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plasmodium berghei glycine cleavage system t-protein is non-essential for parasite survival in vertebrate and invertebrate hosts.t-protein, an aminomethyltransferase, represents one of the four components of glycine cleavage system (gcs) and catalyzes the transfer of methylene group from h-protein intermediate to tetrahydrofolate (thf) forming n(5), n(10)-methylene thf (ch2-thf) with the release of ammonia. the malaria parasite genome encodes t-, h- and l-proteins, but not p-protein which is a glycine decarboxylase generating the aminomethylene group. a putative gcs has been considered to be functional in the parasite mit ...201425454081
themis is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis.we identify an n-ethyl-n-nitrosourea (enu)-induced i23n mutation in the themis protein that causes protection against experimental cerebral malaria (ecm) caused by infection with plasmodium berghei anka. themis(i23n) homozygous mice show reduced cd4(+) and cd8(+) t lymphocyte numbers. ecm resistance in p. berghei anka-infected themis(i23n) mice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. ...201525452553
evidence for the contribution of adult neurogenesis and hippocampal cell death in experimental cerebral malaria cognitive outcome.cognitive dysfunction is a major sign of cerebral malaria (cm). however, the underlying mechanisms of cm cognitive outcome remain poorly understood. a body of evidence suggests that adult neurogenesis may play a role in learning and memory processes. it has also been reported that these phenomena can be regulated by the immune system. we hypothesized that memory dysfunction in cm results from hippocampal neurogenesis impairment mediated by the deregulated immune response during the acute phase o ...201525451296
bioactivity-guided isolation of antiplasmodial constituents from conyza sumatrensis (retz.) e.h. walker.conyza sumatrensis (retz.) e.h. walker (cs) leaves are used for traditional treatment of malaria in cameroon. however, the antimalarial activity of the leaf constituents of this plant is still unexplored. the aim of our investigation was to evaluate the antiplasmodial activity of some bioactive constituents from cs leaves. compounds were isolated from cs leaves and structurally elucidated using extensive spectroscopic analysis. the in vitro antiplasmodial activity of the extracts and pure compou ...201525449289
piperaquine and lumefantrine resistance in plasmodium berghei anka associated with increased expression of ca2+/h+ antiporter and glutathione associated enzymes.we investigated the mechanisms of resistance of two antimalarial drugs piperaquine (pq) and lumefantrine (lm) using the rodent parasite plasmodium berghei as a surrogate of the human parasite, plasmodium falciparum. we analyzed the whole coding sequence of plasmodium berghei chloroquine resistance transporter (pbcrt) and plasmodium berghei multidrug resistance gene 1(pbmdr-1) for polymorphisms. these genes are associated with quinoline resistance in plasmodium falciparum. no polymorphic changes ...201425448357
evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.this study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. compound 1 was able to reduce the in vitro parasite burden, in vitro ...201525431148
anti-malarial activity of a polyherbal product (nefang) during early and established plasmodium infection in rodent models.the emerging resistance of plasmodium species to currently available anti-malarials remains a public health concern, hence the need for new effective, safe and affordable drugs. natural products remain a reliable source of drugs. nefang is a polyherbal anti-malarial of the cameroonian folklore medicine with demonstrated in vitro antiplasmodial and antioxidant activities. it is composed of mangifera indica (bark and leaf), psidium guajava, carica papaya, cymbopogon citratus, citrus sinensis, ocim ...201425421605
histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. we previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor bix-01294 and its analogue tm2-115. here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. bix-01294 and tm2-115 displayed potent in vitro activity, ...201525421480
hemozoin induces hepatic inflammation in mice and is differentially associated with liver pathology depending on the plasmodium strain.malaria is a global disease that clinically affects more than two hundred million people annually. despite the availability of effective antimalarials, mortality rates associated with severe complications are high. hepatopathy is frequently observed in patients with severe malarial disease and its pathogenesis is poorly understood. previously, we observed high amounts of hemozoin or malaria pigment in livers from infected mice. in this study, we investigated whether hemozoin is associated with l ...201425419977
in vitro alterations do not reflect a requirement for host cell cycle progression during plasmodium liver stage infection.prior to invading nonreplicative erythrocytes, plasmodium parasites undergo their first obligate step in the mammalian host inside hepatocytes, where each sporozoite replicates to generate thousands of merozoites. while normally quiescent, hepatocytes retain proliferative capacity and can readily reenter the cell cycle in response to diverse stimuli. many intracellular pathogens, including protozoan parasites, manipulate the cell cycle progression of their host cells for their own benefit, but i ...201525416236
red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites.many red cell polymorphisms are a result of selective pressure by the malarial parasite. here, we add another red cell disease to the panoply of erythrocytic changes that give rise to resistance to malaria. erythrocytes from individuals with erythropoietic protoporphyria (epp) have low levels of the final enzyme in the heme biosynthetic pathway, ferrochelatase. cells from these patients are resistant to the growth of plasmodium falciparum malarial parasites. this phenomenon is due to the absence ...201525414439
in vivo antimalarial activity and toxicological effects of methanolic extract of cocos nucifera (dwarf red variety) husk fibre.phytochemical constituents as well as antimalarial and toxicity potentials of the methanolic extract of the husk fibre of dwarf red variety of cocos nucifera were evaluated in this study.201425412668
complement c5-deficient mice are protected from seizures in experimental cerebral malaria.studies have demonstrated that the membrane attack complex (mac) of complement can evoke seizures when injected directly into rodent brain. in the course of studies that examine the role of complement in the development of experimental cerebral malaria (ecm), we observed fewer seizures in mice deficient in c5, a component required for mac formation. to determine if the mac contributed to the tonic-clonic seizures characteristic of ecm, we performed long-term video-electroencephalography (eeg) on ...201425385326
efficacy of intravenous methylene blue, intravenous artesunate, and their combination in preclinical models of malaria.intravenous artesunate (iv as) is the present treatment of choice for severe malaria, but development of artemisinin resistance indicates that a further agent will be needed. methylene blue (mb) is an approved human agent for iv and oral use, and is already being investigated for oral treatment of uncomplicated malaria. to initiate investigation of iv mb for severe malaria, the efficacy of iv mb was compared to iv as and to their combination in rat and non-human primate malaria models.201425336091
in vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine.several antibiotics have shown promising anti-malarial effects and have been useful for malarial chemotherapy, particularly in combination with standard anti-malarial drugs. tigecycline, a semi-synthetic derivative of minocycline with a unique and novel mechanism of action, is the first clinically available drug in a new class of glycylcycline antibiotics.201425336038
jpc-2997, a new aminomethylphenol with high in vitro and in vivo antimalarial activities against blood stages of plasmodium.4-(tert-butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (jpc-2997) is a new aminomethylphenol compound that is highly active in vitro against the chloroquine-sensitive d6, the chloroquine-resistant w2, and the multidrug-resistant tm90-c2b plasmodium falciparum lines, with 50% inhibitory concentrations (ic50s) ranging from 7 nm to 34 nm. jpc-2997 is >2,500 times less cytotoxic (ic50s > 35 μm) to human (hepg2 and hek293) and rodent (bhk) cell lines than the d6 parasit ...201525331702
plasmodium berghei histamine-releasing factor favours liver-stage development via inhibition of il-6 production and associates with a severe outcome of disease.plasmodium spp., which causes malaria, produces a histamine-releasing factor (hrf), an orthologue of mammalian hrf. histamine-releasing factor produced by erythrocytic stages of the parasite is thought to play a role in the pathogenesis of severe malaria. here, we show in a rodent model that hrf is not important during the erythrocytic but pre-erythrocytic phase of infection, which mainly consists in the transformation in the liver of the mosquito-injected parasite form into the erythrocyte-infe ...201525329441
spatiotemporal requirements for irf7 in mediating type i ifn-dependent susceptibility to blood-stage plasmodium infection.type i ifn signaling suppresses splenic t helper 1 (th1) responses during blood-stage plasmodium berghei anka (pba) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. interferon regulatory factor 7 (irf7) is considered to be a master regulator of type i ifn responses. here, we assessed irf7 for its roles during lethal pba infection and nonlethal plasmodium chabaudi chabaudi as (pcas) i ...201525319247
enantiomerically pure amino-alcohol quinolines: in vitro anti-malarial activity in combination with dihydroartemisinin, cytotoxicity and in vivo efficacy in a plasmodium berghei mouse model.as resistance to marketed anti-malarial drugs continues to spread, the need for new molecules active on plasmodium falciparum-resistant strains grows. pure (s) enantiomers of amino-alcohol quinolines previously displayed a good in vitro anti-malarial activity. therefore, a more thorough assessment of their potential clinical use through a rodent model and an in vitro evaluation of their combination with artemisinin was undertaken.201425319003
medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a softfocus kinase library: part 2.on the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and herg profile while maintaining metabolic stability and in vitro potency. toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against nf54 (sensitive) and k1 (multidrug resistant) strains of the malaria parasite plasmodium falciparum and evaluated for both aqueous solubility and metabolic ...201425313449
design, synthesis and evaluation of antimalarial potential of polyphosphazene linked combination therapy of primaquine and dihydroartemisinin.various polymer drug conjugates (13-16) such as primaquine and dihydroartemisinin conjugated 2-propoxy substituted polyphosphazenes (13), primaquine and dihydroartemisinin conjugated 4-acetamidophenoxy substituted polyphosphazenes (14), primaquine and dihydroartemisinin conjugated 4-formyl substituted polyphosphazenes (15) and primaquine and dihydroartemisinin conjugated 4-aminoethylbenzoate substituted polyphosphazenes (16) were synthesized using substituted polyphosphazenes as polymer and prim ...201525312346
evaluation of the antimalarial potential of icacina senegalensis juss (icacinaceae).to evaluate in vivo antimalarial activity of methanol leaf extract of icacina senegalensis.201425312169
effect of thioredoxin peroxidase-1 gene disruption on the liver stages of the rodent malaria parasite plasmodium berghei.phenotypic observation of thioredoxin peroxidase-1 (tpx-1) gene-disrupted plasmodium berghei (tpx-1 ko) in the liver-stage was performed with an in vitro infection system in order to investigate defective liver-stage development in a mouse infection model. indirect immunofluorescence microscopy assay with anti-circumsporozoite protein antibody revealed that in the liver schizont stage, tpx-1 ko parasite cells were significantly smaller than cells of the wild-type parent strain (wt). indirect imm ...201525284813
antimalarial activity of malaysian plectranthus amboinicus against plasmodium berghei.malaria is a mosquito-borne disease caused by parasitic protozoa from the genus of plasmodium. the protozoans have developed resistance against many of current drugs. it is urgent to find an alternative source of new antimalarial agent. in the effort to discover new antimalarial agents, this research has been conducted on plectranthus amboinicus.201425276063
predictive criteria to study the pathogenesis of malaria-associated ali/ards in mice.malaria-associated acute lung injury/acute respiratory distress syndrome (ali/ards) often results in morbidity and mortality. murine models to study malaria-associated ali/ards have been described; we still lack a method of distinguishing which mice will develop ali/ards before death. this work aimed to characterize malaria-associated ali/ards in a murine model and to demonstrate the first method to predict whether mice are suffering from ali/ards before death. dba/2 mice infected with plasmodiu ...201425276057
modulatory effect of crude aqueous extract of lingzhi or reishi medicinal mushroom, ganoderma lucidum (higher basidiomycetes), on hematological and antioxidant indices in plasmodium berghei-infected mice.hematological and antioxidant effects of the aqueous extract of fruiting bodies of ganoderma lucidum were evaluated in plasmodium berghei-infected mice. extract was administered at doses of 100, 250, and 500 mg/kg body weight by an intragastric tube once daily for 14 d starting from the fourth day after parasite inoculation. at the end of treatment period, mice in each group were sacrificed and blood was collected for hematological and biochemical analyses. a significant (p<0.05) decrease was ob ...201425271985
direct evidence for the atovaquone action on the plasmodium cytochrome bc1 complex.atovaquone, a coenzyme q analogue has been indicated to specifically target the cytochrome bc1 complex of the mitochondrial respiratory chain in the malarial parasite and other protozoan. various mutations in the quinone binding site of the cytochrome b gene of plasmodium spp. such as m133i, l144s, l271v, k272r, y268c, y268s, y268n, and v284f are suggesting to associate with resistance to atovaquone. there is no direct evidence of relation between the mutations and resistance to atovaquone in pl ...201525264100
distinct properties of the egress-related osmiophilic bodies in male and female gametocytes of the rodent malaria parasite plasmodium berghei.gametogenesis is the earliest event after uptake of malaria parasites by the mosquito vector, with a decisive impact on colonization of the mosquito midgut. this process is triggered by a drop in temperature and contact with mosquito molecules. in a few minutes, male and female gametocytes escape from the host erythrocyte by rupturing the parasitophorous vacuole and the erythrocyte membranes. electron-dense, oval-shaped organelles, the osmiophilic bodies (ob), have been implicated in the egress ...201525262869
trpv1 antagonism by capsazepine modulates innate immune response in mice infected with plasmodium berghei anka.thousands of people suffer from severe malaria every year. the innate immune response plays a determinant role in host's defence to malaria. transient receptor potential vanilloid 1 (trpv1) modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. we investigated the effects of capsazepine, a trpv1 antagonist, in malaria. c57bl/6 mice received 10(5) red blood cells infected with plasmodium berghei anka intraperitoneally. noninfected mi ...201425242870
a novel plasmodium-specific prodomain fold regulates the malaria drug target sub1 subtilase.the plasmodium subtilase sub1 plays a pivotal role during the egress of malaria parasites from host hepatocytes and erythrocytes. here we report the crystal structure of full-length sub1 from the human-infecting parasite plasmodium vivax, revealing a bacterial-like catalytic domain in complex with a plasmodium-specific prodomain. the latter displays a novel architecture with an amino-terminal insertion that functions as a 'belt', embracing the catalytic domain to further stabilize the quaternary ...201425204226
loss of toll-like receptor 7 alters cytokine production and protects against experimental cerebral malaria.malaria, caused by plasmodium sp. parasites, is a leading cause of global morbidity and mortality. cerebral malaria, characterized by neurological symptoms, is a life-threatening complication of malaria affecting over 500,000 young children in africa every year. because of the prevalence and severity of cerebral malaria, a better understanding of the underlying molecular mechanisms of its pathology is desirable and could inform future development of therapeutics. this study sought to clarify the ...201425192715
vascular dysfunction as a target for adjuvant therapy in cerebral malaria.cerebral malaria (cm) is a life-threatening complication of plasmodium falciparum malaria that continues to be a major global health problem. brain vascular dysfunction is a main factor underlying the pathogenesis of cm and can be a target for the development of adjuvant therapies for the disease. vascular occlusion by parasitised red blood cells and vasoconstriction/vascular dysfunction results in impaired cerebral blood flow, ischaemia, hypoxia, acidosis and death. in this review, we discuss t ...201425185000
micromagnetic resonance relaxometry for rapid label-free malaria diagnosis.we report a new technique for sensitive, quantitative and rapid detection of plasmodium spp.-infected red blood cells (rbcs) by means of magnetic resonance relaxometry (mrr). during the intraerythrocytic cycle, malaria parasites metabolize large amounts of cellular hemoglobin and convert it into hemozoin crystallites. we exploit the relatively large paramagnetic susceptibility of these hemozoin particles, which induce substantial changes in the transverse relaxation rate of proton nuclear magnet ...201425173428
an investigation into the antimalarial effect of methanolic extract of paullinia pinnata leaves in plasmodium berghei infected mice and course of infection.the aim of this study was to investigate the antimalarial activity of methanolic leaves extract of paullinia pinnata on chloroquine-sensitive plasmodium berghei nk 65 infected mice.201426688604
in vivo antiplasmodial potentials of the combinations of four nigerian antimalarial plants.various combinations of nauclea latifolia root, artocarpus altilis stem bark, murraya koenigii leaf and enantia chlorantha stem bark used in african ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using plasmodium berghei berghei-infected mice. the respective prophylactic and curative ed50 values of 189.4 and 174.5 mg/kg for n. latifolia and chemosuppressive ed50 value of 227.2 mg/kg for a. altilis showed t ...201425162955
damage to the blood-brain barrier during experimental cerebral malaria results from synergistic effects of cd8+ t cells with different specificities.cd8(+) t cells play a pathogenic role in the development of murine experimental cerebral malaria (ecm) induced by plasmodium berghei anka (pba) infection in c57bl/6 mice. only a limited number of cd8(+) epitopes have been described. here, we report the identification of a new epitope from the bergheilysin protein recognized by pba-specific cd8(+) t cells. induction and functionality of these specific cd8(+) t cells were investigated in parallel with previously reported epitopes, using new tools ...201425156726
the subcellular location of ovalbumin in plasmodium berghei blood stages influences the magnitude of t-cell responses.model antigens are frequently introduced into pathogens to study determinants that influence t-cell responses to infections. to address whether an antigen's subcellular location influences the nature and magnitude of antigen-specific t-cell responses, we generated plasmodium berghei parasites expressing the model antigen ovalbumin (ova) either in the parasite cytoplasm or on the parasitophorous vacuole membrane (pvm). for cytosolic expression, ova alone or conjugated to mcherry was expressed fro ...201425156724
evaluation of antimalarial activity of leaves of acokanthera schimperi and croton macrostachyus against plasmodium berghei in swiss albino mice.malaria is one of the most important tropical diseases and the greatest cause of hospitalization and death. recurring problems of drug resistance are reinforcing the need for finding new antimalarial drugs. in this respect, natural plant products are the main sources of biologically active compounds and have potential for the development of novel antimalarial drugs. a study was conducted to evaluate extracts of the leaves of croton macrostachyus and acokanthera schimperi for their in vivo antima ...201425155821
molecular characterization of calreticulin from anopheles stephensi midgut cells and functional assay of the recombinant calreticulin with plasmodium berghei ookinetes.transmission blocking vaccines (tbvs) that target the antigens on the midgut epithelium of anopheles mosquitoes are among the promising tools for the elimination of the malaria parasite. characterization and analysis of effective antigens is the first step to design tbvs. calreticulin (crt), a lectin-like protein, from anopheles albimanus midgut, has shown antigenic features, suggesting a promising and novel tbv target. crt is a highly conserved protein with similar features in vertebrates and i ...201425150160
evaluation of the adjuvant activity of propranolol, a beta-adrenergic receptor antagonist, on efficacy of a malaria vaccine model in balb/c mice.we have previously shown the adjuvant activity of propranolol (prp) (a beta-adrenergic receptor antagonist) using a vaccine model for salmonella typhimurium. in this study prp was used as an adjuvant in combination with plasmodium berghei (p. berghei) whole blood stage (pwbs) antigens. balb/c mice were immunized three times with a 2-week interval, either pwbs vaccine alone or in combination with the adjuvant alum or propranolol. the control group received phosphate buffered saline. evaluation of ...201425150071
orally bioavailable 6-chloro-7-methoxy-4(1h)-quinolones efficacious against multiple stages of plasmodium.the continued proliferation of malaria throughout temperate and tropical regions of the world has promoted a push for more efficacious treatments to combat the disease. unfortunately, more recent remedies such as artemisinin combination therapies have been rendered less effective due to developing parasite resistance, and new drugs are required that target the parasite in the liver to support the disease elimination efforts. research was initiated to revisit antimalarials developed in the 1940s ...201425148516
dominant negative mutant of plasmodium rad51 causes reduced parasite burden in host by abrogating dna double-strand break repair.malaria parasites survive through repairing a plethora of dna double-stranded breaks (dsbs) experienced during their asexual growth. in plasmodium rad51 mediated homologous recombination (hr) mechanism and homology-independent alternative end-joining mechanism have been identified. here we address whether loss of hr activity can be compensated by other dsb repair mechanisms. creating a transgenic plasmodium line defective in hr function, we demonstrate that hr is the most important dsb repair pa ...201425145341
preparation, characterization, and optimization of primaquine-loaded solid lipid nanoparticles.primaquine (pq) is one of the most widely used antimalarial drugs and is the only available drug that combats the relapsing form of malaria. pq use in higher doses is limited by severe tissue toxicity including hematological- and gastrointestinal-related side effects. nanoformulation of drugs in an appropriate drug carrier system has been extensively studied and shown to have the potential to improve bioavailability, thereby enhancing activity, reducing dose frequency, and subsequently reducing ...201425143734
43 kda and 66 kda, two blood stage antigens induce immune response in plasmodium berghei malaria.the hunt for an effective vaccine against malaria still continues. several new target antigens as candidates for vaccine design are being explored and tested for their efficacy. in the present study the sera from mice immunized with 24,000 x g fraction of plasmodium berghei has been used to identify highly immunogenic blood stage antigens. the protective antibodies present in immune sera were covalently immobilized on cnbr activated sepharose 4b and used for affinity chromatography purification ...201425141540
in vitro and in vivo anti-malarial activity of limonoids isolated from the residual seed biomass from carapa guianensis (andiroba) oil production.carapa guianensis is a cultivable tree used by traditional health practitioners in the amazon region to treat several diseases and particularly symptoms related to malaria. abundant residual pressed seed material (rpsm) results as a by-product of carapa or andiroba oil production. the objective of this study was to evaluate the in vitro and in vivo anti-malarial activity and cytotoxicity of limonoids isolated from c. guaianensis rpsm.201425124944
proteomic analysis of the plasmodium male gamete reveals the key role for glycolysis in flagellar motility.gametogenesis and fertilization play crucial roles in malaria transmission. while male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. for example, the pathway of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown.201425124718
2-octadecynoic acid as a dual life stage inhibitor of plasmodium infections and plasmodial fas-ii enzymes.the malaria parasite plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (ls) followed by a blood stage with all clinical manifestation of the disease. in this study, we investigated a series of 2-alkynoic fatty acids (2-afas) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-octadecynoic acid (2-oda) was identified as the best inhibitor of plasmodium berghei parasites with ten times higher potency (ic50= ...201425103602
expression and localization of rhoptry neck protein 5 in merozoites and sporozoites of plasmodium yoelii.host cell invasion by apicomplexan parasites marks a crucial step in disease establishment and pathogenesis. the moving junction (mj) is a conserved and essential feature among parasites of this phylum during host cell invasion, thus proteins that associate at this mj are potential targets of drug and vaccine development. in both toxoplasma gondii and plasmodium falciparum, a micronemal protein, apical membrane antigen 1 (ama1), and rhoptry neck proteins (rons; ron2 and ron4) form an essential c ...201425102354
interaction between rifampicin, amodiaquine and artemether in mice infected with chloroquine resistant plasmodium berghei.artemisinin-based combination therapy (act) remains the most effective chemotherapeutic strategy in the management of malaria. however, reports of reduced susceptibility of plasmodium falciparum to the act justify the need for continued search for alternative anti-malarial drugs. the use of antibiotics with anti-malarial properties represents a potentially valuable chemotherapeutic option for the management of drug resistant infections. thus, the intrinsic anti-malarial activity of the combinati ...201425091936
potent antimalarial activity of acriflavine in vitro and in vivo.malaria continues to be a major health problem globally. there is an urgent need to find new antimalarials. acriflavine (acf) is known as an antibacterial agent and more recently as an anticancer agent. here, we report that acf inhibits the growth of asexual stages of both chloroquine (cq) sensitive and resistant strains of human malarial parasite, plasmodium falciparum in vitro at nanomolar concentration. acf clears the malaria infection in vivo from the bloodstreams of mice infected with plasm ...201425089658
iron overload in plasmodium berghei-infected placenta as a pathogenesis mechanism of fetal death.plasmodium infection during gestation may lead to severe clinical manifestations including abortion, stillbirth, intrauterine growth retardation, and low birth weight. mechanisms underlying such poor pregnancy outcomes are still unclear. in the animal model of severe placental malaria (pm), in utero fetal death frequently occurs and mothers often succumb to infection before or immediately after delivery. plasmodium berghei-infected erythrocytes (ies) continuously accumulate in the placenta, wher ...201425071574
biochemical and antiparasitic properties of inhibitors of the plasmodium falciparum calcium-dependent protein kinase pfcdpk1.pfcdpk1 is a plasmodium falciparum calcium-dependent protein kinase, which has been identified as a potential target for novel antimalarial chemotherapeutics. in order to further investigate the role of pfcdpk1, we established a high-throughput in vitro biochemical assay and used it to screen a library of over 35,000 small molecules. five chemical series of inhibitors were initially identified from the screen, from which series 1 and 2 were selected for chemical optimization. indicative of their ...201425070106
chitinase 3-like 1 is induced by plasmodium falciparum malaria and predicts outcome of cerebral malaria and severe malarial anaemia in a case-control study of african children.severe and fatal malaria are associated with dysregulated host inflammatory responses to infection. chitinase 3-like 1 (chi3l1) is a secreted glycoprotein implicated in regulating immune responses. expression and function of chi3l1 in malaria infection were investigated.201425047113
antiplasmodial potential of homeopathic drugs chelidonium and nosode against plasmodium berghei infection.malaria remains a major global health concern in developing regions of the world. homeopathy, a holistic system of medicine, has a lot to offer in protecting against malaria.201425046315
real-time imaging reveals the dynamics of leukocyte behaviour during experimental cerebral malaria pathogenesis.during experimental cerebral malaria (ecm) mice develop a lethal neuropathological syndrome associated with microcirculatory dysfunction and intravascular leukocyte sequestration. the precise spatio-temporal context in which the intravascular immune response unfolds is incompletely understood. we developed a 2-photon intravital microscopy (2p-ivm)-based brain-imaging model to monitor the real-time behaviour of leukocytes directly within the brain vasculature during ecm. ly6c(hi) monocytes, but n ...201425033406
a novel adjuvant, the mixture of alum and naltrexone, augments vaccine-induced immunity against plasmodium berghei.we previously showed that the mixture of naltrexone (nlt), a general opioid antagonist, and alum, acts as an effective adjuvant in enhancing vaccine-induced t helper 1 (th1) humoral immune responses against toxoplasma gondii. here, we tested the efficacy of the mixture of nlt and alum in the induction of immunity in response to blood stages of plasmodium berghei (bspb) as a model vaccine. balb/c mice were divided into five vaccination groups. mice in the experimental groups received the bspb vac ...201425020077
deletion of c-reactive protein ameliorates experimental cerebral malaria?c-reactive protein (crp) level correlates with parasitemia and severity of malaria, but whether this reflects causality remains unknown.201425002461
dual-stage triterpenoids from an african medicinal plant targeting the malaria parasite.sixteen triterpenoids (1-16), previously isolated from the aerial parts of the african medicinal plant momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of plasmodium berghei, measuring the luminescence intensity in huh-7 cells infected with a firefly luciferase-expressing p. berghei line, pbgfp-luccon. toxicity of compounds (1-16) was assessed on the same cell line through the fluorescence measurement of cell confluency. the highest activi ...201425002232
evaluating experimental cerebral malaria using oxidative stress indicator okd48 mice.cerebral malaria is a fatal complication of malaria. conventional methods for evaluating experimental cerebral malaria have several drawbacks. therefore, we aimed to develop an easy-to-use method for evaluating experimental cerebral malaria using okd48 (keap1-dependent oxidative stress detector, no-48-luciferase) mice to evaluate oxidative stress. okd48 mice infected with plasmodium berghei anka strain (pba) suffered from experimental cerebral malaria and oxidative stress was successfully detect ...201424995619
systemic and cerebral vascular endothelial growth factor levels increase in murine cerebral malaria along with increased calpain and caspase activity and can be reduced by erythropoietin treatment.the pathogenesis of cerebral malaria (cm) includes compromised microvascular perfusion, increased inflammation, cytoadhesion, and endothelial activation. these events cause blood-brain barrier disruption and neuropathology and associations with the vascular endothelial growth factor (vegf) signaling pathway have been shown. we studied this pathway in mice infected with plasmodium berghei anka causing murine cm with or without the use of erythropoietin (epo) as adjunct therapy. elisa and western ...201424995009
implementation of minimally invasive and objective humane endpoints in the study of murine plasmodium infections.summary defining appropriate and objective endpoints for animal research can be difficult. previously we evaluated and implemented a body temperature (bt) of <32 °c as an endpoint for experimental cerebral malaria (ecm) and were interested in a similar endpoint for a model of severe malarial anaemia (sma). furthermore, we investigate the potential of a minimally invasive, non-contact infrared thermometer for repeated bt measurement. ecm was induced with plasmodium berghei anka infection in c57bl ...201424993593
dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei.the aim of the study was to investigate the effects of dietary combination of nigella sativa seed and oil extracts with chloroquine (cq), and how these combinations enhance cq efficacy in mice infected with plasmodium berghei and their survival rates.201424991115
enhanced antimalarial activity by a novel artemether-lumefantrine lipid emulsion for parenteral administration.artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. cremophor el as an emulsion excipient has been shown to cause serious side effects. this study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (le) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. their physical and chemical stab ...201424982079
local immune response to injection of plasmodium sporozoites into the skin.malarial infection is initiated when the sporozoite form of the plasmodium parasite is inoculated into the skin by a mosquito. sporozoites invade hepatocytes in the liver and develop into the erythrocyte-infecting form of the parasite, the cause of clinical blood infection. protection against parasite development in the liver can be induced by injection of live attenuated parasites that do not develop in the liver and thus do not cause blood infection. radiation-attenuated sporozoites (ras) and ...201424981449
plasmodium berghei infection ameliorates atopic dermatitis-like skin lesions in nc/nga mice.atopic diseases are more prevalent in industrialized countries than in developing countries. in addition, significant differences in the prevalence of allergic diseases are observed between rural and urban areas within the same country. this difference in prevalence has been attributed to what is called the 'hygiene hypothesis'. although parasitic infections are known to protect against allergic reactions, the mechanism is still unknown. the aim of this study was to investigate whether or not ma ...201424976451
electron microscopic features of brain edema in rodent cerebral malaria in relation to glial fibrillary acidic protein expression.the mechanisms leading to cerebral malaria (cm) are not completely understood. brain edema has been suggested as having an important role in experimental cm. in this study, cba/cah mice were infected with plasmodium berghei anka blood-stage and when typical symptoms of cm developed on day 7, brain tissues were processed for electron-microscopic and immunohistochemical studies. the study demonstrated ultrastructural hallmarks of cerebral edema by perivascular edema and astroglial dilatation confi ...201424966914
vitamin d inhibits the occurrence of experimental cerebral malaria in mice by suppressing the host inflammatory response.in animal models of experimental cerebral malaria (ecm), neuropathology is associated with an overwhelming inflammatory response and sequestration of leukocytes and parasite-infected rbcs in the brain. in this study, we explored the effect of vitamin d (vd; cholecalciferol) treatment on host immunity and outcome of ecm in c57bl/6 mice during plasmodium berghei anka (pba) infection. we observed that oral administration of vd both before and after pba infection completely protected mice from ecm. ...201424965778
comparing systemic metabolic responses in mice to single or dual infection with plasmodium berghei and heligmosomoides bakeri.concomitant infections with plasmodium and gastrointestinal nematodes are frequently observed in humans. at the metabolic level, the cross-talk between the host and multiple coexisting pathogens is poorly characterized. the purpose of this study was to give a comprehensive insight into the systemic metabolic phenotype of mice with a single or dual infection with plasmodium berghei and heligmosomoides bakeri. four groups of eight nmri female mice were infected with p. berghei or h. bakeri, or wit ...201424960299
synergistic effect of aqueous extract of telfaria occidentalis on the biological activities of artesunate in plasmodium berghei infected mice.resistance to most antimalarial drugs has encouraged the use of herbal preparations along with prescribed orthodox drugs.201324940320
ultrastructure of the lung in a murine model of malaria-associated acute lung injury/acute respiratory distress syndrome.the mechanisms through which infection with plasmodium spp. result in lung disease are largely unknown. recently a number of mouse models have been developed to research malaria-associated lung injury but no detailed ultrastructure studies of the disease in its terminal stages in a murine model have yet been published. the goal was to perform an ultrastructural analysis of the lungs of mice that died with malaria-associated acute lung injury/acute respiratory distress syndrome to better determin ...201424927627
treatment of murine cerebral malaria by artemisone in combination with conventional antimalarial drugs: antiplasmodial effects and immune responses.the decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications of plasmodium falciparum resistance to artemisinins. consequently, drug combinations are recommended for prevention of the induction of resistance. the research here demonstrates the effects of novel combinations o ...201424913162
antiplasmodial effect of anthocleista vogelii on albino mice experimentally infected with plasmodium berghei berghei (nk 65).the objective of the present study was to investigate the antiplasmodial effect of the ethanolic stem bark extract of anthocleista vogelii at different doses in albino mice infected with plasmodium berghei berghei (nk 65). thirty-six mice were divided into six groups of six mice each. five groups (b1-b3, d, and g) were infected with plasmodium berghei berghei parasitized red blood cells. groups d, h, and g served as the controls. six days after infection, mice in groups b1, b2, and b3 were treat ...201424900913
identification and optimization of an aminoalcohol-carbazole series with antimalarial properties.recent observations on the emergence of artemisinin resistant parasites have highlighted the need for new antimalarial treatments. an hts campaign led to the identification of the 1-(1-aminopropan-2-ol)carbazole analogues as potent hits against plasmodium falciparum k1 strain. the sar study and optimization of early adme and physicochemical properties direct us to the selection of a late lead compound that shows good efficacy when orally administrated in the in vivo p. berghei mouse model.201324900603
deorphaning pyrrolopyrazines as potent multi-target antimalarial agents.the discovery of pyrrolopyrazines as potent antimalarial agents is presented, with the most effective compounds exhibiting ec50 values in the low nanomolar range against asexual blood stages of plasmodium falciparum in human red blood cells, and plasmodium berghei liver schizonts, with negligible hepg2 cytotoxicity. their potential mode of action is uncovered by predicting macromolecular targets through avant-garde computer modeling. the consensus prediction method suggested a functional resembl ...201424895172
gene disruption reveals a dispensable role for plasmepsin vii in the plasmodium berghei life cycle.plasmepsins (pm), aspartic proteases of plasmodium, comprises a family of ten proteins that perform critical functions in plasmodium life cycle. except vii and viii, functions of the remaining plasmepsin members have been well characterized. here, we have generated a mutant parasite lacking pm vii in plasmodium berghei using reverse genetics approach. systematic comparison of growth kinetics and infection in both mosquito and vertebrate host revealed that pm vii depleted mutants exhibited no def ...201424893340
effects of the vascular endothelial growth factor receptor-2 (vegfr-2) inhibitor su5416 on in vitro cultures of plasmodium falciparum.vascular endothelial growth factor (vegf) is taken up by parasitized red blood cells during malaria and stimulates intra-erythrocytic growth of plasmodium falciparum in vitro. the cause and consequence of this uptake is not understood.201424885283
investigation of indolglyoxamide and indolacetamide analogues of polyamines as antimalarial and antitrypanosomal agents.pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine a and b (2 and 3) to be weak growth inhibitors of trypanosoma brucei rhodesiense (ic50 59 and 44 μm, respectively) and plasmodium falciparum (k1 dual drug resistant strain) (ic50 41 and 15 μm, respectively), but lacking in selectivity (l6 rat myoblast, ic50 24 μm and 25 μm, respectively). to expand the structure-activity relationship of this compound class towards both parasites, w ...201424879541
vascular dysfunction as a target for adjuvant therapy in cerebral malaria.cerebral malaria (cm) is a life-threatening complication of plasmodium falciparum malaria that continues to be a major global health problem. brain vascular dysfunction is a main factor underlying the pathogenesis of cm and can be a target for the development of adjuvant therapies for the disease. vascular occlusion by parasitised red blood cells and vasoconstriction/vascular dysfunction results in impaired cerebral blood flow, ischaemia, hypoxia, acidosis and death. in this review, we discuss t ...201424863978
antibodies to pfsea-1 block parasite egress from rbcs and protect against malaria infection.novel vaccines are urgently needed to reduce the burden of severe malaria. using a differential whole-proteome screening method, we identified plasmodium falciparum schizont egress antigen-1 (pfsea-1), a 244-kilodalton parasite antigen expressed in schizont-infected red blood cells (rbcs). antibodies to pfsea-1 decreased parasite replication by arresting schizont rupture, and conditional disruption of pfsea-1 resulted in a profound parasite replication defect. vaccination of mice with recombinan ...201424855263
a prospective strategy to restore the tissue damage in malaria infection: approach with chitosan-trypolyphosphate conjugated nanochloroquine in swiss mice.accumulating evidence indicates that wide range of polymer based nanoconjugated drug have the ability to overcome the microbial infection. the present study was to evaluate the effects of nanoconjugated chloroquine (nch) against plasmodium berghei nk65 (p. berghei) infection on selective makers of oxidative damage, antioxidant status, pro-inflammatory and anti-inflammatory cytokines in liver and spleen. p. berghei infected swiss mice were treated with nch (250mg/kg bw for 15 days) compared with ...201424836985
tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials.the use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of plasmodium parasites. our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. in this study, we adapted this approach to a novel class of ...201424824551
role of the aryl hydrocarbon receptor in the immune response profile and development of pathology during plasmodium berghei anka infection.infection with plasmodium falciparum may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality. plasmodium berghei anka infection of mice recapitulates many features of severe human malaria. the aryl hydrocarbon receptor (ahr) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. we found that ahr-knockout (ko) mice infected with p. berghei anka displayed increased par ...201424818665
the protective effect of cd40 ligand-cd40 signalling is limited during the early phase of plasmodium infection.γδ t cells are essential for eliminating plasmodium berghei xat. because administration of the agonistic anti-cd40 antibody can induce elimination of p. berghei xat parasites in γδ t cell-deficient mice, we considered that γδ t cells might activate dendritic cells via cd40 signalling during infection. here we report that administration of the anti-cd40 antibody to γδ t cell-deficient mice 3-10 days post-p. berghei xat infection could eliminate the parasites. our data suggest that dendritic cell ...201424815981
antiplasmodial activity of certain medicinal plants against chloroquine resistant plasmodium berghei infected white albino balb/c mice.in the present study of antimalarial efficacy, aqueous extracts of leaves and unripe fruits of psidium guajava, leaves of ocimum sanctum and leaves of murraya koenigii are evaluated against plasmodium berghei (chloroquine resistant nk65 strain) infected white albino balb/c mice. a 7 days oral administration was adopted with different dosage viz., 350 mg, 750 mg and 1,000 mg/kg body weight as treatment schedule along with parasite (group i) and drug control with chloroquine, 50 mg/kg body weight ...201424808642
development of artemether and lumefantrine co-loaded nanostructured lipid carriers: physicochemical characterization and in vivo antimalarial activity.artemether and lumefantrine combination therapy is well-accepted for uncomplicated malaria treatment. however, the current available formulation has several pharmacokinetic mismatches such as drug degradation in gastrointestinal tract, erratic absorption, etc. hence, need of the hour is the injectable formulation, which can overcome the pharmacokinetic mismatch associated with current available formulation in the market.201624786480
predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model.to develop a mechanism-based model that describes the time course of the malaria parasite in infected mice receiving a combination therapy regimen of dihydroartemisinin and piperaquine.201424777899
endothelial glycocalyx on brain endothelial cells is lost in experimental cerebral malaria.we hypothesized that the glycocalyx, which is important for endothelial integrity, is lost in severe malaria. c57bl/6 mice were infected with plasmodium berghei anka, resulting in cerebral malaria, or p. chabaudi as, resulting in uncomplicated malaria. we visualized the glycocalyx with transmission electron microscopy and measured circulating glycosaminoglycans by dot blot and elisa. the glycocalyx was degraded in brain vasculature in cerebral and to a lesser degree uncomplicated malaria. it was ...201424756075
mice rescued from severe malaria are protected against renal injury during a second kidney insult.malaria is a worldwide disease that leads to 1 million deaths per year. plasmodium falciparum is the species responsible for the most severe form of malaria leading to different complications. beyond the development of cerebral malaria, impairment of renal function is a mortality indicator in infected patients. treatment with antimalarial drugs can increase survival, however the long-term effects of malaria on renal disease, even after treatment with antimalarials, are unknown. the aim of this s ...201424736406
repositioning: the fast track to new anti-malarial medicines?repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. the compound libraries of glaxosmithkline (gsk), pfizer and astrazeneca (az) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of us food and drug administration (fda)-approved drugs and other bio-actives were tested against plasmodium falciparum blood stages.201424731288
anti-malarial activity of indole alkaloids isolated from aspidosperma olivaceum.several species of aspidosperma (apocynaceae) are used as treatments for human diseases in the tropics. aspidosperma olivaceum, which is used to treat fevers in some regions of brazil, contains the monoterpenoid indole alkaloids (mias) aspidoscarpine, uleine, apparicine, and n-methyl-tetrahydrolivacine. using bio-guided fractionation and cytotoxicity testing in a human hepatoma cell line, several plant fractions and compounds purified from the bark and leaves of the plant were characterized for ...201424731256
in vitro and in vivo antiplasmodial activity of three rwandan medicinal plants and identification of their active compounds.in our previous study, we reported the interesting in vitro antiplasmodial activity of some rwandan plant extracts. this gave rise to the need for these extracts to also be evaluated in vivo and to identify the compounds responsible for their antiplasmodial activity. the aim of our study was, on the one hand, to evaluate the antiplasmodial activity in vivo and the safety of the selected rwandan medicinal plants used in the treatment of malaria, with the objective of promoting the development of ...201424710900
memory t cells maintain protracted protection against malaria.immunologic memory is one of the cardinal features of antigen-specific immune responses, and the persistence of memory cells contributes to prophylactic immunizations against infectious agents. adequately maintained memory t and b cell pools assure a fast, effective and specific response against re-infections. however, many aspects of immunologic memory are still poorly understood, particularly immunologic memory inducible by parasites, for example, plasmodium spp., the causative agents of malar ...201424709142
cross-talk between malarial cysteine proteases and falstatin: the bc loop as a hot-spot target.cysteine proteases play a crucial role in the development of the human malaria parasites plasmodium falciparum and plasmodium vivax. our earlier studies demonstrated that these enzymes are equipped with specific domains for defined functions and further suggested the mechanism of activation of cysteine proteases. the activities of these proteases are regulated by a new class of endogenous inhibitors of cysteine proteases (icps). structural studies of the icps of trypanosoma cruzi (chagasin) and ...201424699522
quantitative analysis of cepharanthine in plasma based on semiautomatic microextraction by packed sorbent combined with liquid chromatography.the spread of plasmodium falciparum resistance toward most of the used drugs requires new antimalarial compounds. taking advantage of the biodiversity, the ethnopharmacological approach opens the way for the discovery and the characterization of potent original molecules. previous works led to the selection of a bisbenzylisoquinoline, cepharanthine, extracted from stephania rotunda, which is mainly present in cambodia. a sensitive and selective liquid chromatography method has been developed for ...201424693462
d-glucose concentration is the key factor facilitating liver stage maturation of plasmodium.the course of malaria infection in mammals begins with transmission of plasmodium sporozoites into the skin by anopheles mosquitoes, followed by migration of the sporozoites to the liver. as no symptoms present until hepatic merozoites are released and until they infect erythrocytes in the blood vessels, sporozoites and liver-stage (ls) parasites are promising targets for anti-malaria drugs aiming to prevent mosquito-to-mammal transmission. in vitro ls parasite development system is useful in th ...201424691399
dendritic cells treated with crude plasmodium berghei extracts acquire immune-modulatory properties and suppress the development of autoimmune neuroinflammation.dendritic cells (dcs) are professional antigen-presenting cells specifically targeted during plasmodium infection. upon infection, dcs show impaired antigen presentation and t-cell activation abilities. in this study, we aimed to evaluate whether cellular extracts obtained from plasmodium berghei-infected erythrocytes (pbx) modulate dcs phenotypically and functionally and the potential therapeutic usage of pbx-modulated dcs in the control of experimental autoimmune encephalomyelitis (eae, the mo ...201424689455
in vivo antimalarial efficacy of acetogenins, alkaloids and flavonoids enriched fractions from annona crassiflora mart.annona crassiflora and annonaceae plants are known to be used to treat malaria by traditional healers. in this work, the antimalarial efficacy of different fractions of a. crassiflora, particularly acetogenin, alkaloids and flavonoid-rich fractions, was determined in vivo using plasmodium berghei-infected mice model and toxicity was accessed by brine shrimp assay. the a. crassiflora fractions were administered at doses of 12.5 mg/kg/day in a 4-day test protocol. the results showed that some frac ...201424678811
differential role of t regulatory and th17 in swiss mice infected with plasmodium berghei anka and plasmodium yoelii.the outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. host immune responses in disease including malaria are finely regulated by the opposing effects of th17 and t regulatory (treg) cells. here we have examined the role of treg cells and th17 cells during malaria infection and find that low levels of treg cells possibly influence the outcome of infections with the lethal strain of plasmodium berghei anka (pba). in contrast, h ...201424675415
parasite densities modulate susceptibility of mice to cerebral malaria during co-infection with schistosoma japonicum and plasmodium berghei.malaria and schistosomiasis are endemic and co-exist in the same geographic areas, even co-infecting the same host. previous studies have reported that concomitant infection with schistosoma japonicum could offer protection against experimental cerebral malaria (ecm) in mice. this study was performed to evaluate whether alterations in parasite density could alter this protective effect.201424670210
influence of formulation ratio of the plant components on the antimalarial properties of mama decoction.mangifera indica, alstonia boonei, morinda lucida and azadirachta indica (mama) decoction, commonly prepared and used in nigeria from 1:1:1:1 ratio of mangifera indica l. (anacardiaceae), alstonia boonei de wild (apocynaceae), morinda lucida benth (rubiaceae), and azadirachta indica a. juss (meliaceae) leaves, plus four new variants of this combination were subjected to three in vivo antimalarial test models using chloroquine-sensitive plasmodium berghei berghei to determine the most active unde ...201424658658
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