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new 4-aminoquinoline mannich base antimalarials. 1. effect of an alkyl substituent in the 5'-position of the 4'-hydroxyanilino side chain.a new series of 4-aminoquinoline mannich base derivatives have been synthesized, in which the 3'-diethylamino function of amodiaquine (aq) is replaced by a 3'-tert-butylamino group and an aliphatic hydrocarbon entity is incorporated into the 5'-position of the 4'-hydroxyanilino side chain. seven alkyl mannich base derivatives were screened and found to be active against both chloroquine-sensitive and -resistant strains of plasmodium falciparum in vitro. the propyl and isopropyl alkyl derivatives ...199910425085
morphological analysis of isolated rhoptries from plasmodium yoelii, p. berghei, and p. chabaudi merozoites. 199910425155
new type of febrifugine analogues, bearing a quinolizidine moiety, show potent antimalarial activity against plasmodium malaria parasite.febrifugine (1) and isofebrifugine (2), isolated from the roots of dichroa febrifuga lour. (chinese name: cháng shan), are active principles against malaria. adducts of 1 and 2 with acetone, df-1 (3) and df-2 (4), respectively, were obtained using silica gel and acetone. they showed high activity against p. falciparum malaria in vitro. compound 3 was found to be equally effective against p. berghei in vivo as the clinically used drug chloroquine, whereas 4 showed only 1/24 of the activity of 3. ...199910447961
plants showing antiplasmodial activity--from crude extracts to isolated compounds.the derivation of important antimalarial compounds started with the discovery of cinchona bark powder with wine. subsequently, post world war-i was a period of intensive work in maintaining such ethnobotanical records, in which the use of quinine has remained the drug of choice in malaria. after world war-ii new chemical techniques were used to fractionate and isolate, and also for structure determinations, which led to an ever increasing number of potential antiplasmodial compounds. recently ex ...199810448228
red cell selectivity in malaria: a study of multiple-infected erythrocytes.to characterize red cell susceptibility to invasion in malaria, a selectivity index (si) was calculated as the ratio of observed number of multiple-infected red cells to that expected from a random process (poisson distribution). in patients with falciparum malaria (n = 100) si decreased with increasing parasitaemia (p < 0.001), and correlated inversely with plasma lactate concentrations, chosen prospectively as a measure of disease severity (r = -0.36, p < 0.001). for parasitaemias < 5%, the si ...199910450440
t cell response in malaria pathogenesis: selective increase in t cells carrying the tcr v(beta)8 during experimental cerebral malaria.to characterize the t cells involved in the pathogenesis of cerebral malaria (cm) induced by infection with plasmodium berghei anka clone 1.49l (pba 1.49l), the occurrence of the disease was assessed in mice lacking t cells of either the alphabeta or gammadelta lineage (tcralphabeta(-/-) or tcrgammadelta(-/-)). tcrgammadelta(-/-) mice were susceptible to cm, whereas all tcralphabeta(-/-) mice were resistant, suggesting that t cells of the alphabeta lineage are important in the genesis of cm. the ...199910464176
up-regulation of cytokines in glomerulonephritis associated with murine malaria infection.malaria infections often cause glomerulonephritis (gn), and multiple factors have been implicated in the pathogenesis of glomerular injury. the role of cytokines in malaria associated glomerulonephritis has not been clearly defined. to study the importance of cytokines in malarial nephritis, we investigated the expression of tumour necrosis factor-alpha (tnf-alpha), interleukin-1alpha (il-1alpha), il-6, il-10 and granulocyte macrophage-colony stimulating factor (gm-csf) in kidneys acutely infect ...199910469263
metal chelators/antioxidants: approaches to protect erythrocytic oxidative stress injury during plasmodium berghei infection in mastomys coucha.desferal, n-acetyl penicillamine (metal chelators) and propylgallate, catechin, and reduced glutathione (antioxidants) suppressed the erythrocytic oxidative damage generated during plasmodium berghei infection in mastomys coucha. superoxide anion and lipid peroxide levels were increased and on the contrary, superoxide dismutase activity was noticeably decreased in the infected erythrocytes. metal chelators/antioxidant treatment to infected animals resulted in restoration of o(2)(-), lpo and sod ...199910479467
comparative evaluation of methods of malaria parasite density determination in blood samples from patients & experimental animals.three methods for the quantitation of parasitaemia in malaria were compared with the standard method for ascertaining the accuracy in patients, plasmodium berghei infected mice and p. knowlesi infected rhesus monkeys. technique i, where parasitaemia was calculated from the number of prbcs in 10,000 rbcs in thin blood film and the total rbc count of the host, was used as the standard. technique ii, where parasitaemia was calculated based on the number of prbcs per wbc and average total wbc count ...199910489738
plasmodium berghei: a new rat model for assessment of blood schizonticidal activity. 199910502471
plasmodium berghei: induction of aminopeptidase in malaria-resistant strain of anopheles gambiae. 199910502473
the a-domain and the thrombospondin-related motif of plasmodium falciparum trap are implicated in the invasion process of mosquito salivary glands.sporozoites from all plasmodium species analysed so far express the thrombospondin-related adhesive protein (trap), which contains two distinct adhesive domains. these domains share sequence and structural homology with von willebrand factor type a-domain and the type i repeat of human thrombospondin (tsp). increasing experimental evidence indicates that the adhesive domains bind to vertebrate host ligands and that trap is involved, through an as yet unknown mechanism, in the process of sporozoi ...199910508153
effects of plasmodium berghei infection on cytochromes p-450 2e1 and 3a2.metabolism and disposition of most drugs used to treat malaria are substantially altered in malaria infection. few data are available that specify effects of malaria infection on drug metabolism pathways in humans or animal model systems. in this report, studies were undertaken to determine the effect of plasmodium berghei infection on cytochrome p-450 (cyp450) 2e1 and 3a2-mediated metabolism and enzyme expression in rat liver microsomes. malaria infection (mal) resulted in significant decreases ...199910510746
iron acquisition by plasmodium spp. 199910511692
potentiation by febrifugine of host defense in mice against plasmodium berghei nk65.the effect of febrifugine, the main alkaloidal constituent of an antimalarial crude drug, dichroa febrifuga lour., on protective immunity in mice infected with erythrocytic stage plasmodium berghei nk65 was investigated. febrifugine was administered orally, at a dose of 1 mg/kg/day, to mice before and/or after they were infected intraperitoneally with 2 x 10(6) parasitized red blood cells. then, mortality and the levels of parasitemia and plasma no3- [a degradation product of nitric oxide (no)] ...199910535750
gene gun intradermal dna immunization followed by boosting with modified vaccinia virus ankara: enhanced cd8+ t cell immunogenicity and protective efficacy in the influenza and malaria models.in influenza and malaria, cd8+ t cells play an important role in protective immunity in mice. an immunization strategy consisting of dna priming followed by boosting with recombinant modified vaccinia virus ankara (mva) induces complete protection, associated with high levels of cd8+ t cells, against plasmodium berghei sporozoite challenge in mice. intradermal delivery of dna with a gene gun requires smaller amounts of dna than intramuscular injection, in order to induce similar levels of immune ...199910547421
ctrp is essential for mosquito infection by malaria ookinetes.the malaria parasite suffers severe population losses as it passes through its mosquito vector. contributing factors are the essential but highly constrained developmental transitions that the parasite undergoes in the mosquito midgut, combined with the invasion of the midgut epithelium by the malaria ookinete (recently described as a principal elicitor of the innate immune response in the plasmodium-infected insect). little is known about the molecular organization of these midgut-stage parasit ...199910562534
conservation of a gliding motility and cell invasion machinery in apicomplexan parasites.most apicomplexan parasites, including the human pathogens plasmodium, toxoplasma, and cryptosporidium, actively invade host cells and display gliding motility, both actions powered by parasite microfilaments. in plasmodium sporozoites, thrombospondin-related anonymous protein (trap), a member of a group of apicomplexan transmembrane proteins that have common adhesion domains, is necessary for gliding motility and infection of the vertebrate host. here, we provide genetic evidence that trap is d ...199910579715
targeted disruption of the plasmodium berghei ctrp gene reveals its essential role in malaria infection of the vector mosquito.ctrp (circumsporozoite protein and thrombospondin-related adhesive protein [trap]-related protein) of the rodent malaria parasite plasmodium berghei (pbctrp) makes up a protein family together with other apicomplexan proteins that are specifically expressed in the host-invasive stage 1. pbctrp is produced in the mosquito-invasive, or ookinete, stage and is a protein candidate for a role in ookinete adhesion and invasion of the mosquito midgut epithelium. to demonstrate involvement of pbctrp in t ...199910587361
mutations in the cytochrome b gene of plasmodium berghei conferring resistance to atovaquone.the molecular lesions which underlie the resistance of the malaria parasites to atovaquone, a coenzyme q analogue, were investigated. resistant clones of plasmodium berghei anka strain were isolated following prolonged propagation in mice in the presence of increasing doses of the drug, and their cytochrome b gene sequenced. three mutations were detected, t-c substitution at nt 431, g-a at nt 399 and g-t at nt 850, resulting in amino acid changes in the putative cytochrome b product at residues ...199910593174
a single-chain antibody fragment specific for the plasmodium berghei ookinete protein pbs21 confers transmission blockade in the mosquito midgut.mouse monoclonal antibody 13.1 (mab 13.1) directed against pbs21, a 21-kda sexual-stage surface protein of plasmodium berghei, is known to inhibit oocyst development from gametocytes and ookinetes in the mosquito midgut. to examine the properties and potential uses of a single-chain antibody fragment (scfv) for blocking transmission of malaria parasites to mosquitoes, we have cloned and sequenced the genes encoding variable regions of the immunoglobulin heavy and light chains (v(h) and v(l)) of ...199910593175
the aspartic proteinase from the rodent parasite plasmodium berghei as a potential model for plasmepsins from the human malaria parasite, plasmodium falciparum.the gene encoding an aspartic proteinase precursor (proplasmepsin) from the rodent malaria parasite plasmodium berghei has been cloned. recombinant p. berghei plasmepsin hydrolysed a synthetic peptide substrate and this cleavage was prevented by the general aspartic proteinase inhibitor, isovaleryl pepstatin and by ro40-4388, a lead compound for the inhibition of plasmepsins from the human malaria parasite plasmodium falciparum. southern blotting detected only one proplasmepsin gene in p. berghe ...199910601635
memory phenotype cd8(+) t cells persist in livers of mice protected against malaria by immunization with attenuated plasmodium berghei sporozoites.natural exposure to plasmodium parasites induces short-lived protective immunity. in contrast, exposure to radiation-attenuated sporozoites (gamma spz) promotes long-lasting protection that is in part mediated by cd8(+) t cells that target exoerythrocytic stage antigens. the mechanisms underlying the maintenance of long-lasting protection are currently unclear. the liver is a repository of plasmodium antigens and may support the development and / or homing of memory t cells. while activated cd8( ...199910602007
analysis of immune responses against t- and b-cell epitopes from plasmodium falciparum liver-stage antigen 1 in rodent malaria models and malaria-exposed human subjects in india.liver-stage antigen 1 (lsa-1) is a potential vaccine candidate against preerythrocytic stages of malaria. we report here the immunogenicity of linear synthetic constructs delineated as t(h)-cell determinants from the nonrepeat regions of plasmodium falciparum lsa-1 in murine models and human subjects from areas where malaria is endemic in rajasthan state, india. seven peptide constructs (ls1.1 to ls1.7) corresponding to predicted t-cell sites from both the n- and c-terminal regions and peptide l ...200010603380
a simple magnetic method for the purification of malarial pigment.using a simple magnetic separation apparatus, plasmodium berghei malarial pigment has been purified 200-fold in a single step. the technique exploits the paramagnetic properties of malarial pigment (hemozoin) and provides a simple and rapid method for the isolation of this material with high purification and yield.198410610436
characterization of the merozoite surface protein 4/5 gene of plasmodium berghei and plasmodium yoelii.the genes encoding merozoite surface protein 4/5 (msp4/5) from plasmodium berghei and plasmodium yoelii have been cloned and completely sequenced. comparisons of the predicted protein sequences with those of plasmodium chabaudi msp4/5 and plasmodium falciparum msp4 and msp5 show general structural similarities. all predicted proteins contain hydrophobic signal sequences, potential gpi attachment sequences and a single epidermal growth factor (egf)-like domain at the c-terminus. the amino acid se ...200010613706
the rodent malaria parasite plasmodium berghei does not contain a typical o-type small subunit ribosomal rna gene. 200010613710
in vivo antimalarial activities of quassia amara and quassia undulata plant extracts in mice.extracts obtained from two nigerian simaroubaceae plants, quassia amara l. and quassia undulata (giull and perr) d. dietr were screened for antimalarial properties using a total of six extracts. the plant extracts showed significant antimalarial activities in the 4 day suppressive in vivo antimalarial assay in mice inoculated with red blood cells parasitized with plasmodium berghei berghei. plant extracts were studied at 100 mg and 200 mg per kg body weight mouse per day, respectively. at a conc ...199910617067
role of icam-1 (cd54) in the development of murine cerebral malaria.in susceptible mouse strains, infection of mice with plasmodium berghei anka (pba) results in a lethal complication, cerebral malaria. cerebral malaria is due to the immune response induced by the parasite, which results in an increased production of tnf, known to increase the expression of adhesion molecules on the endothelia. to investigate the role of the adhesion molecule icam-1 (cd54), we infected wild-type (+/+) and icam-1-deficient (-/-) mice with pba. while +/+ mice died 6-8 days after i ...199910617927
novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether.ten novel, second-generation, fluorinated ether and ester analogues of the potent first-generation analogues artemether (4a) and arteether (4b) have been designed and synthesized. all of the compounds demonstrate high antimalarial potency in vitro against the chloroquine-sensitive hb3 and -resistant k1 strains of plasmodium falciparum. the most potent derivative 8 was 15 times more potent than artemisinin (2) against the hb3 strain of p. falciparum. in vivo, versus plasmodium berghei in the mous ...199910639291
molecular characterization of five serine protease genes cloned from anopheles gambiae hemolymph.we identified five new serine protease cdnas from the hemolymph of the malaria vector, anopheles gambiae. all five show sequence similarity to genes thought to be involved in vertebrate or invertebrate defense responses. sp14a, sp14d2 and sp22d demonstrate changes in transcript abundance in response to bacteria injections. sp14a and sp14d2, as well as the previously characterized sp14d1, are induced by infection with the malaria parasite, plasmodium berghei. these three proteases, along with sp1 ...200010646969
malaria-infected erythrocytes serve as biological standards to ensure reliable and consistent scoring of micronucleated erythrocytes by flow cytometry.a procedure for optimizing the configuration of flow cytometers for enumerating micronucleated erythrocytes is described. the method is based on the use of a biological model for micronucleated erythrocytes, the malaria parasite plasmodium berghei. p. berghei endows target cells of interest (erythrocytes) with a micronucleus-like dna content. unlike micronuclei, parasitized red blood cells have a homogenous dna content, and can be very prevalent in circulation. these characteristics make malaria ...200010648906
the effect of nitric oxide on the growth of plasmodium falciparum, p. chabaudi and p. berghei in vitro.protective immune mechanisms to the asexual erythrocytic stages of the malaria parasite plasmodium chabaudi as strain include antibody-independent mechanisms. nitric oxide (no) is produced during the infection and indirect evidence suggests that it can contribute to the antiparasitic mechanisms. we examined the effect of an no producer, s-nitroso-acetyl-penicillamine (snap), on the growth and survival in vitro of p. chabaudi as, p. berghei and p. falciparum. growth of the parasites was monitored ...200010652122
the chemotherapy of rodent malaria. lvi. studies on the development of resistance to natural and synthetic endoperoxides.chloroquine-sensitive plasmodium berghei n and chloroquine-resistant p. yoelii ssp. ns were exposed to selection pressure, in the '2% relapse technique', from artemisinin, artesunate, a bicyclic, synthetic endoperoxide ro 41-3823 (an analogue of arteflene) or fenozan b07, a synthetic 1,2,4-trioxane endoperoxide. whereas resistance against artemisinin did develop to a moderate level in both parasites, only a low level of resistance or none developed to the other compounds, and resistant parasites ...199910656034
plasmodium berghei in the white rat: severe malaria of pregnancy does not occur in the progeny of mothers infected during gestation. 199910656044
covalent binding of polyethylene glycol to the surface of red blood cells as detected and followed up by cell electrophoresis and rheological methods.cyanuric chloride activated polyethylene glycol (peg)-5000 was covalently coupled to murine and human red blood cells (pegylated rbc). our purpose was to camouflage rbc receptors, which is necessary for parasite invasion, a process essential to sustain parasitemia. cell electrophoretic mobility analysis (cem) of pegylated rbc distinguished a new population of cells bearing characteristic cem. pegylation of rbc also modified their rheological properties, which were documented by evaluation of cel ...200010675005
schizontocidal effects of oral artesunate on plasmodium berghei in mice and p knowlesi in monkeys.to study the blood schizontocidal effect of oral artesunate on p berghei in mice and p knowlesi in monkey.199910678113
a search for natural bioactive compounds in bolivia through a multidisciplinary approach. part i. evaluation of the antimalarial activity of plants used by the chacobo indians.thirty extracts of plants traditionally used by the chacobos, a native community living in the amazonian part of bolivia, were screened in vitro and/or in vivo for antimalarial activity. two of the four species designated as antimalarial, geissospermum laeve and maquira coriacea, displayed rather good activity, corroborating their traditional uses. however, they did show a rather high toxicity in vivo. among twelve species used to cure symptoms relevant to malaria, five showed good activity: apu ...200010687869
phenyl beta-methoxyacrylates: a new antimalarial pharmacophore.phenyl beta-methoxyacrylates, linked to an aromatic ring via an olefinic bridge, have been identified as novel, potentially inexpensive, antimalarial agents. the compounds are believed to exert their activity by inhibition of mitochondrial electron transport at the cytochrome bc(1) complex. a series of compounds have been synthesized to define structure-activity relationships affecting antimalarial activity. it was found that the beta-methoxyacrylate was required ortho to the linker and the opti ...200010691682
genome plasticity and sexual differentiation in plasmodium.spontaneous subtelomeric deletions of plasmodium chromosomes have been observed both in natural infections and in laboratory maintained parasites. in the latter case, functions dispensable for asexual parasite multiplication and encoded at the extremities of the chromosomes are easily lost. in particular, spontaneous subtelomeric deletions have been characterised which affect gametocytogenesis both in plasmodium berghei maintained in laboratory animals and in plasmodium falciparum propagated in ...199910697847
plasmodium falciparum cs c-terminal fragment: preclinical evaluation and phase i clinical studies.preclinical evaluation of synthetic peptides corresponding to the c-terminal regions of the circumsporozoite (cs) protein in various plasmodia showed that these preparations were immunogenic and safe upon injection in various animal models. additionally, the corresponding peptide from plasmodium falciparum was widely recognized by sera and pbl obtained from semi-immune adults living in malaria endemic areas. moreover, the cs c-terminal peptide derived from p. berghei conferred protection upon ch ...199910697896
the selectable marker human dihydrofolate reductase enables sequential genetic manipulation of the plasmodium berghei genome.genetic transformation of malaria parasites has been limited by the number of selectable markers available. for the rodent malaria parasite, plasmodium berghei, only a single selection marker has been at hand, utilising the dihydrofolate reductase-thymidylate synthase gene from either p. berghei or toxoplasma gondii to confer resistance to the anti-malarial drug pyrimethamine. here we report the use of the human dihydrofolate reductase (hdhfr) gene as a new selectable marker, which confers resis ...200010699250
reactive changes of retinal microglia during fatal murine cerebral malaria: effects of dexamethasone and experimental permeabilization of the blood-brain barrier.microglial activation and redistribution toward blood vessels are some of the earliest observable events occurring within the central nervous system (cns) during fatal murine cerebral malaria (fmcm). to investigate stimuli that might modulate microglial reactivity during fmcm we have performed two experimental manipulations and observed microglial responses in retinal whole mounts. first, to determine whether increased blood-brain barrier (bbb) permeability in the absence of the malaria parasite ...200010702421
analysis of a malaria sporozoite protein family required for gliding motility and cell invasion. 200010707054
the chemotherapy of rodent malaria. lvii. drug combinations to impede the selection of drug resistance, part 1: which model is appropriate?the principle has finally been accepted that, whenever possible, antimalarial drugs should be deployed in appropriate combinations in endemic areas, in order to minimize the inevitability that monotherapy will, probably sooner than later, select populations of drug-resistant parasites. which laboratory models can predict the combinations of old or novel compounds that are likely to be of practical value in minimizing this risk? very few relevant data on the use of plasmodium falciparum in vitro ...199910707103
enumeration of micronucleated reticulocytes in rat peripheral blood: a flow cytometric study.micronuclei (mn) are routinely enumerated in mouse peripheral blood to index genotoxicity. recent data from the collaborative study group for the micronucleus test (csgmt) [csgmt (the collaborative study group for the micronucleus test), evaluation of the rat micronucleus test with bone marrow and peripheral blood: summary of the 9th collaborative study by csgmt/jems mms, environ. mol. mutagen. 32 (1998) 84-100] suggest that rat peripheral blood may also be appropriate for the enumeration of mn, ...200010708974
nitric oxide in murine malaria: divergent roles in blood and brain suggested by voltametric measures. 199910717761
the chemotherapy of rodent malaria. lviii. drug combinations to impede the selection of drug resistance, part. 2: the new generation--artemisinin or artesunate with long-acting blood schizontocides.the search for combinations of antimalarial drugs that will impede the selection of drug resistance, especially in plasmodium falciparum, is currently focused on the use of a member of the artemisinin family, with a short half-life, in association with a relatively long-acting blood schizontocide. experiments with such 'third-generation' combinations, in mice infected either with chloroquine-sensitive p. berghei or p. chabaudi, or chloroquine-resistant p. yoelii ssp. ns, have produced interestin ...200010723521
acidocalcisomes and a vacuolar h+-pyrophosphatase in malaria parasites.plasmodium berghei trophozoites were loaded with the fluorescent calcium indicator, fura-2 acetoxymethyl ester, to measure their intracellular ca(2+) concentration ([ca(2+)](i)). [ca(2+)](i) was increased in the presence of the sarcoplasmic/endoplasmic reticulum ca(2+)-atpase inhibitor, thapsigargin. trophozoites also possess a significant amount of ca(2+) stored in an acidic compartment. this was indicated by: (1) the increase in [ca(2+)](i) induced by bafilomycin a(1), nigericin, monensin, or ...200010727425
oxidative phosphorylation, ca(2+) transport, and fatty acid-induced uncoupling in malaria parasites mitochondria.respiration, oxidative phosphorylation, calcium uptake, and the mitochondrial membrane potential of trophozoites of the malaria parasite plasmodium berghei were assayed in situ after permeabilization with digitonin. adp promoted an oligomycin-sensitive transition from resting to phosphorylating respiration. respiration was sensitive to antimycin a and cyanide. the capacity of trophozoites to sustain oxidative phosphorylation was additionally supported by the detection of an oligomycin-sensitive ...200010734123
the mosquito transmission of malaria: the effects of atovaquone-proguanil (malarone) and chloroquine.despite its recognized importance, the prevention of patients with malaria from continuing to infect mosquitoes after treatment is not always achieved in practice. an inevitable consequence of the prolonged life-span and relative metabolic stasis of the mature gametocytes of plasmodium falciparum is that they are not cleared by most antimalarials, and few antimalarials block infection in the mosquito vector. previous research on the constituents of malarone, a new 'combined antimalarial', sugges ...200010748906
neutrophils play a critical role in the pathogenesis of experimental cerebral malaria.the role of neutrophils in experimental cerebral malaria (ecm) is not well understood. in this study we used a moab, rb6-8c5, to deplete the peripheral neutrophils of ecm-susceptible cba/nslc mice 24 h before plasmodium berghei anka (pba) infection. we found that early neutrophil depletion prevented the development of ecm and dramatically decreased the sequestration of monocytes and microhaemorrhage in the brain. the depletion of neutrophils also down-regulated tumour necrosis factor-alpha, inte ...200010759773
molecular characterization of a prophenoloxidase cdna from the malaria mosquito anopheles stephensi.some refractory anopheline mosquitoes are capable of killing plasmodium, the causative agent of malaria, by melanotic encapsulation of invading ookinetes. phenoloxidase (po) appears to be involved in the formation of melanin and toxic metabolites in the surrounding capsule. a cdna encoding anopheles stephensi prophenoloxidase (ans-propo) was isolated from a cdna library screened with an amplimer produced by reverse transcriptase polymerase chain reaction (rt-pcr) with degenerate primers designed ...200010762420
scorpine, an anti-malaria and anti-bacterial agent purified from scorpion venom.a novel peptide, scorpine, was isolated from the venom of the scorpion pandinus imperator, with anti-bacterial activity and a potent inhibitory effect on the ookinete (ed(50) 0.7 microm) and gamete (ed(50) 10 microm) stages of plasmodium berghei development. it has 75 amino acids, three disulfide bridges with a molecular mass of 8350 da. scorpine has a unique amino acid sequence, similar only to some cecropins in its n-terminal segment and to some defensins in its c-terminal region. its gene was ...200010767415
direct immunization of malaria dna vaccine into the liver by gene gun protects against lethal challenge of plasmodium berghei sporozoite.the liver is the first target organ for malaria parasites immediately after the bite of an infected mosquito. we studied local immunization of malaria dna vaccines at the site of the liver using a gene gun as a useful tool for in vivo transfection of foreign genes. a malaria dna vaccine consisting of the plasmodium berghei circumsporozoite protein (pbcsp) gene plus the mouse il-12 gene was bombarded directly by a gene gun into mouse liver once or into the skin twice. a marked protective effect w ...200010777689
isolation of antigen from the circulating immune complex in mice infected with plasmodium berghei.circulating immune complex (cic) is known to play a role in pathological glomerular alterations in malaria. however, the nature of the antigens comprising the cic is still not fully understood. we report here the isolation of the antigen in cic and its localisation in mice infected with plasmodium berghei nk65. the antigen was successfully isolated from cic extracted from the blood of mice infected with p. berghei, by using c1q-coated microplates. the molecular mass of the antigen separated from ...200010779574
optimisation of flow cytometric measurement of parasitaemia in plasmodium-infected mice.mouse malaria is often used as a model for drug testing. the results of drug trials are monitored by tedious (and consequently, sometimes inaccurate) microscopic counting of blood smears, or by flow cytometry. we suggest an improved, accurate and time-saving flow cytometric method for determination of parasitaemias in mice infected with plasmodium vinckei petteri or plasmodium berghei. the method involves collection of drops of blood from the tail vein, fixation, storage, permeabilisation, stain ...200010779580
synthesis and antimalarial activity of artemisinin derivatives containing an amino group.in search of water-soluble artemisinin derivatives that are more stable than sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5) were synthesized and tested in mice. all products tested (except 5a and 5b) are the beta isomers. these basic compounds combined with organic acids (oxalic acid, maleic acid, etc. ) to yield the corresponding salts. generally, the maleates have better solubility in water than the corresponding oxalates. the aqueous solutions of these salts ...200010780920
cutting edge: the igg response to the circumsporozoite protein is mhc class ii-dependent and cd1d-independent: exploring the role of gpis in nk t cell activation and antimalarial responses.biochemical analysis has suggested that self gpi anchors are the main natural ligand associated with mouse cd1d molecules. a recent study reported that valpha14+ nk t cells responded to self as well as foreign (parasite-derived) gpis in a cd1d-dependent manner. it further reported that the igg response to the plasmodium berghei malarial circumsporozoite (cs) protein was severely impaired in cd1d-deficient mice, leading to a model whereby nk t cells, upon recognition of cd1d molecules presenting ...200010799852
the role of intrahepatic lymphocytes in mediating protective immunity induced by attenuated plasmodium berghei sporozoites.exposure to irradiated plasmodium sporozoites (gamma-spz) results in protection against malaria. like infectious spz, gamma-spz colonize hepatocytes to undergo maturation. disruption of liver stage development prevents the generation of protection, which appears, therefore, to depend on liver stage antigens. although some mechanisms of protection have been identified, they do not include a role for intrahepatic mononuclear cells (ihmc). we demonstrated that p. berghei gamma-spz-immune murine ihm ...200010807512
[time course of serum nuclease activity in mice infected with plasmodium berghei].the present paper shows that murine serum nuclease activity increases following p.berghei infection. dna activity begins increasing just 48 hours after infection. following 78 hours, it achieves the maximum, by exceeding the baseline level by 6 times. then dna activity starts decreasing and following 94 hours after infection it is just thrice higher than the baseline. serum rna activity shows only 30% increases 72 hours after infection and returns to the baseline following 94 hours. microscopic ...200010808713
immune responses to chloroquine--sensitive and resistant populations of plasmodium berghei in mice.in order to elucidate the role of the host as a factor in the spread of chloroquine resistance, a study of the host's immune responses in chloroquine resistant (cqr) and chloroquine sensitive (cqs) plasmodial infections is essential. course of the infection and the nature of immune responses in mice infected with chloroquine resistant (r) and chloroquine sensitive (s) strains of plasmodium berghei were compared. crude parasite antigen activated t cells from both the groups of mice (r and s) and ...199910810580
role of macrophages in experimental malaria: vi--effect of freund's complete adjuvant in plasmodium berghei infected mice.freund's complete adjuvant (fca) treated group of mice when challenged with lethal plasmodium berghei showed increased survival value; survival period (sp) and median survival day (msd) compared to their respective control groups. k values were affected and mean parasitaemia during infection period was lower than that of control. in general survival rate after 35 days of infection was 10.5% in fca recipients. the survival rate in a particular group of animals which received 0.2 ml fca 3 days bef ...199910810600
in vivo antimalarial activity of the beta-carboline alkaloid manzamine a.manzamine a, a beta-carboline alkaloid present in several marine sponge species, inhibits the growth of the rodent malaria parasite plasmodium berghei in vivo. more than 90% of the asexual erythrocytic stages of p. berghei were inhibited after a single intraperitoneal injection of manzamine a into infected mice. a remarkable aspect of manzamine a treatment is its ability to prolong the survival of highly parasitemic mice, with 40% recovery 60 days after a single injection. oral administration of ...200010817722
divergence of noncoding sequences and of insertions encoding nonglobular domains at a genomic region well conserved in plasmodia.to identify conserved features in the rapidly diverging portions of a well-conserved locus, completely sequenced in plasmodium falciparum and plasmodium berghei, a computational method based on recurrence analysis was exploited. at the level of the genomic sequence, in both species, introns and intergenic sequences-though subject to rapid diversification-do not drift without constraints, but rather coevolve, in the sense that they maintain not only an at-rich base composition, but also a consist ...200010824091
the intraperitoneal plasmodium berghei-pasteur infection of swiss mice is not a system that is able to detect the antiplasmodial activity in the pothomorphe plant extracts that are used as antimalarials in brazilian endemic areas.the antimalarial activity of the hexane and methanol extracts derived from the brazilian plants pothomorphe peltata and pothomorphe umbellata-whose leaves are popularly employed in medicinal folk remedies for the treatment of malaria-was assessed through in vivo tests with the peters method. the extracts were delivered to plasmodium berghei-infected mice via the oral or the subcutaneous route. a suppressive effect on the parasitemia seemed to be evident when data regarding the intraperitoneal in ...200010831392
plasmodium berghei: the antimalarial activity of albendazole in rats is mediated via effects on the hematopoietic system. 200010831394
anti-malarial effect of histone deacetylation inhibitors and mammalian tumour cytodifferentiating agents.the histones of plasmodium falciparum represent a potential new target for anti-malarial compounds. a naturally occurring compound, apicidin, has recently been shown to inhibit the in vitro growth of p. falciparum. apicidin was shown to hyperacetylate histones, suggesting that its mode of action is through histone deacetylase inhibition. we have tested the ability of known histone deacetylase inhibitors, mammalian tumour suppressor compounds, and cytodifferentiating agents to inhibit the in vitr ...200010856511
delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice.we explored the role of urokinase and tissue-type plasminogen activators (upa and tpa), as well as the upa receptor (upar; cd87) in mouse severe malaria (sm), using genetically deficient (-/-) mice. the mortality resulting from plasmodium berghei anka infection was delayed in upa(-/-) and upar(-/-) mice but was similar to that of the wild type (+/+) in tpa(-/-) mice. parasitemia levels were similar in upa(-/-), upar(-/-), and +/+ mice. production of tumor necrosis factor, as judged from the plas ...200010858190
plasmodium berghei: cerebral malaria in cba mice is not clearly related to plasma tnf levels or intensity of histopathological changes.plasmodium berghei anka infection in cba/j mice leads to the development of cerebral malaria (cm) that kills 80-90% of the animals in 6-9 days. this model has been used to study the pathogenesis of cm, which is a major cause of morbidity and mortality in plasmodium falciparum-infected individuals. the role of cytokines in the induction of cm in the murine model has been well documented, but most studies have been restricted to the peak of neurological manifestations. here we used a sequential ap ...200010864512
flow cytometry assay for counting micronucleated erythrocytes: development process.development of any new assay proceeds in several phases. when an assay is intended for regular use to support regulatory decision-making, there are significant additional stages in the development process beyond the initial description of the method. in this paper we discuss some of the studies related to the development of a flow cytometric method for counting micronuclei in rodent erythrocytes. studies related to fixation methods and conditions, standardization of dna staining, and antibody st ...200010873482
determination of mosquito bloodmeal ph in situ by ion-selective microelectrode measurement: implications for the regulation of malarial gametogenesis.malarial gametocytes circulate in the peripheral blood of the vertebrate host as developmentally arrested intra-erythrocytic cells, which only resume development into gametes when ingested into the bloodmeal of the female mosquito vector. the ensuing development encompasses sexual reproduction and mediates parasite transmission to the insect. in vitro the induction of gametogenesis requires a drop in temperature and either a ph increase from physiological blood ph (ca ph 7.4) to about ph 8.0, or ...200010874717
experimental erythrocytic malaria infection induces elevated serum amyloid p production in mice.experimental blood-stage malaria infection of nih mice was observed to induce an acute phase response (apr). infection of mice with either p. chabaudi, p. vinckei (both non-lethal) or p. berghei (lethal infection) resulted in elevated serum amyloid p (sap) production, the major acute phase protein in mice. peak production occurred at the peak of the parasitaemia (approximately day 10 post infection). sap isolated from the serum of p. chabaudi infected mice was shown to inhibit the growth of intr ...200010880833
characterization of a differential immunoscreen epitope of plasmodium falciparum using combinatorial agents.a differential serological screening of a lambdagt11 cdna expression library has identified several clones, which react exclusively to sera samples from persons clinically immune to malaria but not to acute malaria patient sera. one such clone, ipf9, has a 315-bp cdna insert, which was found to be conserved in different strains of the human and rodent malarial parasite plasmodium falciparum and plasmodium berghei, respectively. the induced expression product of ipf9 was used to generate polyclon ...200010886717
synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes.sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane sar and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (wr 148999). the tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in h(2)so(4)/ch(3)cn or by ozonolysis of the corresponding cyclohexanone methyl oximes. those tetraoxanes with alkyl substituents ...200010893313
involvement of ifn-gamma receptor-medicated signaling in pathology and anti-malarial immunity induced by plasmodium berghei infection.ifn-gamma has been implicated in the pathogenesis of experimental cerebral malaria (ecm). we have used mice lacking the alpha chain of the ifn-gamma receptor (ko mice) to define its role in the pathogenesis of ecm. infected ko mice did not develop ecm and showed no leukocyte or parasite sequestration in the brain, and no hemorrhages. the resistance of ko mice to ecm was associated with the absence of any increases of tnf-alpha and icam-1 proteins in the brain, which are both essential for ecm. w ...200010898501
alpha -galactosylceramide-activated valpha 14 natural killer t cells mediate protection against murine malaria.natural killer t (nkt) cells are a unique population of lymphocytes that coexpress a semiinvariant t cell and natural killer cell receptors, which are particularly abundant in the liver. to investigate the possible effect of these cells on the development of the liver stages of malaria parasites, a glycolipid, alpha-galactosylceramide (alpha-galcer), known to selectively activate valpha14 nkt cells in the context of cd1d molecules, was administered to sporozoite-inoculated mice. the administrati ...200010900007
antiplasmodial, analgesic, and anti-inflammatory activities of the aqueous extract of the stem bark of erythrina senegalensis.the in vivo antiplasmodial, analgesic and anti-inflammatory properties of erythrina senegalensis, an ornamental plant commonly used in northern nigeria for the treatment of fevers, was evaluated. aqueous extracts of the stem bark of the plant was used for the study. the in vivo antiplasmodial activity of the aqueous extract against plasmodium berghei was assessed using the suppressive and curative test procedures. analgesic activity was assessed using the acetic acid (0.75%v/v) induced abdominal ...200010904174
effects of interruption of apicoplast function on malaria infection, development, and transmission.a chloroplast-like organelle is present in many species of the apicomplexa phylum. we have previously demonstrated that the plastid organelle of plasmodium faciparum is essential to the survival of the blood-stage malaria parasite in culture. one known function of the plastid organelle in another apicomplexan, toxoplasma gondii, involves the formation of the parasitophorous vacuole. the effects of interruption of plastid function on sporozoites and sexual-stage parasites have not been investigat ...200010924753
essential role of cd8 palmitoylation in cd8 coreceptor function.to investigate the molecular basis that makes heterodimeric cd8alphabeta a more efficient coreceptor than homodimeric cd8alphaalpha, we used various cd8 transfectants of t1.4 t cell hybridomas, which are specific for h-2kd, and a photoreactive derivative of the plasmodium berghei circumsporozoite peptide pbcs 252-260 (syipsaeki). we demonstrate that cd8 is palmitoylated at the cytoplasmic tail of cd8beta and that this allows partitioning of cd8alphabeta, but not of cd8alphaalpha, in lipid rafts. ...200010925291
import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target.the parasite plasmodium berghei imports the enzyme delta-aminolevulinate dehydratase (alad), and perhaps the subsequent enzymes of the pathway from the host red blood cell to sustain heme synthesis. here we have studied the mechanism of this import. a 65-kda protein on the p. berghei membrane specifically bound to mouse red blood cell alad, and a 93-amino-acid fragment (alad-deltanc) of the host erythrocyte alad was able to compete with the full-length enzyme for binding to the p. berghei membra ...200010932227
tissue distribution of indoleamine 2,3-dioxygenase in normal and malaria-infected tissue.an immunohistochemical method was developed, using a polyclonal antibody, to detect the enzyme indoleamine 2,3-dioxygenase (ido) in normal and malaria-infected tissue. plasmodium berghei anka, a cerebral malaria (cm) model, and p. berghei k173, a non-cerebral malaria (ncm) model, were used. it was found that vascular endothelial cells were the primary site of ido expression in both models of malaria infection and that this response was systemic, with the vascular endothelium of brain, heart, lun ...200010939286
dichloroacetate (dca) reduces brain lactate but increases brain glutamine in experimental cerebral malaria: a 1h-nmr study.recent findings that levels of brain lactate and alanine were elevated in murine cerebral malaria led us to investigate the effect of dichloroacetate (dca; 60 mg/kg), an activator of pyruvate dehydrogenase, on the levels of brain metabolites, and on the survival of mice infected with plasmodium berghei anka which normally causes lethal cerebral malaria. dca significantly reduced brain lactate and alanine levels when administered to infected mice, had no effect on the tca cycle-related metabolite ...200010939296
immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain microvasculature.a murine model that closely resembles human cerebral malaria is presented, in which characteristic features of parasite sequestration and inflammation in the brain are clearly demonstrable. "young" (balb/c x c57bl/6)f(1) mice infected with plasmodium berghei (anka) developed typical neurological symptoms 7 to 8 days later and then died, although their parasitemias were below 20%. older animals were less susceptible. immunohistopathology and ultrastructure demonstrated that neurological symptoms ...200010948166
morphine modulation of plasmodial-antigens-induced colony-stimulating factors production by macrophages.morphine abuse is known to cause immunosuppression and enhanced host susceptibility to malaria. we studied the effect of morphine on the plasmodium berghei total-parasite-antigens soluble in culture medium (p.b.sa)-induced production of colony-stimulating factors (csfs) by mouse peritoneal macrophages, in vitro. morphine exerted a concentration-dependent biphasic modulatory effect; at 1 x 10(-4)-1 x 10 x 10(-6) m it slightly inhibited, whereas at 1 x 10(-8)-1 x 10(-10) m it augmented the product ...200010954037
differential interleukin-10 expression in interferon regulatory factor-1 deficient mice during plasmodium berghei blood-stage infection.mice deficient of functional interferon regulatory factor-1 (irf-1-/-) by targeted gene disruption infected with a lethal murine malaria strain, plasmodium berghei anka survived longer than its wild-type littermates despite the inability to induce appreciable amounts of interferon-gamma (ifn-gamma) and nitric oxide. in addition, infected irf-1-/- mice displayed less organ injury with reduced necrosis and inflammation. both wild-type and irf-1-/- mice treated with exogenous interleukin-12 (il-12) ...200010972849
inhibition of the mosquito transmission of plasmodium berghei by malarone (atovaquone-proguanil).sera from patients treated with atovaquone-proguanil (malarone) have previously been shown to inhibit the mosquito transmission of plasmodium falciparum, though the inhibition was not complete and the effect declined 2 weeks after treatment. in marked contrast, the inhibition of transmission of p. berghei by human sera (fed to mosquitoes, with p. berghei gametocytes, via membrane feeders) from volunteers treated with atovaquone-proguanil was total up to day 28 post-treatment and still very signi ...200010983555
distinct roles for pbs21 and pbs25 in the in vitro ookinete to oocyst transformation of plasmodium berghei.we have developed an in vitro culture system for early sporogonic stages of plasmodium berghei, which can be used to study developmental events normally taking place in the midgut of an infected mosquito. these include penetration of insect cells by the mature ookinete, transformation into oocysts and the early development of the latter, sustained through several rounds of nuclear division. the system, based upon co-culture of enriched ookinetes with several established insect cell lines, was us ...200010984433
targeted terminal deletions as a tool for functional genomics studies in plasmodium.we describe a transfection system that induces terminal deletions at specific chromosome ends in malaria parasites using a linear construct containing telomeric repeats at one end and plasmodial sequences able to drive homologous recombination at the other. a site-specific deletion was generated at one extremity of chromosome 5 of plasmodium berghei, which was stably maintained in the parasite population selected after transfection. the telomeric repeat array introduced with the construct reache ...200010984459
characterisation and expression of pbs25, a sexual and sporogonic stage specific protein of plasmodium berghei.following gametogenesis and fertilisation in the bloodmeal within the mosquito midgut, the newly formed zygotes of the malaria parasite develop into motile invasive ookinetes. during this development, surface molecules are synthesised de novo including molecules of 21-28 kda from the zygote-ookinete stages. an antiserum recognising a 26 kda protein of plasmodium berghei was used to clone the corresponding gene from a cdna library, which was shown to be identical to the reported pbs25 gene sequen ...200010989152
hematin polymerization assay as a high-throughput screen for identification of new antimalarial pharmacophores.hematin polymerization is a parasite-specific process that enables the detoxification of heme following its release in the lysosomal digestive vacuole during hemoglobin degradation, and represents both an essential and a unique pharmacological drug target. we have developed a high-throughput in vitro microassay of hematin polymerization based on the detection of (14)c-labeled hematin incorporated into polymeric hemozoin (malaria pigment). the assay uses 96-well filtration microplates and require ...200010991837
genetic vaccination against malaria infection by intradermal and epidermal injections of a plasmid containing the gene encoding the plasmodium berghei circumsporozoite protein.the circumsporozoite protein (csp) from the surface of sporozoite stage plasmodium sp. malaria parasites is among the most important of the malaria vaccine candidates. gene gun injection of genetic vaccines encoding plasmodium berghei csp induces a significant protective effect against sporozoite challenge; however, intramuscular injection does not. in the present study we compared the immune responses and protective effects induced by p. berghei csp genetic vaccines delivered intradermally with ...200010992502
[genetic approach to the study of the sporogonic cycle in plasmodium].the development of transformation and mutagenesis techniques of the two species of plasmodium most studied--plasmodium falciparum (human parasite) and plasmodium berghei (rodent parasite)--opens new perspectives for the molecular study on the parasite sporogonic cycle in the insect vector. the parasite's stages that can be genetically transformed (the asexual erythrocytic stages) and gametocytes. the function of proteins coded by genes present in single copy in the genome can thus be studied aft ...199911000961
the synthetic, oxidized c-terminal fragment of the plasmodium berghei circumsporozoite protein elicits a high protective response.a polypeptide of 69 amino acids (pbcs 242-310) encompassing the c-terminal region of the circumsporozoite protein of plasmodium berghei (pbcs) was generated using solid-phase peptide synthesis. the immunological and protective properties of peptide pbcs 242-310 were studied in balb/c mice (h-2d). two subcutaneous injections, in the presence of ifa at the base of the tail, generated (i) high titers of anti-peptide antibodies which also recognized the native p. berghei cs protein, (ii) cytolytic t ...200011009102
oxygenated chalcones and bischalcones as potential antimalarial agents.oxygenated chalcones (3a,b) and bischalcones (4a-j) have been synthesized and evaluated for antimalarial activity against chloroquine sensitive and resistant strains of plasmodium berghei in mice. some of the screened compounds, 3a, 4c, 4e, 4f and 4i, have shown significant activity at 100 mg/kg dose against sensitive strain.200011012019
the roles of the glycosylphosphatidylinositol anchor on the production and immunogenicity of recombinant ookinete surface antigen pbs21 of plasmodium berghei when prepared in a baculovirus expression system.malarial ookinetes express an immunodominant surface protein (p28) that is a priority candidate for the development of transmission-blocking vaccines. the full length p28 gene from plasmodium berghei [pbs21(1-213)] and a deletion construct [pbs21(1-188)] encoding a protein that lacks the 25 c-terminal amino acids, including the glycosylphosphatidylinositol (gpi) anchor signal, were expressed in insect cells using baculovirus vectors. pbs21(1-213) protein is strongly hydrophobic, found in the cyt ...200011012975
effects of endotoxin and dexamethasone on cerebral malaria in mice.cba/t6 and dba/2j mice inoculated with plasmodium berghei anka (pba) develop cerebral involvement 6-8 days post-inoculation, from which the cba mice almost invariably die and the dba mice recover. dexamethasone (dxm; 80 mg/kg) given to inoculated cba mice twice, on day 3 and again within 48 h, reduced the cerebral symptoms and prevented death from cerebral malaria. plasma tumour necrosis factor (tnf) levels, which increased at the time of the cerebral symptoms, were also reduced in these dxm-tre ...199511023408
a search for natural bioactive compounds in bolivia through a multidisciplinary approach. part iv. is a new haem polymerisation inhibition test pertinent for the detection of antimalarial natural products?the search for new antimalarial agents in plant crude extracts using traditional screening tests is time-consuming and expensive. new in vitro alternative techniques, based on specific metabolic or enzymatic process, have recently been developed to circumvent testing of antimalarial activity in parasite culture. the haem polymerisation inhibition test (hpia) was proposed as a possible routine in vitro assay for the detection of antimalarial activity in natural products. a total of 178 plant extr ...200011025165
some in vitro invasion inhibition of red cells by in vivo nonprotective anti-ldh antibodies of plasmodium berghei.in plasmodium berghei, sephadex g-200 purified lactate dehydrogenase (ldh) fraction immunized mice did not exhibit protection when challenged with 1 x 10(6) p. berghei-parasitized erythrocytes. however, ldh immunized mice seroconverted and showed an antibody titre of 1:2048 by indirect haemagglutination (iha) and 1:160 by indirect fluorescent antibody (ifa) assays. fluorescence was distributed evenly on p. berghei-parasitized red cells showing no specific location of parasite ldh. anti-ldh antib ...200011048428
anti-malarial activity of leaf-extract of hydrangea macrophylla, a common japanese plant.to find a new anti-malarial medicine derived from natural resources, we examined the leaves of 13 common japanese plants in vitro. among them, a leaf-extract of hydrangea macrophylla, a common japanese flower, inhibited the parasitic growth of plasmodium falciparum. the ic50 of hydrangea macrophylla leaf extract to plasmodium falciparum was 0.18 microg/ml. the ic50 to nih 3t3-3 cells, from a normal mouse cell line, was 7.2 microg/ml. thus, selective toxicity was 40. for the in vivo test, we inoc ...200011061572
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