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analysis of immune response patterns in naïve and plasmodium berghei-infected young rats following a ferroquine treatment.the direct antimalarial activity of ferroquine (fq, ssr97193), a chloroquine (cq) derivative, is well established. to determine whether the fq anti-parasite activity affects the host immune properties, we have investigated its effect on several immunological parameters in young rats infected with plasmodium berghei and compared it with that of cq. in uninfected young rats, treatment with either drug did not show any impairment in the cellular distribution of spleen cells in their response to mit ...200516140302
selectively impaired cd8+ but not cd4+ t cell cycle arrest during priming as a consequence of dendritic cell interaction with plasmodium-infected red cells.individuals living in malaria-endemic areas show generally low t cell responses to malaria ags. in this study, we show murine dendritic cell (dc) interaction with parasitized erythrocytes (prbc) arrested their maturation, resulting in impaired ability to stimulate naive, but not recall t cell responses in vitro and in vivo. moreover, within the naive t cell population, prbc-treated dc were selectively deficient in priming cd8(+) but not cd4(+) t cells. indeed, dc that had taken up prbc were show ...200516148095
in vivo antimalarial activities of extracts from amaranthus spinosus l. and boerhaavia erecta l. in mice.extracts obtained from two burkinabe folk medicine plants, spiny amaranth (amaranthus spinosus l., amaranthaceae) and erect spiderling (boerhaavia erecta l., nyctagynaceae) were screened for antimalarial properties with the aim of testing the validity of their traditional uses. the plant extracts showed significant antimalarial activities in the 4-day suppressive antimalarial assay in mice inoculated with red blood cells parasitized with plasmodium berghei berghei. we obtained values for ed(50) ...200616171960
synergistic antimalarial activity of ketones with rufigallol and vitamin c.malaria remains a major cause of human morbidity and mortality worldwide. plasmodium falciparum, the most virulent of the 4 human plasmodium species causing malaria, is potentially life threatening, is increasing in prevalence and is becoming even more resistant to in-use drugs. in light of the growing problem of multi-drug resistance to malarial parasites, the development of new drugs or the use of a combination therapy is of primary importance. a previous report describes a remarkable synergis ...200516174410
plasmodium berghei resists killing by reactive oxygen species.reactive oxygen species (ros) are widely believed to kill malarial parasites. c57bl/6 mice injected with p. berghei inocula incubated with supraphysiological doses of no (< or =150 microm) or with peroxynitrite (220 microm), however, exhibited parasitemia similar to that seen with those given control inocula, and there was no difference in disease development. only treatment of inocula with no doses nearing saturation (> or =1.2 mm) resulted in no detectable parasitemia in the recipients; flow c ...200516177347
performance of flow cytometric analysis for the micronucleus assay--a reconstruction model using serial dilutions of malaria-infected cells with normal mouse peripheral blood.to confirm the performance and statistical power of a flow cytometric method for scoring micronucleated erythrocytes, reconstruction experiments were performed. for these investigations, peripheral blood erythrocytes from untreated mice, with a micronucleated erythrocyte frequency of approximately 0.1% were combined with known quantities of plasmodium berghei (malaria) infected mouse erythrocytes. these cells had an infected erythrocyte frequency of approximately 0.7%, and mimic the dna content ...200616188876
plasmodium berghei: effect of protease inhibitors during gametogenesis and early zygote development.plasmodium berghei: the effect of five protease inhibitors, tpck, tlck, pmsf, leupeptin, and 1,10-phenanthroline on in vitro gametogenesis and early zygote development of p. berghei was investigated. pmsf and leupeptin showed no effect. cysteine/serine protease inhibitors tpck/tlck at concentrations of 75 and 100 microm were effective on inhibiting exflagellation center formation, and this effect was reversible with the addition of l-cysteine. exflagellation center formation was most effectively ...200516198343
mutational analysis of the gpi-anchor addition sequence from the circumsporozoite protein of plasmodium.the plasma membrane of plasmodium sporozoites is uniformly covered by the glycosylphosphatidylinositol (gpi)-anchored circumsporozoite (cs) protein. sporozoites form in the mosquito midgut through a budding process that occurs within a multinucleate oocyst underneath the basal lamina of the gut. earlier genetic studies established that normal sporozoite development requires cs. mutant parasites lacking cs [cs (-)] do not form sporozoites. ultrastructural analysis of the oocysts from these parasi ...200516207248
severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes.severe malarial anemia (sma) is the most frequent life-threatening complication of malaria and may contribute to the majority of malarial deaths worldwide. to explore the mechanisms of pathogenesis, we developed a novel murine model of sma in which parasitemias peaked around 1.0% of circulating red blood cells (rbcs) and yet hemoglobin levels fell to 47% to 56% of baseline. the severity of anemia was independent of the level of peak or cumulative parasitemia, but was linked kinetically to the du ...200616210332
activation of calpains, calpastatin and spectrin cleavage in the brain during the pathology of fatal murine cerebral malaria.neuronal calpains appear to be activated uncontrollably by sustained elevation of cytosolic calcium levels under pathological conditions as well as neurodegenerative diseases. in the present study, we have characterized calpain activation in cytosolic extract of mice cerebral cortex and cerebellum using an experimental model of fatal murine cerebral malaria (fmcm). pathology of fmcm resulted in the increase in activity of calpains in both cerebral cortex and cerebellum. western blot analysis rev ...200616236382
the liver stage of plasmodium berghei inhibits host cell apoptosis.plasmodium berghei is the causative agent of rodent malaria and is widely used as a model system to study the liver stage of plasmodium parasites. the entry of p. berghei sporozoites into hepatocytes has extensively been studied, but little is known about parasite-host interaction during later developmental stages of the intracellular parasite. growth of the parasite far beyond the normal size of the host cell is an important stress factor for the infected cell. cell stress is known to trigger p ...200516238623
high efficiency transfection of plasmodium berghei facilitates novel selection procedures.the use of transfection in the study of the biology of malaria parasites has been limited due to poor transfection efficiencies (frequency of 10(-6) to 10(-9)) and a paucity of selection markers. here, a new method of transfection, using non-viral nucleofector technology, is described for the rodent parasite plasmodium berghei. the transfection efficiency obtained (episomal and targeted integration into the genome) is in the range of 10(-2) to 10(-3). such high transfection efficiency strongly r ...200616242190
antimalarial drug synergism and antagonism: mechanistic and clinical significance.interactions between antimicrobial agents provide clues as to their mechanisms of action and influence the combinations chosen for therapy of infectious diseases. in the treatment of malaria, combinations of drugs, in many cases acting synergistically, are increasingly important in view of the frequency of resistance to single agents. the study of antimalarial drug interactions is therefore of great significance to both treatment and research. it is therefore worrying that the analysis of drug-i ...200516243458
antimalarial activity of 4-(5-trifluoromethyl-1h-pyrazol-1-yl)-chloroquine analogues.the antimalarial activity of chloroquine-pyrazole analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro against a chloroquine resistant plasmodium falciparum clone. parasite growth in the presence of the test drugs was measured by incorporation of [(3)h]hypoxanthine in comparison to controls with no drugs. all but one of the eight (4,5-dihydropyrazol-1-yl) chloroquine 2 derivatives tested showed a sign ...200616257205
an immune-responsive serpin, srpn6, mediates mosquito defense against malaria parasites.we have functionally analyzed the orthologous srpn6 genes from anopheles stephensi and anopheles gambiae using phylogenetic, molecular, reverse genetic, and cell biological tools. the results strongly implicate srpn6 in the innate immune response against plasmodium. this gene belongs to a mosquito-specific gene cluster including three additional anopheles serpins. srpn6 expression is induced by escherichia coli and both rodent and human malaria parasites. the gene is specifically expressed in mi ...200516260729
purinoceptors are involved in the induction of an osmolyte permeability in malaria-infected and oxidized human erythrocytes.in human erythrocytes, infection by the malaria parasite plasmodium falciparum or oxidative stress induces a new organic osmolyte and anion permeability. to examine a role for autocrine purinoceptor signaling during this induction process, erythrocytic purinoceptor expression, and atp release were determined. furthermore, using pharmacological and genetic approaches the dependence on purinoceptor signaling of osmolyte permeability and plasmodium development, both in vitro and in vivo, were asses ...200616267125
towards systematic identification of plasmodium essential genes by transposon shuttle mutagenesis.after the deciphering of the genome sequences of several plasmodium species, efforts must turn to elucidating gene function and identifying essential gene products. however, random approaches are lacking and gene targeting is inefficient in plasmodium. here, we established shuttle transposon mutagenesis in plasmodium berghei. we constructed a mini-tn5 derivative that can transpose into parasite genes cloned in escherichia coli, providing an efficient means of generating knockout fragments. a 10( ...200516284199
generation of gene targeting constructs for plasmodium berghei by a pcr-based method amenable to high throughput applications. 200616290088
cell- rather than antibody-mediated immunity leads to the development of profound thrombocytopenia during experimental plasmodium berghei malaria.experimental malarial thrombocytopenia can reach life-threatening levels and is believed to be due to abs targeting platelets for destruction by the reticuloendothelial system. however, we report that abs account for at most 15% of platelet destruction as plasmodium berghei-infected b cell-deficient mice exhibited profound thrombocytopenia (83%) as did c57bl/6 controls (98%). further, no significant increase in abs bound to intact platelets was observed during infection. p. berghei infection can ...200516301680
antimalarial activities of new pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives.wr227825 is an antimalarial pyrroloquinazolinediamine derivative with a high potency but a low therapeutic index. a series of carbamate, carboxamide, succinimide, and alkylamine derivatives of wr227825 were prepared to search for compounds with an improved therapeutic index. the new acetamides and imide showed potent cell growth inhibition against four clones of plasmodium falciparum (d-6, rcs, w-2, and tm91c235), with a 50% inhibitory concentration of approximately 0.01 ng/ml, and were highly a ...200516304154
an atypical mitogen-activated protein kinase controls cytokinesis and flagellar motility during male gamete formation in a malaria parasite.the transmission of malaria parasites to the mosquito depends critically on the rapid initiation of sexual reproduction in response to triggers from the mosquito midgut environment. we here identify an essential function for an atypical mitogen-activated protein kinase of the rodent malaria parasite plasmodium berghei, pbmap-2, in male sexual differentiation and parasite transmission to the mosquito. a deletion mutant no longer expressing the pbmap-2 protein develops as wild type throughout the ...200516313614
transgenic plasmodium berghei sporozoites expressing beta-galactosidase for quantification of sporozoite transmission.malaria transmission occurs during a blood-meal of an infected anopheles mosquito. visualization and quantification of sporozoites along the journey from the mosquito midgut, where they develop, to the vertebrate liver, their final target organ, is important for understanding many aspects of sporozoite biology. here we describe the generation of plasmodium berghei parasites that express the reporter gene lacz as a stable transgene, under the control of the sporozoite-specific csp promoter. trans ...200616316690
do apoptotic plasmodium-infected hepatocytes initiate protective immune responses? 200616323145
characterization of plasmodium falciparum cgmp-dependent protein kinase (pfpkg): antiparasitic activity of a pkg inhibitor.cyclic gmp-dependent protein kinase (pkg) has been biochemically and genetically validated in toxoplasma gondii as a primary target responsible for the antiparasitic activity of the trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1h pyrrol-3-yl] pyridine (compound 1) [biftu t, feng d, ponpipom m, et al. synthesis and sar of 2,3-diarylpyrrole inhibitors of parasite cgmp-dependent protein kinase as novel anticoccidial agents. bioorg med chem lett 2005;15:3296-301; gurnett ...200616325279
preservation of borrelia kansas and plasmodium berghei.[this corrects the article on p. 224 in vol. 20.].197116349897
gene-expression profiling discriminates between cerebral malaria (cm)-susceptible mice and cm-resistant mice.the development of cerebral malaria (cm) in mice with plasmodium berghei anka infection is under genetic control. brain gene-expression patterns were investigated in well-defined genetically cm-resistant (cm-r; balb/c and dba/2) and cm-susceptible (cm-s; c57bl/6 and cba/j) mice by use of cdna microarrays. by combining transcriptional profiling with rigorous statistical methods and cluster analysis, we identified a set of 69 genes that perfectly discriminated between mouse strains and between cm- ...200616362897
pbcrk-1, the plasmodium berghei orthologue of p. falciparum cdc-2 related kinase-1 (pfcrk-1), is essential for completion of the intraerythrocytic asexual cycle.the molecular mechanisms underlying gametocytogenesis in malaria parasites are not understood. plasmodium falciparum cdc2-related kinase 1 (pfcrk-1), a gene that is expressed predominantly in gametocytes, bears homology to the pitslre subfamily of cyclin-dependent kinases and has been hypothesized to function as a negative regulator of the cell cycle. we attempted to knock-out pbcrk-1, the p. berghei orthologue of pfcrk-1, but were unable to recover p. berghei parasites with a disrupted pbcrk-1 ...200616375894
novel surface display system for proteins on non-genetically modified gram-positive bacteria.a novel display system is described that allows highly efficient immobilization of heterologous proteins on bacterial surfaces in applications for which the use of genetically modified bacteria is less desirable. this system is based on nonliving and non-genetically modified gram-positive bacterial cells, designated gram-positive enhancer matrix (gem) particles, which are used as substrates to bind externally added heterologous proteins by means of a high-affinity binding domain. this binding do ...200616391130
antimalarial and antiplasmodial activities of norneolignans. syntheses and sar.a systematic change of the substituents and side chain of the norneolignan hinokiresinol afforded a 10 fold improvement of the ic(50) value toward inhibition of the growth of plasmodium falciparum. the more potent compounds controlled the parasitemia in mice infected with plasmodium berghei.200616392829
synthesis of 2-azabicyclo[3.2.2]nonanes from bicyclo[2.2.2]octan-2-ones and their activities against trypanosoma brucei rhodesiense and plasmodium falciparum k1.new 2-azabicyclo[3.2.2]nonanes were prepared from antiprotozoal bicyclo[2.2.2]octan-2-ones to investigate the influence of the replacement of the rigid bicyclo-octane structure by the more flexible bicyclo-nonane system on the antiplasmodial and antitrypanosomal activity.200516401404
systemic activation of dendritic cells by toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity.the mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. here we show that infection with a malaria parasite (plasmodium berghei) or simple systemic exposure to bacterial or viral toll-like receptor ligands inhibited cross-priming. reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit t cell prolife ...200616415871
synthesis and antimalarial activity of new 3-arylquinoxaline-2-carbonitrile derivatives.new series of 3-arylquinoxaline-carbonitrile derivatives have been synthesized from various 5-substituted or 5,6-disubstituted benzofuroxanes and tested for their in vitro and in vivo activity against the erythrocytic development of plasmodium falciparum strain with different chloroquine-resistance status. quinoxaline 1,4-dioxide derivatives showed superior antimalarial activity in respect to reduced quinoxaline analogues. the best activity was observed with nonsubstituted quinoxaline 1,4-dioxid ...200516430030
a calcium-dependent protein kinase regulates plasmodium ookinete access to the midgut epithelial cell.plasmodium parasites are fertilized in the mosquito midgut and develop into motile zygotes, called ookinetes, which invade the midgut epithelium. here we show that a calcium-dependent protein kinase, cdpk3, of the rodent malarial parasite (plasmodium berghei) is produced in the ookinete stage and has a critical role in parasite transmission to the mosquito vector. targeted disruption of the cdpk3 gene decreased ookinete ability to infect the mosquito midgut by nearly two orders of magnitude. ele ...200616430692
protective and pathogenic roles of cd8+ t cells during malaria infection.cd8+ t cells play a key role in protection against pre-erythrocytic stages of malaria infection. many vaccine strategies are based on the idea of inducing a strong infection-blocking cd8+ t cell response. here, we summarize what is known about the development, specificity and protective effect of malaria-specific cd8+ t cells and report on recent developments in the field. although work in mouse models continues to make progress in our understanding of the basic biology of these cells, many ques ...200616438672
simultaneous increases in immune-competent cells and nitric oxide in the spleen during plasmodium berghei infection in mice.nitric oxide and other reactive nitrogen intermediates (rni) are thought to be important mediators of both immunological and pathological responses of the vertebrate host to malaria infection. the role of rni has been studied most often by assay of stable rni metabolites (nitrites, nitrates) in blood. this study evaluated the nature of the rni response of mice to malaria by analyzing the subsets of immune-competent cells within the organ displaying increased rni in vivo.200616440118
improved transfection and new selectable markers for the rodent malaria parasite plasmodium yoelii.the rodent malaria plasmodium yoelii is a useful model to study protective immunity to pre-erythrocytic stages of infection, pathogenesis of erythrocytic stages, and vaccine development. however, the utility of the p. yoelii model system has not been fully realized because transfection and genetic manipulation methodologies for this rodent species are less developed than that of another rodent species plasmodium berghei. here we report improved transfection efficiency using the amaxa nucleofecto ...200616458371
kupffer cell function during the erythocytic stage of malaria.previous studies using isolated perfused rat liver in vivo have suggested that during the erythrocytic phase of malaria infection, overall phagocytosis by kupffer cells is enhanced. the aim of the present study was to further investigate the individual phagocytic capacity and prostaglandin e(2) (pge(2)) secretion of isolated kupffer cells in vitro, and the immunohistochemical characteristics of kupffer cells in vivo.200616460493
celtos, a novel malarial protein that mediates transmission to mosquito and vertebrate hosts.the malarial parasite has two hosts in its life cycle, a vertebrate and a mosquito. we report here that malarial invasion into these hosts is mediated by a protein, designated cell-traversal protein for ookinetes and sporozoites (celtos), which is localized to micronemes that are organelles for parasite invasive motility. targeted disruption of the celtos gene in plasmodium berghei reduced parasite infectivity in the mosquito host approximately 200-fold. the disruption also reduced the sporozoit ...200616468982
the effects of blood feeding and exogenous supply of tryptophan on the quantities of xanthurenic acid in the salivary glands of anopheles stephensi (diptera: culicidae).xanthurenic acid (xa), produced as a byproduct during the biosynthesis of insect eye pigment (ommochromes), is a strong inducer of plasmodium gametogenesis at very low concentrations. in previous studies, it was shown that xa is present in anopheles stephensi (diptera: culicidae) mosquito salivary glands and that during blood feeding the mosquitoes ingested their own saliva into the midgut. considering these two facts together, it is therefore likely that xa is discharged with saliva during bloo ...200616469295
total syntheses of hexacyclinol, 5-epi-hexacyclinol, and desoxohexacyclinol unveil an antimalarial prodrug motif. 200616470558
immunopathological consequences of the loss of engulfment genes: the case of abca1.programmed cell death plays a crucial role in the maintenance of cell homeostasis. an initial, effector phase leads to the generation of apoptotic corpses and is closely followed by a swift clearance by professional or amateur phagocytes. several aspects distinguish this latter process of engulfment of dying cells from the classical forms of phagocytosis. they concern all aspects of the process from the recognition of the prey to the final outcome, i.e. immunological silence. the engulfment of d ...200516471259
plasmodium berghei: development of an irreversible experimental malaria model in wistar rats.a protocol to infect five-week-old wistar rats by plasmodium berghei which resulted in 100% mortality was developed in this work. in order to accomplish this goal, the effect of the administration of 10(7) and 10(8) parasitized erythrocytes by i.v. and i.p. route was investigated. the animals inoculated with 10(7) parasitized red blood cells by i.p. and i.v. routes showed 25 and 50% mortality, respectively. inoculation with 10(8) parasitized erythrocytes by both routes resulted in a 100% lethal ...200616494867
[recent advances in the study of artemisinin-related 1,2,4-trioxanes and ozonides (1,2,4-trioxolanes) as antimalarials]. 200516496665
perforin mediated apoptosis of cerebral microvascular endothelial cells during experimental cerebral malaria.cerebral malaria is a serious complication of plasmodium falciparum infection. we have investigated the role of perforin in the pathogenesis of cerebral malaria in a murine model (plasmodium berghei anka (pba) infection). c57bl/6 mice demonstrated the typical neuropathological symptoms of experimental cerebral malaria infection from day 5p.i. and became moribund on day 6p.i. this pathology was not seen in pba-infected, perforin-deficient (pfp-/-) mice. from days 5-6p.i. onwards there was a signi ...200616500656
plasmodium falciparum erythrocyte invasion: a conserved myosin associated complex.host cell invasion by apicomplexan parasites is powered by an actin/myosin motor complex that has been most thoroughly described in toxoplasma gondii tachyzoites. in t. gondii, two inner membrane complex (imc) proteins, the peripheral protein tggap45 and the transmembrane protein tggap50, form a complex with the myosin, tgmyoa, and its light chain, tgmlc1. this complex, referred to as the glideosome, anchors the invasion motor to the imc. we have identified and characterized orthologues of tgmlc ...200616513191
antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a vanuatu marine sponge xestospongia sp.as part of our search for new antimalarial drugs, we have screened for inhibitors of pfnek-1, a protein kinase of plasmodium falciparum, in south pacific marine sponges. on the basis of a preliminary screening, the ethanolic crude extract of a new species of xestospongia collected in vanuatu was selected for its promising activity. a bioassay-guided fractionation led us to isolate xestoquinone which inhibits pfnek-1 with an ic(50) around 1 microm. among a small panel of plasmodial protein kinase ...200616513357
recombinant human erythropoietin prevents the death of mice during cerebral malaria.cerebral involvement during malaria is a complication that leads to seizure, coma, and death. the effect of new neuroprotective therapies has not yet been investigated, although cerebral malaria shares some features with neurological stroke. erythropoietin (epo) is one of the more promising drugs in this area. we measured the effect of epo on the survival of mice infected with plasmodium berghei anka and demonstrated that inoculations of recombinant human epo at the beginning of the clinical man ...200616518761
diels-alder/thiol-olefin co-oxygenation approach to antimalarials incorporating the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore.a diels-alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. iron(ii)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with tempo provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. rea ...200616527481
[cytochrome p-450 and the response to antimalarial drugs].to assess the relationship between the genetic and phenotypic factors linked to the cytochrome p-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex.200616536934
development and application of a positive-negative selectable marker system for use in reverse genetics in plasmodium.a limitation of transfection of malaria parasites is the availability of only a low number of positive selectable markers for selection of transformed mutants. this is exacerbated for the rodent parasite plasmodium berghei as selection of mutants is performed in vivo in laboratory rodents. we here report the development and application of a negative selection system based upon transgenic expression of a bifunctional protein (yfcu) combining yeast cytosine deaminase and uridyl phosphoribosyl tran ...200616537837
plasmodium berghei (anka): infection induces cyp2a5 and 2e1 while depressing other cyp isoforms in the mouse liver.it has been reported that malaria infection impairs hepatic drug clearance and causes a down-regulation of cyp-mediated monooxygenase activities in rodents and humans. in the present study, we investigated the effects of plasmodium berghei infection on the activity of liver monooxygenases in female dba/2 and c57bl/6 mice. in both mouse strains, p. berghei infection decreased activities mediated by cyp1a (erod: dba/2 65.3%, c57bl/6 44.7%) and 2b (brod: dba/2 64.3%, c57bl/6 49.8%) subfamily isofor ...200616540109
a mosquito 2-cys peroxiredoxin protects against nitrosative and oxidative stresses associated with malaria parasite infection.malaria parasite infection in anopheline mosquitoes induces nitrosative and oxidative stresses that limit parasite development, but also damage mosquito tissues in proximity to the response. based on these observations, we proposed that cellular defenses in the mosquito may be induced to minimize self-damage. specifically, we hypothesized that peroxiredoxins (prxs), enzymes known to detoxify reactive oxygen species (ros) and reactive nitrogen oxide species (rnos), protect mosquito cells. we iden ...200616540402
rhop-3 protein conservation among plasmodium species and induced protection against lethal p. yoelii and p. berghei challenge.in the present study, rhop-3 polymorphism among plasmodium falciparum field and laboratory isolates and among rodent plasmodium species was investigated and identified. the rhop-3 gene was found in all plasmodium species so far tested. the overall structure of the rhop-3 protein was found conserved among p. falciparum, plasmodium yoelii, and plasmodium berghei. however, it was more conserved among rodent plasmodium species than between p. falciparum and plasmodium vivax. the most conserved regio ...200616541261
mosquito midguts and malaria: cell biology, compartmentalization and immunology.the malaria parasite plasmodium has an absolute requirement for both a vertebrate and a mosquito host in order to complete its life cycle, and its interactions with the latter provide the focus for this review. the mosquito midgut represents one of the most challenging environments for the survival and development of plasmodium, and is thus also one of the most attractive sites for novel targeted malaria control strategies. during their attempts to cross the midgut epithelium en route to the sal ...200616542314
piperidones with activity against plasmodium falciparum.the increasing resistance of the malaria parasites has enforced new strategies of finding new drug targets. we have isolated two genes involved in spermidine metabolism, encoding deoxyhypusine synthase (dhs) and eukaryotic initiation factor 5a (eif-5a) in the malaria parasites. eif-5a is activated by the formation of the unusual amino acid hypusine. this process occurs in two steps. dhs transfers an aminobutyl moiety from the triamine spermidine to a specific lysine residue in the eif-5a precurs ...200616550432
effective targeting of liposomes to liver and hepatocytes in vivo by incorporation of a plasmodium amino acid sequence.several species of the protozoan plasmodium effectively target mammalian liver during the initial phase of host invasion. the purpose of this study was to demonstrate that a plasmodium targeting amino acid sequence can be engineered into therapeutic nanoparticle delivery systems.200616550476
infection with plasmodium berghei boosts antibody responses primed by a dna vaccine encoding gametocyte antigen pbs48/45.an important consideration in the development of a malaria vaccine for individuals living in areas of endemicity is whether vaccine-elicited immune responses can be boosted by natural infection. to investigate this question, we used plasmodium berghei anka blood-stage parasites for the infection of mice that were previously immunized with a dna vaccine encoding the p. berghei sexual-stage antigen pbs48/45. intramuscular immunization in mice with one or two doses of dna-pbs48/45 or of empty dna v ...200616552033
immunization with a circumsporozoite epitope fused to bordetella pertussis adenylate cyclase in conjunction with cytotoxic t-lymphocyte-associated antigen 4 blockade confers protection against plasmodium berghei liver-stage malaria.the adenylate cyclase toxoid (act) of bordetella pertussis is capable of delivering its n-terminal catalytic domain into the cytosol of cd11b-expressing professional antigen-presenting cells such as myeloid dendritic cells. this allows delivery of cd8+ t-cell epitopes to the major histocompatibility complex (mhc) class i presentation pathway. recombinant detoxified act containing an epitope of the plasmodium berghei circumsporozoite protein (csp), indeed, induced a specific cd8+ t-cell response ...200616552058
using green fluorescent malaria parasites to screen for permissive vector mosquitoes.the plasmodium species that infect rodents, particularly plasmodium berghei and plasmodium yoelii, are useful to investigate host-parasite interactions. the mosquito species that act as vectors of human plasmodia in south east asia, africa and south america show different susceptibilities to infection by rodent plasmodium species. p. berghei and p. yoelii infect both anopheles gambiae and anopheles stephensi, which are found mainly in africa and asia, respectively. however, it was reported that ...200616569221
2-cys peroxiredoxin tpx-1 is involved in gametocyte development in plasmodium berghei.peroxiredoxins (prxs) constitute a ubiquitous family of antioxidant enzymes involved in diverse cellular functions including cell proliferation and differentiation. to investigate the physiologic role of typical 2-cys prx in malaria parasites (tpx-1), we disrupted this gene in the rodent malaria parasite plasmodium berghei (pbtpx-1). the gene-disrupted parasite (prx ko) developed normally in mouse erythrocytes and multiplied at a rate similar to that of the parent strain (wt) during the experime ...200616597467
pathogenic t cells in cerebral malaria.malaria remains a major global health problem and cerebral malaria (cm) is one of the most serious complications of this disease. recent years have seen important advances in our understanding of the pathogenesis of cerebral malaria. parasite sequestration, a hallmark of this syndrome, is thought to be solely responsible for the pathological process. however, this phenomenon cannot explain all aspects of the pathogenesis of cm. the use of an animal model, plasmodium berghei anka in mice, has all ...200616600241
cerebral malaria: role of microparticles and platelets in alterations of the blood-brain barrier.brain lesions of cerebral malaria (cm) are characterised by a sequestration of plasmodium falciparum-parasitised red blood cells (prbc), leucocytes and platelets within brain microvessels, by an excessive release of pro-inflammatory cytokines as well as by disruption of the blood-brain barrier (bbb). we evaluated the possibility that prbc and platelets interact and induce functional alterations in brain endothelium. using an in vitro model of endothelial lesion, we showed that platelets can act ...200616600245
neuronal apoptosis, metallothionein expression and proinflammatory responses during cerebral malaria in mice.cerebral malaria (cm) is an acute encephalopathy in humans due to the infection with plasmodium falciparum. neuro-cognitive impairment following cm occurs in about 10% of the treated survivors, while the precise pathophysiological mechanism remains unknown. metallothionein i + ii (mt-i + ii) are increased during cns pathology and disorders. as previously shown, mt-i + ii are neuroprotective through anti-inflammatory, antioxidant and antiapoptotic functions. we have analyzed neuronal apoptosis an ...200616624296
antiplasmodial activity of cylicodiscus gabunensis.the antimalarial activity of ethanolic stembark extract of cylicodiscus gabunensis was studied in vivo in mice infected with plasmodium berghei berghei during early and established infections as well as for repository activity. the ld(50) of the extract was determined to be 223.6 mg/kg, while doses of 250 mg/kg and above were found to be lethal to mice. cylicodiscus gabunensis extract (20-60 mg/kg/day) exhibited a significant (p<0.05) blood schizontocidal activity in 4-day early infection, repos ...200616635557
new potential antimalarial agents: therapeutic-index evaluation of pyrroloquinazolinediamine and its prodrugs in a rat model of severe malaria.tetra-acetamide pyrroloquinazolinediamine (pqd-a4) and bis-ethylcarbamyl pyrroloquinazolinediamine (pqd-be) are new derivatives of pyrroloquinazolinediamine (pqd) and are being investigated as potential chemotherapeutic agents for the treatment of malaria. comparative studies to assess the therapeutic indices of pqd-a4, pqd-be, and pqd were conducted in plasmodium berghei-infected rats following daily intragastric dosing for three consecutive days. artesunate (as), a standard drug for treatment ...200616641431
antimalarial activity of allicin, a biologically active compound from garlic cloves.the incidence of malaria is increasing, and there is an urgent need to identify new drug targets for both prophylaxis and chemotherapy. potential new drug targets include plasmodium proteases that play critical roles in the parasite life cycle. we have previously shown that the major surface protein of plasmodium sporozoites, the circumsporozoite protein (csp), is proteolytically processed by a parasite-derived cysteine protease, and this processing event is temporally associated with sporozoite ...200616641443
curcumin-artemisinin combination therapy for malaria.artemisinin and curcumin show an additive interaction in killing plasmodium falciparum in culture. in vivo, 3 oral doses of curcumin following a single injection of alpha,beta-arteether to plasmodium berghei-infected mice are able to prevent recrudescence due to alpha,beta-arteether monotherapy and ensure almost 100% survival of the animals.200616641461
natural malaria infection in anopheles gambiae is regulated by a single genomic control region.we surveyed an anopheles gambiae population in a west african malaria transmission zone for naturally occurring genetic loci that control mosquito infection with the human malaria parasite, plasmodium falciparum. the strongest plasmodium resistance loci cluster in a small region of chromosome 2l and each locus explains at least 89% of parasite-free mosquitoes in independent pedigrees. together, the clustered loci form a genomic plasmodium-resistance island that explains most of the genetic varia ...200616645095
set regulation in asexual and sexual plasmodium parasites reveals a novel mechanism of stage-specific expression.transmission of the malaria parasite depends on specialized gamete precursors (gametocytes) that develop in the bloodstream of a vertebrate host. gametocyte/gamete differentiation requires controlled patterns of gene expression and regulation not only of stage and gender-specific genes but also of genes associated with dna replication and mitosis. once taken up by mosquito, male gametocytes undergo three mitotic cycles within few minutes to produce eight motile gametes. here we analysed, in two ...200616677299
cholesterol contributes to the organization of tetraspanin-enriched microdomains and to cd81-dependent infection by malaria sporozoites.tetraspanins constitute a family of widely expressed integral membrane proteins that associate extensively with one another and with other membrane proteins to form specific membrane microdomains distinct from conventional lipid rafts. so far, because of the lack of appropriate tools, the functionality of these microdomains has remained largely unknown. here, using a new monoclonal antibody that only binds to the tetraspanin cd81 associated with other tetraspanins, we show that membrane choleste ...200616687736
estradiol, but not dehydroepiandrosterone, decreases parasitemia and increases the incidence of cerebral malaria and the mortality in plasmodium berghei anka-infected cba mice.the effect of castration and subsequent replacement of dehydroepiandrosterone (dhea) or estradiol on parasitemia, mortality and incidence of cerebral malaria (cm) was evaluated in cba mice infected with plasmodium berghei anka.200616699290
differential gene expression in abdomens of the malaria vector mosquito, anopheles gambiae, after sugar feeding, blood feeding and plasmodium berghei infection.large scale sequencing of cdna libraries can provide profiles of genes expressed in an organism under defined biological and environmental circumstances. we have analyzed sequences of 4541 expressed sequence tags (ests) from 3 different cdna libraries created from abdomens from plasmodium infection-susceptible adult female anopheles gambiae. these libraries were made from sugar fed (s), rat blood fed (rb), and p. berghei-infected (irb) mosquitoes at 30 hours after the blood meal, when most paras ...200616712725
antimalarial activity of some colombian medicinal plants.antimalarial activity of 10 vegetal extracts (9 ethanolic extracts and 1 crude alkaloid extract), obtained from eight species traditionally used in colombia to treat malaria symptoms, was evaluated in culture using plasmodium falciparum chloroquine resistant (fcb2) strain and in vivo on rodent malaria plasmodium berghei. the activity on ferriprotoporphyrin biomineralization inhibition test (fbit) was also assessed. against plasmodium falciparum, eight extracts displayed good activity abuta grand ...200616713157
quinine distribution in pregnant mice with plasmodium berghei malaria.maternal malaria is associated with placental insufficiency that leads to intrauterine growth retardation and reduced birth weight. malaria may impair the exchange of drugs across the placenta especially the transmission of antimalarial drugs to the foetus. the distribution of quinine and its 3-hydroxymetabolite in blood, tissues and foeto-placental unit was evaluated on day 18 of pregnancy of mice infected or not with plasmodium berghei. during pregnancy, quinine distribution volume increases g ...200616716571
endothelin in a murine model of cerebral malaria.cerebral malaria (cm) remains a deadly complication of plasmodium falciparum infection, and children are at high risk of developing encephalopathy as a result of cm. this is probably a consequence of the activation of many of the inflammatory cytokines as well as the glial cells and the vascular endothelium in the brain. we have previously demonstrated that there is a striking reduction in cerebral blood flow by magnetic resonance imaging when mice are infected with plasmodium berghei anka (pba) ...200616741072
the effect of plasmodium berghei malaria on mouse-liver mitochondria. 196016748824
the metabolism of plasmodium berghei, the malaria parasite of rodents. 2. an effect of mepacrine on the metabolism of glucose by the parasite separated from its host cell. 196116748881
effect of artemether administered alone or in combination with praziquantel to mice infected with plasmodium berghei or schistosoma mansoni or both.the artemisinins have become key drugs for the treatment and control of malaria, particularly within artemisinin-based combination therapies. since the artemisinins also exhibit antischistosomal properties, their use in areas where malaria and schistosomiasis are co-endemic may have an effect on both diseases and co-infection might alter drug efficacy. we assessed the antimalarial and antischistosomal efficacies of artemether in mice infected with plasmodium berghei or schistosoma mansoni or bot ...200616750833
studies on the glycoprotein modification in erythrocyte membrane during experimental cerebral malaria.plasmodium berghei anka (pb anka) is a lethal strain of malaria that causes experimental cerebral malaria (ecm) in rodent models. pathology of the disease is associated with the sequestration of the infected rbc (irbc) in the micro vessels of brain. in the present study, we analyzed the nature of the glycoprotein modification occurring in irbc membrane during erythrocytic stages of pb anka infection. titration of naturally occurring glycoproteins with concanavalin a (con a) and wheat germ agglut ...200616753147
the phylogeny of rodent malaria parasites: simultaneous analysis across three genomes.species of plasmodium that naturally infect wild rodents but can also be maintained in laboratory mice have long been used as model systems in which to study the biology of malaria parasites. several of these rodent parasites are now providing useful genomic comparisons to those species that cause malaria in humans. here we examined the phylogenetic relationships of 19 strains of rodent malaria parasites including four species native to african thicket rats (plasmodium berghei, plasmodium chabau ...200716765106
chloroquine efficacy in plasmodium berghei nk65-infected icr mice, with reference to the influence of initial parasite load and starting day of drug administration on the outcome of treatment.we examined whether the initial number of parasites inoculated and the starting day of medication post-infection influenced the antimalarial efficacy of chloroquine (cq) against plasmodium berghei nk65 infection in icr mice. male icr mice were inoculated intraperitoneally with 1 x 10(5), 1x10(6), 1 x 10(7), 1 x 10(8) p. berghei nk65-parasitized erythrocytes (prbc). in the treated group, all mice received an oral dose of 20 mg/kg of cq base for 4 days starting on day 0 after infection. from day 3 ...200616771206
substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery.the plasmodium falciparum cysteine peptidases fp-2 (falcipain-2) and fp-3 (falcipain-3), members of the papain-like cac1 family, are essential haemoglobinases and are therefore potential anti-malarial drug targets. to facilitate a rational drug discovery programme, in the current study we analysed the synthetic substrate and model inhibitor profiles of fp-2 and fp-3 as well as bp-2 (berghepain-2), an orthologue from the rodent parasite plasmodium berghei. with respect to substrate catalysis, fp- ...200616776649
anopheles gambiae immune responses to human and rodent plasmodium parasite species.transmission of malaria is dependent on the successful completion of the plasmodium lifecycle in the anopheles vector. major obstacles are encountered in the midgut tissue, where most parasites are killed by the mosquito's immune system. in the present study, dna microarray analyses have been used to compare anopheles gambiae responses to invasion of the midgut epithelium by the ookinete stage of the human pathogen plasmodium falciparum and the rodent experimental model pathogen p. berghei. inva ...200616789837
plasmodium berghei calcium-dependent protein kinase 3 is required for ookinete gliding motility and mosquito midgut invasion.apicomplexan parasites critically depend on a unique form of gliding motility to colonize their hosts and to invade cells. gliding requires different stage and species-specific transmembrane adhesins, which interact with an intracellular motor complex shared across parasite stages and species. how gliding is regulated by extracellular factors and intracellular signalling mechanisms is largely unknown, but current evidence suggests an important role for cytosolic calcium as a second messenger. st ...200616796674
protein disulfide isomerase assisted protein folding in malaria parasites.in eukaryotes, the formation of protein disulfide bonds among cysteine residues is mediated by protein disulfide isomerases and occurs in the highly oxidised environment of the endoplasmic reticulum. this process is poorly understood in malaria parasites. in this paper, we report the gene isolation, sequence and phylogenetic comparisons, protein structure and thioredoxin-domain analyses of nine protein disulfide isomerases-like molecules from five species of malaria parasites including plasmodiu ...200616806221
plasmodium berghei: in vitro and in vivo activity of dequalinium.bisquinoline compounds have exhibited remarkable activity in vitro and in vivo against plasmodium parasites by inhibition of heme detoxification. we have tested the ability of dequalinium 1,1'-(1,10-decanediyl)bis(4-amino-2-methylquinoline), a known antimicrobial agent, to inhibit beta-hematin synthesis using a non-emzymatic colorimetric assay and globin proteolysis by electrophoretic analysis (sds-page-15%). dequalinium was able to inhibit both processes in vitro with close correlation to a mur ...200716814285
different levels of immunogenicity of two strains of fowlpox virus as recombinant vaccine vectors eliciting t-cell responses in heterologous prime-boost vaccination strategies.the fp9 strain of f has been described as a more immunogenic recombinant vaccine vector than the webster fpv-m (fpw) strain (r. j. anderson et al., j. immunol. 172:3094-3100, 2004). this study expands the comparison to include two separate recombinant antigens and multiple, rather than single, independent viral clones derived from the two strains. dual-poxvirus heterologous prime-boost vaccination regimens using individual clones of recombinant fp9 or fpw in combination with recombinant modified ...200616829611
short report: role of type i/ii scavenger receptors in malarial infection in c57bl/6j mice.although it is well known that sr-a i/ii plays a significant role in host defense against bacterial and viral infection, the contribution of sr-a i/ii to protozoan infection is not well understood. thus, we examined the possible role of sr-a i/ii against murine malarial infection, such as plasmodium. berghei and p. yoelli, by using sr-a i/ii knockout mice with a c57bl/6j genetic background. when sr-a i/ii knockout mice were infected with p. berghei nk65 or p. yoelli 17x, their survival rates wer ...200616837728
exploration of a new type of antimalarial compounds based on febrifugine.febrifugine (1), a quinazoline alkaloid, isolated from dichroa febrifuga roots, shows powerful antimalarial activity against plasmodium falciparum. the use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. however, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. in this study, we synthesized a new series of febrifugine der ...200616854076
synthesis and antimalarial efficacy of aza-fused rhodacyanines in vitro and in the p. berghei mouse model.several aza-fused rhodacyanines were synthesized and assessed for their in vitro and in vivo antimalarial activities against plasmodium falciparum k1 and p. berghei. all synthetic compounds showed strong selective antimalarial in vitro activity. class ii azarhodacyanines, 3, consisting of four heterocyclic units, were found to display good parasitemia suppression and low acute toxicity in vivo. among them, 3c appeared to be the most effective at a dose of 20-25 mg kg(-1) day(-1) (ip).200616854088
toxicity evaluation of artesunate and artelinate in plasmodium berghei-infected and uninfected rats.a recent therapeutic index study in rats demonstrated that i.v. artesunate (as) is safer than artelinate (al). the present study of acute toxicity illustrated an ld(50) of 177 mg/kg and 488 mg/kg for al and as, respectively, following daily i.v. injection for 3 days in plasmodium berghei-infected rats. in uninfected rats, the ld(50) values were 116 mg/kg and 351 mg/kg after a single dose of al and as, respectively. this study showed vascular necrosis in 50% of the animals at 13.5 mg/kg al and at ...200716860356
matrix metalloproteinases, tissue inhibitors of mmps and tace in experimental cerebral malaria.cerebral malaria (cm) is a life-threatening disorder and a major medical problem in developing countries. it is caused by the sequestration of malaria-infected erythrocytes onto brain endothelia, followed by blood-brain barrier (bbb) damage and neurological deficit. in the present study, matrix metalloproteinases (mmps) were analysed in a mouse model of cm with plasmodium berghei anka. increased numbers of gelatinase b (mmp-9)-positive cells, which were also cd11b(+), were detected in the brain. ...200616865090
[cytoadherence in cerebral malaria as particular example of pathology in host--parasite system].cerebral malaria in man and in animals is the consequence of a cascade of events, involving the patological changes, leading to the amplification of the expression of the receptors for cytoadherence on brain capillary endothelial cells. sequestration is the process by which erytrocytes infected with the mature forms of the malaria parasite plasmodium falciparum disappear from circulation and accumulate within venules and capillaries of various organs and tissues. the molecular mechanism in seque ...200116886392
manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids.the merozoite stage of the malaria parasite that infects erythrocytes and causes the symptoms of the disease is initially formed inside host hepatocytes. however, the mechanism by which hepatic merozoites reach blood vessels (sinusoids) in the liver and escape the host immune system before invading erythrocytes remains unknown. here, we show that parasites induce the death and the detachment of their host hepatocytes, followed by the budding of parasite-filled vesicles (merosomes) into the sinus ...200616888102
regulation of sexual development of plasmodium by translational repression.translational repression of messenger rnas (mrnas) plays an important role in sexual differentiation and gametogenesis in multicellular eukaryotes. translational repression and mrna turnover were shown to influence stage-specific gene expression in the protozoan plasmodium. the ddx6-class rna helicase, dozi (development of zygote inhibited), is found in a complex with mrna species in cytoplasmic bodies of female, blood-stage gametocytes. these translationally repressed complexes are normally sto ...200616888139
quantitative isolation and in vivo imaging of malaria parasite liver stages.the liver stages of plasmodium, the causative agent of malaria, are the least explored forms in the parasite's life cycle despite their recognition as key vaccine and drug targets. in vivo experimental access to liver stages of human malaria parasites is practically prohibited and therefore rodent model malaria parasites have been used for in vivo studies. however, even in rodent models progress in the analysis of liver stages has been limited, mainly due to their low abundance and associated di ...200616890231
antiplasmodial activity of homalium letestui.the in vivo antiplasmodial activity of the ethanol root extract of homalium letestui used as a malaria remedy in southern nigeria was evaluated in plasmodium berghei berghei infected mice. homalium letestui root extract (500-1000 mg/kg/day) exhibited significant (p < 0.05) blood schizontocidal activities both in a 4-day early infection test and in an established infection with a considerable mean survival time comparable to that of the standard drug, chloroquine, 5 mg/kg/day. the root extract po ...200616906638
differential gene expression in the ookinete stage of the malaria parasite plasmodium berghei.plasmodium, the malaria parasite, undergoes a complex developmental program in its mosquito vector. the ookinete is the parasite form which invades the mosquito midgut and is an important stage for genetic mixing. to identify genes expressed during ookinete development and mosquito midgut invasion, purified zygotes and ookinetes of the rodent parasite plasmodium berghei were used to construct a suppression subtractive hybridization cdna library, enriched in sequences expressed in the ookinete st ...200616908078
in vitro and in vivo efficacy and in vitro metabolism of 1-phenyl-3-aryl-2-propen-1-ones against plasmodium falciparum.investigation of a series of 1-phenyl-3-aryl-2-propen-1-ones resulted in the identification of nine inhibitors with submicromolar efficacy against at least one plasmodium falciparum strain in vitro. these inhibitors were inactive when given orally in a plasmodium berghei infected mouse model. significant compound degradation occurred upon their exposure to a liver microsome preparation, suggesting metabolic instability may be responsible for the lack of activity in vivo.200616908136
infection by and protective immune responses against plasmodium berghei anka are not affected in macrophage scavenger receptors a deficient mice.scavenger receptors (srs) recognize endogenous molecules modified by pathological processes as well as components of diverse microorganisms. mice deficient for both sr-ai and ii are more susceptible to infections by a variety of bacterial and viral pathogens.200616914051
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