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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
plasmodium liver load following parenteral sporozoite administration in rodents.one of the bottlenecks in the development of a whole sporozoite malaria vaccine is the route and method of sporozoite administration. immunization and challenge of human volunteers by mosquito bites is effective, but cannot be used as a vaccine. intravenous immunization with sporozoites is effective in rodents and non-human primates, and being studied in humans, but is not yet used for licensed vaccines for infectious diseases. intradermal and subcutaneous immunization regimens show a strong dec ...201323063834
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
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
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
sem studies on blood cells of plasmodium berghei infected balb/c mice treated with artesunate and homeopathic medicine china.the therapeutic efficacy of antimalarial drugs and their effect on various organs in the form of surface morphological deformations can be analyzed using scanning electron microscopy (sem). present study has been undertaken on plasmodium berghei (nk-65), a lethal rodent malaria parasite, to monitor the morphological changes in blood cells induced by the treatment with combination of artesunate and homeopathic medicine . combination therapy of artesunate (100 mg/kg) and china ϕ was found to be hi ...201123024494
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
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 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
splenocyte apoptosis in plasmodium berghei anka infection: possible role of tnf-α and tgf-β.cerebral malaria is associated with the circulating levels of tumour necrosis factor alpha (tnf-α) and transforming growth factor β (tgf-β), but association between these two cytokines and implications in splenocyte apoptosis remain largely obscured. we have evaluated the outcome of tgf-β and tnf-α production in the context of splenocyte apoptosis during plasmodium berghei anka (pba) infection. blood-stage pba infection confirmed blood-brain barrier disruption, disarray of white pulp, increase i ...201323009201
development of memory cd8+ t cells and their recall responses during blood-stage infection with plasmodium berghei anka.conditions required for establishing protective immune memory vary depending on the infecting microbe. although the memory immune response against malaria infection is generally thought to be relatively slow to develop and can be lost rapidly, experimental evidence is insufficient. in this report, we investigated the generation, maintenance, and recall responses of ag-specific memory cd8(+) t cells using plasmodium berghei anka expressing ova (pba-ova) as a model system. mice were transferred wi ...201223008449
the evolution and putative function of phosducin-like proteins in the malaria parasite plasmodium.ubiquitous to the proteomes of all living species is the presence of proteins containing the thioredoxin (trx)-domain. the best characterized trx-domain containing proteins include the enzymes involved in cellular redox metabolism facilitated by their cysteine-containing active site. but not all members of the trx-fold superfamily exhibit this catalytic motif, e.g., the phosducin-like (phlp) family of proteins. genome sequencing efforts have uncovered new trx-domain containing proteins, and thei ...201322995278
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
screening inhibitors of p. berghei blood stages using bioluminescent reporter parasites.we describe two improved assays for in vitro and in vivo screening of inhibitors and chemicals for antimalarial activity against blood stages of the rodent malaria parasite, plasmodium berghei. these assays are based on the determination of bioluminescence in small blood samples that is produced by reporter parasites expressing luciferase. luciferase production increases as the parasite develops in a red blood cell and as the numbers of parasites increase during an infection. in the first assay, ...201322990801
quantitative analysis of plasmodium berghei liver stages by bioluminescence imaging.we describe simple and sensitive in vitro and in vivo assays to analyze plasmodium liver stage development using transgenic p. berghei parasites (pbgfp-luccon), which express the bioluminescent reporter protein, luciferase. in these assays, parasite development in hepatocytes is visualized and quantified by real-time bioluminescence imaging both in culture and in live mice. we also describe quantification of in vitro liver-stage development by measuring luminescence using a microplate reader. re ...201322990796
quantification of sporozoite invasion, migration, and development by microscopy and flow cytometry.there is an important role for in vitro assays to better understand the initial steps of malaria infection. in this section, we describe both microscopy-based and flow cytometry-based sporozoite invasion, migration and development assays with the rodent malaria parasites, plasmodium berghei and plasmodium yoelii, and the human malaria parasite, plasmodium falciparum.022990793
bioluminescence imaging of p. berghei schizont sequestration in rodents.we describe a technology for imaging the sequestration of infected red blood cells (irbc) of the rodent malaria parasite plasmodium berghei both in the bodies of live mice and in dissected organs, using a transgenic parasite that expresses luciferase. real-time imaging of sequestered irbc is performed by measuring bioluminescence produced by the enzymatic reaction in parasites between the luciferase enzyme and its substrate luciferin injected into the mice several minutes prior to imaging. the b ...201322990791
recombination-mediated genetic engineering of plasmodium berghei dna.dna of plasmodium berghei is difficult to manipulate in escherichia coli by conventional restriction and ligation methods due to its high content of adenine and thymine (at) nucleotides. this limits our ability to clone large genes and to generate complex vectors for modifying the parasite genome. we here describe a protocol for using lambda red recombinase to modify inserts of a p. berghei genomic dna library constructed in a linear, low-copy, phage-derived vector. the method uses primer extens ...201322990774
transfection of rodent malaria parasites.gene manipulation is an invaluable tool to investigate and understand the biology of an organism. although this technology has been applied to both the human and rodent malarial parasites (rmp), plasmodium berghei in particular offers a more robust system due to a higher and more efficient transformation rate. here, we describe a comprehensive transfection and selection protocol using p. berghei including a variant negative selection protocol administering 5-fluorocytosine to the animals in drin ...201322990773
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
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
[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
bacteria and protozoa differentially modulate the expression of rab proteins.phagocytic cells represent an important line of innate defense against microorganisms. uptake of microorganisms by these cells involves the formation of a phagosome that matures by fusing with endocytic compartments, resulting in killing of the enclosed microbe. small gtpases of the rab family are key regulators of vesicular trafficking in the endocytic pathway. intracellular pathogens can interfere with the function of these proteins in order to subvert host immune responses. however, it is unk ...201222911692
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
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
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
a plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mrnas.calcium-dependent protein kinases (cdpks) play key regulatory roles in the life cycle of the malaria parasite, but in many cases their precise molecular functions are unknown. using the rodent malaria parasite plasmodium berghei, we show that cdpk1, which is known to be essential in the asexual blood stage of the parasite, is expressed in all life stages and is indispensable during the sexual mosquito life-cycle stages. knockdown of cdpk1 in sexual stages resulted in developmentally arrested par ...022817984
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
fighting malaria with engineered symbiotic bacteria from vector mosquitoes.the most vulnerable stages of plasmodium development occur in the lumen of the mosquito midgut, a compartment shared with symbiotic bacteria. here, we describe a strategy that uses symbiotic bacteria to deliver antimalaria effector molecules to the midgut lumen, thus rendering host mosquitoes refractory to malaria infection. the escherichia coli hemolysin a secretion system was used to promote the secretion of a variety of anti-plasmodium effector proteins by pantoea agglomerans, a common mosqui ...201222802646
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
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
nk cells and conventional dendritic cells engage in reciprocal activation for the induction of inflammatory responses during plasmodium berghei anka infection.cerebral malaria (cm) is the most severe syndrome associated with plasmodium falciparum infections. experimental evidence suggests that disease results from the sequestration of parasitized-red blood cells (prbcs) together with inflammatory leukocytes within brain capillaries. we have previously shown that nk cells stimulate migration of cxcr3(+) t cells to the brain of plasmodium berghei anka-infected mice. here we investigated whether interactions between nk cells and dendritic cells (dcs) are ...201322704523
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
morita-baylis-hillman adducts: biological activities and potentialities to the discovery of new cheaper drugs.this review aims to present by the first time the morita-baylis-hillman adducts (mbha) as a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs. now, most these compounds can be prepared fast and on a single synthetic step (one-pot reaction) in high yields and using ecofriendly synthetic protocols. we highlight here the aromatic mbha, which have shown diverse biological activities as anti-leishmania chagasi and leishmania amazonen ...201222632793
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
liver-stage malaria parasites vulnerable to diverse chemical scaffolds.human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. all high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. to address these unmet needs, a high-throughput phenotypic liver-stage plasmodium parasite screen was developed to systematically identify molecules with liver- ...201222586124
endoplasmic reticulum stress and neurodegeneration in experimental cerebral malaria.experimental cerebral malaria (ecm) resulting from plasmodium berghei anka (pba) infection in mice results in neuronal cell death. however, the precise mechanisms leading to neuronal cell death in ecm have not been fully elucidated. in the present study, we report the presence of endoplasmic reticulum (er) stress markers and activation of the unfolded protein response (upr) in the brain during the pathogenesis of ecm. specific findings included activation of pkr-like erkinase, inositol-requiring ...201322584375
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
anti-plasmodial effects of azadirachta indica in experimental cerebral malaria: apoptosis of cerebellar purkinje cells of mice as a marker.malaria is a major public health problem in the world, but treatment of malaria is becoming more difficult due to increasing drug resistance. therefore, the need for alternative drugs is acute.201022558559
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
histopathological effects of sub-chronic lamivudine-artesunate co-administration on the liver of diseased adult wistar rats.lamivudine and artesunate are sometimes co administered in hiv-malaria co morbidity. both drugs are used concurrently in presumptive malaria treatment and simultaneous hiv post exposure prophylaxis.201122540106
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
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
amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted 8-aminoquinolines: synthesis and evaluation of anti-infective, β-haematin inhibition and cytotoxic activities.three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. the synthesized compounds were tested for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant plasmodium falciparum strains, in vitro cytotoxicity in mammalian kidney cells (vero), in vitro antileishmanial activity against leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of ...201222483965
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
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
antiparasitic activities of two sesquiterpenic lactones isolated from acanthospermum hispidum d.c.aerial parts of acanthospermum hispidum d.c. are often used by traditional healers in benin for various diseases and especially for malaria.201222440261
characterization of plasmodium liver stage inhibition by halofuginone.malaria is a devastating parasitic disease that afflicts one-third of the world's population. antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. most therapeutics target blood-stage malaria, whereas only few compounds are active against malaria's liver stage, the first stage of the plasmodium parasite's life cycle within the human host. the identification of inhibitors active against liver-stage malaria would benefit the developme ...201222438279
extrahepatic exoerythrocytic forms of rodent malaria parasites at the site of inoculation: clearance after immunization, susceptibility to primaquine, and contribution to blood-stage infection.plasmodium sporozoites are inoculated into the skin of the mammalian host as infected mosquitoes probe for blood. a proportion of the inoculum enters the bloodstream and goes to the liver, where the sporozoites invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic, or liver, stage. here, we show that a small fraction of the inoculum remains in the skin and begins to develop into exoerythrocytic forms that can persist for days. skin exoerythrocytic forms were observed ...201222431651
anopheles gambiae antiviral immune response to systemic o'nyong-nyong infection.mosquito-borne viral diseases cause significant burden in much of the developing world. although host-virus interactions have been studied extensively in the vertebrate host, little is known about mosquito responses to viral infection. in contrast to mosquitoes of the aedes and culex genera, anopheles gambiae, the principal vector of human malaria, naturally transmits very few arboviruses, the most important of which is o'nyong-nyong virus (onnv). here we have investigated the a. gambiae immune ...201222428080
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
roles of the amino terminal region and repeat region of the plasmodium berghei circumsporozoite protein in parasite infectivity.the circumsporozoite protein (csp) plays a key role in malaria sporozoite infection of both mosquito salivary glands and the vertebrate host. the conserved regions i and ii have been well studied but little is known about the immunogenic central repeat region and the n-terminal region of the protein. rodent malaria plasmodium berghei parasites, in which the endogenous cs gene has been replaced with the avian plasmodium gallinaceum cs (pgcs) sequence, develop normally in the a. stephensi mosquito ...201222393411
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
a putative homologue of cdc20/cdh1 in the malaria parasite is essential for male gamete development.cell-cycle progression is governed by a series of essential regulatory proteins. two major regulators are cell-division cycle protein 20 (cdc20) and its homologue, cdc20 homologue 1 (cdh1), which activate the anaphase-promoting complex/cyclosome (apc/c) in mitosis, and facilitate degradation of mitotic apc/c substrates. the malaria parasite, plasmodium, is a haploid organism which, during its life-cycle undergoes two stages of mitosis; one associated with asexual multiplication and the other wit ...201222383885
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
disruption of plasmepsin-4 and merozoites surface protein-7 genes in plasmodium berghei induces combined virulence-attenuated phenotype.blood stage malaria parasites causing a mild and self limited infection in mice have been obtained with either radiation or chemical mutagenesis showing the possibility of developing an attenuated malaria vaccine. targeted disruption of plasmepsin-4 (pm4) or the merozoite surface protein-7 (msp7) genes also induces a virulence-attenuated phenotype in terms of absence of experimental cerebral malaria (ecm), delayed increase of parasitemia and reduced mortality rate. the decrease in virulence in p ...201122355558
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