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antimalarial pyrido[1,2-a]benzimidazoles.a novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. the most active of these, tdr86919 (4c), showed improved in vitro activity v the drug-resistant k1 strain of plasmodium falciparum relative to chloroquine (ic50 = 0.047 µm v 0.17 µm); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligib ...201121644541
imidazolopiperazines (i): optimization for new antimalarial agents.starting from a hit series from a gnf compound library collection and based on a cell-based proliferation assay of plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. sar for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. the lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. ...201121644570
pharmacokinetics, pharmacodynamics and allometric scaling of chloroquine in a murine malaria model.chloroquine (cq) is an important antimalarial drug for the treatment of special patient groups and as a comparator for pre-clinical testing of new drugs. pharmacokinetic data for cq in animal models are limited, hence we conducted a three-part investigation, comprising: (i) pharmacodynamic studies of cq and cq plus dihydroartemisinin (dha) in plasmodium berghei infected mice; (ii) pharmacokinetic studies of cq in healthy and malaria-infected mice; and (iii) interspecies allometric scaling for cq ...201121646487
exogenous nitric oxide decreases brain vascular inflammation, leakage and venular resistance during plasmodium berghei anka infection in mice.abstract: background: cerebral malaria (cm) is a lethal complication of plasmodium falciparum infections. in the plasmodium berghei anka (pba) murine model, cm is associated with marked brain inflammation, increased expression of endothelial cell adhesion molecules and leukocyte and platelet accumulation in brain vessels, causing vascular occlusion and decreased blood flow, damaging the endothelium and leading to blood-brain barrier breakdown, leakage and hemorrhages. exogenous nitric oxide (no) ...201121649904
alternative splicing of the anopheles gambiae dscam gene in diverse plasmodium falciparum infections.in insects, including anopheles mosquitoes, dscam (down syndrome cell adhesion molecule) appears to be involved in phagocytosis of pathogens, and shows pathogen-specific splice-form expression between divergent pathogen (or parasite) types (e.g. between bacteria and plasmodium or between plasmodium berghei and plasmodium falciparum). here, data are presented from the first study of dscam expression in response to genetic diversity within a parasite species.201121651790
genetic and transcriptional analysis of phosphoinositide-specific phospholipase c in plasmodium.phosphoinositide-specific phospholipase c (pi-plc) is a major regulator of calcium-dependent signal transduction, which has been shown to be important in various processes of the malaria parasite plasmodium. pi-plc is generally implicated in calcium liberation from intracellular stores through the action of its product, inositol-(1,4,5)-trisphosphate, and is itself dependent on calcium for its activation. here we describe the plc genes from plasmodium species. the encoded proteins contain all do ...201121651909
superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites.while subunit vaccines have shown partial efficacy in clinical trials, radiation-attenuated sporozoites (ras) remain the "gold standard" for sterilizing protection against plasmodium infection in human vaccinees. the variability in immunogenicity and replication introduced by the extensive, random dna damage necessary to generate ras could be overcome by genetically attenuated parasites (gap) designed via gene deletion to arrest at defined points during liver-stage development. here, we demonstr ...201121669394
the puf-family rna-binding protein puf2 controls sporozoite conversion to liver stages in the malaria parasite.malaria is a vector-borne infectious disease caused by unicellular, obligate intracellular parasites of the genus plasmodium. during host switch the malaria parasite employs specialized latent stages that colonize the new host environment. previous work has established that gametocytes, sexually differentiated stages that are taken up by the mosquito vector, control expression of genes required for mosquito colonization by translational repression. sexual parasite development is controlled by a ...201121673790
type i interferons suppress cd4(+) t-cell-dependent parasite control during blood-stage plasmodium infection.during blood-stage plasmodium infection, large-scale invasion of rbcs often occurs before the generation of cellular immune responses. in plasmodium berghei anka (pba)-infected c57bl/6 mice, cd4(+) t cells controlled parasite numbers poorly, instead providing early help to pathogenic cd8(+) t cells. expression analysis revealed that the transcriptional signature of cd4(+) t cells from pba-infected mice was dominated by type i ifn (ifn-i) and ifn-╬│-signalling pathway-related genes. a role for if ...201121674481
design and evaluation of primaquine-artemisinin hybrids as a multistage anti-malarial strategy.it is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. the "magic bullet" thought to be necessary to reach eradication should not only provide treatment for all plasmodium sp. that infect human red blood cells but also eliminate the replicative and dormant liver forms of the parasite. moreover, these goals should ideally be achieved by using different mechanisms of action to avoid the development of resistance. to that end, two hy ...201121807973
prevention of experimental cerebral malaria by flt3 ligand during infection with plasmodium berghei anka.dendritic cells are the most potent antigen-presenting cells, but their roles in blood-stage malaria-infection are not fully understood. we examined the effects of flt3 ligand, a cytokine which induces dendritic cell production, in vivo on the course of infection with plasmodium berghei anka. mice treated with flt3 ligand showed preferential expansion of cd8(+) dendritic cells and granulocytes, lower parasitemia, and were protected from the development of lethal experimental cerebral malaria (ec ...201121807908
organelle segregation into plasmodium liver stage merozoites.the liver stage of the plasmodium parasite remains one of the most promising targets for intervention against malaria as it is clinically silent, precedes the symptomatic blood stage and represents a bottleneck in the parasite life cycle. however, many aspects of the development of the parasite during this stage are far from understood. during the liver stage, the parasite undergoes extensive replication, forming tens of thousands of infectious merozoites from each invading sporozoite. this impl ...201121801293
global proteomic analysis of plasma from mice infected with plasmodium berghei anka using two dimensional gel electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry.abstract: background: a global proteomic strategy was used to identify proteins, which are differentially expressed in the murine model of severe malaria in the hope of facilitating future development of novel diagnostic, disease monitoring and treatment strategies. methods: mice (4-week-old cd1 male mice) were infected with plasmodium berghei anka strain, and infection allowed to establish until a parasitaemia of 30% was attained. total plasma and albumin depleted plasma samples from infected a ...201121791037
critical role for a stage-specific actin in male exflagellation of the malaria parasite.male gametogenesis occurs directly after uptake of malaria parasites by the mosquito vector and leads to the release of eight nucleated flagellar gametes. here, we report that one of the two parasite actin isoforms, named actin ii, is essential for this process. disruption of actin ii in plasmodium berghei resulted in viable asexual blood stages, but male gametogenesis was specifically inhibited. upon activation, male gametocyte dna was replicated normally and axonemes assembled, but egress from ...201121790945
comparative efficacy of pre-erythrocytic whole organism vaccine strategies against the malaria parasite.despite major efforts over the past 50 years to develop a malaria vaccine, no product has been licensed yet. irradiated sporozoites are the benchmark for an experimental live-attenuated malaria vaccine that induces potent protection against re-infection in humans and animal models. lasting protection can also be elicited by parasite attenuation via tailored genetic modification or drug cover leading to renewed interest in whole-organism vaccination strategies. in this study, we systematically co ...201121787828
the generation and evaluation of recombinant human iga specific for plasmodium falciparum merozoite surface protein 1-19 (pfmsp119).abstract: background: human immunoglobulin g (igg) plays an important role in mediating protective immune responses to malaria. although human serum immunoglobulin a (iga) is the second most abundant class of antibody in the circulation, its contribution, if any, to protective responses against malaria is not clear. results: to explore the mechanism(s) by which iga may mediate a protective effect, we generated fully human iga specific for the c-terminal 19-kda region of plasmodium falciparum mer ...201121781305
the effect of helminth co-infection on malaria in mice: a meta-analysis.the question of how helminths affect the course of concurrent malaria infection has attracted much interest in recent years. in particular, it has been suggested that by creating an anti-inflammatory immune environment, helminth co-infection may dampen both protective and immunopathological responses to malaria parasites, thus altering malaria infection dynamics and disease severity. both synergistic and antagonistic interactions are reported in the literature, and the causes of variation among ...201121777589
arrested oocyst maturation in plasmodium parasites lacking type ii nadh:ubiquinone dehydrogenase.the plasmodium mitochondrial electron transport chain (mtetc) has received considerable attention as a potential target for new antimalarial drugs. atovaquone, a potent inhibitor of plasmodium cytochrome bc1, in combination with proguanil is recommended for chemoprophylaxis and treatment of malaria. the type ii nadh:ubiquinone oxidoreductase (ndh2) is considered an attractive drug target, since its inhibition is thought to lead to the arrest of the mtetc and, as a consequence, pyrimidine biosynt ...201121771793
antimalarial and analgesic activities of ethanolic leaf extract of panicum maximum.to evaluate antiplasmodial and analgesic activities of ethanolic leaf extract/fractions of panicum maximum.201121771695
bioinformatics analysis and prediction for structure and function of nitric oxide synthase and similar proteins from plasmodium berghei.to search and analyze nitric oxide synthase (nos) and similar proteins from plasmodium berghei(pb).201121771405
n-acetylglucosaminyltransferase v-deficiency increases susceptibility to murine malaria.it is considered that several glycoproteins on erythrocytes in mammalian species are involved in malaria parasite infection. to elucidate the role of n-glycans on malaria parasite infection, we induced experimental murine malaria infection (using plasmodium berghei anka) in mice deficient in n-acetylglucosaminyltransferase v (mgat5), which is one of the enzymes involved in ß1,6-glcnac n-glycan biosynthesis. after infection, mgat5(-/-) mice showed severe body weight loss and parasitemia compared ...201121767537
andrographolide: a novel antimalarial diterpene lactone compound from andrographis paniculata and its interaction with curcumin and artesunate.andrographolide (and), the diterpene lactone compound, was purified by hplc from the methanolic fraction of the plant andrographis paniculata. the compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages of plasmodium falciparum in vitro and plasmodium berghei anka in vivo. ic(50)s for artesunate (as), andrographolide (and), and curcumin (cur) were found to be 0.05, 9.1 and 17.4?µm, respecti ...201121760808
the novel putative transporter npt1 plays a critical role in early stages of plasmodium berghei sexual development.transmission of plasmodium species from a mammalian host to the mosquito vector requires the uptake, during an infected blood meal, of gametocytes, the precursor cells of the gametes. relatively little is known about the molecular mechanisms involved in the developmental switch from asexual development to sexual differentiation or the maturation and survival of gametocytes. here, we show that a gene coding for a novel putative transporter, npt1, plays a crucial role in the development of plasmod ...201121752110
synthetic ozonide drug candidate oz439 offers new hope for a single-dose cure of uncomplicated malaria.ozonide oz439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. oz439 has successfully completed phase i clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing phase iia trials in malaria patients. herein, we describe the discovery of oz439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. in vitro, oz439 is fast-ac ...201121300861
in vivo and in vitro antimalarial activity of 4-nerolidylcatechol.4-nerolidylcatechol (4-nc) isolated from piper peltatum l. (piperaceae) was evaluated for in vitro antiplasmodial activity against plasmodium falciparum (cultures of both standard cqr (k1) and cqs (3d7) strains and two amazonian field isolates) and for in vivo antimalarial activity using the plasmodium berghei-murine model. 4-nc exhibits significant in vitro and moderate in vivo antiplasmodial activity. 4-nc administered orally and subcutaneously at doses of 200, 400 and 600?mg/kg/day suppressed ...201121302338
therapeutical targeting of nucleic acid-sensing toll-like receptors prevents experimental cerebral malaria.excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. proinflammatory cytokines are a direct output of toll-like receptor (tlr) activation during microbial infection. thus, interference with tlr function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. herein, we describe the protective effect and mechanism of action of e6446, a s ...201121303985
ratt: rapid annotation transfer tool.second-generation sequencing technologies have made large-scale sequencing projects commonplace. however, making use of these datasets often requires gene function to be ascribed genome wide. although tool development has kept pace with the changes in sequence production, for tasks such as mapping, de novo assembly or visualization, genome annotation remains a challenge. we have developed a method to rapidly provide accurate annotation for new genomes using previously annotated genomes as a refe ...201121306991
energy metabolism affects susceptibility of anopheles gambiae mosquitoes to plasmodium infection.previous studies showed that anopheles gambiae l3-5 females, which are refractory (r) to plasmodium infection, express higher levels of genes involved in redox-metabolism and mitochondrial respiration than susceptible (s) g3 females. our studies revealed that r females have reduced longevity, faster utilization of lipid reserves, impaired mitochondrial state-3 respiration, increased rate of mitochondrial electron leak and higher expression levels of several glycolytic enzyme genes. furthermore, ...201121320598
gene profiling analysis reveals the contribution of cd24 and p2y6r to the susceptibility of young rats to plasmodium berghei infection.our previous studies have shown that plasmodium berghei infection induces distinct clinical, parasitological and immunological states in young susceptible rats versus adult resistant rats. this susceptibility was mainly found to be related to inadequate cellular responses. in this study we first identified the altered genes in young susceptible rats. unexpectedly, transcriptome analysis did not reveal any alteration of effector cytokines or their receptors. at day 13 p.i., six transcripts corres ...201121323829
synthesis and biological evaluation of benzimidazole-5-carbohydrazide derivatives as antimalarial, cytotoxic and antitubercular agents.a series of n'-substituted-2-(5-nitrofuran or 5-nitrothiophen-2-yl)-3h-benzo[d]imidazole-5-carbohydrazide derivatives were synthesized and investigated for their abilities to inhibit ß-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent plasmodium berghei. selected analogues were screened for their antitubercular activity against sensitive mtb h(37)rv and multidrug-resistant mdr-mtb strains, and cytotoxic activity against a panel of human tumor cell lin ...201121334900
calcium signal regulates temperature-dependent transformation of sporozoites in malaria parasite development.the infection by the malaria parasite of its mammalian host is initiated by the asexual reproduction of the parasite within the host hepatocyte. before the reproduction, the elongated sporozoites undergo a depolarizing morphogenesis to the spherical exo-erythrocytic form (eef). this change can be induced in vitro by shifting the environmental conditions, in the absence of host hepatocytes. using rodent malaria parasites expressing a fret-based calcium sensor, yc3.60, we observed that the intrace ...201121335005
high parasite burdens cause liver damage in mice following plasmodium berghei anka infection independently of cd8(+) t cell-mediated immune pathology.infection of c57bl/6 mice with plasmodium berghei anka induces a fatal neurological disease commonly referred to as experimental cerebral malaria. the onset of neurological symptoms and mortality depend on pathogenic cd8(+) t cells and elevated parasite burdens in the brain. here we provide clear evidence of liver damage in this model, which precedes and is independent of the onset of neurological symptoms. large numbers of parasite-specific cd8(+) t cells accumulated in the liver following p. b ...201121343349
aryl piperazine and pyrrolidine as antimalarial agents. synthesis and investigation of structure-activity relationships.piperazine and pyrrolidine derivatives were synthesised and evaluated for their capacity to inhibit the growth of plasmodium falciparum chloroquine-resistant (fcr-3) strain in culture. the combined presence of a hydroxyl group, a propane chain and a fluor were shown to be crucial for the antiplasmodial activity. five compounds of the aryl-alcohol series inhibited 50% of parasite growth at doses =10 µm. the most active compound 1-(4-fluoronaphthyl)-3-[4-(4-nitro-2-trifluoromethylphenyl)piperazin- ...201121354139
cutting edge: attrition of plasmodium-specific memory cd8 t cells results in decreased protection that is rescued by booster immunization.sterile protection against infection with plasmodium sporozoites requires high numbers of memory cd8 t cells. however, infections with unrelated pathogens, as may occur in areas endemic to malaria, can dramatically decrease pre-existing memory cd8 t cells. it remains unknown whether unrelated infections will compromise numbers of plasmodium-specific memory cd8 t cells and thus limit the duration of antimalarial immunity generated by subunit vaccination. we show that p. berghei circumsporozoite-s ...201121357257
in vitro and in vivo antiplasmodial activities of risedronate and its interference with protein prenylation in plasmodium falciparum.the increasing resistance of malarial parasites to almost all available drugs calls for the identification of new compounds and the detection of novel targets. here, we establish the antimalarial activities of risedronate, one of the most potent bisphosphonates clinically used to treat bone resorption diseases, against blood stages of plasmodium falciparum (50% inhibitory concentration [ic50] of 20.3±1.0 µm). we also suggest a mechanism of action for risedronate against the intraerythrocytic sta ...201121357292
activation of a pak-mek signalling pathway in malaria parasite-infected erythrocytes.merozoites of malaria parasites invade red blood cells (rbcs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. here, we report that a protein kinase-mediated signalling pathway involving host rbc pak1 and mek1, which do not have orthologues in the plasmodium kinome, is selectively stimulated in plasmodium falciparum-infected (versus uninfected) rbcs, as determined by the use of phospho-specific ...201121371233
characterization of plasmodium berghei glutathione synthetase.plasmodium berghei contained 0.454±0.031 u/mg of glutathione synthetyase (gs). gs was purified using solid ammonium sulfate and sephadex g-200 from p. berghei infected mouse erythrocytes. sds-page showed purified gs as a single band protein of 70 kda and its km for ?-glutamylcysteine, glycine and atp being 0.33 mm, 8.3 mm and 0.43 mm respectively with noncompetitive inhibition by gsh. the malaria parasite enzyme was optimally active at 37°c and ph 8.0-8.5. heavy metals significantly inhibited pa ...201121377539
malaria crystalloids: specialized structures for parasite transmission?malaria parasites possess many unique subcellular structures and organelles that are essential for the successful completion of the complex life cycle of plasmodium in the vertebrate host and mosquito vector. among these are the crystalloids: transient structures whose presence is restricted to the mosquito-specific ookinete and young oocyst stages of the parasite. nearly five decades after they were first described, the crystalloids are back in the spotlight, with recent discoveries pointing to ...201121237711
beta interferon suppresses the development of experimental cerebral malaria.cerebral malaria (cm) is a major complication of plasmodium falciparum infection, particularly in children. the pathogenesis of cerebral malaria involves parasitized red blood cell (rbc)-mediated vascular inflammation, immune stimulation, loss of blood-brain barrier integrity, and obstruction of cerebral capillaries. therefore, blunting vascular inflammation and immune cell recruitment is crucial in limiting the disease course. beta interferon (ifn-β) has been used in the treatment of diseases, ...201121245265
anxiety-like behavior and proinflammatory cytokine levels in the brain of c57bl/6 mice infected with plasmodium berghei (strain anka).cerebral malaria (cm) is a severe complication resulting from plasmodium falciparum infection. the underlying mechanisms of cm pathogenesis remain incompletely understood. the imbalance between the release of proinflammatory and anti-inflammatory cytokines has been associated with central nervous system dysfunction found in human and experimental cm. the current study investigated anxiety-like behavior, histopathological changes and release of brain cytokines in c57bl/6 mice infected with plasmo ...201121256928
the malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host.plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. the sporozoite's major surface protein, circumsporozoite protein (csp), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. in this study, we show that csp has two conformational states, an adhesive conformation in which the c-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the n terminus masks this doma ...201121262960
screening of antiplasmodial efficacy of ajuga bracteosa wall ex. benth.the rising problem of plasmodium resistance to the classical antimalarial drugs stresses the need to look for newer antiplasmodial components with effective and new mode of action. in the present study, the traditional medicinal plant ajuga bracteosa has been screened for its antiplasmodial efficacy. the extract was found to possess significant in vitro antiplasmodial efficacy with an ic(50) of 10.0 µg/ml. thus, the extract was further evaluated for its in vivo schizontocidal activity and effica ...201121264476
a chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype a light chain, p. falciparum malaria, and the ebola filovirus.a 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype a light chain metalloprotease. subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the bont/a lc. three-dimensional analyses indicated that half of the originally discovered 1,7-daac structure superimposed well with 4-amino-7-chloroquinoline-based antimalarial agents. thi ...201121265542
evaluation of the use of cocos nucifera as antimalarial remedy in malaysian folk medicine.white flesh extract of cocos nucifera (coconut) was studied to ascertain the ethnopharmacological standing of its antimalarial usage in malaysian folk medicine.201121277969
4-aminoquinoline analogues and its platinum (ii) complexes as antimalarial agents.the high incidence of malaria and drug-resistant strains of plasmodium have turned this disease into a problem of major health importance. one of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. this class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of +¦-haematin (malaria pigment), which is lethal to the parasite. more specifically, 4-aminoquinoline derivates represent ...201121704476
caspase-1 activation of interleukin-1{beta} (il-1{beta}) and il-18 is dispensable for induction of experimental cerebral malaria.malaria infection is initiated by sporozoite invasion of hepatocytes and asexual reproduction of liver stages, processes that are regarded to be "clinically and diagnostically silent." merozoites, which egress from hepatocytes, infect erythrocytes in periodic cycles and induce disease. how the host innate immune system contributes to disease outcomes and to the induction of effector cells during malaria remains unclear. likewise, how the initial liver stages may shape responses to blood-stage pa ...201121708993
toxoplasma gondii peroxiredoxin promotes altered macrophage function, caspase-1-dependent il-1╬▓ secretion enhances parasite replication.abstract: alternatively activated macrophages (aam) are a key feature th2 immunity and have been associated with a variety of roles during helminth infection. the role this cell subset plays in protzoan infection remain relatively unexplored, herein we describe the effects of a redox enzyme (rtgprx) derived from toxoplasma gondii on murine macrophage phenotype in vitro. rtgprx has been previously associated with the maintainence of parasite oxidative balance. here our experiments show that rtgpr ...201121707997
apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in toxoplasma gondii.apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. apicomplexan parasites contain a relict chloroplast, the apicoplast. the apicoplast is indispensable and an attractive drug target. the apicoplast is home to a 1-deoxy-d-xylulose-5-phosphate (doxp) pathway for the synthesis of isoprenoid precursors. this pathway is believed to be the most conserved function of the apicoplast, and fosmidomycin, a specific inhibitor of the pathwa ...201121690250
infection intensity dependent responses of anopheles gambiae to african malaria parasites plasmodium falciparum.malaria remains a devastating disease despite efforts for control and prevention. extensive studies using mostly rodent infection models reveal that successful plasmodium parasite transmission by the african mosquito vector anopheles gambiae depends on finely tuned vector/parasite interactions. here we investigate the transcriptional response of a. gambiae to geographically related plasmodium falciparum populations at varying infection intensities and different infection stages. these responses ...201121844236
cd8+ t effector memory cells protect against liver-stage malaria.identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. we investigated protection against liver-stage malaria conferred by vaccination with adenoviral (ad) and modified vaccinia ankara (mva) vectors expressing pre-erythrocytic malaria ags. by classifying cd8(+) t cells into effector, effector memory (t(em)), and central memory subsets using cd62l and cd127 markers, we fou ...201121715686
antagonistic antimalarial properties of pawpaw leaf aqueous extract in combination with artesunic acid in plasmodium berghei-infected mice.artemisinins, the main stay in the treatment of malaria are used in combinations with other antimalarials to forestall resistance, as artemisinin-combination therapies (acts). however, acts are expensive and some of the non-artemisinin components are not well-tolerated by patients. there are several folkloric and scientific proofs of the efficacy of herbal remedies for malaria. mature leaves of carica papaya is widely used to treat malaria in several african countries. an act involving a medicin ...201121715732
glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones--a new strategy to combat malarial parasites.our work on targeting redox equilibria of malarial parasites propagating in red blood cells has led to the selection of six 1,4-naphthoquinones, which are active at nanomolar concentrations against the human pathogen plasmodium falciparum in culture and against plasmodium berghei in infected mice. with respect to safety, the compounds do not trigger hemolysis or other signs of toxicity in mice. concerning the antimalarial mode of action, we propose that the lead benzyl naphthoquinones are initia ...201121682307
improvement of the observational method for plasmodium berghei oocysts in the midgut of mosquitoes.there is a need for improving the method for counting oocysts of plasmodium berghei in the midgut of anopheles mosquitoes. the two methods currently used, the formalin fixation method and the mercurochrome staining method, have contradicting advantages and disadvantages. in the formalin fixation method, the specimen can be preserved but unstained oocysts were often indistinct from the insect tissue. while in the mercurochrome staining method, stained oocysts can be clearly distinguished from ins ...201121707972
interaction between ciprofloxacin and chloroquine in mice infected with chloroquine resistant plasmodium berghei : interaction between ciprofloxacin and chloroqune.the increasing spread of chloroquine resistant malaria has intensified the search for new antimalarial treatment, especially drugs that can be used in combination. ciprofloxacin (cfx) a fluoroquinolone commonly used to treat bacterial infections has been shown to possess significant antimalarial activity both in vitro and in vivo. thus efforts in this study were devoted to evaluating the antimalarial activity of combination of chloroquine (cq) with varying doses (10, 20, 40 80, 160-ámg/kg body w ...201121826489
lessons from sickle cell disease in the treatment and control of malaria. 201121714653
investigations on the role of a lysozyme from the malaria vector anopheles dirus during malaria parasite development.a cdna encoding a lysozyme was obtained by rapid amplification of cdna ends-polymerase chain reaction (race-pcr) from females of the malaria vector anopheles dirus a (diptera: culicidae). the 623bp lysozyme (adlys c-1) cdna encodes the 120 amino acid mature protein with a predicted molecular mass of 13.4kda and theoretical pi of 8.45. six cysteine residues and a potential calcium binding motif that are present in adlys c-1 are highly conserved relative to those of c-type lysozymes found in other ...201121741400
in the eye of experimental cerebral malaria.cerebral malaria is the most severe complication of plasmodium falciparum infection, accounting for 1 million deaths per year. we characterized the murine disease using in vivo magnetic resonance imaging (mri) at 4.7 t, proving that ischemic edema is responsible for fatality. the aim of the present study was to identify early markers of experimental cerebral malaria using very high field conventional mri (11.75 t). cba/j mice infected with plasmodium berghei anka were observed at an early stage ...201121741941
characterization of a new phosphatase from plasmodium.plasmodium falciparum malaria is the most important parasitic disease worldwide, responsible for an estimated 1 million deaths annually. two p. falciparum genes code for putative phosphoglycerate mutases (pgmases), a widespread protein group characterized by the involvement of histidine residues in their catalytic mechanism. pgmases are responsible for the interconversion between 2 and 3-phosphoglycerate, an intermediate step in the glycolysis pathway. we have determined the crystal structures o ...201121689687
resistance of a rodent malaria parasite to a thymidylate synthase inhibitor induces an apoptotic parasite death and imposes a huge cost of fitness.the greatest impediment to effective malaria control is drug resistance in plasmodium falciparum, and thus understanding how resistance impacts on the parasite's fitness and pathogenicity may aid in malaria control strategy.201121698180
structural basis for the regulation of cysteine-protease activity by a new class of protease inhibitors in plasmodium.plasmodium cysteine proteases are essential for host-cell invasion and egress, hemoglobin degradation, and intracellular development of the parasite. the temporal, site-specific regulation of cysteine-protease activity is a prerequisite for survival and propagation of plasmodium. recently, a new family of inhibitors of cysteine proteases (icps) with homologs in at least eight plasmodium species has been identified. here, we report the 2.6-á+à x-ray crystal structure of the c-terminal, inhibitory ...201121742259
gene deletion from plasmodium falciparum using flp and cre recombinases: implications for applied site-specific recombination.the ability to manipulate the genome and induce site-specific recombination using either flippase (flp) or cre recombinase has been useful in many systems including plasmodium berghei for specific deletion events or to obtain conditional gene expression. to test whether these recombinases are active in plasmodium falciparum we constructed gene knockouts that contain sequences recognised as templates for site-specific recombination. we tested the ability of flp and cre recombinases, expressed con ...201120816845
reduced activity of the epithelial sodium channel in malaria-induced pulmonary oedema in mice.lung complications during malaria infection can range from coughs and impairments in gas transfer to the development of acute respiratory distress syndrome (ards). infecting c57bl/6 mice with plasmodium berghei k173 strain (pbk) resulted in pulmonary oedema, capillaries congested with leukocytes and infected red blood cells (irbcs), and leukocyte infiltration into the lungs. this new model of malaria-associated lung pathology, without any accompanying cerebral complications, allows the investiga ...201120816846
coincident parasite and cd8 t cell sequestration is required for development of experimental cerebral malaria.cerebral malaria (cm) is a fatal complication of plasmodium falciparum infection. using a well defined murine model, we observed the effect on disease outcome of temporarily reducing parasite burden by anti-malarial drug treatment. the anti-malarial treatment regime chosen decreased parasitaemia but did not cure the mice, allowing recrudescence of parasites. these mice were protected against cm, despite their parasitaemia having increased, following treatment cessation, to levels surpassing that ...201120828575
in vivo antimalarial activities of ethanolic crude extracts and fractions of leaf and root of carpolobia lutea.carpolobia lutea (leaves and root) is used traditionally as malarial remedy by the ibibios of niger delta of nigeria and benin. this study was aimed to investigate the antiplasmodial potentials of the crude leaf and root extracts of this plant as well as their fractions in vivo in plasmodium berghei berghei-infected mice to give scientific proof to the ethnobotanical claims and correlate with the reported in vivo activity. the ethanolic extracts of carpolobia lutea leaf (245-735 mg/kg/day) and r ...201121190920
antiplasmodial activity of two marine polyherbal preparations from chaetomorpha antennina and aegiceras corniculatum against plasmodium falciparum.the ocean covers more than 70% of earth surface and hosts most 300,000 described species of plants and animals to use, which have been virtually unexploited for the development of medicines. marine plants are the good source of biologically active entities which exhibit therapeutic properties, when applied single or in combination of different plant extracts (polyherbal). polyherbal preparations are always a complex mixture of different forms and thus different compounds, which might act as agon ...201120844892
antimalarial activity of traditionally used western ghats plants from india and their interactions with chloroquine against chloroquine-tolerant plasmodium berghei.an ethnopharmacological investigation was undertaken on western ghats plants traditionally used to treat malaria; 50 plants were very carefully selected from total of 372 plants, and 216 extracts were prepared and tested for in vivo antiplasmodial activity alone and in combination with chloroquine (cq) against cq-tolerant plasmodium berghei (strain nk65). in in vivo antiplasmodial activity when plant extract alone is used, 81 extracts (or 37.5%) gave 52.90% significant parasitemia inhibition on ...201120846029
triclosan is minimally effective in rodent malaria models. 201121217674
artemether and artesunate show the highest efficacies in rescuing mice with late-stage cerebral malaria and rapidly decrease leukocyte accumulation in the brain.the murine model of cerebral malaria (ecm) caused by plasmodium berghei anka (pba) infection in susceptible mice has been extensively used for studies of pathogenesis and identification of potential targets for human cm therapeutics. however, the model has been seldom explored to evaluate adjunctive therapies for this malaria complication. a first step toward this goal is to define a treatment protocol with an effective antimalarial drug able to rescue mice presenting late-stage ecm. we evaluate ...201121220531
fighting malaria with engineered symbiotic bacteria from vector mosquitoes.the most vulnerable stages of plasmodium development occur in the lumen of the mosquito midgut, a compartment shared with symbiotic bacteria. here, we describe a strategy that uses symbiotic bacteria to deliver antimalaria effector molecules to the midgut lumen, thus rendering host mosquitoes refractory to malaria infection. the escherichia coli hemolysin a secretion system was used to promote the secretion of a variety of anti-plasmodium effector proteins by pantoea agglomerans, a common mosqui ...201222802646
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
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
effects of low protein diet and pregnancy on course of plasmodium berghei infection in mice.pregnancy and malnutrition influence the severity or trend of malaria especially in sub-saharan africa where parasitic infections are highly predominant. this study was used to evaluate the combined effects of low protein diet and pregnancy on the course of plasmodium berghei infection in mice. thirty female balb/c mice were divided into six groups viz: non-infected mice fed on normal diet (nind), infected mice fed on normal diet (ind), noninfected mice fed on low protein diet (nilp), infected m ...201223678649
therapeutic effects of various solvent fractions of alstonia boonei (apocynaceae) stem bark on plasmodium berghei-induced malaria.malaria, the most important parasitic disease afflicting man is the leading cause of mortality and morbidity in the world. chemotherapy remains the mainstay for the treatment and prevention of the disease in the absence of an effective vaccine. the incidence of resistance of malaria parasites to chemotherapy is increasing and complicated. this study was therefore undertaken in order to evaluate the therapeutic effects of fractions of the stem bark of a. boonei on p. berghei-induced malaria using ...201223678633
comparative study of chloroquine and quinine on malaria rodents and their effects on the mouse testis.to evaluate the effects of quinine and chloroquine against male mice infected with plasmodium berghei and their adverse effects on the mice testes.201223569921
[application of flow cytometry in the detection of mouse malaria parasites in living cells].peripheral blood samples were obtained from plasmodium berghei-infected mice, and stained with vybrant dyecycle green and anti-mouse cd71 pe. with normal mouse as negative control, the blood samples were tested by flow cytometry at 0, 30, and 60 min after staining. there was no positive signal in the erythrocytes from negative control and the unstained erythrocytes from the infected mouse. however, the positive signal was detected in the stained erythrocytes from the infected mouse. the results ...201223484270
antiplasmodial potential of the african mistletoe: agelanthus dodoneifolius polh and wiens.preparations of agelanthus dodoneifolius have been used in the traditional nigerian medicine to treat malaria and this practice has remained till date without scientific validation. the antiplasmodial property of the water extract of agelanthus dodoneifolius was evaluated in vivo and in vitro against plasmodium berghei and clinical isolates of plasmodium falciparum, respectively. there was a dose-dependent inhibition of parasitaemia in the in vivo antiplasmodial tests likewise, the in vitro scre ...201223441021
[in vivo antiplasmodial activity of mycale laxissima and clathria echinata sponges].the search of new antimalarial compounds comprises, among its challenges, the development of therapeutic alternatives for cerebral malaria; due to the high mortality and neurological deficiencies that persist after treatment with recommended drugs.201223424801
efficacy of eosin b as a new antimalarial drug in a murine model.the initial success of any adopted anti-infective strategy to malaria is followed by a descent due to the emergence of resistance to it. the search for new drugs and drug targets is a consistent demand in this disease. eosin b, a common laboratory dye, is reported to have good antiparasitic properties in vitro. it was studied for its antiparasitic effect in vivo on chloroquine-sensitive plasmodium berghei murine malaria. eosin b was administered in 2 different doses by either the oral or parente ...201223365788
plasmodium berghei anka infection in icr mice as a model of cerebral malaria.animal models with various combination of host-parasite have long been employed to study malaria pathogenesis. here, we describe the combination of plasmodium berghei anka infection in inbred icr mice as a model of cerebral malaria (cm).201223323093
statins decrease neuroinflammation and prevent cognitive impairment after cerebral malaria.cerebral malaria (cm) is the most severe manifestation of plasmodium falciparum infection in children and non-immune adults. previous work has documented a persistent cognitive impairment in children who survive an episode of cm that is mimicked in animal models of the disease. potential therapeutic interventions for this complication have not been investigated, and are urgently needed. hmg-coa reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. in addition to their ...201223300448
aberrant sporogonic development of dmc1 (a meiotic recombinase) deficient plasmodium berghei parasites.in plasmodium, meiosis occurs in diploid zygotes as they develop into haploid motile ookinetes inside the mosquito. further sporogonic development involves transformation of ookinetes into oocysts and formation of infective sporozoites.201223285059
protective role of brain water channel aqp4 in murine cerebral malaria.tragically common among children in sub-saharan africa, cerebral malaria is characterized by rapid progression to coma and death. in this study, we used a model of cerebral malaria appearing in c57bl/6 wt mice after infection with the rodent malaria parasite plasmodium berghei anka. expression and cellular localization of the brain water channel aquaporin-4 (aqp4) was investigated during the neurological syndrome. semiquantitative real-time pcr comparing uninfected and infected mice showed a red ...201223277579
full-length plasmodium falciparum circumsporozoite protein administered with long-chain poly(i·c) or the toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion elicits potent antibody and cd4+ t cell immunity and protection in mice.the plasmodium falciparum circumsporozoite (cs) protein (csp) is a major vaccine target for preventing malaria infection. thus, developing strong and durable antibody and t cell responses against csp with novel immunogens and potent adjuvants may improve upon the success of current approaches. here, we compare four distinct full-length p. falciparum cs proteins expressed in escherichia coli or pichia pastoris for their ability to induce immunity and protection in mice when administered with long ...201223275094
csp--a model for in vivo presentation of plasmodium berghei sporozoite antigens by hepatocytes.one target of protective immunity against the plasmodium liver stage in balb/c mice is represented by the circumsporozoite protein (csp), and mainly involves its recognition by ifn-γ producing specific cd8+t-cells. in a previous in vitro study we showed that primary hepatocytes from balb/c mice process plasmodium berghei (pb) csp (pbcsp) and present csp-derived peptides to specific h-2k(d) restricted cd8+t-cells with subsequent killing of the presenting cells. we now extend these observations to ...201223272182
visualizing non infectious and infectious anopheles gambiae blood feedings in naive and saliva-immunized mice.anopheles gambiae is a major vector of malaria and lymphatic filariasis. the arthropod-host interactions occurring at the skin interface are complex and dynamic. we used a global approach to describe the interaction between the mosquito (infected or uninfected) and the skin of mammals during blood feeding.201223272060
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
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
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
bacteria and protozoa differentially modulate the expression of rab proteins.phagocytic cells represent an important line of innate defense against microorganisms. uptake of microorganisms by these cells involves the formation of a phagosome that matures by fusing with endocytic compartments, resulting in killing of the enclosed microbe. small gtpases of the rab family are key regulators of vesicular trafficking in the endocytic pathway. intracellular pathogens can interfere with the function of these proteins in order to subvert host immune responses. however, it is unk ...201222911692
morita-baylis-hillman adducts: biological activities and potentialities to the discovery of new cheaper drugs.this review aims to present by the first time the morita-baylis-hillman adducts (mbha) as a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs. now, most these compounds can be prepared fast and on a single synthetic step (one-pot reaction) in high yields and using ecofriendly synthetic protocols. we highlight here the aromatic mbha, which have shown diverse biological activities as anti-leishmania chagasi and leishmania amazonen ...201222632793
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
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
development of memory cd8+ t cells and their recall responses during blood-stage infection with plasmodium berghei anka.conditions required for establishing protective immune memory vary depending on the infecting microbe. although the memory immune response against malaria infection is generally thought to be relatively slow to develop and can be lost rapidly, experimental evidence is insufficient. in this report, we investigated the generation, maintenance, and recall responses of ag-specific memory cd8(+) t cells using plasmodium berghei anka expressing ova (pba-ova) as a model system. mice were transferred wi ...201223008449
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
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
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
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
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
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
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