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cluster of zoonotic cutaneous leishmaniasis (leishmania major) in european travelers returning from turkmenistan.we report a cluster of cutaneous leishmaniasis due to leishmania major in four immunocompetent travelers returning from western turkmenistan and having atypical and/or multiple lesions. treatments with pentamidine or fluconazole were effective. physicians should be aware that some virulent strains of l major currently circulate in central asia.201624165385
[88 years of cutaneous leishmaniasis in morocco].leishmaniasis in its cutaneous form is a public health problem in morocco. the objectives of this study were to assess the development of its epidemiological profile, identify the relevant species, and determine the location of the identified cases and their distribution by year, by sex, and by age. this retrospective epidemiological study covers a period of 88 years and concerns all reported cases of cutaneous leishmaniasis (cl) in morocco from the first description in 1922 until 2010. during t ...201625847883
recombinant leishmania major lipophosphoglycan 3 activates human t-lymphocytes via tlr2-independent pathway.leishmaniasis is one of the most common infectious diseases transmitted by an obligate intracellular genus leishmania. as there is no efficient vaccination strategy for leishmaniasis, new immunostimulatory components may enhance protective immune responses against this parasite. lipophosphoglycan 3 (lpg3) is an essential protein required for lpg assembling. in this study, the ability of recombinant lpg3 (rlpg) and its fragments to activate isolated healthy human t-cells and cytokine secretion wa ...201626181511
4-arylamino-6-nitroquinazolines: synthesis and their activities against neglected disease leishmaniasis.4-arylamino-6-nitroquinazolines (2-25) were synthesized and evaluated for their leishmanicidal activities against leishmania major promastigotes in vitro with ic50 values = 1.87-61.48 μm. among the twenty four synthetic derivatives, 4-[4'-(methylsulfanyl)phenyl]amino-6-nitroquinazoline (21), and 4-(2'-methoxyphenyl)amino-6-nitroquinazoline (8) showed excellent antileishmanial activities with ic50 values 1.87 ± 0.31 and 4.37 ± 0.02 μm, respectively, more active than the standard drug, pentamidine ...201626619389
crystal structure of phosphoglucomutase from leishmania major at 3.5 å resolution.the crystal structure of phosphoglucomutase (lmpgm) from the parasite leishmania major has been solved at 3.5 å resolution. although the active form of the enzyme is monomeric in solution, four molecules (a, b, c, d) were found in the asymmetric unit, of which the pairs (a,d) and (b,c) were of identical inter-subunit geometry. the parasitic enzyme constituted of four domains exhibited the canonical 'heart' shape of the protein, with domains i to iii having a conserved α|β core, while the fourth ...201626607241
development of a new antileishmanial aziridine-2,3-dicarboxylate-based inhibitor with high selectivity for parasite cysteine proteases.leishmaniasis is one of the major neglected tropical diseases of the world. druggable targets are the parasite cysteine proteases (cps) of clan ca, family c1 (cac1). in previous studies, we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylate compounds 13b and 13e, in a series of inhibitors of the cathepsin l (cl) subfamily of the papain clan cac1. both displayed antileishmanial activity in vitro while not showing cytotoxicity against host cells. in further investigations, th ...201626596939
metabolomics-based study of logarithmic and stationary phases of promastigotes in leishmania major by 1h nmr spectroscopy.cutaneous leishmaniasis is one of the most important parasitic diseases in humans. in this disease, one of the responsible organisms is leishmania major, which is transmitted by sandfly vector. there are specific differences in biochemical profiles and metabolite pathways in logarithmic and stationary phases of leishmania parasites. in the present study, 1h nmr spectroscopy was used to examine the metabolites outliers in the logarithmic and stationary phases of promastigotes in l. major to enlig ...201626592771
biophysical characterization of the nucleoside diphosphate kinase of leishmania major and effect of the p95s mutation.nucleoside diphosphate kinases (ndk; ec 2.7.4.6) are enzymes required for maintaining intracellular levels of nucleosides triphosphates (ntp) through transfer the γ-phosphoryl group from a ntp to a ndp. the enzyme is associated with several biological functions including prevention of host atp-mediated cytolysis during pathogenic infections. here we present the biophysical characterization of ndk from leishmania major and the effect of a mutation on the protein structure in solution. the structu ...201626548994
lmabcb3, an atypical mitochondrial abc transporter essential for leishmania major virulence, acts in heme and cytosolic iron/sulfur clusters biogenesis.mitochondria play essential biological functions including the synthesis and trafficking of porphyrins and iron/sulfur clusters (isc), processes that in mammals involve the mitochondrial atp-binding cassette (abc) transporters abcb6 and abcb7, respectively. the mitochondrion of pathogenic protozoan parasites such as leishmania is a promising goal for new therapeutic approaches. leishmania infects human macrophages producing the neglected tropical disease known as leishmaniasis. like most trypano ...201626728034
correction: depletion of udp-glucose and udp-galactose using a degron system leads to growth cessation of leishmania major.[this corrects the article doi: 10.1371/journal.pntd.0004205.].201626735928
plasmenylethanolamine synthesis in leishmania major.ethanolamine glycerophospholipids are ubiquitous cell membrane components. trypanosomatid parasites of the genus leishmania synthesize the majority of their ethanolamine glycerophospholipids as 1-o-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine or plasmenylethanolamine (pme) through the kennedy pathway. pme is a subtype of ether phospholipids also known as ethanolamine plasmalogen whose functions are not well characterized. in this study, we investigated the role of pme synthesis in leishma ...201627062077
coadminstration of l. major amastigote class i nuclease (rlmacin) with lpd nanoparticles delays the progression of skin lesion and the l. major dissemination to the spleen in balb/c mice-based experimental setting.human cutaneous leishmaniasis is a disease caused by eukaryotic single-celled leishmania species, the developmental program of which relies upon blood-feeding adult female sand flies and their dominant mammal blood sources, namely wild rodents in area where human beings exert more or less transient activities. the recourse to model rodents - namely laboratory mice such as c57bl/6 mice - has allowed extracted the immune signatures that account for the healing of the transient cutaneous lesion tha ...201627060774
leishmaniasis in turkey: first clinical isolation of leishmania major from 18 autochthonous cases of cutaneous leishmaniasis in four geographical regions.to report isolation of leishmania major strains obtained from 18 turkish autochthonous cutaneous leishmaniasis (cl) patients infected with l. major between 2011 and 2014.201627037747
targeting leishmania major parasite with peptides derived from a combinatorial phage display library.cutaneous leishmaniasis (cl) is a global problem caused by intracellular protozoan pathogens of the genus leishmania for which there are no suitable vaccine or chemotherapy options. thus, de novo identification of small molecules binding to the leishmania parasites by direct screening is a promising and appropriate alternative strategy for the development of new drugs. in this study, we used a random linear hexapeptide library fused to the gene iii protein of m13 filamentous bacteriophage to sel ...201626995695
trypanosoma cruzi polyamine transporter: its role on parasite growth and survival under stress conditions.trypanosoma cruzi is the etiological agent of chagas disease, a major health problem in latin america. polyamines are polycationic compounds that play a critical role as regulators of cell growth and differentiation. in contrast with other protozoa, t. cruzi is auxotrophic for polyamines because of its inability to synthesize putrescine due to the lack of both, arginine and ornithine decarboxylase; therefore, the intracellular availability of polyamines depends exclusively on transport processes ...201626983938
the mechanistic study of leishmania major dihydro-orotate dehydrogenase based on steady- and pre-steady-state kinetic analysis.leishmania major dihydro-orotate dehydrogenase (dhodhlm) has been considered as a potential therapeutic target against leishmaniasis. dhodhlm, a member of class 1a dhodh, oxidizes dihydro-orotate (dho) to orotate (oro) during pyrimidine biosynthesis using fumarate (fum) as the oxidizing substrate. in the present study, the chemistry of reduction and reoxidation of the flavin mononucleotide (fmn) cofactor in dhodhlm was examined by steady- and pre-steady state kinetics under both aerobic and anae ...201626656485
first detection of leishmania major dna in sergentomyia (sintonius) clydei (sinton, 1928, psychodidae: phlebotominae), from an outbreak area of cutaneous leishmaniasis in tunisia.in recent years there has been growing interest in sergentomyia species. their role in the spread of mammalian leishmaniasis appears repeatedly in the literature and the possibility of its implication in leishmania transmission to humans remains controversial. sergentomyia (sintonius) clydei is one of several cryptic species sharing therefore common morphologic criteria with others species of the subgenera sintonius. little is known about this specie in tunisia. we sampled and identified differe ...201626538476
inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on leishmania major growth and trypanosoma brucei trypanothione reductase.a number of phenothiazine-, phenoxazine- and related tricyclics-derived chloroacetamides were synthesized and evaluated in vitro for antiprotozoal activities against leishmania major (l. major) promastigotes. several analogs were remarkably potent inhibitors, with antileishmanial activities being comparable or superior to those of the reference antiprotozoal drugs. furthermore, we explored the structure-activity relationships of n-10 haloacetamides that influence the potency of such analogs towa ...201626708110
mesenchymal stem cells alter macrophage immune responses to leishmania major infection in both susceptible and resistance mice.mesenchymal stem cells (mscs) are attracted to inflammation site and switch immune system to modulate inflammatory responses. this ability makes mscs the best candidate cells for stem cell therapy of infection diseases. therefore, we aimed to evaluate the modulatory effect of adipose-derived mscs (ad-mscs) on macrophages in leishmania (l.) major infection. macrophages and mscs were isolated from both susceptible (balb/c) and resistance (c57bl/6) strains. after co-culture of ad-mscs with macropha ...201626703818
expression of pd-1/lag-3 and cytokine production by cd4(+) t cells during infection with plasmodium parasites.cd4(+) t cells play critical roles in protection against the blood stage of malarial infection; however, their uncontrolled activation can be harmful to the host. in this study, in which rodent models of plasmodium parasites were used, the expression of inhibitory receptors on activated cd4(+) t cells and their cytokine production was compared with their expression in a bacterial and another protozoan infection. cd4(+) t cells from mice infected with p. yoelii 17xl, p yoelii 17xnl, p. chabaudi, ...201626696540
the nlrp3 inflammasome, il-1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of leishmania major in c57bl/6 mice.infection of c57bl/6 mice with most leishmania major strains results in a healing lesion and clearance of parasites from the skin. infection of c57bl/6 mice with the l. major seidman strain (lmsd), isolated from a patient with chronic lesions, despite eliciting a strong th1 response, results in a nonhealing lesion, poor parasite clearance, and complete destruction of the ear dermis. we show here that in comparison to a healing strain, lmsd elicited early upregulation of il-1β mrna and il-1β-prod ...201626689285
the glycerol-3-phosphate acyltransferase tbgat is dispensable for viability and the synthesis of glycerolipids in trypanosoma brucei.glycerolipids are the main constituents of biological membranes in trypanosoma brucei, which causes sleeping sickness in humans. importantly, they occur as a structural component of the glycosylphosphatidylinositol lipid anchor of the abundant cell surface glycoproteins procyclin in procyclic forms and variant surface glycoprotein in bloodstream form, that play crucial roles for the development of the parasite in the insect vector and the mammalian host, respectively. the present work reports th ...201626909872
evaluation of the in vivo leishmanicidal activity of amphotericin b emulgel: an alternative for the treatment of skin leishmaniasis.the american cutaneous leishmaniasis (acl) is an infectious disease that can be fatal. the first line of treatment is pentavalent antimonies. however, due to its potential to develop resistance, amphotericin b (amb) started to be used as an alternative medicine. current treatments are limited, a fact that has led to a growing interesting in developing new therapies. this study aims to evaluate the therapeutic potential in vivo of an amphotericin b + oleic acid (oa) emulgel in the treatment of cu ...201626902606
egfp reporter protein: its immunogenicity in leishmania-infected balb/c mice.optical reporter genes such as green fluorescent protein (gfp) and luciferase are efficiently and widely used in monitoring and studying the protective/therapeutic potential of candidate agents in leishmaniasis. but several observations and controversial reports have generated a main concern, whether enhanced gfp (egfp) affects immune response. to address this issue, we studied the immunogenicity of egfp in vivo by two lines of stably transfected parasites (leishmania major (egfp) or l. major (e ...201626685673
computing molecular devices in l.major through transcriptome analysis: structured simulation approach.in the modern era of post genomics and transcriptomics, non-coding rnas and non-coding regions of many rnas are a big puzzle when we try deciphering their role in specific gene function. gene function assessment is a main task wherein high throughput technologies provide an impressive body of data that enables the design of hypotheses linking genes to phenotypes. gene knockdown technologies and rna-dependent gene silencing are the most frequent approaches to assess the role of key effectors in a ...201626901858
oral treatment with zinc sulfate increases the expression of th1 cytokines mrna in balb/c mice infected with leishmania major.leishmaniases consist of a group of diseases caused by protozoan parasites of leishmania genus. the outcome of the disease depends on the immune responses of the host as well as the pathogenicity of the strain of the parasite. in murine models, the inoculation of leishmania major into resistant mice results in th1 responses and recovery from the infection. however in the susceptible mice, the same inoculation leads to a profile of th2 responses. zinc (zn) is an essential trace element which is r ...201626896749
the wnt antagonist dickkopf-1 promotes pathological type 2 cell-mediated inflammation.exposure to a plethora of environmental challenges commonly triggers pathological type 2 cell-mediated inflammation. here we report the pathological role of the wnt antagonist dickkopf-1 (dkk-1) upon allergen challenge or non-healing parasitic infection. the increased circulating amounts of dkk-1 polarized t cells to t helper 2 (th2) cells, stimulating a marked simultaneous induction of the transcription factors c-maf and gata-3, mediated by the kinases p38 mapk and sgk-1, resulting in th2 cell ...201626872695
lipid droplet formation, their localization and dynamics during leishmania major macrophage infection.leishmania, the causative agent of vector-borne diseases, known as leishmaniases, is an obligate intracellular parasite within mammalian hosts. the outcome of infection depends largely on the activation status of macrophages, the first line of mammalian defense and the major target cells for parasite replication. understanding the strategies developed by the parasite to circumvent macrophage defense mechanisms and to survive within those cells help defining novel therapeutic approaches for leish ...201626871576
immunotherapeutic effects of chitin in comparison with chitosan against leishmania major infection.chitin and chitosan microparticles (mps) are important immune system stimulators. the aim of this study was to evaluate the protective effects of these compounds in comparison with each other against leishmania infection in balb/c mice infected with leishmania major (l. major). female balb/c mice were injected subcutaneously with 2×10(5) promastigotes. chitin and/or chitosan mps (<40 μm) were subcutaneously injected in the balb/c mice with two-day intervals until two weeks. mice in all groups we ...201626518128
nlrp12 is a neutrophil-specific, negative regulator of in vitro cell migration but does not modulate lps- or infection-induced nf-κb or erk signalling.nod-like receptors (nlr) are a family of cytosolic pattern recognition receptors that include many key drivers of innate immune responses. nlrp12 is an emerging member of the nlr family that is closely related to the well-known inflammasome scaffold, nlrp3. since its discovery, various functions have been proposed for nlrp12, including the positive regulation of dendritic cell (dc) and neutrophil migration and the inhibition of nf-κb and erk signalling in dc and macrophages. we show here that nl ...201626514298
antileishmanial activity of compounds derived from the medicines for malaria venture open access box against intracellular leishmania major amastigotes.leishmaniasis is a complex tropical disease caused by kinetoplastid parasitic protozoa of the genus leishmania and is transmitted by the sand fly insect vector. cutaneous leishmaniasis (cl) is the most common form of this disease, and cl infections often result in serious skin lesions and scars. cl remains a public health problem in many endemic countries worldwide because of the absence of effective, safe, and cost-effective drugs for treatment. one of the strategies we chose to use to find nov ...201626503273
mast cells have no impact on cutaneous leishmaniasis severity and related th2 differentiation in resistant and susceptible mice.the genus leishmania comprises different protozoan parasites which are causative agents of muco-cutaneous and systemic, potentially lethal diseases. after infection with the species leishmania major, resistant mice expand th1 cells which stimulate macrophages for leishmania destruction. in contrast, susceptible mice generate th2 cells which deactivate macrophages, leading to systemic spread of the pathogens. th-cell differentiation is determined within the first days, and th2 cell differentiatio ...201626449668
unusual forms of cutaneous leishmaniasis due to leishmania major.cutaneous leishmaniasis (cl) due to leishmania major (l. major) is common in the middle east; however, this skin infection may be under-diagnosed when it presents atypically.201626347371
novel identification of leishmania major in hemiechinus auritus and molecular detection of this parasite in meriones libycus from an important foci of zoonotic cutaneous leishmaniasis in iran.one of the well-known foci of zoonotic cutaneous leishmaniasis (zcl) in iran is turkemen sahara, which is located in north eastern iran. zcl is a disease of mammals, and humans can become infected as accidental hosts. many researchers have argued that rhombomys opimus is the only main reservoir host of zcl in this region of the golestan province. no other rodents or mammals are thought to host or have been reported to host leishmania parasites in this region. this research was designed and devel ...201624613133
prediction of t cell epitopes from leishmania major potentially excreted/secreted proteins inducing granzyme b production.leishmania-specific cytotoxic t cell response is part of the acquired immune response developed against the parasite and contributes to resistance to reinfection. herein, we have used an immune-informatic approach for the identification, among leishmania major potentially excreted/secreted proteins previously described, those generating peptides that could be targeted by the cytotoxic immune response. seventy-eight nonameric peptides that are predicted to be loaded by hla-a*0201 molecule were ge ...201626771180
the dynamics of lateral gene transfer in genus leishmania - a route for adaptation and species diversification.the genome of leishmania major harbours a comparably high proportion of genes of prokaryote origin, acquired by lateral gene transfer (lgt). some of these are present in closely related trypanosomatids, while some are detected in leishmania only. we have evaluated the impact and destiny of lgt in genus leishmania.201626730948
killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites.protozoan infections are a serious global health problem. natural killer (nk) cells and cytolytic t lymphocytes (ctls) eliminate pathogen-infected cells by releasing cytolytic granule contents--granzyme (gzm) proteases and the pore-forming perforin (pfn)--into the infected cell. however, these cytotoxic molecules do not kill intracellular parasites. cd8(+) ctls protect against parasite infections in mice primarily by secreting interferon (ifn)-γ. however, human, but not rodent, cytotoxic granule ...201626752517
comparative study of viscerotropic pathogenicity of leishmania major amastigotes and promastigotes based on identification of mitochondrial and nucleus sequences.experimental viscerotropic leishmaniasis is regularly caused by leishmania tropica promastigotes. in the current investigation, the viscerotropic pathogenicities of leishmania major amastigotes and promastigotes were compared and evaluated based on their heterogeneity traits and number of inoculated parasites in experimental mammalian hosts. serous exudate from 50 patients was infected, 44 with l. major and 6 with l. tropica; only balb/c mice inoculated with 1-2 × 10(4-6) l. major amastigotes ma ...201626631188
leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence.leishmania major encodes 2 orthologs of the cytokine macrophage migration inhibitory factor (mif), whose functions in parasite growth or in the host-parasite interaction are unknown. to determine the importance of leishmania-encoded mif, both lmmif genes were removed to produce an mif(-/-) strain of l. major this mutant strain replicated normally in vitro but had a 2-fold increased susceptibility to clearance by macrophages. mice infected with mif(-/-) l. major, when compared to the wild-type st ...201626956417
tamoxifen induces apoptosis of leishmania major promastigotes in vitro.tamoxifen is an antagonist of the estrogen receptor and currently used for the treatment of breast cancer. the current treatment of cutaneous leishmaniasis with pentavalent antimony compounds is not satisfactory. therefore, in this study, due to its antileishmanial activity, effects of tamoxifen on the growth of promastigotes and amastigotes of leishmania major iranian strain were evaluated in vitro. promastigotes and amastigotes were treated with different concentrations (1, 5, 10, 20, and 50 μ ...201626951973
zinc(ii)-dipicolylamine coordination complexes as targeting and chemotherapeutic agents for leishmania major.cutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. this study describes the selective targeting of zinc(ii)-dipicolylamine (zndpa) coordination complexes toward leishmania major, one of the species responsible for cutaneous leishmaniasis. fluorescence microscopy of l. major promastigotes treated with a fluores ...201626926632
atenolol reduces leishmania major-induced hyperalgesia and tnf-α without affecting il-1β or keratinocyte derived chemokines (kc).infection with a high dose of the intracellular parasitic protozoan leishmania major induces a sustained hyperalgesia in susceptible balb/c mice accompanied by up-regulation of the pro-inflammatory cytokines il-1β and il-6. interleukin-13 (il-13) has been shown to reduce this hyperalgesia (despite increased levels of il-6) and the levels of il-1β during and after the treatment period. these findings favor the cytokine cascade leading to the production of sympathetic amines (involving tnf-α and k ...201626913003
therapeutic effect of scrophularia striata ethanolic extract against localized cutaneous leishmaniasis caused by leishmania major (mrho/ir/75/er).we evaluated the effect of the ethanolic extract of scrophularia striata on the iranian strain of leishmania major (mrho/ir/75/er) both in vitro and in vivo conditions.201627957441
the labcg2 transporter from the protozoan parasite leishmania is involved in antimony resistance.treatment for leishmaniasis, which is caused by leishmania protozoan parasites, currently relies on a reduced arsenal of drugs. however, the significant increase in the incidence of drug therapeutic failure and the growing resistance to first-line drugs like antimonials in some areas of northern india and nepal limit the control of this parasitic disease. understanding the molecular mechanisms of resistance in leishmania is now a matter of urgency to optimize drugs used and to identify novel dru ...201627021316
identification of "preferred" human kinase inhibitors for sleeping sickness lead discovery. are some kinases better than others for inhibitor repurposing?a kinase-targeting cell-based high-throughput screen (hts) against trypanosoma brucei was recently reported, and this screening set included the published kinase inhibitor set (pkis). from the pkis was identified 53 compounds with pec50 ≥ 6. utilizing the published data available for the pkis, a statistical analysis of these active antiparasitic compounds was performed, allowing identification of a set of human kinases having inhibitors that show a high likelihood for blocking t. brucei cellular ...201626998514
anti-leishmanial activity (in vitro and in vivo) of allicin and allicin cream using leishmania major (sub-strain zymowme lon4) and balb/c mice.leishmania is a unicellular protozoan parasite that produces several human diseases, ranging from localized self-healing cutaneous lesions to deadly visceral infections.201627537199
the role of montanide isa 70 as an adjuvant in immune responses against leishmania major induced by thiol-specific antioxidant-based protein vaccine.leishmaniasis is a parasitic disease caused by several species of the genus leishmania. montanide isa 70 is an adjuvant composed of a natural metabolizable oil and a very refined emulsifier from the manide monooleate family. the tsa (thiol-specific antioxidant) is a important antigen of leishmania major. the purpose of this work was protein-vaccine efficacy as an protection and excellent candidate in the presence montanide. the expression of recombinant protein was confirmed with sds (sodium dod ...201627605780
leishmania major promastigotes evade lc3-associated phagocytosis through the action of gp63.the protozoan leishmania parasitizes macrophages and evades the microbicidal consequences of phagocytosis through the inhibition of phagolysosome biogenesis. in this study, we investigated the impact of this parasite on lc3-associated phagocytosis, a non-canonical autophagic process that enhances phagosome maturation and functions. we show that whereas internalization of l. major promastigotes by macrophages promoted lc3 lipidation, recruitment of lc3 to phagosomes was inhibited through the acti ...201627280768
an electrochemical genosensor for leishmania major detection based on dual effect of immobilization and electrocatalysis of cobalt-zinc ferrite quantum dots.identification of leishmania parasites is important in diagnosis and clinical studies of leishmaniasis. although epidemiological and clinical methods are available, they are not sufficient for identification of causative agents of leishmaniasis. in the present study, quantum dots of magnetic cobalt-zinc ferrite (co0.5zn0.5fe2o4) were synthesized and characterized by physicochemical methods. the quantum dots were then employed as an electrode modifier to immobilize a 24-mer specific single strand ...201627260450
antileishmanial activity of date (phoenix dactylifera l) fruit and pit extracts in vitro.leishmaniasis is considered as a major public health problem worldwide. current drugs in treatment of leishmaniasis have some limitations; thus, the current study was aimed to assess the methanolic extracts of pit and fruit of phoenix dactylifera against leishmania major promastigotes. l major promastigotes were cultured in rpmi 1640 and incubated at 25°c ± 1°c for 24, 48, and 72 hours. for obtaining the ic50 (half maximal inhibitory concentration) value, mtt assay was employed. furthermore, pro ...201627242378
leishmania major and trypanosoma cruzi present distinct dna damage responses.leishmania major and trypanosoma cruzi are medically relevant parasites and interesting model organisms, as they present unique biological processes. despite increasing data regarding the mechanisms of gene expression regulation, there is little information on how the dna damage response (ddr) occurs in trypanosomatids. we found that l. major presented a higher radiosensitivity than t. cruzi. l. major showed g1 arrest and displayed high mortality in response to ionizing radiation as a result of ...201627188657
cathepsin b-deficient mice resolve leishmania major inflammation faster in a t cell-dependent manner.a critical role for intracellular tlr9 has been described in recognition and host resistance to leishmania parasites. as tlr9 requires endolysosomal proteolytic cleavage to achieve signaling functionality, we investigated the contribution of different proteases like asparagine endopeptidase (aep) or cysteine protease cathepsins b (catb), l (catl) and s (cats) to host resistance during leishmania major (l. major) infection in c57bl/6 (wt) mice and whether they would impact on tlr9 signaling. unli ...201627182703
human immune response to salivary proteins of wild-caught phlebotomus papatasi.phlebotomine sand flies are the known vectors of leishmania parasites. new approaches in vaccination against leishmania have investigated the possibility of integrating phlebotomus papatasi salivary proteins to enhance the immune response and protect against the transmission of the infection. the aim of the present study was to screen human immune responses to wild sand fly saliva and evaluate immunogenic salivary proteins. blood samples were collected from donors in control and sand fly infeste ...201627160331
aryl hydrocarbon receptor influences nitric oxide and arginine production and alters m1/m2 macrophage polarization.the aryl hydrocarbon receptor (ahr) is a ligand-activated transcription factor that mediates the toxicity of environmental pollutants. it is also implicated in the regulation of the immune system. ahr-null macrophages overproduce several proinflammatory cytokines following lps-mediated stimulation, suggesting that ahr affects the balance between the inflammatory m1 and anti-inflammatory m2 phenotypes. therefore, the present study aimed to examine whether the loss of ahr modifies macrophage polar ...201627153778
leishmania mexicana: promastigotes and amastigotes secrete protein phosphatases and this correlates with the production of inflammatory cytokines in macrophages.phosphatase activity of leishmania spp. has been shown to deregulate the signalling pathways of the host cell. we here show that leishmania mexicana promastigotes and amastigotes secrete proteins with phosphatase activity to the culture medium, which was higher in the promastigote secretion medium (psm) as compared with the amastigote secretion medium (asm) and was not due to cell lysis, since parasite viability was not affected by the secretion process. the biochemical characterization showed t ...201627220404
codelivery of dna vaccination encoding leif gene and il-12 increases protection against leishmania major infection in balb/c mice.previous studies have shown that leishmania elongation initiation factor (leif) antigen causes a partial immunity against leishmaniasis. the antigen develops type i immunity by overexpression of inflammatory cytokines such as interleukin-12 (il-12), ifn-γ and tnf-α. therefore, we evaluated immune responses induced by the leif gene against leishmania major infection. immunization with leif gene alone or with il-12 induced th1 response and produced higher ifn-γ and lower il-4 levels by splenocytes ...201626868280
cutaneous leishmaniasis: an overlooked etiology of midfacial destructive lesions.midline destructive lesions of the face (mdl) have a wide range of etiologies. cutaneous leishmaniasis (cl) is rarely reported as a possible cause.201626862748
resequencing and assembly of seven complex loci to improve the leishmania major (friedlin strain) reference genome.leishmania parasites cause severe human diseases known as leishmaniasis. these eukaryotic microorganisms possess an atypical chromosomal architecture and the regulation of gene expression occurs almost exclusively at post-transcriptional levels. accordingly, sequencing of the genome of leishmania major, and subsequently the genome of other related species, was paramount for highlighting these peculiar molecular aspects. recently, we carried out an analysis of gene expression by massive sequencin ...201626857920
molecular prevalence and estimated risk of cutaneous leishmaniasis in libya.cutanoeus leishmaniasis (cl) is an endemic disease in the mediterranean area including libya. the aim of the present study is to detect the prevalent leishmania species obtained from smeared cutaneous lesions in addition to studying the diverse sociodemographic risk factors of the reported cases from different provinces of libya.201626850321
[epidemiological and clinical features of cutaneous leishmaniasis in kairouan-tunisia and characteristics in children].cutaneous leishmaniasis (cl) remains highly endemic in tunisia. the governorate of kairouan (center) is one of the most affected particularly by zoonotic form due to leishmania major. the purpose of this study was to describe the epidemiological, clinical and therapeutic features of the disease in this governorate and to identify any particularities in children. three hundred and ninety cases were registered over 2 years (2012 and 2013). the average age was 29 years one month [± 22.7] (34.6% of ...201626850105
in vitro and in vivo antileishmanial activities of pistacia vera essential oil.this study aims to evaluate the in vitro and in vivo antileishmanial activities of pistacia vera essential oil and compare their efficacy with a reference drug, meglumine antimoniate (glucantime®). this essential oil (0-100 µg/ml) was evaluated in vitro against the intracellular amastigote forms of leishmania tropica (mhom/ir/2002/mash2) and then tested on cutaneous leishmaniasis of male balb/c mice by leishmania major (mrho/ir/75/er). in the in vitro assay, it could be observed that p. vera ess ...201626829519
correlation of genetic heterogeneity with cytopathological and epidemiological findings of leishmania major isolated from cutaneous leishmaniasis in southern iran.cutaneous leishmaniasis (cl) has recently grown into a major public health problem in 88 countries of the world, including iran. it is a polymorphic disease which may show various clinicopathological features. although the effect of the genetic diversity of the parasite has been demonstrated as one of the factors influencing clinical manifestations in cl, no data exist regarding the genetic variation of leishmania major and its microscopical features.201627215312
unraveling the alkaline phosphatase inhibition, anticancer, and antileishmanial potential of coumarin-triazolothiadiazine hybrids: design, synthesis, and molecular docking analysis.a series of new coumarin-triazolothiadiazine hybrid compounds (5a-j) was designed and synthesized by using the molecular hybridization concept. the cyclocondensation reaction involves the coumarinyl 4-amino-1,2,4-triazole and a range of bromo-acetophenones, delivering the desired products in good yields. the structures of the synthesized compounds were established on the basis of spectro-analytical data. the prepared compounds were evaluated against alkaline phosphatase (alp) where compound 5j i ...201627214743
tnf-mediated restriction of arginase 1 expression in myeloid cells triggers type 2 no synthase activity at the site of infection.neutralization or deletion of tumor necrosis factor (tnf) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. here, we found that tnf antagonized alternative activation of macrophages and dendritic cells by il-4. tnf inhibited il-4-induced arginase 1 (arg1) expression by decreasing histone acetylation, without affecting stat6 phosphorylation and nuclear translocation. in leishmania major-infected c57bl/6 wild-type mice, ...201627117406
anti-leishmania activity of osthole.treatment of cutaneous leishmaniasis (cl) is occasionally highly resistant to pentavalent antimonials, the gold standard in pharmacotherapy of cl. since there is no effective vaccine, the discovery of natural antileishmanial products as complementary therapeutic agents could be used to improve the current regimens.201627114685
the role of iscomatrix bilayer composition to induce a cell mediated immunity and protection against leishmaniasis in balb/c mice.development of new generation of vaccines against leishmaniasis is possible because long-term protection is usually seen after recovery from cutaneous leishmaniasis. iscomatrix is particulate antigen delivery system composed of antigen, cholesterol, phospholipid and saponin. in this study, the role of iscomatrix bilayer composition made by different phase transition temperature (tc) to induce a type of immune response and protection against leishmaniasis was assessed.201627081463
detection of leishmania major dna within wild caught phlebotomus papatasi and species composition of sand flies in endemic focus of cutaneous leishmaniasis, in western iran.cutaneous leishmaniasis is one of the most important public health problem in many developing countries. the present study was conducted to determine the vector(s), the parasite and the species composition of sand flies in the dehloran county during may-november 2012. sand flies were collected by sticky traps and mounted in puri's medium for species identification. polymerase chain reaction (pcr) techniques of kdna, its1-rdna, followed by restriction fragment length polymorphism (rflp) were used ...201627065601
effect of topical morphine on cutaneous leishmaniasis in an animal model: a preliminary report.pentavalent antimonials remain the choice of treatment for leishmaniasis, despite their toxicity, high cost, and difficult administration. as an alternative, morphine may induce the healing process of cutaneous leishmaniasis by its immunoregulatory characteristics.201627437123
transcription of leishmania major u2 small nuclear rna gene is directed by extragenic sequences located within a trna-like and a trna-ala gene.leishmania and other trypanosomatid parasites possess atypical mechanisms of gene expression, including the maturation of mrnas by trans-splicing and the involvement of rna polymerase iii in transcription of all snrna molecules. since snrnas are essential for trans-splicing, we are interested in the study of the sequences that direct their expression. here we report the characterization of l. major u2 snrna promoter region.201627430335
oral azithromycin versus its combination with miltefosine for the treatment of experimental old world cutaneous leishmaniasis.leishmaniasis is one of the neglected infectious diseases included in the world health organization's list of the top guns of antimicrobial resistance. miltefosine is the first and the only available oral effective therapy for leishmaniasis. for fear of its potential resistance, identification of alternative, effective and safe drugs is urgently needed. therefore, in view of azithromycin promising activity against a number of leishmania species, this work was carried out to evaluate the efficacy ...201627413324
immune responses in dna vaccine formulated with pmma following immunization and after challenge with leishmania major.leishmaniasis is a major infectious disease caused by protozoan parasites of the genus leishmania. despite of many efforts toward vaccine against leishmania no effective vaccine has been approved yet. dna vaccines can generate more powerful and broad immune responses than conventional vaccines. in order to increase immunity, the dna vaccine has been supplemented with adjuvant. in this study a new nano-vaccine containing tsa recombinant plasmid and poly(methylmethacrylate) nanoparticles (act as a ...201627413316
pathways leading to interleukin-12 production and protective immunity in cutaneous leishmaniasis.leishmaniasis affects millions of people worldwide and continues to pose public health problem. there is extensive evidence supporting the critical role for il-12 in initiating and maintaining protective immune response to leishmania infection. although gene deletion studies show that cd40-cd40l interaction is an important pathway for il-12 production by antigen-presenting cells and subsequent development of protective immunity in cutaneous leishmaniasis, several studies have uncovered other pat ...201627394077
insights into the structural patterns of the antileishmanial activity of bi- and tricyclic n-heterocycles.the influence of various structural patterns in a series of novel bi- and tricyclic n-heterocycles on the activity against leishmania major and leishmania panamensis has been studied and compounds that are active in the low micromolar region have been identified. both quinolines and tetrahydrooxazinoindoles (toi) proved to have significant antileishmanial activities, while substituted indoles were inactive. we have also showed that a chloroquine analogue induces leishmania killing by modulating ...201627376396
concomitant immunity induced by persistent leishmania major does not preclude secondary re-infection: implications for genetic exchange, diversity and vaccination.many microbes have evolved the ability to co-exist for long periods of time within other species in the absence of overt pathology. evolutionary biologists have proposed benefits to the microbe from 'asymptomatic persistent infections', most commonly invoking increased likelihood of transmission by longer-lived hosts. typically asymptomatic persistent infections arise from strong containment by the immune system, accompanied by protective immunity; such 'vaccination' from overt disease in the pr ...201627352043
lmsmdb: an integrated database for metabolic and gene regulatory network in leishmania major and schistosoma mansoni.a database that integrates all the information required for biological processing is essential to be stored in one platform. we have attempted to create one such integrated database that can be a one stop shop for the essential features required to fetch valuable result. lmsmdb (l. major and s. mansoni database) is an integrated database that accounts for the biological networks and regulatory pathways computationally determined by integrating the knowledge of the genome sequences of the mention ...201626981382
ribosomal rna genes in the protozoan parasite leishmania major possess a nucleosomal structure.little is known about nucleosome structure and epigenetic regulation of transcription of rrna genes in early-branched eukaryotes. here we analyze the chromatin architecture and distribution of some histone modifications in the rrna genes in the parasitic protozoon leishmania major. southern blots of mnase-partially-digested chromatin with dna probes spanning the whole rrna gene repeat showed that the intergenic spacer presents a tight nucleosomal structure, whereas the promoter region is practic ...201626963795
lack of galectin-3 increases jagged1/notch activation in bone marrow-derived dendritic cells and promotes dysregulation of t helper cell polarization.galectin-3, an endogenous glycan-binding protein, is abundantly expressed at sites of inflammation and immune cell activation. although this lectin has been implicated in the control of t helper (th) polarization, the mechanisms underlying this effect are not well understood. here, we investigated the role of endogenous galectin-3 during the course of experimental leishmania major infection using galectin-3-deficient (lgals3(-/-)) mice in a balb/c background and the involvement of notch signalin ...201627344022
in vitro anti-leishmanial activity of satureja hortensis and artemisia dracunculus extracts on leishmania major promastigotes.cutaneous leishmaniasis is one of the important skin diseases with diverse clinical manifestations. with an incidence of 0.7-1.3 million cases annually, this disease is often reported from six countries, including iran. accordingly, the purpose of this study was to evaluate the anti-leishmanial effect of the three plant hydroalcoholic extracts including fleawort (plantago psyllium l.), savory (satureja hortensis l.) and tarragon (artemisia dracunculus l.) on leishmania major promastigotes. the h ...201627876985
evaluation of the alum-naloxone adjuvant activity against experimental murine leishmaniasis due to l. major.leishmaniasis is caused by intracellular parasites of leishmania species, which are transmitted by the bite of the sandfly. recovery and protection against the infection depends on the induction of a strong th1 type of immune response. vaccination of mice with the opioid antagonist naloxone can promote the activation of the th1 responses. we studied the efficacy of the mixture of naloxone and alum, as an adjuvant, to enhance immune responses and induce protection against leishmania major infecti ...201627876902
in vitro efficacy of ethanolic extract of artemisia absinthium (asteraceae) against leishmania major l. using cell sensitivity and flow cytometry assays.leishmaniasis is one of the most neglected human diseases with an estimated global burden ranking second in mortality and fourth in morbidity among the tropical infections. chemotherapy involving the use of drugs like glucantime is the mainstay treatment in endemic areas of iran. drug resistance is increasingly prevalent, so search for alternative therapy is gathering pace. medicinal herbs, like wormwood artemisia, have chemical compounds effective against a number of pathogens. in this study, t ...201627605775
in vivo/in vitro immune responses to l. major isolates from patients with no clinical response to glucantime.leishmaniasis is a major health problem in some endemic areas of tropical and subtropical areas of the world. interleukin-12 (il-12) and interferon gamma (ifn-γ) are essential cytokines associated with initiation of th1 response. the main objective of this study was to evaluate of the type of immune response to l. major isolates from patients with no clinical response to antimonite (glucantime).201627563636
an epidemic outbreak of cutaneous leishmaniasis presenting as suppurative folliculitis: a study of 6 cases.folliculitis is defined as the inflammation of the follicles. the most common cause of folliculitis is infection. here, we report an unusual cause of suppurative infundibulitis-which had not yet been described in the literature-due to leishmania infection, and exemplified by 6 cases that occurred in the setting of an epidemic outbreak. the 6 individuals were immigrants from morocco. most of them were men (4 men and 2 women), and most of them were less than 30 years old (apart from one 40-year-ol ...201627655127
crystal structure of an fe-s cluster-containing fumarate hydratase enzyme from leishmania major reveals a unique protein fold.fumarate hydratases (fhs) are essential metabolic enzymes grouped into two classes. here, we present the crystal structure of a class i fh, the cytosolic fh from leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4fe-4s] cluster. our 2.05 å resolution data further reveal a dimeric architecture for this fh that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. besides the active site ...201627528683
immunization against cutaneous leishmaniasis by alginate microspheres loaded with autoclaved leishmania major (alm) and quillaja saponins.leishmania antigens are weak immunogens and need to be potentiated by various adjuvants and delivery systems. alginate microspheres as antigen delivery system and quillaja saponins (qs) as immunoadjuvant have been used to enhance the immune response against autoclaved leishmania major (alm). microspheres were prepared by an emulsification technique and characterized for size, encapsulation efficiency and release profile of encapsulates. balb/c mice were immunized three times in 3-weeks intervals ...201627642328
myeloid cell-derived hif-1α promotes control of leishmania major.hypoxia-inducible factor-1α (hif-1α), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. however, whether and to what extent hif-1α expressed by myeloid cells contributes to the innate immune response against leishmania major parasites is unknown. we observed that leishmania-infected humans and l. major-infected c57bl/6 mice exhibited substantial amounts of hif-1α in acute cutaneous lesions. in vitro, hif-1α was required for leishman ...201627798163
epidemiology of the outbreak, vectors and reservoirs of cutaneous leishmaniasis in mali: a systematic review and meta-analysis.to compile available data and to estimate the burden, characteristics and risks factors of cutaneous leishmaniasis (cl) in mali.201627794393
ruthenium-clotrimazole complex has significant efficacy in the murine model of cutaneous leishmaniasis.in previous studies we reported a novel series of organometallic compounds, ru(ii) complexed with clotrimazole, displaying potent trypanosomatid activity with unnoticeable toxicity toward normal mammalian cells. in view of the promising activity of ru-clotrimazole complexes against leishmania major (l. major), the present work sought to investigate the anti-leishmanial activity of the am162 complex in the murine model of cutaneous leishmaniasis. in addition, to facilitate the design of new thera ...201627693373
topical treatment with a two-component gel releasing nitric oxide cures c57bl/6 mice from cutaneous leishmaniasis caused by leishmania major. 201627249422
leishmania uses mincle to target an inhibitory itam signaling pathway in dendritic cells that dampens adaptive immunity to infection.c-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. here, we have found that human and mouse mincle bind to a ligand released by leishmania, a eukaryote parasite that evades an effective immune response. mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after leishmania major intradermal ear infection. mincle deficiency enhanced adaptive immunity against the parasite, ...201627742545
toll-like receptor 2 (tlr2) plays a role in controlling cutaneous leishmaniasis in vivo, but does not require activation by parasite lipophosphoglycan.leishmaniasis is a neglected tropical disease affecting millions of individuals worldwide. despite several studies reporting involvement of the innate immune receptor toll-like receptor 2 (tlr2) in the recognition of surface glycolipids from leishmania parasites in vitro, the role of tlr2 and its co-receptors during cutaneous leishmaniasis infection in vivo is unknown.201627716391
validation of a thin-layer chromatography/densitometry method for the characterization of invertase activity.this paper presents a kinetic study of invertase, a specific fructofuranosidase cloned from the leishmania major genome. the kinetic parameters of the β-d-fructofuranosidase from leishmania major (bfra) were determined using thin-layer chromatography (tlc) and uv-densitometry (tlc@uv) specifically developed for the separation and detection of three carbohydrates namely sucrose, glucose and fructose. separation was performed on tlc silica gel 60 f254 plates impregnated with sodium bisulphate and ...201627912968
molecular characterization of 5s ribosomal rna genes and transcripts in the protozoan parasite leishmania major.eukaryotic 5s rrna, synthesized by rna polymerase iii (pol iii), is an essential component of the large ribosomal subunit. most organisms contain hundreds of 5s rrna genes organized into tandem arrays. however, the genome of the protozoan parasite leishmania major contains only 11 copies of the 5s rrna gene, which are interspersed and associated with other pol iii-transcribed genes. here we report that, in general, the number and order of the 5s rrna genes is conserved between different species ...201627707420
exploring the leishmania hydrophilic acylated surface protein b (haspb) export pathway by live cell imaging methods.leishmania major is a human-infective protozoan parasite transmitted by the bite of the female phlebotomine sand fly. the l. major hydrophilic acylated surface protein b (haspb) is only expressed in infective parasite stages suggesting a role in parasite virulence. haspb is a "nonclassically" secreted protein that lacks a conventional signal peptide, reaching the cell surface by an alternative route to the classical er-golgi pathway. instead haspb trafficking to and exposure on the parasite plas ...201627665560
gene-specific sex effects on eosinophil infiltration in leishmaniasis.sex influences susceptibility to many infectious diseases, including some manifestations of leishmaniasis. the disease is caused by parasites that enter to the skin and can spread to the lymph nodes, spleen, liver, bone marrow, and sometimes lungs. parasites induce host defenses including cell infiltration, leading to protective or ineffective inflammation. these responses are often influenced by host genotype and sex. we analyzed the role of sex in the impact of specific gene loci on eosinophil ...201627895891
structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of leishmania major pteridine reductase 1 inhibitors.leishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. although l. major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. the lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (ptr1) plays a major role. for this reason, this en ...201627517809
ecological niche modeling of main reservoir hosts of zoonotic cutaneous leishmaniasis in iran.zoonotic cutaneous leishmaniasis (zcl), caused by leishmania major, is a common zoonotic vector-borne disease in iran. close contact with infected reservoir hosts increases the probability of transmission of leishmania parasite infections to susceptible humans. four gerbil species (rodentia: gerbillidae) serve as the main reservoir hosts for zcl in different endemic foci of iran. these species include rhombomys opimus, meriones libycus, meriones hurrianae and tatera indica; while notable infecti ...201627150212
real-time pcr using fret technology for old world cutaneous leishmaniasis species differentiation.recently, there has been a re-emergence of cutaneous leishmaniasis in endemic countries and an increase in imported cases in non-endemic countries by travelers, workers, expatriates, immigrants, and military force personnel. old world cutaneous leishmaniasis is caused primarily by leishmania major, l. tropica and l. aethiopica. despite their low sensitivity, diagnosis traditionally includes microscopic and histopathological examinations, and in vitro cultivation. several conventional pcr techniq ...201627141967
transcriptionally driven dna replication program of the human parasite leishmania major.faithful inheritance of eukaryotic genomes requires the orchestrated activation of multiple dna replication origins (oris). although origin firing is mechanistically conserved, how origins are specified and selected for activation varies across different model systems. here, we provide a complete analysis of the nucleosomal landscape and replication program of the human parasite leishmania major, building on a better evolutionary understanding of replication organization in eukarya. we found tha ...201627477279
leishmania major infection-induced vegf-a/vegfr-2 signaling promotes lymphangiogenesis that controls disease.cutaneous leishmaniasis causes a spectrum of diseases from self-healing to severe nonhealing lesions. defining the factors contributing to lesion resolution may help in developing new therapies for those patients with chronic disease. we found that infection with leishmania major increases the expression of vascular endothelial growth factor-a and vascular endothelial growth factor receptor (vegfr)-2 and is associated with significant changes in the blood and lymphatic vasculature at the site of ...201627474074
genetic micro-heterogeneity of leishmania major in emerging foci of zoonotic cutaneous leishmaniasis in tunisia.tunisia is endemic for zoonotic cutaneous leishmaniasis (zcl), a parasitic disease caused by leishmania (l.) major. zcl displays a wide clinical polymorphism, with severe forms present more frequently in emerging foci where naive populations are dominant. in this study, we applied the multi-locus microsatellite typing (mlmt) using ten highly informative and discriminative markers to investigate the genetic structure of 35 tunisian leishmania (l.) major isolates collected from patients living in ...201627137082
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