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filaria-induced il-10 suppresses murine cerebral malaria.filarial nematodes achieve long survival in their hosts due to their capacity to modulate immune responses. therefore, immunomodulation by filarial nematodes may alter responses to concomitant infections such as malaria. cerebral malaria (cm), a severe complication of plasmodium falciparum infections, is triggered as a consequence of the immune response developed against malaria parasites. the question arises whether prior infection with helminth parasites is beneficial against cm. in the presen ...201020420933
in vitro and in vivo antimalarial and cytotoxic activity of five plants used in congolese traditional medicine.the in vitro antiplasmodial activity and cytotoxicity of methanolic and dichloromethane extracts from five congolese plants were evaluated. the plants were selected following an ethnobotanical survey conducted in d.r. congo and focusing on plants used traditionally to treat malaria. the in vivo antimalarial activity of aqueous and methanolic extracts active in vitro was also determined in mice infected by plasmodium berghei berghei.201020430094
prophylactic and curative activities of extracts from warburgia ugandensis sprague (canellaceae) and zanthoxylum usambarense (engl.) kokwaro (rutaceae) against plasmodium knowlesi and plasmodium berghei.this work reports the anti-plasmodial activities of warburgia ugandensis and zanthoxylum usambarense commonly used as phytomedicines against malaria by some kenyan communities.201020435133
differential effects of c3d on the immunogenicity of gene gun vaccines encoding plasmodium falciparum and plasmodium berghei msp1(42).the complement fragment c3d mediates b-cell activation via simultaneous engagement of the b-cell receptor and cd21 by antigen/c3d conjugates. several studies demonstrated the potential of c3d as a molecular adjuvant for vaccination. in this work, c3d exerted differential effects on humoral immune responses after gene gun immunization of mice with plasmids encoding the malaria blood stage antigen msp1(42) depending on the nature of the protein (plasmodium falciparum vs. plasmodium berghei msp), t ...201020438877
crystallization and preliminary structural characterization of the two actin-depolymerization factors of the malaria parasite.the malaria parasite plasmodium depends on its actin-based motor system for motility and host-cell invasion. actin-depolymerization factors are important regulatory proteins that affect the rate of actin turnover. plasmodium has two actin-depolymerization factors which seem to have different functions and display low sequence homology to the higher eukaryotic family members. plasmodium actin-depolymerization factors 1 and 2 have been crystallized. the crystals diffracted x-rays to maximum resolu ...201020445265
in vivo antimalarial evaluation of gomphostenins.the present study aims to evaluate the in vivo antimalarial potential of the leaf extract of gomphostemma niveum and two new compounds; named as gomphostenin (gn-6) and acetyl gomphostenin (gn-10) isolated and purified from this plant against plasmodium berghei in mice.201020452412
platelet factor 4 regulation of monocyte klf4 in experimental cerebral malaria.cerebral malaria continues to be a difficult to treat complication of plasmodium falciparum infection in children. we have shown that platelets can have major deleterious immune functions in experimental cerebral malaria (ecm). one of the platelet derived mediators we have identified as particularly important is platelet factor 4/cxcl4. our prior work demonstrated that pf4(-/-) mice are protected from ecm, have reduced plasma cytokines, and have reduced t-cell trafficking to the brain. we now sh ...201020454664
lipophilic bisphosphonates are potent inhibitors of plasmodium liver-stage growth.nitrogen-containing bisphosphonates, drugs used to treat bone resorption diseases, also have activity against a broad range of protists, including blood-stage plasmodium spp. here, we show that new-generation "lipophilic" bisphosphonates designed as anticancer agents that block protein prenylation also have potent activity against plasmodium liver stages, with a high (>100) therapeutic index. treatment of mice with the bisphosphonate bph-715 and challenge with plasmodium berghei sporozoites reve ...201020457823
beneficial effect of aurothiomalate on murine malaria.premature death of plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. aurothiomalate has previously been shown to trigger erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. phosphatidylserine-exposing cells are rapidly cleared from circulating blood. the present study thus tested whether sodium aurothiomalate influences the intraerythrocytic parasite dev ...201020459650
in vitro and in vivo anti-malarial activity of boerhavia elegans and solanum surattense.there is an urgent need to identify new anti-malarial drug targets for both prophylaxis and chemotherapy, due to the increasing problem of drug resistance to malaria parasites. in the present study, the aim was to discover novel, effective plant-based extracts for the activity against malaria.201020462416
the kennedy phospholipid biosynthesis pathways are refractory to genetic disruption in plasmodium berghei and therefore appear essential in blood stages.phosphatidylcholine (pc) and phosphatidylethanolamine (pe) are the main membrane phospholipids (pls) of plasmodium parasites and can be generated by the de novo (kennedy) cdp-choline and cdp-ethanolamine pathways and by the cdp-diacylglycerol dependent pathway. the kennedy pathways initiate from exogenous choline and ethanolamine involving choline kinase (ck) and ethanolamine kinase (ek), followed by the choline-phosphate cytidylyltransferase (cct) and ethanolamine-phosphate cytidylyltransferase ...201020478340
in vitro antiplasmodial and phytochemical study of five artemisia species from iran and in vivo activity of two species.the extract from artemisia annua, containing artemisinin, has been proven active against multidrug resistant plasmodium falciparum in previous studies. the purpose of this paper was to study five artemisia species from iran for their in vitro and in vivo antimalarial property and detection of artemisinin in the active species by chromatographic and spectroscopic methods including nuclear magnetic resonance (nmr) spectroscopy. dried plants were extracted by 80% ethanol, and total extracts were in ...201020480374
plasmodium infection alters anopheles gambiae detoxification gene expression.anopheles gambiae has been shown to change its global gene expression patterns upon plasmodium infection. while many alterations are directly related to the mosquito's innate immune response, parasite invasion is also expected to generate toxic by-products such as free radicals. the current study aimed at identifying which loci coding for detoxification enzymes are differentially expressed as a function of plasmodium berghei infection in midgut and fat body tissues.201020482856
vitamin c deficiency fails to protect mice from malaria.nutritional deficiencies are frequent in malaria-endemic areas. it seems that micronutrient antioxidants play an important role in malaria parasite's proliferation. thus, the effect of vitamin c deficiency on malaria infection was examined in mice. when vitamin c deficient mice, l-gulono-gamma-lactone oxidase gene knockout mice which are unable to synthesize ascorbic acid, were infected with a lethal dose of plasmodium berghei nk65-infected red blood cells, the knockout mice showed similar paras ...201020484858
plasmodium chabaudi chabaudi malaria parasites can develop stable resistance to atovaquone with a mutation in the cytochrome b gene.plasmodium falciparum, has developed resistance to many of the drugs in use. the recommended treatment policy is now to use drug combinations. the atovaquone-proguanil (ap) drug combination, is one of the treatment and prophylaxis options. atovaquone (atq) exerts its action by inhibiting plasmodial mitochondria electron transport at the level of the cytochrome bc1 complex. plasmodium falciparum in vitro resistance to atq has been associated with specific point mutations in the region spanning co ...201020492669
arthemeter-loaded lipid nanoparticles produced by modified thin-film hydration: pharmacokinetics, toxicological and in vivo anti-malarial activity.artemether-loaded lipid nanoparticles (arm-lnp) composed of 5% (w/v) lipid mass were produced by a modified thin-film hydration method using glyceryl trimyristate (solid lipid) and soybean oil (as liquid lipid in a concentration ranging from 0 to 45% (w/v) with respect to the total lipid mass). the particles were loaded with 10% of the anti-malarial arm and surface-tailored with a combination of non-ionic, cationic or anionic surfactants. arm-lnp were further characterized for their mean particl ...201020493255
inhibition of plasmodium sporozoites infection by targeting the host cell.there is a great need of new drugs against malaria because of the increasing spread of parasite resistance against the most commonly used drugs in the field. we found that monensin, a common veterinary antibiotic, has a strong inhibitory effect in plasmodium berghei and plasmodium yoelii sporozoites hepatocyte infection in vitro. infection of host cells by another apicomplexan parasite with a similar mechanism of host cell invasion, toxoplasma tachyzoites, was also inhibited. treatment of mice w ...201020493847
vegf promotes malaria-associated acute lung injury in mice.the spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (cm), acute lung injury (ali), acute respiratory distress syndrome (ards), pregnancy-associated malaria (pam) or severe anemia (sa). rodent models that mimic human cm, pam and sa syndromes have been established. here, we show that dba/2 mice infected with p. berghei anka constitute a new model for malaria-associated ...201020502682
comparison of plasmodium berghei challenge models for the evaluation of pre-erythrocytic malaria vaccines and their effect on perceived vaccine efficacy.the immunological mechanisms responsible for protection against malaria infection vary among plasmodium species, host species and the developmental stage of parasite, and are poorly understood. a challenge with live parasites is the most relevant approach to testing the efficacy of experimental malaria vaccines. nevertheless, in the mouse models of plasmodium berghei and plasmodium yoelii, parasites are usually delivered by intravenous injection. this route is highly artificial and particularly ...201020507620
protective effect of amiodarone in malaria.according to previous observations, amiodarone triggers suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and exposure of phosphatidylserine at the erythrocyte surface. eryptosis may in turn accelerate the clearance of plasmodium-infected erythrocytes. the present study tested whether amiodarone augments phosphatidylserine exposure of plasmodium-infected erythrocytes, interferes with the development of parasitemia and thus influences the course of malaria. the in ...201020510873
crystal structure of arginase from plasmodium falciparum and implications for l-arginine depletion in malarial infection .the 2.15 a resolution crystal structure of arginase from plasmodium falciparum, the parasite that causes cerebral malaria, is reported in complex with the boronic acid inhibitor 2(s)-amino-6-boronohexanoic acid (abh) (k(d) = 11 microm). this is the first crystal structure of a parasitic arginase. various protein constructs were explored to identify an optimally active enzyme form for inhibition and structural studies and to probe the structure and function of two polypeptide insertions unique to ...201020527960
adf2 is required for transformation of the ookinete and sporozoite in malaria parasite development.malaria parasites undergo two rounding-up transformations in their life cycle: the ookinete-to-oocyst transformation in the mosquito midgut, and the sporozoite-to-eef (exo-erythrocytic form) differentiation in the host hepatocyte. both events are characterized by the loss of polarity, implying that cytoskeletal reorganization is involved. in other eukaryotes, regulation of the actin skeleton is fundamental to subcellular remodeling. although filamentous actin is well known to be involved in the ...201020529666
genome wide analysis of inbred mouse lines identifies a locus containing ppar-gamma as contributing to enhanced malaria survival.the genetic background of a patient determines in part if a person develops a mild form of malaria and recovers, or develops a severe form and dies. we have used a mouse model to detect genes involved in the resistance or susceptibility to plasmodium berghei malaria infection. to this end we first characterized 32 different mouse strains infected with p. berghei and identified survival as the best trait to discriminate between the strains. we found a locus on chromosome 6 by linking the survival ...201020531941
murine malaria is associated with significant hearing impairment.plasmodium falciparum malaria has been suspected to cause hearing loss. developmental, cognitive and language disorders have been observed in children, surviving cerebral malaria. this prospective study aims to evaluate whether malaria influences hearing in mice.201020540722
a possible key molecule for the invasion of the plasmodium berghei ookinetes into the midgut epithelium of anopheles gambiae mosquitoes.in order to identify molecules necessary for the invasion of the mosquito midgut epithelium by plasmodia, interaction assays between both these structures were devised.201020554998
metamorphosis of the malaria parasite in the liver is associated with organelle clearance.malaria parasites encounter diverse conditions as they cycle between their vertebrate host and mosquito vector. within these distinct environments, the parasite undergoes drastic transformations, changing both its morphology and metabolism. plasmodium species that infect mammals must first take up residence in the liver before initiating red blood cell infection. following penetration into hepatocytes, the parasite converts from an invasion-competent, motile, elongated sporozoite to a metabolica ...201020567259
synthesis and evaluation of alpha-halogenated analogues of 3-(acetylhydroxyamino)propylphosphonic acid (fr900098) as antimalarials.three alpha-halogenated analogues of 3-(acetylhydroxyamino)propylphosphonic acid (fr900098) have been synthesized from diethyl but-3-enylphosphonate using a previously described method for the alpha-halogenation of alkylphosphonates. these analogues were evaluated for antimalarial potential in vitro against plasmodium falciparum and in vivo in the p. berghei mouse model. all three analogues showed higher in vitro and/or in vivo potency than the reference compounds.201020568776
spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria.the antiplasmodial activity of a series of spirotetrahydro beta-carbolines is described. racemic spiroazepineindole (1) was identified from a phenotypic screen on wild type plasmodium falciparum with an in vitro ic(50) of 90 nm. structure-activity relationships for the optimization of 1 to compound 20a (ic(50) = 0.2 nm) including the identification of the active 1r,3s enantiomer and elimination of metabolic liabilities is presented. improvement of the pharmacokinetic profile of the series transl ...201020568778
in vitro and in vivo antimalarial evaluation of semi-synthetic derivatives of gomphostenin.a novel series of semi-synthetic gomphostenin derivatives (1-9) were prepared utilizing c-14 hydroxyl group for the first time and studied for their antimalarial properties. in vitro antiplasmodial activity was evaluated against both the chloroquine sensitive and resistant strains of plasmodium falciparum. most of the compounds exhibited superior or comparable antiplasmodial activity compared to parent compound, that is, gomphostenin (gn). based upon in vitro antiplasmodial activity, compounds w ...201020570512
glutathione reductase-null malaria parasites have normal blood stage growth but arrest during development in the mosquito.malaria parasites contain a complete glutathione (gsh) redox system, and several enzymes of this system are considered potential targets for antimalarial drugs. through generation of a gamma-glutamylcysteine synthetase (gamma-gcs)-null mutant of the rodent parasite plasmodium berghei, we previously showed that de novo gsh synthesis is not critical for blood stage multiplication but is essential for oocyst development. in this study, phenotype analyses of mutant parasites lacking expression of gl ...201020573956
dimeric cyclohexane-1,3-dione oximes inhibit wheat acetyl-coa carboxylase and show anti-malarial activity.a series of dimeric 1,3-cyclohexanedione oxime ethers were synthesized and found to have significant antiplasmodial activity with ic(50)'s in the range 3-12 microm. the most active dimer was tested in the plasmodium berghei mouse model of malaria and at a dose of 48 mg/kg gave a 45% reduction in parasitaemia. several commercial herbicides, all known to be inhibitors of maize acetyl-coa carboxylase, were also tested for antimalarial activity, but were essentially inactive with the exception of bu ...201020580556
arp1, an actin-related protein, in plasmodium berghei.actin-related proteins (arps) constitute a family of eukaryotic cytoskeletal proteins involved in such diverse events as cell motility, cytokinesis, vesicle transport, and chromatin remodelling. previously, in a study of plasmodium berghei gene expression in ookinetes and oocysts, we detected stage-specific increased expression of a gene encoding an arp. here we further characterize this gene and the encoded protein. we present a phylogenetic and three-dimensional modelling analysis as well as c ...201020580650
the plasmodium eukaryotic initiation factor-2alpha kinase ik2 controls the latency of sporozoites in the mosquito salivary glands.sporozoites, the invasive form of malaria parasites transmitted by mosquitoes, are quiescent while in the insect salivary glands. sporozoites only differentiate inside of the hepatocytes of the mammalian host. we show that sporozoite latency is an active process controlled by a eukaryotic initiation factor-2alpha (eif2alpha) kinase (ik2) and a phosphatase. ik2 activity is dominant in salivary gland sporozoites, leading to an inhibition of translation and accumulation of stalled mrnas into granul ...201020584882
cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy.neurological impairments are frequently detected in children surviving cerebral malaria (cm), the most severe neurological complication of infection with plasmodium falciparum. the pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. in the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatme ...201020585569
divergent roles of irak4-mediated innate immune responses in two experimental models of severe malaria.severe malaria represents a clinical spectrum of disease. we propose that innate immune inflammatory responses to malaria play key roles in the pathogenesis and clinical outcomes of distinct severe malaria syndromes. to investigate this hypothesis, mice deficient in irak4, central to toll-like receptor (tlr)-mediated signaling, were studied in two experimental models of malaria: plasmodium berghei (pba) and plasmodium chabaudi (pccas). irak4(-/-)mice had decreased pro-inflammatory cytokine produ ...201020595480
accumulation of plasmodium berghei-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice.cerebral malaria is the most severe complication of human infection with plasmodium falciparum. it was shown that plasmodium berghei anka-induced cerebral malaria was prevented in 100% of mice depleted of cd8+ t cells 1 day prior to the development of neurological signs. however, the importance of parasites in the brains of these mice was never clearly investigated. moreover, the relevance of this model to human cerebral malaria has been questioned many times, especially concerning the relative ...201020605973
exploiting cross-priming to generate protective cd8 t-cell immunity rapidly.the number of memory cd8 t cells generated by infection or vaccination correlates strongly with the degree of protection observed in infection and tumor models. therefore, rapid induction of protective numbers of effector and memory cd8 t cells may be crucial in the case of malignancy, pandemic infection, or bioterrorism. many studies have shown that amplifying t-cell numbers by prime-boost vaccination is most effective with a substantial time interval between immunizations. in contrast, immuniz ...201020616089
natural immunization against malaria: causal prophylaxis with antibiotics.malaria remains the most prevalent vector-borne infectious disease and has the highest rates of fatality. current antimalarial drug strategies cure malaria or prevent infections but lack a sustained public health impact because they fail to expedite the acquisition of protective immunity. we show that antibiotic administration during transmission of the parasite plasmodium berghei results in swift acquisition of long-lived, life cycle-specific protection against reinfection with live sporozoites ...201020630856
targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling.the balance between gsh-levels and oxidative stress is critical for cell survival. the gsh-levels of erythrocytes are dramatically decreased during infection with plasmodium spp. we therefore investigated the consequences of targeting gsh for erythrocyte and plasmodium survival in vitro and in vivo using dimethylfumarate (dmf) at therapeutically established dosage. we first show that noninfected red blood cells (rbc) exposed to dmf undergo changes typical of apoptosis or eryptosis, such as cell ...201020631250
essential role for il-27 receptor signaling in prevention of th1-mediated immunopathology during malaria infection.successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. the pathways that maintain this immunological balance during malaria infection remain poorly defined. in this study, we demonstrate that il-27r-deficient (wsx-1(-/-)) mice are highly susceptible to plasmodium berghei nk65 infection, developing exacerbated th1-mediated immune respons ...201020631310
anopheles gambiae prs1 modulates plasmodium development at both midgut and salivary gland steps.invasion of the mosquito salivary glands by plasmodium is a critical step for malaria transmission. from a sage analysis, we previously identified several genes whose expression in salivary glands was regulated coincident with sporozoite invasion of salivary glands. to get insights into the consequences of these salivary gland responses, here we have studied one of the genes, prs1 (plasmodium responsive salivary 1), whose expression was upregulated in infected glands, using immunolocalization an ...201020634948
activity of a trisubstituted pyrrole in inhibiting sporozoite invasion and blocking malaria infection.malaria infection is initiated by plasmodium sporozoites infecting the liver. preventing sporozoite infection would block the obligatory first step of the infection and perhaps reduce disease severity. in addition, such an approach would decrease plasmodium vivax hypnozoite formation and therefore disease relapses. here we describe the activity of a trisubstituted pyrrole, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1h-pyrrol-3-yl] pyridine, in inhibiting motility, invasion, and consequent ...201020643897
extreme cd8 t cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites.radiation-attenuated plasmodium sporozoites (ras) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. importantly, these "whole-parasite" vaccines are currently under evaluation in human clinical trials. studies with inbred mice reveal that ras-induced cd8 t cells targeting liver-stage parasites are critical for protection. however, the paucity of defined t cell epitopes for these parasites has precluded precise understanding of the specific ch ...201020657824
protein kinase c θ deficiency increases resistance of c57bl/6j mice to plasmodium berghei infection-induced cerebral malaria.protein kinase c θ (pkcθ) functions as a core component of the immunological synapse and serves as a key protein in the integrated t-cell antigen receptor (tcr)/cd28-induced signaling cascade leading to t-cell activation. however, the involvement of pkcθ in host-mediated immune responses to pathogens has not been thoroughly investigated. we tested the consequences of pkcθ ablation on the host response to infection by plasmodium berghei anka (pba). we found that both pkcθ(+/+) and pkcθ(-/-) c57bl ...201020660606
self-microemulsifiyng suppository formulation of β-artemether.parasitic diseases are of immense global significance as around 30% of world's population experiences parasitic infections. among these, malaria is the most life-threatening disease. various routes of administration have been explored for delivering antimalarial actives. the present investigation aims at formulating self-microemulsifying suppositories of β-artemether with faster onset of action and prolonged effect to be administered by rectal route. these were compared with conventional polyeth ...201020661674
synthesis, structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds.we have previously shown that a "reversed chloroquine (rcq)" molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in p. falciparum ( burgess , s. j. ; selzer , a. ; kelly , j. x. ; smilkstein , m. j. ; riscoe , m. k. ; peyton , d. h. j. med. chem. 2006 , 49 , 5623 . andrews , s. ; burgess , s. j. ; skaalrud , d. ; kelly , j. x. ; peyton , d. h. j. med. chem. 2010 , 53 , 916 ). here, we present an investigation into the structu ...201020684562
curcuminoids-loaded lipid nanoparticles: novel approach towards malaria treatment.in the present work, curcuminoids-loaded lipid nanoparticles for parenteral administration were successfully prepared by a nanoemulsion technique employing high-speed homogenizer and ultrasonic probe. for the production of nanoparticles, trimyristin, tristerin and glyceryl monostearate were selected as solid lipids and medium chain triglyceride (mct) as liquid lipid. scanning electron microscopy (sem) revealed the spherical nature of the particles with sizes ranging between 120 and 250 nm measur ...201020688493
an early commitment to expression of a particular tcrvbeta chain on cd8(+) t cells responding to attenuated plasmodium berghei sporozoites is maintained following challenge with infectious sporozoites.protection induced by irradiated plasmodium berghei sporozoites (pbgamma-spz) in mice is linked to cd8(+) t cells specific for exo-erythrocytic-stage ags, and intrahepatic memory cd8(+) t cells are associated with protracted protection. however, the ag specificity of the protective cd8(+) t cells remains largely unknown. in this study, we characterized the tcr vbeta usage by intrahepatic cd8(+) t cells during gamma-spz immunization and after the challenge with infectious pb sporozoites. the repe ...201020691016
artemisone effective against murine cerebral malaria.artemisinins are the newest class of drug approved for malaria treatment. due to their unique mechanism of action, rapid effect on plasmodium, and high efficacy in vivo, artemisinins have become essential components of malaria treatment. administration of artemisinin derivatives in combination with other anti-plasmodials has become the first-line treatment for uncomplicated falciparum malaria. however, their efficiency in cases of cerebral malaria (cm) remains to be determined.201020691118
differential expression of proteins in the midgut of anopheles albimanus infected with plasmodium berghei.the main vector for transmission of malaria in mexico is the anopheles albimanus mosquito. the midgut of disease-transmitting mosquitoes carries out a variety of functions that are related to blood feeding. we analyzed the midgut of a. albimanus infected with plasmodium berghei (resistant mosquito) using a proteomic approach to identify putative short peptides that are enriched in the midgut after blood feeding. mosquito midguts were analyzed by two-dimensional electrophoresis to determine the c ...201020692341
novel inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model.plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. dihydroorotate dehydrogenase (dhodh) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. a high throughput screen and subsequent medicinal chemistry program identified a series of n-alkyl-5-(1h-benzimidazol-1-yl)thiophene-2-carboxamides with low nan ...201020702404
experimental cerebral malaria progresses independently of the nlrp3 inflammasome.cerebral malaria is the most severe complication of plasmodium falciparum infection in humans and the pathogenesis is still unclear. using the p. berghei anka infection model of mice, we investigated a potential involvement of nlrp3 and the inflammasome in the pathogenesis of cerebral malaria. nlrp3 mrna expression was upregulated in brain endothelial cells after exposure to p. berghei anka. although beta-hematin, a synthetic compound of the parasites heme polymer hemozoin, induced the release o ...201019950187
the comparative antimalarial properties of weak base and neutral synthetic ozonides.thirty-three n-acyl 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. for these ozonides, weak base functional groups were not required for high antimalarial potency against plasmodium falciparum in vitro, but were necessary for high antimalarial efficacy in plasmodium berghei-infected mice. a wide range of logp/d(ph)(7.4) values were tolerated, although more lipophilic ozonides tended to be less metabolically stable.201019962893
alpha-tocopherol transfer protein inhibition is effective in the prevention of cerebral malaria in mice.nutritional status likely plays an important role in determining the outcome of protozoan infections. despite the evidence of plasmodium sensitivity to oxidative stress, the potential role of vitamin e, a free radical scavenger, on the outcome of cerebral malaria (cm) has yet to be elucidated.201019923370
synthesis and antimalarial evaluation of 1, 3, 5-trisubstituted pyrazolines.a series of 1,3,5-trisubstituted pyrazolines were synthesized and evaluated for in vitro antimalarial efficacy against chloroquine sensitive (mrc-02) as well as chloroquine resistant (rkl9) strains of plasmodium falciparum. the activity was at nano molar concentration. beta-hematin formation inhibition activity (bhia(50)) of the pyrazolines were determined and correlated with antimalarial activity. a reasonably good correlation (r=0.62) was observed between antimalarial activity (ic(50)) and bhi ...201019926176
the murine cerebral malaria phenomenon.p.berghei anka infection in cba or cb57bl/6 mice is used widely as a murine 'model' of human cerebral malaria (hcm), despite markedly different histopathological features. the pathology of the murine model is characterised by marked inflammation with little or no intracerebral sequestration of parasitised erythrocytes, whereas hcm is associated with intense intracerebral sequestration, often with little inflammatory response. there are now more than ten times as many studies each year of the mur ...201019932638
plasmodium berghei crystalloids contain multiple lccl proteins.malaria crystalloids are unique organelles of unknown function that are present only in the mosquito-specific ookinete and early oocyst stages of the parasite. recently, crystalloid formation in plasmodium berghei was linked to the parasite protein pbsr, a member of the plasmodium lccl protein family composed of six modular multidomain proteins involved in sporozoite development and infectivity. here, we show by fluorescent protein tagging that two other lccl protein family members are targeted ...201019932717
role of plasmodium berghei cgmp-dependent protein kinase in late liver stage development.the liver is the first organ infected by plasmodium sporozoites during malaria infection. in the infected hepatocytes, sporozoites undergo a complex developmental program to eventually generate hepatic merozoites that are released into the bloodstream in membrane-bound vesicles termed merosomes. parasites blocked at an early developmental stage inside hepatocytes elicit a protective host immune response, making them attractive targets in the effort to develop a pre-erythrocytic stage vaccine. he ...201019940133
phosphothioate oligodeoxynucleotides inhibit plasmodium sporozoite gliding motility.plasmodium sporozoites, transmitted to the mammalian host through a mosquito bite, travel to the liver, where they invade hepatocytes, and develop into a form that is then able to infect red blood cells. in spite of the importance of innate immunity in controlling microbial infections, almost nothing is known about its role during the liver stage of a malaria infection. here, we tested whether synthetic cpg phosphothioate (ps) oligodeoxynucleotides (odns), which bind to toll-like receptor 9 (tlr ...201019912239
analgesic and antimalarial activities of crude leaf extract and fractions of acalypha wilkensiana.antiplasmodial and analgesic activities of leaf extract and fractions of acalypha wilkensiana were evaluated to ascertain the folkloric claim of its antimalarial and analgesic activities.201019892007
identification of a novel cerebral malaria susceptibility locus (berr5) on mouse chromosome 19.cerebral malaria (cm) is an acute, generally lethal condition characterized by high fever, seizures and coma. the genetic component to cm can be investigated in mouse models that vary in degree of susceptibility to infection with plasmodium berghei anka. using survival time to measure susceptibility in an informative f2 cross (n=257), we identified linkage to chromosome 19 (berr5 (berghei resistance locus 5), lod=4.69) controlling, in part, the differential response between resistant balb/c and ...201019865103
neither mosquito saliva nor immunity to saliva has a detectable effect on the infectivity of plasmodium sporozoites injected into mice.malaria infection is initiated when a female anopheles mosquito probing for blood injects saliva, together with sporozoites, into the skin of its mammalian host. prior studies had suggested that saliva may enhance sporozoite infectivity. using rodent malaria models (plasmodium berghei and p. yoelii), we were unable to show that saliva had any detectable effect on sporozoite infectivity. this is encouraging for plans to immunize humans with washed, attenuated p. falciparum sporozoites because man ...201019884338
a dispensable plasmodium locus for stable transgene expression.the ribosomal small subunit locus has been used for transgene expression in the rodent malaria parasites, plasmodium berghei and plasmodium yoelii, but this strategy utilizes single crossover integration and is thus prone to reversion by plasmid excision. targeting of the ribosomal subunit locus may also have a negative effect on oocyst development in the mosquito. in p. berghei, the p230 paralog locus has been used for transgene expression. here, we show that the p. yoelii s1 locus (sporozoite ...201020045029
meutxkbeta1, a scorpion venom-derived two-domain potassium channel toxin-like peptide with cytolytic activity.recent studies have demonstrated that scorpion venom contains unique two-domain peptides with the peculiarity of possessing different functions, i.e. neurotoxic and cytolytic activities. here we report systematic characterization of a new two-domain peptide (named meutxkbeta1) belonging to the tstxkbeta molecular subfamily from the scorpion mesobuthus eupeus by molecular cloning, biochemical purification, recombinant expression, functional assays, cd and nmr studies. its full-length bioactive fo ...201020045493
schistosoma mansoni infection reduces the incidence of murine cerebral malaria.plasmodium and schistosoma are two of the most common parasites in tropical areas. deregulation of the immune response to plasmodium falciparum, characterized by a th1 response, leads to cerebral malaria (cm), while a th2 response accompanies chronic schistosomiasis.201020051114
a single fluorescence-based lamp reaction for identifying multiple parasites in mosquitoes.vector-borne diseases, such as malaria and lymphatic filariasis, are co-endemic in large parts of the world. to develop a multiplex amplification method for the simultaneous detection of multiple insect-borne infectious diseases, we used lamp with fluorescently labeled primers to identify the spect2 gene of plasmodium berghei and the cytochrome oxidase subunit i gene of dirofilaria immitis in mosquitoes. this technique could detect as few as 100 p. berghei-infected red blood cell-equivalents or ...201020064511
synergistic and additive effects of epigallocatechin gallate and digitonin on plasmodium sporozoite survival and motility.most medicinal plants contain a mixture of bioactive compounds, including chemicals that interact with intracellular targets and others that can act as adjuvants to facilitate absorption of polar agents across cellular membranes. however, little is known about synergistic effects between such potential drug candidates and adjuvants. to probe for such effects, we tested the green tea compound epigallocatechin gallate (egcg) and the membrane permeabilising digitonin on plasmodium sporozoite motili ...201020072627
integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents.parasitic infections cause a myriad of responses in their mammalian hosts, on immune as well as on metabolic level. a multiplex panel of cytokines and metabolites derived from four parasite-rodent models, namely, plasmodium berghei-mouse, trypanosoma brucei brucei-mouse, schistosoma mansoni-mouse, and fasciola hepatica-rat were statistically coanalyzed. (1)h nmr spectroscopy and multivariate statistical analysis were used to characterize the urine and plasma metabolite profiles in infected and n ...201020092362
cerebral malaria: a vasculopathy. 201020093501
immunopathology and dexamethasone therapy in a new model for malaria-associated acute respiratory distress syndrome.malaria infection is often complicated by malaria-associated acute respiratory distress syndrome (ma-ards), characterized by pulmonary edema and hemorrhages. no efficient treatments are available for ma-ards and its pathogenesis remains poorly understood.201020093644
characterization of two linear cationic antimalarial peptides in the scorpion mesobuthus eupeus.plasmodium falciparum is a pathogen of human malaria which causes millions of deaths per year due to the ever-increasing drug resistance by the parasite, and thus novel antimalarial agents are urgently needed. in this work, we report two cdna clones from the scorpion mesobuthus eupeus venom gland, which encode peptides inhibiting the development of plasmodium berghei, killing intraerythrocytic p. falciparum, and toxic to the drosophila s2 cell at micromolar concentrations. one peptide of 24 amin ...201020097251
differential effector pathways regulate memory cd8 t cell immunity against plasmodium berghei versus p. yoelii sporozoites.malaria results in >1,000,000 deaths per year worldwide. although no licensed vaccine exists, much effort is currently focused on subunit vaccines that elicit cd8 t cell responses directed against plasmodium parasite liver stage ags. multiple immune-effector molecules play a role in antimicrobial immunity mediated by memory cd8 t cells, including ifn-gamma, perforin, trail, fas ligand, and tnf-alpha. however, it is not known which pathways are required for memory cd8 t cell-mediated immunity aga ...201020097864
murine cerebral malaria is associated with a vasospasm-like microcirculatory dysfunction, and survival upon rescue treatment is markedly increased by nimodipine.brain hemodynamics in cerebral malaria (cm) is poorly understood, with apparently conflicting data showing microcirculatory hypoperfusion and normal or even increased blood flow in large arteries. using intravital microscopy to assess the pial microvasculature through a closed cranial window in the murine model of cm by plasmodium berghei anka, we show that murine cm is associated with marked decreases (mean: 60%) of pial arteriolar blood flow attributable to vasoconstriction and decreased blood ...201020110412
a semi-automated method for counting fluorescent malaria oocysts increases the throughput of transmission blocking studies.malaria transmission is now recognized as a key target for intervention. evaluation of the plasmodium oocyst burden in the midguts of anopheles spp. is important for many of assays investigating transmission. however, current assays are very time-consuming, manually demanding and patently subject to observer-observer variation.201020113492
parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through potent macrophage stimulation.there is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. microparticles (mps), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflammatory activity in other disease states. here we demonstrate that mps, derived from the plasma of malaria infected mice, but not naive mice, induce pot ...201020126448
life cycle studies of the hexose transporter of plasmodium species and genetic validation of their essentiality.a plasmodium falciparum hexose transporter (pfht) has previously been shown to be a facilitative glucose and fructose transporter. its expression in xenopus laevis oocytes and the use of a glucose analogue inhibitor permitted chemical validation of pfht as a novel drug target. following recent re-annotations of the p. falciparum genome, other putative sugar transporters have been identified. to investigate further if pfht is the key supplier of hexose to p. falciparum and to extend studies to di ...201020132450
antimalarial and antitubercular nostocarboline and eudistomin derivatives: synthesis, in vitro and in vivo biological evaluation.the synthesis of nine nostocarboline derivatives with substitutions of the 2-methyl group by alkyl, aryl and functionalized residues, 10 symmetrical bis cationic dimers linking 6-cl-norharmane through the 2-position and fifteen derivatives of the marine alkaloids eudistomin n and o is reported. these compounds were evaluated in vitro against four parasites (trypanosoma brucei rhodesiense stib 900, trypanosoma cruzi tulahuen c2c4, leishmania donovani mhom-et-67/l82 axenic amastigotes, and plasmod ...201020133138
inflammatory changes in the central nervous system are associated with behavioral impairment in plasmodium berghei (strain anka)-infected mice.experimental cerebral malaria is a neuroinflammatory condition that results from the host immune response to the parasite. using intravital microscopy, we investigated leukocyte recruitment in the brain microcirculation and the temporal relationship of this process to the behavioral changes observed in plasmodium berghei (strain anka)-infected c57bl/6 mice. we found that leukocyte recruitment was increased from day 5 post-infection (p.i.) onwards. histopathological changes and increased levels o ...201020138873
concomitant infection decreases the malaria burden but escalates relapsing fever borreliosis.about 500 million cases of malaria occur annually. however, a substantial number of patients who actually have relapsing fever (rf) borrelia infection can be misdiagnosed with malaria due to similar manifestations and geographic distributions of the two diseases. more alarmingly, a high prevalence of concomitant infections with malaria and rf borrelia has been reported. therefore, we used a mouse model to study the effects of such mixed infection. we observed a 21-fold increase in spirochete tit ...201020145098
new imidazolidinedione derivatives as antimalarial agents.a series of new n-alky- and n-alkoxy-imidazolidinediones was prepared and assessed for prophylactic and radical curative activities in mouse and rhesus monkey models. new compounds are generally metabolically stable, weakly active in vitro against plasmodium falciparum clones (d6 and w2) and in mice infected with plasmodium berghei sporozoites. representative compounds 8e and 9c showed good causal prophylactic activity in rhesus monkeys dosed 30 mg/kg/day for 3 consecutive days by im, delayed pa ...201021282058
[cryopreservation of plasmodia with malaria models and establishment of a cryobank.]objective: cryopreservation is simply a method of keeping living cells frozen with the chance of regaining cellular viability, functions and antigenic structures whenever required, after heating. methods: in the present study, dimethyl sulphoxide (dmso) was mixed with the red blood cells having 20% of parasitemia obtained from the mice infected with plasmodium yoelii and plasmodium berghei at a final concentration of 15%. for cryopreservation: both test tubes containing each plasmodium species w ...201021391181
antibody responses to 43 and 48 kda antigens of blood-stage plasmodium berghei in balb/c mice.progress towards a vaccine against malaria is advancing rapidly with several candidate antigens being tested for their safety and efficacy. in present investigation, two polypeptides (43 and 48 kda) of plasmodium berghei (nk-65) were identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis. immunogenicity and protective efficacy of both these polypeptides formulated in saponin has been compared in balb/c mice against challenge infection with p. berghei. antibody responses were eva ...201021966123
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
discovery of novel benzo[a]phenoxazine ssj-183 as a drug candidate for malaria.malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. even inhabitants of temperate zones are exposed to the danger of malaria infection because of travel and global warming. novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. a search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. the deri ...201024900219
alterations in the brain transcriptome in plasmodium berghei anka infected mice.we have used cdna microarrays to compare gene expression profiles in brains from normal mice to those infected with the anka strain of plasmodium berghei, a model of cerebral malaria. for each of three brains in each group, we computed ratios of all quantifiable genes with a composite reference sample and then computed ratios of gene expression in infected brains compared to untreated controls. of the almost 12,000 unigenes adequately quantified in all arrays, approximately 3% were significantly ...201023467761
synthesis and antimalarial evaluation of some 4-quinazolinone derivatives based on febrifugine.a series of 2-substituted and 2,3-substituted quinazolin -4(3h)-one derivatives were designed and synthesized based on the structure of febrifugine. the structures of the new compounds were confirmed by spectral analysis. the in vivo biological activity test results indicated that those compounds exhibited antimalarial activities against plasmodium berghei in mice, at a dose of 5 mg/kg. compared to chloroquine and artemisinin, these compounds have the advantages of shorter synthetic routes and c ...201022247880
in vivo antimalarial effects of iranian flora artemisia khorassanica against plasmodium berghei and pharmacochemistry of its natural components.the aim of this study was to evaluate the antimalarial effects of iranian flora artemisia khorassanica against plasmodium bergheiin vivo and pharmacochemistry of its natural components.201022347230
marilones a-c, phthalides from the sponge-derived fungus stachylidium sp.the marine-derived fungus stachylidium sp. was isolated from the sponge callyspongia sp. cf. c. flammea. culture on a biomalt medium supplemented with sea salt led to the isolation of three new phthalide derivatives, i.e., marilones a-c (1-3), and the known compound silvaticol (4). the skeleton of marilones a and b is most unusual, and its biosynthesis is suggested to require unique biochemical reactions considering fungal secondary metabolism. marilone a (1) was found to have antiplasmodial act ...201122238541
Antimalaria Effect of the Ethanolic Stem Bark Extracts of Ficus platyphylla Del.The antimalarial effect of the ethanolic stem bark extract of Ficus platyphylla Del was evaluated against Plasmodium berghei infection in mice. Nontreated, experimental control mice died of fulminant parasitemia from day 7 to 9 post-infection but mice treated with the extract at 300?mg/kg showed markedly reduced parasitaemia bouts of 43.50% and a mean survival time of 28 days postinfection. The plant extract prevented a drastic reduction in PCV showing its efficacy in ameliorating anaemic condit ...201122174991
hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection.hepcidin is one of the regulators of iron metabolism. the expression of hepcidin is induced in spleens and livers of mice infected with pathogenic bacteria. recent studies have indicated that serum hepcidin level is also increased in human subjects infected with plasmodium falciparum. the mechanism of the regulation of hepcidin expression and its role in the infection of malaria remains unknown. in this study, we determined the expression of hepcidin in livers of mice infected with plasmodium be ...201122084434
heterogeneous and tissue-specific regulation of effector t cell responses by ifn-gamma during plasmodium berghei anka infection.ifn-γ and t cells are both required for the development of experimental cerebral malaria during plasmodium berghei anka infection. surprisingly, however, the role of ifn-γ in shaping the effector cd4(+) and cd8(+) t cell response during this infection has not been examined in detail. to address this, we have compared the effector t cell responses in wild-type and ifn-γ(-/-) mice during p. berghei anka infection. the expansion of splenic cd4(+) and cd8(+) t cells during p. berghei anka infection ...201121880980
Antimalarial activity of imidazo[2,1-a]isoindol-5-ol derivatives and related compounds.The synthesis of several series of imidazo[2,1-a]isoindol-5-ol derivatives and the results of their evaluation against Plasmodium falciparum are presented and discussed. The effects of electron-withdrawing or-donating substituents on different parts of the molecule, as well as those produced by the incorporation of an additional fused ring, were analyzed. Several compounds showed significant antimalarial activity in vitro with IC(50) values as low as 60 nM and a certain efficacy in vivo by reduc ...201121940072
Coartemether Induced Oxidative and Hepatic Damage in Plasmodium berghei Strain Anka Infected Mice.This study investigated the effect of coartemether on antioxidant and hepatotoxic biomarkers in Plasmodium berghei infected mice. Erythrocyte, hepatic and renal superoxide dismutase (2.71 ± 0.51; 1.96 ± 0.87; 2.84 ± 0.22 Units/mg protein respectively) and catalase (4.10 ± 0.10; 8.25 ± 1.24; 6.28 ± 0.11 Units/mg protein respectively) activities were significantly (p < 0.05) elevated in "parasitized and treated" (PnT) animals. Renal glutathione level (19.02 ± 0.20 µg/mL) was elevated in PnT animal ...201122057281
high-throughput multi-parameter flow-cytometric analysis from micro-quantities of plasmodium-infected blood.despite significant technological and conceptual advances over the last century, evaluation of the efficacy of anti-malarial vaccines or drugs continues to rely principally on direct microscopic visualisation of parasites on thick and/or thin giemsa-stained blood smears. this requires technical expertise of the microscopist, is highly subjective and error-prone, and does not account for aberrations such as anaemia. many published methods have shown that flow cytometric analysis of blood is a hig ...201121907206
experimental cerebral malaria develops independently of card9 signalling.the outcome of infection depends on multiple layers of immune regulation with innate immunity playing a decisive role in shaping protection or pathogenic sequelae of acquired immunity. the contribution of pattern recognition receptors and adaptor molecules in immunity to malaria remains poorly understood. here we interrogate the role of the caspase recruitment domain-containing protein 9 (card9) signalling pathway in the development of experimental cerebral malaria (ecm) using the murine plasmod ...201122158744
FLP/FRT-mediated conditional mutagenesis in pre-erythrocytic stages of Plasmodium berghei.We describe here a highly efficient procedure for conditional mutagenesis in Plasmodium. The procedure uses the site-specific recombination FLP-FRT system of yeast and targets the pre-erythrocytic stages of the rodent Plasmodium parasite P. berghei, including the sporozoite stage and the subsequent liver stage. The technique consists of replacing the gene under study by an FRTed copy (i.e., flanked by FRT sites) in the erythrocytic stages of a parasite clone that expresses the flip (FLP) recombi ...201121886105
A carbamate-based approach to primaquine prodrugs: Antimalarial activity, chemical stability and enzymatic activation.O-Alkyl and O-aryl carbamate derivatives of the antimalarial drug primaquine were synthesised as potential prodrugs that prevent oxidative deamination to the inactive metabolite carboxyprimaquine. Both O-alkyl and O-aryl carbamates undergo hydrolysis in alkaline and pH 7.4 phosphate buffers to the parent drug, with O-aryl carbamates being ca. 10(6)-10(10) more reactive than their O-alkyl counterparts. In human plasma O-alkyl carbamates were stable, whereas in contrast their O-aryl counterparts r ...201122189276
inactivation of a plasmodium apicoplast protein attenuates formation of liver merozoites.malaria parasites undergo a population expansion inside the host liver before disease onset. developmental arrest inside host hepatocytes elicits protective immune responses. therefore, elucidation of the molecular mechanisms leading to mature hepatic merozoites, which initiate the pathogenic blood phase, also informs anti-malaria vaccine strategies. using targeted gene deletion in the rodent model malaria parasite plasmodium berghei, we show that a plasmodium-specific apicoplast protein plays a ...201121848587
nogo-a expression in the brain of mice with cerebral malaria.cerebral malaria (cm) is associated with a high rate of transient or persistent neurological sequelae. nogo-a, a protein that is highly expressed in the endoplasmic reticulum (er) of the mammalian central nervous system (cns), is involved in neuronal regeneration and synaptic plasticity in the injured cns. the current study investigates the role of nogo-a in the course of experimental cm. c57bl/6j mice were infected with plasmodium berghei anka blood stages. brain homogenates of mice with differ ...201121980529
a gfp-actin reporter line to explore microfilament dynamics across the malaria parasite lifecycle.malaria parasite motility relies on an internal parasite actomyosin motor that, when linked to the host cell substrate, propels motile zoites forward. despite their key role in this process, attempts to visualize actin microfilaments (f-actin) during motility and under native microscopy conditions have not to date been successful. towards facilitating their visualization we present here a plasmodium berghei transgenic line in which a green fluorescent protein (gfp)-actin fusion is constitutively ...201122138565
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