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influence of paclitaxel on parasitemia and survival of plasmodium berghei infected mice.paclitaxel triggers suicidal erythrocyte death or eryptosis, characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage. eryptosis of infected erythrocytes may delay development of parasitemia and thus favourably influence the course of malaria. the present study explored whether paclitaxel influences in vitro parasite growth and eryptosis of plasmodium falciparum infected human erythrocytes and in vivo parasitemia and survival of plasmodium berghei infected mi ...200919255513
glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study.cerebral malaria (cm) is associated with high mortality and morbidity caused by a high rate of transient or persistent neurological sequelae. studies on immunomodulatory and neuroprotective drugs as ancillary treatment in murine cm indicate promising potential. the current study was conducted to evaluate the efficacy of glatiramer acetate (ga), an immunomodulatory drug approved for the treatment of relapsing remitting multiple sclerosis, in preventing the death of c57bl/6j mice infected with pla ...200919250545
polymeric linear peptide chimeric vaccine-induced antimalaria immunity is associated with enhanced in vitro antigen loading.immunization of mice with plasmodium berghei or plasmodium yoelii synthetic linear peptide chimeras (lpcs) based on the circumsporozoite protein protects against experimental challenge with viable sporozoites. the immunogenicity of lpcs is significantly enhanced by spontaneous polymerization. to better understand the antigenic properties of polymeric antimalarial peptides, we studied the immune responses elicited in mice immunized with a polymer or a monomer of a linear peptide construct specifi ...200919237530
variant-specific immunity to plasmodium berghei in pregnant mice.we have investigated the immunological basis of pregnancy-related plasmodium berghei recrudescence in immune mice with substantial preexisting immunity. specifically, we examined the relevance of this experimental model to the study of pregnancy-associated malaria (pam) caused by p. falciparum in women with substantial preexisting protective immunity. we used mice with immunity induced prior to pregnancy and employed flow cytometry to assess their levels of immunoglobulin g (igg) recognizing ant ...200919237516
primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the n-terminus as potential antimalarial prodrugs.primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the n-terminus were synthesized and evaluated as potential transmission-blocking antimalarial prodrugs. all compounds were hydrolyzed to the parent dipeptide derivative of primaquine in neutral and basic solutions, with half lives ranging from 0.7 to 31 h at 37 degrees c, depending on the nature of the substituents present in the imidazolidin-4-one moiety and in the c-terminal amino acid directly coupled to primaquine. the ...200919232784
the role of nitric oxide and its up/downstream molecules in malaria: cytotoxic or preventive?the current study investigated the involvement of nitric oxide (no) and related molecules in malaria target organs of outbred mf1 mice during lethal plasmodium berghei and non-lethal p. c. chabaudi infections, in order to evaluate whether changes in no production are beneficial or detrimental to the host. a number of methods have been applied to test this hypothesis, including griess microassay, electrochemical assay, rt-pcr and western blot. the results show that reactive nitrogen intermediate ...200319230570
molecular biology and biochemistry of malarial parasite pyrimidine biosynthetic pathway.metabolic pathways in the malarial parasite are markedly different from the host, eg, hemoglobin, fatty acids, folate and nucleic acids. understanding of metabolic function will illuminate new chemotherapeutic targets for drug development, including the identification of target(s) for drugs in current use. the parasite-contained pyrimidine biosynthetic pathway is essential for growth and development in the human host. plasmodium falciparum carbonic anhydrase, producing hco3- as a pyrimidine prec ...200319230569
the glutathione biosynthetic pathway of plasmodium is essential for mosquito transmission.infection of red blood cells (rbc) subjects the malaria parasite to oxidative stress. therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. plasmodium spp. have thioredoxin and glutathione (gsh) systems that are thought to play a major role as antioxidants during blood stage infection. in this report, we analyzed a critical component of the gsh biosynthesis pathway using reverse genetics. plasmodium berghei parasites lacking expression of g ...200919229315
major surface glycoproteins of insect forms of trypanosoma brucei are not essential for cyclical transmission by tsetse.procyclic forms of trypanosoma brucei reside in the midgut of tsetse flies where they are covered by several million copies of glycosylphosphatidylinositol-anchored proteins known as procyclins. it has been proposed that procyclins protect parasites against proteases and/or participate in tropism, directing them from the midgut to the salivary glands. there are four different procyclin genes, each subject to elaborate levels of regulation. to determine if procyclins are essential for survival an ...200919223969
novel inhibitor of plasmodium histone deacetylase that cures p. berghei-infected mice.histone deacetylases (hdac) are potential targets for the development of new antimalarial drugs. the growth of plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent hdac inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. furthermore, most established hdac inhibitors concurrently show broad toxicities against parasites and human cells and high drug concentrati ...200919223622
a baculovirus dual expression system-based malaria vaccine induces strong protection against plasmodium berghei sporozoite challenge in mice.we have previously shown that a recombinant baculovirus that displays plasmodium berghei circumsporozoite protein (pbcsp), a homolog of the leading human malaria vaccine candidate, on the viral envelope protected 60% of mice against p. berghei infection. here, we describe a second-generation baculovirus vaccine based on the "baculovirus dual expression system," which drives pbcsp expression by a dual promoter that consists of tandemly arranged baculovirus-derived polyhedrin and mammal-derived cy ...200919223476
candidate selection and preclinical evaluation of n-tert-butyl isoquine (gsk369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century.n-tert-butyl isoquine (4) (gsk369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at liverpool, mmv, and gsk pharmaceuticals. this molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against plasmodium falciparum in vitro and rodent malaria parasites in vivo. the optimized chemistry delivered this novel synthetic ...200919222165
identification of a transcription factor in the mosquito-invasive stage of malaria parasites.gene expression in plasmodium parasites undergoes significant changes in each developmental stage, but the transcription factors (tfs) regulating these changes have not been identified. we report here a plasmodium tf (ap2-o) that activates gene expression in ookinetes, the mosquito-invasive form, and has a dna-binding domain structurally related to that of a plant tf, apetala2 (ap2). ap2-o mrna is pre-synthesized by intraerythrocytic female gametocytes and translated later during ookinete develo ...200919220746
host-parasite interactions revealed by plasmodium falciparum metabolomics.intracellular pathogens have devised mechanisms to exploit their host cells to ensure their survival and replication. the malaria parasite plasmodium falciparum relies on an exchange of metabolites with the host for proliferation. here we describe a mass spectrometry-based metabolomic analysis of the parasite throughout its 48 hr intraerythrocytic developmental cycle. our results reveal a general modulation of metabolite levels by the parasite, with numerous metabolites varying in phase with the ...200919218089
anti-malarial activities of andrographis paniculata and hedyotis corymbosa extracts and their combination with curcumin.herbal extracts of andrographis paniculata (ap) and hedyotis corymbosa (hc) are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south asian sub-continent. methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (mrc-pf-20) and resistant (mrc-pf-303) strains of plasmodium falciparum for their anti-malarial activity.200919216765
the immunomodulatory effect of sambucol on leishmanial and malarial infections.a nontoxic dose of sambucol, an immunomodulator commercially sold as an immune stimulator, was examined in murine models of leishmaniasis and malaria. sambucol causes a shift in the immune response, as demonstrated in human monocyte cultures, to th1 (inflammation-associated) responses. treatment of leishmania-infected mice with sambucol delayed the development of the disease. as there was no direct in vitro anti-leishmanial effect, the observed partial protection in vivo is most likely related t ...200919214946
challenges in the determination of early predictors of cerebral malaria: lessons from the human disease and the experimental murine models.cerebral malaria (cm) is a life-threatening complication of malaria caused by plasmodium falciparum, and it claims around two million lives a year, mainly those of children in sub-saharan africa. a number of works, particularly in murine models of cm, showed that several mediators are involved in the development of the disease, including monocytes, t lymphocytes, cytokines, chemokines, platelets, nitric oxide scavengers and heme, among others, but a comprehensive understanding of the pathogenesi ...200919212133
effect of dequalinium on the oxidative stress in plasmodium berghei-infected erythrocytes.the bisquinoline drug dequalinium (dq) has demonstrated remarkable activity against some infection diseases, including malaria. oxidative stress represents a biochemical target for potential antimalarials. in this work, we have tested the ability of this compound to modify the oxidative status in plasmodium berghei-infected erythrocytes. after hemolysis, activities of superoxide dismutase (sod), catalase (cat), glutathione cycle, and dehydrogenase enzymes were investigated. the activity of gluco ...200919205739
anopheles fibrinogen-related proteins provide expanded pattern recognition capacity against bacteria and malaria parasites.the fibrinogen-related protein family (frep, also known as fbn) is an evolutionarily conserved immune gene family found in mammals and invertebrates. it is the largest pattern recognition receptor gene family in anopheles gambiae, with as many as 59 putative members, while the drosophila melanogaster genome has only 14 known frep members. our sequence and phylogenetic analysis suggest that this remarkable gene expansion in the mosquito is the result of tandem duplication of the fibrinogen domain ...200919193639
disruption of plasmodium sporozoite transmission by depletion of sporozoite invasion-associated protein 1.accumulation of infectious plasmodium sporozoites in anopheles spp. salivary glands marks the final step of the complex development of the malaria parasite in the insect vector. sporozoites are formed inside midgut-associated oocysts and actively egress into the mosquito hemocoel. traversal of the salivary gland acinar cells correlates with the sporozoite's capacity to perform continuous gliding motility. here, we characterized the cellular role of the plasmodium berghei sporozoite invasion-asso ...200919181869
pharmacodynamics and pharmacokinetics studies of phenoxazinium derivatives for antimalarial agent.in vivo antimalarial drug candidates screening test was carried out on a series of water-soluble 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives. among them, 3-(diethylamino)-7-(piperidin-1-yl)phenoxazin-5-ium chloride (ssj-206) showing highest efficacy was chosen for further pharmcodynamics and pharmacokinetics study. it was supported from these data that the phenoxazinium salts, ssj-206, would be one of hopeful candidates as an oral antimalarial drug.200919181530
in vivo anti-malarial effect of the beta-amino alcohol 1t on plasmodium berghei.glycerol derivatives are a class of compounds, which are easy and inexpensive to produce with potent anti-malarial activities against blood stages of plasmodium falciparum in vitro. in the present study, one of these compounds, termed 1t, which had the lowest ic(50) values, was assessed in a murine malarial model. nuclear magnetic resonance imaging and balb/c mice infected with plasmodium berghei anka strain were treated in a 4-day suppressive test. mice received a once-daily intraperitoneal adm ...200919172294
synthesis and antimalarial activities of cyclen 4-aminoquinoline analogs.in an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline hbr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-zn(2+) complex]. the bisquinoline displays the most potent in vitro and in vivo antimalarial activities. it displays 50% inhibitory ...200919171802
rab11a-controlled assembly of the inner membrane complex is required for completion of apicomplexan cytokinesis.the final step during cell division is the separation of daughter cells, a process that requires the coordinated delivery and assembly of new membrane to the cleavage furrow. while most eukaryotic cells replicate by binary fission, replication of apicomplexan parasites involves the assembly of daughters (merozoites/tachyzoites) within the mother cell, using the so-called inner membrane complex (imc) as a scaffold. after de novo synthesis of the imc and biogenesis or segregation of new organelles ...200919165333
[construction and expression of plasmodium berghei chimeric protein in pichia pastoris and its immunogenicity in mice].to produce an erythrocytic stage chimeric protein of plasmodium berghei in pichia pastoris and evaluate its immunogenicity.200819157293
distinct roles of plasmodium rhomboid 1 in parasite development and malaria pathogenesis.invasion of host cells by the malaria parasite involves recognition and interaction with cell-surface receptors. a wide variety of parasite surface proteins participate in this process, most of which are specific to the parasite's particular invasive form. upon entry, the parasite has to dissociate itself from the host-cell receptors. one mechanism by which it does so is by shedding its surface ligands using specific enzymes. rhomboid belongs to a family of serine proteases that cleave cell-surf ...200919148267
gfp-targeting allows visualization of the apicoplast throughout the life cycle of live malaria parasites.the plasmodium parasite, during its life cycle, undergoes three phases of asexual reproduction, these being repeated rounds of erythrocytic schizogony, sporogony within oocysts on the mosquito midgut wall and exo-erythrocytic schizogony within the hepatocyte. during each phase of asexual reproduction, the parasite must ensure that every new daughter cell contains an apicoplast, as this organelle cannot be formed de novo and is essential for parasite survival. to date, studies visualizing the api ...200919143588
plasmodium male development gene-1 (mdv-1) is important for female sexual development and identifies a polarised plasma membrane during zygote development.successful development of plasmodium sexual stages is essential for parasite survival, but the genes involved are poorly understood. we 'knocked out' the male development gene-1 (mdv-1) locus in plasmodium berghei and found it to be important in female gametocyte activation. indirect immunofluorescence assays show mdv-1 has a punctate cytoplasmic distribution in gametocytes. after activation of both females and males, mdv-1 is more peripherally located but in males exclusively it becomes concent ...200919136003
salivary gland transcriptome analysis during plasmodium infection in malaria vector anopheles stephensi.understanding the tissue-specific molecular cross-talk mechanism during the mosquito-parasite interaction is of prime importance in the design of new strategies for malaria control. because mosquito salivary glands are the final destination for the parasite maturation and transmission of vector-borne diseases, identification and characterization of salivary genes and their products are equally important in order to access their effect on the infectivity of the parasite. during the last five year ...200919128996
identification and bioinformatic characterization of a multidrug resistance associated protein (abcc) gene in plasmodium berghei.the atp-binding cassette (abc) superfamily is one of the largest evolutionarily conserved families of proteins. abc proteins play key roles in cellular detoxification of endobiotics and xenobiotics. overexpression of certain abc proteins, among them the multidrug resistance associated protein (mrp), contributes to drug resistance in organisms ranging from human neoplastic cells to parasitic protozoa. in the present study, the plasmodium berghei mrp gene (pbmrp) was partially characterized and th ...200919118502
intranasal administration of the synthetic polypeptide from the c-terminus of the circumsporozoite protein of plasmodium berghei with the modified heat-labile toxin of escherichia coli (ltk63) induces a complete protection against malaria challenge.needle-free procedures are very attractive ways to deliver vaccines because they diminish the risk of contamination and may reduce local reactions, pain or pain fear especially in young children with a consequence of increasing the vaccination coverage for the whole population. for this purpose, the possible development of a mucosal malaria vaccine was investigated. intranasal immunization was performed in balb/c mice using a well-studied plasmodium berghei model antigen derived from the circums ...200919111883
indolizidine, antiinfective and antiparasitic compounds from prosopis glandulosa var. glandulosa.a new potent antiinfective and antiparasitic 2,3-dihydro-1h-indolizinium chloride (1) was isolated from prosopis glandulosa var. glandulosa. three additional new (2-4) and one known (5) indolizidines were also isolated, and the dihydrochloride salts of 1-3 (compounds 6, 7, and 8) were prepared. structures were determined by 1d and 2d nmr and mass spectra. compound 1 showed potent in vitro antifungal activity against cryptococcus neoformans and aspergillus fumigatus (ic(50) values = 0.4 and 3.0 m ...200919105653
anopheles mosquitoes: not just flying malaria vectors... especially in the field.the polymorphism of genes involved in the immunity of malaria vectors has been the subject of several recent studies with mosquitoes from natural populations. most of the genes examined are known for their role against plasmodium berghei and not necessarily for their role against plasmodium falciparum. it seems, therefore, to be highly important not only to be cautious when linking natural selection with malaria epidemiology but also to consider the importance of other parasites and the environm ...200919095498
influence of amitriptyline on eryptosis, parasitemia and survival of plasmodium berghei-infected mice.plasmodia express a sphingomyelinase, which is apparently required for their development. on the other hand, the sphingomyelinase product ceramide has previously been shown to delay parasite development. moreover, ceramide triggers suicidal erythrocyte death or eryptosis, characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage. accelerated eryptosis of infected erythrocytes is considered to clear infected erythrocytes from circulating blood and, thus, to fav ...200819088422
passive transfer of plasmodium falciparum msp-2 pseudopeptide-induced antibodies efficiently controlled parasitemia in plasmodium berghei-infected mice.we have developed monoclonal antibodies directed against the pseudopeptide psi-130, derived from the highly conserved malarial antigen plasmodium falciparum merozoite surface protein 2 (msp-2), for obtaining novel molecular tools with potential applications in the control of malaria. following isotype switching, these antibodies were tested for their ability to suppress blood-stage parasitemia through passive immunization in malaria-infected mice. some proved totally effective in suppressing a l ...200919071172
wave expansion of cd34+ progenitor cells in the spleen in rodent malaria.defense against malaria depends upon amplification of the spleen structure and function for the clearance of parasitized red blood cells (prbc). we studied the distribution and amount of cd34(+) cells in the spleens of mice infected with rodent malaria. we sought to identify these cells in the spleen and determine their relationship to infection. c57bl/6j mice were infected with self-resolving, plasmodium chabaudi cr, or one of the lethal rodent malaria strains, p. chabaudi aj and p. berghei ank ...200919068215
egf domain ii of protein pb28 from plasmodium berghei interacts with monoclonal transmission blocking antibody 13.1.development of a vaccine against malaria is a major global health concern. the p28 proteins expressed on the surface of ookinetes of plasmodium are the targets of transmission blocking antibodies. injection of p28 proteins in vertebrate hosts induces antibodies that inhibit oocyst formation, blocking transmission of the parasite from mosquitos to human hosts. p28 proteins are crucial for parasite protection inside the mosquito midgut. despite their importance, structural details of p28 family me ...200919066995
the fatty acid biosynthesis enzyme fabi plays a key role in the development of liver-stage malarial parasites.the fatty acid synthesis type ii pathway has received considerable interest as a candidate therapeutic target in plasmodium falciparum asexual blood-stage infections. this apicoplast-resident pathway, distinct from the mammalian type i process, includes fabi. here, we report synthetic chemistry and transfection studies concluding that plasmodium fabi is not the target of the antimalarial activity of triclosan, an inhibitor of bacterial fabi. disruption of fabi in p. falciparum or the rodent para ...200819064257
possible involvement of ifn-gamma in early mortality of plasmodium berghei nk65-infected balb/c mice after febrifugine treatment.parasitemia patterns, survival and cytokine levels of plasmodium berghei nk65-infected balb/c mice, treated orally with the alkaloidal mixture of febrifugine and isofebrifugine at a dose of 1 mg/kg twice a day for 4 consecutive days were monitored. whereas the untreated mice showed a progressive increase in parasitemia and ultimate death, the alkaloid mixture-treated group showed a transient suppression of parasitemia during the course of treatment. however, the parasitemia increased on disconti ...200819062681
screening of antiplasmodial properties among some traditionally used iranian plants.an investigation of plants was undertaken through interviews and literature surveys on plants used to treat malaria or cancer or microbial diseases in iran.200919059470
reduced protective effect of plasmodium berghei immunization by concurrent schistosoma mansoni infection.studies on concomitant schistosomiasis and human and experimental malaria have shown a variation in the immunospecific response, as well as an increase in the severity of both parasitoses. in the present study, a murine co-infection model was used to determine the effects of a co-infection with schistosoma mansoni and plasmodium berghei on the protective immunity acquired by repeated malarial infections and subsequent curative treatment with chloroquine. our results have demonstrated that, compa ...200819057817
failure of two distinct anti-apoptotic approaches to reduce mortality in experimental cerebral malaria.cerebral malaria is responsible for a high proportion of mortality in human plasmodium falciparum infection. previous studies have reported the presence of apoptosis in endothelial cells, astrocytes, neurons, and glial cells in experimental murine cerebral malaria caused by infection with plasmodium berghei anka. using this model, we tested two strategies, which have been shown to improve survival in murine models of sepsis: 1) treatment with z-vad, a pancaspase inhibitor; and 2) overexpression ...200819052286
concurrent infection with heligmosomoides polygyrus modulates murine host response against plasmodium berghei anka infection.we investigated whether concurrent infection with heligmosomoides polygyrus, an intestinal nematode, modulated anti-malaria parasite immunity and development of experimental cerebral malaria (ecm) in mice. the c57bl/6 mice infected with plasmodium berghei anka showed typical symptoms of ecm. interestingly, preceding h. polygyrus infection did not alter ecm development, despite accelerated p. berghei growth in vivo. our observation provides a new insight that ecm can be induced in a fashion indep ...200819052285
filarial infection induces protection against p. berghei liver stages in mice.chronic helminth infections such as filariasis in human hosts can be life long, since parasites are equipped with a repertoire of immune evasion strategies. in many areas where helminths are prevalent, other infections such as malaria are co-endemic. it is still an ongoing debate, how one parasite alters immune responses against another. to dissect the relationships between two different parasites residing in the same host, we established a murine model of co-infection with the filarial nematode ...200919049828
synthesis of chlorovinyl sulfones as structural analogs of chalcones and their antiplasmodial activities.the synthesis of novel chlorovinyl sulfone-like chalcone derivatives and their antimalarial activity against cultured plasmodium falciparum parasites, hemozoin formation, hemoglobin hydrolysis and murine malaria model are described. compounds were prepared via claisen-schmidt condensation from available chloromethylphenyl sulfones with substituted aldehydes. antiplasmodial ic(50) activity of these compounds ranged between 0.025 and 10 microm, those that blocked p. falciparum development at low m ...200919036479
letter to the editor on effect of cyclosporine on parasitemia and survival of plasmodium berghei-infected mice. 200919032941
hiv protease inhibitors inhibit the development of preerythrocytic-stage plasmodium parasites.recent studies have demonstrated that human immunodeficiency virus (hiv) protease inhibitors (pis) exert inhibitory effects on erythrocytic stages of the human-malaria parasite plasmodium falciparum in vitro and on erythrocytic stages of the rodent-malaria parasite plasmodium chabaudi in vivo. although it remains unclear how hiv pis inhibit the parasite, the effect seen on parasite development in the erythrocytic stages is potent. the effect on preerythrocytic stages has not yet been investigate ...200919032102
alteration of the parasite plasma membrane and the parasitophorous vacuole membrane during exo-erythrocytic development of malaria parasites.the rodent malaria parasite plasmodium berghei develops in hepatocytes within 48-52h from a single sporozoite into up to 20,000 daughter parasites, so-called merozoites. the cellular and molecular details of this extensive proliferation are still largely unknown. here we have used a transgenic, rfp-expressing p. berghei parasite line and molecular imaging techniques including intravital microscopy to decipher various aspects of parasite development within the hepatocyte. in late schizont stages, ...200919026596
synthesis and evaluation of 1,1'-hydrocarbylenebis(indazol-3-ols) as potential antimalarial drugs.bis(indazol-3-ol) derivatives (5, 30-38) were prepared by alkylation of 3-alkoxyindazoles with alpha,omega-dibromides, followed by removal of the o-protecting groups. these compounds were subsequently evaluated as inhibitors of biocrystallization of ferriprotoporphyrin ix (heme) to hemozoin, a plasmodium detoxification specific process. most bis(5-nitroindazol-3-ols) were good inhibitors, however, a denitro analogue (38), the intermediate bis(3-alkoxyindazoles) (15-29) as well as bis(indazolin-3 ...200919025734
cutting edge: selective blockade of light-lymphotoxin beta receptor signaling protects mice from experimental cerebral malaria caused by plasmodium berghei anka.studies in experimental cerebral malaria (ecm) in mice have identified t cells and tnf family members as critical mediators of pathology. in this study we report a role for light-lymphotoxin beta receptor (ltbetar) signaling in the development of ecm and control of parasite growth. specific blockade of light-ltbetar, but not light-herpesvirus entry mediator interactions, abrogated the accumulation of parasites and the recruitment of pathogenic cd8(+) t cells and monocytes to the brain during inf ...200819017933
role for the plasmodium sporozoite-specific transmembrane protein s6 in parasite motility and efficient malaria transmission.malaria transmission occurs by intradermal deposition of plasmodium sporozoites during the infectious bite of a female anopheles mosquito. after formation in midgut-associated oocysts sporozoites actively enter mosquito salivary glands and subsequently invade host hepatocytes where they transform into clinically silent liver stages. to date, two sporozoite-specific transmembrane proteins have been identified that perform vital functions in natural malaria transmission. the sporozoite invasin tra ...200919016774
compounds structurally related to ellagic acid show improved antiplasmodial activity.the cancer chemopreventive agent ellagic acid (ea) is a known inhibitor of glutathione s-transferases (gsts) and possesses antiplasmodial activities in the upper-nanomolar range. in the recent drug development approach, the properties of the active site of plasmodium falciparum gst were exploited for inhibitor design by introducing one or two additional hydroxyl groups into ea, yielding flavellagic acid (fea) and coruleoellagic acid (cea), respectively. indeed, the inhibition of p. falciparum gs ...200919015351
secreted antibody is required for immunity to plasmodium berghei.infection with plasmodium berghei is lethal to mice, causing high levels of parasitemia, severe anemia, and death. however, when mice are treated with antimalarial drugs during acute infection, they have enhanced immunity to subsequent infections. with this infection and cure model of immunity, we systematically examined the basis of adaptive immunity to infection using immunodeficient mice. in order to induce adaptive immunity, mice were infected with blood-stage parasites. when the mice develo ...200919001073
trep, a novel protein necessary for gliding motility of the malaria sporozoite.the invasive stages of parasites of the protozoan phylum apicomplexa have the capacity to traverse host tissues and invade host cells using a unique type of locomotion called gliding motility. gliding motility is powered by a sub-membranous actin-myosin motor, and the force generated by the motor is transduced to the parasite surface by transmembrane proteins of the apicomplexan-specific thrombospondin-related anonymous protein (trap) family. these proteins possess short cytoplasmic tails that i ...200919000911
structural basis for parasite-specific functions of the divergent profilin of plasmodium falciparum.profilins are key regulators of actin dynamics. they sequester actin monomers, forming a pool for rapid polymer formation stimulated by proteins such as formins. apicomplexan parasites utilize a highly specialized microfilament system for motility and host cell invasion. their genomes encode only a small number of divergent actin regulators. we present the first crystal structure of an apicomplexan profilin, that of the malaria parasite plasmodium falciparum, alone and in complex with a polyprol ...200819000816
antiplasmodial activity of root extract and fractions of croton zambesicus.antiplasmodial activity of root extract and fractions of croton zambesicus were evaluated to ascertain the folkloric claim of its antimalarial activity and elucidate its antiplasmodial mechanism of action.200918996464
kinome-wide rnai screen implicates at least 5 host hepatocyte kinases in plasmodium sporozoite infection.plasmodium sporozoites, the causative agent of malaria, are injected into their vertebrate host through the bite of an infected anopheles mosquito, homing to the liver where they invade hepatocytes to proliferate and develop into merozoites that, upon reaching the bloodstream, give rise to the clinical phase of infection. to investigate how host cell signal transduction pathways affect hepatocyte infection, we used rnai to systematically test the entire kinome and associated genes in human huh7 ...200818989463
anopheles gambiae apl1 is a family of variable lrr proteins required for rel1-mediated protection from the malaria parasite, plasmodium berghei.we previously identified by genetic mapping an anopheles gambiae chromosome region with strong influence over the outcome of malaria parasite infection in nature. candidate gene studies in the genetic interval, including functional tests using the rodent malaria parasite plasmodium berghei, identified a novel leucine-rich repeat gene, apl1, with functional activity against p. berghei.200818989366
the n-terminal domain of plasmodium falciparum circumsporozoite protein represents a target of protective immunity.the n-terminal domain of the circumsporozoite protein (csp) has been largely neglected in the search for a malaria vaccine in spite of being a target of inhibitory antibodies and protective t cell responses in mice. thus, in order to develop this region as a vaccine candidate to be eventually associated with other candidates and, in particular, with the very advanced c-terminal counterpart, synthetic constructs representing n- and c-terminal regions of plasmodium falciparum and plasmodium berghe ...200918984024
proteomic profiling of plasmodium sporozoite maturation identifies new proteins essential for parasite development and infectivity.plasmodium falciparum sporozoites that develop and mature inside an anopheles mosquito initiate a malaria infection in humans. here we report the first proteomic comparison of different parasite stages from the mosquito -- early and late oocysts containing midgut sporozoites, and the mature, infectious salivary gland sporozoites. despite the morphological similarity between midgut and salivary gland sporozoites, their proteomes are markedly different, in agreement with their increase in hepatocy ...200818974882
mdr1a (abcb1)-deficient cf-1 mutant mice are susceptible to cerebral malaria induced by plasmodium berghei anka.under experimental conditions, plasmodium berghei infection causes cerebral malaria (cm) in susceptible strains of mice such as c57bl/6 and cba/ca, whereas balb/c or dba/2j strains serve as a model for cm-resistant mice. the aim of the present study was to investigate the susceptibility of the cf1 mouse strain, carrying a spontaneous mutation of the mdr1a gene, to infection with plasmodium berghei anka (pba). the mdr1a gene codes for p-glycoprotein (p-gp/abcb1), an efflux pump that is one of the ...200818973419
gene disruption of plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes.difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated plasmodium parasites. immunizations with sporozoites that are attenuated by radiation (ras) can induce strong protective immunity both in humans and rodent models of malaria. recently, in rodent parasites it has been shown that through the deletion of a single gene, sporozoites can also become attenuated in liver stage development and, ...200818958160
semisynthesis and antiplasmodial activity of the quinoline alkaloid aurachin e.a one-step synthesis of the rare aurachin e (1) from the easily accessible aurachin c (2) and cyanogen bromide is described. 3-bromocarbamoylquinoline (5) is formed in a side reaction with concomitant loss of the 3-farnesyl residue. in an alternative approach, aurachin d (3) was reacted with phosgene and sodium azide to form the imidazolone ring of 1 via n-acylation. unexpectedly, the initial reaction occurred at the carbonyl group of 3 to give 1h-pyrrolo[3,2-c]quinoline 4. the reaction sequence ...200818922036
[not available]. 194818874862
screening of medicinal plants from reunion island for antimalarial and cytotoxic activity.nine plants from reunion island, selected using ethnopharmacology and chemotaxonomy, were investigated for their potential antimalarial value.200818848979
analysis of mutant plasmodium berghei parasites lacking expression of multiple pbccp genes.plasmodium encodes a family of six secreted multi-domain adhesive proteins, termed pccps, which are released from gametocytes during emergence within the mosquito midgut. the expression and cellular localization of pccp proteins predict a role either in gametocyte development or within the mosquito midgut during the transition from gametes into the ookinete stage. however, mutant parasites lacking expression of any single pccp protein show a phenotype at the oocyst stage with a failure of oocyst ...200918848846
complement factors c1q, c3 and c5 in brain and serum of mice with cerebral malaria.the patho-mechanisms leading to brain damage due to cerebral malaria (cm) are yet not fully understood. immune-mediated and ischaemic mechanisms have been implicated. the role of complement factors c1q, c3 and c5 for the pathogenesis of cm were investigated in this study.200818847493
protective cd8 t cells against plasmodium liver stages: immunobiology of an 'unnatural' immune response.summary: immunization with high doses of irradiated sporozoites delivered by the bites of infected mosquitoes has been shown to induce protective responses against malaria, mediated in part by cd8(+) t cells. in contrast, natural transmission involving low exposure to live sporozoite antigen fails to elicit strong immunity. in this review, we examine how irradiated sporozoite immunization breaks the natural host-parasite interaction and induces protective cd8(+) t cells. upon biting, the malaria ...200818837788
synthesis and antimalarial activity of pyrazolo and pyrimido benzothiazine dioxide derivatives.a series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent plasmodium berghei. compounds 3-amino-7-chloro-9-(2'-methylphenyl)-1,9-dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2b and 2,4-diamino-8-chloro-10h-phenyl-pyrimido-[5,4-b]benzothiazine 5,5-dioxide 3a were the most promising as inhibitors of hem ...200918835067
rapid identification of plasmodium-carrying mosquitoes using loop-mediated isothermal amplification.with an aim to develop a quick and simple method to survey pathogen-transmitting vectors, lamp (loop-mediated isothermal amplification) was applied to the identification of plasmodium-carrying mosquitoes, specifically a plasmodium-transmitting experimental model using rodent malaria parasite (plasmodium berghei) and anopheline mosquitoes (anopheles stephensi). the detection sensitivity limit of the lamp reaction amplifying the spect2 gene was determined to be 1 x 10(2) purified plasmodium parasi ...200818809384
localisation of laminin within plasmodium berghei oocysts and the midgut epithelial cells of anopheles stephensi.abstract:200818808667
transgenic rodent plasmodium berghei parasites as tools for assessment of functional immunogenicity and optimization of human malaria vaccines. 200818806208
carbonic anhydrase inhibitors: inhibition of plasmodium falciparum carbonic anhydrase with aromatic/heterocyclic sulfonamides-in vitro and in vivo studies.a library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds has been assayed for inhibition of the carbonic anhydrase (ca, ec 4.2.1.1) from the malaria parasite plasmodium falciparum (pfca). low micromolar and submicromolar in vitro inhibitors were detected, whereas several compounds showed ex vivo anti-p. falciparum activity, in cell cultures. one derivative, that is, 4-(3,4-dichlorophenylureido)thioureido-benzenesulfonamide was an effective in vitro pfca inhibitor ...200818805693
complete protection against p. berghei malaria upon heterologous prime/boost immunization against circumsporozoite protein employing salmonella type iii secretion system and bordetella adenylate cyclase toxoid.sterile immunity against malaria can be achieved by the induction of ifngamma-producing cd8(+) t cells that target infected hepatocytes presenting epitopes of the circumsporozoite protein (csp). in the present study we evaluate the protective efficacy of a heterologous prime/boost immunization protocol based on the delivery of the cd8(+) epitope of plasmodium berghei csp into the mhc class i presentation pathway, by either a type iii secretion system of live recombinant salmonella and/or by dire ...200818804138
the analgesic and antiplasmodial activities and toxicology of vernonia amygdalina.vernonia amygdalina possesses several bioactive compounds and is used in traditional medicines of southwestern uganda, along with other regions. its analgesic potential has not been investigated thus far. the present study examines the antinociceptive potential of the aqueous leaf extract (50-200 mg/kg) using three models of nociception (acetic acid-induced writhing, formalin test, and tail-flick test), antiplasmodial activity, and toxicology of the extract. the results show the extract signific ...200818800909
blood-stage plasmodium infection induces cd8+ t lymphocytes to parasite-expressed antigens, largely regulated by cd8alpha+ dendritic cells.although cd8(+) t cells do not contribute to protection against the blood stage of plasmodium infection, there is mounting evidence that they are principal mediators of murine experimental cerebral malaria (ecm). at present, there is no direct evidence that the cd8(+) t cells mediating ecm are parasite-specific or, for that matter, whether parasite-specific cd8(+) t cells are generated in response to blood-stage infection. to resolve this and to define the cellular requirements for such priming, ...200818799734
growth-inhibitory effect of a fucoidan from brown seaweed undaria pinnatifida on plasmodium parasites.the present study was undertaken to investigate the inhibitory effects of fucoidan, a sulfated polysaccharide isolated from the edible brown seaweed undaria pinnatifida, on the growth of plasmodium parasites. in order to assess the anti-malarial activity of fucoidan, growth inhibition activities were evaluated using cultured plasmodium falciparum parasites in vitro and on plasmodium berghei-infected mice in vivo. fucoidan significantly inhibited the invasion of erythrocytes by p. falciparum mero ...200918791738
use of a drosophila model to identify genes regulating plasmodium growth in the mosquito.we performed a forward genetic screen, using drosophila as a surrogate mosquito, to identify host factors required for the growth of the avian malaria parasite, plasmodium gallinaceum. we identified 18 presumed loss-of-function mutants that reduced the growth of the parasite in flies. presumptive mutation sites were identified in 14 of the mutants on the basis of the insertion site of a transposable element. none of the identified genes have been previously implicated in innate immune responses ...200818791251
plasmodium berghei: lack of antimalarial activity of an analogue of folate precursor, 2,4-diamino-6-hydroxymethylpteridine in a mouse model.it was earlier hypothesized that the malarial parasite may convert precursors of folate analogues to synthesize de novo inhibitors toxic to itself, but not to the mammalian cell. it was suggested that one such analogue, 2,4-diamino-6-hydroxymethylpteridine (dap) may be converted to aminopterin (amp), a known dihydrofolate reductase inhibitor. in the present study, we evaluated the ability of dap to inhibit proliferation of plasmodium berghei nk65 in mice, with(out) folinic acid rescue. cumulativ ...200818789931
effect of cyclosporine on parasitemia and survival of plasmodium berghei infected mice.cyclosporine triggers suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and exposure of phosphatidylserine at the erythrocyte surface. the present study explored whether cyclosporine influences eryptosis of plasmodium infected erythrocytes, development of parasitemia and thus the course of the disease. annexin v binding was utilized to depict phosphatidylserine exposure and forward scatter in facs analysis to estimate erythrocyte volume. in vitro infection of huma ...200818789889
oxidative folding of synthetic polypeptides s-protected as tert-butylthio derivatives.a new method for oxidative folding of synthetic polypeptides assembled by stepwise solid phase synthesis is introduced. folding is obtained in excellent yields by reacting s-tert-butylthiolated polypeptides with a 100-fold molar excess of cysteine at 37 degrees c in a slightly alkaline buffer containing chaotropic salts, and in the presence of air-oxygen. this novel protocol has been applied to the folding of s-tert-butylthiolated human thymus and activation-regulated chemokine (hu-tarc) derivat ...200818781562
memory cd8 t cell responses exceeding a large but definable threshold provide long-term immunity to malaria.infection of mice with sporozoites of plasmodium berghei or plasmodium yoelii has been used extensively to evaluate liver-stage protection by candidate preerythrocytic malaria vaccines. unfortunately, repeated success of such vaccines in mice has not translated readily to effective malaria vaccines in humans. thus, mice may be used better as models to dissect basic parameters required for immunity to plasmodium-infection than as preclinical vaccine models. in turn, this basic information may aid ...200818780790
intracellular calcium levels in the plasmodium berghei ookinete.ookinetes are the motile and invasive stages of plasmodium parasites in the mosquito host. here we explore the role of intracellular ca2+ in ookinete survival and motility as well as in the formation of oocysts in vitro in the rodent malaria parasite plasmodium berghei. treatment with the ca2+ ionophore a23187 induced death of the parasite, an effect that could be prevented if the ookinetes were co-incubated with insect cells before incubation with the ionophore. treatment with the intracellular ...200818775093
immunological profile of a plasmodium vivax ama-1 n-terminus peptide-carbon nanotube conjugate in an infected plasmodium berghei mouse model.we have covalently conjugated an n-terminus plasmodium vivax apical membrane antigen-1 (ama-1) peptide to functionalized carbon nanotubes (f-cnt). immunological characterization of this molecular conjugate revealed that the immunogen-ama-1 peptide was appropriately presented after being conjugated to cnts as well as being recognized by balb/c polyclonal antibodies. subsequent experiments lead us to assess the ama-1 peptide alone, as well as the cnt-peptide conjugate regarding rodent malarial inf ...200818771700
computational analysis of constraints on noncoding regions, coding regions and gene expression in relation to plasmodium phenotypic diversity.malaria-causing plasmodium species exhibit marked differences including host choice and preference for invading particular cell types. the genetic bases of phenotypic differences between parasites can be understood, in part, by investigating constraints on gene expression and genic sequences, both coding and regulatory.200818769675
hyperbaric oxygen prevents early death caused by experimental cerebral malaria.cerebral malaria (cm) is a syndrome characterized by neurological signs, seizures and coma. despite the fact that cm presents similarities with cerebral stroke, few studies have focused on new supportive therapies for the disease. hyperbaric oxygen (hbo) therapy has been successfully used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis.200818769544
influence of chlorpromazine on eryptosis, parasitemia and survival of plasmodium berghe infected mice.chlorpromazine has previously been shown to trigger suicidal erythrocyte death or eryptosis, which is characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage. premature suicidal death of infected erythrocytes is in turn considered to delay development of parasitemia and thus favourably influence the clinical course of malaria. the present experiments have been performed to explore whether chlorpromazine influences in vitro parasite growth and eryptosis of pl ...200818769053
design and in vivo pharmacodynamic evaluation of nanostructured lipid carriers for parenteral delivery of artemether: nanoject.the objective of the present investigation was to explore the potential of nanostructured lipid carriers (nlc) for the intravenous delivery of artemether (arm), a poorly water-soluble antimalarial agent. the nlc of arm (nanoject) were formulated by employing a microemulsion template technique. the nlc were evaluated for particle size, encapsulation efficiency, in vitro drug release and in vitro hemolysis. the antimalarial activity of the nanoject and conventional arm injectable formulation was e ...200818765274
reverse genetics screen identifies six proteins important for malaria development in the mosquito.transmission from the vertebrate host to the mosquito vector represents a major population bottleneck in the malaria life cycle that can successfully be targeted by intervention strategies. however, to date only about 25 parasite proteins expressed during this critical phase have been functionally analysed by gene disruption. we describe the first systematic, larger scale generation and phenotypic analysis of plasmodium berghei knockout (ko) lines, characterizing 20 genes encoding putatively sec ...200818761621
a role of ige and cd23/no immune pathway in age-related resistance of lewis rats to plasmodium berghei anka?in contrast to young rats, adult rats given i.p. plasmodium berghei anka (pba) control the parasitaemia and repair their anaemia. here, we investigated whether ige and cd23/no immune pathway could be implicated in this age-related resistance of adult rats to pba. eight-week-old rats displayed significantly higher levels of plasma total ige (p=0.01) and soluble cd23 (p=0.003) during the peak of parasitaemia, compared to 4-week-old rats. ige fc-binding antibody or aminoguanidine administration to ...200818761417
recombinant scorpine: a multifunctional antimicrobial peptide with activity against different pathogens.scorpine is an antimicrobial peptide whose structure resembles a hybrid between a defensin and a cecropin. it exhibits antibacterial activity and inhibits the sporogonic development of parasites responsible for murine malaria. in this communication we report the production of scorpine in a heterelogous system, using a specific vector containing its cloned gene. the recombinantly expressed scorpine (rscp) in (anopheles gambie) cells showed antibacterial activity against (bacillus subtilis) and (k ...200818726072
synthesis, antimalarial activity, and intracellular targets of mefas, a new hybrid compound derived from mefloquine and artesunate.a new synthetic antimalarial drug, a salt derived from two antimalarial molecules, mefloquine (mq) and artesunate (as), here named mefas, has been tested for its pharmacological activity. combinations of as plus mq hydrochloride are currently being used in areas with drug-resistant plasmodium falciparum parasites; although as clears parasitemia in shorter time periods than any other antimalarial drug, it does not cure infected patients; in addition, mq causes side effects and is rather expensive ...200818710907
chemically attenuated plasmodium sporozoites induce specific immune responses, sterile immunity and cross-protection against heterologous challenge.vaccination with plasmodium sporozoites attenuated by irradiation or genetic manipulation induces a protective immune response in rodent malaria models. recently, vaccination with chemically attenuated p. berghei sporozoites (cas) has also been shown to elicit sterile immunity in mice. here we show that vaccination with cas of p. yoelii also protects against homologous infection and that a p. berghei cas vaccine cross protects against heterologous challenge with p. yoelii sporozoites. vaccinatio ...200818672017
control of pathogenic cd8+ t cell migration to the brain by ifn-gamma during experimental cerebral malaria.previous studies have shown that ifn-gamma is essential for the pathogenesis of cerebral malaria (cm) induced by plasmodium berghei anka (pba) in mice. however, the exact role of ifn-gamma in the pathway (s) leading to cm has not yet been described. here, we used 129p2sv/ev mice which develop cm between 7 and 14 days post-infection with pba. in this strain, both cd4(+) and cd8(+) t cells were involved in the effector phase of cm. when 129p2sv/ev mice deficient in the ifn-gamma receptor alpha cha ...200818665903
electrospray ionization-ion trap mass spectrometry study of pqaapro and pqproaa mimetic derivatives of the antimalarial primaquine.electrospray ionization-ion trap mass spectrometry (esi-ms) of imidazolidin-4-one peptidomimetic derivatives of the antimalarial drug primaquine (pq) is reported. these compounds contain the imidazolidin-4-one moiety either at the n- or the c-terminal of a dipeptide backbone, thus respectively mimicking pq-amino acid-proline (pqaapro) and pqproaa derivatives of pq. both the peptidomimetics and precursors previously developed by us are promising drug candidates, as they were found to be active ag ...200818657994
gene expression, antiparasitic activity, and functional evolution of the drosomycin family.drosophila employs various antimicrobial peptides as effective weapons to defend against diverse pathogens. drosomycin is an inducible antifungal peptide initially isolated from the drosophila melanogaster haemolymph. here we report the expression pattern of seven drosomycin genes in four different developmental stages (egg, larva, pupa and adult). results show that drosomycin and drosomycin-2 are expressed in larva, pupa and adult, whereas drosomycin-1 and drosomycin-6 were not detected in all ...200818657321
concurrent gastro-intestinal nematode infection does not alter the development of experimental cerebral malaria.concurrent helminth infections have been suggested to be associated with protection against cerebral malaria in humans, a condition characterised by systemic inflammation. here we show that a concurrent chronic gastro-intestinal nematode infection does not alter the course of murine cerebral malaria. mice infected with heligmosomoides polygyrus, and co-infected with plasmodium berghei anka 14 days later, developed malaria parasitemia, weight loss and anemia, at the same rate as mice without nema ...200818656411
development of smedds using natural lipophile: application to beta-artemether delivery.the objective of the present investigation was to formulate self-microemulsifying drug delivery systems (smedds) using a novel, indigenous natural lipophile (n-lct) as an oily phase. smedds based on n-lct and commercially available modified oil (capryol 90) were formulated and their application in improving the delivery of a lipophilic anti-malarial drug, beta-artemether (bam) was also evaluated. bam-loaded smedds were characterized with respect to mean globule size and in vitro drug release pro ...200818652886
imc1b is a putative membrane skeleton protein involved in cell shape, mechanical strength, motility, and infectivity of malaria ookinetes.membrane skeletons are cytoskeletal elements that have important roles in cell development, shape, and structural integrity. malaria parasites encode a conserved family of putative membrane skeleton proteins related to articulins. one member, imc1a, is expressed in sporozoites and localizes to the pellicle, a unique membrane complex believed to form a scaffold onto which the ligands and glideosome are arranged to mediate parasite motility and invasion. imc1b is a closely related structural paral ...200818650444
global metabolic responses of nmri mice to an experimental plasmodium berghei infection.we present a metabolism-driven top-down systems biology approach to characterize metabolic changes in the mouse resulting from an infection with plasmodium berghei, using high-resolution (1)h nmr spectroscopy and multivariate data analysis techniques. twelve female nmri mice were infected intravenously with approximately 20 million p. berghei-parasitized erythrocytes. urine and plasma samples were collected 4-6 h before infection, and at days 1, 2, 3, and 4 postinfection. multivariate analysis o ...200818646786
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