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gallic and ellagic acids: two natural immunomodulator compounds solve infection of macrophages by leishmania major.leishmaniasis is a complex of parasitic protozoan diseases caused by more than 20 different species of parasites from leishmania genus. conventional treatments are high costly, and promote a sort of side effects. besides, protozoan resistance to treatments has been reported. natural products have been investigated as a source of new therapeutic alternatives, not only acting directly against the parasite but also being able to synergistically act on the host immune system in order to control para ...201728643086
a computational methodology to overcome the challenges associated with the search for specific enzyme targets to develop drugs against leishmania major.we present an approach for detecting enzymes that are specific of leishmania major compared with homo sapiens and provide targets that may assist research in drug development. this approach is based on traditional techniques of sequence homology comparison by similarity search and markov modeling; it integrates the characterization of enzymatic functionality, secondary and tertiary protein structures, protein domain architecture, and metabolic environment. from 67 enzymes represented by 42 enzym ...201728638238
biodistribution and in vivo antileishmanial activity of 1,2-distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine liposome-intercalated amphotericin b.1,2-distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (dshemspc) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. our previous study revealed that liposome (lip)-intercalated amphotericin b (amb) prepared from dshemspc (dshemspc-amb-lip) possesses excellent colloidal properties and in vitro antifungal and antileishmanial activities similar to those of the liposomal amb preparation ambisom ...201728630182
a dicre recombinase-based system for inducible expression in leishmania major.here we present the establishment of an inducible system based on the dimerizable cre recombinase (dicre) for controlled gene expression in the protozoan parasite leishmania. rapamycin-induced dicre activation promoted efficient flipping and expression of gene products in a time and dose-dependent manner. the dicre flipping activity induced the expression of target genes from both integrated and episomal contexts broadening the applicability of the system. we validated the system by inducing the ...201728629935
autophagy downstream of endosomal toll-like receptor signaling in macrophages is a key mechanism for resistance to leishmania major infection.leishmaniasis is caused by protozoan parasites of the genus leishmania in mammalians, these parasites survive and replicate in macrophages and parasite elimination by macrophages is critical for host resistance. endosomal toll-like receptors (tlrs) have been shown to be crucial for resistance to leishmania major in vivo for example, mice in the resistant c57bl/6 genetic background that are triple-deficient for tlr3, -7, and -9 (tlr3/7/9(-/-)) are highly susceptible to l. major infection. tlr3/7/ ...201728607148
b-1 cells modulate the murine macrophage response to leishmania major infection.to investigate the modulatory effect of b-1 cells on murine peritoneal macrophages infected with leishmania major (l. major) in vitro.201728588758
crystal structure and functional analysis of leishmania major pseudoperoxidase.leishmania major pseudoperoxidase (lmpp) is a recently discovered heme protein expressed by the human pathogen. previous in vivo and in vitro studies suggest that lmpp is a crucial element of the pathogen's defense mechanism against the reactive nitrogen species peroxynitrite produced during the host immune response. to shed light on the potential mechanism of peroxynitrite detoxification, we have determined the 1.76-å x-ray crystal structure of lmpp, revealing a striking degree of homology with ...201728584975
the midgut microbiota plays an essential role in sand fly vector competence for leishmania major.for many arthropod vectors, the diverse bacteria and fungi that inhabit the gut can negatively impact pathogen colonization. our attempts to exploit antibiotic treatment of colonized phlebotomus duboscqi sand flies in order to improve their vector competency for leishmania major resulted instead in flies that were refractory to the development of transmissible infections due to the inability of the parasite to survive and to colonize the anterior midgut with infective, metacyclic stage promastig ...201728580630
a crispr cas9 high-throughput genome editing toolkit for kinetoplastids.clustered regularly interspaced short palindromic repeats (crispr), crispr-associated gene 9 (cas9) genome editing is set to revolutionize genetic manipulation of pathogens, including kinetoplastids. crispr technology provides the opportunity to develop scalable methods for high-throughput production of mutant phenotypes. here, we report development of a crispr-cas9 toolkit that allows rapid tagging and gene knockout in diverse kinetoplastid species without requiring the user to perform any dna ...201728573017
tumor suppressor p53 induces apoptosis of host lymphocytes experimentally infected by leishmania major, by activation of bax and caspase-3: a possible survival mechanism for the parasite.apoptosis of infected host macrophages by leishmania spp. is mainly addressed as one of the survival mechanisms of the parasite. however, there is no eligible data about whether tumor suppressor p53 could induce the apoptosis of host lymphocytes-treated leishmania major via the mitochondrial intrinsic pathway. in this study, the amastigotes of l. major obtained from ten cutaneous leishmaniases (cl) patients were separately isolated and cultured in n.n.n and rpmi 1640 media. l. major was definite ...201728560572
leishmania labcg1 and labcg2 transporters are involved in virulence and oxidative stress: functional linkage with autophagy.the g subfamily of abc (atp-binding cassette) transporters of leishmania include 6 genes (abcg1-g6), some with relevant biological functions associated with drug resistance and phospholipid transport. several studies have shown that leishmania labcg2 transporter plays a role in the exposure of phosphatidylserine (ps), in virulence and in resistance to antimonials. however, the involvement of this transporter in other key biological processes has not been studied.201728558770
characterization of the protein tyrosine phosphatase lmprl-1 secreted by leishmania major via the exosome pathway.similar to other intracellular pathogens, leishmania parasites are known to evade the antimicrobial effector functions of host immune cells. to date, however, only a few virulence factors have been described for leishmania major, one of the causative agents of cutaneous leishmaniasis. here, we have characterized the expression and function of an l. major phosphatase, which we termed lmprl-1. this enzyme shows a strong structural similarity to the human phosphatases of regenerating liver (prl-1, ...201728507071
tlc-uv hyphenated with maldi-tofms for the screening of invertase substrates in plant extracts.in this study, thin-layer chromatography (tlc) hyphenated with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (maldi-tofms) was developed for the screening of invertase substrates in complex matrices. bfra, a specific β-d-fructofuranosidase from leishmania major, was chosen as a model enzyme to screen biological activity in plant extracts due to its capacity to hydrolyze specific carbohydrates. tlc was considered to be a reliable technique for screening substrates ( ...201728501191
pyrrole-indolinone su11652 targets the nucleoside diphosphate kinase from leishmania parasites.nucleoside diphosphate kinases (ndks) are key enzymes in the purine-salvage pathway of trypanosomatids and have been associated with the maintenance of host-cell integrity for the benefit of the parasite, being potential targets for rational drug discovery and design. the ndk from leishmania major (lmndk) and mutants were expressed and purified to homogeneity. thermal shift assays were employed to identify potential inhibitors for lmndk. calorimetric experiments, site-directed mutagenesis and mo ...201728499874
genetic metabolic complementation establishes a requirement for gdp-fucose in leishmania.to survive in its sand fly vector, the trypanosomatid protozoan parasite leishmania first attaches to the midgut to avoid excretion, but eventually it must detach for transmission by the next bite. in leishmania major strain friedlin, this is controlled by modifications of the stage-specific adhesin lipophosphoglycan (lpg). during differentiation to infective metacyclics, d-arabinopyranose (d-arap) caps the lpg side-chain galactose residues, blocking interaction with the midgut lectin ppgalec, t ...201728465349
eyelid cutaneous leishmaniasis: a case report.cutaneous leishmaniasis (cl) is the most common parasitic disease transmitted by vectors in iran. cl is endemic in many urban and rural parts of iran and usually caused by two species of leishmania as l. major and l. tropica transmitted to humans from parasite reservoirs by the bite of female sandflies. we report a case of ocular leishmaniasis with eyelid involvement presentation. the patient was a 70-yr-old housewife woman referred to health care center in city of kashan, central iran in 2012. ...201728451564
use of two-photon microscopy to study leishmania major infection of the skin.intra-vital two-photon microscopy (2p-ivm) allows for in-situ investigation of tissue organization, cell behavior and the dynamic interactions between different cell types in their natural environment. this methodology has also expanded our understanding of the immune response against pathogens. leishmania are protozoan intracellular parasites that have adapted to successfully establish infection within the context of an inflammatory response in the skin following transmission by the bite of an ...201728434998
skin-resident cd4+ t cells protect against leishmania major by recruiting and activating inflammatory monocytes.tissue-resident memory t cells are required for establishing protective immunity against a variety of different pathogens, although the mechanisms mediating protection by cd4+ resident memory t cells are still being defined. in this study we addressed this issue with a population of protective skin-resident, ifnγ-producing cd4+ memory t cells generated following leishmania major infection. we previously found that resident memory t cells recruit circulating effector t cells to enhance immunity. ...201728419151
leishmania major large rab gtpase is highly immunogenic in individuals immune to cutaneous and visceral leishmaniasis.we previously identified a leishmania (l.) major large rab gtpase (lmlrab), a new atypical rab gtpase protein. it is highly conserved in leishmania species while displaying low level of homology with mammalian homologues. leishmania small rab gtpases proteins have been involved in regulation of exocytic and endocytic pathways whereas the role of large rab gtpases proteins has not been characterized yet. we report here the immunogenicity of both recombinant rlmlrab and rlmlrabc, in individuals wi ...201728416006
an integrated approach towards the discovery of novel non-nucleoside leishmania major pteridine reductase 1 inhibitors.despite the fact that leishmania ssp are pteridine auxotrophs, dihydrofolate reductase-thymidylate synthase (dhfr-ts) inhibitors are ineffective against leishmania major. on the other hand pteridine reductase 1 (ptr1) inhibitors proved to be lethal to the parasite. aiming at identifying hits that lie outside the chemical space of known ptr1 inhibitors, pharmacophore models that differentiate true-binders from decoys and explain the structure-activity relationships of known inhibitors were employ ...201728407565
epidemiological profile of cutaneous leishmaniasis in morocco, 2004-2013.the main objective of our study is to provide a comprehensive overview of the situation of cutaneous leishmaniasis in morocco. we therefore conducted a retrospective descriptive study covering the decade 2004-2013. data were collected from the moroccan ministry of health's annual reports about the national program against leishmaniasis. these data show a regression in the cases due to leishmania major and the persistence of l. tropica transmission. mapping cutaneous leishmaniasis cases reported ...201728406415
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