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1.
Marie-Christine Brotherton Sylvie Bourassa Philippe Leprohon Danielle Légaré Guy G. Poirier Arnaud Droit Marc Ouellette 《PloS one》2013,8(11)
Background
Antimonials remain the primary antileishmanial drugs in most developing countries. However, drug resistance to these compounds is increasing and our understanding of resistance mechanisms is partial.Methods/Principal Findings
In the present study, quantitative proteomics using stable isotope labelling of amino acids in cell culture (SILAC) and genome next generation sequencing were used in order to better characterize in vitro generated Leishmania infantum antimony resistant mutant (Sb2000.1). Using the proteomic method, 58 proteins were found to be differentially regulated in Sb2000.1. The ABC transporter MRPA (ABCC3), a known marker of antimony resistance, was observed for the first time in a proteomic screen. Furthermore, transfection of its gene conferred antimony resistance in wild-type cells. Next generation sequencing revealed aneuploidy for 8 chromosomes in Sb2000.1. Moreover, specific amplified regions derived from chromosomes 17 and 23 were observed in Sb2000.1 and a single nucleotide polymorphism (SNP) was detected in a protein kinase (LinJ.33.1810-E629K).Conclusion/Significance
Our results suggest that differentially expressed proteins, chromosome number variations (CNVs), specific gene amplification and SNPs are important features of antimony resistance in Leishmania. 相似文献2.
Background
Human leishmaniasis is caused by more than 20 Leishmania species and has a wide range of symptoms. Our recent studies have demonstrated the essential role of sphingolipid degradation in the virulence of Leishmania (Leishmania) major, a species responsible for localized cutaneous leishmaniasis in the Old World. In this study, we investigated the function of sphingolipid degradation in Leishmania (Leishmania) amazonensis, an etiological agent of localized and diffuse cutaneous leishmaniasis in South America.Methodology/Principal Findings
First, we identified the enzyme LaISCL which is responsible for sphingolipid degradation in L. amazonensis. Primarily localized in the mitochondrion, LaISCL shows increased expression as promastigotes progress from replicative log phase to non-replicative stationary phase. To study its function, null mutants of LaISCL (Laiscl−) were generated by targeted gene deletion and complemented through episomal gene add-back. In culture, loss of LaISCL leads to hypersensitivity to acidic pH and poor survival in murine macrophages. In animals, Laiscl− mutants exhibit severely attenuated virulence towards C57BL6 mice but are fully infective towards BALB/c mice. This is drastically different from wild type L. amazonensis which cause severe pathology in both BALB/c and C57BL 6 mice.Conclusions/Significance
A single enzyme LaISCL is responsible for the turnover of sphingolipids in L. amazonensis. LaISCL exhibits similar expression profile and biochemical property as its ortholog in L. major. Deletion of LaISCL reduces the virulence of L. amazonensis and the outcome of Laiscl−-infection is highly dependent on the host''s genetic background. Therefore, compared to L. major, the role of sphingolipid degradation in virulence is substantially different in L. amazonensis. Future studies may reveal whether sphingolipid degradation is required for L. amazonensis to cause diffuse cutaneous infections in humans. 相似文献3.
Leishmania major LmACR2 is a pentavalent antimony reductase that confers sensitivity to the drug pentostam 总被引:4,自引:0,他引:4
Zhou Y Messier N Ouellette M Rosen BP Mukhopadhyay R 《The Journal of biological chemistry》2004,279(36):37445-37451
Arsenicals and antimonials are first line drugs for the treatment of trypanosomal and leishmanial diseases. To create the active form of the drug, Sb(V) must be reduced to Sb(III). Because arsenic and antimony are related metalloids, and arsenical resistant Leishmania strains are frequently cross-resistant to antimonials, we considered the possibility that Sb(V) is reduced by a leishmanial As(V) reductase. The sequence for the arsenate reductase of Saccharomyces cerevisiae, ScAcr2p, was used to clone the gene for a homologue, LmACR2, from Leishmania major. LmACR2 was able to complement the arsenate-sensitive phenotype of an arsC deletion strain of Escherichia coli or an ScACR2 deletion strain of Saccharomyces cerevisiae. Transfection of Leishmania infantum with LmACR2 augmented Pentostam sensitivity in intracellular amastigotes. LmACR2 was purified and shown to reduce both As(V) and Sb(V). This is the first report of an enzyme that confers Pentostam sensitivity in intracellular amastigotes of Leishmania. We propose that LmACR2 is responsible for reduction of the pentavalent antimony in Pentostam to the active trivalent form of the drug in Leishmania. 相似文献
4.
Kárita Cláudia Freitas-Lidani Iara J de Messias-Reason Edna Aoba Y Ishikawa 《Memórias do Instituto Oswaldo Cruz》2014,109(4):442-447
The aim of the present study was to detect natural infection by Leishmania
(Leishmania) infantum in Lutzomyia longipalpis captured
in Barcarena, state of Pará, Brazil, through the use of three primer sets. With this
approach, it is unnecessary to previously dissect the sandfly specimens. DNA of
280 Lu. longipalpis female specimens were extracted from the
whole insects. PCR primers for kinetoplast minicircle DNA (kDNA), the mini-exon gene
and the small subunit ribosomal RNA (SSU-rRNA) gene of Leishmania
were used, generating fragments of 400 bp, 780 bp and 603 bp, respectively.
Infection by the parasite was found with the kDNA primer in 8.6% of the cases, with
the mini-exon gene primer in 7.1% of the cases and with the SSU-rRNA gene primer in
5.3% of the cases. These data show the importance of polymerase chain reaction as a
tool for investigating the molecular epidemiology of visceral leishmaniasis by
estimating the risk of disease transmission in endemic areas, with the kDNA primer
representing the most reliable marker for the parasite. 相似文献
5.
Sanchita Das Priyanka Shah Rajendra K. Baharia Rati Tandon Prashant Khare Shyam Sundar Amogh A. Sahasrabuddhe M. I. Siddiqi Anuradha Dube 《PLoS neglected tropical diseases》2013,7(12)
Background
Sodium antimony gluconate (SAG) unresponsiveness of Leishmania donovani (Ld) had effectively compromised the chemotherapeutic potential of SAG. 60s ribosomal L23a (60sRL23a), identified as one of the over-expressed protein in different resistant strains of L.donovani as observed with differential proteomics studies indicates towards its possible involvement in SAG resistance in L.donovani. In the present study 60sRL23a has been characterized for its probable association with SAG resistance mechanism.Methodology and principal findings
The expression profile of 60s ribosomal L23a (60sRL23a) was checked in different SAG resistant as well as sensitive strains of L.donovani clinical isolates by real-time PCR and western blotting and was found to be up-regulated in resistant strains. Ld60sRL23a was cloned, expressed in E.coli system and purified for raising antibody in swiss mice and was observed to have cytosolic localization in L.donovani. 60sRL23a was further over-expressed in sensitive strain of L.donovani to check its sensitivity profile against SAG (Sb V and III) and was found to be altered towards the resistant mode.Conclusion/Significance
This study reports for the first time that the over expression of 60sRL23a in SAG sensitive parasite decreases the sensitivity of the parasite towards SAG, miltefosine and paramomycin. Growth curve of the tranfectants further indicated the proliferative potential of 60sRL23a assisting the parasite survival and reaffirming the extra ribosomal role of 60sRL23a. The study thus indicates towards the role of the protein in lowering and redistributing the drug pressure by increased proliferation of parasites and warrants further longitudinal study to understand the underlying mechanism. 相似文献6.
Deise Riba Coelho Elaine Silva Miranda Tatiana Dillenburg Saint’Pierre Francisco José Roma Paumgartten 《Memórias do Instituto Oswaldo Cruz》2014,109(4):420-427
Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony
(SbV) drugs used since the mid-1940s. Notwithstanding the fact that
they are first-choice drugs for the treatment of leishmaniases, there are gaps in our
knowledge of their toxicological profile, mode of action and kinetics. Little is
known about the distribution of antimony in tissues after SbV
administration. In this study, we evaluated the Sb content of tissues from male rats
24 h and three weeks after a 21-day course of treatment with MA (300 mg
SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and
organs were determined by inductively coupled plasma-mass spectrometry. In rats, as
with in humans, the Sb blood levels after MA dosing can be described by a
two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 >> 24 h)
elimination phase. The spleen was the organ that accumulated the highest amount of
Sb, while bone and thyroid ranked second in descending order of tissues according to
Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs,
adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal
muscle, testes, stomach > brain). The pathophysiological consequences of Sb
accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone
warrant further studies. 相似文献
7.
Rubens Monte-Neto Marie-Claude N. Laffitte Philippe Leprohon Priscila Reis Frédéric Frézard Marc Ouellette 《PLoS neglected tropical diseases》2015,9(2)
Background
Antimony resistance complicates the treatment of infections caused by the parasite Leishmania.Methodology/Principal Findings
Using next generation sequencing, we sequenced the genome of four independent Leishmania guyanensis antimony-resistant (SbR) mutants and found different chromosomal alterations including aneuploidy, intrachromosomal gene amplification and gene deletion. A segment covering 30 genes on chromosome 19 was amplified intrachromosomally in three of the four mutants. The gene coding for the multidrug resistance associated protein A involved in antimony resistance was also amplified in the four mutants, most likely through chromosomal translocation. All mutants also displayed a reduced accumulation of antimony mainly due to genomic alterations at the level of the subtelomeric region of chromosome 31 harboring the gene coding for the aquaglyceroporin 1 (LgAQP1). Resistance involved the loss of LgAQP1 through subtelomeric deletions in three mutants. Interestingly, the fourth mutant harbored a single G133D point mutation in LgAQP1 whose role in resistance was functionality confirmed through drug sensitivity and antimony accumulation assays. In contrast to the Leishmania subspecies that resort to extrachromosomal amplification, the Viannia strains studied here used intrachromosomal amplification and locus deletion.Conclusions/Significance
This is the first report of a naturally occurred point mutation in AQP1 in antimony resistant parasites. 相似文献8.
9.
Dayane Priscilla de Souza Queiroz Carlos Alexandre Carollo M?nica Cristina Toffoli Kadri Yasmin Silva Rizk Vanessa Carneiro Pereira de Araujo Paulo Eduardo de Oliveira Monteiro Patrik Oening Rodrigues Elisa Teruya Oshiro Maria de Fátima Cepa Matos Carla Cardozo Pinto de Arruda 《Memórias do Instituto Oswaldo Cruz》2016,111(3):147-154
The polar hydroethanolic extract from Selaginella sellowii(SSPHE)
has been previously proven active on intracellular amastigotes (in vitro test) and
now was tested on hamsters infected with Leishmania (Leishmania)
amazonensis (in vivo test). SSPHE suppressed a 100% of the parasite load
in the infection site and draining lymph nodes at an intralesional dose of 50
mg/kg/day × 5, which was similar to the results observed in hamsters treated with
N-methylglucamine antimonate (Sb) (28 mg/Kg/day × 5). When orally
administered, SSPHE (50 mg/kg/day × 20) suppressed 99.2% of the parasite load in
infected footpads, while Sb suppressed 98.5%. SSPHE also enhanced the release of
nitric oxide through the intralesional route in comparison to Sb. The chemical
fingerprint of SSPHE by high-performance liquid chromatography with diode-array
detection and tandem mass spectrometry showed the presence of biflavonoids and high
molecular weight phenylpropanoid glycosides. These compounds may have a synergistic
action in vivo. Histopathological study revealed that the intralesional treatment
with SSPHE induced an intense inflammatory infiltrate, composed mainly of mononuclear
cells. The present findings reinforce the potential of this natural product as a
source of future drug candidates for American cutaneous leishmaniasis. 相似文献
10.
Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum
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Philippe Leprohon Danielle Lgar Frdric Raymond ric Madore Gary Hardiman Jacques Corbeil Marc Ouellette 《Nucleic acids research》2009,37(5):1387-1399
Antimonials remain the first line drug against the protozoan parasite Leishmania but their efficacy is threatened by resistance. We carried out a RNA expression profiling analysis comparing an antimony-sensitive and -resistant (Sb2000.1) strain of Leishmania infantum using whole-genome 70-mer oligonucleotide microarrays. Several genes were differentially expressed between the two strains, several of which were found to be physically linked in the genome. MRPA, an ATP-binding cassette (ABC) gene known to be involved in antimony resistance, was overexpressed in the antimony-resistant mutant along with three other tandemly linked genes on chromosome 23. This four gene locus was flanked by 1.4 kb repeated sequences from which an extrachromosomal circular amplicon was generated in the resistant cells. Interestingly, gene expression modulation of entire chromosomes occurred in the antimony-resistant mutant. Southern blots analyses and comparative genomic hybridizations revealed that this was either due to the presence of supernumerary chromosomes or to the loss of one chromosome. Leishmania parasites with haploid chromosomes were viable. Changes in copy number for some of these chromosomes were confirmed in another antimony-resistant strain. Selection of a partial revertant line correlated antimomy resistance levels and the copy number of aneuploid chromosomes, suggesting a putative link between aneuploidy and drug resistance in Leishmania. 相似文献
11.
Jarina Pena DaMata Bárbara Pinheiro Mendes Kátia Maciel-Lima Cristiane Alves Silva Menezes Walderez Ornelas Dutra Lirlandia Pires Sousa Maria Fátima Horta 《PloS one》2015,10(10)
Leishmania is an intracellular parasite in vertebrate hosts, including man. During infection, amastigotes replicate inside macrophages and are transmitted to healthy cells, leading to amplification of the infection. Although transfer of amastigotes from infected to healthy cells is a crucial step that may shape the outcome of the infection, it is not fully understood. Here we compare L. amazonensis and L. guyanensis infection in C57BL/6 and BALB/c mice and investigate the fate of macrophages when infected with these species of Leishmania in vitro. As previously shown, infection of mice results in distinct outcomes: L. amazonensis causes a chronic infection in both strains of mice (although milder in C57BL/6), whereas L. guyanensis does not cause them disease. In vitro, infection is persistent in L. amazonensis-infected macrophages whereas L. guyanensis growth is controlled by host cells from both strains of mice. We demonstrate that, in vitro, L. amazonensis induces apoptosis of both C57BL/6 and BALB/c macrophages, characterized by PS exposure, DNA cleavage into nucleosomal size fragments, and consequent hypodiploidy. None of these signs were seen in macrophages infected with L. guyanensis, which seem to die through necrosis, as indicated by increased PI-, but not Annexin V-, positive cells. L. amazonensis-induced macrophage apoptosis was associated to activation of caspases-3, -8 and -9 in both strains of mice. Considering these two species of Leishmania and strains of mice, macrophage apoptosis, induced at the initial moments of infection, correlates with chronic infection, regardless of its severity. We present evidence suggestive that macrophages phagocytize L. amazonensis-infected cells, which has not been verified so far. The ingestion of apoptotic infected macrophages by healthy macrophages could be a way of amastigote spreading, leading to the establishment of infection. 相似文献
12.
Leishmania spp.: development of pentostam-resistant clones in vitro by discontinuous drug exposure 总被引:4,自引:0,他引:4
Antimony unresponsiveness in mucocutaneous and visceral leishmaniasis is a serious clinical problem. Information on the mechanisms and characteristics of drug resistance in parasites that suggest chemotherapeutic strategies to overcome resistance is of practical importance. We developed nine lines of Leishmania resistant to drugs, the major emphasis being on pentavalent antimony (Sb) complexed to carbohydrate in the form of sodium stibogluconate (Pentostam), one of the only two antileishmanial agents with a clearly favorable therapeutic index. Resistance to Pentostam (33- to 212-fold increase) was obtained in promastigotes of Leishmania in vitro by exposure to gradually increasing concentrations of drug over several passages. Resistance to Sb was found to be either stable or unstable. Stable resistance to Sb required (greater than 3) exposures of the initial sensitive clones to Pentostam and tended to stabilize with increased time under pressure. In general, resistance obtained in a clone after only a few (less than or equal to 3) step treatments was low and unstable. Differences in the susceptibility to Pentostam were found between strains isolated from patients with American cutaneous leishmaniasis. In addition, natural isolates of Leishmania from patients represented a heterogeneous population of parasites as demonstrated by a biphasic concentration response to Sb (typical of mixed population dynamics) and by marked differences in susceptibility to Pentostam among clones prepared from single isolates. These results suggest that the emergence of parasite resistance to antimonial treatment is a potential risk of inadequate dose therapy. 相似文献
13.
Kimbra G. Turner Paola Vacchina Maricela Robles-Murguia Mariha Wadsworth Mary Ann McDowell Miguel A. Morales 《PLoS neglected tropical diseases》2015,9(7)
Trypanosomatid parasites of the genus Leishmania are the causative agents of leishmaniasis, a neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of leishmaniasis include pentavalent antimonials and amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal. Miltefosine (MIL) is the first oral treatment available for leishmaniasis. Originally developed for cancer chemotherapy, the mechanism of action of MIL in Leishmania spp. is largely unknown. While treatment with MIL has proven effective, higher tolerance to the drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated MIL-resistant cultures of L. major and characterized the fitness of MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected, MIL-resistant parasites demonstrate decreased susceptibility to MIL, which reduces after the drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to miltefosine does not lead to an increased competitive fitness in L. major. 相似文献
14.
Antimony dextran glycoside (RL-712, manufactured by Rosco A/S Pharmaceutical Taastrup, Denmark) produced a remarkable decrease in Leishmania donovani densities in hamster spleen and liver when administered in a single intraperitoneal (ip) dose of 500 mg Sb/kg body weight or in 600 mg Sb/kg body weight divided into two or three equal parts injected at weekly intervals beginning 15 days after intracardial inoculation of 10 million amastigotes, and also in a single ip dose of 300 mg Sb/kg body weight 14, 7, and 0 days before intracardial inoculation of 10 million amastigotes. No parasites were detected on using a single dose of 500 mg Sb/kg body weight followed by 100 mg Sb/kg body weight one week later.When the drug was administered in a dose of 500 mg Sb/kg body weight either 10 days before subcutaneous inoculation of 60 million promastigotes or eight days before intracardial inoculation of five million promastigotes, no parasites were recovered by smear or culture from the spleen and liver.Results show the prophylactic and therapeutic actions of this drug against L. donovani in the hamster. 相似文献
15.
Visceral leishmaniasis, also known as kala-azar (KA) is generally caused byLeishmania donovani. Organic pentavalent antimonials (SbV) is the first line of treatment for KA. However, the number of KA patients unresponsive
to treatment with Sb(V) is steadily increasing in India and elsewhere. The primary objective of this work is to determine
the factor(s) associated with the rise of unresponsiveness. Analysis of the clonal population of parasites clearly indicated
that wild type parasites isolated from KA patients who were clinically cured after treatment with Sb(V), were a mixture of
resistant and sensitive cells. The resistant promastigotes were also resistant as amastigotesin vivo. It was further observed that Stibanate sensitive parasites can be made resistant to the drug by repeated passages in experimental
animals followed by incomplete treatment with suboptimal doses of the drug. These results suggest that the steady rise in
Sb(V) unresponsiveness of KA patients in India is due to infection with resistant parasites, generated as a result of irregular
and often incomplete treatment of the patients. 相似文献
16.
Raquel García-Hernández José Ignacio Manzano Santiago Castanys Francisco Gamarro 《PLoS neglected tropical diseases》2012,6(12)
Drug combinations for the treatment of leishmaniasis represent a promising and challenging chemotherapeutic strategy that has recently been implemented in different endemic areas. However, the vast majority of studies undertaken to date have ignored the potential risk that Leishmania parasites could develop resistance to the different drugs used in such combinations. As a result, this study was designed to elucidate the ability of Leishmania donovani to develop experimental resistance to anti-leishmanial drug combinations. The induction of resistance to amphotericin B/miltefosine, amphotericin B/paromomycin, amphotericin B/SbIII, miltefosine/paromomycin, and SbIII/paromomycin was determined using a step-wise adaptation process to increasing drug concentrations. Intracellular amastigotes resistant to these drug combinations were obtained from resistant L. donovani promastigote forms, and the thiol and ATP levels and the mitochondrial membrane potential of the resistant lines were analysed. Resistance to drug combinations was obtained after 10 weeks and remained in the intracellular amastigotes. Additionally, this resistance proved to be unstable. More importantly, we observed that promastigotes/amastigotes resistant to one drug combination showed a marked cross-resistant profile to other anti-leishmanial drugs. Additionally, the thiol levels increased in resistant lines that remained protected against the drug-induced loss of ATP and mitochondrial membrane potential. We have therefore demonstrated that different resistance patterns can be obtained in L. donovani depending upon the drug combinations used. Resistance to the combinations miltefosine/paromomycin and SbIII/paromomycin is easily obtained experimentally. These results have been validated in intracellular amastigotes, and have important relevance for ensuring the long-term efficacy of drug combinations. 相似文献
17.
Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (Sb(III)) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, Sb(III) decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, Sb(III) inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance. 相似文献
18.
Miriam Berzunza-Cruz ángel Rodríguez-Moreno Gabriel Gutiérrez-Granados Constantino González-Salazar Christopher R. Stephens Mircea Hidalgo-Mihart Carlos F. Marina Eduardo A. Rebollar-Téllez Dulce Bailón-Martínez Cristina Domingo Balcells Carlos N. Ibarra-Cerde?a Víctor Sánchez-Cordero Ingeborg Becker 《PLoS neglected tropical diseases》2015,9(1)
Leishmania (Leishmania) mexicana causes cutaneous leishmaniasis, an endemic zoonosis affecting a growing number of patients in the southeastern states of Mexico. Some foci are found in shade-grown cocoa and coffee plantations, or near perennial forests that provide rich breeding grounds for the sand fly vectors, but also harbor a variety of bat species that live off the abundant fruits provided by these shade-giving trees. The close proximity between sand flies and bats makes their interaction feasible, yet bats infected with Leishmania (L.) mexicana have not been reported. Here we analyzed 420 bats from six states of Mexico that had reported patients with leishmaniasis. Tissues of bats, including skin, heart, liver and/or spleen were screened by PCR for Leishmania (L.) mexicana DNA. We found that 41 bats (9.77%), belonging to 13 species, showed positive PCR results in various tissues. The infected tissues showed no evidence of macroscopic lesions. Of the infected bats, 12 species were frugivorous, insectivorous or nectarivorous, and only one species was sanguivorous (Desmodus rotundus), and most of them belonged to the family Phyllostomidae. The eco-region where most of the infected bats were caught is the Gulf Coastal Plain of Chiapas and Tabasco. Through experimental infections of two Tadarida brasiliensis bats in captivity, we show that this species can harbor viable, infective Leishmania (L.) mexicana parasites that are capable of infecting BALB/c mice. We conclude that various species of bats belonging to the family Phyllostomidae are possible reservoir hosts for Leishmania (L.) mexicana, if it can be shown that such bats are infective for the sand fly vector. Further studies are needed to determine how these bats become infected, how long the parasite remains viable inside these potential hosts and whether they are infective to sand flies to fully evaluate their impact on disease epidemiology. 相似文献
19.
Isabella Aparecida Salerno Pimentel Carolina de Siqueira Paladi Simone Katz Wagner Alves de Souza Júdice Rodrigo L. O. R. Cunha Clara Lúcia Barbiéri 《PloS one》2012,7(11)
Tellurium compounds have shown several biological properties and recently the leishmanicidal effect of one organotellurane was demonstrated. These findings led us to test the effect of the organotellurium compound RF07 on Leishmania (Leishmania) chagasi, the agent of visceral leishmaniasis in Latin America. In vitro assays were performed in L. (L.) chagasi-infected bone marrow derived macrophages treated with different concentrations of RF07. In in vivo experiments Golden hamsters were infected with L. (L.) chagasi and injected intraperitoneally with RF07 whereas control animals received either Glucantime or PBS. The effect of RF07 on cathepsin B activity of L. (L.) chagasi amastigotes was assayed spectrofluorometrically using fluorogenic substrates. The main findings were: 1) RF07 showed significant leishmanicidal activity against intracellular parasites at submicromolar concentrations (IC50 of 529.7±26.5 nM), and the drug displayed 10-fold less toxicity to macrophages (CC50 of 5,426±272.8 nM); 2) kinetics assays showed an increasing leishmanicidal action of RF07 at longer periods of treatment; 3) one month after intraperitoneal injection of RF07 L. (L.) chagasi-infected hamsters showed a reduction of 99.6% of parasite burden when compared to controls that received PBS; 4) RF07 inhibited the cathepsin B activity of L. (L.) chagasi amastigotes. The present results demonstrated that the tellurium compound RF07 is able to destroy L. (L.) chagasi in vitro and in vivo at concentrations that are non toxic to the host. We believe these findings support further study of the potential of RF07 as a possible alternative for the chemotherapy of visceral leishmaniasis. 相似文献
20.
Yasmin Silva Rizk Alice Fischer Marillin de Castro Cunha Patrik Oening Rodrigues Maria Carolina Silva Marques Maria de Fátima Cepa Matos M?nica Cristina Toffoli Kadri Carlos Alexandre Carollo Carla Cardozo Pinto de Arruda 《Memórias do Instituto Oswaldo Cruz》2014,109(8):1050-1056
This study is the first phytochemical investigation of Selaginella sellowii
and demonstrates the antileishmanial activity of the hydroethanolic extract
from this plant (SSHE), as well as of the biflavonoids amentoflavone and
robustaflavone, isolated from this species. The effects of these substances were
evaluated on intracellular amastigotes of Leishmania (Leishmania)
amazonensis, an aetiological agent of American cutaneous leishmaniasis.
SSHE was highly active against intracellular amastigotes [the half maximum inhibitory
concentration (IC50) = 20.2 µg/mL]. Fractionation of the extract led to the isolation
of the two bioflavonoids with the highest activity: amentoflavone, which was about
200 times more active (IC50 = 0.1 μg/mL) and less cytotoxic than SSHE (IC50 = 2.2 and
3 μg/mL, respectively on NIH/3T3 and J774.A1 cells), with a high selectivity index
(SI) (22 and 30), robustaflavone, which was also active against L.
amazonensis (IC50 = 2.8 µg/mL), but more cytotoxic, with IC50 = 25.5
µg/mL (SI = 9.1) on NIH/3T3 cells and IC50 = 3.1 µg/mL (SI = 1.1) on J774.A1 cells.
The production of nitric oxide (NO) was lower in cells treated with amentoflavone
(suggesting that NO does not contribute to the leishmanicidal mechanism in this
case), while NO release was higher after treatment with robustaflavone. S.
sellowii may be a potential source of biflavonoids that could provide
promising compounds for the treatment of cutaneous leishmaniasis. 相似文献