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batf3-dependent cd103+ dendritic cells are major producers of il-12 that drive local th1 immunity against leishmania major infection in mice.the role of different dc subsets in priming and maintenance of immunity against leishmania major (l. major) infection is debated. the transcription factor basic leucine zipper transcription factor, atf-like 3 (batf3) is essential for the development of mouse cd103(+) dcs and some functions of cd8α(+) dcs. we found that cd103(+) dcs were significantly reduced in the dermis of batf3-deficient c57bl/6 mice. batf3(-/-) mice developed exacerbated and unresolved cutaneous pathology following a low dos ...201525312824
cutaneous leishmaniasis responds to daylight-activated photodynamic therapy: proof of concept for a novel self-administered therapeutic modality.cutaneous leishmaniasis (cl) is endemic in israel, with hundreds of new cases reported in recent years. photodynamic therapy (pdt) is highly effective for treatment of cl, but requires equipment available only at specialized centres. daylight-activated pdt (da-pdt) abolishes the need for artificial light sources and allows the patient to administer the treatment with no professional assistance.201525363817
effects of combined therapy with silymarin and glucantime on leishmaniasis induced by leishmania major in balb/c mice.leishmania major is resistant to the traditional treatments in many parts of the world. pgpa, a member of (abc) transporter superfamily, has been identified in leishmania involved in antimony resistance. silymarin can inhibit pgpa. the aim of this study was to determine the effect of combined therapy with glucantime and silymarin on cutaneous leishmaniasis. the effects of silymarin on response of l. major to glucantime were evaluated with amastigote macrophage and mice model of leishmaniasis. im ...201524623031
depletion of udp-glucose and udp-galactose using a degron system leads to growth cessation of leishmania major.interconversion of udp-glucose (udp-glc) and udp-galactose (udp-gal) by the udp-glc 4´-epimerase intimately connects the biosynthesis of these two nucleotide sugars. their de novo biosynthesis involves transformation of glucose-6-phosphate into glucose-1-phosphate by the phosphoglucomutase and subsequent activation into udp-glc by the specific udp-glc pyrophosphorylase (ugp). besides ugp, leishmania parasites express an uncommon udp-sugar pyrophosphorylase (usp) able to activate both galactose-1 ...201526529232
the activity of ozonated olive oil against leishmania major promastigotes.cutaneous leishmaniasis is a common and endemic disease in khorasan province in north-east of iran. the pentavalant antimony (sb v) is the mainstay of treatment that has many side effects and resistance to the drug has been reported. the microbicidal effect of ozone was proven in different microorganisms. since there is no study in this respect and to achieve a low cost and effective treatment, we decided to evaluate the efficacy of ozone against promastigotes of leishmania major, in vitro.201526523224
metabolic, immune, and gut microbial signals mount a systems response to leishmania major infection.parasitic infections such as leishmaniasis induce a cascade of host physiological responses, including metabolic and immunological changes. infection with leishmania major parasites causes cutaneous leishmaniasis in humans, a neglected tropical disease that is difficult to manage. to understand the determinants of pathology, we studied l. major infection in two mouse models: the self-healing c57bl/6 strain and the nonhealing balb/c strain. metabolic profiling of urine, plasma, and feces via prot ...201525369177
the jordanian mid jordan valley is a classic focus of leishmania major as revealed by rflp of 56 isolates and 173 its-1-pcr-positive clinical samples.the identity of the causative species of cutaneous leishmaniasis (cl) in the endemic jordanian mid jordan valley (jmidjv) was investigated using the polymerase chain reaction (pcr) amplifying the ribosomal internal transcribed spacer 1 (its-1) followed by the restriction fragment length polymorphism (rflp). the geographical distribution of cl and the usefulness of its1 pcr in diagnosis of suspected cl in the study area were also addressed. over the period from 2004 to 2009, 56 clinical isolates ...201525450773
ox40l-ox40 pathway plays distinct roles in regulating th2 responses but does not determine outcome of cutaneous leishmaniasis caused by leishmania mexicana and leishmania major.ox40 ligand (ox40l)-ox40 pathway has been shown to enhance th2 responses and play a role in pathogenesis of cutaneous leishmaniasis (cl) caused by leishmania major. using ox40l(-/-) balb/c mice we analyzed the role of this pathway in determining the outcome to cl caused by l. mexicana and compared to l. major. contrary to our expectations, ox40l(-/-) mice were highly susceptible to both l. major (lv39) and l. mexicana (m379) and developed large non-healing lesions containing parasites comparable ...201525447125
characterisation of polyglutamylases in trypanosomatids.microtubules are subject to post-translational modifications, which are thought to have crucial roles in the function of complex microtubule-based organelles. among these, polyglutamylation was relatively recently discovered, and was related to centrosome stability, axonemal maintenance and mobility, and neurite outgrowth. in trypanosomatids, parasitic protozoa where microtubules constitute the essential component of the cytoskeleton, the function of polyglutamylated microtubules is unknown. her ...201525444861
dramatic increase in laboratory-diagnosed human cutaneous leishmaniasis cases in southern israel, 2007-2013.cutaneous leishmaniasis (cl) is an endemic zoonosis in southern israel. in recent years, substantial urbanization has been taking place in this region. the introduction of populations into endemic foci was previously reported to facilitate human cl outbreaks. our aim was to describe a continuous cl outbreak in southern israel, through laboratory reports of cl diagnosis.201525622937
synthesis, characterization and urease inhibition, in vitro anticancer and antileishmanial studies of ni(ii) complexes with n,n,n'-trisubstituted thioureas.a series of n,n,n'-trisubstituted thioureas (1-12) and their ni(ii) complexes (1a-12a) were synthesized and characterized by multinuclear ((1)h and (13)c) nmr, ft-ir spectroscopy and lc-ms techniques in combination with elemental analysis. the crystal structures of both ligands and ni(ii) chelates of type ni(l-o, s)2 were determined by single crystal x-ray diffraction analysis. all the complexes were adopted to have square planar geometry, where the n,n,n'-trisubstituted thioureas showed bidenta ...201525604966
lysophosphatidylcholine exacerbates leishmania major-dendritic cell infection through interleukin-10 and a burst in arginase1 and indoleamine 2,3-dioxygenase activities.leishmania major is an obligate intracellular parasite hosted by phagocytes, including dendritic cells (dcs). lysophosphatidylcholine (lpc) a pro-oxidant by-product of phospholipase a2 activity can modulate the maturation and function of dcs. however, little is known about its role in l. major infection. this study examined the effects of lpc and lipopolysaccharide (lps) in balb/c mouse-derived dc infection by l. major promastigotes, in vitro. our results showed early divergent effects of lps an ...201525601495
phlebotomus papatasi exposure cross-protects mice against leishmania major co-inoculated with phlebotomus duboscqi salivary gland homogenate.leishmania parasites are inoculated into host skin together with sand fly saliva and multiple exposures to uninfected sand fly bites protect mice against leishmania infection. however, sand fly vectors differ in composition of the saliva and therefore the protection elicited by their salivary proteins was shown to be species-specific. on the other hand, the optimal vaccine based on sand fly salivary proteins should be based on conserved salivary proteins conferring cross-reactivity. in the prese ...201525597641
deficiency of prolactin-inducible protein leads to impaired th1 immune response and susceptibility to leishmania major in mice.although the strategic production of prolactin-inducible protein (pip) at several ports of pathogen entry into the body suggests it might play a role in host defense, no study has directly implicated it in immunity against any infectious agent. here, we show for the first time that pip deficiency is associated with reduced numbers of cd4(+) t cells in peripheral lymphoid tissues and impaired cd4(+) th1-cell differentiation in vitro. in vivo, cd4(+) t cells from ova-immunized, pip-deficient mice ...201525594453
targeting sterol metabolism for the development of antileishmanials.membrane sterol profiles differ between humans and leishmania parasites, and the sterol pathway has been investigated for potential therapeutic targets. recently, mutants of the c14α-sterol demethylase in leishmania major were found to have several major alterations such as increased membrane fluidity, hypersensitivity to heat stress, and severe reduction of virulence.201525498194
anti leishmanial effect of zinc sulphate on the viability of leishmania tropica and l. major promastigotes.cutaneous leishmaniasis (cl) is an endemic disease in developing countries. although pentamidine orantimonite (glucantime) has been recommended for cutaneous leishmaniasis treatment by the world health organization, there are some concerns too such as high cost, side effects, need for frequent injections, and restricted efficacy. therefore, different methods have been used for cl treatment so far.201425485055
glycosome turnover in leishmania major is mediated by autophagy.autophagy is a central process behind the cellular remodeling that occurs during differentiation of leishmania, yet the cargo of the protozoan parasite's autophagosome is unknown. we have identified glycosomes, peroxisome-like organelles that uniquely compartmentalize glycolytic and other metabolic enzymes in leishmania and other kinetoplastid parasitic protozoa, as autophagosome cargo. it has been proposed that the number of glycosomes and their content change during the leishmania life cycle a ...201425484087
evaluation of protective effect of il-22 and il-12 on cutaneous leishmaniasis in balb/c mice.to investigate the protective effect of il-22 and il-12 on cutaneous leishmaniasisin balb/c mice.201425479621
blocking junctional adhesion molecule c enhances dendritic cell migration and boosts the immune responses against leishmania major.the recruitment of dendritic cells to sites of infections and their migration to lymph nodes is fundamental for antigen processing and presentation to t cells. in the present study, we showed that antibody blockade of junctional adhesion molecule c (jam-c) on endothelial cells removed jam-c away from junctions and increased vascular permeability after l. major infection. this has multiple consequences on the output of the immune response. in resistant c57bl/6 and susceptible balb/c mice, we foun ...201425474593
the existence of only one haplotype of leishmania major in the main and potential reservoir hosts of zoonotic cutaneous leishmaniasis using different molecular markers in a focal area in iran.leishmania major is the causative agent of zoonotic cutaneous leishmaniasis (zcl), and great gerbils are the main reservoir hosts in iran. abarkouh in central iran is an emerging focal point for which the reservoir hosts of zcl are unclear. this research project was designed to detect any leishmania parasites in different wild rodent species.201425467262
electrostatic channeling in p. falciparum dhfr-ts: brownian dynamics and smoluchowski modeling.we perform brownian dynamics simulations and smoluchowski continuum modeling of the bifunctional plasmodium falciparum dihydrofolate reductase-thymidylate synthase (p. falciparum dhfr-ts) with the objective of understanding the electrostatic channeling of dihydrofolate generated at the ts active site to the dhfr active site. the results of brownian dynamics simulations and smoluchowski continuum modeling suggest that compared to leishmania major dhfr-ts, p. falciparum dhfr-ts has a lower but sig ...201425418308
cd8+ t cells are preferentially activated during primary low dose leishmania major infection but are completely dispensable during secondary anti-leishmania immunity.we previously showed that cd8+ t cells are required for optimal primary immunity to low dose leishmania major infection. however, it is not known whether immunity induced by low dose infection is durable and whether cd8+ t cells contribute to secondary immunity following recovery from low dose infection. here, we compared primary and secondary immunity to low and high dose l. major infections and assessed the influence of infectious dose on the quality and magnitude of secondary anti-leishmania ...201425412267
tlr9 activation is triggered by the excess of stimulatory versus inhibitory motifs present in trypanosomatidae dna.dna sequences purified from distinct organisms, e.g. non vertebrate versus vertebrate ones, were shown to differ in their tlr9 signalling properties especially when either mouse bone marrow-derived- or human dendritic cells (dcs) are probed as target cells. here we found that the dc-targeting immunostimulatory property of leishmania major dna is shared by other trypanosomatidae dna, suggesting that this is a general trait of these eukaryotic single-celled parasites. we first documented, in vitro ...201425392997
the efficacy of hydro alcoholic extract of seidlitzia rosmarinus on experimental zoonotic cutaneous leishmaniasis lesions in murine model.leishmaniasis is one of the most important parasitic infectious diseases in the world. since last century, many efforts have been made to control and treat the disease, but appropriate vaccines, pesticides and medicines are not available or even eligible. the purpose of this study was to evaluate the effect of hydro-alcoholic extract of seidlitzia rosmarinus on the lesions of experimental cutaneous leishmaniasis (cl) in balb/c mice.201425386402
peganum harmala aqueous and ethanol extracts effects on lesions caused by leishmania major (mrho/ir/75/er) in balb/c mice.leishmaniasis is one of the six most common parasitic infections in the tropical regions. there are different therapeutic modalities, however therapeutic resistance is developed and resulted in numerous problems. therefore, evaluation of other therapeutic modalities is performed extensively.201425368792
memorial: nancy mccartney-francis, 1950-2014. 201425360038
a study to investigate the biological activity of proteoglycan mixture extract from convolvulus arvensis.convolvulus arvensis l. (convolvulaceae), bindweeds, is inhabitant to iran and its proteoglycan mixture (pgm) has been reported to possess different biological activities. in the present study, we aimed to investigate different properties of pgm including anti-tumor, anti-angiogenesis and immunostimulatory activities.201425324459
investigation of caspase-1 activity and interleukin-1β production in murine macrophage cell lines infected with leishmania major.to investigate the caspase-1 dependent inflammatory pathway activity and interleukin-1β (il-1β) secretion in murine macrophage cell lines j774g8 infected with leishmania major (l. major) using caspase-1 activity assay and elisa.201425312194
leishmaniasis transmission: distribution and coarse-resolution ecology of two vectors and two parasites in egypt.in past decades, leishmaniasis burden has been low across egypt; however, changing environment and land use has placed several parts of the country at risk. as a consequence, leishmaniasis has become a particularly difficult health problem, both for local inhabitants and for multinational military personnel.201424603738
structural and thermodynamic basis of the inhibition of leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates.farnesyl diphosphate synthase (fpps) is an essential enzyme involved in the biosynthesis of sterols (cholesterol in humans and ergosterol in yeasts, fungi and trypanosomatid parasites) as well as in protein prenylation. it is inhibited by bisphosphonates, a class of drugs used in humans to treat diverse bone-related diseases. the development of bisphosphonates as antiparasitic compounds targeting ergosterol biosynthesis has become an important route for therapeutic intervention. here, the x-ray ...201424598749
structure of the sas-6 cartwheel hub from leishmania major.centrioles are cylindrical cell organelles with a ninefold symmetric peripheral microtubule array that is essential to template cilia and flagella. they are built around a central cartwheel assembly that is organized through homo-oligomerization of the centriolar protein sas-6, but whether sas-6 self-assembly can dictate cartwheel and thereby centriole symmetry is unclear. here we show that leishmania major sas-6 crystallizes as a 9-fold symmetric cartwheel and provide the x-ray structure of thi ...201424596152
transcription factor irf4 regulates germinal center cell formation through a b cell-intrinsic mechanism.in response to antigenic stimulation, mature b cells interact with follicular helper t cells in specialized structures called germinal centers (gcs), which leads to the development of memory b cells and ab-secreting plasma cells. the transcription factor ifn regulatory factor 4 (irf4) is essential for the formation of follicular helper t cells and thus gcs, although whether irf4 plays a distinct role in gc b cells remains contentious. rnaseq analysis on ex vivo-derived mouse b cell populations s ...201424591370
engagement of nkg2d on bystander memory cd8 t cells promotes increased immunopathology following leishmania major infection.one of the hallmarks of adaptive immunity is the development of a long-term pathogen specific memory response. while persistent memory t cells certainly impact the immune response during a secondary challenge, their role in unrelated infections is less clear. to address this issue, we utilized lymphocytic choriomeningitis virus (lcmv) and listeria monocytogenes immune mice to investigate whether bystander memory t cells influence leishmania major infection. despite similar parasite burdens, lcmv ...201424586170
hypoxia in leishmania major skin lesions impairs the no-dependent leishmanicidal activity of macrophages.cure of infections with leishmania major is critically dependent on the ability of macrophages to induce the type 2 nitic oxide (no) synthase (nos2) that produces high levels of no in the presence of ample oxygen. therefore, we analyzed the oxygen levels found in leishmanial skin lesions and their effect on the nos2-dependent leishmanicidal activity of macrophages (mφ). when l. major skin lesions of self-healing c57bl/6 mice reached their maximum size, the infected tissue displayed low oxygen le ...201424583949
molecular modeling and molecular dynamics simulations of gpi 14 in leishmania major: insight into the catalytic site for active site directed drug design.leishmania major causes cutaneous form of leishmaniasis affecting 21 million people in developing countries. overuse of the chemotherapeutics against leishmaniasis has resulted in the development of drug resistance in the parasite. to surmount this emerging threat we have attempted to target the surface molecules. glycosylphosphatidylinositol is one such molecule that is present abundantly and thus our work revolves around the enzyme mannosyltransferase (gpi 14), an enzyme essential to add manno ...201424583312
leishmania metacaspase: an arginine-specific peptidase.the purpose of this chapter is to give insights into metacaspase of leishmania protozoan parasites as arginine-specific cysteine peptidase. the physiological role of metacaspase in leishmania is still a matter of debate, whereas its peptidase enzymatic activity has been well characterized. among the different possible expression systems, metacaspase-deficient yeast cells (δyca1) have been instrumental in studying the activity of leishmania major metacaspase (lmjmca). here, we describe techniques ...201424567103
pentamidine exerts in vitro and in vivo anti trypanosoma cruzi activity and inhibits the polyamine transport in trypanosoma cruzi.pentamidine is an antiprotozoal and fungicide drug used in the treatment of leishmaniasis and african trypanosomiasis. despite its extensive use as antiparasitic drug, little evidence exists about the effect of pentamidine in trypanosoma cruzi, the etiological agent of chagas' disease. recent studies have shown that pentamidine blocks a polyamine transporter present in leishmania major; consequently, its might also block these transporters in t. cruzi. considering that t. cruzi lacks the ability ...201424560964
high infection frequency, low diversity of leishmania major and first detection of leishmania turanica in human in northern iran.smears of suspected patients infected with zoonotic cutaneous leishmaniasis (zcl) were stained and examined under a light microscopic observation. dna of parasites within human ulcers was extracted directly from their smears. nested pcr was used to amplify a fragment containing the internal transcribed spacers of the ribosomal rna genes (its-rdna) of lesihmania parasites in human from turkemen sahara located in the northeastern part of iran. based on rflp method by digesting bsuri restriction en ...201424530890
collective nitric oxide production provides tissue-wide immunity during leishmania infection.nitric oxide (no) production is critical for the host defense against intracellular pathogens; however, it is unclear whether no-dependent control of intracellular organisms depends on cell-intrinsic or cell-extrinsic activity of no. for example, no production by infected phagocytes may enable these cells to individually control their pathogen burden. alternatively, the ability of no to diffuse across cell membranes might be critical for infection control. here, using a murine ear infection mode ...201424614106
a comparative analysis of trypanosomatid snare proteins.the kinetoplastida are flagellated protozoa evolutionary distant and divergent from yeast and humans. kinetoplastida include trypanosomatids, and a number of important pathogens. trypanosoma brucei, trypanosoma cruzi and leishmania spp. inflict significant morbidity and mortality on humans and livestock as the etiological agents of human african trypanosomiasis, chagas' disease and leishmaniasis respectively. for all of these organisms, intracellular trafficking is vital for maintenance of the h ...201424269876
development of a fluorescent enzyme-linked dna aptamer-magnetic bead sandwich assay and portable fluorometer for sensitive and rapid leishmania detection in sandflies.a fluorescent peroxidase-linked dna aptamer-magnetic bead sandwich assay is described which detects as little as 100 ng of soluble protein extracted from leishmania major promastigotes with a high molarity chaotropic salt. lessons learned during development of the assay are described and elucidate the pros and cons of using fluorescent dyes or nanoparticles and quantum dots versus a more consistent peroxidase-linked amplex ultra red (aur; similar to resazurin) fluorescence version of the assay. ...201424222436
interleukin 4 (il-4) gene promoter polymorphisms in rhombomys opimus, the main reservoir of zoonotic cutaneous leishmaniasis.great gerbils (rhombomys opimus) are the most common gerbils in center to northeast of iran as well as central asia and serve as reservoirs for the zoonotic agents, including leishmania major, the principal etiologic agent of zoonotic cutaneous leishmaniasis (zcl). the outcome of l. major infection in gerbils is not uniform. among several immune-related factors including cytokine genes, the polymorphism in interleukin 4 (il-4) promoter gene showed a great impact on outcome and pathological sympt ...201424209596
evaluating aziridinyl nitrobenzamide compounds as leishmanicidal prodrugs.many of the nitroaromatic agents used in medicine function as prodrugs and must undergo activation before exerting their toxic effects. in most cases, this is catalyzed by flavin mononucleotide (fmn)-dependent type i nitroreductases (ntrs), a class of enzyme absent from higher eukaryotes but expressed by bacteria and several eukaryotic microbes, including trypanosomes and leishmania. here, we utilize this difference to evaluate whether members of a library of aziridinyl nitrobenzamides have acti ...201424165190
development of an ex vivo lymph node explant model for identification of novel molecules active against leishmania major.leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (elec) derived from the draining lymph nodes o ...201424126577
f₁ cross-breed between susceptible balb/c and resistant swiss mice infected with leishmania major exhibit an intermediate phenotype for lesion sizes and type 1 cytokines but show low level of total igg antibodies.our current understanding of the host immune response during leishmaniases largely derives from studies performed in mice due to the intrusive techniques required to study infected human patients. swiss mice are highly resistant to leishmania infections in concordance with observed response in humans, while balb/c mice indicate a high-susceptibility phenotype. developing a cross-breed between balb/c and swiss mice may have important consequences on disease development, immune responses and paras ...201424498914
irf4 in dendritic cells inhibits il-12 production and controls th1 immune responses against leishmania major.irf4 is a transcription factor from the irf factor family that plays pivotal roles in the differentiation and function of t and b lymphocytes. although irf4 is also expressed in dendritic cells (dcs) and macrophages, its roles in these cells in vivo are not clearly understood. in this study, conditional knockout mice that lack irf4 in dcs or macrophages were generated and infected with leishmania major. mice lacking dc expression of irf4 showed reduced footpad swelling compared with c57bl/6 mice ...201424489086
comparison of conventional, molecular, and immunohistochemical methods in diagnosis of typical and atypical cutaneous leishmaniasis.localized cutaneous leishmaniasis (cl) typically presents as papules, crusted nodules, plaques, or noduloulcerative lesions. atypical cl does not show these features or mimic malignant lesion. in atypical forms, cl may be overlooked because of its similarity to other dermal diseases.201424476521
antileishmanial lead structures from nature: analysis of structure-activity relationships of a compound library derived from caffeic acid bornyl ester.bioassay-guided fractionation of a chloroform extract of valeriana wallichii (v. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against leishmania major (l. major) promastigotes (ic50 = 48.8 µm). to investigate the structure-activity relationship (sar), a library of compounds based on 1 was synthesized and tested in vitro against l. major and l. donovani promastigotes, and l. major amastigotes. cytotoxicity was determined usi ...201424473204
the ferrous-dioxy complex of leishmania major globin coupled heme containing adenylate cyclase: the role of proximal histidine on its stability.recently we have described the globin-coupled heme containing adenylate cyclase from leishmania major (hemac-lm) that shows an o2 dependent camp signaling (sen santara, et. al. proc. natl. acad. sci. u.s.a. 110, 16790-16795 (2013)). the heme iron of hemac-lm is expected to participate in oxygen binding and activates adenylate cyclase activity during catalysis, but its interactions with o2 are uncharacterized. we have utilized the hemac-lm and stopped-flow methods to study the formation and decay ...201424424241
lmapa2g4, a homolog of human ebp1, is an essential gene and inhibits cell proliferation in l. major.we have identified lmapa2g4, a homolog of the human proliferation-associated 2g4 protein (also termed ebp1), in a phosphoproteomic screening. multiple sequence alignment and cluster analysis revealed that lmapa2g4 is a non-peptidase member of the m24 family of metallopeptidases. this pseudoenzyme is structurally related to methionine aminopeptidases. a null mutant system based on negative selection allowed us to demonstrate that lmapa2g4 is an essential gene in leishmania major. over-expression ...201424421916
infection with leishmania major induces a cellular stress response in macrophages.we investigated early cellular responses induced by infection with leishmania major in macrophages from resistant c57/bl6 mice. infection increased production of reactive oxygen species by resident, but not inflammatory peritoneal macrophages. in addition, infection increased activation of stress-activated protein kinases/c-jun n-terminal kinases (sapk/jnk) in resident, but not in inflammatory peritoneal macrophages. infection also increased expression of membrane and soluble fasl, but infected ...201424416445
the role of il-4 and il-13 in cutaneous leishmaniasis.murine models of leishmania major infection in the 1980s revealed two distinct, counter-regulatory populations of cd4(+) t helper (th) cells, delineated th1 and th2, and their archetypal cytokines, interferon gamma (ifn-γ) and interleukin (il)-4/il-13, which promoted resistance/susceptibility to infection, respectively. however, the introduction of global cytokine-deficient mice in the 1990s revealed pleiotropic immune-regulatory mechanisms of il-4 and il-13 that either controlled or exacerbated ...201424412597
cystathionine γ-lyase, an enzyme related to the reverse transsulfuration pathway, is functional in leishmania spp.leishmania parasites seem capable of producing cysteine by de novo biosynthesis, similarly to bacteria, some pathogenic protists, and plants. in leishmania spp., cysteine synthase (cs) and cystathionine β-synthase (cbs) are expected to participate in this metabolic process. moreover, the reverse transsulfuration pathway (rtp) is also predicted to be operative in this trypanosomatid because cbs also catalyzes the condensation of serine with homocysteine, and a gene encoding a putative cystathioni ...201424410980
ccr7 facilitates the pro-inflammatory function of dendritic cells in experimental leishmaniasis.cutaneous leishmaniasis, caused by the parasite leishmania major, results in lesions at the site of infection, which are self-healing in resistant hosts. however, in the absence of the chemokine receptor ccr7, mice are unable to heal the lesion and develop chronic disease. these b6.ccr7(-/-) mice display an increased number of th2 cells and immunosuppressive cytokine levels, as well as more regulatory t cells. as ccr7 is expressed on activated dendritic cells (dcs), and these cells require ccr7 ...201424410820
epidermal expression of i-tac (cxcl11) instructs adaptive th2-type immunity.to decipher early promoters of the local microenvironment for th2-type immunity, we wanted to identify gene patterns that were induced by leishmania major in the infected skin of susceptible, th2-prone balb/c, but not of resistant, th1-prone c57bl/6 mice. we found a marked up-regulation of the chemokine i-tac (cxcl11) during the first 2 d of infection in the epidermis of susceptible but not of resistant mice. accordingly, local injection of i-tac (2×1 μg) in resistant mice on the first day of in ...201424398292
lectin coated mgo nanoparticle: its toxicity, antileishmanial activity, and macrophage activation.the purpose of this research was to evaluate toxicity of uncoated magnesium oxide nanoparticles (mgo nps), mgo nps coated with peanut agglutinin (pna) lectin, and pna alone on the promastigotes of leishmania major (l. major) and macrophages of balb/c mice. on the other hand, antileishmanial property of uncoated mgo nps, lectin coated mgo nps, and pna lectin alone was evaluated, and also macrophage activation was investigated after treatment with these materials by measurement of nitrite, h2o2, a ...201424393043
toll-like receptors and cd40 modulate each other's expression affecting leishmania major infection.toll-like receptors (tlrs) recognize pathogen-associated molecular patterns and results in innate immune system activation that results in elicitation of the adaptive immune response. one crucial modulator of the adaptive immune response is cd40. however, whether these molecules influence each other's expression and functions is not known. therefore, we examined the effects of tlrs on cd40 expression on macrophages, the host cell for the protozoan parasite leishmania major. while polyinosinic-po ...201424387292
high density of leishmania major and rarity of other mammals' leishmania in zoonotic cutaneous leishmaniasis foci, iran.only leishmania major is well known as a causative agent of zoonotic cutaneous leishmaniasis (zcl) in iran. our objective was to find leishmania parasites circulating in reservoir hosts, sand flies and human simultaneously.201424382378
anti-leishmanial activities of extracts and isolated compounds from drechslera rostrata and eurotium tonpholium.the fungal extract of drechslera rostrata and eurotium tonpholium showed a significant anti-leishmanial activity against leishmania major; ic50 was 28.8 and 28.2 μg/ml, respectively. seven compounds, five from d. rostrata (h1-h5) and two from e. tonpholium (h6 and h7), were isolated and identified using different spectroscopic analysis including (1) hnmr, (13) cnmr, hetero-nuclear multiple bond connectivity (hmbc), hetero-nuclear multiple quantum correlation (hmqc), and ei-ms. the isolated compo ...201424375822
homology modeling of t. cruzi and l. major nadh-dependent fumarate reductases: ligand docking, molecular dynamics validation, and insights on their binding modes.leishmania major and trypanosoma cruzi are the main causes of leishmaniasis and chagas disease, two endemic parasitosis identified as neglected diseases by the world health organization. fumarate reductase (fr) is a central enzyme in the conversion of fumarate to succinate, an energy releasing path essential for the survival of these protozoans which is also absent in their mammalian hosts. fr can thus be considered as a good candidate for targeting specific inhibition by new drugs designed agai ...201424370672
effect of root bark extract of berberis vulgaris l. on leishmania major on balb/c mice.leishmaniasis is one of the most important diseases transmitted by arthropod. this disease is present in 88 countries. approximately 400 million people are at risk, and 12 million are involved. we aimed to examine the application of ethanolic extract of the root bark of berberis vulgaris l. for treatment of mice infected with cutaneous leishmaniasis. at first, 40 balb/c mice were infected to leishmania major promastigotes and were divided in two groups a and b. then, each of a and b groups were ...201424337510
inhibition of caspase-8 activity promotes protective th1- and th2-mediated immunity to leishmania major infection.we investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to leishmania major parasites. splenic cd4 t cells undergo activation-induced apoptosis, and blockade of fasl-fas interaction increased ifn-γ and il-4 cytokine responses to l. major antigens. to block death receptor-induced death, we used mice expressing a t cell-restricted transgene for vflip. inhibition of caspase-8 activation in vflip mice enhanced th1 and th2 cytokine respo ...201424072877
immunogenicity evaluation of a rationally designed polytope construct encoding hla-a*0201 restricted epitopes derived from leishmania major related proteins in hla-a2/dr1 transgenic mice: steps toward polytope vaccine.there are several reports demonstrating the role of cd8 t cells against leishmania species. therefore peptide vaccine might represent an effective approach to control the infection. we developed a rational polytope-dna construct encoding immunogenic hla-a2 restricted peptides and validated the processing and presentation of encoded epitopes in a preclinical mouse model humanized for the mhc-class-i and ii.201425310094
[clinical, epidemiological and evolutionary aspects in 157 cases of cutaneous leishmaniasis in morocco]. 201425309671
[four cutaneous leishmaniosis case resistant to meglumine antimoniate treatment].the aim of the study was to treatment of cutaneous leishmaniasis caused by meglumine antimoniate resistant leishmania major with lucilia sericata larvae.201425308455
remote sensing, land cover changes, and vector-borne diseases: use of high spatial resolution satellite imagery to map the risk of occurrence of cutaneous leishmaniasis in ghardaïa, algeria.ghardaïa, central algeria, experienced a major outbreak of cutaneous leishmaniasis (cl) in 2005. two leishmania species occur in this region: leishmania major (mon-25) and leishmania killicki (mon-301). the two species are transmitted respectively by the sandflies phlebotomus papatasi and phlebotomus sergenti and probably involve rodent reservoirs with different ecologies, suggesting distinct epidemiological patterns and distribution areas. the aims of this study were to establish risk maps for ...201425305006
detection of high levels of anti-α-galactosyl antibodies in sera of patients with old world cutaneous leishmaniasis: a possible tool for diagnosis and biomarker for cure in an elimination setting.in the kingdom of saudi arabia (ksa), old world cutaneous leishmaniasis (cl) is mainly caused by leishmania major and leishmania tropica parasites. diagnosis of cl is predominately made by clinicians, who at times fail to detect the disease and are unable to identify parasite species. here, we report the development of a chemiluminescent enzyme-linked immunosorbent assay (cl-elisa) to measure the levels of anti-α-galactosyl antibodies in human sera. using this assay, we have found that individua ...201425297927
ecotin-like isp of l. major promastigotes fine-tunes macrophage phagocytosis by limiting the pericellular release of bradykinin from surface-bound kininogens: a survival strategy based on the silencing of proinflammatory g-protein coupled kinin b2 and b1 receptors.inhibitors of serine peptidases (isps) expressed by leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (ne), a serine protease that couples phagocytosis to the prooxidative tlr4/pkr pathway. here we investigated the functional interplay between isp-expressing l. major and the kallikrein-kinin system (kks). enzymatic assays showed that ne inhibitor or recombinant isp-2 inhibited kks activation in human plasma activated by dextran sulfate. intravital ...201425294952
altered expression of an rbp-associated arginine methyltransferase 7 in leishmania major affects parasite infection.protein arginine methylation is a widely conserved post-translational modification performed by arginine methyltransferases (prmts). however, its functional role in parasitic protozoa is still under-explored. the leishmania major genome encodes five prmt homologs, including prmt7. here we show that lmjprmt7 expression and arginine monomethylation are tightly regulated in a lifecycle stage-dependent manner. lmjprmt7 levels are higher during the early promastigote logarithmic phase, negligible at ...201425294169
characterization of the pattern of ribosomal protein l19 production during the lifecycle of leishmania spp.leishmania is a genus of protozoan parasites causing a wide clinical spectrum of diseases in humans. analysis of a region of chromosome 6 from leishmania major (iribar et al.) showed that the transcript of a putative l19 ribosomal protein (rpl19) was most abundant at the amastigote stage. we therefore decided to characterize l19 protein abundance throughout the lifecycle of leishmania. differential expression of the l19 gene during development has been observed for all leishmania species studied ...201425290356
cathepsin b in antigen-presenting cells controls mediators of the th1 immune response during leishmania major infection.resistance and susceptibility to leishmania major infection in the murine model is determined by the capacity of the host to mount either a protective th1 response or a th2 response associated with disease progression. previous reports involving the use of cysteine cathepsin inhibitors indicated that cathepsins b (ctsb) and l (ctsl) play important roles in th1/th2 polarization during l. major infection in both susceptible and resistant mouse strains. although it was hypothesized that these effec ...201425255101
immunoliposomes containing soluble leishmania antigens (sla) as a novel antigen delivery system in murine model of leishmaniasis.development of new generation of vaccines against leishmaniasis requires adjuvants to elicit the type and intensity of immune response needed for protection. the coupling of target-specific antibodies to the liposomal surface to create immunoliposomes has appeared as a promising way in achieving a liposome active targeting. in this study, immunoliposomes were prepared by grafting non-immune mouse igg onto the liposomal surface. the influence of active targeted immunoliposomes on the type and int ...201425246326
mhc class ii restricted innate-like double negative t cells contribute to optimal primary and secondary immunity to leishmania major.although it is generally believed that cd4(+) t cells play important roles in anti-leishmania immunity, some studies suggest that they may be dispensable, and that mhc ii-restricted cd3(+)cd4(-)cd8(-) (double negative, dn) t cells may be more important in regulating primary anti-leishmania immunity. in addition, while there are reports of increased numbers of dn t cells in leishmania-infected patients, dogs and mice, concrete evidence implicating these cells in secondary anti-leishmania immunity ...201425233487
genotype profile of leishmania major strains isolated from tunisian rodent reservoir hosts revealed by multilocus microsatellite typing.zoonotic cutaneous leishmaniasis (zcl) caused by leishmania (l.) major parasites represents a major health problem with a large spectrum of clinical manifestations. psammomys (p.) obesus and meriones (m.) shawi represent the most important host reservoirs of these parasites in tunisia. we already reported that infection prevalence is different between these two rodent species. we aimed in this work to evaluate the importance of genetic diversity in l. major parasites isolated from different prov ...201425203305
[ankle and foot ulcerations in a diabetic patient revealing cutaneous leishmaniasis].cutaneous leishmaniasis is a parasitic disease that typically manifests as a typical crusted ulcer called the oriental sore. its localization on the lower limbs can be mistaken for a leg ulcer.201425201090
pegylated bisacycloxypropylcysteine, a diacylated lipopeptide ligand of tlr6, plays a host-protective role against experimental leishmania major infection.tlrs recognize pathogen-expressed ags and elicit host-protective immune response. although tlr2 forms heterodimers with tlr1 or tlr6, recognizing different ligands, differences in the functions of these heterodimers remain unknown. in this study, we report that in leishmania major-infected macrophages, the expression of tlr1 and tlr2, but not tlr6, increased; tlr2-tlr2 association increased, but tlr2-tlr6 association diminished. lentivirus-expressed tlr1-short hairpin rna (shrna) or tlr2-shrna a ...201425194056
timing is everything: dendritic cell subsets in murine leishmania infection.mouse models of leishmania major infection have shown that a predominant cd4(+) t helper type 1 cell (th1) response leads to protection, while t helper type 2 cell (th2) predominance confers susceptibility. dendritic cells (dcs) are antigen-presenting cells that orchestrate the t cell response. the immune response to l. major involves direct antigen presentation by migrating dcs or transfer of antigens to resident dcs to prime t cells. in this review, we discuss the timing and consequences of an ...201425190685
shp-1 plays a crucial role in cd40 signaling reciprocity.cd40 plays dual immunoregulatory roles in leishmania major infection and tumor regression. the functional duality emerges from cd40-induced reciprocal p38mapk and erk-1/2 phosphorylations. because phosphotyrosine-based signaling in hematopoietic cells is regulated by the phosphotyrosine phosphatase shp-1, which is not implied in cd40 signaling, we examined whether shp-1 played any roles in cd40-induced reciprocal signaling and anti-leishmanial function. we observed that a weaker cd40 stimulation ...201425187664
performance of an elisa and indirect immunofluorescence assay in serological diagnosis of zoonotic cutaneous leishmaniasis in iran.serological assays have been extensively evaluated for diagnosis of visceral leishmaniasis (vl) and considered as a routine method for diagnosis of vl while these methods are not properly evaluated for diagnosis of cutaneous leishmaniasis (cl). this study aimed to assess the performance of indirect immunofluorescent-antibody test (ifa) and enzyme-linked immunosorbent assay (elisa) for serodiagnosis of cutaneous leishmaniasis in iran. sixty-one sera samples from parasitologically confirmed cl pat ...201425177349
characterization of leishmania major phosphatidylethanolamine methyltransferases lmjpem1 and lmjpem2 and their inhibition by choline analogs.phosphatidylcholine (pc) is the most abundant phospholipid in the membranes of the human parasite leishmania. it is synthesized via two metabolic routes, the de novo pathway that starts with the uptake of choline, and the threefold methylation of phosphatidylethanolamine. choline was shown to be dispensable for leishmania; thus, the methylation pathway likely represents the primary route for pc production. here, we have identified and characterized two phosphatidylethanolamine methyltransferases ...201425176160
foxp3 expression and frequency of regulatory t cells in healed individuals from leishmania major infection and the asymptomatic cases.two groups of residents in an endemic area of leishmania major infection in iran with positive leishmanin skin tests who were either asymptomatic or had healed cutaneous leishmaniasis lesions were compared with respect to their t helper responses. the percentages of regulatory t cells (treg; cd4(+)cd25(high) foxp3(+)) from the peripheral blood and cd4(+) t cells producing intracellular cytokines (il-4, il-10, il-17 and ifn-γ) from the stimulated pbmcs were evaluated by flow cytometry and the exp ...201425167770
in vitro activity and cytotoxicity of crocus sativus extract against leihmania major (mrho/ir/75/er).leishmaniasis is a complex protozoan disease comprising a wide range of clinical manifestations that is usually divided into visceral leishmaniasis, cutaneous leishmaniasis, and muco-cutaneous leishmaniasis depending on leishmania parasite species and host's immune system responses. most of the drugs produced for the treatment of leishmaniasis, from the first used to the most recently accepted, are toxic, resistance issues and poorly tolerated. the purpose of this study is to evaluate the effect ...201425159304
effect of polyvinyl alcohol (pva) containing artemether in treatment of cutaneous leishmaniasis caused by leishmania major in balb/c mice.polyvinyl alcohol (pva) is one of the well-known polymers, which has been used in numerous biomedical applications because of its good biocompatibility.201425147717
identification of leishmania isolates from healing and nonhealing cutaneous leishmaniasis patients using internal transcribed spacer region pcr.cutaneous leishmaniasis (cl) is a parasitic disease in most parts of iran, especially in the isfahan province. the most common form of cl is a self-healing lesion but in rare situations, infection might develop to non-healing forms. clinical symptoms and treatment process might be influenced by several agents such as host immune response and parasite strains. in this study, the isolates which caused healing and nonhealing forms of cl in isfahan were characterized by internal transcribed spacer ( ...201425147707
therapeutic effect of hedera helix alcoholic extract against cutaneous leishmaniasis caused by leishmania major in balb/c mice.cutaneous leishmaniasis (cl) is common and endemic in many areas of iran, caused by species of a protozoan parasite belonging to the genus leishmania. there is not any effective vaccine against leishmaniasis; so, therapy is important for prevention and separation of disease. herbal extract for treatment of cl is cost-effective, applicable topically to lesions, and can avoid the development of drug resistance.201425147703
th1 platform immune responses against leishmania major induced by thiol-specific antioxidant-based dna vaccines.the thiol-specific antioxidant (tsa) is an antigen of leishmania major which is believed to be the most promising molecule as a vaccine candidate against leishmaniasis.201425147675
myeloid-derived suppressor cell functionality and interaction with leishmania major parasites differ in c57bl/6 and balb/c mice.myeloid-derived suppressor cells (mdscs) represent a heterogeneous population of cd11b+ cells. according to the surface molecules ly6g and ly6c (where ly6g and ly6c are lymphocyte antigen 6, locus g and c, respectively), mdscs are further divided into monocytic (mo-mdscs, cd11b+ /ly6c(high) /ly6g-) and polymorphonucleated suppressor cells (pmn-mdscs, cd11b+ /ly6c(int) /ly6g+). most published manuscripts focus on the suppressive role of mdscs in cancer, whereas their impact on adaptive immunity a ...201425142017
innate immunity to leishmania infection: within phagocytes.infection by leishmania takes place in the context of inflammation and tissue repair. besides tissue resident macrophages, inflammatory macrophages and neutrophils are recruited to the infection site and serve both as host cells and as effectors against infection. recent studies suggest additional important roles for monocytes and dendritic cells. this paper addresses recent experimental findings regarding the regulation of leishmania major infection by these major phagocyte populations. in addi ...201425110400
leishmanicidal and apoptotic activities of oleuropein on leishmania major.leishmania is a unicellular protozoan parasite causing a wide range of human diseases ranging from localized self-healing cutaneous lesions to fatal visceral infections.201425109414
involvement of different cd4(+) t cell subsets producing granzyme b in the immune response to leishmania major antigens.the nature of effector cells and the potential immunogenicity of leishmania major excreted/secreted proteins (lmes) were evaluated using peripheral blood mononuclear cells (pbmcs) from healed zoonotic cutaneous leishmaniasis individuals (hzcl) and healthy controls (hc). first, we found that pbmcs from hzcl individuals proliferate and produce high levels of ifn-γ and granzyme b (grb), used as a marker of activated cytotoxic t cells, in response to the parasite antigens. ifn-γ is produced by cd4(+ ...201425104882
regulation of transcription termination by glucosylated hydroxymethyluracil, base j, in leishmania major and trypanosoma brucei.base j, β-d-glucosyl-hydroxymethyluracil, is an epigenetic modification of thymine in the nuclear dna of flagellated protozoa of the order kinetoplastida. j is enriched at sites involved in rna polymerase (rnap) ii initiation and termination. reduction of j in leishmania tarentolae via growth in brdu resulted in cell death and indicated a role of j in the regulation of rnap ii termination. to further explore j function in rnap ii termination among kinetoplastids and avoid indirect effects associ ...201425104019
the direct boil-lamp method: a simple and rapid diagnostic method for cutaneous leishmaniasis.needle biopsy is widely used for the diagnosis of cutaneous leishmaniasis (cl) to obtain specimens for histology and culture. however, the use of such invasive procedures causes discomfort, requires technical expertise, and carries risks of bleeding and iatrogenic infection. therefore, developing substitutive non-invasive diagnostic tools for cl will help reduce the risk of secondary infection and the exposure of both infected individuals and medical professionals. here we employed loop-mediated ...201425086375
multiple chemical scaffolds inhibit a promising leishmania drug target.the need for an effective oral therapy for leishmaniasis is addressed through the study of the target n-myristoyltransferase from leishmania major.201425075340
langerhans cells promote early germinal center formation in response to leishmania-derived cutaneous antigens.efficient formation of early gcs depends on the close interaction between gc b cells and antigen-primed cd4(+) follicular helper t cells (tfh ). a tight and stable formation of tfh /b cell conjugates is required for cytokine-driven immunoglobulin class switching and somatic hypermutation of gc b cells. recently, it has been shown that the formation of tfh /b cell conjugates is crucial for b-cell differentiation and class switch following infection with leishmania major parasites. however, the su ...201425070244
computational identification of microrna-like elements in leishmania major.leishmaniasis represents endemic infections that occur predominantly, in tropical and sub-tropical regions. the current situation for the chemotherapy of leishmaniasis is more promising than it has been for several decades with both new drugs and new formulations of old drugs either recently approved or in clinical trials. investigations focused on parasite biology and identification of novel drug targets have become of great importance. the identification and characterization of microrna (mirna ...201425069447
a survey of reservoir hosts in two foci of cutaneous leishmaniasis in kerman province, southeast of iran.in the old world, cutaneous leishmaniasis (cl) is zoonoses and natural vertebrate hosts of cl parasites are mammals. this study was carried out on natural infection rates of leishmania parasites in reservoir hosts in one new focus of zoonotic cutaneous leishmaniasis (zcl) and in suspected reservoir in an old focus of acl in iran. the sampling of rodents using sherman traps was carried out and pcr technique was used for detection and identification of leishmania species in bahreman district, kerm ...201425035578
evaluation of the leishmanicidal activity of rutaceae and lauraceae ethanol extracts on golden syrian hamster (mesocricetus auratus) peritoneal macrophages.traditional medicine has provided a number of therapeutic solutions for the control of infectious agents, cancers, and other diseases. after screening a wide variety of colombian plant extracts, we have identified promising antileishmanial activity in ethanol extracts from ocotea macrophylla (lauraceae) and zanthoxyllum monophyllum (rutaceae). in this study, we evaluated the in vitro activity of two ethanol extracts, one from ocotea macrophylla and the other from zanthoxyllum monophyllum and one ...201425035529
aberrant host defense against leishmania major in the absence of slpi.slpi, a potent epithelial and myeloid-derived serine protease inhibitor with antimicrobial and anti-inflammatory functions, is induced by the intracellular parasite leishmania major, and increased slpi expression is evident within lesions that follow l. major infection. in contrast to self-resolving infection in c57bl/6 wt mice, slpi(-/-) mice launch a strong th1 response to l. major, yet fail to control infection and develop destructive, nonhealing lesions with systemic spread of parasites. bec ...201425030421
stability and toxicity of heteroleptic organometallic bi(v) complexes towards leishmania major.eleven heteroleptic bi(v) complexes of the form [biph3(o2cr)2] have been synthesised and fully characterised. the carboxylate ligands are derived from a series of simple substituted benzoic acids, four of which are common non-steroidal anti-inflammatories (nsaids). the solid-state structures of eight of the complexes were determined by single crystal x-ray diffraction, and all were shown to adopt a typical trigonal bipyramidal geometry with chelating carboxylate ligands. nine of the complexes we ...201425019320
comparison of immune regulatory factors in acute and chronic lesions of cutaneous leishmaniasis due to leishmania major.adaptive immune response is an important factor in the healing process and development of protection in cutaneous leishmaniasis (cl). little information is available in human cl about the importance of the balance between effector and regulatory immune responses. therefore, the aim of this study was to asses messenger ribonucleic acid (mrna) expression of interleukin-10 (il-10), il-4, transforming growth factor-β1 (tgf-β1), interferon-g (ifn-γ), and forkhead box p3 (foxp3) (as a marker of regula ...201425002892
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