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stage-specific depletion of myosin a supports an essential role in motility of malarial ookinetes.functional analysis of plasmodium genes by classical reverse genetics is currently limited to mutants that are viable during erythrocytic schizogony, the pathogenic phase of the malaria parasite where transfection is performed. here, we describe a conceptually simple experimental approach to study the function of genes essential to the asexual blood stages in a subsequent life cycle stage by a promoter-swap approach. as a proof of concept we targeted the unconventional class xiv myosin myoa, whi ...201121899701
quantitation of brain edema and localisation of aquaporin 4 expression in relation to susceptibility to experimental cerebral malaria.the pathogenic mechanisms underlying the occurrence of cerebral malaria (cm) are still incompletely understood but, clearly, cerebral complications may result from concomitant microvessel obstruction and inflammation. the extent to which brain edema contributes to pathology has not been investigated. using the model of p. berghei anka infection, we compared brain microvessel morphology of cm-susceptible and cm-resistant mice. by quantitative planimetry, we provide evidence that cm is characteriz ...201121904632
high-throughput multi-parameter flow-cytometric analysis from micro-quantities of plasmodium-infected blood.despite significant technological and conceptual advances over the last century, evaluation of the efficacy of anti-malarial vaccines or drugs continues to rely principally on direct microscopic visualisation of parasites on thick and/or thin giemsa-stained blood smears. this requires technical expertise of the microscopist, is highly subjective and error-prone, and does not account for aberrations such as anaemia. many published methods have shown that flow cytometric analysis of blood is a hig ...201121907206
The interplay between tubulins and P450 cytochromes during Plasmodium berghei invasion of Anopheles gambiae midgut.Plasmodium infection increases the oxidative stress inside the mosquito, leading to a significant alteration on transcription of Anopheles gambiae detoxification genes. Among these detoxification genes several P450 cytochromes and tubulins were differently expressed, suggesting their involvement in the mosquito's response to parasite invasion. P450 cytochromes are usually involved in the metabolism and detoxification of several compounds, but are also regulated by several pathogens, including ma ...201121912622
proteolytic breakdown of cytoskeleton induces neurodegeneration during pathology of murine cerebral malaria.fatal murine cerebral malaria is known to induce cellular degeneration by altering cellular morphology and integrity of cell. the morphology and integrity of the cell mainly depends on the cytoskeletal network of the cell. increased proteolysis of cytoskeletal proteins accompanied by aggravated suicidal proteases activation leads to cellular degeneration. in the present study, we investigated the roles of apoptotic and necrotic cell death proteases, caspase-3, calpain-1 and cathepsin-b in the pr ...201121914552
Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) and its carboxylic acid derivatives.Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cy ...201121924377
characterization and tissue-specific expression patterns of the plasmodium chabaudi cir multigene family.variant antigens expressed on the surface of parasitized red blood cells (prbcs) are important virulence factors of malaria parasites. whereas plasmodium falciparum erythrocyte membrane proteins 1 (pfemp1) are responsible for sequestration of mature parasites, little is known about putative ligands mediating cytoadherence to host receptors in other plasmodium species. candidates include members of the pir superfamily found in the human parasite plasmodium vivax (vir), in the simian pathogen plas ...201121929749
Protection from experimental cerebral malaria with a single dose of radiation-attenuated, blood-stage Plasmodium berghei parasites.Whole malaria parasites are highly effective in inducing immunity against malaria. Due to the limited success of subunit based vaccines in clinical studies, there has been a renewed interest in whole parasite-based malaria vaccines. Apart from attenuated sporozoites, there have also been efforts to use live asexual stage parasites as vaccine immunogens.201121935405
Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds.The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC(50) values as low as 60 nM and a certain efficacy in vivo by reduc ...201121940072
the anti-malarial activity of bivalent imidazolium salts.a series of compounds containing bivalent imidazolium rings and one triazolium analog were synthesized and evaluated for their ability to inhibit the replication of plasmodium falciparum cultures. the activity and selectivity of the compounds for p. falciparum cultures were found to depend on the presence of electron-deficient rings that were spaced an appropriate distance apart. the activity of the compounds was not critically dependent on the nature of the linker between the electron-deficient ...201121944972
plasmodium ookinetes coopt mammalian plasminogen to invade the mosquito midgut.ookinete invasion of the mosquito midgut is an essential step for the development of the malaria parasite in the mosquito. invasion involves recognition between a presumed mosquito midgut receptor and an ookinete ligand. here, we show that enolase lines the ookinete surface. an antienolase antibody inhibits oocyst development of both plasmodium berghei and plasmodium falciparum, suggesting that enolase may act as an invasion ligand. importantly, we demonstrate that surface enolase captures plasm ...201121949403
antimalarial activity of physalins b, d, f, and g.the antimalarial activities of physalins b, d, f, and g (1-4), isolated from physalis angulata, were investigated. in silico analysis using the similarity ensemble approach (sea) database predicted the antimalarial activity of each of these compounds, which were shown using an in vitro assay against plasmodium falciparum. however, treatment of p. berghei-infected mice with 3 increased parasitemia levels and mortality, whereas treatment with 2 was protective, causing a parasitemia reduction and a ...201121954931
PbGEST mediates malaria transmission to both mosquito and vertebrate host.The malaria life cycle relies on the successful transfer of the parasite between its human and mosquito hosts. We identified a Plasmodium berghei secreted protein (PBANKA_131270) that plays distinct roles in both the mammal-to-mosquito and the mosquito-to-mammal transitions. This protein, here named gamete egress and sporozoite traversal (GEST), plays an important role in the egress of male and female gametes from the vertebrate red blood cell. Interestingly, GEST is also required following the ...201121958024
antibody responses to 43 and 48 kda antigens of blood-stage plasmodium berghei in balb/c mice.progress towards a vaccine against malaria is advancing rapidly with several candidate antigens being tested for their safety and efficacy. in present investigation, two polypeptides (43 and 48 kda) of plasmodium berghei (nk-65) were identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis. immunogenicity and protective efficacy of both these polypeptides formulated in saponin has been compared in balb/c mice against challenge infection with p. berghei. antibody responses were eva ...201021966123
critical role of the neutrophil-associated high-affinity receptor for ige in the pathogenesis of experimental cerebral malaria.the role of the ige-fcεri complex in malaria severity in plasmodium falciparum-hosting patients is unknown. we demonstrate that mice genetically deficient for the high-affinity receptor for ige (fcεriα-ko) or for ige (ige-ko) are less susceptible to experimental cerebral malaria (ecm) after infection with plasmodium berghei (pbanka). mast cells and basophils, which are the classical ige-expressing effector cells, are not involved in disease as mast cell-deficient and basophil-depleted mice devel ...201121967768
deletion of a malaria invasion gene reduces death and anemia, in model hosts.malaria parasites induce complex cellular and clinical phenotypes, including anemia, cerebral malaria and death in a wide range of mammalian hosts. host genes and parasite 'toxins' have been implicated in malarial disease, but the contribution of parasite genes remains to be fully defined. here we assess disease in balb/c mice and wistar rats infected by the rodent malaria parasite plasmodium berghei with a gene knock out for merozoite surface protein (msp) 7. msp7 is not essential for infection ...201121980474
nogo-a expression in the brain of mice with cerebral malaria.cerebral malaria (cm) is associated with a high rate of transient or persistent neurological sequelae. nogo-a, a protein that is highly expressed in the endoplasmic reticulum (er) of the mammalian central nervous system (cns), is involved in neuronal regeneration and synaptic plasticity in the injured cns. the current study investigates the role of nogo-a in the course of experimental cm. c57bl/6j mice were infected with plasmodium berghei anka blood stages. brain homogenates of mice with differ ...201121980529
Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening.Plasmodium vivax is the most prevalent cause of human malaria in tropical regions outside the African continent. The lack of a routine continuous in vitro culture of this parasite makes it difficult to develop specific drugs for this disease. To facilitate the development of anti-P. vivax drugs, bacterial and yeast surrogate models expressing the validated P. vivax target dihydrofolate reductase-thymidylate synthase (DHFR-TS) have been generated; however, they can only be used as primary screeni ...201121981896
blood-stage plasmodium berghei infection generates a potent, specific cd8+ t-cell response despite residence largely in cells lacking mhc i processing machinery.murine cerebral malaria is a complex disease caused by plasmodium berghei anka infection. several cell types, including cd8(+) t cells, are essential effectors of disease. although the use of transgenic parasites expressing model antigens has revealed the induction of cytotoxic t lymphocytes (ctl) specific for these model antigens, there is no direct evidence for a response to authentic blood-stage parasite antigens, nor any knowledge of its magnitude. our studies show that there is a dramatic p ...201121998471
immunization with genetically attenuated p52-deficient plasmodium berghei sporozoites induces a long-lasting effector memory cd8+ t cell response in the liver.abstract:201122004696
cytofluorometric detection of rodent malaria parasites using red-excited fluorescent dyes.flow cytometry is a potentially efficient approach for the quantification of parasitemias in experimental malaria infections and drug susceptibility assays using rodent malaria models such as plasmodium berghei. in this study, we used two red dna-binding fluorochromes, rhodamine 800 (r800) and ld700, to measure parasitemia levels in whole blood samples from mice infected with p. berghei. blood samples were treated with rnase a to eliminate rna-derived signals. propidium iodide, which stains both ...201122015734
A scalable pipeline for highly effective genetic modification of a malaria parasite.In malaria parasites, the systematic experimental validation of drug and vaccine targets by reverse genetics is constrained by the inefficiency of homologous recombination and by the difficulty of manipulating adenine and thymine (A+T)-rich DNA of most Plasmodium species in Escherichia coli. We overcame these roadblocks by creating a high-integrity library of Plasmodium berghei genomic DNA (>77% A+T content) in a bacteriophage N15-based vector that can be modified efficiently using the lambda Re ...201122020067
Coartemether Induced Oxidative and Hepatic Damage in Plasmodium berghei Strain Anka Infected Mice.This study investigated the effect of coartemether on antioxidant and hepatotoxic biomarkers in Plasmodium berghei infected mice. Erythrocyte, hepatic and renal superoxide dismutase (2.71 ± 0.51; 1.96 ± 0.87; 2.84 ± 0.22 Units/mg protein respectively) and catalase (4.10 ± 0.10; 8.25 ± 1.24; 6.28 ± 0.11 Units/mg protein respectively) activities were significantly (p < 0.05) elevated in "parasitized and treated" (PnT) animals. Renal glutathione level (19.02 ± 0.20 µg/mL) was elevated in PnT animal ...201122057281
Triterpenoids as inhibitors of erythrocytic and liver stages of Plasmodium infections.Bioassay-guided fractionation of the methanol extract of Momordica balsamina led to the isolation of two new cucurbitane-type triterpenoids, balsaminol F (1) and balsaminoside B (2), along with the known glycosylated cucurbitacins, cucurbita-5,24-diene-3ß,23(R)-diol-7-O-ß-d-glucopyranoside (3) and kuguaglycoside A (4). Compound 1 was acylated yielding two new triesters, triacetylbalsaminol F (5) and tribenzoylbalsaminol F (6). The structures were elucidated based on spectroscopic methods includi ...201122071523
expressed sequence tag analysis of the erythrocytic stage of plasmodium berghei.rodent malaria parasites, such as plasmodium berghei, are practical and useful model organisms for human malaria research because of their analogies to the human malaria in terms of structure, physiology, and life cycle. exploiting the available genetic sequence information, we constructed a cdna library from the erythrocytic stages of p. berghei and analyzed the expressed sequence tag (est). a total of 10,040 ests were generated and assembled into 2,462 clusters. these est clusters were compare ...201122072821
hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection.hepcidin is one of the regulators of iron metabolism. the expression of hepcidin is induced in spleens and livers of mice infected with pathogenic bacteria. recent studies have indicated that serum hepcidin level is also increased in human subjects infected with plasmodium falciparum. the mechanism of the regulation of hepcidin expression and its role in the infection of malaria remains unknown. in this study, we determined the expression of hepcidin in livers of mice infected with plasmodium be ...201122084434
imaging of plasmodium liver stages to drive next-generation antimalarial drug discovery.most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. we applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. from this sc ...201122096101
Ethnobotanical study of antimalarial plants in Shinile District, Somali Region, Ethiopia, and in vivo evaluation of selected ones against Plasmodium berghei.The study documented medicinal plants that are traditionally used for treatment of malaria in Shinile District, eastern Ethiopia, and evaluated selected medicinal plants for their antiplasmodial activities against Plasmodium berghei.201222101085
Kinetic of humoral and memory B cell response induced by Plasmodium falciparum Merozoite Surface Protein-119 in mice.The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP-1(19)) has been shown to mediate antibody mediated protective immunity to blood-stage malaria infection. But the serological memory to this antigen tends to be short-lived and little is known of the mechanisms that regulate the formation of B cell memory to MSP-1(19) antigen. We studied the formation of B cell memory response after immunization with recombinant PfMSP-1(19).Immunization with PfMSP-1(19) resulted in dela ...201122104109
erythrocyte remodeling in plasmodium berghei infection: the contribution of sep family members.the malaria parasite plasmodium largely modifies the infected erythrocyte through the export of proteins to multiple sites within the host cell. this remodeling is crucial for pathology and translocation of virulence factors to the erythrocyte surface. in this study, we investigated localization and export of small exported proteins/early transcribed membrane proteins (sep/etramps), conserved within plasmodium genus. this protein family is characterized by a predicted signal peptide, a short lys ...201122106924
In vitro culture of Plasmodium berghei-ANKA maintains infectivity of mouse erythrocytes inducing cerebral malaria.ABSTRACT: BACKGROUND: Infection with Plasmodium berghei is a widely used model of murine malaria and a powerful tool for reverse genetic and pathogenesis studies. However, the efficacy of in vitro reinvasion of erythrocytes is generally low, limiting in vitro studies. METHODS: Plasmodium berghei ANKA-infected blood obtained from a susceptible infected mouse was cultured in various conditions and in vitro parasitaemia was measured every day to evaluate the rate of reinvasion. RESULTS: High quali ...201122118493
malaria-infected mice are completely cured by one 6 mg/kg oral dose of a new monomeric trioxane sulfide combined with mefloquine.sixteen new anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in plasmodium berghei infected mice. of these 16 new anilides administered orally as one 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, only sulfide 3-artesanilide 12d was completely curative: on day 30 after infection, all mice in this group had no detectable parasitemia, gained as much weight as the uninfected control mice, and behaved normally.201122128829
mitochondrial lipoic acid scavenging is essential for plasmodium berghei liver stage development.lipoic acid is an essential cofactor for enzymes that participate in key metabolic pathways in most organisms. while in mammalian cells lipoylated proteins reside exclusively in the mitochondria, apicomplexan parasites of the genus plasmodium harbor two independent lipoylation pathways in the mitochondrion and the apicoplast, a second organelle of endosymbiotic origin. protein lipoylation in the apicoplast relies on de novo lipoic acid synthesis while lipoylation of proteins in the mitochondrion ...201122128915
a gfp-actin reporter line to explore microfilament dynamics across the malaria parasite lifecycle.malaria parasite motility relies on an internal parasite actomyosin motor that, when linked to the host cell substrate, propels motile zoites forward. despite their key role in this process, attempts to visualize actin microfilaments (f-actin) during motility and under native microscopy conditions have not to date been successful. towards facilitating their visualization we present here a plasmodium berghei transgenic line in which a green fluorescent protein (gfp)-actin fusion is constitutively ...201122138565
artemisinin and artemisinin plus curcumin liposomal formulations: enhanced antimalarial efficacy against plasmodium berghei-infected mice.the therapeutic efficacies of novel liposomal delivery systems based on artemisinin or artemisinin-based combination therapy with curcumin have been investigated and reported in this study. the developed liposomal formulations had proper characteristics as drug carriers for parental administration in terms of particle size, polydispersity, encapsulation efficacy and ζ-potential. their physical and chemical stabilities were also evaluated. furthermore, the in vivo antimalarial activity of artemis ...201122142592
evaluation of immunity against malaria using luciferase-expressing plasmodium berghei parasites.abstract: background: measurement of liver stage development is of key interest in malaria biology and vaccine studies. parasite development in liver cells can be visualized in real-time, both in culture and in live mice, using a transgenic plasmodium berghei parasite, pbgfp-luccon, expressing the bioluminescent reporter luciferase. this study explores the benefit of using these parasites for the evaluation of immunity against malaria, compared to qrt-pcr techniques in vivo and in vitro. metho ...201122152047
experimental cerebral malaria develops independently of card9 signalling.the outcome of infection depends on multiple layers of immune regulation with innate immunity playing a decisive role in shaping protection or pathogenic sequelae of acquired immunity. the contribution of pattern recognition receptors and adaptor molecules in immunity to malaria remains poorly understood. here we interrogate the role of the caspase recruitment domain-containing protein 9 (card9) signalling pathway in the development of experimental cerebral malaria (ecm) using the murine plasmod ...201122158744
nematode-induced interference with the anti-plasmodium cd8(+) t-cell response can be overcome by optimizing antigen administration.malaria is still responsible for up to 1 million deaths per year worldwide, highlighting the need for protective malaria vaccines. helminth infections that are prevalent in malaria endemic areas can modulate immune responses of the host. here we show that strongyloides ratti, a gut-dwelling nematode that causes transient infections, did not change the efficacy of vaccination against plasmodium berghei. an ongoing infection with litomosoides sigmodontis, a tissue-dwelling filaria that induces chr ...201122161305
Antimalaria Effect of the Ethanolic Stem Bark Extracts of Ficus platyphylla Del.The antimalarial effect of the ethanolic stem bark extract of Ficus platyphylla Del was evaluated against Plasmodium berghei infection in mice. Nontreated, experimental control mice died of fulminant parasitemia from day 7 to 9 post-infection but mice treated with the extract at 300?mg/kg showed markedly reduced parasitaemia bouts of 43.50% and a mean survival time of 28 days postinfection. The plant extract prevented a drastic reduction in PCV showing its efficacy in ameliorating anaemic condit ...201122174991
independent roles of apical membrane antigen 1 and rhoptry neck proteins during host cell invasion by apicomplexa.during invasion, apicomplexan parasites form an intimate circumferential contact with the host cell, the tight junction (tj), through which they actively glide. the tj, which links the parasite motor to the host cell cytoskeleton, is thought to be composed of interacting apical membrane antigen 1 (ama1) and rhoptry neck (ron) proteins. here we find that, in plasmodium berghei, while both ama1 and ron4 are important for merozoite invasion of erythrocytes, only ron4 is required for sporozoite inva ...201122177563
reduced cd36-dependent tissue sequestration of plasmodium-infected erythrocytes is detrimental to malaria parasite growth in vivo.adherence of parasite-infected red blood cells (irbc) to the vascular endothelium of organs plays a key role in the pathogenesis of plasmodium falciparum malaria. the prevailing hypothesis of why irbc adhere and sequester in tissues is that this acts as a mechanism of avoiding spleen-mediated clearance. irbc of the rodent parasite plasmodium berghei anka sequester in a fashion analogous to p. falciparum by adhering to the host receptor cd36. to experimentally determine the significance of seques ...201122184632
A carbamate-based approach to primaquine prodrugs: Antimalarial activity, chemical stability and enzymatic activation.O-Alkyl and O-aryl carbamate derivatives of the antimalarial drug primaquine were synthesised as potential prodrugs that prevent oxidative deamination to the inactive metabolite carboxyprimaquine. Both O-alkyl and O-aryl carbamates undergo hydrolysis in alkaline and pH 7.4 phosphate buffers to the parent drug, with O-aryl carbamates being ca. 10(6)-10(10) more reactive than their O-alkyl counterparts. In human plasma O-alkyl carbamates were stable, whereas in contrast their O-aryl counterparts r ...201122189276
wolbachia strain walbb enhances infection by the rodent malaria parasite plasmodium berghei in anopheles gambiae mosquitoes.wolbachia, a common bacterial endosymbiont of insects, has been shown to protect its hosts against a wide range of pathogens. however, not all strains exert a protective phenotype on their host. here we assess the affect of two divergent wolbachia strains, walbb from aedes albopticus and wmelpop from drosophila melanogaster, on the vector competence of anopheles gambiae challenged with plasmodium berghei. we show the walbb strain significantly increases p. berghei oocyst levels in the mosquito m ...201122210220
genome comparison of human and non-human malaria parasites reveals species subset-specific genes potentially linked to human disease.genes underlying important phenotypic differences between plasmodium species, the causative agents of malaria, are frequently found in only a subset of species and cluster at dynamically evolving subtelomeric regions of chromosomes. we hypothesized that chromosome-internal regions of plasmodium genomes harbour additional species subset-specific genes that underlie differences in human pathogenicity, human-to-human transmissibility, and human virulence. we combined sequence similarity searches wi ...201122215999
antimalarial potency of the leaf extract of aspilia africana (pers.) c.d. adams.to investigate the antimalarial activity of ethanol extract of aspilia africana (a. africana) leaf.201222221756
flow cytometric enumeration of plasmodium berghei-infected red blood cells stained with sybr green i.high-throughput methods for evaluation of in vivo efficacy of candidate compounds against plasmodium parasites are necessary during the antimalarial drug development process. it is essential that enumeration of parasitemia in the infected blood from experimental host animals is accurate and reliable. flow cytometric enumeration of parasitized cells stained with fluorescent dye is a rapid alternative method to conventional microscopic counting. in this study, a protocol for flow cytometric enumer ...201222222185
atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model.one of the major complications of plasmodium falciparum infection is cerebral malaria (cm), which causes one million deaths worldwide each year, results in long-term neurological sequelae and the treatment for which is only partially effective. statins are recognized to have an immunomodulatory action, attenuate sepsis and have a neuroprotective effect. atorvastatin (ava) has shown in vitro anti-malarial activity and has improved the activity of mefloquine (mq) and quinine.201222233563
in vivo antiplasmodial activities of aqueous extract of bridelia ferruginea stem bark against plasmodium berghei berghei in mice.bridelia ferruginea benth (euphorbiaceae) is an indigenous medicinal plant in nigeria. it is usually a gnarled shrub which sometimes reaches the size of a tree in suitable condition. decoctions of parts of this plant have been employed in ethno medicine in many parts of africa for treatment of many ailments including malaria fever.201222235887
il-12rβ2 is essential for the development of experimental cerebral malaria.a th1 response is required for the development of plasmodium berghei anka (pba)-induced experimental cerebral malaria (ecm). the role of pro-th1 il-12 in malaria is complex and controversial. in this study, we addressed the role of il-12rβ2 in ecm development. c57bl/6 mice deficient for il-12rβ2, il-12p40, or il-12p35 were analyzed for ecm development after blood-stage pba infection in terms of ischemia and blood flow by noninvasive magnetic resonance imaging and angiography, t cell recruitment, ...201222238458
marilones a-c, phthalides from the sponge-derived fungus stachylidium sp.the marine-derived fungus stachylidium sp. was isolated from the sponge callyspongia sp. cf. c. flammea. culture on a biomalt medium supplemented with sea salt led to the isolation of three new phthalide derivatives, i.e., marilones a-c (1-3), and the known compound silvaticol (4). the skeleton of marilones a and b is most unusual, and its biosynthesis is suggested to require unique biochemical reactions considering fungal secondary metabolism. marilone a (1) was found to have antiplasmodial act ...201122238541
highly dynamic host actin reorganization around developing plasmodium inside hepatocytes.plasmodium sporozoites are transmitted by anopheles mosquitoes and infect hepatocytes, where a single sporozoite replicates into thousands of merozoites inside a parasitophorous vacuole. the nature of the plasmodium-host cell interface, as well as the interactions occurring between these two organisms, remains largely unknown. here we show that highly dynamic hepatocyte actin reorganization events occur around developing plasmodium berghei parasites inside human hepatoma cells. actin reorganizat ...201222238609
testing in mice the hypothesis that melanin is protective in malaria infections.malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. modern humans originated in africa and lost skin melanization as they migrated to temperate regions of the globe. although it is well documented that loss of melanization improved cutaneous vitamin d synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melani ...201222242171
synthesis and antimalarial evaluation of some 4-quinazolinone derivatives based on febrifugine.a series of 2-substituted and 2,3-substituted quinazolin -4(3h)-one derivatives were designed and synthesized based on the structure of febrifugine. the structures of the new compounds were confirmed by spectral analysis. the in vivo biological activity test results indicated that those compounds exhibited antimalarial activities against plasmodium berghei in mice, at a dose of 5 mg/kg. compared to chloroquine and artemisinin, these compounds have the advantages of shorter synthetic routes and c ...201022247880
clotrimazole nanoemulsion for malaria chemotherapy. part ii: stability assessment, in vivo pharmacodynamic evaluations and toxicological studies.the aim of present investigation was to evaluate the potential of clotrimazole as antimalarial drug. due to poor aqueous solubility and high lipophilicity, it was previously formulated in a nanoemulsion based system. the intrinsic effects of nanoemulsion on improvement of antimalarial activity of clotrimazole were assessed in mice infected with plasmodium berghei and compared to its suspension formulation. in four-day suppressive test, mice treated with 10mg/kg clotrimazole nanoemulsion showed t ...201222265913
curcumin-arteether combination therapy of plasmodium berghei-infected mice prevents recrudescence through immunomodulation.earlier studies in this laboratory have shown the potential of artemisinin-curcumin combination therapy in experimental malaria. in a parasite recrudescence model in mice infected with plasmodium berghei (anka), a single dose of alpha,beta-arteether (art) with three oral doses of curcumin prevented recrudescence, providing almost 95% protection. the parasites were completely cleared in blood with art-alone (ae) or art+curcumin (ac) treatments in the short-term, although the clearance was faster ...201222276114
antimalarial plant remedies from burkina faso: their potential for prophylactic use.saye, a combination remedy prepared from cochlospermum planchonii hook.f. (cochlospermaceae), cassia alata l. (fabaceae) and phyllanthus amarus schumach. et thonn. (euphorbiaceae), n'dribala, a cochlospermum planchonii root decoction, and a fruit preparation of azadirachta indica a. juss. (meliaceae) are plant remedies of the folk medicine in burkina faso and are commonly used by traditional healers for the treatment of malaria.201222301449
antiplasmodial and analgesic activities of clausena anisata.antiplasmodial and analgesic activities of the leaf extract and fractions of clausena anisata (c. anisata) were evaluated for antimalarial and analgesic activities.201222305787
antimalarial effects of iranian flora artemisia sieberi on plasmodium berghei in vivo in mice and phytochemistry analysis of its herbal extracts.the aim of this study is pharmacochemistry of iranian flora artemisia sieberi and its antimalarial effects on plasmodium berghei in vivo. this is the first application of a. sieberi for treatment of murine malaria. a. sieberi were collected at flowering stage from the khorassan and semnan provinces of iran; the aerial parts were air-dried at room temperature and then powdered. the powder was macerated in methanol, filtered with bokhner hopper and solvent was separated in rotary evaporator. total ...201222315701
the ctla-4 and pd-1/pd-l1 inhibitory pathways independently regulate host resistance to plasmodium-induced acute immune pathology.the balance between pro-inflammatory and regulatory immune responses in determining optimal t cell activation is vital for the successful resolution of microbial infections. this balance is maintained in part by the negative regulators of t cell activation, ctla-4 and pd-1/pd-l, which dampen effector responses during chronic infections. however, their role in acute infections, such as malaria, remains less clear. in this study, we determined the contribution of ctla-4 and pd-1/pd-l to the regula ...201222319445
the exported plasmodium berghei protein ibis1 delineates membranous structures in infected red blood cells.the importance of pathogen-induced host cell remodelling has been well established for red blood cell infection by the human malaria parasite plasmodium falciparum. exported parasite-encoded proteins, which often possess a signature motif, termed plasmodium export element (pexel) or host-targeting (ht) signal, are critical for the extensive red blood cell modifications. to what extent remodelling of erythrocyte membranes also occurs in non-primate hosts and whether it is in fact a hallmark of al ...201222329949
proteomic analysis of plasmodium in the mosquito: progress and pitfalls.here we discuss proteomic analyses of whole cell preparations of the mosquito stages of malaria parasite development (i.e. gametocytes, microgamete, ookinete, oocyst and sporozoite) of plasmodium berghei. we also include critiques of the proteomes of two cell fractions from the purified ookinete, namely the micronemes and cell surface. whereas we summarise key biological interpretations of the data, we also try to identify key methodological constraints we have met, only some of which we were ab ...201222336136
assessing the adequacy of attenuation of genetically modified malaria parasite vaccine candidates.the critical first step in the clinical development of a malaria vaccine, based on live-attenuated plasmodium falciparum sporozoites, is the guarantee of complete arrest in the liver. we report on an approach for assessing adequacy of attenuation of genetically attenuated sporozoites in vivo using the plasmodium berghei model of malaria and p. falciparum sporozoites cultured in primary human hepatocytes. we show that two genetically attenuated sporozoite vaccine candidates, δp52+p36 and δfabb/f, ...201222342550
the generation and evaluation of two panels of epitope-matched mouse igg1, igg2a, igg2b and igg3 antibodies specific for plasmodium falciparum and plasmodium yoelii merozoite surface protein 1-19 (msp1(19)).murine immunoglobulin g (igg) plays an important role in mediating protective immune responses to malaria. we still know relatively little about which igg subclasses protect against this disease in mouse models, although igg2a and igg2b are considered to be the most potent and dominate in successful passive transfer experiments in rodent malarias. to explore the mechanism(s) by which the different mouse igg subclasses may mediate a protective effect, we generated mouse igg1, igg2a, igg2b and igg ...201222343045
in vivo antimalarial effects of iranian flora artemisia khorassanica against plasmodium berghei and pharmacochemistry of its natural components.the aim of this study was to evaluate the antimalarial effects of iranian flora artemisia khorassanica against plasmodium bergheiin vivo and pharmacochemistry of its natural components.201022347230
efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by plasmodium berghei anka.low nitric oxide (no) bioavailability plays a role in the pathogenesis of human as well as of experimental cerebral malaria (ecm) caused by plasmodium berghei anka (pba). ecm is partially prevented by administration of the no-donor dipropylenetriamine nonoate (dpta-no) at high concentration (1 mg/mouse), which also induces major side effects such as a sharp drop in blood pressure. we asked whether alternative strategies to improve no bioavailability with minor side effects would also be effectiv ...201222348145
artesunate-loaded chitosan/lecithin nanoparticles: preparation, characterization, and in vivo studies.artesunate (ast), the most widely used artemisnin derivative, has poor aqueous solubility and suffers from low oral bioavailability (~40%). under these conditions, nanoparticles with controlled and sustained released properties can be a suitable solution for improving its biopharmaceuticals properties. this work reports the preparation and characterization of auto-assembled chitosan/lecithin nanoparticles loaded with ast and ast complexed with β-cyclodextrin (β-cd) to boost its antimalarial acti ...201222348223
bacterium-like particles as multi-epitope delivery platform for plasmodium berghei circumsporozoite protein induce complete protection against malaria in mice.virus-like particles have been regularly used as an antigen delivery system for a number of plasmodium peptides or proteins. the present study reports the immunogenicity and protective efficacy of bacterium-like particles (blps) generated from lactococcus lactis and loaded with plasmodium berghei circumsporozoite protein (pbcsp) peptides.201222348325
mixed vector immunization with recombinant adenovirus and mva can improve vaccine efficacy while decreasing antivector immunity.substantial protection can be provided against the pre-erythrocytic stages of malaria by vaccination first with an adenoviral and then with an modified vaccinia virus ankara (mva) poxviral vector encoding the same me.trap transgene. we investigated whether the two vaccine components adenovirus (ad) and mva could be coinjected as a mixture to enhance protection against malaria. a single-shot mixture at specific ratios of ad and mva (ad+mva) enhanced cd8(+) t cell-dependant protection of mice agai ...201222354374
disruption of plasmepsin-4 and merozoites surface protein-7 genes in plasmodium berghei induces combined virulence-attenuated phenotype.blood stage malaria parasites causing a mild and self limited infection in mice have been obtained with either radiation or chemical mutagenesis showing the possibility of developing an attenuated malaria vaccine. targeted disruption of plasmepsin-4 (pm4) or the merozoite surface protein-7 (msp7) genes also induces a virulence-attenuated phenotype in terms of absence of experimental cerebral malaria (ecm), delayed increase of parasitemia and reduced mortality rate. the decrease in virulence in p ...201122355558
identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum type ii nadh:quinone oxidoreductase (pfndh2).following a program undertaken to identify hit compounds against nadh:ubiquinone oxidoreductase (pfndh2), a novel enzyme target within the malaria parasite plasmodium falciparum, hit to lead optimization led to identification of ck-2-68, a molecule suitable for further development. in order to reduce clogp and improve solubility of ck-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound sl-2-25 (8b ...201222364417
a putative homologue of cdc20/cdh1 in the malaria parasite is essential for male gamete development.cell-cycle progression is governed by a series of essential regulatory proteins. two major regulators are cell-division cycle protein 20 (cdc20) and its homologue, cdc20 homologue 1 (cdh1), which activate the anaphase-promoting complex/cyclosome (apc/c) in mitosis, and facilitate degradation of mitotic apc/c substrates. the malaria parasite, plasmodium, is a haploid organism which, during its life-cycle undergoes two stages of mitosis; one associated with asexual multiplication and the other wit ...201222383885
3,5-diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential.a novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available softfocus kinase library. the compounds were evaluated in vitro for their antiplasmodial activity against k1 (chloroquine and drug-resistant strain) and nf54 (chloroquine-susceptible strain) as well as for their cytotoxicity. synthesis and structure-activity studies identified a number of promising compounds with selective an ...201222390538
s-nitrosoglutathione prevents experimental cerebral malaria.administration of the exogenous nitric oxide (no) donor dipropylenetriamine-nonoate (dpta-no) to mice during plasmodium berghei anka (pba) infection largely prevents development of experimental cerebral malaria (ecm). however, a high dose (1 mg/mouse twice a day) is necessary and causes potent side effects such as marked hypotension. in the present study we evaluated whether an alternative, physiologically relevant no donor, s-nitrosoglutathione (gsno), was able to prevent ecm at lower doses wit ...201222391863
roles of the amino terminal region and repeat region of the plasmodium berghei circumsporozoite protein in parasite infectivity.the circumsporozoite protein (csp) plays a key role in malaria sporozoite infection of both mosquito salivary glands and the vertebrate host. the conserved regions i and ii have been well studied but little is known about the immunogenic central repeat region and the n-terminal region of the protein. rodent malaria plasmodium berghei parasites, in which the endogenous cs gene has been replaced with the avian plasmodium gallinaceum cs (pgcs) sequence, develop normally in the a. stephensi mosquito ...201222393411
role of oxidative stress and apoptosis in the placental pathology of plasmodium berghei infected mice.placental malaria is a common clinical complication during pregnancy and is associated with abortion, premature delivery, intrauterine growth retardation and low birth weight. the present study was designed to delineate the underlying mechanism of placental pathology during malarial infection with special reference to oxidative stress and apoptosis. experimentally, pregnant balb/c mice were infected with plasmodium berghei infected red blood cells on gestation day 10. the presence of malarial in ...201222396790
extracellular atp triggers proteolysis and cytosolic ca²⁺ rise in plasmodium berghei and plasmodium yoelii malaria parasites.plasmodium has a complex cell biology and it is essential to dissect the cell-signalling pathways underlying its survival within the host.201222420332
a high-coverage artificial chromosome library for the genome-wide screening of drug-resistance genes in malaria parasites.the global spread of drug-resistant parasites is a serious problem for the treatment of malaria. although identifying drug-resistance genes is crucial for the efforts against resistant parasites, an effective approach has not yet been developed. here, we report a robust method for identifying resistance genes from parasites by using a plasmodium artificial chromosome (pac). large genomic dna fragments (10-50 kb) from the drug-resistant rodent malaria parasite plasmodium berghei were ligated into ...201222426943
anopheles gambiae antiviral immune response to systemic o'nyong-nyong infection.mosquito-borne viral diseases cause significant burden in much of the developing world. although host-virus interactions have been studied extensively in the vertebrate host, little is known about mosquito responses to viral infection. in contrast to mosquitoes of the aedes and culex genera, anopheles gambiae, the principal vector of human malaria, naturally transmits very few arboviruses, the most important of which is o'nyong-nyong virus (onnv). here we have investigated the a. gambiae immune ...201222428080
extrahepatic exoerythrocytic forms of rodent malaria parasites at the site of inoculation: clearance after immunization, susceptibility to primaquine, and contribution to blood-stage infection.plasmodium sporozoites are inoculated into the skin of the mammalian host as infected mosquitoes probe for blood. a proportion of the inoculum enters the bloodstream and goes to the liver, where the sporozoites invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic, or liver, stage. here, we show that a small fraction of the inoculum remains in the skin and begins to develop into exoerythrocytic forms that can persist for days. skin exoerythrocytic forms were observed ...201222431651
characterization of plasmodium liver stage inhibition by halofuginone.malaria is a devastating parasitic disease that afflicts one-third of the world's population. antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. most therapeutics target blood-stage malaria, whereas only few compounds are active against malaria's liver stage, the first stage of the plasmodium parasite's life cycle within the human host. the identification of inhibitors active against liver-stage malaria would benefit the developme ...201222438279
antiparasitic activities of two sesquiterpenic lactones isolated from acanthospermum hispidum d.c.aerial parts of acanthospermum hispidum d.c. are often used by traditional healers in benin for various diseases and especially for malaria.201222440261
in vitro and in vivo antimalarial activity of essential oils and chemical components from three medicinal plants found in northeastern brazil.the prophylactic and therapeutic arsenal against malaria is quite restricted and all the antimalarials currently in use have limitations. thus, there is a need to investigate medicinal plants in the search for phytochemicals which can be developed into drugs. in our investigation, essential oils (eos) were obtained from vanillosmopsis arborea (gardner) baker, lippia sidoides cham. and croton zehntneri pax & k. hoffm., aromatic plants abundant in northeastern brazil, which are found in the caatin ...201222441836
improved plasmodium berghei lines for conditional mutagenesis.conditional mutagenesis is a powerful tool for genetic analysis in plasmodium berghei. it allows the study of proteins that function both during the parasite's pre-erythocytic and erythrocytic development. currently available parasite lines used for conditional mutagenesis were constructed in the nk65 strain, and express a dna recombinase under the control of pre-erythrocytic stage-specific promoters. however, the integration of the recombinase in these lines is unstable leading to inconsistent ...201222450301
cross-species immunity following immunization with a circumsporozoite protein-based vaccine for malaria.malaria continues to be a major public health concern, and there are concerted efforts to eliminate it. the quest for a vaccine remains a top priority, and vaccines based on the circumsporozoite protein (csp) are among the lead candidates, with the rts,s vaccine currently undergoing phase 3 testing in africa. previous studies have reported anti-csp antibody-mediated enhancement of in vitro invasion of homologous sporozoites. this effect has been shown to be concentration dependent; high-level an ...201222457289
improved negative selection protocol for plasmodium berghei in the rodent malarial model.an improved methodology is presented here for transgenic plasmodium berghei lines that express the negative selectable marker yfcu (a bifunctional protein that combines yeast cytosine deaminase and uridyl phosphoribosyl transferase (uprt)) and substitutes delivery of selection drug 5-fluorocytosine (5fc) by intraperitoneal injection for administration via the drinking water of the mice. the improved methodology is shown to be as effective, less labour-intensive, reduces animal handling and anima ...201222463060
amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted 8-aminoquinolines: synthesis and evaluation of anti-infective, β-haematin inhibition and cytotoxic activities.three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. the synthesized compounds were tested for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant plasmodium falciparum strains, in vitro cytotoxicity in mammalian kidney cells (vero), in vitro antileishmanial activity against leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of ...201222483965
endogenous galectin-3 controls experimental malaria in a species-specific manner.galectins are evolutionarily conserved glycan-binding proteins with pleiotropic roles in innate and adaptive immune responses. galectin-3 has been implicated in several immunological processes as well as in pathogen recognition through specific binding to glycosylated receptors on the surface of host cells or microorganisms. in spite of considerable evidence supporting a role for galectin-3 in host-pathogen interactions, the relevance of this lectin in the regulation of the host defence mechanis ...201222486577
an epithelial serine protease, agesp, is required for plasmodium invasion in the mosquito anopheles gambiae.plasmodium parasites need to cross the midgut and salivary gland epithelia to complete their life cycle in the mosquito. however, our understanding of the molecular mechanism and the mosquito genes that participate in this process is still very limited.201222509400
histopathological effects of sub-chronic lamivudine-artesunate co-administration on the liver of diseased adult wistar rats.lamivudine and artesunate are sometimes co administered in hiv-malaria co morbidity. both drugs are used concurrently in presumptive malaria treatment and simultaneous hiv post exposure prophylaxis.201122540106
plasmodium berghei: influence of infection on the oxidant and antioxidants levels in pregnant balb/c mice.malarial infection during pregnancy has been associated with maternal anemia and death, abortion, still-birth and is a major cause of low birth weight, an important risk factor for infant morbidity and mortality in endemic areas. the present study was designed to delineate the oxidative stress in various organs (liver, spleen, kidney, brain and placenta) of pregnant plasmodium berghei infected balb/c mice. it was observed that pregnant-infected mice had higher parasitaemia than nonpregnant-infec ...201222542801
plasmodium subtilisin-like protease 1 (sub1): insights into the active-site structure, specificity and function of a pan-malaria drug target.release of the malaria merozoite from its host erythrocyte (egress) and invasion of a fresh cell are crucial steps in the life cycle of the malaria pathogen. subtilisin-like protease 1 (sub1) is a parasite serine protease implicated in both processes. in the most dangerous human malarial species, plasmodium falciparum, sub1 has previously been shown to have several parasite-derived substrates, proteolytic cleavage of which is important both for egress and maturation of the merozoite surface to e ...201222543039
effects of vitamin e administration on plasmodium berghei induced pathological changes and oxidative stress in mice.the effects of daily intraperitoneal doses of 1000 i.u/kg body weight of vitamin e on the course of plasmodium berghei nk 65 infection and the parasite-induced anemia as well as alterations in the relative weight of some selected organs and antioxidant status in mice were investigated. the number of parasitized red cells were not initially affected by the vitamin administration but were persistently lowered after 11th day post infection to the termination of the experiment. the p. berghei infect ...201222543609
anti-plasmodial effects of azadirachta indica in experimental cerebral malaria: apoptosis of cerebellar purkinje cells of mice as a marker.malaria is a major public health problem in the world, but treatment of malaria is becoming more difficult due to increasing drug resistance. therefore, the need for alternative drugs is acute.201022558559
curcuminoids-loaded liposomes in combination with arteether protects against plasmodium berghei infection in mice.curcuminoids are poorly water-soluble compounds with promising antimalarial activity. to overcome some of the drawbacks of curcuminoids, we explored the potential of liposomes for the intravenous delivery of curcuminoids in a model of mouse malaria. the curcuminoids-loaded liposomes were formulated from phosphatidylcholine (soy pc) by the thin-film hydration method. antimalarial activity of curcuminoids-loaded liposomes alone and in combination with α/β arteether when administered intravenously, ...201222561991
generation of quinolone antimalarials targeting the plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria.there is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. a failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. here we prese ...201222566611
in vivo hemozoin kinetics after clearance of plasmodium berghei infection in mice.hemozoin (hz) is released into the blood stream after rupture of infected red blood cells (irbcs) at the end of each parasite replication cycle. this free hz is ingested by circulating and resident phagocytes. the presence of hz in tissues after clearance of infection has been previously reported. still, little is known about the kinetics of hz in vivo, during and after plasmodium infection. it is particularly important to understand hz kinetics after malaria infections as it has been reported t ...201222567535
the antiplasmodial and radical scavenging activities of flavonoids of erythrina burttii.the acetone extract of the root bark of erythrina burttii showed in vitro antiplasmodial activity against the chloroquine-sensitive (d6) and chloroquine-resistant (w2) strains of plasmodium falciparum with ic(50) values of 0.97 ± 0.2 and 1.73 ± 0.5 μg/ml respectively. the extract also had radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (dpph) radical with an ec(50) value of 12.0 μg/ml. the isoflav-3-enes burttinol-a and burttinol-c, and the 2-arylbenzofuran derivative burttinol ...201222575309
improved methods for haemozoin quantification in tissues yield organ-and parasite-specific information in malaria-infected mice.despite intensive research, malaria remains a major health concern for non-immune residents and travelers in malaria-endemic regions. efficient adjunctive therapies against life-threatening complications such as severe malarial anaemia, encephalopathy, placental malaria or respiratory problems are still lacking. therefore, new insights into the pathogenesis of severe malaria are imperative. haemozoin (hz) or malaria pigment is produced during intra-erythrocytic parasite replication, released in ...201222583751
endoplasmic reticulum stress and neurodegeneration in experimental cerebral malaria.experimental cerebral malaria (ecm) resulting from plasmodium berghei anka (pba) infection in mice results in neuronal cell death. however, the precise mechanisms leading to neuronal cell death in ecm have not been fully elucidated. in the present study, we report the presence of endoplasmic reticulum (er) stress markers and activation of the unfolded protein response (upr) in the brain during the pathogenesis of ecm. specific findings included activation of pkr-like erkinase, inositol-requiring ...201322584375
liver-stage malaria parasites vulnerable to diverse chemical scaffolds.human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. all high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. to address these unmet needs, a high-throughput phenotypic liver-stage plasmodium parasite screen was developed to systematically identify molecules with liver- ...201222586124
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