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antileishmanial activity mediated by apoptosis and structure-based target study of peganine hydrochloride dihydrate: an approach for rational drug design.the aim of this study was to resolve the putative pathway responsible for death induced by peganine hydrochloride dihydrate isolated from peganum harmala seeds at cellular, structural and molecular level in leishmania donovani, a causative agent of fatal visceral leishmaniasis.200818694906
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
[an atypical presentation of visceral leshmaniasis in an immunocompetent patient]. 200818339497
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
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
th1-stimulatory polyproteins of soluble leishmania donovani promastigotes ranging from 89.9 to 97.1 kda offers long-lasting protection against experimental visceral leishmaniasis.our earlier studies identified a fraction (f2) of leishmania donovani soluble promastigote antigen belonging to 97.4-68 kda for its ability to stimulate th1-type cellular responses in cured visceral leishmaniasis (vl) patients as well as in cured hamsters. a further fractionation of f2-fraction into seven subfractions (f2.1-f2.7) and re-assessment for their immunostimulatory responses revealed that out of these, only four (f2.4-f2.7) belonging to 89.9-97.1 kda, stimulated remarkable th1-type cel ...200818762224
comparison of treatment regimens of kala-azar based on culture & sensitivity of amastigotes to sodium antimony gluconate.present treatment strategies for kala-azar (visceral leishmaniasis, vl) include use of first line drug sodium antimony gluconate (sag) to all patients but a large number of patients do not get relief with this drug. if a patient does not respond to a full course of sag, a second or third line drug is given. we undertook this study to test whether an improved outcome can be achieved by employing a strategy of treatment based on culture and sensitivity of amastigotes to sag compared with conventio ...200818765878
hemophagocytic lymphohistiocytosis associated with epstein barr virus and leishmania donovani coinfection in a child from cyprus.we present a case of a 9-month-old girl from cyprus with hemophagocytic lymphohistiocytosis associated with epstein barr virus and leishmania donovani coinfection. treatment with liposomal amphotericin b resulted in a dramatic resolution of clinical and laboratory abnormalities. to our knowledge, this is the first reported case of a coinfection-associated hemophagocytic lymphohistiocytosis and the first clinical report of visceral leishmaniasis infection in europe by l. donovani.200818776766
leishmania donovani infection down-regulates tlr2-stimulated il-12p40 and activates il-10 in cells of macrophage/monocytic lineage by modulating mapk pathways through a contact-dependent mechanism.the failure of leishmania, an intracellular pathogen, to stimulate a pro-inflammatory response following entry into macrophages has been well reported. this occurs in spite of the fact that ligands for the toll-like receptors (tlr) have been recently shown on the parasite surface and their role in disease protection well documented. the outcome of infection in leishmaniasis is determined by the th1 versus th2 nature of the effector response and the generation of il-12 and il-10 by the infected m ...200818778366
isolation and identification of leishmania donovani from phlebotomus orientalis, in an area of eastern sudan with endemic visceral leishmaniasis. 200818782494
protective immunity against challenge with leishmania (leishmania) chagasi in beagle dogs vaccinated with recombinant a2 protein.in this study, we investigated in dogs the immunogenicity and protective immunity against leishmania (leishmania) chagasi infection induced by vaccination with a formulation containing the recombinant a2 protein, an amastigote specific antigen, and saponin. vaccinated animals produced significantly increased levels of total igg and igg2, but not igg1 anti-a2 antibodies, and remained negative in conventional leishmaniasis serodiagnostic methods. significantly increased ifn-gamma and low il-10 lev ...200818786587
actin-depolymerizing factor, adf/cofilin, is essentially required in assembly of leishmania flagellum.adf/cofilins are ubiquitous actin dynamics-regulating proteins that have been mainly implicated in actin-based cell motility. trypanosomatids, e.g. leishmania and trypanosoma, which mediate their motility through flagellum, also contain a putative adf/cofilin homologue, but its role in flagellar motility remains largely unexplored. we have investigated the role of this protein in assembly and motility of the leishmania flagellum after knocking out the adf/cofilin gene by targeted gene replacemen ...200818793337
long-term use of an antiinflammatory, curcumin, suppressed type 1 immunity and exacerbated visceral leishmaniasis in a chronic experimental model.inflammation is considered the underlying cause of numerous disorders, and the practice of taking antiinflammatories as diet supplements has become increasingly prevalent. this study addresses the bioavailablity of a well-established dietary antiinflammatory, curcumin, and examines its effect on adaptive immunity. visceral leishmaniasis is a major parasitic disease which protection relies on cell-mediated immunity and production of nitric oxide. we found that long-term, low-dose, oral consumptio ...200818794851
vcam-1 and vla-4 modulate dendritic cell il-12p40 production in experimental visceral leishmaniasis.vascular cell adhesion molecule-1 (vcam-1) interacts with its major ligand very late antigen-4 (vla-4) to mediate cell adhesion and transendothelial migration of leukocytes. we report an important role for vcam-1/vla-4 interactions in the generation of immune responses during experimental visceral leishmaniasis caused by leishmania donovani. our studies demonstrate that these molecules play no direct role in the recruitment of leukocytes to the infected liver, but instead contribute to il-12p40- ...200818802456
prophylactic efficacy of high-molecular-weight antigenic fractions of a recent clinical isolate of leishmania donovani against visceral leishmaniasis.t-cell mediated immune responses are key determinants to the natural course of infection caused by intracellular parasites such as leishmania. thus, t-cell activating proteins of these microbes continue to generate active interest particularly in view of their possible role in the design and development of newer and more effective vaccines. we have recently reported the presence of t-cell immunostimulatory antigens with the high-molecular-weight (mw) fractions (134-64.2 kda) of whole leishmania ...200818803606
diagnostic accuracy of a new leishmania pcr for clinical visceral leishmaniasis in nepal and its role in diagnosis of disease.to develop a new pcr for leishmania detection and to estimate its diagnostic accuracy in a visceral leishmaniasis (vl) endemic area.200818803611
comparison of the immunomodulatory effects of l. donovani and l. major excreted-secreted antigens, particulate and soluble extracts and viable parasites on human dendritic cells.in an experimental model of human monocyte-derived dendritic cells (dcs), the immunophenotype of mature dcs infected with leishmania donovani and leishmania major showed a weak decrease in the cell surface expression of cd40, cd86, hla-dr and dc-sign compared with uninfected control dcs. this immunomodulatory effect was more pronounced after stimulation with excreted-secreted antigens (esa) of both species but absent after stimulation with particulate and soluble extracts. infection with viable ...200818804505
antileishmanial, antimalarial and antimicrobial activities of the extract and isolated compounds from austroplenckia populnea (celastraceae).austroplenckia populnea (celastraceae), known as "marmelinho do campo", is used in brazilian folk medicine as antimicrobial, anti-inflammatory, and antitumoural agent. the aim of the present work was to evaluate the antimicrobial, antileishmanial and antimalarial activities of the crude hydroalcoholic extract of a. populnea (che) and some of its isolated compounds. the phytochemical study of the che was carried out affording the isolation of methyl populnoate (1), populnoic acid (2), and stigmas ...200818810991
l. (l.) chagasi in aids and visceral leishmaniasis (kala-azar) co-infection.concomitant skin lesions in visceral leishmaniasis (vl) or kala-azar are rare, being more common the description of post-kala-azar dermal leishmaniasis occurring post treatment of kala-azar. skin lesions caused by leishmania donovani are frequently seen in the aids-vl co-infection. in brazil cutaneous or mucosal forms of tegumentary leishmaniasis concomitant with aids are more commonly registered. here we present a case of aids-vl co-infection, with unusual cutaneous and digestive compromising a ...200818813767
intracellular survival of leishmania species that cause visceral leishmaniasis is significantly reduced by hiv-1 protease inhibitors.visceral leishmaniasis is now recognized as an opportunistic disease in individuals infected with human immunodeficiency virus type 1 (hiv-1). although the usefulness of hiv-1 protease inhibitors (pis) in antiretroviral regimens is well documented, little is known about their potential impact in the setting of leishmania/hiv-1 coinfections. we now report that, although selected pis do not inhibit the growth of leishmania infantum promastigotes alone in culture, these drugs significantly inhibit ...200818816190
hiv, visceral leishmaniasis and parkinsonism combined with diabetes mellitus and hyperuricaemia: a case report.abstract:200818817545
withdrawn:curcumin, a dietary polyphenol, emerges as a novel inhibitor of dna topoisomerase i of kinetoplastid parasite leishmania donovani.this paper published as an immediate publication on 29 september 2008 was withdrawn by the editorial board of the biochemical journal on 12 december 2008.200818823279
enzyme-linked immunosorbent assay to detect urinary antibody against recombinant rkrp42 antigen made from leishmania donovani for the diagnosis of visceral leishmaniasis.we recently reported the production of the recombinant kinesin-related protein of leishmania donovani with a molecular weight of 42 kd (rkrp42) and the value of the antigen in serum-based elisa for the diagnosis of visceral leishmaniasis (vl). in this study, the rkrp42 antigen was validated with elisa using urine samples (rkrp42 urine elisa). the urine-based elisa showed 94% sensitivity (108 positives among 115 vl samples) and 99.6% specificity (239 negatives among 240 non-vl samples). the sensi ...200818840751
synthesis and antiprotozoal activity of cationic 2-phenylbenzofurans.a series of cationically substituted 2-phenylbenzofurans 1- 49 have been synthesized, and their in vitro antiprotozoal properties against trypanosoma brucei rhodesiense, plasmodium falciparum, and leishmania donovani, as well as cytotoxicity against mammalian cells, have been evaluated. eight dications exhibited antitrypanosomal activities comparable to that of pentamidine and melarsoprol. twenty-six compounds were more active than pentamidine, and seven dications demonstrated increased activiti ...200818841956
monoclonal gammopathy after visceral leishmaniasis: just a coincidence?the authors describe a case of monoclonal gammopathy occurring about six months after a visceral leishmaniasis. a literature survey suggests that strong antigenic stimulation caused by visceral leishmaniasis can induce monoclonal gammopathy in a predisposed subject.200818843217
pharmacological and biological screening of ascorbigen: protection against glucose-induced endothelial cell toxicity.cruciferous vegetables contain significant amounts of ascorbigen and related substances with known molecular structures. this study tested the hypothesis that ascorbigen demonstrates antioxidant properties and protects human umbilical cord endothelial cells against hyperglycemic toxicity in vitro. it was observed that ascorbigen, in micromolar concentrations, protected against endothelial cell death from glucose toxicity. additionally, ascorbigen at 3.0 mm shifted the concentration response curv ...200818844288
selection of the most promising 2-substituted quinoline as antileishmanial candidate for clinical trials.the antileishmanial evaluation of more than one hundred 2-substituted quinolines led us to identify three compounds for further studies: compound 1 (2-n-propylquinoline), compound 2 (2-(2methoxyethenyl)quinoline) and compound 3 (2-(2-hydroxyprop-2-enyl)quinoline). the final selection of a potential drug candidate was mainly based on chemical stability and acute oral toxicity as discriminating criteria. the most stable compound in various conditions was 2-n-propylquinoline (compound 1). only reve ...200818849137
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
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
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
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
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
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
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
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
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
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
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
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
complete cure of experimental visceral leishmaniasis with amphotericin b in stearylamine-bearing cationic liposomes involves down-regulation of il-10 and favorable t cell responses.visceral leishmaniasis caused by leishmania donovani is a life-threatening disease involving uncontrolled parasitization of liver, spleen, and bone marrow. most available drugs are toxic. moreover, relapse after seemingly successful therapy remains a chronic problem. in this study, we evaluated a new therapeutic approach based on combination of a low dose of amphotericin b (amb) in association with suboptimum dose of stearylamine (sa)-bearing cationic liposomes, itself having leishmanicidal acti ...200818606693
role of aquaglyceroporin (aqp1) gene and drug uptake in antimony-resistant clinical isolates of leishmania donovani.antimonial-containing drugs are the first line of treatment against leishmaniasis. resistance to antimonials in leishmania is proposed to be due to reduced uptake of trivalent antimony (sbiii) through the aquaglyceroporin (aqp1). we investigated the uptake of sbiii and involvement of aquaglyceroporin in developing antimony resistance phenotype in leishmania donovani clinical isolates. sbiii accumulation, copy number of aqp1 gene, and transcript levels were compared in antimony-sensitive versus - ...200818606765
evaluation of direct agglutination test, rk39 test, and elisa for the diagnosis of visceral leishmaniasis.the study reports an evaluation of the direct agglutination test (dat) with use of promastigote/amastigote antigen, rk39 strip test, and elisa for diagnosis of visceral leishmaniasis (vl). out of 94 clinically suspected vl patients, 16 (17%) were seropositive by all the techniques; in addition, 6 were positive in rk39 strip test and elisa. on retrospective analysis, out of 16 positive by all the techniques, 11 (69%) had demonstrable leishmania donovani (ld) bodies in their bone marrow samples, w ...200818606766
leishmania donovani pteridine reductase 1: biochemical properties and structure-modeling studies.pteridine reductase 1 (ptr1, ec 1.5.1.33) is a nadph dependent short-chain reductase (sdr) responsible for the salvage of pterins in the protozoan parasite leishmania. this enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, therefore, for successful antifolate chemotherapy to be developed against leishmania, it must target both enzyme activities. based on homology model drawn on recombinant pteridine reductase isolated from a clinical isolate of l. donovani, we carrie ...200818617167
visceral leishmanisis in paediatrics: a study of 367 cases in southwest iran.kala-azar (visceral leishmaniasis [vl]) is endemic in southern iran. we retrospectively evaluated 367 infants and children suffering from vl at hospitals affiliated to the shiraz university of medical sciences in fars province, southwest iran). seasonal variations were observed with more cases presenting in late winter, spring and fewer in summer. the predominant clinical features in these patients were chronic fever, pallor, weight loss, abdominal distention and hepatosplenomegaly. lymphadenopa ...200818628558
immune response following miltefosine therapy in a patient with post-kala-azar dermal leishmaniasis.we report a case of post-kala-azar dermal leishmaniasis in which real-time pcr was exploited to measure changes in cytokine transcripts in lesion tissue before and after oral miltefosine treatment. unlike antimonial therapy elevated levels of ifngamma transcripts were noted, whereas tnfalpha, il-10 and transforming growth factor-beta declined similar to that observed after therapy with antimonials. a significant increase in ifngamma and cd40 levels seen after miltefosine therapy could enhance pa ...200818639311
parallel synthesis and antileishmanial activity of ether-linked phospholipids.the synthesis and antileishmanial activity of 18 edelfosine analogues are described. compounds were obtained in parallel combining solid phase and solution phase synthesis. the most active analogue is characterized by the octadecyl group in position 2 of the glycerol chain. considering that this substitution determines the loss of antitumor activity, a different mechanism of antileishmanial action can be hypothesized.200818644723
mutational study of the "catalytic tetrad" of dna topoisomerase ib from the hemoflagellate leishmania donovani: role of asp-353 and asn-221 in camptothecin resistance.leishmania donovani, the causative organism for visceral leishmaniasis, contains a unique bisubunit dna-topoisomerase ib (ldtopib). the catalytically active enzyme is a heterodimer constituted by a large subunit (ldtopil) containing a non-conserved n-terminal end and the phylogenetically conserved core domain, whereas the small subunit (ldtopis) harbors the c-terminal domain with the characteristic tyrosine residue in the active site. site-directed mutagenesis was used to substitute the basic am ...200818655776
induction of th1-type cellular responses in cured/exposed leishmania-infected patients and hamsters against polyproteins of soluble leishmania donovani promastigotes ranging from 89.9 to 97.1 kda.earlier, we have identified soluble antigenic fraction ranging from 68 to 97.4 kda (f2-fraction) of leishmania donovani promastigote, which induced th1-immunostimulatory cellular responses in both cured leishmania patients/hamsters and exhibited significant prophylactic potential against experimental visceral leishmaniasis (vl). in the present study, we have further fractionated f2-fraction by continuous elution sds-page and subjected them to re-evaluation for their ability to induce cellular re ...200818656517
fml vaccine against canine visceral leishmaniasis: from second-generation to synthetic vaccine.the leishmania donovani glycoprotein fraction, known as fml, successfully underwent preclinical and clinical (phase i-iii) vaccine trials against canine visceral leishmaniasis (92-95% of protection and 76-80% of vaccine efficacy) when formulated with a qs21 saponin-containing adjuvant. it became the licensed leishmune vaccine for canine prophylaxis in brazil. the immune response raised by the vaccine is long lasting, immunotherapeutic and reduces dog infectivity blocking the transmission of the ...200818665780
immunogenicity assay of the leishmune vaccine against canine visceral leishmaniasis in brazil.leishmune is the industrialized version of the fml-saponin vaccine which has been shown to develop 92-95% protection in vaccinated dogs and 76-80% vaccine efficacy against field canine visceral leishmaniasis (cvl) in brazil. leishmune has been proven to be safe and tolerable and a transmission-blocking vaccine which renders vaccinated dogs non-infectious to sand fly vectors. in the present investigation, 550 healthy seronegative dogs of endemic and epidemic areas of brazil were monitored for lei ...200818675868
antiprotozoal activities of heterocyclic-substituted xanthones from the marine-derived fungus chaetomium sp.investigations of the marine-derived fungus chaetomium sp. led to the isolation of the new natural products chaetoxanthones a, b, and c (1-3). compounds 1 and 2 are substituted with a dioxane/tetrahydropyran moiety rarely found in natural products. compound 3 was identified as a chlorinated xanthone substituted with a tetrahydropyran ring. the configurational analysis of these compounds employed cd spectroscopy, modified mosher's method, and selective noe gradient measurements. compound 2 showed ...200818683985
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
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 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
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
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
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
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
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
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
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
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
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
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
leishmania donovani promastigotes on 'chocolate' agar. 200818577335
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 leishmaniasis in cyprus. 200818582830
withanolide z, a new chlorinated withanolide from withania somnifera.reverse-phase preparative hplc analysis of the n-butanol fraction of the methanolic extract of withania somnifera dunal (leaves) afforded a novel chlorinated withanolide, namely withanolide z (1), along with four known withanolides, withanolide b (2), withanolide a (3), 27-hydroxywithanolide b (4) and withaferin a (5). their structures were elucidated by ir, ms, cd and a combination of 1 d and 2 d nmr spectral analyses. the leishmania donovani dna topoisomerase i inhibitory activities of the iso ...200818988152
in pursuit of natural product leads: synthesis and biological evaluation of 2-[3-hydroxy-2-[(3-hydroxypyridine-2-carbonyl)amino]phenyl]benzoxazole-4-carboxylic acid (a-33853) and its analogues: discovery of n-(2-benzoxazol-2-ylphenyl)benzamides as novel antileishmanial chemotypes.the first synthesis and biological evaluation of antibiotic 31 (a-33853) and its analogues are reported. initial screening for inhibition of l. donovani, t. b. rhodesiense, t. cruzi, and p. falciparum cultures followed by determination of ic(50) in l. donovani and cytotoxicity on l6 cells revealed 31 to be 3-fold more active than miltefosine, a known antileishmanial drug. compounds 14, 15, and 25 selectively inhibited l. donovani at nanomolar concentrations and showed much lower cytotoxicity.200818989953
synthesis of bodipy-labeled alkylphosphocholines with leishmanicidal activity, as fluorescent analogues of miltefosine.two general synthetic methods are described, by which the highly fluorescent and photostable bodipy group can be inserted in and aligned with the alkyl backbone of linear lipids. these methods have been used to prepare strongly emitting analogues of the leishmanicidal drug miltefosine, in which the antiparasite activity in vitro of the original drug is preserved.200818990566
discovery of novel vaccine candidates and drug targets against visceral leishmaniasis using proteomics and transcriptomics.among the three clinical forms (cutaneous, mucosal and visceral) of leishmaniasis visceral (vl) one is the most devastating type caused by the invasion of the reticuloendothelial system of human by leishmania donovani, l. infantum and l. chagasi. india and sudan account for about half the world's burden of vl. current control strategy is based on chemotherapy, which is difficult to administer, expensive and becoming ineffective due to the emergence of drug resistance. an understanding of resista ...200818991606
visceral leishmaniasis on the indian sub-continent: a multi-centre study of the costs of three interventions for the control of the sandfly vector, phlebotomus argentipes.the sandflies that transmit the parasites causing human visceral leishmaniasis (vl) can be controlled by several methods, including indoor residual spraying (irs), the use of long-lasting insecticidal nets (llin) and ecological vector management (evm). the financial costs of each of these three methods of sandfly control have recently been assessed and compared, in a multi-centre study based on the indian sub-continent. in each of the four study sites (two in nepal and one each in india and bang ...200819000390
antileishmanial constituents of the panamanian endophytic fungus edenia sp.bioassay-directed fractionation of extracts from the fermentation broth and mycelium of the fungus edenia sp. led tothe isolation of five antileishmanial compounds, preussomerin eg1 (1), palmarumycin cp2 (2), palmarumycin cp17 (3), palmarumycin cp18 (4), and cj-12,371 (5). compounds 3 and 4 are new natural products, and this is only the second report of compound 1. the structures of compounds 1-5 were established by spectroscopic analyses (hrms and nmr). all metabolites caused significant inhibi ...200819007286
acute erythroid toxicity in visceral leishmaniasis: a rare complication of antimonial therapy.the spectrum of side-effects of sodium stibogluconate is well described, however, little is known regarding the acute erythroid toxicity caused by this drug. we hereby present a case with this unusual complication of antimonial therapy. a 6-year-old male with leishmaniasis was started on parenteral sodium stibogluconate. during the course of treatment, his hemoglobin (hb) dropped from 7.2 g/dl to 3.5 g/dl. bone-marrow aspirate showed karyorrhexis in many erythroid precursors with several leishma ...200819008592
sandflies and sandfly-borne infections of humans in central europe in the light of climate change.in europe, sandflies (diptera: psychodidae: phlebotominae) are typical mediterranean faunal elements of low expansivity, which are widely distributed in more than 20 species in many parts of southern europe. a few species have extended their distribution to the northwest invading extramediterranean regions (western, eastern europe); any occurrence in central europe north of the alps was excluded until recently. since 1999 sandflies have been found in several parts in germany and in belgium; orig ...200819066768
antiparasitic, nematicidal and antifouling constituents from juniperus berries.a bioassay-guided fractionation of juniperus procera berries yielded antiparasitic, nematicidal and antifouling constituents, including a wide range of known abietane, pimarane and labdane diterpenes. among these, abieta-7,13-diene (1) demonstrated in vitro antimalarial activity against plasmodium falciparum d6 and w2 strains (ic(50) = 1.9 and 2.0 microg/ml, respectively), while totarol (6), ferruginol (7) and 7beta-hydroxyabieta-8,13-diene-11,12-dione (8) inhibited leishmania donovani promastig ...200819067375
diffuse cutaneous leishmaniasis associated with the immune reconstitution inflammatory syndrome.leishmaniasis is an emerging disease in hiv-infected persons; visceral leishmaniasis is an aids-defining opportunistic infection. the parasite that causes this infection is usually transmitted by the sandfly and occasionally by nonsterile needles among intravenous drug users. diffuse cutaneous leishmaniasis (dcl) is a rare anergic variant of leishmanial infection with the characteristic presentation of numerous nonulcerating nodules with an abundant parasite load, lack of visceral involvement, n ...200819126013
two cases of kala-azar in haryana with no evidence of local transmission. 200819127677
dual culture method to determine the relationship of gut bacteria of sandfly (phlebotomus argentipes) with promastigotes of leishmania donovani.a simple dual culture agar plating technique has been developed and evaluated for its efficiency in determining the relationship of gut bacteria of sandfly with leishmania donovani promastigotes. there are about twenty morphologically distinct bacterial colonies have been isolated from the gut homogenate of phlebotomus argentipes. in dual culture method, each bacterial isolate was inoculated in one half of the plate and the promastigotes of leishmania was inculcated in the other half by streakin ...200819301698
insights from the analysis of a predicted model of gp63 in leishmania donovani.leishmaniasis is a protozoal disease of human that occurs in most parts of the world. by considering the progress of bioinformatics in molecular modeling, major surface glycoprotein of leishmania donovani (gp63) structure was modeled using homology modeling with high accuracy based on the x-ray crystal structure of the leishmania major gp63 as a template, and then analyzed 3d structure of gp63 which can reveal exact facts about its structure and interaction. the objective of this study was to fi ...200819238247
clinical and laboratory comparison of different brands of amphotericin b used for the treatment of kala-azar: an observational study.the communication presents clinical response of cases of visceral leishmaniasis to treatment by two different brands of amphotericin b. fungizone was found to be slightly better than amphotericin b, however, the difference is not statistically significant.200819579720
bisphosphonate inhibition of a plasmodium farnesyl diphosphate synthase and a general method for predicting cell-based activity from enzyme data.we screened 26 bisphosphonates against a farnesyl diphosphate synthase from plasmodium vivax, finding a poor correlation between enzyme and cell growth inhibition (r(2) = 0.06). to better predict cell activity data, we then used a combinatorial descriptor search in which pic(50)(cell) = a pic(50)(enzyme) + bb + cc + d, where b and c are descriptors (such as slogp), and a-d are coefficients. r(2) increased from 0.01 to 0.74 (for a leave-two-out test set of 26 predictions). the method was then fur ...200819053772
leishmania-induced irak-1 inactivation is mediated by shp-1 interacting with an evolutionarily conserved ktim motif.parasites of the leishmania genus can rapidly alter several macrophage (mø) signalling pathways in order to tame down the innate immune response and inflammation, therefore favouring their survival and propagation within their mammalian host. having recently reported that leishmania and bacterial lps generate a significantly stronger inflammatory response in animals and phagocytes functionally deficient for the src homology 2 domain-containing protein tyrosine phosphatase (shp-1), we hypothesize ...200819104650
anti-leishmanial polyclonal antibodies to assess the performance characteristics of leishmanial antigen detection elisa.the polyclonal antibodies raised in rabbits against amastigote antigen extract were purified and fractionated, and igg class antibodies and from the same antibodies, a peroxidase conjugate (labeled antibodies) reagent were prepared. the antibodies and the labeled antibodies were analyzed for efficacy of the homologous extracted antigens by capture elisa. the titration curves of the anti-amastigote igg antibody against extracted antigens showed that both free antibody and corresponding labeled an ...200819209783
proteomic approaches for discovery of new targets for vaccine and therapeutics against visceral leishmaniasis.visceral leishmaniasis (vl) is the most devastating type caused by leishmania donovani, leishmania infantum, and leishmania chagasi. the therapeutic mainstay is still based on the antiquated pentavalent antimonial against which resistance is now increasing. unfortunately, due to the digenetic life cycle of parasite, there is significant antigenic diversity. there is an urgent need to develop novel drug/vaccine targets against vl for which the primary goal should be to identify and characterize t ...200821136840
erythrocyte glutathione status in human visceral leishmaniasis.a glutathione redox cycle is a major antioxidant defense system for the detoxification of reactive oxygen species within erythrocytes. reactive oxygen species such as superoxide anions, hydrogen peroxide and hydroxyl radicals are generated as a host defense mechanism for killing of engulfed leishmania donovani, a causative agent of visceral leishmaniasis, are capable of damaging lipids and other biomolecules when produced in excess. erythrocytes are most vulnerable to reactive oxygen species. in ...200823105731
inhibition of growth of leishmania donovani promastigotes by newly synthesized 1,3,4-thiadiazole analogs.leishmania donovani, the causative agent of visceral leishmaniasis, is transmitted by sand flies and replicates intracellularly in their mammalian host cells. the emergence of drug-resistant strains has hampered efforts to control the spread of the disease worldwide. forty-four 1,3,4-thiadiazole derivatives and related compounds were tested in vitro for possible anti-leishmanial activity against the promastigotes of l. donovani. micromolar concentrations of these agents were used to study the in ...200923964165
a localized foci of kala-azar in a village of chandi phc (nalnda district). 200922010490
antiplasmodial, anti-trypanosomal, anti-leishmanial and cytotoxicity activity of selected tanzanian medicinal plants.the antiplasmodial, anti-trypanosomal and anti-leishmanial activity of 25 plant extracts obtained from seven tanzanian medicinal plants: annickia (enantia) kummeriae (annonaceae), artemisia annua (asteraceae), pseudospondias microcarpa (anacardiaceae), drypetes natalensis (euphorbiaceae), acridocarpus chloropterus (malpighiaceae), maytenus senegalensis (celastraceae) and neurautanenia mitis (papilonaceae), were evaluated in vitro against plasmodium falciparum k1, trypanosoma brucei rhodesiense s ...200920734703
simple data-reduction method for high-resolution lc-ms data in metabolomics.metabolomics lc-ms experiments yield large numbers of peaks, few of which can be identified by database matching. many of the remaining peaks correspond to derivatives of identified peaks (e.g., isotope peaks, adducts, fragments and multiply charged molecules). in this article, we present a data-reduction approach that automatically identifies these derivative peaks.200921083103
characterization of plasma membrane bound inorganic pyrophosphatase from leishmania donovani promastigotes and amastigotes.currently, a major problem in the management of visceral leishmaniasis or kala-azar, especially in the indian subcontinent, is the growing unresponsiveness to conventional antimonial therapy. membrane bound pyrophophatase (ppases) do not exist in plasma membrane from mammals. thus, h(+)-ppases from leishmania plasma membrane might be potential target in rational chemotherapy of the disease caused by leishmania parasites.200921503171
uptake of biodegradable gel-assisted lbl nanomatrix by leishmania donovani-infected macrophages.the aim of this study was to develop novel gel-assisted layer-by-layer (lbl) nanomatrix with high payload of doxorubicin (dox) and to assess its efficacy against leishmania donovani. the biodegradable lbl nanomatrix was fabricated using lbl technique using polyions (protamine and sodium alginate) on decomposable core. the developed system was characterized in vitro in terms of layer-by-layer growth and payload efficiency. the efficacy of optimized formulations was evaluated against l. donovani s ...200919904614
structure of cyclophilin from leishmania donovani bound to cyclosporin at 2.6 a resolution: correlation between structure and thermodynamic data.drug development against leishmania donovani, the pathogen that causes visceral leishmaniasis in humans, is currently an active area of research given the widespread prevalence of the disease and the emergence of resistant strains. the immunosuppressive drug cyclosporin is known to have antiparasitic activity against a variety of pathogens. the receptor for cyclosporin is the protein cyclophilin, which is a ubiquitous peptidylprolyl isomerase. the crystal structure of cyclophilin from l. donovan ...200919923714
dendritic cells matured by inflammation induce cd86-dependent priming of naive cd8+ t cells in the absence of their cognate peptide antigen.dendritic cells (dc) licensed by the interaction between pathogen products and pattern recognition receptors can activate naive t cells to undergo ag-dependent proliferation and cytokine production. in contrast, dc induced to mature by trans-acting inflammatory stimuli are believed to only be capable of supporting ag-dependent proliferative responses. in this study, we show that uninfected dc matured as a consequence of leishmania-induced inflammation induce cd8(+) t cells to proliferate in the ...200919917700
ubiquitin conjugation of open reading frame f dna vaccine leads to enhanced cell-mediated immune response and induces protection against both antimony-susceptible and -resistant strains of leishmania donovani.resistance of leishmania donovani to sodium antimony gluconate has become a critical issue in the current, prolonged epidemic in india. hence, there is an urgent need for a vaccine that is protective against both antimony-susceptible and -resistant strains of l. donovani. the multigene ld1 locus located on chromosome 35 of leishmania is amplified in approximately 15% of the isolates examined. the open reading frame f (orff), a potential vaccine candidate against visceral leishmaniasis, is part o ...200919933862
immunogenicity and efficacy of single antigen gp63, polytope and polytopehsp70 dna vaccines against visceral leishmaniasis in experimental mouse model.polytope approach of genetic immunization is a promising strategy for the prevention of infectious disease as it is capable of generating effective cell mediated immunity by delivering the t cell epitopes assembled in series. leishmaniasis is a significant world wide health problem for which no vaccine exists. in this study we have compared immunogenicity and efficacy of three types of dna vaccines: single antigen gp63 (gp63/pcdna), polytope (poly/pcdna) and polytope fused with hsp70 (poly/hsp/p ...200919956549
membrane bound pyrophosphatase and p-type adenosine triphosphatase of leishmania donovani as possible chemotherapeutic targets: similarities and differences in inhibitor sensitivities.the activities of inorganic pyrophosphatase (ppase) and adenosine triphosphatase (atpase) were studied in the plasma membrane of leishmania donovani promastigotes and amastigotes. it was shown that the specific activity of ppase was greater than that of atpase in the promastigote plasma membrane. we characterized h+-ppase present in the plasma membrane of l. donovani and investigated its possible role in the survival of promastigote and amastigote. ppase activity was stimulated by k+ and sodium ...200919961421
[virulence-associated gene profiling of different leishmania spp].to investigate the expression level of virulence-associated genes in promastigotes and amastigotes of different leishmania spp.200920066984
visceral leishmaniasis in aba-roba, south-western ethiopia: prevalence and incidence of active and subclinical infections.between august 1997 and february 2005, a prospective study of human visceral leishmaniasis (vl) was undertaken in two villages in the konso district of south-western ethiopia, to provide epidemiological indices of subclinical infection and active vl. six cross-sectional surveys at 6-month intervals (ending in august 2000) were complemented by a single survey in february 2005. the prevalences and incidences of leishmanial infection and active vl, which were determined using leishmanin skin tests ...200920030990
germatranyl substituted organotin (iv) carboxylates: synthesis spectroscopic characterization and biological activities.eight new organotin (iv) derivatives of general formula [n(ch2ch2o)3gech(r1)ch2coo](4-n)snr(2)n, where n= 2, r(2) = c2h5 (1-5); r(1) = ch3 (1); c6h5 (2); p-ch3c6h4 (3); p-fc6h4(4); p-ch3oc6h4 (5) and n = 3, r(2) = ch2c6h5 (6-8), r(1) = ch3 (6); c6h5 (7); p-ch3c6h4 (8) have been synthesized by the reaction of di- or tri-organotin chloride with the corresponding germatranyl (substituted) propionic acid in the appropriate mole ratios using triethylamine as a base. the synthesized compounds were cha ...200920041833
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