Findings: The Ross-Macdonald model and a biodiversity-oriented model were parameterized using newly collected data and data from the literature. The basic reproduction number (R0) estimated employing Ross-Macdonald model indicated that malaria cases occur in the study location. However, no malaria cases have been reported since 1980. In contrast, the biodiversity-oriented model corroborated the absence of malaria transmission. In addition, the diffuse competition mechanism was negatively correlated with the risk of malaria transmission, which suggests a protective effect provided by the forest ecosystem. There is a non-linear, unimodal correlation between the mechanism of dead-end transmission of parasites and the risk of malaria transmission, suggesting a protective effect only under certain circumstances (e.g., a high abundance of wild warm-blooded animals). Conclusions/Significance: To achieve biological conservation and to eliminate Plasmodium parasites in human populations, the World Health Organization Malaria Eradication Research Agenda should take biodiversity issues into consideration. © 2013 Laporta et al.

Estrutura eletrônica de materiais orgânicos: moléculas antimalariais de sulfonamidas e anilinoquinolinas

Pós-graduação em Ciência e Tecnologia de Materiais - FC

Análise da expressão e silenciamento de genes do trato digestivo de Anopheles aquasalis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Obtenção de derivados semissintéticos dos alcalóides (-) - cassina e (-) e espectalina e avaliação do potencial antimalárico

Pós-graduação em Química - IQ

Produção de um anticorpo policlonal anti-Duffy de Bos taurus taurus para detecção e quantificação do antígeno em eritrócitos bovinos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Aspectos filogenéticos e sorológicos envolvidos na caracterização das variantes da proteína circunsporozoítica de Palsmodium vivax

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)