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leishmanicidal compounds from the fruits of piper longum.one new alkaloid amide, piperlongumide (1) [n-isobutyl-19-(3',4'-methylenedioxyphenyl)-2e,4e nonadecadienamide], and six known compounds with leishmanicidal activity against promastigotes and axenic amastigotes of leishmania donovani were isolated from the n-hexane fraction of the fruits of piper longum. the structure of 1 was elucidated by spectroscopic evidences.201222576441
a highly basic sequence at the n-terminal region is essential for targeting the dna replication protein orc1 to the nucleus in leishmania donovani.the conserved eukaryotic dna replication protein orc1 is one of the constituents of pre-replication complexes that assemble at or very near origins prior to replication initiation. orc1 has been shown to be constitutively nuclear in leishmania major. this study investigates the sequences involved in nuclear localization of orc1 in leishmania donovani, the causative agent of visceral leishmaniasis. nuclear localization signals (nlss) have been reported in only a few leishmania proteins. functiona ...201222575896
evaluation of nephroprotective and immunomodulatory activities of antioxidants in combination with cisplatin against murine visceral leishmaniasis.most available drugs against visceral leishmaniasis are toxic, and growing limitations in available chemotherapeutic strategies due to emerging resistant strains and lack of an effective vaccine against visceral leishmaniasis deepens the crisis. antineoplastic drugs like miltefosine have in the past been effective against the parasitic infections. an antineoplastic drug, cisplatin (cis-diamminedichloroplatinum ii; cddp), is recognized as a dna-damaging drug which also induces alteration of cell- ...201222563510
comparison of electrospray ionization, atmospheric pressure chemical ionization and atmospheric pressure photoionization for a lipidomic analysis of leishmania donovani.a comparison of electrospray ionization (esi), atmospheric pressure chemical ionization (apci) and atmospheric pressure photoionization (appi) for the analysis of a wide range of lipids has been performed on standard mixtures and extracts of leishmania donovani promastigotes resistant to amphotericin b (amb). calibration model, precision, limits of detection and quantification (lod and loq) were assessed for each source. appi provided the highest signal, signal-to-noise (s/n), and sensitivity fo ...201222560453
novel 3-nitro-1h-1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents.a series of novel 3-nitro-1h-1,2,4-triazole-based (and in some cases 2-nitro-1h-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. out of 36 compounds tested, 29 (mostly 3-nitro-1h-1,2,4-triazoles) displayed significant activity against trypanosoma cruzi intracellular amastigotes (ic(50) ranging from 28 nm to 3.72 μm) without concomitant toxicity to l6 host cells (selectivity 66-2782). twen ...201222550999
selective inhibitors of protozoan protein n-myristoyltransferases as starting points for tropical disease medicinal chemistry programs.inhibition of n-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. in order to identify inhibitors of protozoan nmts, we chose to screen a diverse subset of the pfizer corporate collection against plasmodium falciparum and leishmania donovani nmts. primary screening hits against either enzyme were tested for selectivity over both human nmt isoforms (hs1 and hs2) and for broad-spectrum anti- ...201222545171
enhanced leishmanicidal activity of cryptopeptide chimeras from the active n1 domain of bovine lactoferrin.two antimicrobial cryptopeptides from the n1 domain of bovine lactoferrin, lactoferricin (lfcin17-30) and lactoferrampin (lfampin265-284), together with a hybrid version (lfchimera), were tested against the protozoan parasite leishmania. all peptides were leishmanicidal against leishmania donovani promastigotes, and lfchimera showed a significantly higher activity over its two composing moieties. besides, it was the only peptide active on leishmania pifanoi axenic amastigotes, already showing ac ...201222543751
evaluation of leishmania donovani protein disulfide isomerase as a potential immunogenic protein/vaccine candidate against visceral leishmaniasis.in leishmania species, protein disulfide isomerase (pdi)--a redox chaperone, is reported to be involved in its virulence and survival. this protein has also been identified, through proteomics, as a th1 stimulatory protein in the soluble lysate of a clinical isolate of leishmania donovani (ldpdi). in the present study, the molecular characterization of ldpdi was carried out and the immunogenicity of recombinant ldpdi (rldpdi) was assessed by lymphocyte proliferation assay (ltt), nitric oxide (no ...201222539989
a proteogenomic approach to map the proteome of an unsequenced pathogen - leishmania donovani.visceral leishmaniasis or kala azar is the most severe form of leishmaniasis and is caused by the protozoan parasite leishmania donovani. there is no published report on l. donovani genome sequence available till date, although the genome sequences of three related leishmania species are already available. thus, we took a proteogenomic approach to identify proteins from two different life stages of l. donovani. from our analysis of the promastigote (insect) and amastigote (human) stages of l. do ...201222539434
antiprotozoal and antimicrobial compounds from the plant pathogen septoria pistaciarum.four new 1,4-dihydroxy-5-phenyl-2-pyridinone alkaloids, 17-hydroxy-n-(o-methyl)septoriamycin a (1), 17-acetoxy-n-(o-methyl)septoriamycin a (2), 13-(s)-hydroxy-n-(o-methyl)septoriamycin a (3), and 13-(r)-hydroxy-n-(o-methyl)septoriamycin a (4), together with the known compounds (+)-cercosporin (5), (+)-14-o-acetylcercosporin (6), (+)-di-o-acetylcercosporin (7), lumichrome, and brassicasterol, were isolated from an ethyl acetate extract of a culture medium of septoria pistaciarum. methylation of s ...201222530813
leishmania-induced biphasic ceramide generation in macrophages is crucial for uptake and survival of the parasite.the initial macrophage-leishmania donovani interaction results in the formation of membrane platforms, termed lipid rafts, that help in the entry of the parasite. therefore, it is imperative that the parasite designs a strategy to modulate its uptake and survival within the macrophages. herein, we report leishmania-triggered biphasic ceramide generation. in the first phase, l. donovani promastigotes induce activation of acid sphingomyelinase (asmase), which catalyzes the formation of ceramide fr ...201222517914
the efficacy of aerosol treatment with non-ionic surfactant vesicles containing amphotericin b in rodent models of leishmaniasis and pulmonary aspergillosis infection.amphotericin b (amb) is used to treat both fungal and leishmanial infections, which are of major significance to human health. clinical use of free amb is limited by its nephrotoxicity, whereas liposomal amb is costly and requires parenteral administration, thus development of novel formulations with enhanced efficacy, minimal toxicity and that can be applied via non-invasive routes is required. in this study we analysed the potential of non-ionic surfactant vesicles (niv) given by nebulisation ...201222516093
a morphologically distinct phlebotomus argentipes population from active cutaneous leishmaniasis foci in central sri lanka.although the reported aetiological agent of cutaneous leishmaniasis (cl) in sri lanka is leishmania donovani, the sandfly vector remains unknown. ninety-five sandflies, 60 females and 35 males, collected in six localities in the district of matale, central sri lanka, close to current active transmission foci of cl were examined for taxonomically relevant characteristics. eleven diagnostic morphological characters for female sandflies were compared with measurements described for indian and sri l ...201222510837
a novel recombinant leishmania donovani p45, a partial coding region of methionine aminopeptidase, generates protective immunity by inducing a th1 stimulatory response against experimental visceral leishmaniasis.the development of a vaccine against visceral leishmaniasis (vl) conferring long-lasting immunity remains a challenge. identification and proteomic characterization of parasite proteins led to the detection of p45, a member of the methionine aminopeptidase family. to our knowledge the present study is the first known report that describes the molecular and immunological characterization of p45. recombinant leishmania donovani p45 (rldp45) induced cellular responses in cured hamsters and generate ...201222502587
overexpression of s4d mutant of leishmania donovani adf/cofilin impairs flagellum assembly by affecting actin dynamics.leishmania, like other eukaryotes, contains large amounts of actin and a number of actin-related and actin binding proteins. our earlier studies have shown that deletion of the gene corresponding to leishmania actin-depolymerizing protein (adf/cofilin) adversely affects flagellum assembly, intracellular trafficking, and cell division. to further analyze this, we have now created adf/cofilin site-specific point mutants and then examined (i) the actin-depolymerizing, g-actin binding, and actin-bou ...201222492507
identification and characterization of a novel leishmania donovani antigen for serodiagnosis of visceral leishmaniasis.despite several drawbacks, rk39-based rapid immunochromatographic test is widely used for the diagnosis of visceral leishmaniasis (vl) in the indian subcontinent. there is an urgent need to develop a better antigen. in this study we separated crude soluble antigens of leishmania donovani by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and hybridized with pool sera from pre- and post-treated vl patients, 6 months follow-up, endemic healthy (ehc), and nonendemic healthy controls (nehc ...201222492143
amino acid, dipeptide and pseudodipeptide conjugates of ring-substituted 8-aminoquinolines: synthesis and evaluation of anti-infective, β-haematin inhibition and cytotoxic activities.three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. the synthesized compounds were tested for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant plasmodium falciparum strains, in vitro cytotoxicity in mammalian kidney cells (vero), in vitro antileishmanial activity against leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of ...201222483965
b cell: t cell interactions occur within hepatic granulomas during experimental visceral leishmaniasis.hepatic resistance to leishmania donovani infection in mice is associated with the development of granulomas, in which a variety of lymphoid and non-lymphoid populations accumulate. although previous studies have identified b cells in hepatic granulomas and functional studies in b cell-deficient mice have suggested a role for b cells in the control of experimental visceral leishmaniasis, little is known about the behaviour of b cells in the granuloma microenvironment. here, we first compared the ...201222479545
synthesis and antikinetoplastid activities of 3-substituted quinolinones derivatives.a new family of quinolinone derivatives has been synthesized and evaluated for their antikinetoplastid activities against leishmania donovani and trypanosoma brucei brucei. results from these structure-activity relationship studies enabled identification of compounds 3a and 4g as the most active compounds against l. donovani promastigotes and amastigotes parasites (ic(50) values in a range of 2-11 μm). additionally, compound 3b has emerged from this study as the most active compound in the serie ...201222472166
terpenoidal constituents of eucalyptus loxophleba ssp. lissophloia.eucalyptus has been a source of a number of biologically active compounds. the anti-leishmanial activity of terpenoids from eucalyptus loxophleba (benth.) ssp. lissophloia (myrtaceae) has not yet been investigated.201222468852
invariant nkt cells drive hepatic cytokinic microenvironment favoring efficient granuloma formation and early control of leishmania donovani infection.the development of inflammatory granulomas around infected kupffer cells is necessary for hepatic parasite clearance during visceral leishmaniasis. invariant nkt (inkt) cells are predominant t cells in the mouse liver and can synthesize large quantities of il-4 and ifn-γ, two cytokines involved in granuloma formation. this study analyzed the role of inkt cells in the hepatic immune response during leishmania donovani infection, using a murine model of wild-type (wt) and inkt cell-deficient (jα18 ...201222457760
peroxisome proliferator-activated receptor-γ-mediated polarization of macrophages in leishmania infection.infection is the outcome of a contest between a pathogen and its host. in the disease leishmaniasis, the causative protozoan parasites are harbored inside the macrophages. leishmania species adapt strategies to make the infection chronic, keeping a balance between their own and the host's defense so as to establish an environment that is favorable for survival and propagation. activation of peroxisome proliferator-activated receptor (ppar) is one of the tactics used. this ligand-activated nuclea ...201222448168
therapeutic immunization with radio-attenuated leishmania parasites through i.m. route revealed protection against the experimental murine visceral leishmaniasis.after our promising results from prophylactic and therapeutic study (i.p. route) with the radio-attenuated leishmania donovani parasites against experimental murine visceral leishmaniasis, we prompted to check their therapeutic efficacy through i.m route. balb/c mice were infected with highly virulent l. donovani parasites. after 75 days, mice were treated with gamma (γ)-irradiated parasites. a second therapeutic immunization was given after 15 days of first immunization. the protection against ...201222437790
marginal zone b cells regulate antigen-specific t cell responses during infection.marginal zone b cells (mzb) participate in the early immune response to several pathogens. in this study, we show that in μmt mice infected with leishmania donovani, cd8 t cells displayed a greater cytotoxic potential and generated more effector memory cells compared with infected wild type mice. the frequency of parasite-specific, ifn-γ(+) cd4 t cells was also increased in μmt mice. b cells were able to capture parasites, which was associated with upregulation of surface igm and myd88-dependent ...201222412197
differential peptide binding to cd40 evokes counteractive responses.the antigen-presenting cell–expressed cd40 is implied in the regulation of counteractive immune responses such as induction of pro-inflammatory and anti-inflammatory cytokines interleukin (il)–12 and il-10, respectively. the mechanism of this duality in cd40 function remains unknown. here, we investigated whether such duality depends on ligand binding. based on cd40 binding, we identifed two dodecameric peptides, peptide-7 and peptide-19, from the phage peptide library. peptide-7 induces il-10 a ...201222406255
preparation and antiprotozoal evaluation of promising β-carboline alkaloids.the synthesis of β-carbolines and their in vitro antiplasmodial and antileishmanial activities were described herein. these molecules have also been studied concerning their in vitro cytotoxicity toward the human cell line thp1, in order to calculate their respective selectivity indexes (si). among the 20 tested molecules, four exhibited significant antiplasmodial activity on the w2 multi-resistant plasmodium falciparum strain (0.7 < ic₅₀ < 1.7 μm), in comparison with two references drugs (chlor ...201222397756
molecular docking and in vitro antileishmanial evaluation of chromene-2-thione analogues.leishmaniases are an epidemic in various countries, and the parasite is developing resistance against available drugs. thus, development of new drugs against leishmania is an open area of investigation for synthetic organic chemists. to meet this challenge, a series of chromene-2-thione derivatives have been synthesized and docked into the active site of trypanothione reductase (tryr) enzyme required for redox balance of the parasite. these were screened on promastigote, axenic amastigote, and i ...201224936236
augmentation of antileishmanial efficacy of miltefosine in combination with tuftsin against experimental visceral leishmaniasis.current drugs for the treatment of visceral leishmaniasis are inadequate, and their efficacies are also compromised due to suppression of immune function during the course of infection. miltefosine is the only promising orally active antileishmanial drug, but due to its long half-life, there is risk of development of resistance. to overcome these problems, efforts are needed to develop combination therapy of miltefosine with effective immunostimulating agents where a decrease of parasitic burden ...201222392136
regulation and spatial organization of pcna in trypanosoma brucei.as in most eukaryotic cells, replication is regulated by a conserved group of proteins in the early-diverged parasite trypanosoma brucei. only a few components of the replication machinery have been described in this parasite and regulation, sub-nuclear localization and timing of replication are not well understood. we characterized the proliferating cell nuclear antigen in t. brucei (tbpcna) to establish a spatial and temporal marker for replication. interestingly, pcna distribution and regulat ...201222387477
safety and skin delayed-type hypersensitivity response in vervet monkeys immunized with leishmania donovani sonicate antigen delivered with adjuvants.in this study, we report on the safety and skin delayed-type hypersensitivity (dth), responses of the leishmania donovani whole cell sonicate antigen delivered in conjunction with alum-bcg (albcg), montanide isa 720 (misa) or monophosphoryl lipid a (mpla) in groups of vervet monkeys. following three intradermal injections of the inoculums on days 0, 28 and 42, safety and dth responses were assessed. preliminary tumor necrosis factor alpha (tnf-α) and interferon gamma (ifn-γ) levels were also mea ...201222370752
genetic dissection of pyrimidine biosynthesis and salvage in leishmania donovani.protozoan parasites of the leishmania genus express the metabolic machinery to synthesize pyrimidine nucleotides via both de novo and salvage pathways. to evaluate the relative contributions of pyrimidine biosynthesis and salvage to pyrimidine homeostasis in both life cycle stages of leishmania donovani, individual mutant lines deficient in either carbamoyl phosphate synthetase (cps), the first enzyme in pyrimidine biosynthesis, uracil phosphoribosyltransferase (uprt), a salvage enzyme, or both ...201222367196
miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: role of tlr4 and tlr9.visceral leishmaniasis (vl) caused by the protozoan parasite, leishmania donovani, is associated with irregular fever, weight loss, hepatosplenomegaly and anemia. the therapeutic arsenal against vl is limited and the recent advent of a novel immunomodulatory drug, miltefosine has shown promising results for effective treatment of vl but its dependence on toll like receptors (tlr) has not been explored. in this study, we have shown that the non-cytotoxic dose (5 μm) of miltefosine could render si ...201222361489
synthesis, biological evaluation, and structure-activity relationships of n-benzoyl-2-hydroxybenzamides as agents active against p. falciparum (k1 strain), trypanosomes, and leishmania.in our efforts to identify novel chemical scaffolds for the development of new antiprotozoal drugs, a compound library was screened against toxoplasma gondii tachyzoites with activity discovered for n-(4-ethylbenzoyl)-2-hydroxybenzamide 1a against t. gondii as described elsewhere. synthesis of a compound set was guided by t. gondii sar with 1r found to be superior for t. gondii , also active against thai and sierra leone strains of plasmodium falciparum , and with superior admet properties as de ...201222352841
leishmania donovani mitochondrial iron superoxide dismutase a is released into the cytosol during miltefosine induced programmed cell death.the oxidative phosphorylation process is the main source of endogenous reactive oxygen species (ros) such as superoxide in mitochondria. in mammals, manganese superoxide dismutase plays an important role in detoxification of superoxide before it interferes with mitochondrial function and causes programmed cell death. here, we investigated the role of leishmania donovani mitochondrial iron superoxide dismutase-a (ldfesoda) in protecting the parasite from oxidative stress and in the control of pro ...201222342963
cloning, overexpression and characterization of leishmania donovani triosephosphate isomerase.triosephosphate isomerase (tim) is a major enzyme in the glycolytic pathway, which catalyzes the interconversion of glyceraldehyde 3-phosphate to dihydroxyacetone phosphate. here, we report cloning, expression and purification of a catalytically active recombinant tim of leishmania donovani (ldtim). the recombinant ldtim had a ph optimum in the range of 7.2-9.0, found stable at 25°c for 30 min and k(m) and v(max) for the substrate glyceraldehyde 3-phosphate was 0.328±0.02mm and 10.05mm/min/mg, r ...201222342510
coibanoles, a new class of meroterpenoids produced by pycnoporus sanguineus.three new terpenoids of mixed biosynthetic origin were isolated from the culture filtrate of the endophytic fungus pycnoporus sanguineus. their structures were determined by extensive spectroscopic analyses. we have named these tricyclic and tetracyclic metabolites 'coibanoles a-c' in reference to coiba island and coiba national park, panamá, from which the plant and endophyte were collected. the extract was inactive to the human parasites trypanosoma cruzi, leishmania donovani, and plasmodium f ...201225177062
comparative modeling of hgprt enzyme of l. donovani and binding affinities of different analogs of gmp.hypoxanthine-guanine phosphoribosyl transferase (hgprt; ec 2.4.2.8) is a central enzyme in the purine recycling pathway. parasitic protozoa (leishmania donovani) cannot synthesize purines de novo and utilize the salvage pathway to produce purine bases. thus, this enzyme is targeted in drug discovery and development. the model of the monomeric l. donovani hgprt showed that this enzyme is an α/β type protein with a prtase type i folding pattern. among all of the computationally screened compounds, ...201222327112
identification of novel s-adenosyl-l-homocysteine hydrolase inhibitors through homology-model-based virtual screening, synthesis, and biological evaluation.the present study describes a successful application of computational approaches to identify novel leishmania donovani (ld) adohcyase inhibitors utilizing the differences for ld adohcyase nad(+) binding between human and ld parasite. the development and validation of the three-dimensional (3d) structures of ld adohcyase using the l. major adohcyase as template has been carried out. at the same time, cloning of the ld adohcyase gene from clinical strains, its overexpression and purification have ...201222324915
comparative study of rk39 leishmania antigen for serodiagnosis of visceral leishmaniasis: systematic review with meta-analysis.the rk39 recombinant protein is derived from a specific antigen produced by the leishmania donovani complex, and has been used in the last two decades for the serodiagnosis of visceral leishmaniasis. we present here a systematic review and meta-analysis of studies evaluating serologic assays to diagnose visceral leishmaniasis to determine the accuracy of rk39 antigen in comparison to the use of other antigen preparations.201222303488
biomarkers of antimony resistance: need for expression analysis of multiple genes to distinguish resistance phenotype in clinical isolates of leishmania donovani.resistance to antimony is a major cause of failure to therapy in a large proportion of visceral leishmaniasis cases. methods to distinguish resistant and sensitive parasite are urgently needed as the standard in vitro intracellular drug susceptibility assays are cumbersome and time consuming. differential expression profiling studies have led to the identification of several antimony resistance-associated genes; however, their efficacy as a potential biomarker for monitoring antimony resistance ...201222302478
therapeutic vaccination with recombinant adenovirus reduces splenic parasite burden in experimental visceral leishmaniasis.therapeutic vaccines, when used alone or in combination therapy with antileishmanial drugs, may have an important place in the control of a variety of forms of human leishmaniasis. here, we describe the development of an adenovirus-based vaccine (ad5-kh) comprising a synthetic haspb gene linked to a kmp11 gene via a viral 2a sequence. in nonvaccinated leishmania donovani-infected balb/c mice, haspb- and kmp11-specific cd8(+) t cell responses were undetectable, although igg1 and igg2a antibodies ...201222301630
the anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis.safer and more effective oral drugs are required to treat visceral leishmaniasis, a parasitic disease that kills 50,000 to 60,000 people each year in parts of asia, africa, and latin america. here, we report that fexinidazole, a drug currently in phase 1 clinical trials for treating african trypanosomiasis, shows promise for treating visceral leishmaniasis. this 2-substituted 5-nitroimidazole drug is rapidly oxidized in vivo in mice, dogs, and humans to sulfoxide and sulfone metabolites. both me ...201222301556
antileishmanial activity of cryptolepine analogues and apoptotic effects of 2,7-dibromocryptolepine against leishmania donovani promastigotes.cryptolepine (5-methyl-10h-indolo [3, 2-b] quinoline), an indoloquinoline alkaloid (1) isolated from a medicinal plant traditionally used in western africa for treatment of malaria, has been shown to possess broad spectrum biological activity in addition to its antiplasmodial effect. here, the antileishmanial properties of 11 synthetic derivatives of cryptolepine against leishmania donovani parasites have been evaluated for the first time. 2,7-dibromocryptolepine (8; ic50 0.5 ± 0.1 μm) was found ...201222297912
leishmania donovani: immunostimulatory cellular responses of membrane and soluble protein fractions of splenic amastigotes in cured patient and hamsters.visceral leishmaniasis (vl), caused by the intracellular parasite leishmania donovani, l. chagasi and l. infantum is characterized by defective cell-mediated immunity (cmi) and is usually fatal if not treated properly. an estimated 350 million people worldwide are at risk of acquiring infection with leishmania parasites with approximately 500,000 cases of vl being reported each year. in the absence of an efficient and cost-effective antileishmanial drug, development of an appropriate long-lastin ...201222292030
synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photo-dimers.previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines a and b to be modest growth inhibitors of mycobacterium tuberculosis and a range of tropical diseases including plasmodium falciparum and leishmania donovani. in an effort to expand the structure-activity relationship of this compound class towards infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalyticall ...201222285027
asiaticoside induces tumour-necrosis-factor-α-mediated nitric oxide production to cure experimental visceral leishmaniasis caused by antimony-susceptible and -resistant leishmania donovani strains.the aim of this study was to investigate and characterize the efficacy of asiaticoside in an experimental model of visceral leishmaniasis caused by antimony-susceptible (ag83) and -resistant (ge1f8r and k39) leishmania donovani.201222258930
leishmania donovani whole cell antigen delivered with adjuvants protects against visceral leishmaniasis in vervet monkeys (chlorocebus aethiops).in a previous immunogenicity and efficacy study in mice, montanide isa 720 (misa) was indicated to be a better adjuvant than bacillus calmette guerin vaccine (bcg) for a leishmania vaccine. in the present study, we report the safety, immunogenicity and efficacy of leishmania donovani (l. donovani) sonicated antigen delivered with alum-bcg (albcg), misa or monophosphoryl lipid a (mpla) in vervet monkeys following intradermal inoculums. vaccinated and control animals were challenged with virulent ...201223554725
combination of paromomycin and miltefosine promotes tlr4-dependent induction of antileishmanial immune response in vitro.to evaluate the in vitro activity of antileishmanial drugs, paromomycin and miltefosine, to generate th-1-biased immunomodulation in hosts against intracellular leishmania donovani.201222761329
genetic markers for ssg resistance in leishmania donovani and ssg treatment failure in visceral leishmaniasis patients of the indian subcontinent.the current standard to assess pentavalent antimonial (ssg) susceptibility of leishmania is a laborious in vitro assay of which the result has little clinical value because ssg-resistant parasites are also found in ssg-cured patients. candidate genetic markers for clinically relevant ssg-resistant parasites identified by full genome sequencing were here validated on a larger set of clinical strains. we show that 3 genomic locations suffice to specifically detect the ssg-resistant parasites found ...201222753945
genetic typing reveals monomorphism between antimony sensitive and resistant leishmania donovani isolates from visceral leishmaniasis or post kala-azar dermal leishmaniasis cases in india.resistance to pentavalent antimonials has emerged as a major hurdle to the treatment and control of visceral leishmaniasis (vl), also known as kala-azar (ka), caused by leishmania donovani. in india, over 60% of ka patients are unresponsive to the first-line drug sodium antimony gluconate (sag). resistance determinants in laboratory strains are partly known; however, the mechanism operating in field isolates is not well understood. in this study, we attempted to analyze the genetic polymorphism ...201222752721
leishmania donovani pteridine reductase 1: comparative protein modeling and protein-ligand interaction studies of the leishmanicidal constituents isolated from the fruits of piper longum.visceral leishmaniasis or kala-azar is caused by the dimorphic parasite leishmania donovani in the indian subcontinent. treatment options for kala-azar are currently inadequate due to various limitations. currently, drug discovery for leishmaniases is oriented towards rational drug design; the aim is to identify specific inhibitors that target particular metabolic activities as a possible means of controlling the parasites without affecting the host. leishmania salvages pteridin from its host an ...201222752544
evidence for involvement of th17 type responses in post kala azar dermal leishmaniasis (pkdl).post kala-azar dermal leishmaniasis (pkdl), a dermal sequel of visceral leishmaniasis, caused by leishmania donovani, constitutes an important reservoir for the parasite. parallel functioning of counter acting immune responses (th1/th2) reflects a complex immunological scenario, suggesting the involvement of additional regulatory molecules in the disease pathogenesis.201222724038
an image-based high-content screening assay for compounds targeting intracellular leishmania donovani amastigotes in human macrophages.leishmaniasis is a tropical disease threatening 350 million people from endemic regions. the available drugs for treatment are inadequate, with limitations such as serious side effects, parasite resistance or high cost. driven by this need for new drugs, we developed a high-content, high-throughput image-based screening assay targeting the intracellular amastigote stage of different species of leishmania in infected human macrophages. the in vitro infection protocol was adapted to a 384-well-pla ...201222720099
frequency of visceral leishmaniasis in abbottabad from 2005 to 2009.leishmaniasis is a parasitic disease caused by a haemoflagellate leishmania, transmitted to humans through bites of female sand fly. the objective of this study was to assess the frequency of leishmaniasis in abbottabad and nearby areas including villages of nawanshehr, dhodial, gamavan, sheikhulbandi, kakul and malikpura.201222338418
[kala azar - lethal course of visceral leishmaniasis. synchronous infection with leishmania donovani/infantum complex and leishmania major in a patient after mediterranean vacation].infections with leishmania spp. are endemic in areas of the tropics and subtropics. an increased incidence of human infections has been reported in southern europe, where zoonotic leishmaniasis is common. the systemic, visceral infection is caused by the leishmania donovani/infantum complex and may be fatal when untreated.201223064668
efficacy and tolerability of oleylphosphocholine (olpc) in a laboratory model of visceral leishmaniasis.the alkylphospholipid oleylphosphocholine (olpc) is a structural analogue of miltefosine and may represent a potential therapeutic backup for the treatment of visceral leishmaniasis (vl). this laboratory study compared the in vitro and in vivo activity profile of both olpc and miltefosine.201222782488
immunopathogenesis of non-healing american cutaneous leishmaniasis and progressive visceral leishmaniasis.the outcomes of leishmania infection are determined by host immune and nutrition status, parasite species, and co-infection with other pathogens. while subclinical infection and self-healing cutaneous leishmaniasis (cl) are common, uncontrolled parasite replication can lead to non-healing local lesions or visceral leishmaniasis (vl). it is known that infection control requires th1-differentiation cytokines (il-12, il-18, and il-27) and th1 cell and macrophage activation. however, there is no gen ...201223053396
synthesis, dna binding and antileishmanial activity of low molecular weight bis-arylimidamides.the effects of reducing the molecular weight of the antileishmanial compound db766 on dna binding affinity, antileishmanial activity and cytotoxicity are reported. the bis-arylimidamides were prepared by the coupling of aryl s-(2-naphthylmethyl)thioimidates with the corresponding amines. specifically, we have prepared new series of bis-arylimidamides which include 3a, 3b, 6, 9a, 9b, 9c, 13, and 18. three compounds 9a, 9c, and 18 bind to dna with similar or moderately lower affinity to that of db ...201222840696
subclinical leishmaniasis associated with infertility and chronic prostatitis in a dog.a stud dog was presented for acquired infertility. haematospermia and teratozoospermia were found on two ejaculates 2 weeks apart. a presumptive diagnosis of prostatitis was made follo-wing ultrasound examination. an ultrasound-guided needle core biopsy was performed under general anaesthesia, revealing a mild chronic macrophagic and plasma cell prostatitis with intracytoplasmic amastigotes consistent with leishmania spp. infection. presence of leishmania infantum, leishmania donovani or leishma ...201222690941
antimicrobial metabolites from the paracel islands sponge agelas mauritiana.four new alkaloids, (-)-8'-oxo-agelasine d (2), ageloxime b (3), (+)-2-oxo-agelasidine c (4), and 4-bromo-n-(butoxymethyl)-1h-pyrrole-2-carboxamide (5), and the known compound (-)-ageloxime d (1) were isolated from the marine sponge agelas mauritiana. their chemical structures were established on the basis of spectroscopic analysis. compounds 1 and 3 both showed antifungal activity against cryptococcus neoformans and antileishmanial activity against leishmania donovani in vitro. compound 3 also ...201222360686
kinetics and docking studies of two potential new inhibitors of the nucleoside hydrolase from leishmania donovani.in this study the recombinant enzyme nucleoside hydrolase of leishmania donovani (rldnh) was expressed in escherichia coli in connection with maltose binding protein (mbp). the rldnh-mbp showed efficient a significant in vitro activity with inosine as substrate. from the coupled reaction with xanthine oxidase (xo) it was possible to determine the kinetic constants of rldnh-mbp as k(m) (434 ± 109 μm) and v(max) (0.20 ± 0.02 μm). in addition, two nucleoside analogs (compounds 1 and 2) were tested ...201222947894
identification and characterization of a novel ribose 5-phosphate isomerase b from leishmania donovani.leishmaniasis is a group of tropical diseases caused by protozoan parasites of the genus leishmania. due to the emergence of resistance to the available antileishmanial drugs there is an immediate need to identify molecular targets on which to base future treatment strategies. ribose 5-phosphate isomerase (rpi; ec 5.3.1.6) is a key enzyme of the pentose phosphate pathway (ppp) which catalyses the reversible aldose-ketose isomerization between ribose 5-phosphate (r5p) and ribulose 5-phosphate (ru ...201222483752
leishmania donovani hslv does not interact stably with hslu proteins.genes for hslvu-type peptidases are found in bacteria and in a few select eukaryota, among those such important pathogens as plasmodium spp. and leishmania spp. in this study, we performed replacements of all three hslv/hslu gene homologues and found one of those, hslv, to be essential for leishmania donovani viability. the leishmania hslv gene can also partially relieve the thermosensitive phenotype of a combined hslvu/lon/clpxp knockout mutant of escherichia coli, indicating a conserved functi ...201222370310
reassessment of immune correlates in human visceral leishmaniasis as defined by cytokine release in whole blood.depressed cell-mediated immunity in human visceral leishmaniasis (vl) (also known as kala-azar), revealed as the inability of peripheral blood mononuclear cells (pbmcs) to respond to leishmania antigen, remains a hallmark of and is thought to underlie the progressive nature of this disease. we recently reported the ability of a whole-blood, gamma interferon (ifn-γ) release assay to detect subclinical infections among healthy individuals living in an area where kala-azar is endemic (bihar, india) ...201222539471
multilocus microsatellite typing (mlmt) of strains from turkey and cyprus reveals a novel monophyletic l. donovani sensu lato group.new foci of human cl caused by strains of the leishmania donovani (l. donovani) complex have been recently described in cyprus and the çukurova region in turkey (l. infantum) situated 150 km north of cyprus. cypriot strains were typed by multilocus enzyme electrophoresis (mlee) using the montpellier (mon) system as l. donovani zymodeme mon-37. however, multilocus microsatellite typing (mlmt) has shown that this zymodeme is paraphyletic; composed of distantly related genetic subgroups of differen ...201222348162
a unique modification of the eukaryotic initiation factor 5a shows the presence of the complete hypusine pathway in leishmania donovani.deoxyhypusine hydroxylase (dohh) catalyzes the final step in the post-translational synthesis of an unusual amino acid hypusine (n(€)-(4-amino-2-hydroxybutyl) lysine), which is present on only one cellular protein, eukaryotic initiation factor 5a (eif5a). we present here the molecular and structural basis of the function of dohh from the protozoan parasite, leishmania donovani, which causes visceral leishmaniasis. the l. donovani dohh gene is 981 bp and encodes a putative polypeptide of 326 amin ...201222438895
leishmanicidal and anticandidal activity of constituents of indian edible mushroom astraeus hygrometricus.two new lanostane-type triterpenes, 1 and 2, were isolated from astraeus hygrometricus. the structures were established by ir, (1)h- and (13)c-nmr, ms, and x-ray crystallographic experiments. the triterpenes exhibited excellent in vitro toxicities against candida albicans, comparable to standard antifungal antibiotics. the triterpene 2 significantly inhibited the growth of leishmania donovani promastigotes in vitro. the triterpene skeleton may be considered a template structure in search for new ...201222899612
the narrow active-site cleft of o-acetylserine sulfhydrylase from leishmania donovani allows complex formation with serine acetyltransferases with a range of c-terminal sequences.cysteine is a crucial substrate for the synthesis of glutathione and trypanothione, which in turn maintain intracellular redox homeostasis and defend against oxidative stress in the pathogen leishmania donovani. here, the identification, sequencing, characterization and crystal structure at 1.79 å resolution of o-acetylserine sulfhydrylase (oass), a cysteine-biosynthetic pathway enzyme from l. donovani (ldoass), are reported. it shows binding to the serine acetyltransferase (sat) c-terminal pept ...201222868756
antitrypanosomal alkaloids from the marine bacterium bacillus pumilus.fractionation of the ethyl acetate extract of the marine bacterium bacillus pumilus isolated from the black coral antipathes sp. led to the isolation of five compounds: cyclo-(l-leu-l-pro) (1), 3-hydroxyacetylindole (2), n-acetyl-β-oxotryptamine (3), cyclo-(l-phe-l-pro) (4), and 3-formylindole (5). the structures of compounds 1-5 were established by spectroscopic analyses, including hresitof-ms and nmr (1h, 13c, hsqc, hmbc and cosy). compounds 2, 3 and 5 caused the inhibition on the growth of tr ...201222990456
manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!!some of the most successful pathogens of human, such as mycobacterium tuberculosis (mtb), hiv, and leishmania donovani not only establish chronic infections but also remain a grave global threat. these pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. costimulatory molecul ...201222719245
identification of leishmania infantum chagasi proteins in urine of patients with visceral leishmaniasis: a promising antigen discovery approach of vaccine candidates.visceral leishmaniasis (vl) is a serious lethal parasitic disease caused by leishmania donovani in asia and by leishmania infantum chagasi in southern europe and south america. vl is endemic in 47 countries with an annual incidence estimated to be 500,000 cases. this high incidence is due in part to the lack of an efficacious vaccine. here, we introduce an innovative approach to directly identify parasite vaccine candidate antigens that are abundantly produced in vivo in humans with vl. we combi ...201222443237
antimicrobial, anti-inflammatory, antiparasitic, and cytotoxic activities of laennecia confusa.the current paper investigated the potential benefit of the traditional mexican medicinal plant laennecia confusa (cronquist) g. l. nesom (asteraceae). fractions from the hexane, chloroform, methanol, and aqueous extracts were analyzed for antibacterial, antifungal, anti-inflammatory, and antiparasitic activities. the antimicrobial activity of the extracts and fractions was assessed on bacterial and fungal strains, in addition to the protozoa leishmania donovani, using a microdilution assay. the ...201222623891
Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis.Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 µM). Of these, PP-9 and PP-10 were the most effective in vitro and demo ...201222024817
leishmania donovani argininosuccinate synthase is an active enzyme associated with parasite pathogenesis.gene expression analysis in leishmania donovani (ld) identified an orthologue of the urea cycle enzyme, argininosuccinate synthase (ldass), that was more abundantly expressed in amastigotes than in promastigotes. in order to characterize in detail this newly identified protein in leishmania, we determined its enzymatic activity, subcellular localization in the parasite and affect on virulence in vivo.201223094117
leishmania promastigotes: building a safe niche within macrophages.upon their internalization by macrophages, leishmania promastigotes inhibit phagolysosome biogenesis. the main factor responsible for this inhibition is the promastigote surface glycolipid lipophosphoglycan (lpg). this glycolipid has a profound impact on the phagosome, causing periphagosomal accumulation of f-actin and disruption of phagosomal lipid microdomains. functionally, this lpg-mediated inhibition of phagosome maturation is characterized by an impaired assembly of the nadph oxidase and t ...201223050244
antiparasitic antioxidant phenylpropanoids and iridoid glycosides from tecoma mollis.a radical scavenging guided phytochemical study on the stem bark of tecoma mollis afforded seven active phenylpropanoid glycosides (1-7), including a new one (4), and one iridoid (8). the structures of the isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. compounds (1-7) displayed promising antioxidant activity (dpph assay) in relation to ascorbic acid (positive control). the antimicrobial activity for compounds (1-8) was evaluated ag ...201222245081
adenine aminohydrolase from leishmania donovani: a unique enzyme in parasite purine metabolism.adenine aminohydrolase (aah) is an enzyme that is not present in mammalian cells and is found exclusively in leishmania among the protozoan parasites that infect humans. aah plays a paramount role in purine metabolism in this genus by steering 6-aminopurines into 6-oxypurines. l. donovani aah is 38% and 23% identical to the saccharomyces cerevisiae aah and human adenosine deaminase enzymes, respectively, catalyzes adenine deamination to hypoxanthine with an apparent k(m) of 15.4 μm, and does n ...201222238346
epidemiology of imported cutaneous leishmaniasis at the hospital for tropical diseases, london, united kingdom: use of polymerase chain reaction to identify the species.abstract. this study reviewed all patients diagnosed with imported cutaneous leishmaniasis (cl) at the hospital for tropical diseases in london, united kingdom, over an 11-year period. diagnostic and epidemiologic information was collected prospectively for all patients with imported cl to this hospital during 1998-2009. a total of 223 patients were given a diagnosis of cl. ninety patients were diagnosed with old world cl, which was caused most commonly by leishmania donovani complex (n = 20). a ...201222232460
potential antileishmanial effect of three medicinal plants.the antileishmanial activity of three organic solvent extracts and water residue of the plants: acacia nilotica (mimosaceae) (husk), ambrosia miratima (astraceae) (aerial shoot) and azadarichta indica (meliaceae) (leaves) were tested in vitro against leishmania donovani promastigotes. the study revealed that the extracts of a. nilotica and a. miratima have effectious antileishmanial activity at concentrations (ic(50)) less than 8 μg/ml, while the extracts of a. indica lack antileishmanial activi ...201223326001
human visceral leishmaniasis in kermanshah province, western iran, during 2011-2012.visceral leishmaniasis (vl) or kala-azar is a parasitic disease caused by the species of leishmania donovani complex. it is endemic in some parts of provinces of iran. according to the reported cases of vl in kermanshah province in recent years, this study was conducted to determine the seroprevalence of vl in high risk villages of the province.201223323091
asymmetric synthesis and anti-protozoal activity of the 8,4'-oxyneolignans virolin, surinamensin and analogues.the asymmetric synthesis of 8,4'-oxyneolignans (-)-virolin, (-)-surinamensin and a number of analogues has been achieved. a divergent synthesis was used, with all compounds being elaborated from a single chiral aldehyde derived from ethyl lactate. in the 15 compounds that were tested, the level of substitution on the a-ring was found to directly influence the activity against leishmania donovani whilst the activity against plasmodium falciparum was influenced by numerous substitution and stereoc ...201223313632
imipramine is an orally active drug against both antimony sensitive and resistant leishmania donovani clinical isolates in experimental infection.in an endeavor to find an orally active and affordable antileishmanial drug, we tested the efficacy of a cationic amphiphilic drug, imipramine, commonly used for the treatment of depression in humans. the only available orally active antileishmanial drug is miltefosine with long half life and teratogenic potential limits patient compliance. thus there is a genuine need for an orally active antileishmanial drug. previously it was shown that imipramine, a tricyclic antidepressant alters the proton ...201223301108
a parasite rescue and transformation assay for antileishmanial screening against intracellular leishmania donovani amastigotes in thp1 human acute monocytic leukemia cell line.leishmaniasis is one of the world's most neglected diseases, largely affecting the poorest of the poor, mainly in developing countries. over 350 million people are considered at risk of contracting leishmaniasis, and approximately 2 million new cases occur yearly(1). leishmania donovani is the causative agent for visceral leishmaniasis (vl), the most fatal form of the disease. the choice of drugs available to treat leishmaniasis is limited (2);current treatments provide limited efficacy and many ...201223299097
leishmania donovani develops resistance to drug combinations.drug combinations for the treatment of leishmaniasis represent a promising and challenging chemotherapeutic strategy that has recently been implemented in different endemic areas. however, the vast majority of studies undertaken to date have ignored the potential risk that leishmania parasites could develop resistance to the different drugs used in such combinations. as a result, this study was designed to elucidate the ability of leishmania donovani to develop experimental resistance to anti-le ...201223285310
identification of drosophila gene products required for phagocytosis of leishmania donovani.the identity and function of host factors required for efficient phagocytosis and intracellular maintenance of the protozoan parasite leishmania donovani are poorly understood. utilising the phagocytic capability of drosophila s2 cells, together with available tools for modulating gene expression by rnai, we have developed an experimental system in which to identify host proteins of this type on a genome-wide scale. we have shown that l. donovani amastigotes can be phagocytosed by s2 cells, in w ...201223272175
leishmania donovani zymodeme mon-37 isolated from an autochthonous visceral leishmaniasis patient in sri lanka.although the strain causing cutaneous leishmaniasis (cl) in sri lanka was first identified in 2003, the strain causing visceral leishmaniasis (vl) has not yet been identified. we report the first isoenzyme typing of a strain causing vl in sri lanka at an early stage of emergence of vl in the country. the parasite was isolated from a 57-year-old civil soldier who had been in the jungle in the vavuniya district in the northern province of sri lanka for a period of nearly 6 months immediately befor ...201223265615
apoptotic marker expression in the absence of cell death in staurosporine-treated leishmania donovani.the protozoan parasite leishmania donovani undergoes several developmental transitions in its insect and vertebrate hosts that are induced by environmental changes. the roles of protein kinases in these adaptive differentiation steps and their potential as targets for antiparasitic intervention are only poorly characterized. here, we used the generic protein kinase inhibitor staurosporine to gain insight into how interference with phosphotransferase activities affects the viability, growth, and ...201223263009
vaccine development against leishmania donovani.visceral leishmaniasis (vl) caused by leishmania donovani and leishmania infantum/chagasi represents the second most challenging infectious disease worldwide, leading to nearly 500,000 new cases and 60,000 deaths annually. zoonotic vl caused by l. infantum is a re-emergent canid zoonoses which represents a complex epidemiological cycle in the new world where domestic dogs serve as a reservoir host responsible for potentially fatal human infection and where dog culling is the only measure for res ...201222615707
kdna genetic signatures obtained by lssp-pcr analysis of leishmania (leishmania) infantum isolated from the new and the old world.visceral leishmaniasis (vl) caused by species from the leishmania donovani complex is the most severe form of the disease, lethal if untreated. vl caused by leishmania infantum is a zoonosis with an increasing number of human cases and millions of dogs infected in the old and the new world. in this study, l. infantum (syn. l.chagasi) strains were isolated from human and canine vl cases. the strains were obtained from endemic areas from brazil and portugal and their genetic polymorphism was ascer ...201222912862
immunobiology of visceral leishmaniasis.visceral leishmaniasis (vl), commonly known as kala-azar, is caused by leishmania donovani and leishmania infantum (leishmania chagasi in the americas). these leishmania species infect macrophages throughout the viscera, and parasites are typically found in the spleen, liver, and bone marrow. patients with active disease typically exhibit marked immunosuppression, lack reactivity to the leishmania skin test (lst), a delayed type hypersensitivity test, and their peripheral blood mononuclear cells ...201222912637
prevalence of sand flies and leishmania donovani infection in a natural population of female phlebotomus argentipes in bihar state, india.leishmaniasis is a vector-borne disease, and in the indian subcontinent the female phlebotomus argentipes is the vector for leishmania donovani. however, data on the extent of sand fly infection rates in natural settings using molecular methods have not been extensively reported in india. in this study a pcr technique was applied targeting the 18s rrna encoding region to determine the prevalence of leishmania infection in female p. argentipes captured in the field. for this study, sand flies wer ...201222217179
differential regulation of the immune response in the spleen and liver of mice infected with leishmania donovani.immunity to pathogens requires generation of effective innate and adaptive immune responses. leishmania donovani evades these host defense mechanisms to survive and persist in the host. a better understanding and identification of mechanisms that l. donovani employs for its survival is critical for developing novel therapeutic interventions that specifically target the parasite. this paper will highlight some of the mechanisms that the parasite utilizes for its persistence and also discuss how t ...201221811511
Immunity to visceral leishmaniasis using genetically defined live-attenuated parasites.Leishmaniasis is a protozoan parasitic disease endemic to the tropical and subtropical regions of the world, with three major clinical forms, self-healing cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL). Drug treatments are expensive and often result in the development of drug resistance. No vaccine is available against leishmaniasis. Subunit Leishmania vaccine immunization in animal models has shown some efficacy but little or none in humans. How ...201221912560
diverse viscerotropic isolates of leishmania all express a highly conserved secretory nuclease during human infections.previously, we characterized a gene encoding the unique nuclease (ldnuc(s)) from a sudanese isolate of the human pathogen leishmania donovani. this parasite secretory enzyme is involved in the salvage of host-derived purines and is constitutively expressed by both developmental forms of the parasite. currently, we assessed whether an ldnuc(s)-like nuclease was conserved among other geographically disparate isolates of l. donovani and whether this enzyme was produced by intracellular amastigotes ...201222020747
Myeloid cell IL-10 production in response to leishmania involves inactivation of glycogen synthase kinase-3ß downstream of phosphatidylinositol-3 kinase.Leishmania disease expression has been linked to IL-10. In this study, we investigated the regulation of IL-10 production by macrophages infected with Leishmania donovani. Infection of either murine or human macrophages brought about selective phosphorylation of Akt-2 in a PI3K-dependent manner. These events were linked to phosphorylation and inactivation of glycogen synthase kinase-3ß (GSK-3ß) at serine 9, as the latter was abrogated by inhibition of either PI3K or Akt. One of the transcription ...201222140263
Genome-wide SNP and microsatellite variation illuminate population-level epidemiology in the Leishmania donovani species complex.The species of the Leishmania donovani species complex cause visceral leishmaniasis, a debilitating infectious disease transmitted by sandflies. Understanding molecular changes associated with population structure in these parasites can help unravel their epidemiology and spread in humans. In this study, we used a panel of standard microsatellite loci and genome-wide SNPs to investigate population-level diversity in L. donovani strains recently isolated from a small geographic area spanning Indi ...201222119748
Radio-attenuated leishmanial parasites as immunoprophylactic agent against experimental murine visceral leishmaniasis.The present study intends to evaluate the role of radio-attenuated leishmania parasites as immunoprophylactic agents for experimental murine visceral leishmaniasis. BALB/c mice were immunized with gamma (?)-irradiated Leishmania donovani. A second immunization was given after 15days of first immunization. After two immunizations, mice were infected with virulent L. donovani promastigotes. Protection against Kala-azar (KA) was estimated from spleen and liver parasitic burden along with the measur ...201222019416
Downregulation of Mitogen-Activated Protein Kinase 1 of Leishmania donovani Field Isolates Is Associated with Antimony Resistance.Emergence of resistance to pentavalent antimonials has become a severe obstacle in the treatment of visceral leishmaniasis (VL) on the Indian subcontinent. The mechanisms operating in laboratory-generated strains are somewhat known, but the determinants of clinical antimony resistance are not well understood. By utilizing a DNA microarray expression profiling approach, we identified a gene encoding mitogen-activated protein kinase 1 (MAPK1) for the kinetoplast protozoan Leishmania donovani (LdMA ...201222064540
Identification of TLR inducing Th1-responsive Leishmania donovani amastigote-specific antigens.Leishmania is known to elicit Th2 response that causes leishmaniasis progression; on the other hand, Th1 cytokines restricts amastigote growth and disease progression. In this study, we report the potential of two leishmanial antigens (65 and 98 kDa, in combination) which enhance strong macrophage effector functions, viz., production of respiratory burst enzymes, nitric oxide, and Th1 cytokines. The identification of antigens were done by resolving the crude soluble antigens on SDS-PAGE and elut ...201221858498
Development of Vaccines against Visceral Leishmaniasis.Leishmaniasis is a neglected disease resulting in a global morbidity of 2,090 thousand Disability-Adjusted Life Years and a mortality rate of approximately 60,000 per year. Among the three clinical forms of leishmaniasis (cutaneous, mucosal, and visceral), visceral leishmaniasis (VL) accounts for the majority of mortality, as if left untreated VL is almost always fatal. Caused by infection with Leishmania donovani or L. infantum, VL represents a serious public health problem in endemic regions a ...201221912561
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