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Sara M. Robledo - One of the best experts on this subject based on the ideXlab platform.
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Hydrazone Derivatives Enhance AntiLeishmanial Activity of Thiochroman-4-ones
2018Co-Authors: Esteban Vargas, Sara M. Robledo, Fernando Echeverri, Yulieth Upegui, Wiston QuiñonesAbstract:Cutaneous Leishmaniasis (CL) is a neglected tropical disease, which causes severe skin lesions. Due to the lack of effective vaccines, and toxicity or reduced effectiveness of available drugs in addition to complex and prolonged treatments, there is an urgent need to develop alternatives for the treatment for CL with different mechanisms of action. In our effort to search for new promising hits against Leishmania parasites we prepared 18 acyl hydrazone derivatives of thiochroman-4-ones. Compounds were evaluated for their in vitro antiLeishmanial activity against the intracellular amastigote form of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Our results show that derivatization of the thiochroman-4-ones with acyl hydrazones significantly enhances the antiLeishmanial activity. Among the compounds tested semicarbazone and thiosemicarbazone derivatives of thioflavanone 19 and 20 displayed the highest antiLeishmanial activities, with EC50 values of 5.4 and 5.1 µM and low cytotoxicities (100.2 and 50.1 µM respectively), resulting in higher indexes of selectivity (IS).
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Synthesis and Evaluation of Thiochroman-4-One Derivatives as Potential Leishmanicidal Agents
Molecules (Basel Switzerland), 2017Co-Authors: Esteban Vargas, Sara M. Robledo, Fernando Echeverri, Iván D. Vélez, Wiston QuiñonesAbstract:The S-containing heterocyclic compounds benzothiopyrans or thiochromones stand out as having promising biological activities due to their structural relationship with chromones (benzopyrans), which are widely known as privileged scaffolds in medicinal chemistry. In this work, we report the synthesis of 35 thiochromone derivatives and the in vitro antiLeishmanial and cytotoxic activities. Compounds were tested against intracellular amastigotes of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Compounds bearing a vinyl sulfone moiety, 4h, 4i, 4j, 4k, 4l and 4m, displayed the highest antiLeishmanial activity, with EC50 values lower than 10 μM and an index of selectivity over 100 for compounds 4j and 4l. When the double bond or the sulfone moiety was removed, the activity decreased. Our results show that thiochromones bearing a vinyl sulfone moiety are endowed with high antiLeishmanial activity and low cytotoxicity.
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Hydrazone Derivatives Enhance AntiLeishmanial Activity of Thiochroman-4-ones
2017Co-Authors: Esteban Vargas, Sara M. Robledo, Fernando Echeverri, Yulieth A. Upegui, Wiston QuiñonesAbstract:Cutaneous Leishmaniasis (CL) is a neglected tropical disease, which causes severe skin lesions. Due to the lack of effective vaccines, treatment can be complex and prolonged, high toxicity, side effects and high cost, there is an urgent need to develop alternatives for the treatment for CL that may have different mechanisms of action. In our effort to search for new promising hits against Leishmania parasites we prepared 18 acyl hydrazone derivatives of thiochroman-4-ones. Compounds were evaluated for their in vitro antiLeishmanial activity against intracellular amastigotes form of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2); our results show that derivatization with acyl hydrazones significantly enhance the antiLeishmanial activity, among the compounds tested semicarbazone (19) and thiosemicarbazone (20) derivatives of thioflavanone display the highest antiLeishmanial activities with EC50 values of 5.4 and 5.1 µM both with low cytotoxicities, 100.2 a 50.1 µM resulting in high selectivity index (SI).
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The Akt-like kinase of Leishmania panamensis: As a new molecular target for drug discovery
Acta tropica, 2017Co-Authors: Didier Tirado-duarte, Sara M. Robledo, Marcel Marín-villa, Rodrigo Ochoa, Gustavo Blandón-fuentes, Maurilio J. Soares, Ruben Eduardo Varela-mirandaAbstract:The Akt-like kinase of Leishmania spp. is a cytoplasmic orthologous protein of the serine/threonine kinase B-PKB/human-Akt group, which is involved in the cellular survival of these parasites. By the application of a computational strategy we obtained two specific inhibitors of the Akt-like protein of L. panamensis (UBMC1 and UBMC4), which are predicted to bind specifically to the pleckstrin domain (PH) of the enzyme. We show that the Akt-like of Leishmania panamensis is phospho-activated in parasites under nutritional and thermic stress, this phosphorylation is blocked by the UBMC1 and UMBC2 and such inhibition leads to cell death. Amongst the effects caused by the inhibitors on the parasites we found high percentage of hypodiploidy and loss of mitochondrial membrane potential. Ultrastructural studies showed highly vacuolated cytoplasm, as well as shortening of the flagellum, loss of nuclear membrane integrity and DNA fragmentation. Altogether the presented results suggest that the cell death caused by UMBC1 and UMBC4 may be associated to an apoptosis-like process. The compounds present an inhibitory concentration (IC50) over intracellular amastigotes of L. panamensis of 9.2±0.8μM for UBMC1 and 4.6±1.9μM for UBMC4. The cytotoxic activity for UBMC1 and UBMC4 in human macrophages derived from monocytes (huMDM) was 29±1.2μM and >40μM respectively. Our findings strongly support that the presented compounds can be plausible candidates as a new therapeutic alternative for the inhibition of specific kinases of the parasite.
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Leishmanicidal and cytotoxic activity of extracts and saponins from Ilex laurina (Aquifoliaceae)
Tropical Journal of Pharmaceutical Research, 2016Co-Authors: Juan M. Pérez, Sara M. Robledo, Diana L Munoz, Wilson Cardona, Fernando Alzate, Angie HerreraAbstract:Purpose: To evaluate the leishmanicidal and cytotoxic activity of alcohol and non-alcohol extracts and saponins from Ilex laurina . Methods: Extracts were obtained by percolation with solvents of different polarities: hexane, dichloromethane, ethyl acetate and ethanol. The ethyl acetate extract was subjected to silica gel column chromatography eluting with a step gradient of dichloromethane-methanol. All products were evaluated in vitro for leishmanicidal activity against amastigotes of Leishmania panamensis and cytotoxicity on U-937 cells. Results: Two saponins were isolated from the ethyl acetate extract. The ethyl acetate extract showed high leishmanicidal activity against intracellular amastigotes of L. panamensis (EC 50 , 7.5 ± 1.5 μg/mL) and low activity against axenic amastigotes (EC 50 , 52.8 ±1.6 μg/mL); this extract showed also high cytotoxicity (LC 50 , 57.7 ± 12.1 μg/mL). Saponin 2 exhibited high activity against intracellular amastigotes (EC 50 , 5.9 ± 0.5 μg/mL) but also showed high cytotoxicity on U-937 cells (EC 50 , 25.7 ± 6.1 μg/mL). This compound showed similar leishmanicidal activity and cytotoxicity to meglumine antimoniate and amphotericin B, respectively, drugs currently used for the treatment of Leishmaniasis. Conclusions: Based on these results, Ilex laurina is a potential source of compounds that can lead to the development of new therapeutic alternatives against Leishmaniasis. Keywords: Leishmaniasis, Antiprotozoal, Saponin, Ilex laurina , Aquifoliaceae
Ricardo Lleonart - One of the best experts on this subject based on the ideXlab platform.
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Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice.
PLoS neglected tropical diseases, 2021Co-Authors: Carlos M. Restrepo, Alejandro Llanes, Ricardo Lleonart, L. Herrera, Esteban Ellis, Patricia L. FernándezAbstract:Leishmania parasites can trigger different host immune responses that result in varying levels of disease severity. The C57BL/6 and BALB/c mouse strains are among the host models commonly used for characterizing the immunopathogenesis of Leishmania species and the possible antiLeishmanial effect of novel drug candidates. C57BL/6 mice tend to be resistant to Leishmania infections, whereas BALB/c mice display a susceptible phenotype. Studying species-specific interactions between Leishmania parasites and different host systems is a key step to characterize and validate these models for in vivo studies. Here, we use RNA-Seq and differential expression analysis to characterize the transcriptomic profiles of C57BL/6 and BALB/c peritoneal-derived macrophages in response to Leishmania panamensis infection. We observed differences between BALB/c and C57BL/6 macrophages regarding pathways associated with lysosomal degradation, arginine metabolism and the regulation of cell cycle. We also observed differences in the expression of chemokine and cytokine genes associated with regulation of immune responses. In conclusion, infection with L. panamensis induced an inflammatory gene expression pattern in C57BL/6 macrophages that is more consistently associated with a classic macrophage M1 activation, whereas in BALB/c macrophages a gene expression pattern consistent with an intermediate inflammatory response was observed.
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gene expression patterns associated with Leishmania panamensis infection in macrophages from balb c and c57bl 6 mice
PLOS Neglected Tropical Diseases, 2021Co-Authors: Carlos M. Restrepo, Alejandro Llanes, Ricardo Lleonart, L. Herrera, Esteban Ellis, Patricia L. FernándezAbstract:Leishmania parasites can trigger different host immune responses that result in varying levels of disease severity. The C57BL/6 and BALB/c mouse strains are among the host models commonly used for characterizing the immunopathogenesis of Leishmania species and the possible antiLeishmanial effect of novel drug candidates. C57BL/6 mice tend to be resistant to Leishmania infections, whereas BALB/c mice display a susceptible phenotype. Studying species-specific interactions between Leishmania parasites and different host systems is a key step to characterize and validate these models for in vivo studies. Here, we use RNA-Seq and differential expression analysis to characterize the transcriptomic profiles of C57BL/6 and BALB/c peritoneal-derived macrophages in response to Leishmania panamensis infection. We observed differences between BALB/c and C57BL/6 macrophages regarding pathways associated with lysosomal degradation, arginine metabolism and the regulation of cell cycle. We also observed differences in the expression of chemokine and cytokine genes associated with regulation of immune responses. In conclusion, infection with L. panamensis induced an inflammatory gene expression pattern in C57BL/6 macrophages that is more consistently associated with a classic macrophage M1 activation, whereas in BALB/c macrophages a gene expression pattern consistent with an intermediate inflammatory response was observed.
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AntiLeishmanial activity of a new chloroquine analog in an animal model of Leishmania panamensis infection
International journal for parasitology. Drugs and drug resistance, 2020Co-Authors: L. Herrera, Alejandro Llanes, Jennifer Álvarez, Kissy Degracia, Carlos M. Restrepo, René Rivera, David E. Stephens, Hang T. Dang, Oleg V. Larionov, Ricardo LleonartAbstract:Abstract Leishmania panamensis is a relevant causative agent of tegumentary Leishmaniasis in several Latin American countries. Available antiLeishmanial drugs have several limitations including relatively high toxicity, difficult administration, high production costs and the emergence of resistance in circulating strains. Therefore, the identification of new molecules as potential therapeutics for Leishmaniasis is of great relevance. Here, we developed a murine model of L. panamensis infection and evaluated the effect of a new compound in vivo. After treatment of animals with the compound, we observed a significant reduction of inflammation and parasite load at the inoculation site, in a dose-dependent manner. We observed a reduction in IL-10 production by popliteal lymph nodes cells of infected mice. These results pave the way for future evaluation of this compound as a potential antiLeishmanial drug or as a suitable scaffold for lead optimization strategies.
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Environmental Conditions May Shape the Patterns of Genomic Variations in Leishmania panamensis.
Genes, 2019Co-Authors: Carlos M. Restrepo, José Antonio Suárez, Alejandro Llanes, Jennifer Álvarez, Eymi M. Cedeño, Jim H. Chang, Margarita Ríos, Homero Penagos, Ricardo LleonartAbstract:Due to the absence of transcriptional regulation of gene expression in Leishmania parasites, it is now well accepted that several forms of genomic variations modulate the levels of critical proteins through changes in gene dosage. We previously observed many of these variations in our reference laboratory strain of L. panamensis (PSC-1 strain), including chromosomes with an increased somy and the presence of a putative linear minichromosome derived from chromosome 34. Here, we compared the previously described genomic variations with those occurring after exposure of this strain to increasing concentrations of trivalent antimony (SbIII), as well as those present in two geographically unrelated clinical isolates of L. panamensis. We observed changes in the somy of several chromosomes, amplifications of several chromosomal regions, and copy number variations in gene arrays after exposure to SbIII. Occurrence of amplifications potentially beneficial for the Sb-resistant phenotype appears to be associated with the loss of other forms of amplification, such as the linear minichromosome. In contrast, we found no evidence of changes in somy or amplification of relatively large chromosomal regions in the clinical isolates. In these isolates, the predominant amplifications appear to be those that generate genes arrays; however, in many cases, the amplified arrays have a notably higher number of copies than those from the untreated and Sb-treated laboratory samples.
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Insights into the structural patterns of the antiLeishmanial activity of bi- and tricyclic N-heterocycles
Organic & biomolecular chemistry, 2016Co-Authors: L. Herrera, Ricardo Lleonart, David E. Stephens, Oleg V. Larionov, Abigail D'avila, Kathryn G. George, Hadi D. Arman, Yu Zhang, George Perry, Patricia L. FernándezAbstract:The influence of various structural patterns in a series of novel bi- and tricyclic N-heterocycles on the activity against Leishmania major and Leishmania panamensis has been studied and compounds that are active in the low micromolar region have been identified. Both quinolines and tetrahydrooxazinoindoles (TOI) proved to have significant antiLeishmanial activities, while substituted indoles were inactive. We have also showed that a chloroquine analogue induces Leishmania killing by modulating macrophage activation.
Iván D. Vélez - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Evaluation of Thiochroman-4-One Derivatives as Potential Leishmanicidal Agents
Molecules (Basel Switzerland), 2017Co-Authors: Esteban Vargas, Sara M. Robledo, Fernando Echeverri, Iván D. Vélez, Wiston QuiñonesAbstract:The S-containing heterocyclic compounds benzothiopyrans or thiochromones stand out as having promising biological activities due to their structural relationship with chromones (benzopyrans), which are widely known as privileged scaffolds in medicinal chemistry. In this work, we report the synthesis of 35 thiochromone derivatives and the in vitro antiLeishmanial and cytotoxic activities. Compounds were tested against intracellular amastigotes of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Compounds bearing a vinyl sulfone moiety, 4h, 4i, 4j, 4k, 4l and 4m, displayed the highest antiLeishmanial activity, with EC50 values lower than 10 μM and an index of selectivity over 100 for compounds 4j and 4l. When the double bond or the sulfone moiety was removed, the activity decreased. Our results show that thiochromones bearing a vinyl sulfone moiety are endowed with high antiLeishmanial activity and low cytotoxicity.
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Synthesis, Leishmanicidal and Cytotoxic Activity of Triclosan-Chalcone, Triclosan-Chromone and Triclosan-Coumarin Hybrids
Molecules (Basel Switzerland), 2014Co-Authors: Elver Otero, Sara M. Robledo, Wilson Cardona, Iván D. Vélez, Miguel Carda, Sebastián Vergara, Carlos Rojas, Felipe OtálvaroAbstract:Twelve hybrids derived from triclosan were obtained via Williamson etherification of O-triclosan alkyl bromide plus chalcone and O-coumarin or O-chromone alkyl bromide plus triclosan, respectively. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antiLeishmanial activity against L. (V) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. Compounds 7–9 and 17, were active against Leishmania parasites (EC50 = 9.4; 10.2; 13.5 and 27.5 µg/mL, respectively) and showed no toxicity toward mammalian cells (>200 µg/mL). They are potential candidates for antiLeishmanial drug development. Compounds 25–27, were active and cytotoxic. Further studies using other cell types are needed in order to discriminate whether the toxicity shown by these compounds is against tumor or non-tumor cells. The results indicate that compounds containing small alkyl chains show better selectivity indices. Moreover, Michael acceptor moieties may modify both the leishmanicidal activity and cytotoxicity. Further studies are required to evaluate if the in vitro activity against Leishmania panamensis demonstrated here is also observed in vivo.
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Association of acenaphthoporphyrins with liposomes for the photodynamic treatment of Leishmaniasis.
Photochemistry and photobiology, 2010Co-Authors: Daniel M. Gardner, Sara M. Robledo, Viviana M. Taylor, David L. Cedeño, Shruti Padhee, Marjorie A. Jones, Timothy D. Lash, Iván D. VélezAbstract:Acenaphthoporphyrins are potential photosensitizers for photodynamic therapy, but their hydrophobicity limits their potential. Liposomes have been widely investigated as delivery vehicles that can transport hydrophobic drugs in biological systems. Here we study the association of acenaphthoporphyrins with liposomes made up of dimyristoyl phosphatidylcholine (DMPC), and to liposomes made up of a mixture of DMPC, cholesterol (Chol) and distearoyl phosphatidylglycerol (DSPG) in a 2:1:0.8 molar ratio to evaluate how liposome composition affects association constants. In liposomes consisting only of DMPC, the smaller monoacenaphthoporphyrin had the largest association constant of 5.5 x 10(4) m(-1) while the larger adj-diacenaphthoporphyrin and opp-diacenaphthoporphyrin (ODP) had smaller association constants at 1.8 x 10(4) and 1.5 x 10(4) m(-1), respectively. The addition of liposomal Chol and DSPG has little effect on the magnitudes of the association constants. Polarization studies show that the acenaphthoporphyrins are driven far into the lipid bilayer to minimize polar-nonpolar interactions. Confocal microscopy confirms that the DMPC liposomes transport the porphyrins into promastigotes of Leishmania tarentolae. The compounds associated with DMPC:Chol:DSPG liposomes are effective in vitro against axenic and intracellular amastigotes of the pathogenic Leishmania panamensis. The effectiveness of the compounds is enhanced upon exposure of cultures to visible light.
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Antiparasite and antimycobacterial activity of passifloricin analogues
Tetrahedron, 2006Co-Authors: Wilson Cardona, Sara M. Robledo, Winston Quiñones, Iván D. Vélez, Juan Murga, Jorge García-fortanet, Miguel Carda, Diana Cardona, Fernando EcheverriAbstract:Abstract Several structural analogues of the polyketide passifloricin lactone were synthesized using asymmetric stereoselective allylations and ring-closing methateses as key reactions. These compounds were active in vitro against intracellular amastigotes of Leishmania panamensis (strain UA140), trophozoites of Plasmodium falciparum (strain NF54), and Mycobacterium tuberculosis (strain H37Rv). However, in spite of the significative antiparasitic activity of some synthetic analogues a high cytotoxicity was also observed. Based on these results a lactam derivative was also synthesized. This compound maintained a good level of activity with less toxicity.
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EFECTO DE HIDRAZONAS SOBRE AMASTIGOTES INTRACELULARES DE Leishmania panamensis Y UNA PROTEASA DE CISTEÍNA PARASITARIA EFFECT OF HYDRAZONES AGAINST INTRACELLULAR AMASTIGOTES OF Leishmania panamensis AND A PARASITIC CYSTEIN PROTEASE
2006Co-Authors: Diana L Munoz, Winston Quiñones, Fernando Echeverri, Iván D. Vélez, Diana Cardona, Álvaro Cardona, Lina María Carrillo, Sara M. RobledoAbstract:In this paper, the synthesis of hydrazones derived from cromano, thiocroman, alkyl and aril hydrazones is described, as well as their leishmanicidal activity and their effect on cysteine proteases from L. (V) panamensis. A series of novel phenylthiochromane and benzyl and naphtyl derivatives are synthesized and evaluated for their cytotoxic and antiLeishmanial activities. Their effect on parasite cysteine protease is also evaluated. Only phenylthiochromane derivatives display some activity against Leishmania (V) panamensis but all compounds are inactive against parasitic cystein protease. These results may suggest a different mechanism of action for these compounds.
Juan David Ramírez - One of the best experts on this subject based on the ideXlab platform.
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Major changes in chromosomal somy, gene expression and gene dosage driven by SbIII in Leishmania braziliensis and Leishmania panamensis.
Scientific reports, 2019Co-Authors: Luz H. Patino, Lissa Cruz-saavedra, Hideo Imamura, Paula Pavia, Carlos Muskus, Claudia Méndez, Jean-claude Dujardin, Juan David RamírezAbstract:Leishmania braziliensis and Leishmania panamensis are two species clinically and epidemiologically important, among others because of their relative resistance to first-line drugs (antimonials). The precise mechanism underlying the ability of these species to survive antimony treatment remains unknown. Therefore, elucidating the pathways mediating drug resistance is essential. We herein experimentally selected resistance to trivalent antimony (SbIII) in the reference strains of L. braziliensis (MHOM/BR75/M2904) and L. panamensis (MHOM/COL/81L13) and compared whole genome and transcriptome alterations in the culture promastigote stage. The results allowed us to identify differences in somy, copy number variations in some genes related to antimony resistance and large-scale copy number variations (deletions and duplications) in chromosomes with no somy changes. We found mainly in L. braziliensis, a direct relation between the chromosomal/local copy number variation and the gene expression. We identified differentially expressed genes in the resistant lines that are involved in antimony resistance, virulence, and vital biological processes in parasites. The results of this study may be useful for characterizing the genetic mechanisms of these Leishmania species under antimonial pressure, and for clarifying why the parasites are resistant to first-line drug treatments.
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Spatial distribution, Leishmania species and clinical traits of Cutaneous Leishmaniasis cases in the Colombian army.
PLoS neglected tropical diseases, 2017Co-Authors: Luz H. Patino, Claudia Méndez, Omaira Rodríguez, Yanira Romero, Daniel Velandia, Maria Teresa Alvarado, Julie Perez, María Clara Duque, Juan David RamírezAbstract:In Colombia, the cutaneous Leishmaniasis (CL) is the most common manifestation across the army personnel. Hence, it is mandatory to determine the species associated with the disease as well as the association with the clinical traits. A total of 273 samples of male patients with CL were included in the study and clinical data of the patients was studied. PCR and sequencing analyses (Cytb and HSP70 genes) was performed to identify the species and the intra-specific genetic variability. A georeferenced database was constructed to identify the spatial distribution of Leishmania species isolated. The identification of five species of Leishmania that circulate in the areas where army personnel are deployed is described. Predominant infecting Leishmania species corresponds to L. braziliensis (61.1%), followed by Leishmania panamensis (33.5%), with a high distribution of both species at geographical and municipal level. The species L. guyanensis, L. mexicana and L. lainsoni were also detected at lower frequency. We also showed the identification of different genotypes within L. braziliensis and L. panamensis. In conclusion, we identified the Leishmania species circulating in the areas where Colombian army personnel are deployed, as well as the high intra-specific genetic variability of L. braziliensis and L. panamensis and how these genotypes are distributed at the geographic level. © 2017 Patino et al.
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Spatial distribution, Leishmania species and clinical traits of Cutaneous Leishmaniasis cases in the Colombian army
2017Co-Authors: Luz H. Patino, Claudia Méndez, Omaira Rodríguez, Yanira Romero, Daniel Velandia, Julie Perez, María Clara Duque, Maria Alvarado, Juan David RamírezAbstract:In Colombia, the cutaneous Leishmaniasis (CL) is the most common manifestation across the army personnel. Hence, it is mandatory to determine the species associated with the disease as well as the association with the clinical traits. A total of 273 samples of male patients with CL were included in the study and clinical data of the patients was studied. PCR and sequencing analyses (Cytb and HSP70 genes) were performed to identify the species and the intra-specific genetic variability. A georeferenced database was constructed to identify the spatial distribution of Leishmania species isolated. The identification of five species of Leishmania that circulate in the areas where army personnel are deployed is described. Predominant infecting Leishmania species corresponds to L. braziliensis (61.1%), followed by Leishmania panamensis (33.5%), with a high distribution of both species at geographical and municipal level. The species L. guyanensis, L. mexicana and L. lainsoni were also detected at lower frequency. We also showed the identification of different genotypes within L. braziliensis and L. panamensis. In conclusion, we identified the Leishmania species circulating in the areas where Colombian army personnel are deployed, as well as the high intra-specific genetic variability of L. braziliensis and L. panamensis and how these genotypes are distributed at the geographic level.
Alejandro Llanes - One of the best experts on this subject based on the ideXlab platform.
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Gene expression patterns associated with Leishmania panamensis infection in macrophages from BALB/c and C57BL/6 mice.
PLoS neglected tropical diseases, 2021Co-Authors: Carlos M. Restrepo, Alejandro Llanes, Ricardo Lleonart, L. Herrera, Esteban Ellis, Patricia L. FernándezAbstract:Leishmania parasites can trigger different host immune responses that result in varying levels of disease severity. The C57BL/6 and BALB/c mouse strains are among the host models commonly used for characterizing the immunopathogenesis of Leishmania species and the possible antiLeishmanial effect of novel drug candidates. C57BL/6 mice tend to be resistant to Leishmania infections, whereas BALB/c mice display a susceptible phenotype. Studying species-specific interactions between Leishmania parasites and different host systems is a key step to characterize and validate these models for in vivo studies. Here, we use RNA-Seq and differential expression analysis to characterize the transcriptomic profiles of C57BL/6 and BALB/c peritoneal-derived macrophages in response to Leishmania panamensis infection. We observed differences between BALB/c and C57BL/6 macrophages regarding pathways associated with lysosomal degradation, arginine metabolism and the regulation of cell cycle. We also observed differences in the expression of chemokine and cytokine genes associated with regulation of immune responses. In conclusion, infection with L. panamensis induced an inflammatory gene expression pattern in C57BL/6 macrophages that is more consistently associated with a classic macrophage M1 activation, whereas in BALB/c macrophages a gene expression pattern consistent with an intermediate inflammatory response was observed.
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gene expression patterns associated with Leishmania panamensis infection in macrophages from balb c and c57bl 6 mice
PLOS Neglected Tropical Diseases, 2021Co-Authors: Carlos M. Restrepo, Alejandro Llanes, Ricardo Lleonart, L. Herrera, Esteban Ellis, Patricia L. FernándezAbstract:Leishmania parasites can trigger different host immune responses that result in varying levels of disease severity. The C57BL/6 and BALB/c mouse strains are among the host models commonly used for characterizing the immunopathogenesis of Leishmania species and the possible antiLeishmanial effect of novel drug candidates. C57BL/6 mice tend to be resistant to Leishmania infections, whereas BALB/c mice display a susceptible phenotype. Studying species-specific interactions between Leishmania parasites and different host systems is a key step to characterize and validate these models for in vivo studies. Here, we use RNA-Seq and differential expression analysis to characterize the transcriptomic profiles of C57BL/6 and BALB/c peritoneal-derived macrophages in response to Leishmania panamensis infection. We observed differences between BALB/c and C57BL/6 macrophages regarding pathways associated with lysosomal degradation, arginine metabolism and the regulation of cell cycle. We also observed differences in the expression of chemokine and cytokine genes associated with regulation of immune responses. In conclusion, infection with L. panamensis induced an inflammatory gene expression pattern in C57BL/6 macrophages that is more consistently associated with a classic macrophage M1 activation, whereas in BALB/c macrophages a gene expression pattern consistent with an intermediate inflammatory response was observed.
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AntiLeishmanial activity of a new chloroquine analog in an animal model of Leishmania panamensis infection
International journal for parasitology. Drugs and drug resistance, 2020Co-Authors: L. Herrera, Alejandro Llanes, Jennifer Álvarez, Kissy Degracia, Carlos M. Restrepo, René Rivera, David E. Stephens, Hang T. Dang, Oleg V. Larionov, Ricardo LleonartAbstract:Abstract Leishmania panamensis is a relevant causative agent of tegumentary Leishmaniasis in several Latin American countries. Available antiLeishmanial drugs have several limitations including relatively high toxicity, difficult administration, high production costs and the emergence of resistance in circulating strains. Therefore, the identification of new molecules as potential therapeutics for Leishmaniasis is of great relevance. Here, we developed a murine model of L. panamensis infection and evaluated the effect of a new compound in vivo. After treatment of animals with the compound, we observed a significant reduction of inflammation and parasite load at the inoculation site, in a dose-dependent manner. We observed a reduction in IL-10 production by popliteal lymph nodes cells of infected mice. These results pave the way for future evaluation of this compound as a potential antiLeishmanial drug or as a suitable scaffold for lead optimization strategies.
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Environmental Conditions May Shape the Patterns of Genomic Variations in Leishmania panamensis.
Genes, 2019Co-Authors: Carlos M. Restrepo, José Antonio Suárez, Alejandro Llanes, Jennifer Álvarez, Eymi M. Cedeño, Jim H. Chang, Margarita Ríos, Homero Penagos, Ricardo LleonartAbstract:Due to the absence of transcriptional regulation of gene expression in Leishmania parasites, it is now well accepted that several forms of genomic variations modulate the levels of critical proteins through changes in gene dosage. We previously observed many of these variations in our reference laboratory strain of L. panamensis (PSC-1 strain), including chromosomes with an increased somy and the presence of a putative linear minichromosome derived from chromosome 34. Here, we compared the previously described genomic variations with those occurring after exposure of this strain to increasing concentrations of trivalent antimony (SbIII), as well as those present in two geographically unrelated clinical isolates of L. panamensis. We observed changes in the somy of several chromosomes, amplifications of several chromosomal regions, and copy number variations in gene arrays after exposure to SbIII. Occurrence of amplifications potentially beneficial for the Sb-resistant phenotype appears to be associated with the loss of other forms of amplification, such as the linear minichromosome. In contrast, we found no evidence of changes in somy or amplification of relatively large chromosomal regions in the clinical isolates. In these isolates, the predominant amplifications appear to be those that generate genes arrays; however, in many cases, the amplified arrays have a notably higher number of copies than those from the untreated and Sb-treated laboratory samples.
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Genome-wide discovery and development of polymorphic microsatellites from Leishmania panamensis parasites circulating in central Panama.
Parasites & vectors, 2015Co-Authors: Carlos Mario Restrepo, Alejandro Llanes, Carolina De La Guardia, Ricardo LleonartAbstract:Background The parasite Leishmania panamensis is the main cause of Leishmaniasis in Panama. The disease is largely uncontrolled, with a rising incidence and no appropriate control measures. While microsatellites are considered some of the best genetic markers to study population genetics and molecular epidemiology in these and other parasites, none has been developed for L. panamensis.