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potent and selective antiplasmodial activity of the cyanobacterial alkaloid nostocarboline and its dimers.the quaternary beta-carbolinium alkaloid nostocarboline from the cyanobacterium nostoc 78-12a and 10 bis-cationic dimeric derivatives were evaluated against four protozoan parasites and low micromolar values against trypanosoma brucei, submicromolar values against leishmania donovani and low nanomolar values against plasmodium falciparum k1 were determined. selectivity against rat myoblasts (l6 cells) was found to be up to >2500-fold.200818606541
kala-azar (visceral leishmaniasis) from khotang.kala-azar is a chronic infection of reticuloendothelial system caused by flagellated protozoan, leishmania donovani injected into human host by the bite of the sand fly (phlebotomous) previously infected by biting and sucking the blood of a patient of leishmaniasis. it is characterized by irregular fever of long duration, large spleen and liver, anaemia, leucopenia and progressive emaciation. this article reports a case of a 10 year old girl from khotang, a nonendemic zone for kala-azar, who pre ...200618603904
the development of a real-time pcr assay for the quantification of leishmania infantum dna in canine blood.recent research has demonstrated the high sensitivity of real time pcr (qpcr) in the diagnosis of leishmania infantum infection. the goal of this study was to develop and evaluate a qpcr detection system for the diagnosis of visceral leishmaniosis (vl) in dogs. specific primer sets were developed for the leishmania donovani complex, in which a fragment of 132 bp of kdna from l. infantum was amplified. the reaction was performed using the abi prism 7000 system with abi prism software used to carr ...200918603455
kinetic studies and bioactivity of potential manzamine prodrugs.the manzamines represent a class of marine natural products that show considerable promise in the control of malaria but generate gi distress in rodents when administered orally in high doses. in an effort to generate manzamine prodrugs with improved antimalarial activity and reduced gi toxicity, we prepared acetylated 8-hydroxymanzamine a analogues including 8-acetoxymanzamine a (3) and 8,12-diacetoxymanzamine a (4), and 8-methoxymanzamine a (5) beginning with 8-hydroxymanzamine a (2). the semi ...200818598080
epitope mapping and protective immunity elicited by adenovirus expressing the leishmania amastigote specific a2 antigen: correlation with ifn-gamma and cytolytic activity by cd8+ t cells.a2 was identified as an amastigote virulence factor of leishmania (leishmania) donovani and as a candidate antigen for vaccine development against visceral leishmaniasis. here, predicted hydrophilic, class i and ii mhc-binding synthetic peptides were used to define epitopes recognized by a2-specific antibodies, cd8+ t and cd4+ t cells, respectively. immunization of balb/c mice with adenovirus expressing a2 (ada2) resulted in low antibody response, contrasting with high levels of ifn-gamma produc ...200818588933
identification, purification, and characterization of a secretory serine protease in an indian strain of leishmania donovani.an aprotinin sensitive serine protease was identified in the culture supernatant of the indian strain of leishmania donovani (mhom/in/1983/ag83). the protease was subsequently purified and characterized. the apparent molecular mass of the enzyme was 115 kda in sds-page under non-reducing condition, while on reduction it showed a 56 kda protein band indicating that the protease is a dimeric protein. the purified enzyme was optimally active at the ph and temperature of 7.5 and 28 degrees c, respec ...200918587671
leishmania donovani leishmaniasis in cyprus. 200818582830
a diagnostic assay based on variable intergenic region distinguishes between leishmania donovani and leishmania infantum.we have developed a pcr assay that in a single reaction distinguishes between leishmania infantum and leishmania donovani strains on the basis of different size of the amplicon. the targeted intergenic region between putative biopterin transporter and nucleotide binding protein on chromosome 35 is highly variable, species-specific and can be amplified from clinical samples. based on the assay, five tested leishmania archibaldi and l. infantun strains from the sudan and ethiopia clearly belong to ...200818578169
leishmania donovani promastigotes on 'chocolate' agar. 200818577335
clinical manifestations of cutaneous leishmaniasis in sri lanka - possible evidence for genetic susceptibility among the sinhalese.human cutaneous leishmaniasis (cl) caused by leishmania donovani, a pathogen more usually associated with visceral leishmaniasis, is now endemic in sri lanka. this report details the characteristics of 200 patients with locally acquired cl, who were recruited prospectively for an ongoing study into the genetic susceptibility to cl in sri lanka. in each case, the cl was confirmed by the demonstration of amastigotes in a direct smear and/or promastigotes in a culture. although only 82% of the sri ...200818577329
accelerated control of visceral leishmania donovani infection in interleukin-6-deficient mice.in patients with visceral leishmaniasis, increased levels of circulating interleukin-6 (il-6) regularly accompany fully expressed, progressive infections (kala-azar). to experimentally test the role of il-6, responses to an intracellular leishmania donovani infection in the livers of il-6(-/-) and wild-type mice were compared. il-6(-/-) mice showed an enhanced control of the infection and earlier, rapid parasite killing along with additional evidence of a stimulated antileishmanial th1-cell-type ...200818573898
rapid fluorescent assay for screening drugs on leishmania amastigotes.a rapid fluorescent viability assay employing alamarblue was optimized for use with leishmania axenic amastigotes, the stage of the parasite responsible for disease pathology. the activity of two protein kinase inhibitors, staurosporine and h-89, as well as amphotericin b, on promastigotes and amastigotes of leishmania donovani and leishmania tropica was compared. both protein kinase inhibitors inhibited promastigote growth at lower concentrations than amastigotes, while the gi(50) for amphoteri ...200818573286
antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides.a series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against leishmania donovani. six compounds exhibited ic(50) values lower than standard drugs. brief sar analysis revealed that substitution is important to the activity. nitrothiophene analogues were more potent than the nitrofuran ones. this was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of fr ...200818571927
comparison of the expression profiles of promastigotes and axenic amastigotes in leishmania donovani using serial analysis of gene expression.in this study, we examined the transcriptome of leishmania donovani promastigotes and axenic amastigotes to identify differentially regulated mrnas utilizing the serial analysis of gene expression (sage). the axenic culture of amastigotes was initiated from stationary phase promastigotes. transformation from promastigote to amastigote occurred when cultures in medium 199 (ph 5.5), supplemented with 20% (v/v) fetal bovine serum, were transferred from 26 degrees c to 37 degrees c. a total of 20,29 ...200818568446
the caspase-independent algorithm of programmed cell death in leishmania induced by baicalein: the role of ldendog, ldfen-1 and ldtatd as a dna 'degradesome'.in the post-genomic perspective, the quest of programmed cell death (pcd) mechanisms in kinetoplastid parasites lies in the identification and characterization of cell death executer proteins. here, we show that baicalein (bln), a potent topoisomerase ib inhibitor, generates an oxidative stress in the parasites leading to altered physiological and morphological parameters, which are characteristic of pcd. for the first time we elucidate that, caspase-independent activation of a novel effector mo ...200818566607
vector control by insecticide-treated nets in the fight against visceral leishmaniasis in the indian subcontinent, what is the evidence?visceral leishmaniasis (vl) is a deadly vector-borne disease that causes an estimated 500 000 new cases a year. in india, nepal and bangladesh, vl is caused by leishmania donovani, which is transmitted from man to man by the sandfly phlebotomus argentipes. in 2005, these three countries signed a memorandum of understanding to eliminate vl from the region. integrated vector management is one of the pillars of this elimination strategy, alongside early case detection and treatment. we reviewed the ...200818564350
oral miltefosine treatment in children with visceral leishmaniasis: a brief review.visceral leishmaniasis (vl) or kala-azar is an infection disease caused by hemiflagellate protozoan parasites (leishmania donovani) and transmitted to humans by the phlebotomine sandfly. leishmaniasis is distributed worldwide and 13 million people are estimated to be infected, with about 1.8 million new cases each year. all antileishmanial drugs are toxic and most have to be used parenterally for prolonged period. the therapy has been further complicated by large number of infected children and ...200818553005
bayesian latent class models with conditionally dependent diagnostic tests: a case study.in the assessment of the accuracy of diagnostic tests for infectious diseases, the true disease status of the subjects is often unknown due to the lack of a gold standard test. latent class models with two latent classes, representing diseased and non-diseased subjects, are often used to analyze this type of data. in its basic format, latent class analysis requires the observed outcomes to be statistically independent conditional on the disease status. in most diagnostic settings, this assumptio ...200818551515
mollamides b and c, cyclic hexapeptides from the indonesian tunicate didemnum molle.two new cyclic hexapeptides, mollamides b (1) and c (2), were isolated from the indonesian tunicate didemnum molle along with the known peptide keenamide a (3). the structures were established using 1d and 2d nmr experiments. the relative configuration of mollamide b at the thiazoline moiety was determined using molecular modeling coupled with nmr-derived restraints. their absolute configuration was determined using marfey's method. the new peptides have been evaluated for their antimicrobial, a ...200818543965
in vivo efficacy of calceolarioside a against experimental visceral leishmaniasis.bioactivity-guided fractionation has led to the successful isolation of calceolarioside a ( 1) from the methanolic extract of night jasmine leaves. the in vitro antileishmanial activity of compound 1 was determined (ic (50) = 20 microg/ml). its in vivo efficacy was noted at 20 mg/kg body weight when it reduced the hepatic and splenic parasite burden by 79 and 84 %, respectively, in an established model of l. donovani ag83 infected golden hamster. furthermore, synergistic potentiations of compoun ...200818543147
an unconventional form of actin in protozoan hemoflagellate, leishmania.leishmania actin was cloned, overexpressed in baculovirus-insect cell system, and purified to homogeneity. the purified protein polymerized optimally in the presence of mg2+ and atp, but differed from conventional actins in its following properties: (i) it did not polymerize in the presence of mg2+ alone, (ii) it polymerized in a restricted range of ph 7.0-8.5, (iii) its critical concentration for polymerization was found to be 3-4-fold lower than of muscle actin, (iv) it predominantly formed bu ...200818539603
in vitro antileishmanial activity of fluoro-artemisinin derivatives against leishmania donovani.the antileishmanial activity of 19 fluoro-artemisinin derivatives was evaluated in vitro against the promastigote forms of leishmania donovani. the most active compound bb 201, an amino derivative, exhibited an ic50 at about 1microm and no cross-resistance was found on miltefosine-resistant and sitamaquine-resistant lines. despite these promising data, no activity was observed on intramacrophage amastigote stage. although the membranes that have to be crossed by the compounds and ph conditions b ...200818538529
phase transfer catalyzed synthesis of bis-quinolines: antileishmanial activity in experimental visceral leishmaniasis and in vitro antibacterial evaluation.a one-pot synthesis of some novel bis-quinolines has been achieved under phase transfer catalyzed conditions using 8-hydroxy quinoline derivatives as substrates. the synthesized analogues were evaluated for antileishmanial activity against leishmania donovani promastigotes and amastigotes. the entire bis-quinolines showed efficacy in both in vitro and in vivo studies. compound 5 (1,1-bis-[(5-chloro-8-quinolyl)oxy]methane) exhibited the most significant activity. compounds 4 (1,1-bis-[(8-quinolyl ...200918538452
leishmania invasion and phagosome biogenesis.whereas bacterial pathogens take over the control of their host cell actin cytoskeleton by delivering an array of protein effectors through specialized secretion systems, promastigotes of the protozoan parasite leishmania donovani rely entirely upon a cell surface glycolipid to achieve this feat. here, we review recent evidence that l. donovani promastigotes subvert host macrophage actin dynamics during the establishment of infection and we discuss the potential mechanisms involved.200818512351
reactive oxygen species and imbalance of calcium homeostasis contributes to curcumin induced programmed cell death in leishmania donovani.curcumin, a polyphenol compound, has been recognized as a promising anti-cancer drug. the purpose of the present study was to investigate the cytotoxicity of curcumin to leishmania donovani, the causative agent for visceral leishmaniasis. flow cytometric analysis revealed that curcumin induced cell cycle arrest at g2/m phase. incubation of leishmania promastigotes with curcumin caused exposure of phosphatidylserine to the outer leaflet of plasma membrane. this event is preceded by curcumin-induc ...200818506627
the efficacy of indoor cdc light traps for collecting the sandfly phlebotomus argentipes, vector of leishmania donovani.the efficacy of light traps for collecting sandflies (diptera: psychodidae) varies both inter-specifically and intra-specifically (by gender and physiological status) as a result of significant differences in phototropic and other behavioural characteristics. the efficacy of miniature cdc light traps for collecting phlebotomus argentipes annandale & brunetti, a vector of leishmania donovani laveran & mesnil (kinetoplastida: trypanosomatidae), was assessed in the indian state of bihar. sandflies ...200818498610
unified qsar approach to antimicrobials. part 3: first multi-tasking qsar model for input-coded prediction, structural back-projection, and complex networks clustering of antiprotozoal compounds.several pathogen parasite species show different susceptibilities to different antiparasite drugs. unfortunately, almost all structure-based methods are one-task or one-target quantitative structure-activity relationships (ot-qsar) that predict the biological activity of drugs against only one parasite species. consequently, multi-tasking learning to predict drugs activity against different species by a single model (mt-qsar) is vitally important. in the two previous works of the present series ...200818485714
synthesis and in vitro antiprotozoal activities of water-soluble, inexpensive 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives.3,7-bis(dialkylamino)phenoxazinium salts were synthesized and evaluated for in vitro activities against plasmodium falciparum, trypanosoma cruzi, t. brucei rhodesiense, and leishmania donovani. notably, the compounds showed potent antiprotozoal activities, especially against p. falciparum and t. cruzi. the compounds with alkyl side chains less than three carbons in length possessed good activities with high selective indices.200818476684
elevated levels of igg3 and igg4 subclass in paediatric cases of kala azar.visceral leishmaniasis (vl) or kala azar (ka) is a systemic disease caused by the parasites of the leishmania donovani complex. control measures rely on treatment with antileishmanial agents, however, fraught with problems such as toxicity or drug resistance. the incidence rate is on the rise for children, for reasons yet undefined. previously we have shown significantly elevated level of il-10 in children compared to adult ka cases. here, antileishmanial antibody and c-reactive protein (crp) le ...200818466200
activation of invariant nkt cells exacerbates experimental visceral leishmaniasis.we report that natural killer t (nkt) cells play only a minor physiological role in protection from leishmania donovani infection in c57bl/6 mice. furthermore, attempts at therapeutic activation of invariant nkt (inkt) cells with alpha-galactosylceramide (alpha-galcer) during l. donovani infection exacerbated, rather than ameliorated, experimental visceral leishmaniasis. the inability of alpha-galcer to promote anti-parasitic immunity did not result from inefficient antigen presentation caused b ...200818463695
pursuit of medical knowledge: charles donovan (1863-1951) on kala-azar in india.kala-azar was a lethal disease in colonial india. charles donovan of the indian medical service (ims) in madras discovered the parasite independently in 1903 while william boog leishman was carrying out his research in great britain. donovan's discovery ended the confusion prevalent over the anomalous and puzzling cases of malarial fevers in india and proved they were not related to malaria. this added to the promotion of medical knowledge, initiated further research and created enthusiasm among ...200818463075
antileishmanial activity of nano-amphotericin b deoxycholate.the aim of the present study was to compare the efficacy of a nano form of amphotericin b deoxycholate with that of conventional amphotericin b deoxycholate for the treatment of visceral leishmaniasis.200818453526
antileishmanial activity in vitro and in vivo of constituents of sea cucumber actinopyga lecanora.in the search of new antileishmanial drugs from marine resources, we have investigated actinopyga lecanora, a coral reef sea cucumber, for its in vitro and in vivo activities. methanol extract and n-butanol fraction of a. lecanora exhibited excellent leishmania donovani inhibition. among the two glycosides isolated from n-butanol fraction, holothurin b (2) displayed excellent in vitro and moderate in vivo leishmanicidal activity, whereas holothurin a (1) revealed only moderate action. these find ...200818452039
increased levels of interleukin-10 and igg3 are hallmarks of indian post-kala-azar dermal leishmaniasis.post-kala-azar dermal leishmaniasis (pkdl), an established sequela of visceral leishmaniasis (vl), is proposed to facilitate anthroponotic transmission of vl, especially during interepidemic periods. immunopathological mechanisms responsible for indian pkdl are still poorly defined.200818444882
[multiplex pcr for analysis of the plasmodium falciparum drug resistance molecular markers].to develop a multiplex pcr protocol for amplification of five plasmodium falciparum drug resistance related genes, thereby facilitate the rapid and high throughput analysis of the drug resistance molecular markers.200718441889
characterization and localization of orff gene from the ld1 locus of leishmania donovani.the leishmania genome project has identified new genes at a rapid rate. the 32.8-megabase haploid genome of leishmania major (friedlin strain) is published and the comparative analysis of genome sequences of two other species, leishmania infantum and leishmanai braziliensis has been done. the haploid genome of leishmania major (friedlin strain) has around 8272 protein-coding genes, of which only 36% can be ascribed a putative function. out of these open reading frames around 910 leishmania major ...200818423903
inactivation of leishmania donovani infantum and trypanosoma cruzi in red cell suspensions with thiazole orange.methods for pathogen inactivation are currently available in some european countries for treatment of plasma and platelet (plt) components; no approved method for treatment of red cells (rbcs) or whole blood is ready for implementation. in a previous study, thiazole orange (to), a dye commonly used to count reticulated rbcs and plts, exhibited potent photoactivity against human immunodeficiency virus-1 and several model viruses in rbc suspensions. the aim of this study is to further evaluate the ...200818422841
concordant hiv infection and visceral leishmaniasis in ethiopia: the influence of antiretroviral treatment and other factors on outcome.coinfection with human immunodeficiency virus (hiv) and leishmania donovani visceral leishmaniasis (vl) in africa is an emerging, poorly understood disease.200818419422
probing the structures of leishmanial farnesyl pyrophosphate synthases: homology modeling and docking studies.leishmania donovani and leishmania major farnesyl pyrophosphate synthase ( ldfpps and lmfpps) are potential targets for the development of antileishmanial therapy. the protein sequence for ldfpps was recently elucidated in our laboratory. highly refined homology models were generated using the protein sequences of ldfpps and the closely related lmfpps enzyme. a ligand-refined model of lmfpps with a bound bisphosphonate ligand was generated using restraint-guided molecular mechanics followed by q ...200818419114
immuno stimulating glycophosphosphingolipid antigen from leishmania donovani is recognized by visceral leishmaniasis patient sera.surface antigens on leishmania promastigotes and infected macrophages are obvious targets in immunoprophylaxis for leishmanial infection. the glycophosphosphingolipid (gspl) antigen isolated from leishmania donovani surface membrane was recognized by sera from patients with visceral leishmaniasis. gspl was also expressed on the membrane of parasite-infected macrophages. the effect of gspl on the production of reactive oxygen species (ros) and reactive nitrogen intermediates (rni) was studied usi ...200818405984
potantial utility of disulfiram against leishmaniasis. 200818403799
quantitative real-time pcr is not more sensitive than "conventional" pcr. 200818400914
post-translational modification of cellular proteins during leishmania donovani differentiation.the pathogenic intracellular parasites leishmania donovani cycle between sand fly gut and the human macrophage phagolysosome, differentiating from extracellular promastigotes to intracellular amastigote forms. using isobaric tagging for relative and absolute quantifications (itraq/lc-ms/ms) proteomic methodology, we recently described the ordered gene expression changes during this process. while protein abundance changes in leishmania were documented, little is known about their ptms. here we u ...200818398879
comparative kinetics of cofactor association and dissociation for the human and trypanosomal s-adenosylhomocysteine hydrolases. 2. the role of helix 18 stability.the s-adenosyl- l-homocysteine (adohcy) hydrolases (sahh) from homo sapiens (hs-sahh) and from the parasite trypanosoma cruzi (tc-sahh) are very similar in structure and catalytic properties but differ in the kinetics and thermodynamics of association and dissociation of the cofactor nad (+). the binding of nad (+) and nadh in sahh appears structurally to be mediated by helix 18, formed by seven residues near the c-terminus of the adjacent subunit. helix-propensity estimates indicate decreasing ...200818393535
antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate.8-aminoquinolines are an important class of antiparasitic agents, with broad utility and excellent efficacy, but also limitations due to hematological toxicities, primarily methemoglobinemia and hemolysis. one representative from this class, (+/-)-8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate (npc1161c), proved extremely efficacious in animal models of malaria and pneumocystis pneumonia. this racemic mixture was separated into its component enanti ...200818378716
evolutionary conservation of rna editing in the genus leishmania.rna editing in kinetoplastids is the process by which vital genetic informations are restored through insertion and deletion of uridine residues in coding sequences, particularly those of the mitochondrial pre-mrna. mammalian infecting leishmania were not analyzed before for the presence of rna editing to establish whether the mechanism is still in use in higher lineages of the genus. the cytochrome oxidase gene of leishmania tarentolae is known to be edited at its 3' end with grna encoded in th ...200818378193
hypopigmented post-kala-azar dermal leishmaniasis. 200818377613
expression and characterization of a recombinant kinesin antigen from an old indian strain (dd8) of leishmania donovani and comparing it with a commercially available antigen from a newly isolated (ke16) strain of l. donovani.recently we had prepared a recombinant antigen (ld-rke16) from a newly isolated indian strain of leishmania donovani (mhom/in/ke16/1998) with high sensitivity and specificity and the same has been commercialized. while comparing the sequence data of kinesin gene of this (ke16) strain and its expressed protein with another commercially available recombinant antigen (lc-rk39) from kinesin gene of l. chagasi we found significant genetic and amino acid variations. this prompted us to undertake the p ...200818374635
toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors.macrophage function has been demonstrated to be subject to modulation by progesterone. however, as this steroid hormone can act through the glucocorticoid receptor as well as the progesterone receptor, the mechanism of action has not been precisely characterized. to determine the mode of action, we compared the ability of progesterone, norgestrel (a synthetic progesterone-receptor-specific agonist) and dexamethasone (a synthetic glucocorticoid receptor agonist) to modulate macrophage function fo ...200818373668
mode of action of fenarimol against leishmania spp.this paper evaluates the effects of certain herbicides on leishmania spp., their mechanism of action, and the evolutionary origin of the relevant susceptible leishmanial targets. we demonstrated that a relatively nontoxic herbicide, fenarimol, successfully interferes with a leishmanial target, which is probably a relic of an ancient ancestor. fenarimol impairs the function of leishmanial 14alpha-sterol demethylase, a key enzyme in the sterol biosynthetic pathway. therefore, fenarimol or its deri ...200818372651
transcriptional inhibition of interleukin-12 promoter activity in leishmania spp.-infected macrophages.to establish and persist within a host, leishmania spp. parasites delay the onset of cell-mediated immunity by suppressing interleukin-12 (il-12) production from host macrophages. although it is established that leishmania spp.-infected macrophages have impaired il-12 production, the mechanisms that account for this suppression remain to be completely elucidated. using a luciferase reporter assay assessing il-12 transcription, we report here that leishmania major, leishmania donovani, and leishm ...200818372625
an integrated pipeline for the development of novel panels of mapped microsatellite markers for leishmania donovani complex, leishmania braziliensis and leishmania major.a panel of microsatellites mapped to the leishmania genome might make it possible to find associations between specific loci and phenotypic traits. to identify such loci, a perl programme was written that scans the sequence of a genome and writes all loci containing microsatellites to a mysql database. the programme was applied to the sequences of the l. braziliensis, l. infantum and l. major genomes. the database is publicly available over the internet: http://www.genomics.liv.ac.uk/tryps/resou ...200818371241
novel bisbenzimidazoles with antileishmanial effectiveness.a small library of 2,2'-[(alpha,omega-alkanediylbis(oxyphenylene)]bis-1h-benzimidazoles has been prepared and screened in vitro against pneumocystis carinii, trypanosoma brucei rhodesiense, and leishmania donovani. among the six tested compounds two derivatives emerged as promising hits characterized by ic(50) values lower than that determined for pentamidine against l. donovani.200818367395
antiparasitic chemotherapy: tinkering with the purine salvage pathway.distinguishable differences between infectine organisms and their respective hosts with respect to metabolism and macromolecular structure provide scopes for detailed characterization of target proteins and/or macromolecules as the focus for the development of selective inhibitors. in order to develop a rational approach to antiparasitic chemotherapy, finding differences in the biochemical pathways of the parasite with respect to the host it infects is therefore of primary importance. like most ...200818365663
arsenite resistance in leishmania and possible drug targets.pregarded as the second-most dreaded parasitic disease after malaria (who). visceral leishmaniasis or kala-azar, caused by leishmania donovani, is the most fatal form of leishmaniasis afflicting millions of people worldwide. no vaccination is available against leishmaniasis and fast spreading drug resistance in these parasitic organisms is posing a major medical threat. all these emphasize the need for new drugs and molecular targets along with reappraisal of existing therapeutics. identificatio ...200818365654
kinesin motor domain of leishmania donovani as a future vaccine candidate.visceral leishmaniasis (vl) is one of the important parasitic diseases, with approximately 350 million people at risk. due to the nonavailability of an ideal drug, development of a safe, effective, and affordable vaccine could be a solution for control and prevention of this disease. the present study was carried out to examine the immunological potential of kinesin protein from the microtubule locus of leishmania donovani as a suitable vaccine candidate. in silico analysis of this region reveal ...200818353921
synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity.taking advantage of the structural features of natural products showing anti-trypanosomatid activity, we designed and synthesized a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives. the library was obtained following a parallel approach and using readily available synthons. all the derivatives showed inhibitory activity toward either trypanosoma or leishmania species, with 8, 10, and 16 being the most active compounds against trypanosoma brucei rhodesiens ...200818353643
immunomodulatory role of arabinosylated lipoarabinomannan on leishmania donovani infected murine macrophages.arabinosylated lipoarabinomannan (ara-lam), a surface glycolipid antigen isolated from avirulent mycobacterium smegmatis is involved in modulation of host cell signaling. in this study, we investigated ara-lam-mediated modulation of impaired immune responses during visceral leishmaniasis caused by protozoan parasite leishmania donovani. ara-lam treatment at dose of 3 microg/ml in l. donovani infected murine peritoneal macrophages as well as j774a.1 macrophage cell line exhibited a distinct up-re ...200718341212
[an atypical presentation of visceral leshmaniasis in an immunocompetent patient]. 200818339497
influence of brugia malayi life stages and bmafii fraction on experimental leishmania donovani infection in hamsters.the influence of live brugia malayi parasites and a sephadex g-200 fraction of the adult parasite extract (bmafii) on the progression of leishmania donovani infection was studied. inbred hamsters were first infected with b. malayi infective 3rd stage larvae (l3), adult worms or microfilariae (mf), and then with l. donovani amastigotes (ld), or vice versa or received both the infections simultaneously; a group of animals were first immunized with bmafii and then infected with ld. l. donovani para ...200818329620
the direct agglutination test as an alternative method for the diagnosis of canine and human visceral leishmaniasis.visceral leishmaniasis is the most severe clinical form of leishmaniasis and is often fatal without proper treatment. therefore, early and accurate diagnosis is important, but often difficult in endemic areas.200718320110
leishmania requires rab7-mediated degradation of endocytosed hemoglobin for their growth.leishmania is unable to synthesize heme and must acquire it from exogenous source, the mechanism of which is not known. we have shown that leishmania endocytoses hemoglobin (hb) and subsequently degrade it probably to generate heme. to understand how internalized hb is degraded, we have cloned and expressed rab7 homolog from leishmania donovani. interestingly, rab7 in leishmania is found to be localized both on early and late endocytic compartment and regulates both uptake and degradation of end ...200818319337
a community-based, comparative evaluation of direct agglutination and rk39 strip tests in the early detection of subclinical leishmania donovani infection.in the indian state of bihar, the sensitivities and specificities of direct agglutination tests (dat) and rk39 test strips for the detection of leishmania donovani infection in humans were explored and found to be generally good (92%-100%). when 172 asymptomatic individuals [16 'case-contacts' who lived in the same households as past or current, confirmed cases of visceral leishmaniasis (vl) and 156 other subjects from neighbouring households] were tested, the same 36 (21%) individuals, includin ...200818318933
leishmania major infection activates nf-kappab and interferon regulatory factors 1 and 8 in human dendritic cells.the salient feature of dendritic cells (dc) is the initiation of appropriate adaptive immune responses by discriminating between pathogens. using a prototypic model of intracellular infection, we previously showed that leishmania major parasites prime human dc for efficient interleukin-12 (il-12) secretion. l. major infection is associated with self-limiting cutaneous disease and powerful immunity. in stark contrast, the causative agent of visceral leishmaniasis, leishmania donovani, does not pr ...200818316378
crucial role of cytosolic tryparedoxin peroxidase in leishmania donovani survival, drug response and virulence.leishmania donovani, the causative agent of visceral leishmaniasis, uses a cascade of enzymes that include cytosolic tryparedoxin peroxidase (ctxnpx) for detoxification of peroxides, an event pivotal for survival of digenic parasites living in two disparate biological environments. in this study, we observed an increase in promastigote ctxnpx levels after exposure to h(2)o(2) and this group did not show any cell death; however, exposure to a combination of h(2)o(2) and nitric oxide resulted in s ...200818312262
leishmanial lipid suppresses tumor necrosis factor alpha, interleukin-1beta, and nitric oxide production by adherent synovial fluid mononuclear cells in rheumatoid arthritis patients and induces apoptosis through the mitochondrial-mediated pathway.leishmanial lipid is a strong immunosuppressor of host cells. inhibition of the inflammatory responses of synovial cells through induction of apoptosis is one of the main targets of therapeutic intervention in rheumatoid arthritis (ra). this study was undertaken to examine the antiinflammatory and apoptosis-inducing effects of leishmanial lipid on adherent synovial fluid mononuclear cells (sfmcs) in patients with ra.200818311833
quantitative evaluation of interleukin-12 p40 gene expression in peripheral blood mononuclear cells.the heterodimeric cytokine il-12 (composed of a p35 and a p40 subunit) is produced primarily by monocytes, macrophages and b cells. in vitro and in vivo experiments have demonstrated the crucial role of il-12 in initiating and establishing both innate immunity and t cell-mediated resistance to intracellular pathogens, including leishmania donovani, toxoplasma gondii, listeria monocytogenes, and mycobacterium tuberculosis. assessment of cytokine expression has thus become crucial to understand ho ...200818300039
antigen detection from urine of kala-azar cases by latex agglutination test.a recently developed latex agglutination method known as "katex" for detecting leishmanial antigen in urine of kala-azar patients was evaluated on 97 kala-azar cases and 35 controls in the department of microbiology, mymensingh medical college during the period from march' 2004 to february' 2005. the method yielded sensitivity as 100% and 82.8% in 33 confirmed and 64 ict positive cases respectively. since 8.6% controls showed antigen positive results, so specificity of katex was calculated as 91 ...200818285726
quercetin interferes with iron metabolism in leishmania donovani and targets ribonucleotide reductase to exert leishmanicidal activity.the possibility of developing antileishmanial drugs was evaluated by intervention in the parasite's iron metabolism, utilizing quercetin (qr) under in vivo conditions, and identifying the target of this lipophilic metal chelator against leishmania donovani.200818285311
isolation and characterization of new cannabis constituents from a high potency variety.phytochemical investigation of a high potency variety of cannabis sativa l. resulted in the isolation of six new metabolites, (+/-)-6,7-trans-epoxycannabigerolic acid ( 2), (+/-)-6,7- cis-epoxycannabigerolic acid ( 3), (+/-)-6,7- cis-epoxycannabigerol ( 4), (+/-)-6,7-trans-epoxycannabigerol ( 5), 5'-methyl-4-pentylbiphenyl-2,2',6-triol ( 7), and 7-methoxycannabispirone ( 8), along with seven known compounds namely, cannabigerolic acid ( 1), 5'-methoxycannabigerolic acid ( 6), cannabispirone ( 9) ...200818283614
proteomic analysis of the secretome of leishmania donovani.leishmania and other intracellular pathogens have evolved strategies that support invasion and persistence within host target cells. in some cases the underlying mechanisms involve the export of virulence factors into the host cell cytosol. previous work from our laboratory identified one such candidate leishmania effector, namely elongation factor-1alpha, to be present in conditioned medium of infectious leishmania as well as within macrophage cytosol after infection. to investigate secretion o ...200818282296
a novel approach to regulate experimental visceral leishmaniasis in murine macrophages using ccr5 sirna.early infection with leishmania donovani during visceral leishmaniasis (vl) results in the enhanced expression of c-c chemokine receptor 5 (ccr5) in macrophages. ccr5 expression at different time points of infection revealed increased expression at protein and mrna level from 3 to 24 h and beyond 24 h expression of ccr5 is downregulated. to better understand the functional role of ccr5 during leishmania infection, rna interference strategy has been used to modulate macrophage function by targeti ...200818282231
a new heck reaction modification using ketone mannich bases as enone precursors: parallel synthesis of anti-leishmanial chalcones.a new heck-type reaction for the synthesis of chalcones has been established using mannich bases as enone precursors. the novel reaction proceeds rapidly in air atmosphere under ligandless conditions and can be adapted for library synthesis in a parallel reactor station. screening of the synthesized chalcones revealed n-{4-[(1e)-3-oxo-3-(3-pyridinyl)-1-propenyl]phenyl}benzamide (3f) to be a potent anti-leishmanial agent.200818276134
an ethanolic extract of leaves of piper betle (paan) linn mediates its antileishmanial activity via apoptosis.an unprecedented increase in the incidence of unresponsiveness to antimonial compounds has highlighted the urgent need to develop new antileishmanial agents. the leaves of piper betle (locally known as paan) have long been in use in the indian indigenous system of medicine for its antimicrobial properties but its antileishmanial potential has not been studied. accordingly, an ethanolic extract of leaves of piper betle (pb) was tested for its antileishmanial activity that was evidenced in both pr ...200818273645
oral therapy with sertraline, a selective serotonin reuptake inhibitor, shows activity against leishmania donovani.this study was executed to investigate the efficacy of oral therapy and preliminary leishmanicidal mechanism of sertraline, a selective serotonin reuptake inhibitor widely used for the management of depression, against leishmania donovani, a causative agent of visceral leishmaniasis (vl).200818272513
kala-azar: an endemic focus in bombay.1. a series of 16 cases of kala-azar encountered at the acworth leper home during a period of 14 months is described. 2. positive proof is adduced to show that the whole outbreak is of indigenous origin. this consists of (a) the long uninterrupted duration (more than 3 years) of some of these patients' stay in bombay (b) demonstration of the presence of sand-flies in the vicinity (c) demonstration of the presence of infected sand-flies. 3. the danger of the spread of infection from the endemic f ...194918268800
in vitro and in vivo activity of aloe vera leaf exudate in experimental visceral leishmaniasis.the leishmanicidal activity of aloe vera leaf exudate (avl) has been demonstrated in promastigotes and axenic amastigotes, but its effectiveness in animal models has not been evaluated. the presence of alkaloids, triterpenes, cyanidines, proanthocyanidines, tannins, and saponins in avl was identified. its effectiveness in four leishmania donovani strains was studied both in promastigotes (ic50 ranged from 70-115 microg/ml) and amastigotes (ic50 ranged from 3.1-11.4 microg/ml). in amastigotes, th ...200818266009
development of a real-time polymerase chain reaction assay for the quantification of leishmania species and the monitoring of systemic distribution of the pathogen.we have developed a highly accurate and sensitive real-time polymerase chain reaction (pcr) assay to detect and quantify leishmania parasites. the assay targets gp63, a highly conserved gene in leishmania. we demonstrate that, with a single assay, we are able to detect and quantify several species of leishmania. our assay system detects leishmania donovani and leishmania major down to 0.1 parasite. the dynamic range of the assay extends over 6 log cycles of target, with an average correlation co ...200818255247
selection and phenotype characterisation of sitamaquine-resistant promastigotes of leishmania donovani.a leishmania donovani promastigote line resistant to 160microm sitamaquine, named sita-160r, was selected in vitro by continuous stepwise drug pressure. sita-160r line was able to infect murine peritoneal macrophages in vitro in the same manner as the wild-type line (wt) but was less infective for balb/c mice than its parent wt clone. this line was about five and three times more resistant to sitamaquine than the wt line on promastigote and intramacrophage amastigote forms, respectively. no cros ...200818249083
chemotherapy of leishmaniasis part-viii: synthesis and bioevaluation of novel chalcones.some novel dihydro-alpha-ionone based chalcones have been synthesized and evaluated for their in vitro antileishmanial activity in promastigote and amastigote model. some of the compounds showed 100% inhibition at 5 and 2 microm/ml concentration.200818243420
a novel atp-binding cassette transporter, abcg6 is involved in chemoresistance of leishmania.atp-binding cassette (abc) transporters constitute the biggest family of membrane proteins involved in drug resistance and other biological activities. resistance of leishmanial parasites to therapeutic drugs continues to escalate in developing countries and in many instances it is due to overexpressed abc efflux pumps. progressively adapted camptothecin (cpt)-resistant parasites show overexpression of a novel abc transporter, which was classified as abcg6. transfection and overexpression of lda ...200818243364
molecular characterization and expression of a novel kinesin which localizes with the kinetoplast in the human pathogen, leishmania donovani.using a variety of molecular and cell biological approaches, we identified, characterized and expressed a novel kinesin, ldk39b in the protozoan pathogen leishmania donovani. results of rt-pcr revealed two distinct ldk39b products with different splice leader mini-exon sites, indicative of two potentially mature mrna transcripts. analyses indicated that ldk39b had a calculated molecular mass of >261, 327 da and contained multiple amino acid repeat units. several gfp-ldk39b fusion constructs were ...200818240272
involvement of a leishmania thymidine kinase in flagellum formation, promastigote shape and growth as well as virulence.leishmania promastigote cells transmitted by their insect vector get phagocytosed by macrophages and convert into the amastigote form. in a recently performed proteomic study, a thymidine kinase (tk) was found to be preferentially expressed in amastigotes. western blot analysis showing a marked increase in tk protein synthesis during stage differentiation from promastigotes to amastigotes confirmed this result. after comparison of the amino acid sequence of leishmania donovani and leishmania maj ...200818222009
design and synthesis of potent antileishmanial cycloalkylidene-substituted ether phospholipid derivatives.two series of novel ether phospholipids (eps) have been synthesized. the first includes cyclodecylidene- or cyclopentadecylidene-substituted eps carrying n,n,n-trimethylammonium or n-methylpiperidino or n-methylmorpholino head groups. the second series encompasses more rigid head groups in combination with cycloalkylidene moieties in the lipid portion. in addition, hydrogenated derivatives were obtained. all the new analogues, except 33, were 1.5- to 62-fold more potent than miltefosine against ...200818220332
cutaneous leishmaniasis, sri lanka.cutaneous leishmaniasis (cl) is an emerging disease in sri lanka. of 116 patients with clinical symptoms suggestive of cl, 86 were confirmed positive for leishmania donovani. most patients had single dry lesions, usually on the face. patients were from 5 of the 7 agroclimatic zones in sri lanka.200718214182
flowers in a bone marrow aspiration. 200818213653
phosphoproteomic analysis of leishmania donovani pro- and amastigote stages.following transmission to the vertebrate host, the protozoan parasite leishmania donovani differentiates into the pathogenic amastigote stage that is adapted for intracellular survival. this developmental transition is induced by environmental factors including elevated temperature and acidic ph and is likely transduced by signaling cascades involving protein kinases and their downstream phosphoprotein substrates. these signaling networks are highly adapted to the specific nutritional and physio ...200818203260
indian mucosal leishmaniasis due to leishmania donovani infection. 200818199877
virulence attenuation of a udp-galactose/n-acetylglucosamine beta1,4 galactosyltransferase expressing leishmania donovani promastigote.protozoan parasites of the genus leishmania are the causative agent of leishmaniasis, a disease whose manifestations in humans range from mild cutaneous lesions to fatal visceral infections. human visceral leishmaniasis is caused by leishmania donovani. long-term culture in vitro leads to the attenuation of the parasite. this loss of parasite virulence is associated with the expression of a developmentally regulated udp-galactose/n-acetylglucosamine beta 1-4 galactosyltransferase and galactose t ...200818197475
gp63 in stable cationic liposomes confers sustained vaccine immunity to susceptible balb/c mice infected with leishmania donovani.visceral leishmaniasis is deadly if not treated, and development of a vaccine with long-term immunity remains a challenge. in this study, we showed that cationic distearoyl phosphatidylcholine (dspc) liposomes, when used as vaccine adjuvant with the immunodominant 63-kda glycoprotein (gp63) of leishmania donovani promastigotes, induced significant protection against progressive visceral leishmaniasis in susceptible balb/c mice. gp63 used without adjuvant elicited partial protection but in associ ...200818195029
revival of a focus of visceral leishmaniasis in central sudan. 200818186981
human placental extract offers protection against experimental visceral leishmaniasis: a pilot study for a phase-i clinical trial.an aqueous extract of human placenta (hpe) was found to offer protection against established experimental visceral leishmaniasis in balb/c mice and hamsters, whether the leishmania donovani strain involved was one that was sensitive or resistant to pentavalent antimony. intraperitoneal administration of the extract, into mice or hamsters that had been infected 2 months previously, led to antileishmanial t-cell proliferation among splenic mononuclear cells, the generation of host-protective cytok ...200818186975
safety and effectiveness of amphotericin b deoxycholate for the treatment of visceral leishmaniasis in uganda.between september 2003 and april 2004, the supply of antimonial drugs to amudat hospital, in north-eastern uganda, was interrupted and all cases of visceral leishmaniasis presenting at the hospital could only be treated with amphotericin b deoxycholate (amb). this allowed the safety and effectiveness of the amb to be evaluated, in comparison with an historical cohort of patients treated, at the same hospital, with meglumine antimoniate (sb(v)). demographic and clinical data were collected before ...200818186974
2-(3-aryl-3-oxopropen-1-yl)-9-tert-butyl-paullones: a new antileishmanial chemotype.a screening program directed to find new agents against leishmania donovani, the parasite causing visceral leishmaniasis, revealed that paullones attenuate the proliferation of axenic amastigotes. because these structures were not active in a test system involving infected macrophages, a structure optimization campaign was carried out. concomitant introduction of an unsaturated side chain into the 2-position and a tert-butyl substituent into the 9-position of the parent scaffold led to compounds ...200818186603
risk factors of visceral leishmaniasis in east africa: a case-control study in pokot territory of kenya and uganda.in east africa, visceral leishmaniasis (vl) is endemic in parts of sudan, ethiopia, somalia, kenya and uganda. it is caused by leishmania donovani and transmitted by the sandfly vector phlebotomus martini. in the pokot focus, reaching from western kenya into eastern uganda, formulation of a prevention strategy has been hindered by the lack of knowledge on vl risk factors as well as by lack of support from health sector donors. the present study was conducted to establish the necessary evidence-b ...200818184669
presence of anti-lepp12 antibody: a marker for diagnostic and prognostic evaluation of visceral leishmaniasis.the diagnostic potential of recombinant lepp12 (rlepp12) antigen cloned from leishmania infantum was assessed in l. donovani infections by western blotting. ninety-two serum samples, including 30 patients with active kala-azar (ka), 17 post-treated ka patients (ka-pt), 20 post-kala-azar dermal leishmaniasis (pkdl) patients and 25 controls, were analysed for rlepp12, rk39 and dat positivity. all ka samples taken at pre-treatment stage were positive for lepp12 antibodies. seventeen of these were e ...200818177681
wild-type leishmania donovani promastigotes block maturation, increase integrin expression and inhibit detachment of human monocyte-derived dendritic cells--the influence of phosphoglycans.the protective immune response against the parasite, including the role of dendritic cells (dc) in the course of infection, plays a fundamental role. this study shows that wild-type (wt) leishmania promastigotes and specifically the phosphoglycans family of virulence-associated antigens inhibit human monocyte-derived dendritic cells (modc) maturation and detachment to distinct surfaces. immature phagocytosis of leishmania donovani promastigotes by immature modc results in the increased expressio ...200818177309
post-kala-azar dermal leishmaniasis with visceral leishmaniasis, or a rare presentation of visceral leishmaniasis with extensive skin manifestations. 200718173544
adenosine kinase mediates high affinity adenosine salvage in trypanosoma brucei.african sleeping sickness is caused by trypanosoma brucei. this extracellular parasite lacks de novo purine biosynthesis, and it is therefore dependent on exogenous purines such as adenosine that is taken up from the blood and other body fluids by high affinity transporters. the general belief is that adenosine needs to be cleaved to adenine inside the parasites in order to be used for purine nucleotide synthesis. we have found that t. brucei also can salvage this nucleoside by adenosine kinase ...200818167353
antileishmanial activity of piceatannol isolated from euphorbia lagascae seeds.in the search for biologically active compounds from euphorbia lagascae spreng, an herbaceous plant native to southeast of iberic peninsula, a stilbene, two coumarins and two 12-deoxyphorbol diterpene esters were isolated by chromatographic methods, from the methanol extracts of its defatted seeds. the structures of these compounds were elucidated by a combination of physical and spectral data (ir, ms and high-resolution (1)h-nmr and (13)c-nmr spectroscopy utilizing cosy, hmbc, hmqc and noesy ex ...200818167046
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