immune stimulation and malaria infection impose reproductive costs in anopheles gambiae via follicular apoptosis.the employment of defense mechanisms is recognized as a costly life-history trait. in the malaria vector anopheles gambiae, reproductive costs have been associated with both humoral and cellular innate immune responses and also with malaria infection. the resorption of developing oocytes associated with malaria infection is preceded by the programmed cell death, or apoptosis, of follicular cells. here we demonstrate that apoptosis in ovarian follicular epithelial cells also occurs when mosquitoe ...200616213176
evaluating the costs of mosquito resistance to malaria parasites.costly resistance mechanisms have been cited as an explanation for the widespread occurrence of parasitic infections, yet few studies have examined these costs in detail. a malaria-mosquito model has been used to test this concept by making a comparison of the fitness of highly susceptible lines of mosquitoes with lines that are resistant to infection. malaria infection is known to cause a decrease in fecundity and fertility of mosquitoes; resistant mosquitoes were thus predicted to be fitter th ...200516526504
studies on drug metabolizing enzymes during arteether treatment of plasmodium yoelii nigeriensis infected mice cerebral microvessels.human cerebral malaria is caused by a protozoan parasitic with no cure till date. the isolation of brain capillaries i.e. microvessels has permitted the in vitro study related to cerebral function. microvessels were isolated from normal and p. yoelii infected mice brain cortex and subjected to biochemical characterization by the following enzyme markers viz alkaline phosphatase, gamma-glutamyi transpeptidase and monoamine oxidase and electron microscopically. limited studies have been carried ou ...200516637400
orally active 1,2,4-trioxanes: synthesis and antimalarial assessment of a new series of 9-functionalized 3-(1-arylvinyl)-1,2,5-trioxaspiro[5.5]undecanes against multi-drug-resistant plasmodium yoelii nigeriensis in mice.using easily accessible keto-trioxanes 7a-g as the starting materials, a series of new variously functionalized 1,2,4-trioxanes 10-36 have been prepared and evaluated for antimalarial activity against multi-drug-resistant plasmodium yoelii nigeriensis in mice in the dose range of 24 mg/kg x 4 days to 96 mg/kg x 4 days by oral route. trioxanes 10, 12, 14, 16, 18, 20, and 22 have shown promising antimalarial activity. trioxanes 14 and 18, the two most active compounds of the series, provide 100% a ...200616640340
blood schizontocidal activity of selected 1,2,4-trioxanes (fenozans) against the multidrug-resistant strain of plasmodium yoelii nigeriensis (mdr) in vivo.blood schizontocidal activity of 10 selected cis-fused cyclopenteno-1,2,4-trioxanes (namely fenozan compound nos 6, 7, 11, 27, 32, 39, 44, 45, 48 and 51) have been re-investigated to establish their curative doses against the multidrug-resistant plasmodium yoelii nigeriensis strain, which is lethal in swiss mice. freshly prepared formulations of these compounds prepared either in neutral groundnut (peanut) oil or in dimethyl sulfoxide (dmso)-tween-water, were compared for their antimalarial acti ...200616764736
new orally active derivatives of artemisinin with high efficacy against multidrug-resistant malaria in mice.a new series of ether derivatives of dihydroartemisinin have been prepared and evaluated for their antimalarial activity against multidrug-resistant plasmodium yoelii nigeriensis in mice by oral route. these new derivatives 7-17 are highly lipophilic (log p in the range of 5.51 to 7.19) as compared with beta-arteether (log p 3.84), and several of them are two- to four-fold more active than beta-arteether. among the ether derivatives, alpha-isomers are more active than the beta-isomers. the ether ...200617125275
synthesis and antimalarial evaluation of a series of piperazinyl flavones.a series of 27 flavonoid derivatives containing a piperazinyl chain have been synthesized and tested for their antiplasmodial activity. diverse substitution patterns on piperazinyl and flavone moieties were examined and found to affect the activity differently. the most active compounds, which have a 2,3,4-trimethoxybenzylpiperazinyl chain attached to the flavone at the 7-phenol group, showed in vitro activity against chloroquine-sensitive (thai) and -resistant (fcb1,k1) plasmodium falciparum st ...200717166718
prophylactic potential of liposomized integral membrane protein of plasmodium yoelii nigeriensis against blood stage infection in balb/c mice.triton x-114 phase separated integral membrane proteins (imps) of a multidrug resistant strain of plasmodium yoelii nigeriensis (p. yoelii) were screened for their potential to impart protection against malaria infection in balb/c mice. as revealed by immunoblotting, antibodies present in parasite specific sera from convalescent (protected) as well as immunized (partially protected) animals recognized different membrane proteins. a thorough investigation reveals that p. yoelii specific convalesc ...200717241709
new adamantane-based spiro 1,2,4-trioxanes orally effective against rodent and simian 6-arylvinyl- and 6-adamantylvinyl-substituted 1,2,4-trioxanes (13a-g and 14a,b) have been prepared and evaluated for antimalarial activity against multidrug resistant plasmodium yoelii nigeriensis in mice by both oral and intramuscular routes. while all the 6-arylvinyl-substituted trioxanes, 13a-f, showed promising activity, none of the 6-adamantylvinyl-substituted trioxanes, 13g and 14a,b, exhibited significant activity. trioxane, 13f, the most active compound of the series, provided 100% a ...200717266204
effect of plasmodium yoelii nigeriensis infection on hepatic and splenic glutathione-s-transferase(s) in swiss albino and db/+ mice: efficacy of mefloquine and menadione in antimalarial chemotherapy.the present report deals with the status of hepatic and splenic glutathione-s-transferase (gst) activities in mice during experimental infection with plasmodium yoelii nigeriensis and subsequent treatment of infected mice with mefloquine (mf) and menadione (md). the infection caused significant decline in the hepatic and splenic glutathione-s-transferase (gst) activities of albino and db/+ mice. the decline was observed in the levels of both cytosolic and microsomal gst(s) of liver and spleen in ...200717352848
effect of chloroquine on gene expression of plasmodium yoelii nigeriensis during its sporogonic development in the mosquito vector.the anti-malarial chloroquine can modulate the outcome of infection during the plasmodium sporogonic development, interfering with plasmodium gene expression and subsequently, with transmission. the present study sets to identify plasmodium genes that might be regulated by chloroquine in the mosquito vector.200717605769
orally active 1,2,4-trioxepanes: synthesis and antimalarial activity of a series of 7-arylvinyl-1,2,4-trioxepanes against multidrug-resistant plasmodium yoelii in swiss mice.7-arylvinyl-1,2,4-trioxepanes 7a-d, 8a-d, 9a-d, 10a-d, 11a-c, and 12a-c, prepared by photooxygenation of homoallylic alcohols 5a-d, were evaluated against multi-drug resistant plasmodium yoelii nigeriensis in swiss mice by oral and intramuscular routes. trioxepane 11c, the most active compound of the series, showed more than 98% suppression of parsitaemia at 96 mg/kg by both oral and intramuscular routes. this is the first report on in vivo active 1,2,4-trioxepanes.200818054238
orally active esters of dihydroartemisinin: synthesis and antimalarial activity against multidrug-resistant plasmodium yoelii in mice.a series of artemisinin derived esters 7a-j, incorporating pharmacologically privileged substructure, such as biphenyl, adamantane and fluorene, have been prepared and evaluated for antimalarial activity against multidrug-resistant (mdr) plasmodium yoelii nigeriensis by oral route. several of these compounds were found to be more active than the antimalarial drugs beta-arteether 4 and artesunic acid 5. ester 7i, the most active compound of the series, provided 100% and 80% protection to the infe ...200818206370
anti-protozoan activities of harungana madagascariensis stem bark extract on trichomonads and malaria.the ethanolic stem bark extract of harungana madagascariensis (hypericaceae), (choisy) poir were evaluated for their activities on trichomonas gallinae (rivolta) stabler isolated from the pigeon (columba livia). it was also tested for their anti-malarial activity on n67 plasmodium yoelii nigeriensis (in vivo) in mice and on plasmodium falciparum isolates in vitro.200818372133
comparison of male reproductive success in malaria-refractory and susceptible strains of anopheles female mosquitoes that transmit malaria, the benefits of being refractory to the plasmodium parasite are balanced by the immunity costs in the absence of infection. male mosquitoes, however, gain no advantage from being refractory to blood-transmitted parasites, so that any costs associated with an enhanced immune system in the males limit the evolution of female refractoriness and has practical implications for the release of transgenic males.200818534029
adjuvanticity and protective immunity of plasmodium yoelii nigeriensis blood-stage soluble antigens encapsulated in fusogenic our previous studies we established fusogenic properties of lipids isolated from edible yeast saccharomyces cerevisiae (s. cerevisiae). we demonstrated that liposomes prepared from s. cerevisiae membrane lipid (saccharosome) can deliver encapsulated antigen into cytosol of the antigen presenting cells and elicit antigen specific cell mediated as well as humoral immune responses. in this study, we evaluated immunological behavior of saccharosome encapsulated cytosolic proteins (sag) of plasmod ...200918996429
rodent malaria-resistant strains of the mosquito, anopheles gambiae, have slower population growth than -susceptible between anti-parasite defence mechanisms and other life history traits limit the evolution of host resistance to parasites and have important implications for understanding diseases such as malaria. mosquitoes have not evolved complete resistance to malaria parasites and one hypothesis is that anti-malaria defence mechanisms are costly.200919379508
search for new pharmacophores for antimalarial activity. part iii: synthesis and bioevaluation of new 6-thioureido-4-anilinoquinazolines.syntheses and in vitro antimalarial evaluation of 42 new thioureidoquinazolines have been carried out. several analogs showed promising antimalarial effect in the in vitro investigation against chloroquine-sensitive 3d7 strain of plasmodium falciparum whereas one of the compounds shows 50% curative effect in the mouse model at an oral dose of 100mg/kg x 4 days against multidrug resistant plasmodium yoelii nigeriensis.200919586687
both hemolytic anemia and malaria parasite-specific factors increase susceptibility to nontyphoidal salmonella enterica serovar typhimurium infection in mice.severe pediatric malaria is an important risk factor for developing disseminated infections with nontyphoidal salmonella serotypes (nts). while recent animal studies on this subject are lacking, early work suggests that an increased risk for developing systemic nts infection during malaria is caused by hemolytic anemia, which leads to reduced macrophage microbicidal activity. here we established a model for oral salmonella enterica serotype typhimurium challenge in mice infected with plasmodium ...201020100860
synthesis and antimalarial assessment of a new series of orally active amino-functionalized spiro 1,2,4-trioxanes.keto-trioxanes 7a-d, easily accessible in two steps from allylic alcohols 5a-d, underwent reductive amination with substituted anilines to furnish amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and 11a-i. all these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant plasmodium yoelii nigeriensis in swiss mice. 2-naphthalene-based trioxanes 9c and 9i, the most active compounds of the series, provided 100% protection to the malaria-infected mice at 24 mg ...201020936847
site-specific integration and expression of an anti-malarial gene in transgenic anopheles gambiae significantly reduces plasmodium infections.diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. to circumvent these limitati ...201121283619
antiplasmodial activity of artecyclopentyl mether a new artemisinin derivative and its effect on pathogenesis in plasmodium yoelii nigeriensis infected an effort to evaluate novel derivatives from artemisinin, possessing potential antimalarial activity, a new derivative artecyclopentyl mether (cpm-1) was derivatized and evaluated for its dose-dependent efficacy in plasmodium yoelii nigeriensis infected mice. the survivability of mice at 7.5 mg/kg was >28 days with negligible parasitaemia and recovered anemia (66.16-72.62%). artecyclopentyl mether was also found to modulate the pro- and anti-inflammatory cytokines (ifn-γ, 39.64-56.92%; tnf, 4 ...201121541755
clarithromycin, a cytochrome p450 inhibitor, can reverse mefloquine resistance in plasmodium yoelii nigeriensis- infected swiss mice.summaryduring the last 2 decades there have been numerous reports of the emergence of mefloquine resistance in southeast asia and nearly 50% resistance is reported in thailand. a world health organization report (2001) considers mefloquine as an important component of act (artesunate+mefloquine) which is the first line of treatment for the control of uncomplicated/multi-drug resistant (mdr) plasmodium falciparum malaria. in view of the emergence of resistance towards this drug, it is proposed to ...201121756423
linker-based hemisuccinate derivatives of artemisinin: synthesis and antimalarial assessment against multidrug-resistant plasmodium yoelii nigeriensis in mice (1).artesunic acid 5, the hemisuccinate derivative of dihydroartemisinin 2, is the only clinically useful water-soluble derivative of artemisinin 1. however, being a lactol ester, it is rapidly hydrolyzed back to dihydroartemisinin in aqueous alkaline solution, a reaction that seriously limits its utility. a new series of potentially more stable linker-based hemisuccinate derivatives 12a-i and 14a-c have been prepared. the process involved acid-catalyzed reaction of dihydroartemisinin with various d ...201222216834
larval nutrition differentially affects adult fitness and plasmodium development in the malaria vectors anopheles gambiae and anopheles stephensi.mosquito fitness is determined largely by body size and nutritional reserves. plasmodium infections in the mosquito and resultant transmission of malaria parasites might be compromised by the vector's nutritional status. we studied the effects of nutritional stress and malaria parasite infections on transmission fitness of anopheles mosquitoes.201324326030
plasmodium yoelii nigeriensis (n67) is a robust animal model to study malaria transmission by south american anopheline mosquitoes.malaria is endemic in the american continent and the amazonian rainforest is the region with the highest risk of transmission. however, the lack of suitable experimental models to infect malaria vectors from the americas has limited the progress to understand the biology of transmission in this region. anopheles aquasalis, a major vector in coastal areas of south america, was found to be highly refractory to infection with two strains of plasmodium falciparum (nf54 and 7g8) and with plasmodium b ...201627911924
ketoconazole, a cytochrome p(450) inhibitor can potentiate the antimalarial action of α/β arteether against mdr plasmodium yoelii nigeriensis.the emergence of multidrug resistant (mdr) strains of plasmodium falciparum in south east asia and other tropical countries, is posing serious challenge for the international efforts to eradicate malaria. new drug target/act/non-act combinations need to be discovered to control the spread of mdr malaria. the present communication deals with antimalarial potential of a new combination comprising of ketoconazole (ktz) (an antifungal/inhibitor of cyp3a4) and artemisinin derivative α/β arteether (ar ...201323391499
antimalarial interaction of quinine and quinidine with clarithromycin.quinine (qn) and quinidine (qnd) have been commonly used as effective and affordable antimalarials for over many years. quinine primarily is used for severe malaria treatment. however, plasmodia resistance to these drugs and poor patient compliance limits their administration to the patients. the declining sensitivity of the parasite to the drugs can thus be dealt with by combining with a suitable partner drug. in the present study qn/qnd was assessed in combination with clarithromycin (cltr), a ...201323137860
increased cd40 expression enhances early sting-mediated type i interferon response and host survival in a rodent malaria model.both type i interferon (ifn-i) and cd40 play a significant role in various infectious diseases, including malaria and autoimmune disorders. cd40 is mostly known to function in adaptive immunity, but previous observations of elevated cd40 levels early after malaria infection of mice led us to investigate its roles in innate ifn-i responses and disease control. using a plasmodium yoelii nigeriensis n67 and c57bl/6 mouse model, we showed that infected cd40-/- mice had reduced sting and serum ifn-β ...201627716849
new orally active diphenylmethyl-based ester analogues of dihydroartemisinin: synthesis and antimalarial assessment against multidrug-resistant plasmodium yoelii nigeriensis in mice.a new series of ester analogues of artemisinin 8a-f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g-j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (mdr) plasmodium yoelii nigeriensis in swiss mice via oral route. these diphenylmethyl-based ester analogues 8a-f were found to be 2-4 folds more active than the antimalarial drugs β-arteether 4 and artesunic acid 5. ester 8a, the most active compound of the series, pro ...201626898813
arteether nanoemulsion for enhanced efficacy against plasmodium yoelii nigeriensis malaria: an approach by enhanced bioavailability.the present work is focused on the preparation of nanoemulsions (nes) loaded with arteether (art) for its enhanced efficacy against malaria parasites. art-nes have been prepared using high pressure homogenization (hph) technique with the aim of improving its solubility and thus its bioavailability. art-nes were optimized in terms of pressure and number of cycles. globule size and size distributions were chosen as quality parameters. the maximum drug loading was achieved up to 93 ± 7.4% with glob ...201525616971
the dichotomy (generation of mabs with functional heterogeneity) in antimalarial immune response in vaccinated/protected mice: a new concept in our understanding of the protective immune mechanisms in malaria.globally, vaccines have emerged as one of the most effective, safe, and cost-effective public health interventions, and are known to save 2-3 million lives, annually. however, despite various commendable efforts, a suitable human malaria vaccine is yet to see the light of the day. the lack of our complete understanding of the molecular mechanisms of pathogenesis and immune protection in malaria appears to be responsible for this state. earlier, our laboratory has reported that swiss mice vaccina ...201424632591
correlation between plasmodium yoelii nigeriensis susceptibility to artemisinin and alkylation of heme by the drug.evidence of artemisinin (art) resistance in all of the greater mekong region is currently of major concern. understanding of the mechanisms of resistance developed by plasmodium against artemisinin and its derivatives is urgently needed. we here demonstrated that art was able to alkylate heme in mice infected by the art-susceptible strain of plasmodium yoelii nigeriensis, y-control. after long-term drug pressure, the parasite strain (y-art3) was 5-fold less susceptible to art than y-control. in ...201323752508
effect of chloroquine, methylene blue and artemether on red cell and hepatic antioxidant defence system in mice infected with plasmodium yoelii nigeriensis.reactive oxygen species are mediators of tissue injury and are involved in malaria infection. in this study, the status of red cell and hepatic oxidative stress and antioxidant defence indices were investigated during plasmodium yoelii nigeriensis (p. yoelii) infection, and treatment with chloroquine (cq), methylene blue (mb) or artemether (art) in mice. p. yoelii infection caused a significant (p < 0.05) increase in oxidative stress as evidenced by the elevated level of malondialdehyde. this wa ...201323604568
synthesis and antimalarial activity of 3,3-spiroanellated 5,6-disubstituted 1,2,4-trioxanes.novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant plasmodium yoelii nigeriensis in swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. the most active compound of the series (compound 25) provided 100% protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. in this model, β-arteether p ...201324900640
qsar, docking and admet studies of artemisinin derivatives for antimalarial activity targeting plasmepsin ii, a hemoglobin-degrading enzyme from p. falciparum.this work presents the development of quantitative structure activity relationship (qsar) model to predict the antimalarial activity of artemisinin derivatives. the structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. screening through qsar model suggested that compounds a24, a24a, a53, a54, a62 and a64 possess significant antimalarial activity. linear model is developed by the multiple linear regression method ...201222670592
plasmodium-salmonella co-infection induces intense inflammatory responsanirban pal, phd, cisr-central institute of medicinal and aromatic plants, lucknow, uttar pradesh indiae, oxidative stress and liver damage: a mice model study for therapeutic strategy.impairment of host immune response in malaria favours bacteraemia caused by typhoidal or non-typhoidal serovars of salmonella enterica. ofloxacin and artesunate are the drugs that are clinically proven for treating typhoid and malaria respectively. the study evaluates the host responses upon treatment with antibiotic (ofloxacin) and anti-malarial (artesunate) in a standardized mice model harbouring co-infection. balb/c mice (18-22 gm) were simultaneously co-infected with plasmodium yoelii nigeri ...201829394238
mechanism of splenic cell death and host mortality in a plasmodium yoelii malaria model.malaria is a fatal disease that displays a spectrum of symptoms and severity, which are determined by complex host-parasite interactions. it has been difficult to study the effects of parasite strains on disease severity in human infections, but the mechanisms leading to specific disease phenotypes can be investigated using strains of rodent malaria parasites that cause different disease symptoms in inbred mice. using a unique mouse malaria model, here we investigated the mechanisms of splenic c ...201728874800
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