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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
alterations in urine, serum and brain metabolomic profiles exhibit sexual dimorphism during malaria disease progression.metabolic changes in the host in response to plasmodium infection play a crucial role in the pathogenesis of malaria. alterations in metabolism of male and female mice infected with plasmodium berghei anka are reported here.201020412601
antiplasmodial activity of ajuga bracteosa against plasmodium berghei infected balb/c mice.the present work was undertaken to evaluate antiplasmodial activity of ethanolic leaves extract of traditional medicinal plant ajuga bracteosa in plasmodium berghei infected balb/c mice along with its phytochemical screening and acute toxicity test to support its traditional use as a remedy for malaria.201020418560
functional evaluation of plasmodium export signals in plasmodium berghei suggests multiple modes of protein export.the erythrocytic stage development of malaria parasites occurs within the parasitophorous vacuole inside the infected-erythrocytes, and requires transport of several parasite-encoded proteins across the parasitophorous vacuole to several locations, including the cytosol and membrane of the infected cell. these proteins are called exported proteins; and a large number of such proteins have been predicted for plasmodium falciparum based on the presence of an n-terminal motif known as the plasmodiu ...201020419102
oral activated charcoal prevents experimental cerebral malaria in mice and in a randomized controlled clinical trial in man did not interfere with the pharmacokinetics of parenteral artesunate.safe, cheap and effective adjunct therapies preventing the development of, or reducing the mortality from, severe malaria could have considerable and rapid public health impact. oral activated charcoal (oac) is a safe and well tolerated treatment for acute poisoning, more recently shown to have significant immunomodulatory effects in man. in preparation for possible efficacy trials in human malaria, we sought to determine whether oac would i) reduce mortality due to experimental cerebral malaria ...201020419161
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
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
suppression of plasmodium berghei parasitemia by licl in an animal infection model.malaria, caused by the plasmodium parasite is still a health problem worldwide due to resistance of the pathogen to current anti-malarials. the search for new anti-malarial agents has become more crucial with the emergence of chloroquine-resistant plasmodium falciparum strains. protein kinases such as mitogen-activated protein kinase (mapk), mapk kinase, cyclin-dependent kinase (cdk) and glycogen synthase kinase- 3(gsk-3) of parasitic protozoa are potential drug targets. gsk-3 is an enzyme that ...201021399604
in vitro and in vivo antiplasmodial activity and cytotoxicity of water extracts of phyllanthus emblica, terminalia chebula, and terminalia bellerica.to evaluate the in vitro and in vivo antiplasmodial activity and the cytotoxicity of phyllanthus emblica linn, terminalia chebula retz, and terminalia bellerica (gaertn) roxb extracts.201021294406
modification of oxidative status in plasmodium berghei-infected erythrocytes by e-2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline compared to chloroquine.e-2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline (iq) is a new quinoline derivative which has been reported as a haemoglobin degradation and ss-haematin formation inhibitor. the haemoglobin proteolysis induced by plasmodium parasites represents a source of amino acids and haeme, leading to oxidative stress in infected cells. in this paper, we evaluated oxidative status in plasmodium berghei-infected erythrocytes in the presence of iq using chloroquine (cq) as a control. a ...200919876558
antimalarial activity of ultra-short peptides.ultra-short peptides 1-9 were designed and synthesized with phenylalanine, ornithine and proline amino acid residues and their effect on antimalarial activity was analyzed. on the basis of the ic(50) data for these compounds, the effects of nature, polarity, and amino acid sequence on plasmodium berghei schizont cultures were analyzed too. tetrapeptides phe-orn-phe-orn (4) and lys-phe-phe-orn (5) showed a very important activity with ic(50) values of 3.31 and 2.57 microm, respectively. these two ...200920032878
glutathione reductase and thioredoxin reductase: novel antioxidant enzymes from plasmodium berghei.malaria parasites adapt to the oxidative stress during their erythrocytic stages with the help of vital thioredoxin redox system and glutathione redox system. glutathione reductase and thioredoxin reductase are important enzymes of these redox systems that help parasites to maintain an adequate intracellular redox environment. in the present study, activities of glutathione reductase and thioredoxin reductase were investigated in normal and plasmodium berghei-infected mice red blood cells and th ...200919967095
experimental splenectomies and malaria in mice.to evaluate the importance of spleen in malaric infection in murino model, comparing the parasitemia and the titles of immunoglobulins in the different groups.200920011827
discovery of plasmodium modulators by genome-wide analysis of circulating hemocytes in anopheles gambiae.insect hemocytes mediate important cellular immune responses including phagocytosis and encapsulation and also secrete immune factors such as opsonins, melanization factors, and antimicrobial peptides. however, the molecular composition of these important immune cells has not been elucidated in depth, because of their scarcity in the circulating hemolymph, their adhesion to multiple tissues and the lack of primary culture methods to produce sufficient material for a genome-wide analysis. in this ...200919940242
a nonadjuvanted polypeptide nanoparticle vaccine confers long-lasting protection against rodent malaria.we have designed and produced a prototypic malaria vaccine based on a highly versatile self-assembling polypeptide nanoparticle (sapn) platform that can repetitively display antigenic epitopes. we used this platform to display a tandem repeat of the b cell immunodominant repeat epitope (dppppnpn)(2)d of the malaria parasite plasmodium berghei circumsporozoite protein. administered in saline, without the need for a heterologous adjuvant, the sapn construct p4c-mal conferred a long-lived, protecti ...200919915055
accelerated clearance of plasmodium-infected erythrocytes in sickle cell trait and annexin-a7 deficiency.the course of malaria does not only depend on the virulence of the parasite plasmodium but also on properties of host erythrocytes. here, we show that infection of erythrocytes from human sickle cell trait (hba/s) carriers with ring stages of p. falciparum led to significantly enhanced pge(2) formation, ca(2+) permeability, annexin-a7 degradation, phosphatidylserine (ps) exposure at the cell surface, and clearance by macrophages. p. berghei-infected erythrocytes from annexin-a7-deficient (annexi ...200919910682
limited role of cd4+foxp3+ regulatory t cells in the control of experimental cerebral malaria.cerebral malaria (cm) associated with plasmodium berghei anka (pba) infection is an accepted model of human cm. cm during pba infection critically depends on sequestration of t cells into the brain. several studies aimed to address the role of regulatory t cells (t(reg)) in modulating this pathogenic t cell response. however, these studies are principally hampered due to the fact that until recently no reagents were available to deplete foxp3(+) t(reg) specifically. to study the function of t(re ...200919890049
a role for immune responses against non-cs components in the cross-species protection induced by immunization with irradiated malaria sporozoites.immunization with irradiated plasmodium sporozoites induces sterile immunity in rodents, monkeys and humans. the major surface component of the sporozoite the circumsporozoite protein (cs) long considered as the antigen predominantly responsible for this immunity, thus remains the leading candidate antigen for vaccines targeting the parasite's pre-erythrocytic (pe) stages. however, this role for cs was questioned when we recently showed that immunization with irradiated sporozoites (irrspz) of a ...200919890387
determination of the expression of lymphocyte surface markers and cytokine levels in a mouse model of plasmodium berghei.this study aimed to determine the changes in lymphocyte surface markers and cytokine profiles during a malarial infection in a mouse model of malaria. mononuclear cells obtained from the spleens of the mice infected with plasmodium berghei (p. berghei) were stained with anti-mouse cd3, anti-mouse cd4, anti-mouse cd8, anti-mouse cd19, anti-mouse cd152, anti-mouse pan natural killer (nk), anti-mouse cd80 monoclonal antibodies and expression of surface markers was evaluated by flow cytometry. in th ...200919845111
dissecting the genetic basis of resistance to malaria parasites in anopheles gambiae.the ability of anopheles gambiae mosquitoes to transmit plasmodium parasites is highly variable between individuals. however, the genetic basis of this variability has remained unknown. we combined genome-wide mapping and reciprocal allele-specific rna interference (rasrnai) to identify the genomic locus that confers resistance to malaria parasites and demonstrated that polymorphisms in a single gene encoding the antiparasitic thioester-containing protein 1 (tep1) explain a substantial part of t ...200919797663
statins fail to improve outcome in experimental cerebral malaria and potentiate toll-like receptor-mediated cytokine production by murine macrophages.cerebral malaria is responsible for a large proportion of the estimated one million deaths caused by plasmodium falciparum malaria annually. this disease is associated with excessive pro-inflammatory cytokine production resulting from dysregulated host responses to infection. on the basis of reports indicating potent activity against host-mediated inflammatory disorders such as sepsis, we examined the activity of statins (3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors) on malaria-ass ...200919815878
anopheles mortality is both age- and plasmodium-density dependent: implications for malaria transmission.daily mortality is an important determinant of a vector's ability to transmit pathogens. original simplifying assumptions in malaria transmission models presume vector mortality is independent of age, infection status and parasite load. previous studies illustrate conflicting evidence as to the importance of plasmodium-induced vector mortality, but very few studies to date have considered the effect of infection density on mosquito survival.200919822012
the crystal structures of macrophage migration inhibitory factor from plasmodium falciparum and plasmodium berghei.malaria, caused by plasmodium falciparum and related parasites, is responsible for millions of deaths each year, mainly from complications arising from the blood stages of its life cycle. macrophage migration inhibitory factor (mif), a protein expressed by the parasite during these stages, has been characterized in mammals as a cytokine involved in a broad spectrum of immune responses. it also possesses two catalytic activities, a tautomerase and an oxidoreductase, though the physiological signi ...200919827093
preliminary studies on the effects of orally-administered transforming growth factor-beta on protozoan diseases in mice.transforming growth factor beta-1 (tgf-beta1) is a pleiotropic cytokine with both pro- and antiinflammatory properties, depending on its environment and concentration. the present study evaluated the effects of orally-delivered tgf-beta1 on mice parenterally-infected with various protozoan parasites. we report that while orally-administered tgf-beta1 seems to confer partial protection against murine chronic babesiosis and acute trypanosomosis, no beneficial clinical effects were observed against ...200919827745
structure-activity relationship studies of manzamine a: amidation of positions 6 and 8 of the beta-carboline moiety.twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. the amides of manzamine a (1) showed significantly reduced cytotoxicity against vero cells, although were less active than 1. the structure-activity analysis showed that linear, short alkyl groups adjacent to the amide carbonyl at position 8 are favored for antimalarial activity, while bulky and cyclic groups at position 6 provided the most active amides. most of the amides showed poten ...200919833520
signalling in malaria parasites. the malsig consortium.depending on their developmental stage in the life cycle, malaria parasites develop within or outside host cells, and in extremely diverse contexts such as the vertebrate liver and blood circulation, or the insect midgut and hemocoel. cellular and molecular mechanisms enabling the parasite to sense and respond to the intra- and the extra-cellular environments are therefore key elements for the proliferation and transmission of plasmodium, and therefore are, from a public health perspective, stra ...200919839262
altered nucleotide receptor expression in a murine model of cerebral malaria.in cerebral malaria, the most severe complication of malaria, both neurotransmission mechanisms and energy metabolism are affected. to understand how metabolic changes modify neurotransmission, we examined p2 receptor expression in a murine model of cerebral malaria. quantitative polymerase chain reaction experiments revealed that parasite deposition was greatest in the cerebellum, compared with other areas of the brain, suggesting a correlation between brain parasitemia and loss of control of m ...200919758097
the ig domain protein cd9p-1 down-regulates cd81 ability to support plasmodium yoelii infection.invasion of hepatocytes by plasmodium sporozoites is a prerequisite for establishment of a malaria natural infection. the molecular mechanisms underlying sporozoite invasion are largely unknown. we have previously reported that cd81 is required on hepatocytes for infection by plasmodium falciparum and plasmodium yoelii sporozoites. cd81 belongs to the tetraspanin superfamily of transmembrane proteins. by interacting with each other and with other transmembrane proteins, tetraspanins may play a r ...200919762465
a cyclic gmp signalling module that regulates gliding motility in a malaria parasite.the ookinete is a motile stage in the malaria life cycle which forms in the mosquito blood meal from the zygote. ookinetes use an acto-myosin motor to glide towards and penetrate the midgut wall to establish infection in the vector. the regulation of gliding motility is poorly understood. through genetic interaction studies we here describe a signalling module that identifies guanosine 3', 5'-cyclic monophosphate (cgmp) as an important second messenger regulating ookinete differentiation and mot ...200919779564
structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues.based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. none of the bicyclic compounds was significantly active against the chloroquine-resistant strain plasmodium falciparum k1, in contrast to the tricyclic der ...200919781948
highly efficient subcloning of rodent malaria parasites by injection of single merosomes or detached cells.this protocol describes a method for obtaining rodent plasmodium parasite clones with high efficiency, which takes advantage of the normal course of plasmodium in vitro exoerythrocytic development. at the completion of development, detached cells/merosomes form, which contain hundreds to thousands of merozoites. as all parasites within a single detached cell/merosome derive from the same sporozoite, we predicted them to be genetically identical. to prove this, hepatoma cells were infected simult ...200919745825
screening of antiplasmodial properties among some traditionally used iranian plants.an investigation of plants was undertaken through interviews and literature surveys on plants used to treat malaria or cancer or microbial diseases in iran.200919059470
paternal effect of the nuclear formin-like protein misfit on plasmodium development in the mosquito vector.malaria parasites must undergo sexual and sporogonic development in mosquitoes before they can infect their vertebrate hosts. we report the discovery and characterization of misfit, the first protein with paternal effect on the development of the rodent malaria parasite plasmodium berghei in anopheles mosquitoes. misfit is expressed in male gametocytes and localizes to the nuclei of male gametocytes, zygotes and ookinetes. gene disruption results in mutant ookinetes with reduced genome content, ...200919662167
anopheles gambiae pgrplc-mediated defense against bacteria modulates infections with malaria parasites.recognition of peptidoglycan (pgn) is paramount for insect antibacterial defenses. in the fruit fly drosophila melanogaster, the transmembrane pgn recognition protein lc (pgrp-lc) is a receptor of the imd signaling pathway that is activated after infection with bacteria, mainly gram-negative (gram-). here we demonstrate that bacterial infections of the malaria mosquito anopheles gambiae are sensed by the orthologous pgrplc protein which then activates a signaling pathway that involves the rel/nf ...200919662170
ca/c1 peptidases of the malaria parasites plasmodium falciparum and p. berghei and their mammalian hosts--a bioinformatical analysis.in genome-wide screens we studied ca/c1 peptidases of malaria-causing plasmodia and their hosts (man and mouse). for plasmodium falciparum and p. berghei, several new ca/c1 peptidase genes encoding proteases of the l- and b-family with specific promoter modules were identified. in addition, two new human ca/c1 peptidase loci and one new mouse gene locus were found; otherwise, the sets of ca/c1 peptidase genes in man and mouse seem to be complete now. in each species studied there is a multitude ...200919663681
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