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mixed vector immunization with recombinant adenovirus and mva can improve vaccine efficacy while decreasing antivector immunity.substantial protection can be provided against the pre-erythrocytic stages of malaria by vaccination first with an adenoviral and then with an modified vaccinia virus ankara (mva) poxviral vector encoding the same me.trap transgene. we investigated whether the two vaccine components adenovirus (ad) and mva could be coinjected as a mixture to enhance protection against malaria. a single-shot mixture at specific ratios of ad and mva (ad+mva) enhanced cd8(+) t cell-dependant protection of mice agai ...201222354374
mitochondrial peroxidase tpx-2 is not essential in the blood and insect stages of plasmodium berghei.malaria parasites actively proliferate in the body of their vertebrate and insect hosts, and are subjected to the toxic effects of reactive oxygen species. the antioxidant defenses of malaria parasites are considered to play essential roles in their survival and are thus considered promising targets for intervention. we sought to identify the cellular function of thioredoxin peroxidase-2 (tpx-2), which is expressed in the mitochondria, by disrupting the tpx-2 gene (pbtpx-2) of the rodent malaria ...201223146411
identification of an ap2-family protein that is critical for malaria liver stage development.liver-stage malaria parasites are a promising target for drugs and vaccines against malaria infection. however, little is currently known about gene regulation in this stage. in this study, we used the rodent malaria parasite plasmodium berghei and showed that an ap2-family transcription factor, designated ap2-l, plays a critical role in the liver-stage development of the parasite. ap2-l-depleted parasites proliferated normally in blood and in mosquitoes. however, the ability of these parasites ...201223144823
natural transmission of plasmodium berghei exacerbates chronic tuberculosis in an experimental co-infection model.human populations are rarely exposed to one pathogen alone. particularly in high incidence regions such as sub-saharan africa, concurrent infections with more than one pathogen represent a widely underappreciated public health problem. two of the world's most notorious killers, malaria and tuberculosis, are co-endemic in impoverished populations in the tropics. however, interactions between both infections in a co-infected individual have not been studied in detail. both pathogens have a major i ...201223110184
antibiotic and antimalarial quinones from fungus-growing ant-associated pseudonocardia sp.three new members of the angucycline class of antibiotics, pseudonocardones a-c (1-3), along with the known antibiotics 6-deoxy-8-o-methylrabelomycin (4) and x-14881 e (5) have been isolated from the culture of a pseudonocardia strain associated with the fungus-growing ant apterostigma dentigerum. compounds 4 and 5 showed antibiotic activity against bacillus subtilis 3610 and liver-stage plasmodium berghei, while 1-3 were inactive or only weakly active in a variety of biological assays. compound ...201223025282
conformational co-dependence between plasmodium berghei lccl proteins promotes complex formation and stability.malaria parasites express a conserved family of lccl-lectin adhesive-like domain proteins (laps) that have essential functions in sporozoite transmission. in plasmodium falciparum all six family members are expressed in gametocytes and form a multi-protein complex. intriguingly, knockout of p. falciparum lccl proteins adversely affects expression of other family members at protein, but not at mrna level, a phenomenon termed co-dependent expression. here, we investigate this in plasmodium berghei ...201222877575
tricks in plasmodium's molecular repertoire--escaping 3'utr excision-based conditional silencing of the chloroquine resistance transporter gene.in the human malaria parasite plasmodium falciparum, the major determinant of chloroquine resistance, p. falciparum chloroquine resistance transporter (pfcrt), likely plays an essential role in asexual blood stages, thus precluding conventional gene targeting approaches. we attempted to conditionally silence the expression of its ortholog in plasmodium berghei (pbcrt) through flp recombinase-mediated excision of the 3'untranslated region (utr) during mosquito passage. however, parasites maintain ...201223023047
a unique protein phosphatase with kelch-like domains (ppkl) in plasmodium modulates ookinete differentiation, motility and invasion.protein phosphorylation and dephosphorylation (catalysed by kinases and phosphatases, respectively) are post-translational modifications that play key roles in many eukaryotic signalling pathways, and are often deregulated in a number of pathological conditions in humans. in the malaria parasite plasmodium, functional insights into its kinome have only recently been achieved, with over half being essential for blood stage development and another 14 kinases being essential for sexual development ...201223028336
variation in apoptosis mechanisms employed by malaria parasites: the roles of inducers, dose dependence and parasite stages.plasmodium berghei ookinetes exhibit an apoptotic phenotype when developing within the mosquito midgut lumen or when cultured in vitro. markers of apoptosis increase when they are exposed to nitric oxide or reactive oxygen species but high concentrations of hydrogen peroxide cause death without observable signs of apoptosis. chloroquine and other drugs have been used to induce apoptosis in erythrocytic stages of plasmodium falciparum and to formulate a putative pathway involving cysteine proteas ...201222929459
4(1h)-quinolones with liver stage activity against plasmodium berghei.with the exception of primaquine, tafenoquine, and atovaquone, there are very few antimalarials that target liver stage parasites. in this study, a transgenic plasmodium berghei parasite (1052cl1; pbgfp-luc(con)) that expresses luciferase was used to assess the anti-liver stage parasite activity of ici 56,780, a 7-(2-phenoxyethoxy)-4(1h)-quinolone (peq), as well as two 3-phenyl-4(1h)-quinolones (p4q), p4q-146 and p4q-158, by using bioluminescent imaging (bli). results showed that all of the comp ...201223129047
an epithelial serine protease, agesp, is required for plasmodium invasion in the mosquito anopheles gambiae.plasmodium parasites need to cross the midgut and salivary gland epithelia to complete their life cycle in the mosquito. however, our understanding of the molecular mechanism and the mosquito genes that participate in this process is still very limited.201222509400
plasmodium berghei δp52&p36 parasites develop independent of a parasitophorous vacuole membrane in huh-7 liver cells.the proteins p52 and p36 are expressed in the sporozoite stage of the murine malaria parasite plasmodium berghei. δp52&p36 sporozoites lacking expression of both proteins are severely compromised in their capability to develop into liver stage parasites and abort development soon after invasion; presumably due to the absence of a parasitophorous vacuole membrane (pvm). however, a small proportion of p. berghei δp52&p36 parasites is capable to fully mature in hepatocytes causing breakthrough bloo ...201223227206
qsar analysis of benzophenone derivatives as antimalarial agents.a set of benzophenone derivatives was evaluated for the antimalarial activity against plasmodium berghei in mice and the mean survival time of mice for all the compounds was determined. the qsar analysis was carried out for the fourteen benzophenone derivatives using different physicochemical descriptors. the multiple linear regression analysis was used to correlate the physicochemical descriptors with the antimalarial activity of the benzophenone derivatives from the training set and the best q ...201223204621
structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines.in an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (k1) and sensitive (nf54) strains in the low nanomolar range. some compounds displayed a significant reduction in potency in the herg channel inhibition assay compared to previously reported frontrunner analogues. several o ...201223189922
mimicking the intramolecular hydrogen bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents.the intramolecular hydrogen bond formed between a protonated amine and a neighboring h-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. here we describe isoquine-based compounds in which the intramolecular h-bond is mimicked by a methylene linker. the antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were exami ...201223145816
agrochemicals against malaria, sleeping sickness, leishmaniasis and chagas disease.in tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and chagas disease standing in the forefront. many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. in order to identify new antiprotozoal agents, more than 600 co ...201223145187
validation of the proteasome as a therapeutic target in plasmodium using an epoxyketone inhibitor with parasite-specific toxicity.the plasmodium proteasome has been suggested to be a potential antimalarial drug target; however, toxicity of inhibitors has prevented validation of this enzyme in vivo. we report a screen of a library of 670 analogs of the recent us food and drug administration-approved inhibitor, carfilzomib, to identify compounds that selectively kill parasites. we identified one compound, pr3, that has significant parasite killing activity in vitro but dramatically reduced toxicity in host cells. we found th ...201223142757
flow cytometry-assisted rapid isolation of recombinant plasmodium berghei parasites exemplified by functional analysis of aquaglyceroporin.the most critical bottleneck in the generation of recombinant plasmodium berghei parasites is the mandatory in vivo cloning step following successful genetic manipulation. this study describes a new technique for rapid selection of recombinant p. berghei parasites. the method is based on flow cytometry to isolate isogenic parasite lines and represents a major advance for the field, in that it will speed the generation of recombinant parasites as well as cut down on animal use significantly. high ...201223137753
a lactate dehydrogenase elisa-based assay for the in vitro determination of plasmodium berghei sensitivity to anti-malarial drugs.plasmodium berghei rodent malaria is a well-known model for the investigation of anti-malarial drug efficacy in vivo. however, the availability of drug in vitro assays in p. berghei is reduced when compared with the spectrum of techniques existing for plasmodium falciparum. new alternatives to the current manual or automated methods described for p. berghei are attractive. the present study reports a new elisa drug in vitro assay for p. berghei using two monoclonal antibodies against the parasit ...201223126583
compounds from sorindeia juglandifolia (anacardiaceae) exhibit potent anti-plasmodial activities in vitro and in vivo.discovering new lead compounds against malaria parasites is a crucial step to ensuring a sustainable global pipeline for effective anti-malarial drugs. as far as we know, no previous phytochemical or pharmacological investigations have been carried out on sorindeia juglandifolia. this paper describes the results of an anti-malarial activity-driven investigation of the fruits of this cameroonian plant.201223171238
reduced plasmodium berghei sporozoite liver load associates with low protective efficacy after intradermal immunization.studies in animal models suggest that protection against malaria induced by intradermal (id) administration of sporozoites is less effective compared to intravenous injection (iv). we investigated in a murine model the protective efficacy and immune responses after id or iv immunization of sporozoites. mice were immunized via either iv or id route with plasmodium berghei sporozoites in combination with chloroquine treatment (cps) (allowing full liver stage development) or by γ-radiation-attenuat ...201223171040
comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog.indole alkaloids ellipticine (1), cryptolepine triflate (2a), rationally designed 11-(4-piperidinamino)cryptolepine hydrogen dichloride (2b) and olivacine (3) (an isomer of 1) were evaluated in vitro against plasmodium falciparum and in vivo in plasmodium berghei-infected mice. 1-3 inhibited p. falciparum (ic₅₀≤1.4 μm, order of activity: 2b>1>2a>3). in vitro toxicity to murine macrophages was evaluated and revealed selectivity indices (si) of 10-12 for 2a and si>2.8×10² for 1, 2b and 3. 1 admini ...201223092722
thymic alterations induced by plasmodium berghei: expression of matrix metalloproteinases and their tissue inhibitors.the thymus plays a crucial role in the generation of t-cells, and so our laboratory has been interested in the study of the intrathymic events that occur during infection diseases and may cause disruption in its functions. previously, we showed that thymus from experimentally plasmodium berghei-infected mice present histological alterations with high levels of apoptosis, changes in cell migration-related molecules, and premature egress of immature thymocytes to periphery. in addition, parasites ...201223089194
linear and cyclic dipeptides with antimalarial activity.several natural and synthetic polypeptides possess important antimalarial activity. shorter peptides with potent antimalarial activity have also been described, among them linear di-, tri-, tetra- and pentapeptides and their cyclic analogs. in an attempt to find dipeptides with antimalarial activities we show that linear and cyclic dipeptides, the latter known as diketopiperazines, still retain the fundamental core to preserve antimalarial activity. thirteen linear dipeptides and ten diketopiper ...201223084276
altered regulation of akt signaling with murine cerebral malaria, effects on long-term neuro-cognitive function, restoration with lithium treatment.neurological and cognitive impairment persist in more than 20% of cerebral malaria (cm) patients long after successful anti-parasitic treatment. we recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ecm). we also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible bioche ...201223082110
in vivo antimalarial activity of ajuga remota water extracts against plasmodium berghei in mice.we investigated the in vivo activity of crude water extracts of ajuga remota benth (labiatae) against plasmodium berghei in mice using plants harvested from two areas in kenya where the plant is commonly used to treat malaria. the extract was tested using a 4-day test at a dose of 30 mg/kg/day (equivalent to 0.2 ml solution per mouse). wet leaf extract was the most effective with 90.4% suppression of parasitemia. extract from air-dried and powdered flowers were the least effective with 17.2% sup ...201223077832
shaping acoustic fields as a toolset for microfluidic manipulations in diagnostic technologies.ultrasonics offers the possibility of developing sophisticated fluid manipulation tools in lab-on-a-chip technologies. here we demonstrate the ability to shape ultrasonic fields by using phononic lattices, patterned on a disposable chip, to carry out the complex sequence of fluidic manipulations required to detect the rodent malaria parasite plasmodium berghei in blood. to illustrate the different tools that are available to us, we used acoustic fields to produce the required rotational vortices ...201222949692
[immunological analysis of piperaquine-resistant murine model of plasmodium berghei anka strain].to analyze the immunological characteristics of murine model of piperaquine sensitive (pqs) line and resistant (pqr) line of plasmodium berghei (pb) anka strain.201222913181
anti-plasmodial activity of dicoma tomentosa (asteraceae) and identification of urospermal a-15-o-acetate as the main active compound.natural products could play an important role in the challenge to discover new anti-malarial drugs. in a previous study, dicoma tomentosa (asteraceae) was selected for its promising anti-plasmodial activity after a preliminary screening of several plants traditionally used in burkina faso to treat malaria. the aim of the present study was to further investigate the anti-plasmodial properties of this plant and to isolate the active anti-plasmodial compounds.201222909422
intravenous β-artemether formulation (arm nlc) as a superior alternative to commercial artesunate formulation.to compare the in vivo pharmacodynamic efficacy of intravenously administered artemether nanostructured lipid carrier (arm nlc) with commercial artesunate (c-ast) at different dose levels.201222899802
antimalarial potential of nosode 30 and 200 against plasmodium berghei infection in balb/c mice.homeopathy is considered as an emerging area of alternative medicine which could be established for the global health care. one of the greatest objections to this science lies in its inability to explain the mechanism of action of the micro doses based on scientific experiments and proofs. the present study has been undertaken to screen in vivo antimalarial activity of malaria co nosode 30 and nosode 200 against plasmodium berghei infection in balb/c mice.201222898477
malaria-infected mice live until at least day 30 after a new artemisinin-derived thioacetal thiocarbonate combined with mefloquine are administered together in a single, low, oral dose.in only three steps and in 21-67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane c-10 thioacetals was prepared. upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, plasmodium berghei-infected mice survived on average 29.8 days after infection. two of the four mice in this group had no parasites detectable in their blood on day 30 after infection, and they behaved normally and appear ...201222891714
modulation of lipoprotein cholesterol levels in plasmodium berghei malarial infection by crude aqueous extract of ganoderma lucidum.in this study, attempt is made to establish changes in serum and liver lipoprotein cholesterols accompanying plasmodium berghei malarial infection in mice treated with aqueous extract of ganoderma lucidum at 100, 250, and 500 mg/kg body weight in comparison with 15 mg/kg chloroquine (cq). significant increases in all the lipoprotein fractions were observed in infected untreated mice compared with normal control mice. treatment with 100 and 250 mg/kg g. lucidum extract produced significant reduct ...201222888413
proteomics of the rodent malaria parasite using matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight tandem mass spectrometry.plasmodium berghei strain nk65 is a rodent malaria parasite species widely used as a model of the human-infectious malaria parasite. because a rodent malaria parasite model allows issues to be addressed which would not be possible with human-infectious species, e.g., mode of action and in vivo screening, a convenient method to analyze the malaria parasite proteome is required. the proteins of p. berghei separated using two-dimensional polyacrylamide gel electrophoresis were analyzed using matrix ...201222878638
bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against plasmodium falciparum dihydroorotate dehydrogenase.plasmodium falciparum causes approximately 1 million deaths annually. however, increasing resistance imposes a continuous threat to existing drug therapies. we previously reported a number of potent and selective triazolopyrimidine-based inhibitors of p. falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against p. falciparum in mic ...201222877245
synthesis and evaluation of hybrid drugs for a potential hiv/aids-malaria combination therapy.malaria and hiv are among the most important global health problems of our time and together are responsible for approximately 3 million deaths annually. these two diseases overlap in many regions of the world including sub-saharan africa, southeast asia and south america, leading to a higher risk of co-infection. in this study, we generated and characterized hybrid molecules to target plasmodium falciparum and hiv simultaneously for a potential hiv/malaria combination therapy. hybrid molecules ...201222858300
the alveolin imc1h is required for normal ookinete and sporozoite motility behaviour and host colonisation in plasmodium berghei.alveolins, or inner membrane complex (imc) proteins, are components of the subpellicular network that forms a structural part of the pellicle of malaria parasites. in plasmodium berghei, deletions of three alveolins, imc1a, b, and h, each resulted in reduced mechanical strength and gliding velocity of ookinetes or sporozoites. using time lapse imaging, we show here that deletion of imc1h (pbanka_143660) also has an impact on the directionality and motility behaviour of both ookinetes and sporozo ...201222844474
metabolic fingerprints of serum, brain, and liver are distinct for mice with cerebral and noncerebral malaria: a ¹h nmr spectroscopy-based metabonomic study.cerebral malaria (cm) is a life-threatening disease in humans caused by plasmodium falciparum, leading to high mortality. plasmodium berghei anka (pba) infection in c57bl/6 mice induces pathologic symptoms similar to that in human cm. however, experimental cm incidence in mice is variable, and there are no known metabolic correlates/fingerprints for the animals that develop cm. here, we have used (1)h nmr-based metabonomics to investigate the metabolic changes in the mice with cm with respect to ...201222838963
decreased redox-sensitive erythrocyte cation channel activity in aquaporin 9-deficient mice.survival of the malaria pathogen plasmodium falciparum in host erythrocytes requires the opening of new permeability pathways (npps) in the host cell membrane, accomplishing entry of nutrients, exit of metabolic waste products such as lactate and movement of inorganic ions such as cl⁻, na⁺ and ca²⁺. the molecular identity of npps has remained largely elusive but presumably involves several channels, which partially can be activated by oxidative stress in uninfected erythrocytes. one npp candidat ...201222836670
the novel eta receptor antagonist hjp-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative.to investigate the association between vasculopathy and survival during experimental cerebral malaria (ecm), and to determine whether targeting the endothelin-1 (et-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival.201222820174
in vivo antiplasmodial activities of ethanolic extract and fractions of eleucine indica.to evaluate the in vivo antiplasmodial activities of the extract and fractions (n-hexane, chloroform, ethylacetate, butanol, aqueous) of the whole plant in plasmodium berghei berghei infected mice.201222805716
distinct placental malaria pathology caused by different plasmodium berghei lines that fail to induce cerebral malaria in the c57bl/6 mouse.placental malaria (pm) is one major feature of malaria during pregnancy. a murine model of experimental pm using balb/c mice infected with plasmodium berghei anka was recently established, but there is need for additional pm models with different parasite/host combinations that allow to interrogate the involvement of specific host genetic factors in the placental inflammatory response to plasmodium infection.201222799533
comparative study on the effects of chloroquine and artesunate on histopathological damages caused by plasmodium berghei in four vital organs of infected albino mice.the aim of the present study was to investigate the positive influence of chloroquine and artesunate on the pathological damages caused by plasmodium berghei on vital organs of mice in an established infection. healthy adult albino mice with average weight of 25 g were used for the study. treated group was administered orally with 100 mg/kg of chloroquine and artesunate, respectively. control animals were given water for the same period. histological examination of the liver, spleen, lungs, and ...201222792509
induction of antisporozoite antibodies by biting of transgenic anopheles stephensi delivering malarial antigen via blood feeding.we produced a transgenic mosquito expressing a rodent malaria vaccine candidate antigen in the salivary gland. three tandemly repeated amino acid units from the repeat region of circumsporozoite protein of plasmodium berghei (pbcs3r) fused to red fluorescent protein (monomeric dsred) was chosen as a vaccine candidate antigen. immunoblot and fluorescence microscopic analyses showed the transgene expression in the female salivary gland. the transgene product was released from the proboscis as a co ...201222787718
the host endocytic pathway is essential for plasmodium berghei late liver stage development.the obligate intracellular liver stage of the plasmodium parasite represents a bottleneck in the parasite life cycle and remains a promising target for therapeutic intervention. during this stage, parasites undergo dramatic morphological changes and achieve one of the fastest replication rates among eukaryotic species. nevertheless, relatively little is known about the parasite interactions with the host hepatocyte. using immunofluorescence, live cell imaging and electron microscopy, we show tha ...201222780869
identification and in-vitro adme assessment of a series of novel anti-malarial agents suitable for hit-to-lead chemistry.triage of a set of antimalaria hit compounds, identified through high throughput screening against the chloroquine sensitive (3d7) and resistant (dd2) parasite plasmodium falciparum strains identified several novel chemotypes suitable for hit-to-lead chemistry investigation. the set was further refined through investigation of their in vitro adme properties, which identified templates with good potential to be developed further as antimalarial agents. one example was profiled in an in vivo murin ...201224900512
novel 4-aminoquinoline-pyrimidine based hybrids with improved in vitro and in vivo antimalarial activity.a class of hybrid molecules consisting of 4-aminoquinoline and pyrimidine were synthesized and tested for antimalarial activity against both chloroquine (cq)-sensitive (d6) and chloroquine (cq)-resistant (w2) strains of plasmodium falciparum through an in vitro assay. eleven hybrids showed better antimalarial activity against both cq-sensitive and cq-resistant strains of p. falciparum in comparison to standard drug cq. four molecules were more potent (7-8-fold) than cq in d6 strain, and eight mo ...201224900509
enhancement of dendritic cell activation via cd40 ligand-expressing γδ t cells is responsible for protective immunity to plasmodium parasites.previous reports have shown that γδ t cells are important for the elimination of malaria parasites in humans and mice. however, how γδ t cells are involved in protective immunity against blood-stage malaria remains unknown. we infected γδ t-cell-deficient (tcrδ-ko) mice and control wild-type mice with plasmodium berghei xat, which is a nonlethal strain. although infected red blood cells were eliminated within 30 d after infection, tcrδ-ko mice could not clear the infected red blood cells, showed ...201222778420
a plasmodium-encoded cytokine suppresses t-cell immunity during malaria.the inability to acquire protective immunity against plasmodia is the chief obstacle to malaria control, and inadequate t-cell responses may facilitate persistent blood-stage infection. malaria is characterized by a highly inflammatory cytokine milieu, and the lack of effective protection against infection suggests that memory t cells are not adequately formed or maintained. using a genetically targeted strain of plasmodium berghei, we observed that the plasmodium ortholog of macrophage migratio ...201222778413
effects of experimental cerebral malaria in memory, brain-derived neurotrophic factor and acetylcholinesterase activity [correction for acitivity] in the hippocampus of survivor mice.malaria is the most important human parasitic disease and cerebral malaria (cm), its main neurological complication, is characterized by neurological and cognitive damage in both human and animal survivors. the brain-derived neurotrophic factor (bdnf) appears to be involved with activity-dependent synaptic plasticity. there is great interest regarding its role in learning and memory as well as acetylcholinesterase activity (ache) that is implicated in many cognitive functions and probably plays ...201222750161
erythropoietin treatment alleviates ultrastructural myelin changes induced by murine cerebral malaria.cerebral malaria (cm) is a severe complication of malaria with considerable mortality. in addition to acute encephalopathy, survivors frequently suffer from neurological sequelae. the pathogenesis is incompletely understood, hampering the development of an effective, adjunctive therapy, which is not available at present. previously, erythropoietin (epo) was reported to significantly improve the survival and outcome in a murine cm model. the study objectives were to assess myelin thickness and ul ...201222741599
identification of a new chemical class of antimalarials.the increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (moas). here, we describe a compound representative of a new class of antimalarials. this molecule, act-213615, potently inhibits in vitro erythrocytic growth of all tested plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (ic(50)) values in the low single-digit nanomolar range. like the clini ...201222732921
cutting edge: clec9a+ dendritic cells mediate the development of experimental cerebral malaria.plasmodium infections trigger strong innate and acquired immune responses, which can lead to severe complications, including the most feared and often fatal cerebral malaria (cm). to begin to dissect the roles of different dendritic cell (dc) subsets in plasmodium-induced pathology, we have generated a transgenic strain, clec9a-diphtheria toxin receptor that allows us to ablate in vivo clec9a(+) dcs. specifically, we have analyzed the in vivo contribution of this dc subset in an experimental cm ...201222732587
ifn-γ-producing cd4+ t cells promote experimental cerebral malaria by modulating cd8+ t cell accumulation within the brain.it is well established that ifn-γ is required for the development of experimental cerebral malaria (ecm) during plasmodium berghei anka infection of c57bl/6 mice. however, the temporal and tissue-specific cellular sources of ifn-γ during p. berghei anka infection have not been investigated, and it is not known whether ifn-γ production by a single cell type in isolation can induce cerebral pathology. in this study, using ifn-γ reporter mice, we show that nk cells dominate the ifn-γ response durin ...201222723523
lamivudine-artesunate co-administration affects glucose metabolism in healthy and diseased wistar rats.hiv-malaria co morbidity frequently requires the co administration of lamivudine and artesunate, in malaria endemic areas where hiv is also a problem. this situation is a frequent occurrence in developing countries of the tropics, like nigeria where the burden of malaria and hiv is heavy. the co administration of these drugs may result in interactions with possible physiologic and/or therapeutic consequences. this study investigated the effect of lamivudine-artesunate co administration on body w ...201222713939
novel 4-aminoquinoline analogs highly active against the blood and sexual stages of plasmodium in vivo and in vitro.new drugs to treat malaria must act rapidly and be highly potent against asexual blood stages, well tolerated, and affordable to residents of regions of endemicity. this was the case with chloroquine (cq), a 4-aminoquinoline drug used for the prevention and treatment of malaria. however, since the 1960s, plasmodium falciparum resistance to this drug has spread globally, and more recently, emerging resistance to cq by plasmodium vivax threatens the health of 70 to 320 million people annually. des ...201222710117
expansion of experimental genetics approaches for plasmodium berghei with versatile transfection vectors.experimental reverse genetic approaches have proven powerful in the study of the biology of the malaria parasite. the murine malaria model parasite plasmodium berghei is the genetically most amendable plasmodium species and allows full access to the entire life cycle in vivo. here, we describe a next-generation, highly versatile transfection vector set that facilitates advancing experimental genetic strategies towards a genome-wide scale. through 36 consecutive cloning and 17 subcloning steps an ...201222705315
in vivo antiplasmodial activities of aqueous extract of bridelia ferruginea stem bark against plasmodium berghei berghei in mice.bridelia ferruginea benth (euphorbiaceae) is an indigenous medicinal plant in nigeria. it is usually a gnarled shrub which sometimes reaches the size of a tree in suitable condition. decoctions of parts of this plant have been employed in ethno medicine in many parts of africa for treatment of many ailments including malaria fever.201222235887
atorvastatin treatment is effective when used in combination with mefloquine in an experimental cerebral malaria murine model.one of the major complications of plasmodium falciparum infection is cerebral malaria (cm), which causes one million deaths worldwide each year, results in long-term neurological sequelae and the treatment for which is only partially effective. statins are recognized to have an immunomodulatory action, attenuate sepsis and have a neuroprotective effect. atorvastatin (ava) has shown in vitro anti-malarial activity and has improved the activity of mefloquine (mq) and quinine.201222233563
flow cytometric enumeration of plasmodium berghei-infected red blood cells stained with sybr green i.high-throughput methods for evaluation of in vivo efficacy of candidate compounds against plasmodium parasites are necessary during the antimalarial drug development process. it is essential that enumeration of parasitemia in the infected blood from experimental host animals is accurate and reliable. flow cytometric enumeration of parasitized cells stained with fluorescent dye is a rapid alternative method to conventional microscopic counting. in this study, a protocol for flow cytometric enumer ...201222222185
antimalarial potency of the leaf extract of aspilia africana (pers.) c.d. adams.to investigate the antimalarial activity of ethanol extract of aspilia africana (a. africana) leaf.201222221756
antiplasmodial and antiulcer activities of melanthera scadens.to evaluate the antimalarial and antiulcerogenic activities of leaf extract and fractions of melanthera scandens (m. scandens).201223569827
antimalarial and hepatoprotective effects of crude ethanolic extract of lingzhi or reishi medicinal mushroom, ganoderma lucidum (w.curt.:fr.)p.karst. (higher basidiomycetes), in plasmodium berghei-infected mice.this study was aimed at investigating the in vivo antimalarial activity (using some biochemical indices) of crude aqueous extracts of the fruiting bodies of ganoderma lucidum, a mushroom with well-established medicinal properties. a rodent malaria parasite, plasmodium berghei (1 × 107), was inoculated intraperitoneally into swiss albino mice. the test groups were administered g. lucidum extract and chloroquine (cq, as standard drug), while the control groups were administered the same amount of ...201223510214
apicoplast triose phosphate transporter (tpt) gene knockout is lethal for plasmodium.the c3, c5, c6 type sugar phosphate transporters bring sugars inside apicoplast, thus providing energy, reducing power and elements like carbon to apicoplast. plasmodium berghei has two c3 type sugar phosphate transporters in the membrane of apicoplast: triose phosphate transporter (tpt) and phosphoenolpyruvate transporter (ppt). here we report that p. berghei tpt knockout parasites failed to survive. however, ppt knockout parasite behaved similar to the wild type in the blood stages. the absenc ...201223041242
measuring the blockade of malaria transmission--an analysis of the standard membrane feeding assay.the standard membrane feeding assay (smfa) is currently considered to be the 'gold standard' for assessing the effectiveness of malaria transmission blocking interventions (tbis) in vivo. the operation and analysis of smfas has varied between laboratories: field scientists often measure tbi efficacy as a reduction in the prevalence of infected mosquitoes whilst laboratory scientists are more likely to quote efficacy as a change in the number of oocysts within the mosquito. these metrics give out ...201223023048
a high-throughput assay for the identification of malarial transmission-blocking drugs and vaccines.following the cessation of the global malaria eradication initiative in the 1970s, the prime objective of malarial intervention has been to reduce morbidity and mortality. this motivated the development of high throughput assays to determine the impact of interventions on asexual bloodstage parasites. in response to the new eradication agenda, interrupting parasite transmission from the human to the mosquito has been recognised as an important and additional target for intervention. current assa ...201223023046
modulation of interleukin-18 release produced positive outcomes on parasitaemia development and cytokines production during malaria in mice.the involvement of interleukin-18 (il-18) and the effects of modulating its release on the course of malaria infection were investigated using plasmodium berghei anka infection in icr mice as a model. results demonstrated that plasma il-18 concentrations in malarial mice were significantly elevated and positively correlated with the percentage parasitaemia development. significant expressions of il-18 were also observed in the brain, spleen and liver tissues. slower development of parasitaemia w ...201223018504
small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in plasmodium falciparum.epigenetic factors such as histone methylation control the developmental progression of malaria parasites during the complex life cycle in the human host. we investigated plasmodium falciparum histone lysine methyltransferases as a potential target class for the development of novel antimalarials. we synthesized a compound library based upon a known specific inhibitor (bix-01294) of the human g9a histone methyltransferase. two compounds, bix-01294 and its derivative tm2-115, inhibited p. falcipa ...201223011794
the in vivo antimalarial activity of methylene blue combined with pyrimethamine, chloroquine and quinine.the effectiveness of methylene blue (mb) combined with pyrimethamine (pyr), chloroquine (cq) or quinine (q) was examined in a classical four-day suppressive test against a causative agent of rodent malaria, plasmodium berghei. a marked potentiation was observed when mb was administered at a non-curative dose of 15 mg/kg/day in combination with pyr (0.19 mg/kg/day) or q (25 mg/kg/day). no synergy was found between mb (15 mg/kg) and cq (0.75 mg/kg). our results suggest that the combination of mb w ...201222990975
sequential plasmodium chabaudi and plasmodium berghei infections provide a novel model of severe malarial anemia.lack of an adequate animal model of plasmodium falciparum severe malarial anemia (sma) has hampered the understanding of this highly lethal condition. we developed a model of sma by infecting c57bl/6 mice with p. chabaudi followed after recovery by p. berghei infection. p. chabaudi/p. berghei-infected mice had an initial 9- to 10-day phase of relatively low parasitemia and severe anemia, followed by a second phase of hyperparasitemia, more profound anemia, reticulocytosis, and death 14 to 21 day ...201222689817
new agilent platform dna microarrays for transcriptome analysis of plasmodium falciparum and plasmodium berghei for the malaria research community.dna microarrays have been a valuable tool in malaria research for over a decade but remain in limited use in part due their relatively high cost, poor availability, and technical difficulty. with the aim of alleviating some of these factors next-generation dna microarrays for genome-wide transcriptome analysis for both plasmodium falciparum and plasmodium berghei using the agilent 8 x 15 k platform were designed.201222681930
synthesis, characterization of chitosan-tripolyphosphate conjugated chloroquine nanoparticle and its in vivo anti-malarial efficacy against rodent parasite: a dose and duration dependent approach.various strategies to deliver antimalarials using nanocarriers have been evaluated. however, taking into account the peculiarities of malaria parasites, the focus is placed mainly polymer-based chitosan nanocarriers. our purpose of the study is to develop chitosan-tripolyphosphate (cs-tpp) nanoparticles (nps) conjugated chloroquine in application for attenuation of plasmodium berghei infection in swiss mice. nps were prepared by ionotropic gelation between cs and sodium tpp. in the study, the in ...201222664460
targeting toll-like receptors by chloroquine protects mice from experimental cerebral malaria.excessive production of proinflammatory cytokines, elicited mostly by th1 cells, is an important cause of cerebral malaria (cm). dendritic cells (dcs), a critical link between innate and adaptive immune responses, rely heavily on toll-like receptor (tlr) signaling. using c57bl/6 mice infected with plasmodium berghei anka (pba) as an experimental cm model, we first confirmed that inhibition of tlr9 by suppressive oligodeoxynucleotides protected mice from cm. in addition to being a well-known anti ...201222659438
critical roles of the mitochondrial complex ii in oocyst formation of rodent malaria parasite plasmodium berghei.it is generally accepted that the mitochondria play central roles in energy production of most eukaryotes. in contrast, it has been thought that plasmodium spp., the causative agent of malaria, rely mainly on cytosolic glycolysis but not mitochondrial oxidative phosphorylation for energy production during blood stages. however, plasmodium spp. possesses all genes necessary for the tricarboxylic acid (tca) cycle and most of the genes for electron transport chain (etc) enzymes. therefore, it remai ...201222628552
effective adjunctive therapy by an innate defense regulatory peptide in a preclinical model of severe malaria.case fatality rates for severe malaria remain high even in the best clinical settings because antimalarial drugs act against the parasite without alleviating life-threatening inflammation. we assessed the potential for host-directed therapy of severe malaria of a new class of anti-inflammatory drugs, the innate defense regulator (idr) peptides, based on host defense peptides. the plasmodium berghei anka model of experimental cerebral malaria was adapted to use as a preclinical screen by combinin ...201222623740
harmine is a potent antimalarial targeting hsp90 and synergizes with chloroquine and artemisinin.previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of guiera senegalensis from mali in west africa. we independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited plasmodium falciparum heat shock protein 90 (pfhsp90) atp-binding domain. in this study, we confirmed harmine-pfhsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [k(d)] of 40 μm). in contrast, the ...201222615284
the role of cgmp signalling in regulating life cycle progression of plasmodium.the 3'-5'-cyclic guanosine monophosphate (cgmp)-dependent protein kinase (pkg) is the main mediator of cgmp signalling in the malaria parasite. this article reviews the role of pkg in plasmodium falciparum during gametogenesis and blood stage schizont rupture, as well as the role of the plasmodium berghei orthologue in ookinete differentiation and motility, and liver stage schizont development. the current views on potential effector proteins downstream of pkg and the mechanisms that may regulat ...201222613210
formulation design and in vivo antimalarial evaluation of lipid-based drug delivery systems for oral delivery of β-arteether.β-arteether, an effective artemisinin derivative, is used in the treatment of malaria but available only as an intramuscular injection. the objective of this work was to develop lipid-based formulations for oral administration of β-arteether. self-emulsifying drug delivery systems (seddss) of low cost and with accessible excipients (groundnut or sesame oil, maisine 35-1, tween 80 or cremophor el, and absolute ethanol) were formulated. in 250 ml of simulated gastric medium, 1g of these sedds solu ...201222609572
improved methods for haemozoin quantification in tissues yield organ-and parasite-specific information in malaria-infected mice.despite intensive research, malaria remains a major health concern for non-immune residents and travelers in malaria-endemic regions. efficient adjunctive therapies against life-threatening complications such as severe malarial anaemia, encephalopathy, placental malaria or respiratory problems are still lacking. therefore, new insights into the pathogenesis of severe malaria are imperative. haemozoin (hz) or malaria pigment is produced during intra-erythrocytic parasite replication, released in ...201222583751
the antiplasmodial and radical scavenging activities of flavonoids of erythrina burttii.the acetone extract of the root bark of erythrina burttii showed in vitro antiplasmodial activity against the chloroquine-sensitive (d6) and chloroquine-resistant (w2) strains of plasmodium falciparum with ic(50) values of 0.97 ± 0.2 and 1.73 ± 0.5 μg/ml respectively. the extract also had radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (dpph) radical with an ec(50) value of 12.0 μg/ml. the isoflav-3-enes burttinol-a and burttinol-c, and the 2-arylbenzofuran derivative burttinol ...201222575309
in vivo hemozoin kinetics after clearance of plasmodium berghei infection in mice.hemozoin (hz) is released into the blood stream after rupture of infected red blood cells (irbcs) at the end of each parasite replication cycle. this free hz is ingested by circulating and resident phagocytes. the presence of hz in tissues after clearance of infection has been previously reported. still, little is known about the kinetics of hz in vivo, during and after plasmodium infection. it is particularly important to understand hz kinetics after malaria infections as it has been reported t ...201222567535
generation of quinolone antimalarials targeting the plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria.there is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. a failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. here we prese ...201222566611
curcuminoids-loaded liposomes in combination with arteether protects against plasmodium berghei infection in mice.curcuminoids are poorly water-soluble compounds with promising antimalarial activity. to overcome some of the drawbacks of curcuminoids, we explored the potential of liposomes for the intravenous delivery of curcuminoids in a model of mouse malaria. the curcuminoids-loaded liposomes were formulated from phosphatidylcholine (soy pc) by the thin-film hydration method. antimalarial activity of curcuminoids-loaded liposomes alone and in combination with α/β arteether when administered intravenously, ...201222561991
effects of vitamin e administration on plasmodium berghei induced pathological changes and oxidative stress in mice.the effects of daily intraperitoneal doses of 1000 i.u/kg body weight of vitamin e on the course of plasmodium berghei nk 65 infection and the parasite-induced anemia as well as alterations in the relative weight of some selected organs and antioxidant status in mice were investigated. the number of parasitized red cells were not initially affected by the vitamin administration but were persistently lowered after 11th day post infection to the termination of the experiment. the p. berghei infect ...201222543609
plasmodium subtilisin-like protease 1 (sub1): insights into the active-site structure, specificity and function of a pan-malaria drug target.release of the malaria merozoite from its host erythrocyte (egress) and invasion of a fresh cell are crucial steps in the life cycle of the malaria pathogen. subtilisin-like protease 1 (sub1) is a parasite serine protease implicated in both processes. in the most dangerous human malarial species, plasmodium falciparum, sub1 has previously been shown to have several parasite-derived substrates, proteolytic cleavage of which is important both for egress and maturation of the merozoite surface to e ...201222543039
plasmodium berghei: influence of infection on the oxidant and antioxidants levels in pregnant balb/c mice.malarial infection during pregnancy has been associated with maternal anemia and death, abortion, still-birth and is a major cause of low birth weight, an important risk factor for infant morbidity and mortality in endemic areas. the present study was designed to delineate the oxidative stress in various organs (liver, spleen, kidney, brain and placenta) of pregnant plasmodium berghei infected balb/c mice. it was observed that pregnant-infected mice had higher parasitaemia than nonpregnant-infec ...201222542801
endogenous galectin-3 controls experimental malaria in a species-specific manner.galectins are evolutionarily conserved glycan-binding proteins with pleiotropic roles in innate and adaptive immune responses. galectin-3 has been implicated in several immunological processes as well as in pathogen recognition through specific binding to glycosylated receptors on the surface of host cells or microorganisms. in spite of considerable evidence supporting a role for galectin-3 in host-pathogen interactions, the relevance of this lectin in the regulation of the host defence mechanis ...201222486577
improved negative selection protocol for plasmodium berghei in the rodent malarial model.an improved methodology is presented here for transgenic plasmodium berghei lines that express the negative selectable marker yfcu (a bifunctional protein that combines yeast cytosine deaminase and uridyl phosphoribosyl transferase (uprt)) and substitutes delivery of selection drug 5-fluorocytosine (5fc) by intraperitoneal injection for administration via the drinking water of the mice. the improved methodology is shown to be as effective, less labour-intensive, reduces animal handling and anima ...201222463060
the effect of otostegia persica in combination with chloroquine on chloroquine-sensitive and chloroquine-resistant strains of plasmodium berghei using in-vivo fixed ratios method.malaria is one of the worldwide parasitic diseases which threaten the life of hundreds of millions of people at the malarious areas each year. the emergence of chloroquine-resistant strains of plasmodium falciparum in most of the malarious areas has encountered the relevant countries with some difficulties about treating the acute cases of the disease particulary if the monotherapy regimen has been used. because of many advantages for the combination therapy, the effectiveness of chloroquine (cq ...201224250482
cross-species immunity following immunization with a circumsporozoite protein-based vaccine for malaria.malaria continues to be a major public health concern, and there are concerted efforts to eliminate it. the quest for a vaccine remains a top priority, and vaccines based on the circumsporozoite protein (csp) are among the lead candidates, with the rts,s vaccine currently undergoing phase 3 testing in africa. previous studies have reported anti-csp antibody-mediated enhancement of in vitro invasion of homologous sporozoites. this effect has been shown to be concentration dependent; high-level an ...201222457289
improved plasmodium berghei lines for conditional mutagenesis.conditional mutagenesis is a powerful tool for genetic analysis in plasmodium berghei. it allows the study of proteins that function both during the parasite's pre-erythocytic and erythrocytic development. currently available parasite lines used for conditional mutagenesis were constructed in the nk65 strain, and express a dna recombinase under the control of pre-erythrocytic stage-specific promoters. however, the integration of the recombinase in these lines is unstable leading to inconsistent ...201222450301
in vitro and in vivo antimalarial activity of essential oils and chemical components from three medicinal plants found in northeastern brazil.the prophylactic and therapeutic arsenal against malaria is quite restricted and all the antimalarials currently in use have limitations. thus, there is a need to investigate medicinal plants in the search for phytochemicals which can be developed into drugs. in our investigation, essential oils (eos) were obtained from vanillosmopsis arborea (gardner) baker, lippia sidoides cham. and croton zehntneri pax & k. hoffm., aromatic plants abundant in northeastern brazil, which are found in the caatin ...201222441836
a high-coverage artificial chromosome library for the genome-wide screening of drug-resistance genes in malaria parasites.the global spread of drug-resistant parasites is a serious problem for the treatment of malaria. although identifying drug-resistance genes is crucial for the efforts against resistant parasites, an effective approach has not yet been developed. here, we report a robust method for identifying resistance genes from parasites by using a plasmodium artificial chromosome (pac). large genomic dna fragments (10-50 kb) from the drug-resistant rodent malaria parasite plasmodium berghei were ligated into ...201222426943
extracellular atp triggers proteolysis and cytosolic ca²⁺ rise in plasmodium berghei and plasmodium yoelii malaria parasites.plasmodium has a complex cell biology and it is essential to dissect the cell-signalling pathways underlying its survival within the host.201222420332
role of oxidative stress and apoptosis in the placental pathology of plasmodium berghei infected mice.placental malaria is a common clinical complication during pregnancy and is associated with abortion, premature delivery, intrauterine growth retardation and low birth weight. the present study was designed to delineate the underlying mechanism of placental pathology during malarial infection with special reference to oxidative stress and apoptosis. experimentally, pregnant balb/c mice were infected with plasmodium berghei infected red blood cells on gestation day 10. the presence of malarial in ...201222396790
s-nitrosoglutathione prevents experimental cerebral malaria.administration of the exogenous nitric oxide (no) donor dipropylenetriamine-nonoate (dpta-no) to mice during plasmodium berghei anka (pba) infection largely prevents development of experimental cerebral malaria (ecm). however, a high dose (1 mg/mouse twice a day) is necessary and causes potent side effects such as marked hypotension. in the present study we evaluated whether an alternative, physiologically relevant no donor, s-nitrosoglutathione (gsno), was able to prevent ecm at lower doses wit ...201222391863
3,5-diaryl-2-aminopyridines as a novel class of orally active antimalarials demonstrating single dose cure in mice and clinical candidate potential.a novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available softfocus kinase library. the compounds were evaluated in vitro for their antiplasmodial activity against k1 (chloroquine and drug-resistant strain) and nf54 (chloroquine-susceptible strain) as well as for their cytotoxicity. synthesis and structure-activity studies identified a number of promising compounds with selective an ...201222390538
identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum type ii nadh:quinone oxidoreductase (pfndh2).following a program undertaken to identify hit compounds against nadh:ubiquinone oxidoreductase (pfndh2), a novel enzyme target within the malaria parasite plasmodium falciparum, hit to lead optimization led to identification of ck-2-68, a molecule suitable for further development. in order to reduce clogp and improve solubility of ck-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound sl-2-25 (8b ...201222364417
artesunate-loaded chitosan/lecithin nanoparticles: preparation, characterization, and in vivo studies.artesunate (ast), the most widely used artemisnin derivative, has poor aqueous solubility and suffers from low oral bioavailability (~40%). under these conditions, nanoparticles with controlled and sustained released properties can be a suitable solution for improving its biopharmaceuticals properties. this work reports the preparation and characterization of auto-assembled chitosan/lecithin nanoparticles loaded with ast and ast complexed with β-cyclodextrin (β-cd) to boost its antimalarial acti ...201222348223
efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by plasmodium berghei anka.low nitric oxide (no) bioavailability plays a role in the pathogenesis of human as well as of experimental cerebral malaria (ecm) caused by plasmodium berghei anka (pba). ecm is partially prevented by administration of the no-donor dipropylenetriamine nonoate (dpta-no) at high concentration (1 mg/mouse), which also induces major side effects such as a sharp drop in blood pressure. we asked whether alternative strategies to improve no bioavailability with minor side effects would also be effectiv ...201222348145
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