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expression profiles of peroxiredoxins in liver stage of the rodent malaria parasite plasmodium berghei.mrna and protein expression profiles for three peroxiredoxins (tpx-1, tpx-2 and 1-cys prx) of liver stage plasmodium berghei were examined through quantitative reverse transcription-pcr (rt-pcr) and indirect immunofluorescence microscopy assay (ifa). rt-pcr experiments revealed that mrna expression for the tpx-1 was detected shortly after the sporozoite infection and kept expressed until the schizont stage. in contrast, the mrna expression for 1-cys prx had begun increasing when the parasite dev ...201323237790
plasmodium berghei sporozoite challenge of vaccinated balb/c mice leads to the induction of humoral immunity and improved function of cd8(+) memory t cells.protection against malaria can be achieved by induction of a strong cd8(+) t-cell response against the plasmodium circumsporozoite protein (csp), but most subunit vaccines suffer from insufficient memory responses. in the present study, we analyzed the impact of postimmunization sporozoite challenge on the development of long-lasting immunity. balb/c mice were immunized by a heterologous prime/boost regimen against plasmodium berghei csp that induces a strong cd8(+) t-cell response and sterile p ...201323229763
identification and optimization of an aminoalcohol-carbazole series with antimalarial properties.recent observations on the emergence of artemisinin resistant parasites have highlighted the need for new antimalarial treatments. an hts campaign led to the identification of the 1-(1-aminopropan-2-ol)carbazole analogues as potent hits against plasmodium falciparum k1 strain. the sar study and optimization of early adme and physicochemical properties direct us to the selection of a late lead compound that shows good efficacy when orally administrated in the in vivo p. berghei mouse model.201324900603
synergistic effect of aqueous extract of telfaria occidentalis on the biological activities of artesunate in plasmodium berghei infected mice.resistance to most antimalarial drugs has encouraged the use of herbal preparations along with prescribed orthodox drugs.201324940320
proposal for a new therapy for drug-resistant malaria using plasmodium synthetic lethality inference.many antimalarial drugs kill malaria parasites, but antimalarial drug resistance (adr) and toxicity to normal cells limit their usefulness. to solve this problem, we suggest a new therapy for drug-resistant malaria. the approach consists of data integration and inference through homology analysis of yeast-human-plasmodium. if one gene of a plasmodium synthetic lethal (sl) gene pair has a mutation that causes adr, a drug targeting the other gene of the sl pair might be used as an effective treatm ...201324533301
interleukin-27 exhibited anti-inflammatory activity during plasmodium berghei infection in mice.interleukin-27 (il-27) has a pleiotropic role either as a pro-inflammatory or anti-inflammatory cytokine in inflammatory related diseases. the role and involvement of il-27 during malaria was investigated and the effects of modulating its release on the production of major inflammatory cytokines and the histopathological consequences in major affected organs during the infection were evaluated. results showed that il-27 concentration was significantly elevated throughout the infection but no pos ...201324522137
antimalarial properties of artemisia vulgaris l. ethanolic leaf extract in a plasmodium berghei murine malaria model.artemisinin isolated from artemisia annua is the most potent antimalarial drug against chloroquine-resistant plasmodium falciparum malaria. artemisia vulgaris, an invasive weed, is the only artemisia species available in sri lanka. a pilot study was undertaken to investigate the antiparasitic activity of an a. vulgaris ethanolic leaf extract (avele) in a p. berghei anka murine malaria model that elicits pathogenesis similar to falciparum malaria.201324499850
evaluation of haematological changes in plasmodium-berghei-infected mice administered with aqueous extract of phyllantus amarus.this study was designed to evaluate the changes in some hematological parameters of p-berghei-infected mice treated with aqueous extract of phyllantus amarus, a plant that is used traditionally to treat malaria patients in some nigerian communities. the aqueous extract of the leaves at 200, 400 and 600 mg kg(-1) body weight/day dose levels were used to treat the test groups immediately after infection for the suppressive test and 72 hours post infection for the curative test while a standard ant ...201324498819
aspidosperma (apocynaceae) plant cytotoxicity and activity towards malaria parasites. part i: aspidosperma nitidum (benth) used as a remedy to treat fever and malaria in the amazon.infusions of aspidosperma nitidum (apocynaceae) wood bark are used to treat fever and malaria in the amazon region. several species of this family are known to possess indole alkaloids and other classes of secondary metabolites, whereas terpenoids, an inositol and the indole alkaloids harmane-3 acid and braznitidumine have been described in a. nitidum . in the present study, extracts from the wood bark, leaves and branches of this species were prepared for assays against malaria parasites and cy ...201324402150
effect of artesunate based combination therapy with homeopathic medicine china on liver and kidney of plasmodium berghei infected mice.present study has been undertaken to evaluate antimalarial potential and safety of artesunate based combination therapy with homeopathic medicine china (ϕ/30 potency) against plasmodium berghei (nk-65), a lethal rodent malaria parasite. in combination therapy, the oral administration of artesunate (100 mg/kg) + china ϕ/30 proved to be highly efficacious as it completely cleared the blood stage infection. during the follow up period up to day 28, no recrudescence was observed and the survival rat ...201324431543
in vitro and in vivo characterization of the antimalarial lead compound ssj-183 in plasmodium models.the objective of this work was to characterize the in vitro (plasmodium falciparum) and in vivo (plasmodium berghei) activity profile of the recently discovered lead compound ssj-183. the molecule showed in vitro a fast and strong inhibitory effect on growth of all p. falciparum blood stages, with a tendency to a more pronounced stage-specific action on ring forms at low concentrations. furthermore, the compound appeared to be equally efficacious on drug-resistant and drug-sensitive parasite str ...201324255594
further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria.cerebral malaria (cm) is a clinical syndrome resulting from plasmodium falciparum infection. a wide range of clinical manifestations follow the disease including cognitive dysfunction, seizures and coma. cm pathogenesis remains incompletely understood and without treatment this condition is invariably fatal. artesunate has been accepted as the most effective drug for treating severe malaria. besides its antiparasitic activity, an anti-inflammatory property has also been reported. in the current ...201324180288
cytokine response to pregnancy-associated recrudescence of plasmodium berghei infection in mice with pre-existing immunity to malaria.during childhood, residents of areas with stable transmission of plasmodium falciparum parasites acquire substantial protective immunity to malaria, and adults therefore rarely experience clinical disease episodes. however, susceptibility to infection reappears in pregnant women, particularly primigravidae. this is due to appearance of antigenic parasite variants that are restricted to pregnancy. variant-specific immunity also governs pregnancy-associated recrudescence of plasmodium berghei infe ...201324180253
oxidative stress and micronutrient therapy in malaria: an in vivo study in plasmodium berghei infected mice.free radical production from oxidative stress induced by malaria infection plays a major role in the pathogenesis of malaria. however, the use of agents with antioxidant activity may interfere with malaria progression. the study involves an in vivo evaluation of the role of some antioxidant micronutrients in the modulation of malaria infection. rodent malaria model using plasmodium berghei nk-65 strain (chloroquine sensitive) was used for the study. forty five mice of either sex weighing 20.05 + ...201324171263
ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo.the precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. here, we describe a method to exploit aberrant levels of mobile ferrous iron (fe(ii)) for selective drug delivery in vivo. this approach makes use of a 1,2,4-trioxolane moiety, which serves as an fe(ii)-sensitive "trigger," making drug release contingent on fe(ii)-promoted trioxolane fragmentation. we demon ...201324145449
flavones as isosteres of 4(1h)-quinolones: discovery of ligand efficient and dual stage antimalarial lead compounds.malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi-resistant strains of plasmodium falciparum poses a great challenge to controlling the disease. a diverse set of flavones, isosteric to 4(1h)-quinolones, were prepared and profiled for their antiplasmodial activity against the blood stage of p. falciparum w2 strain, and the liver stage of the rodent parasite plasmodium berghei. ligand efficient leads were identified as dual stage antimalarials, s ...201324125849
computational and experimental analysis identified 6-diazo-5-oxonorleucine as a potential agent for treating infection by plasmodium falciparum.plasmodium falciparum (pf) is the most severe malaria parasite. it is developing resistance quickly to existing drugs making it indispensable to discover new drugs. effective drugs have been discovered targeting metabolic enzymes of the parasite. in order to predict new drug targets, computational methods can be used employing database information of metabolism. using this data, we performed recently a computational network analysis of metabolism of pf. we analyzed the topology of the network to ...201324121016
tlr4 ligand formulation causes distinct effects on antigen-specific cell-mediated and humoral immune responses.the formulation of tlr ligands and other immunomodulators has a critical effect on their vaccine adjuvant activity. in this work, the synthetic tlr4 ligand gla was formulated with three distinct vaccine delivery system platforms (aqueous suspension, liposome, or oil-in-water emulsion). the effect of the different formulations on the adaptive immune response to protein subunit vaccines was evaluated in the context of a recombinant malaria antigen, plasmodium berghei circumsporozoite protein (pbcs ...201324120675
anti-plasmodial activity of some zulu medicinal plants and of some triterpenes isolated from them.mimusops caffra e. mey. ex a.dc and mimusops obtusifolia lam (both members of the sapotaceae family), and hypoxis colchicifolia bak (family hypoxidaceae) are used by traditional healers in zululand to manage malaria. anti-plasmodial investigation of the crude extracts and some triterpenes isolated from the plants showed activity against a chloroquine sensitive (cqs) strain of plasmodium falciparum (d10). among the crude extracts the leaves of m. caffra exhibited the highest activity, with an ic₅ ...201324108397
structure-activity-relationship studies around the 2-amino group and pyridine core of antimalarial 3,5-diarylaminopyridines lead to a novel series of pyrazine analogues with oral in vivo activity.replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. however, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. the 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the k1 (multidrug resistant) and nf54 (sensitive) strains of plasmodium falciparum in ...201324099149
a purine analog synergizes with chloroquine (cq) by targeting plasmodium falciparum hsp90 (pfhsp90).drug resistance, absence of an effective vaccine, and inadequate public health measures are major impediments to controlling plasmodium falciparum malaria worldwide. the development of antimalarials to which resistance is less likely is paramount. to this end, we have exploited the chaperone function of p. falciparum hsp90 (pfhsp90) that serves to facilitate the expression of resistance determinants.201324098696
the transcription factor t-bet regulates parasitemia and promotes pathogenesis during plasmodium berghei anka murine malaria.the pathogenesis of experimental cerebral malaria (ecm) is an immunologic process, mediated in part by th1 cd4(+) t cells. however, the role of the th1 cd4(+) t cell differentiation program on the ability to control parasitemia and susceptibility to ecm disease during blood stage malaria has never been assessed directly. using the plasmodium berghei anka murine model of ecm and mice deficient for the transcription factor t-bet (the master regulator of th1 cells) on the susceptible c57bl/6 backgr ...201324078698
two putative protein export regulators promote plasmodium blood stage development in vivo.protein export is considered an essential feature of malaria parasite blood stage development. here, we examined five components of the candidate plasmodium translocon of exported proteins (ptex), a complex thought to mediate protein export across the parasitophorous vacuole membrane into the host cell. using the murine malaria model parasite plasmodium berghei, we succeeded in generating parasite lines lacking ptex88 and thioredoxin 2 (trx2). repeated attempts to delete the remaining three tran ...201324076174
metabolic profiling framework for discovery of candidate diagnostic markers of malaria.despite immense efforts to combat malaria in tropical and sub-tropical regions, the potency of this vector-borne disease and its status as a major driver of morbidity and mortality remain undisputed. we develop an analytical pipeline for characterizing plasmodium infection in a mouse model and identify candidate urinary biomarkers that may present alternatives to immune-based diagnostic tools. we employ (1)h nuclear magnetic resonance (nmr) profiling followed by multivariate modeling to discover ...201324067624
screening of novel malaria dna vaccine candidates using full-length cdna library.no licensed malaria vaccine exists, in spite of intensive development efforts. we have been investigating development of a dna vaccine to prevent malaria infection. to date, we have established a full-length cdna expression library from the erythrocytic-stage murine malaria parasite, plasmodium berghei. we found that immunization of mice with combined 2000 clones significantly prolonged survival after challenge infection and that splenocytes from the immunized mice showed parasite-specific cytok ...201324055215
the evolution and diversity of a low complexity vaccine candidate, merozoite surface protein 9 (msp-9), in plasmodium vivax and closely related species.the merozoite surface protein-9 (msp-9) has been considered a target for an anti-malarial vaccine since it is one of many proteins involved in the erythrocyte invasion, a critical step in the parasite life cycle. orthologs encoding this antigen have been found in all known species of plasmodium parasitic to primates. in order to characterize and investigate the extent and maintenance of msp-9 genetic diversity, we analyzed dna sequences of the following malaria parasite species: plasmodium falci ...201324044894
pre-existing schistosoma japonicum infection alters the immune response to plasmodium berghei infection in c57bl/6 mice.since helminths and malaria parasites are often co-endemic, it is important to clarify the immunoregulatory mechanism that occurs during the process of co-infection. a previous study confirmed that dendritic cells (dcs) are involved in the establishment and regulation of the t-cell-mediated immune response to malaria infection. in the current study, distinct response profiles for splenic dcs and regulatory t cell (treg) responses were assessed to evaluate the effects of a pre-existing schistosom ...201324034228
identification of the plasmodium berghei resistance locus 9 linked to survival on chromosome 9.one of the main causes of mortality from severe malaria in plasmodium falciparum infections is cerebral malaria (cm). an important host genetic component determines the susceptibility of an individual to develop cm or to clear the infection and become semi-immune. as such, the identification of genetic loci associated with susceptibility or resistance may serve to modulate disease severity.201324025732
an oral malaria therapy: curcumin-loaded lipid-based drug delivery systems combined with β-arteether.curcumin (cc), a potential antimalarial drug, has poor water solubility, stability and oral bioavailability. to circumvent these pitfalls, lipid-based drug delivery systems (lbddss) with a high cc loading (30 mg/g) were formulated. in a biorelevant gastric medium, cc-lbddss formed particle sizes in the range of 30-40 nm. during in vitro lipolysis, 90-95% of the cc remained solubilized, whereas 5-10% of the cc precipitated as an amorphous solid, with a high rate of re-dissolution in a biorelevant ...201324021359
density-dependent blood stage plasmodium falciparum suppresses malaria super-infection in a malaria holoendemic population.recent studies of plasmodium berghei malaria in mice show that high blood-stage parasitemia levels inhibit the development of subsequent liver-stage infections. whether a similar inhibitory effect on liver-stage plasmodium falciparum by blood-stage infection occurs in humans is unknown. we have analyzed data from a treatment-time-to-infection cohort of children < 10 years of age residing in a malaria holoendemic area of kenya where people experience a new blood-stage infection approximately ever ...201324019439
synthesis and in vitro and in vivo evaluation of antimalarial polyamines.we recently reported that 1,14-diphenylacetamide derivatives of spermine exhibit potent nm in vitro growth inhibition properties of plasmodium falciparum. in an effort to expand the structure-activity relationship of this compound class towards malaria, we have prepared and biologically tested a library that includes benzamide and 3-phenylpropanamide 'capping acid' groups, and polyamines that include spermine (pa3-4-3) and chain extended analogues pa3-8-3 and pa3-12-3. 2-hydroxy and 2,5-dimethox ...201323995215
protection of renal function by green tea extract during plasmodium berghei infection.impairment of renal function from oxidative stress during malaria infection is one of the leading causes of death in endemic areas. since blood urea nitrogen and creatinine levels in plasma can be used as markers for monitoring renal damage, this study investigated the effect of green tea extract on reduction of blood urea nitrogen and creatinine levels during malaria infection using plasmodium berghei anka infected mice as in vivo model. for in vivo testing, icr mice were infected with 1 × 10(7 ...201323988625
mice lacking inducible nitric oxide synthase develop exacerbated hepatic inflammatory responses induced by plasmodium berghei nk65 infection.infection of mice with plasmodium berghei nk65 represents a well-recognized malaria model in which infection is accompanied by an intense hepatic inflammatory response. enzyme-inducible nitric oxide synthase is an important regulator of inflammation and leukocyte recruitment in microvessels, but these functions have yet to be evaluated in experimental malaria. in this study, we assessed the involvement of inducible nitric oxide synthase in inflammatory responses to murine experimental malaria in ...201323988520
azadirachta indica ethanolic extract protects neurons from apoptosis and mitigates brain swelling in experimental cerebral malaria.cerebral malaria is a rapidly developing encephalopathy caused by the apicomplexan parasite plasmodium falciparum. drugs currently in use are associated with poor outcome in an increasing number of cases and new drugs are urgently needed. the potential of the medicinal plant azadirachta indica (neem) for the treatment of experimental cerebral malaria was evaluated in mice.201323984986
antimalarial activity of cocos nucifera husk fibre: further studies.in this study, the antimalarial and toxicity potentials of husk fibre extracts of five nigerian varieties of cocos nucifera were evaluated in vitro. the only active extract fraction, west african tall (wat) ethyl acetate extract fraction, was then evaluated for its phytochemical constituents, antimalarial and toxicity potentials at varying doses (31.25-500 mg/kg body weight) using various organ function indices. the results revealed that wat ethyl acetate extract fraction (wateaef) contained alk ...201323983800
phytochemical analysis and antimalarial activity aqueous extract of lecaniodiscus cupanioides root.root aqueous extract of lecaniodiscus cupanioides was evaluated for antimalarial activity and analyzed for its phytochemical constituents. twenty-four (24) albino mice were infected by intraperitoneal injection of standard inoculum of chloroquine sensitive plasmodium berghei (nk 65). the animals were randomly divided into 6 groups of 3 mice each. group 1 served as the control while groups ii-iv were orally administered 50, 150, and 250 mg/kg body weights of extract. groups 5 and 6 received 1.75 ...201323983718
anti-erythropoietin antibody levels and its association with anaemia in different strains of semi-immune mice infected with plasmodium berghei anka.malaria anaemia is still a major public health problem and its pathogenesis still unclear. interestingly, the progression of anaemia is at relatively low parasitaemia with some mortality in the semi-immune individuals in the endemic areas despite adequate erythropoietin (epo) synthesis. a recent study has shown that treatment with exogenous anti-erythropoietin (anti-epo) antibodies (ab) of infected mice gives protection against malaria infection, suggesting an important role for anti-epo ab in m ...201323978045
the curative and prophylactic effects of xylopic acid on plasmodium berghei infection in mice.efforts have been intensified to search for more effective antimalarial agents because of the observed failure of some artemisinin-based combination therapy (act) treatments of malaria in ghana. xylopic acid, a pure compound isolated from the fruits of the xylopia aethiopica, was investigated to establish its attributable prophylactic, curative antimalarial, and antipyretic properties. the antimalarial properties were determined by employing xylopic acid (10-100 mg/kg) in icr mice infected with ...201323970953
cd36 and fyn kinase mediate malaria-induced lung endothelial barrier dysfunction in mice infected with plasmodium berghei.severe malaria can trigger acute lung injury characterized by pulmonary edema resulting from increased endothelial permeability. however, the mechanism through which lung fluid conductance is altered during malaria remains unclear. to define the role that the scavenger receptor cd36 may play in mediating this response, c57bl/6j (wt) and cd36-/- mice were infected with p. berghei anka and monitored for changes in pulmonary endothelial barrier function employing an isolated perfused lung system. w ...201323967147
identification of piggybac-mediated insertions in plasmodium berghei by next generation sequencing.the piggybac transposon system provides a powerful forward genetics tool to study gene function in plasmodium parasites via random insertion mutagenesis and phenotypic screening. the identification of genotype of piggybac mutants in the plasmodium genome is thus an indispensable step in forward genetic analysis. several pcr-based approaches have been used to identify the piggybac insertion sites in plasmodium falciparum and plasmodium berghei, but all are tedious and inefficient. next generation ...201323961915
metabolite extract of streptomyces hygroscopicus hygroscopicus inhibit the growth of plasmodium berghei through inhibition of ubiquitin - proteasome system.streptomyces hygroscopicus hygroscopicus, a member of family of actinomycetes produces eponemycin a proteasome inhibitor that can inhibit ubiquitin-proteasome system (ups) function in eukaryotic cell. previous study showed that coronamycin, an active substrate isolated from streptomyces sp. can act as anti-plasmodial, antibacterial, and antifungal, however the research did not show the mechanism of coronamycin in inhibiting the growth of plasmodium. this research was done to reveal if eponemycin ...201323959495
antimalarial and safety evaluation of pluchea lanceolata (dc.) oliv. & hiern: in-vitro and in-vivo study.many of the effective therapeutic strategies have been derived from ethnopharmacologically used natural products. pluchea lanceolata is an herb employed in indian folk medicine for malaria like fever but it lacks proper pharmacological intervention.201323954323
cytoadherence of plasmodium berghei-infected red blood cells to murine brain and lung microvascular endothelial cells in vitro.sequestration of infected red blood cells (irbc) within the cerebral and pulmonary microvasculature is a hallmark of human cerebral malaria (hcm). the interaction between irbc and the endothelium in hcm has been studied extensively and is linked to the severity of malaria. experimental cm (ecm) caused by plasmodium berghei anka reproduces most features of hcm, although the sequestration of rbc infected by p. berghei anka (pba-irbc) has not been completely delineated. the role of pba-irbc sequest ...201323940206
malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection.heme metabolism is central to malaria parasite biology. the parasite acquires heme from host hemoglobin in the intraerythrocytic stages and stores it as hemozoin to prevent free heme toxicity. the parasite can also synthesize heme de novo, and all the enzymes in the pathway are characterized. to study the role of the dual heme sources in malaria parasite growth and development, we knocked out the first enzyme, δ-aminolevulinate synthase (alas), and the last enzyme, ferrochelatase (fc), in the he ...201323935500
irf8-regulated genomic responses drive pathological inflammation during cerebral malaria.interferon regulatory factor 8 (irf8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. bxh2 mice harbor a severely hypomorphic allele at irf8 (irf8(r294c)) that causes susceptibility to infection with intracellular pathogens including mycobacterium tuberculosis. we report that bxh2 are completely resistant to the development of cerebral malaria (ecm) following plasmodium berghei anka infection. comparative transcriptional profiling of brain rna ...201323853600
translational repression controls temporal expression of the plasmodium berghei lccl protein complex.plasmodium lccl proteins comprise a family of six proteins that function as a protein complex and have essential roles in sporozoite transmission. in plasmodium berghei, family members pblap1, pblap2 and pblap3 have been shown to be expressed in gametocytes and, following gametogenesis and fertilization, to be targeted to distinctive multivesicular organelles termed crystalloids that form in the ookinete. here, we show by gfp-tagging that pblap4, pblap5 and pblap6, like their family members, are ...201323684590
mechanisms of protective immune responses induced by the plasmodium falciparum circumsporozoite protein-based, self-assembling protein nanoparticle vaccine.a lack of defined correlates of immunity for malaria, combined with the inability to induce long-lived sterile immune responses in a human host, demonstrate a need for improved understanding of potentially protective immune mechanisms for enhanced vaccine efficacy. protective sterile immunity (>90%) against the plasmodium falciparum circumsporozoite protein (csp) has been achieved using a transgenically modified plasmodium berghei sporozoite (tg-pb/pfcsp) and a self-assembling protein nanopartic ...201323607541
the survival of memory cd8 t cells that is mediated by il-15 correlates with sustained protection against malaria.ag-specific memory t cell responses elicited by infections or vaccinations are inextricably linked to long-lasting protective immunity. studies of protective immunity among residents of malaria endemic areas indicate that memory responses to plasmodium ags are not adequately developed or maintained, as people who survive episodes of childhood malaria are still vulnerable to either persistent or intermittent malaria infections. in contrast, multiple exposures to radiation-attenuated plasmodium be ...201323589611
quantitative bioluminescent imaging of pre-erythrocytic malaria parasite infection using luciferase-expressing plasmodium yoelii.the liver stages of plasmodium parasites are important targets for the development of anti-malarial vaccine candidates and chemoprophylaxis approaches that aim to prevent clinical infection. analyzing the impact of interventions on liver stages in the murine malaria model system plasmodium yoelii has been cumbersome and requires terminal procedures. in vivo imaging of bioluminescent parasites has previously been shown to be an effective and non-invasive alternative to monitoring liver stage burd ...201323593316
a key role for lipoic acid synthesis during plasmodium liver stage development.the successful navigation of malaria parasites through their life cycle, which alternates between vertebrate hosts and mosquito vectors, requires a complex interplay of metabolite synthesis and salvage pathways. using the rodent parasite plasmodium berghei, we have explored the synthesis and scavenging pathways for lipoic acid, a short-chain fatty acid derivative that regulates the activity of α-ketoacid dehydrogenases including pyruvate dehydrogenase. in plasmodium, lipoic acid is either synthe ...201323490300
plasmodium berghei mapk1 displays differential and dynamic subcellular localizations during liver stage development.mitogen-activated protein kinases (mapks) regulate key signaling events in eukaryotic cells. in the genomes of protozoan plasmodium parasites, the causative agents of malaria, two genes encoding kinases with significant homology to other eukaryotic mapks have been identified (mapk1, mapk2). in this work, we show that both genes are transcribed during plasmodium berghei liver stage development, and analyze expression and subcellular localization of the pbmapk1 protein in liver stage parasites. li ...201323544094
plasmodium yoelii inhibitor of cysteine proteases is exported to exomembrane structures and interacts with yoelipain-2 during asexual blood-stage development.plasmodium falciparum (pf) blood stages express falstatin, an inhibitor of cysteine proteases (icp), which is implicated in regulating proteolysis during red blood cell infection. recent data using the plasmodium berghei rodent malaria model suggested an additional role for icp in the infection of hepatocytes by sporozoites and during liver-stage development. here we further characterize the role of icp in vivo during infection with plasmodium yoelii (py) and pf. we found that py-icp was refract ...201323421981
the plasmodium berghei ca(2+)/h(+) exchanger, pbcax, is essential for tolerance to environmental ca(2+) during sexual development.ca(2+) contributes to a myriad of important cellular processes in all organisms, including the apicomplexans, plasmodium and toxoplasma. due to its varied and essential roles, free ca(2+) is tightly regulated by complex mechanisms. these mechanisms are therefore of interest as putative drug targets. one pathway in ca(2+) homeostatic control in apicomplexans uses a ca(2+)/h(+) exchanger (a member of the cation exchanger family, cax). the p. falciparum cax (pfcax) has recently been characterised i ...201323468629
perturbations of plasmodium puf2 expression and rna-seq of puf2-deficient sporozoites reveal a critical role in maintaining rna homeostasis and parasite transmissibility.malaria's cycle of infection requires parasite transmission between a mosquito vector and a mammalian host. we here demonstrate that the plasmodium yoelii pumilio-fbf family member puf2 allows the sporozoite to remain infectious in the mosquito salivary glands while awaiting transmission. puf2 mediates this solely through its rna-binding domain (rbd) likely by stabilizing or hastening the degradation of specific mrnas. puf2 traffics to sporozoite cytosolic granules, which are negative for severa ...201323356439
costs of crowding for the transmission of malaria parasites.the utility of using evolutionary and ecological frameworks to understand the dynamics of infectious diseases is gaining increasing recognition. however, integrating evolutionary ecology and infectious disease epidemiology is challenging because within-host dynamics can have counterintuitive consequences for between-host transmission, especially for vector-borne parasites. a major obstacle to linking within- and between-host processes is that the drivers of the relationships between the density, ...201323789029
features of autophagic cell death in plasmodium liver-stage parasites.analyzing molecular determinants of plasmodium parasite cell death is a promising approach for exploring new avenues in the fight against malaria. three major forms of cell death (apoptosis, necrosis and autophagic cell death) have been described in multicellular organisms but which cell death processes exist in protozoa is still a matter of debate. here we suggest that all three types of cell death occur in plasmodium liver-stage parasites. whereas typical molecular markers for apoptosis and ne ...201323388496
expression of cytosolic peroxiredoxins in plasmodium berghei ookinetes is regulated by environmental factors in the mosquito bloodmeal.the plasmodium ookinete develops over several hours in the bloodmeal of its mosquito vector where it is exposed to exogenous stresses, including cytotoxic reactive oxygen species (ros). how the parasite adapts to these challenging conditions is not well understood. we have systematically investigated the expression of three cytosolic antioxidant proteins, thioredoxin-1 (trx-1), peroxiredoxin-1 (tpx-1), and 1-cys peroxiredoxin (1-cys prx), in developing ookinetes of the rodent parasite plasmodium ...201323382676
novel type ii fatty acid biosynthesis (fas ii) inhibitors as multistage antimalarial agents.malaria is a potentially fatal disease caused by plasmodium parasites and poses a major medical risk in large parts of the world. the development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. in addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. at this point, a patient might already be suffering from the symptoms associated wi ...201323341167
endogenous mouse mammary tumor viruses (mtv): new roles for an old virus in cancer, infection, and immunity.mouse mammary tumor viruses are beta-retroviruses that exist in both exogenous (mmtv) and endogenous (mtv) forms. exogenous mmtv is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. mmtv has provided a number of critical models for studying both viral infection as well as human breast cancer. in addition to the horizontally transmitted mmtv, most inbred mouse strains contain permanently integrated mtv proviruses within their genome that ...201324324930
synthesis and antiprotozoal activity of original porphyrin precursors and derivatives.importance of heme in african trypanosomes, leishmania sp. and plasmodium sp. metabolisms justifies considering the potential of porphyrins and their precursors and derivatives as potential antiparasitic agents by interfering with heme metabolism. consequently, twenty-four porphyrin precursors and derivatives were evaluated against leishmania donovani, trypanosoma brucei and plasmodium sp. the best active compound against trypanosoma brucei brucei was a new porphyrin derivative; compound 4i, wit ...201323851117
potential of lichen secondary metabolites against plasmodium liver stage parasites with fas-ii as the potential target.chemicals targeting the liver stage (ls) of the malaria parasite are useful for causal prophylaxis of malaria. in this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against ls parasites of plasmodium berghei. inhibition of p. falciparum blood stage (bs) parasites was also assessed to determine stage specificity. compound 4 displayed the highest ls activity and stage specificity (ls ic50 value 2.3 μm, bs ic50 value 47. ...201323806111
recombination-mediated genetic engineering of plasmodium berghei dna.dna of plasmodium berghei is difficult to manipulate in escherichia coli by conventional restriction and ligation methods due to its high content of adenine and thymine (at) nucleotides. this limits our ability to clone large genes and to generate complex vectors for modifying the parasite genome. we here describe a protocol for using lambda red recombinase to modify inserts of a p. berghei genomic dna library constructed in a linear, low-copy, phage-derived vector. the method uses primer extens ...201322990774
defining the range of pathogens susceptible to ifitm3 restriction using a knockout mouse model.the interferon-inducible transmembrane (ifitm) family of proteins has been shown to restrict a broad range of viruses in vitro and in vivo by halting progress through the late endosomal pathway. further, single nucleotide polymorphisms (snps) in its sequence have been linked with risk of developing severe influenza virus infections in humans. the number of viruses restricted by this host protein has continued to grow since it was first demonstrated as playing an antiviral role; all of which ente ...201324278312
bacteria- and imd pathway-independent immune defenses against plasmodium falciparum in anopheles gambiae.the mosquito anopheles gambiae uses its innate immune system to control bacterial and plasmodium infection of its midgut tissue. the activation of potent imd pathway-mediated anti-plasmodium falciparum defenses is dependent on the presence of the midgut microbiota, which activate this defense system upon parasite infection through a peptidoglycan recognition protein, pgrplc. we employed transcriptomic and reverse genetic analyses to compare the p. falciparum infection-responsive transcriptomes o ...201324019865
targeted mutagenesis in the malaria mosquito using tale nucleases.anopheles gambiae, the main mosquito vector of human malaria, is a challenging organism to manipulate genetically. as a consequence, reverse genetics studies in this disease vector have been largely limited to rna interference experiments. here, we report the targeted disruption of the immunity gene tep1 using transgenic expression of transcription-activator like effector nucleases (talens), and the isolation of several tep1 mutant a. gambiae lines. these mutations inhibited protein production a ...201323977401
malaria infection does not affect the sensitivity of peripheral receptor neurons in anopheles stephensi.mosquitoes transmit many important diseases including malaria, dengue and yellow fever. disease transmission from one vertebrate host to another depends on repeated blood feedings by single mosquitoes. in order for the mosquito to acquire the blood that it needs to complete oogenesis, the insect must locate a suitable host. olfactory cues (including carbon dioxide) released by the host and detected by the mosquito are the primary signals that vector insects use for host location. previous studie ...201323642231
the role of hemocytes in anopheles gambiae antiplasmodial immunity.hemocytes synthesize key components of the mosquito complement-like system, but their role in the activation of antiplasmodial responses has not been established. the effect of activating toll signaling in hemocytes on plasmodium survival was investigated by transferring hemocytes or cell-free hemolymph from donor mosquitoes in which the suppressor cactus was silenced. these transfers greatly enhanced antiplasmodial immunity, indicating that hemocytes are active players in the activation of the ...201323886925
marked biological differences between insecticide resistant and susceptible strains of anopheles funestus infected with the murine parasite plasmodium berghei.anopheles funestus is one of the major malaria vectors in africa but research on this species has been restricted due to the lack of viable laboratory colonies. the vectorial capacity of natural populations of an. funestus is well known but its ability to host plasmodium in the laboratory and the development cycle of the parasite within this mosquito species was, until very recently, unknown. in this study we compared laboratory strains of an. funestus that were resistant and susceptible to pyre ...201323782642
wild anopheles funestus mosquito genotypes are permissive for infection with the rodent malaria parasite, plasmodium berghei.malaria parasites undergo complex developmental transitions within the mosquito vector. a commonly used laboratory model for studies of mosquito-malaria interaction is the rodent parasite, p. berghei. anopheles funestus is a major malaria vector in sub-saharan africa but has received less attention than the sympatric species, anopheles gambiae. the imminent completion of the a. funestus genome sequence will provide currently lacking molecular tools to describe malaria parasite interactions in th ...201323593423
plasmodium berghei sporozoites acquire virulence and immunogenicity during mosquito hemocoel transit.malaria is a vector-borne disease caused by the single-cell eukaryote plasmodium. the infectious parasite forms are sporozoites, which originate from midgut-associated oocysts, where they eventually egress and reach the mosquito hemocoel. sporozoites actively colonize the salivary glands in order to be transmitted to the mammalian host. whether residence in the salivary glands provides distinct and vital cues for the development of infectivity remains unsolved. in this study, we systematically c ...201324379288
enterobacter-activated mosquito immune responses to plasmodium involve activation of srpn6 in anopheles stephensi.successful development of plasmodium in the mosquito is essential for the transmission of malaria. a major bottleneck in parasite numbers occurs during midgut invasion, partly as a consequence of the complex interactions between the endogenous microbiota and the mosquito immune response. we previously identified srpn6 as an immune component which restricts plasmodium berghei development in the mosquito. here we demonstrate that srpn6 is differentially activated by bacteria in anopheles stephensi ...201323658788
experimental genetics of plasmodium berghei nfu in the apicoplast iron-sulfur cluster biogenesis pathway.eukaryotic pathogens of the phylum apicomplexa contain a non-photosynthetic plastid, termed apicoplast. within this organelle distinct iron-sulfur [fe-s] cluster proteins are likely central to biosynthesis pathways, including generation of isoprenoids and lipoic acid. here, we targeted a nuclear-encoded component of the apicoplast [fe-s] cluster biosynthesis pathway by experimental genetics in the murine malaria parasite plasmodium berghei. we show that ablation of the gene encoding a nitrogen f ...201323805304
chemobiosynthesis of new antimalarial macrolides.we have synthesized new derivatives of the macrolide antibiotics erythromycin and azithromycin. novel deoxysugar moieties were attached to these standard antibiotics by biotransformation using a heterologous host. the resulting compounds were tested against several standard laboratory and clinically isolated bacterial strains. in addition, they were also tested in vitro against standard and drug-resistant strains of human malaria parasites (plasmodium falciparum) and the liver stages of the rode ...201323208707
antibody to a conserved antigenic target is protective against diverse prokaryotic and eukaryotic pathogens.microbial capsular antigens are effective vaccines but are chemically and immunologically diverse, resulting in a major barrier to their use against multiple pathogens. a β-(1→6)-linked poly-n-acetyl-d-glucosamine (pnag) surface capsule is synthesized by four proteins encoded in genetic loci designated intercellular adhesion in staphylococcus aureus or polyglucosamine in selected gram-negative bacterial pathogens. we report that many microbial pathogens lacking an identifiable intercellular adhe ...201323716675
a nondiscriminating glutamyl-trna synthetase in the plasmodium apicoplast: the first enzyme in an indirect aminoacylation pathway.the malaria parasite plasmodium falciparum and related organisms possess a relict plastid known as the apicoplast. apicoplast protein synthesis is a validated drug target in malaria because antibiotics that inhibit translation in prokaryotes also inhibit apicoplast protein synthesis and are sometimes used for malaria prophylaxis or treatment. we identified components of an indirect aminoacylation pathway for gln-trna(gln) biosynthesis in plasmodium that we hypothesized would be essential for api ...201324072705
efficacy of a plasmodium vivax malaria vaccine using chad63 and modified vaccinia ankara expressing thrombospondin-related anonymous protein as assessed with transgenic plasmodium berghei parasites.plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in southeast asia and latin america. despite this dramatic burden, very few vaccines have been assessed in humans. the clinically relevant vectors modified vaccinia virus ankara (mva) and the chimpanzee adenovirus chad63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to in ...201324379295
dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites.drugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds--dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles--with promising activity against the liver stage. focused structure-activity studies on the dihydroquinazolinone scaffol ...201324366746
copper-transporting atpase is important for malaria parasite fertility.homeostasis of the trace element copper is essential to all eukaryotic life. copper serves as a cofactor in metalloenzymes and catalyses electron transfer reactions as well as the generation of potentially toxic reactive oxygen species. here, we describe the functional characterization of an evolutionarily highly conserved, predicted copper-transporting p-type atpase (cutp) in the murine malaria model parasite plasmodium berghei. live imaging of a parasite line expressing a fluorescently tagged ...201324237419
the malarial serine protease sub1 plays an essential role in parasite liver stage development.transmission of the malaria parasite to its vertebrate host involves an obligatory exoerythrocytic stage in which extensive asexual replication of the parasite takes place in infected hepatocytes. the resulting liver schizont undergoes segmentation to produce thousands of daughter merozoites. these are released to initiate the blood stage life cycle, which causes all the pathology associated with the disease. whilst elements of liver stage merozoite biology are similar to those in the much bette ...201324348254
hypoxia promotes liver-stage malaria infection in primary human hepatocytes in vitro.homeostasis of mammalian cell function strictly depends on balancing oxygen exposure to maintain energy metabolism without producing excessive reactive oxygen species. in vivo, cells in different tissues are exposed to a wide range of oxygen concentrations, and yet in vitro models almost exclusively expose cultured cells to higher, atmospheric oxygen levels. existing models of liver-stage malaria that utilize primary human hepatocytes typically exhibit low in vitro infection efficiencies, possib ...201324291761
inhibitor of cysteine proteases is critical for motility and infectivity of plasmodium sporozoites.malaria is transmitted when motile sporozoites are injected into the dermis by an infected female anopheles mosquito. inside the mosquito vector, sporozoites egress from midgut-associated oocysts and eventually penetrate the acinar cells of salivary glands. parasite-encoded factors with exclusive vital roles in the insect vector can be studied by classical reverse genetics. here, we characterized the in vivo roles of plasmodium berghei falstatin/icp (inhibitor of cysteine proteases). this protei ...201324281719
a small molecule glycosaminoglycan mimetic blocks plasmodium invasion of the mosquito midgut.malaria transmission-blocking (t-b) interventions are essential for malaria elimination. small molecules that inhibit the plasmodium ookinete-to-oocyst transition in the midgut of anopheles mosquitoes, thereby blocking sporogony, represent one approach to achieving this goal. chondroitin sulfate glycosaminoglycans (cs-gags) on the anopheles gambiae midgut surface are putative ligands for plasmodium falciparum ookinetes. we hypothesized that our synthetic polysulfonated polymer, vs1, acting as a ...201324278017
plasmodium berghei calcium dependent protein kinase 1 is not required for host cell invasion.plasmodium calcium dependent protein kinase (cdpk1) is required for the development of sexual stages in the mosquito. in addition, it is proposed to play an essential role in the parasite's invasive stages possibly through the regulation of the actinomyosin motor and micronemal secretion. we demonstrate that plasmodium berghei cdpk1 is dispensable in the parasite's erythrocytic and pre-erythrocytic stages. we successfully disrupted p. berghei cdpk1 (pbcdpk1) by homologous recombination. the reco ...201324265753
trem2 governs kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection.plasmodium liver stage infection is a target of interest for the treatment of and vaccination against malaria. here we used forward genetics to search for mechanisms underlying natural host resistance to infection and identified triggering receptor expressed on myeloid cells 2 (trem2) and mhc class ii molecules as determinants of plasmodium berghei liver stage infection in mice. locus belr1 confers resistance to malaria liver stage infection. the use of newly derived subcongenic mouse lines allo ...201324218563
cd8+ t cells specific for a malaria cytoplasmic antigen form clusters around infected hepatocytes and are protective at the liver stage of infection.following anopheles mosquito-mediated introduction into a human host, plasmodium parasites infect hepatocytes and undergo intensive replication. accumulating evidence indicates that cd8(+) t cells induced by immunization with attenuated plasmodium sporozoites can confer sterile immunity at the liver stage of infection; however, the mechanisms underlying this protection are not clearly understood. to address this, we generated recombinant plasmodium berghei anka expressing a fusion protein of an ...201323897612
comparative susceptibility of different biological forms of anopheles stephensi to plasmodium berghei anka strain.there are varying degrees of compatibility between malaria parasite-mosquito species, and understanding this compatibility may be crucial for developing effective transmission-blocking vaccines. this study investigates the compatibility of different biological forms of a malaria vector, anopheles stephensi, to plasmodium berghei anka strain.201324086525
expression profiling of plasmodium berghei hsp70 genes for generation of bright red fluorescent parasites.live cell imaging of recombinant malarial parasites encoding fluorescent probes provides critical insights into parasite-host interactions and life cycle progression. in this study, we generated a red fluorescent line of the murine malarial parasite plasmodium berghei. to allow constitutive and abundant expression of the mcherry protein we profiled expression of all members of the p. berghei heat shock protein 70 (hsp70) family. we identified pbhsp70/1, an invariant ortholog of plasmodium falcip ...201324013507
development of a chimeric plasmodium berghei strain expressing the repeat region of the p. vivax circumsporozoite protein for in vivo evaluation of vaccine efficacy.the development of vaccine candidates against plasmodium vivax-the most geographically widespread human malaria species-is challenged by technical difficulties, such as the lack of in vitro culture systems and availability of animal models. chimeric rodent plasmodium parasites are safe and useful tools for the preclinical evaluation of new vaccine formulations. we report the successful development and characterization of chimeric plasmodium berghei parasites bearing the type i repeat region of p ...201323716612
immunisation against a serine protease inhibitor reduces intensity of plasmodium berghei infection in mosquitoes.the mosquito innate immune response is able to clear the majority of plasmodium parasites. this immune clearance is controlled by a number of regulatory molecules including serine protease inhibitors (serpins). to determine whether such molecules could represent a novel target for a malaria transmission-blocking vaccine, we vaccinated mice with anopheles gambiae serpin-2. antibodies against anopheles gambiae serpin-2 significantly reduced the infection of a heterologous anopheles species (anophe ...201323872520
morphogenesis of plasmodium zoites is uncoupled from tensile strength.a shared feature of the motile stages (zoites) of malaria parasites is a cortical cytoskeletal structure termed subpellicular network (spn), thought to define and maintain cell shape. plasmodium alveolins comprise structural components of the spn, and alveolin gene knockout causes morphological abnormalities that coincide with markedly reduced tensile strength of the affected zoites, indicating the alveolins are prime cell shape determinants. here, we characterize a novel spn protein of plasmodi ...201323773015
the etramp family member sep2 is expressed throughout plasmodium berghei life cycle and is released during sporozoite gliding motility.the early transcribed membrane proteins etramps belong to a family of small, transmembrane molecules unique to plasmodium parasite, which share a signal peptide followed by a short lysine-rich stretch, a transmembrane domain and a variable, highly charged c-terminal region. etramps are usually expressed in a stage-specific manner. in the blood stages they localize to the parasitophorous vacuole membrane and, in described cases, to vesicle-like structures exported to the host erythrocyte cytosol. ...201323840634
the metabolism of primaquine to its active metabolite is dependent on cyp 2d6.the efficacy of the 8-aminoquinoline (8aq) drug primaquine (pq) has been historically linked to cyp-mediated metabolism. although to date no clear evidence exists in the literature that unambiguously assigns the metabolic pathway or specific metabolites necessary for activity, recent literature suggests a role for cyp 2d6 in the generation of redox active metabolites.201323782898
transgenic parasites stably expressing full-length plasmodium falciparum circumsporozoite protein as a model for vaccine down-selection in mice using sterile protection as an endpoint.circumsporozoite protein (csp) of plasmodium falciparum is a protective human malaria vaccine candidate. there is an urgent need for models that can rapidly down-select novel csp-based vaccine candidates. in the present study, the mouse-mosquito transmission cycle of a transgenic plasmodium berghei malaria parasite stably expressing a functional full-length p. falciparum csp was optimized to consistently produce infective sporozoites for protection studies. a minimal sporozoite challenge dose wa ...201323536694
identification of targets of cd8⁺ t cell responses to malaria liver stages by genome-wide epitope profiling.cd8⁺ t cells mediate immunity against plasmodium liver stages. however, the paucity of parasite-specific epitopes of cd8⁺ t cells has limited our current understanding of the mechanisms influencing the generation, maintenance and efficiency of these responses. to identify antigenic epitopes in a stringent murine malaria immunisation model, we performed a systematic profiling of h(2b)-restricted peptides predicted from genome-wide analysis. we describe the identification of plasmodium berghei (pb ...201323675294
a cascade of dna-binding proteins for sexual commitment and development in plasmodium.commitment to and completion of sexual development are essential for malaria parasites (protists of the genus plasmodium) to be transmitted through mosquitoes. the molecular mechanism(s) responsible for commitment have been hitherto unknown. here we show that pbap2-g, a conserved member of the apicomplexan ap2 (apiap2) family of dna-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in plasmodium berghei, a malaria parasite of rodents. pbap2-g ...201424572359
whole pichia pastoris yeast expressing measles virus nucleoprotein as a production and delivery system to multimerize plasmodium antigens.yeasts are largely used as bioreactors for vaccine production. usually, antigens are produced in yeast then purified and mixed with adjuvants before immunization. however, the purification costs and the safety concerns recently raised by the use of new adjuvants argue for alternative strategies. to this end, the use of whole yeast as both production and delivery system appears attractive. here, we evaluated pichia pastoris yeast as an alternative vaccine production and delivery system for the ci ...201424475165
simple, sensitive and quantitative bioluminescence assay for determination of malaria pre-patent period.the first phase of malaria infection occurs in the liver and is clinically silent. inside hepatocytes each plasmodium sporozoite replicate into thousands of erythrocyte-infectious merozoites that when released into the blood stream result in clinical symptoms of the disease. the time between sporozoite inoculation and the appearance of parasites in the blood is defined as the pre-patent period, which is classically analysed by time-consuming and labor-intensive techniques, such as microscopy and ...201424400642
tafenoquine and npc-1161b require cyp 2d metabolism for anti-malarial activity: implications for the 8-aminoquinoline class of anti-malarial compounds.tafenoquine (tq) is an 8-aminoquinoline (8aq) that has been tested in several phase ii and phase iii clinical studies and is currently in late stage development as an anti-malarial prophylactic agent. npc-1161b is a promising 8aq in late preclinical development. it has recently been reported that the 8aq drug primaquine requires metabolic activation by cyp 2d6 for efficacy in humans and in mice, highlighting the importance of pharmacogenomics in the target population when administering primaquin ...201424386891
stress granules and plasmodium liver stage infection.organisms have evolved numerous strategies to control infection by an array of intracellular pathogens. one cell autonomous pathogen control strategy is global inhibition of protein synthesis via stress granule (sg) formation. sgs are induced by stressful stimuli such as oxidative stress and nutrient deprivation, and are known to counteract both viral and bacterial infections. pathogens, in turn, may actively block an infected cell's ability to form sgs. in vitro and in vivo, many liver stage ma ...201424357231
phenylalanine metabolism regulates reproduction and parasite melanization in the malaria mosquito.the blood meal of the female malaria mosquito is a pre-requisite to egg production and also represents the transmission route for the malaria parasite. the proper and rapid assimilation of proteins and nutrients in the blood meal creates a significant metabolic challenge for the mosquito. to better understand this process we generated a global profile of metabolite changes in response to blood meal of anopheles gambiae, using gas chromatography-mass spectrometry (gc-ms). to disrupt a key pathway ...201424409310
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