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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
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
deletion of an atp-binding cassette protein subfamily c transporter in leishmania donovani results in increased virulence.genome comparison of leishmania species sequenced to date has identified several hundred differentially distributed genes which are present as functional genes in some species but as pseudogenes or absent in others. it is not clear whether these differentially distributed genes are important for disease, redundant or even harmful for a particular leishmania species though a few of these genes have been implicated in leishmania infection tissue tropism. the l. infantum linj.24.1510 gene is an atp ...201222841683
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
antifungal depsidone metabolites from cordyceps dipterigena, an endophytic fungus antagonistic to the phytopathogen gibberella fujikuroi.among thirty four endophytic fungal strains screened for in vitro antagonism, the endophytic fungus cordyceps dipterigena was found to strongly inhibit mycelial growth of the plant pathogenic fungus gibberella fujikuroi. two new depsidone metabolites, cordycepsidone a (1) and cordycepsidone b (2), were isolated from the pda culture extract of c. dipterigena and identified as being responsible for the antifungal activity. elucidation of their chemical structures was carried out using 1d and 2d nm ...201222707798
intracellular pathogen leishmania donovani activates hypoxia inducible factor-1 by dual mechanism for survival advantage within macrophage.recent evidence established a crucial role for mammalian oxygen sensing transcription factor hypoxia inducible factor-1 (hif-1) in innate immunity against intracellular pathogens. in response to most of these pathogens host phagocytes increase transcription of hif-1α, the regulatory component of hif-1 to express various effector molecules against invaders. leishmania donovani (ld), a protozoan parasite and the causative agent of fatal visceral leishmaniasis resides in macrophages within mammalia ...201222701652
mechanistic insights into the dual inhibition strategy for checking leishmaniasis.leishmaniasis (1) is an endemic disease mainly caused by the protozoan leishmania donovani (ld). polyamines have been identified as essential organic compounds for the growth and survival of ld. these are synthesized in ld by polyamine synthesis pathway comprising of many enzymes such as ornithine decarboxylase (odc), spermidine synthase (ss), and s-adenosylmethionine decarboxylase. inhibition of these enzymes in ld offers a viable prospect to check its growth and development. in the present wor ...201222694167
synthesis and biological evaluation of tricyclic guanidine analogues of batzelladine k for antimalarial, antileishmanial, antibacterial, antifungal and anti-hiv activities.fifty analogues of batzelladine k were synthesized and evaluated for in vitro antimalarial (plasmodium falciparum), antileishmanial (leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (hiv-1) activities. analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive d6 strain with ic50 1.25 and 0.88 μm and chloroquine-resistant w2 strain with ic50 1.64 and 1.07 μm, respectively. analogues 12c and 14c having nonyl substitution showed the mo ...201226404724
involvement of the leishmania donovani virulence factor a2 in protection against heat and oxidative stress.leishmania is an obligate intracellular protozoan parasite that infects cells of the reticulo-endothelial system. host defences against leishmania include fever and oxidant production, and the parasite has developed a number of defence mechanisms to neutralize the host response. the leishmania donovani a2 family of proteins has been shown to be essential for survival in mammalian visceral organs. here we provide evidence that a2 proteins protect the parasite against host defences, namely heat st ...201222691540
leishmania donovani exploits host deubiquitinating enzyme a20, a negative regulator of tlr signaling, to subvert host immune response.tlrs, which form an interface between mammalian host and microbe, play a key role in pathogen recognition and initiation of proinflammatory response thus stimulating antimicrobial activity and host survival. however, certain intracellular pathogens such as leishmania can successfully manipulate the tlr signaling, thus hijacking the defensive strategies of the host. despite the presence of lipophosphoglycan, a tlr2 ligand capable of eliciting host-defensive cytokine response, on the surface of le ...201222685311
a leishmaniasis study: structure-based screening and molecular dynamics mechanistic analysis for discovering potent inhibitors of spermidine synthase.protozoa leishmania donovani (ld) is the main cause of the endemic disease leishmaniasis. spermidine synthase (ss), an important enzyme in the synthetic pathway of polyamines in ld, is an essential element for the survival of this protozoan. targeting ss may provide an important aid for the development of drugs against ld. however, absence of tertiary structure of spermidine synthase of leishmania donovani (lss) limits the possibilities of structure based drug designing. presence of the same enz ...201222684087
aubr(3) mediated glycosidations: synthesis of tetrasaccharide motif of the leishmania donovani lipophosphoglycan.tetrasaccharide cap present in lipophosphoglycan of the leishmania donovani responsible for visceral leishmaniaisis is synthesized as a fully protected propargyl glycoside. aubr(3) mediated selective glycosylation of propargyl 1,2-orthoester in the presence of propargyl glycoside is employed as a key step to obtain propargyl containing oligomers. further, propargyl tetrasaccharide is connected with a long chain hydrocarbon containing azidothiol functionality situated at two terminal ends via 'cl ...201222660966
drug susceptibility in leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis.with widespread resistance to antimonials in visceral leishmaniasis (vl) in the indian subcontinent, miltefosine (mil) has been introduced as the first line therapy. surveillance of mil susceptibility in natural populations of leishmania donovani is vital to preserve it and support the vl elimination program.201222629478
tlr-mediated distinct ifn-γ/il-10 pattern induces protective immunity against murine visceral leishmaniasis.resistance to murine visceral leishmaniasis (vl) correlates with the development of an ifn-γ predominant immune response. beta1,4-galactose terminal glycans are potent inducers of ifn-γ. here, we demonstrate the efficacy of a 29 kda β1,4-galactose terminal glycoprotein (gp29) of leishmania donovani (ld) in an in vitro macrophage model and an in vivo mouse model of vl. gp29 induced splenic macrophages to release no and ros in appreciable amounts that resulted in effective parasite clearance from ...201222622993
coinfection of leptomonas seymouri and leishmania donovani in indian leishmaniasis.leishmania donovani is considered the causative organism of visceral leishmaniasis (vl) and post-kala-azar dermal leishmaniasis (pkdl). testing of 4/29 dna samples from vl and pkdl patients as well as 2/7 field isolates showed an aberrant internal transcribed spacer 1 (its1) restriction fragment length polymorphism (rflp) pattern, which upon sequencing strongly matched leptomonas seymouri, thus confirming its presence in indian leishmaniasis.201222622439
defeating leishmania resistance to miltefosine (hexadecylphosphocholine) by peptide-mediated drug smuggling: a proof of mechanism for trypanosomatid chemotherapy.miltefosine (hexadecylphosphocholine, hepc), the first orally active drug successful against leishmaniasis, is especially active on the visceral form of the disease. resistance mechanisms are almost exclusively associated to dysfunction in hepc uptake systems. in order to evade the requirements of its cognate receptor/translocator, hepc-resistant leishmania donovani parasites (r40 strain) were challenged with constructs consisting of an ω-thiol-functionalized hepc analogue conjugated to the cell ...201222609351
discovery of a new antileishmanial hit in 8-nitroquinoline series.a series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward leishmania donovani promastigotes. in parallel, the in vitro cytotoxicity of these molecules was assessed on the murine j774 and human hepg2 cell lines. thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an ic(50) value of 6.6 μm and cc(50) values ≥ 100 μm, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference ( ...201222608675
synthesis and anti-leishmanial activity of 1-aryl-β-carboline derivatives against leishmania donovani.β-carbolines from various natural and synthetic sources have been known to show diverse biological activities. as a part of our current ongoing project to search for potent natural product-derived anti-leishmanial compounds, we have synthesized a series of substituted 1-aryl-β-carboline derivatives. a total of 22 compounds were synthesized and tested in vitro against leishmania donovani, out of which 6 compounds (4, 5, 10, 11, 19 and 22) showed notably more activity than the standard miltefosine ...201222608390
glycyrrhizic acid suppresses cox-2-mediated anti-inflammatory responses during leishmania donovani infection.the aim of the present study was to characterize glycyrrhizic acid (ga) and assess its immunomodulatory potential in a model of experimental visceral leishmaniasis.201222589456
successful therapeutic splenectomy in an hiv patient with relapsing visceral leishmaniasis.a 43-year-old hiv-positive ethiopian immigrant presented with persistent diarrhoea, hepatosplenomegaly and pancytopaenia. visceral leishmaniasis was diagnosed by multiple gastrointestinal tract biopsies. blood polymerase chain reaction (pcr) was positive for leishmania donovani. despite highly active antiretroviral therapy (haart) and multiple courses of antileishmanial treatments, including liposomal amphotericin and sodium stibogluconate, the patient had multiple relapses. cd4 counts remained ...201222581957
leishmania donovani: cd2 biased immune response skews the sag mediated therapy for a predominant th1 response in experimental infection.we have evaluated the effect of combining cd2 with conventional antimonial (sb) therapy in protection in balb/c mice infected with either drug sensitive or resistant strain of leishmania donovani with 3×10(7) parasites via-intra-cardiac route. mice were treated with anti cd2 adjunct sag sub-cutaneously twice a week for 4 weeks. assessment for measurement of weight, spleen size, anti-leishmania antibody titer, t cell and anti-leishmanial macrophage function was carried out day 0, 10, 22 and 34 po ...201222580024
leishmania donovani recombinant iron superoxide dismutase b1 protein in the presence of tlr-based adjuvants induces partial protection of balb/c mice against leishmania major infection.in this study, we tested the protective efficacy of recombinant leishmania donovani iron superoxide dismutase b1 (sodb1) against leishmania major infection in balb/c mice. mice were challenged with l. major 3weeks after the second boost immunization with rsodb1 alone or in the presence of adjuvants. injection of balb/c mice with rsodb1 alone elicited both humoral and cellular immune responses. administration of rsodb1 with cpg odn or gla-se (a synthetic toll-like receptor 4 agonist) adjuvant res ...201222580023
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
[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
di-cationic arylimidamides act against neospora caninum tachyzoites by interference in membrane structure and nucleolar integrity and are active against challenge infection in mice.neospora caninum is considered to be the main cause of bovine abortion in europe and the usa, leading to considerable financial impact. losses are caused directly by abortions or indirectly through breeding of calves with impaired viability. due to the lack of effective chemotherapy against bovine neosporosis, there is a need to develop new anti-protozoal compounds, which would either eliminate the parasite or avoid its transmission. in order to identify compounds of interest, the in vitro activ ...201224533272
expression of concern: ahlin e et al.,"anti-citrullinated peptide antibodies and rheumatoid factor in sudanese patients with leishmania donovani infection", rev bras reumatol 2011; 51(6):572-86. 201223090367
molecular and parasitological detection of leishmania spp. in dogs caught in palmas, to, brazil.this study evaluated occurrences of leishmania infantum in dogs in the municipality of palmas, tocantins, comparing diagnostic data obtained using the polymerase chain reaction (pcr) and parasitological diagnosis. blood samples and lymph node aspirates were collected from 63 dogs of males and females and various ages and races, with or without owners, between august 2009 and june 2010. slides containing smears of lymph node aspirates were stained with giemsa stained. in pcr, the 145 bp target se ...201223070439
hyperlipidemia offers protection against leishmania donovani infection: role of membrane cholesterol.leishmania donovani (ld), the causative agent of visceral leishmaniasis (vl), extracts membrane cholesterol from macrophages and disrupts lipid rafts, leading to their inability to stimulate t cells. restoration of membrane cholesterol by liposomal delivery corrects the above defects and offers protection in infected hamsters. to reinforce further the protective role of cholesterol in vl, mice were either provided a high-cholesterol (atherogenic) diet or underwent statin treatment. subsequent ld ...201223060454
leishmania donovani triose phosphate isomerase: a potential vaccine target against visceral leishmaniasis.visceral leishmaniasis (vl) is one of the most important parasitic diseases with approximately 350 million people at risk. due to the non availability of an ideal drug, development of a safe, effective, and affordable vaccine could be a solution for control and prevention of this disease. in this study, a potential th1 stimulatory protein- triose phosphate isomerase (tpi), a glycolytic enzyme, identified through proteomics from a fraction of leishmania donovani soluble antigen ranging from 89.9- ...201223049855
leishmanicidal activity of two naphthoquinones against leishmania donovani.here we studied ability of two naphthoquinones to inhibit leishmania growth (2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (tr 001) and 2,3-dibromo-1,4-naphthoquinone (tr 002). tr 001 was more efficient than tr 002 in inducing killing of promastigotes and intracellular amastigotes. these values compare well to those obtained with the standard first-line antileishmanial agent sodium stibogluconate (ssg). tr 001 also induced significantly more nitric oxide (no) production than tr 002 or ssg. taken ...201223037165
chemotherapy of leishmaniasis. part xi: synthesis and bioevaluation of novel isoxazole containing heteroretinoid and its amide derivatives.novel isoxazole containing heteroretinoid (4) and its amide derivatives (5a-j) have been synthesized and evaluated for their in vivo antileishmanial activity against leishmania donovani in hamsters. compounds 3, 5a, 5d, 5k and 5l inhibited 70-76% parasite growth at 50 mg kg(-1) ×5 days. the present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent.201223031597
chemotherapy of leishmaniasis. part ix: synthesis and bioevaluation of aryl substituted ketene dithioacetals as antileishmanial agents.a new series of aryl substituted ketene dithioacetals 6a-h was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against leishmania donovani. two compounds exhibited significant in vitro activity against intracellular amastigotes of l. donovani with ic(50) values 3.56 and 5.12 μm and were found promising as compared with reference drug, miltefosine. on the basis of good selectivity indices (s.i.), they were further tested for their in vivo response against l. dono ...201223031588
the lignan niranthin poisons leishmania donovani topoisomerase ib and favours a th1 immune response in mice.niranthin, a lignan isolated from the aerial parts of the plant phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. in the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. the compound induces topoisomerase i-mediated dna-protein adduct formation inside leishmania cells and triggers apoptosis by activation of cellular nucleases. we also show that niranthin inhibits the relaxation activity of heterodimeric type ib topoisome ...201223027614
conjugation of quinones with natural polyamines: toward an expanded antitrypanosomatid profile.a combinatorial library of quinone-polyamine conjugates designed to optimize the antitrypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid-phase approach. the conjugates were evaluated against the three most important human trypanosomatid pathogens (trypanosoma brucei rhodesiense, trypanosoma cruzi, and leishmania donovani), and several showed promising activity. a subset also inhibited trypanothione reductase in vitro and induced oxidase activity of the enzyme. a highly p ...201223153330
cysteine cross-linking defines the extracellular gate for the leishmania donovani nucleoside transporter 1.1 (ldnt1.1).equilibrative nucleoside transporters are a unique family of proteins that enable uptake of nucleosides/nucleobases into a wide range of eukaryotes and internalize a myriad of drugs used in the treatment of cancer, heart disease, aids, and parasitic infections. in previous work we generated a structural model for such a transporter, the ldnt1.1 nucleoside permease from the parasitic protozoan leishmania donovani, using ab initio computation. the model suggested that aromatic residues present in ...201223150661
cxcl10 is critical for the generation of protective cd8 t cell response induced by antigen pulsed cpg-odn activated dendritic cells.the visceral form of leishmaniasis is the most severe form of the disease and of particular concern due to the emerging problem of hiv/visceral leishmaniasis (vl) co-infection in the tropics. till date miltefosine, amphotericin b and pentavalent antimony compounds remain the main treatment regimens for leishmaniasis. however, because of severe side effects, there is an urgent need for alternative improved therapies to combat this dreaded disease. in the present study, we have used the murine mod ...201223144947
cloning, characterization and sub-cellular localization of gamma subunit of t-complex protein-1 (chaperonin) from leishmania donovani.t-complex protein-1 (tcp1) complex, a chaperonin class of protein, ubiquitous in all genera of life, is involved in intracellular assembly and folding of various proteins. the gamma subunit of tcp1 complex (tcp1γ), plays a pivotal role in the folding and assembly of cytoskeleton protein(s) as an individual or complexed with other subunits. here, we report for the first time cloning, characterization and expression of the tcp1γ of leishmania donovani (ldtcp1γ), the causative agent of indian kala- ...201223137535
a rapid method to assess the stage differentiation in leishmania donovani by flow cytometry.in this study we describe a rapid and novel method to assess the morphological stage differentiation in leishmania donovani by flow cytometry (fcm). fcm is fast, accurate, and inexpensive to study the stage differentiation of promastigote into l. donovani axenic amastigote (ldaxam). the non-flourimetric fcm method is easy to perform; with requirement of little expertise, and provides unambiguous results. it is an advanced tool, requires minimal time, and no fluorescent dyes. the gradual increase ...201223022521
a pentapeptide signature motif plays a pivotal role in leishmania dna topoisomerase ib activity and camptothecin sensitivity.leishmania donovani - the causative agent of visceral leishmaniasis - has several evolutionary characteristics that make the disease difficult to combat. among these differences, a rare heterodimeric dna topoisomerase ib has been reported thus opening a new promising field in the therapy of leishmaniasis. several studies of the human enzyme have pointed to the importance of the linker domain in respect to camptothecin sensitivity. at present, it has been impossible to pinpoint the regions that m ...201223000572
effect of allicin on promastigotes and intracellular amastigotes of leishmania donovani and l. infantum.anti-leishmanial activity of allicin (=diallyl thiosulphinate) has been tested in vitro against promastigotes and intracellular amastigotes of leishmania donovani and leishmania infantum. macrophage infections have been carried out in vitro in the murine cell line j774 and ex vivo with peritoneal macrophages from balb/c mice with a modified method to isolate metacyclic promastigotes. the compound has shown a significant in vitro effect on the multiplication of promastigotes of l. donovani and l. ...201222995646
first total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the leishmania topoisomerase ib enzyme.the fatty acids (±)-2-methoxy-6z-heptadecenoic acid (1), (±)-2-methoxy-6-heptadecynoic acid (2) and (±)-2-methoxyheptadecanoic acid (3) were synthesized and their inhibitory activity against the leishmania dna topoisomerase ib enzyme (ldtopib) determined. acids 1 and 2 were synthesized from 4-bromo-1-pentanol, the former in ten steps and in 7% overall yield, while the latter in seven steps and in 14% overall yield. acid 3 was prepared in six steps and in 42% yield from 1-hexadecanol. acids 1-3 i ...201223118491
synthesis and structure-activity relationships of lansine analogues as antileishmanial agents.clear and rational thinking: a series of rationally designed, lansine-derived carbazoles was synthesized and evaluated for activity against promastigotes and amastigotes of leishmania donovani, the causative agent of leishmaniasis. some structural modifications gave rise to compounds with enhanced activity and selectivity over lansine, allowing structure-activity relationships to be elucidated and providing a foundation for the further development of this pharmacophore.201222987791
rflps of its, its1 and hsp70 amplicons and sequencing of its1 of recent clinical isolates of kala-azar from india and bangladesh confirms the association of l. tropica with the disease.visceral leishmaniasis or kala-azar (ka) is a serious health concern in india. in the present study, restriction fragment length polymorphism (rflp) of three genetic markers viz., internal transcribed spacer (its), its1 and heat shock protein 70 (hsp70) have been employed for typing the clinical isolates [n=15] of ka and post kala-azar dermal leishmaniosis (pkdl) collected from india and bangladesh in the period of 2006-2010. experimentally, its, its1 and hsp70 regions of genomes of all the clin ...201222960646
retraction: human recombinant migration inhibitory factor activates human macrophages to kill leishmania donovani. 201222956762
extracts of artemisia annua leaves and seeds mediate programmed cell death in leishmania donovani.leishmaniasis is one of the major tropical parasitic diseases, and the condition ranges in severity from self-healing cutaneous lesions to fatal visceral manifestations. there is no vaccine available against visceral leishmaniasis (vl) (also known as kala-azar in india), and current antileishmanial drugs face major drawbacks, including drug resistance, variable efficacy, toxicity and parenteral administration. we report here that n-hexane fractions of artemisia annua leaves (aal) and seeds (aas) ...201222956747
identification of th1-responsive leishmanial excretory-secretory antigens (lesas).the objective of this study was to evaluate the immunomodulatory role of leishmanial excretory-secretory antigens (lesas) released by in vitro cultured protozoan parasite leishmania donovani promastigotes. a total of seventeen excretory-secretory proteins of relative molecular weights 11, 13, 16, 18, 21, 23, 26, 29, 33, 35, 42, 51, 54, 58, 64, 70 and 80 kda were identified. the proteins were divided into five fractions (f1-f5) along with the whole lesas, these fractions were evaluated for their ...201222955114
marchantin a, a macrocyclic bisbibenzyl ether, isolated from the liverwort marchantia polymorpha, inhibits protozoal growth in vitro.in vitro anti-plasmodial activity-guided fractionation of a diethyl ether extract of the liverwort species marchantia polymorpha, collected in iceland, led to isolation of the bisbibenzyl ether, marchantin a. the structure of marchantin a (1) was confirmed by nmr and hreims. marchantin a inhibited proliferation of the plasmodium falciparum strains, nf54 (ic(50)=3.41μm) and k1 (ic(50)=2.02μm) and showed activity against other protozoan species trypanosoma brucei rhodesiense, t. cruzi and leishman ...201222951393
il-10-producing th1 cells and disease progression are regulated by distinct cd11c⁺ cell populations during visceral leishmaniasis.il-10 is a critical regulatory cytokine involved in the pathogenesis of visceral leishmaniasis caused by leishmania donovani and clinical and experimental data indicate that disease progression is associated with expanded numbers of cd4⁺ ifnγ⁺ t cells committed to il-10 production. here, combining conditional cell-specific depletion with adoptive transfer, we demonstrate that only conventional cd11c(hi) dcs that produce both il-10 and il-27 are capable of inducing il-10-producing th1 cells in vi ...201222911108
visceral leishmaniasis: a case report.although leishmaniasis is widely prevalent in the eastern states of india namely bihar, jharkhand, uttar pradesh and west bengal, diagnosing the illness is still difficult. we present a case of a 20-year-old agricultural labourer with a history of recurrent fever, progressive weakness and abdominal discomfort associated with loss of appetite for six months followed by petechial hemorrhages over body.on examination there was hepato-splenomegaly. a diagnosis of visceral leishmaniasis (kala-azar) w ...201222905054
pentacyclic ingamine alkaloids, a new antiplasmodial pharmacophore from the marine sponge petrosid ng5 sp5.two new pentacyclic ingamine alkaloids, namely 22(s)-hydroxyingamine a (2) and dihydroingenamine d (3), together with the known ingamine a (1), have been isolated from marine sponge petrosid ng5 sp5 (family petrosiidae) obtained from the open repository of the national cancer institute, usa. the structures of compounds 1-3 were determined using 1d and 2d nmr, and hresims techniques. the absolute configuration of both the c9 and c22 of 2 was determined as (s) using a modified mosher esterificatio ...201222903383
the role of nf-κb activation during protection against leishmania infection.members of the nuclear factor-κb (nf-κb) family of transcription factors regulate a variety of molecules involved in host defense against pathogens. a prominent role of nf-κb in innate and adoptive immunity is based on the regulation of inducible transcription of various genes whose products are essential components of the immune response such as cytokines, chemokines, and adhesion molecules. since the discovery of the five members of the nf-κb transcription factor family, rela, c-rel, relb, p50 ...201222901377
deletion of mitochondrial associated ubiquitin fold modifier protein ufm1 in leishmania donovani results in loss of β-oxidation of fatty acids and blocks cell division in the amastigote stage.recently, we described the existence of the ubiquitin fold modifier 1 (ufm1) and its conjugation pathway in leishmania donovani. we demonstrated the conjugation of ufm1 to proteins such as mitochondrial trifunctional protein (mtp) that catalyses β-oxidation of fatty acids in l. donovani. to elucidate the biological roles of the ufm1-mediated modifications, we made an l. donovani ufm1 null mutant (ufm1(-/-)). loss of ufm1 and consequently absence of ufm1 conjugation with mtp resulted in diminishe ...201222897198
the histone acetyl transferase ldhat1 from leishmania donovani is regulated by s-phase cell cycle kinase.histone acetyl transferases (hats) are important histone modifiers that affect critical cellular processes like transcription, dna replication and repairs through highly dynamic chromatin remodelling. our earlier studies recognized ldhat1 as a substrate of the s-phase cell cycle kinase ldcyc1-crk3 from leishmania donovani. here, we confirm through site-directed mutagenesis that rxl-like cyclin-binding (cy) motif dependent interaction of ldhat1 with ldcyc1 is essential for its phosphorylation at ...201222889278
post-kala-azar dermal leishmaniasis in visceral leishmaniasis-endemic communities in bihar, india.we assessed the prevalence of post-kala-azar dermal leishmaniasis (pkdl), a late cutaneous manifestation of visceral leishmaniasis (vl), in 16 vl-endemic communities in bihar, india. the prevalence of confirmed pkdl cases was 4.4 per 10 000 individuals and 7.8 if probable cases were also considered. the clinical history and treatment of the post-kala-azar dermal leishmaniasis cases are discussed.201222882665
development of luciferase expressing leishmania donovani axenic amastigotes as primary model for in vitro screening of antileishmanial compounds.the development of new therapeutic leads against leishmaniasis relies primarily on screening of a large number of compounds on multiplication of clinically irrelevant transgenic promastigotes. the advent of the successful in vitro culture of axenic amastigotes allows the development of transgenic axenic amastigotes as a primary screen which can test compounds in a high throughput mode like promastigotes, still representative of the clinically relevant mammalian amastigotes stage. the present stu ...201222945482
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