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Antimicrob Agents Chemother ; 64(12)2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-32928735


In this study, we demonstrated the potential associative effect of combining conventional amphotericin B (Amph B) with gallic acid (GA) and with ellagic acid (EA) in topical formulations for the treatment of cutaneous leishmaniasis in BALB/c mice. Preliminary stability tests of the formulations and in vitro drug release studies with Amph B, GA, Amph B plus GA, EA, and Amph B plus EA were carried out, as well as assessment of the in vivo treatment of BALB/c mice infected with Leishmania major After 40 days of infection, the animals were divided into 6 groups and treated twice a day for 21 days with a gel containing Amph B, GA, Amph B plus GA, EA, or Amph B plus EA, and the negative-control group was treated with the vehicle. In the animals that received treatment, there was reduction of the lesion size and reduction of the parasitic load. Histopathological analysis of the treatments with GA, EA, and combinations with Amph B showed circumscribed lesions with the presence of fibroblasts, granulation tissue, and collagen deposition, as well as the presence of activated macrophages. The formulations containing GA and EA activated macrophages in all evaluated parameters, resulting in the activation of cells of the innate immune response, which can generate healing and protection. GA and EA produced an associative effect with Amph B, which makes them promising for use with conventional Amph B in the treatment of cutaneous leishmaniasis.

Biosci. j. (Online) ; 36(3): 956-967, 01-05-2020. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1147179


The visceral establishment of Leishmania infantum in dogs may result in kidney and bladder tissue injury, with L. infantum ending up in urine. This study therefore aimed at investigating the presence of Leishmania sp. in urinary sediments, and correlating the results with those from renal and bladder serum biochemistry and histopathology. Thirty dogs with negative Nested-Polymerase Chain Reaction (PCR) for E. canis were used in the experiment, and were divided into three groups: control group (10 dogs), neither leishmaniasis nor clinical changes; group I (15 dogs), leishmaniasis but no Leishmania sp. in urine; and group II (5 dogs), leishmaniasis, as well as Leishmania sp. in urine. All animals were submitted to clinical, serological, and parasitological diagnosis for leishmaniasis, biochemical exams, and kidney and bladder histopathology. The parasite was also detected in the bladder imprint of one group II dog. Group II dogs presented with very low albumin concentrations, low albumin/globulin ratios, and kidney and bladder lesions. In the kidneys, hydropic degeneration, thickened Bowman's capsule, and thickening of the tubular capsule were detected in all dogs with positive urinary sediment. However, no significant difference in these renal changes was observed between groups. The intensity and distribution of bladder inflammatory infiltrates were significantly (p-value < 0.05, Kruskal-Wallis' and Dunn's tests) higher in group II dogs, compared with those of the other groups. The presence of Leishmania the urine of infected dogs appeared to be related to low serum albumin concentrations and more severe bladder lesions

O estabelecimento visceral de Leishmania infantum em cães pode resultar em lesões nos tecidos dos rins e da bexiga, favorecendo a chegando do parasito até a urina. Portanto, este estudo teve como objetivo investigar a presença de Leishmania sp. em sedimentos urinários e correlacionar os resultados com os achados de quantificações bioquímicas séricas e histopatologia de rim e bexiga. Trinta cães com Nested-Reação em Cadeia da Polimerase (PCR) negativa para E. canis foram utilizados no experimento e foram divididos em três grupos: grupo controle (10 cães), negativos para leishmaniose e sem alterações clínicas; grupo I (15 cães), com leishmaniose, mas sem Leishmania sp. na urina; e grupo II (5 cães), com leishmaniose e com Leishmaniasp. na urina. Todos os animais foram submetidos a diagnóstico clínico, sorológico e parasitológico para leishmaniose, exames bioquímicos e histopatologia de rim e bexiga. O parasito foi detectado no imprimt de bexiga de um cão do grupo II. Os cães do grupo II apresentaram concentrações muito baixas de albumina, baixa relação albumina/globulina e lesões nos rins e na bexiga. Nos rins, foram detectadas degeneração hidrópica, espessamento da cápsula de Bowman e espessamento da cápsula tubular, em todos os cães com sedimento urinário positivo. No entanto, nenhuma diferença significativa nessas alterações renais foi observada entre os grupos. A intensidade e a distribuição dos infiltrados inflamatórios da bexiga foram significativamente (p-valor < 0,05, testes de Kruskal-Wallis e Dunn) maiores nos cães do grupo II, em comparação com a dos outros grupos. A presença de Leishmania sp. na urina de cães infectados parece estar relacionada a baixa concentração sérica de albumina e a lesões mais graves na bexiga.

Urina , Leishmaniose , Cães
Toxicol In Vitro ; 63: 104750, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31862617


The present study was directed to the in vitro antileishmanial, cytotoxic and immunomodulatory effects of Garcinielliptone FC (GFC) against promastigote and macrophage-internalized amastigote forms of Leishmania amazonensis. GFC showed in vitro cytotoxicity against BALB/c peritoneal macrophages with CC50 of 74.90 µM. The hemolytic activity against sheep erythrocytes only demonstrated a decrease of 20.42% in cell viability at the highest tested concentration tested (1326.0 µM). GFC promoted in vitro growth inhibition of both promastigote and intracellular amastigotes with IC50 values of 14.06 and 1.91 µM, respectively, with 7.3-fold higher Selectivity Index (SI) for intracellular amastigotes (SI = 39.21) than for promastigotes (SI = 5.33). Interestingly, the pre-treatment of macrophages or promastigotes with GFC promoted decrease of infected macrophages and number of recovered amastigotes, respectively. Also, GFC was able to markedly promote macrophages activation by increase of phagocytic capability and nitrite production at concentrations able to solve infection of macrophages by L. amazonensis, suggesting the possible involvement of immunomodulatory modulation of macrophages leading to solve the infection. GFC is an emerging and promising chemical compound for the studies focused on the assessment of its therapeutic potential on in vivo experimental models of leishmaniasis.

Antiprotozoários/farmacologia , Fatores Imunológicos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Leishmania , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos BALB C , Nitritos/metabolismo , Fagocitose/efeitos dos fármacos , Ovinos
Drug Dev Ind Pharm ; 44(10): 1713-1723, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29961344


OBJECTIVE: This work aimed to develop and characterize a topical emulgel of amphotericin B (AmB) with bacuri butter (Platonia insignis Mart.) and evaluate its antileishmanial activity using in vitro assays. SIGNIFICANCE: Leishmaniasis is considered an infectious disease, with high incidence and capacity to produce deformities. The first-line treatment recommended by WHO, with pentavalent antimonials, is aggressive and very toxic. Therefore, the development of topical treatments can emerge as a promising and less offensive alternative. METHODS: The developed formulations were evaluated for organoleptic characteristics, centrifugation resistance, globule size, pH, electrical conductivity, viscosity, spreadability, drug content, preliminary stability, in vitro release profile, evaluation of antileishmanial activity using promastigotes forms of Leishmania major as infecting agents, macrophage cytotoxicity and selectivity index (IS). RESULTS: Formulated emulsions presented organoleptic characteristics compatible with its constituents; pH values were suitable for topical application, ranging from 4.73 to 5.02; introduced non-Newtonian shear thinning system; drug content was within the established standards, and the most suitable kinetic model of release was the first order. Regarding the in vitro assays, formulations containing both 1% and 3% of AmB presented similar outcomes, indicating a synergism between the bacuri butter and the drug, possibly showing a reduction on cytotoxicity to host cells. CONCLUSIONS: It was concluded that the formulations developed showed promising antileishmanial action and high potential for topical use.

Anfotericina B/química , Antiprotozoários/química , Leishmaniose Cutânea , Extratos Vegetais/química , Administração Tópica , Anfotericina B/administração & dosagem , Animais , Antiprotozoários/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Emulsões/administração & dosagem , Emulsões/química , Feminino , Géis , Leishmaniose Cutânea/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/administração & dosagem
PeerJ ; 6: e4656, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29736332


Background: Tissue engineering has been shown to exhibit great potential for the creation of biomaterials capable of developing into functional tissues. Cellular expansion and integration depends on the quality and surface-determinant factors of the scaffold, which are required for successful biological implants. The objective of this research was to characterize and evaluate the in vitro characteristics of rabbit bone marrow mesenchymal stem cells (BM-MSCs) associated with a bacterial cellulose membrane (BCM). We assessed the adhesion, expansion, and integration of the biomaterial as well as its ability to induce macrophage activation. Finally, we evaluated the cytotoxicity and toxicity of the BCM. Methods: Samples of rabbit bone marrow were collected. Mesenchymal stem cells were isolated from medullary aspirates to establish fibroblast colony-forming unit assay. Osteogenic, chondrogenic, and adipogenic differentiation was performed. Integration with the BCM was assessed by scanning electron microscopy at 1, 7, and 14 days. Cytotoxicity was assessed via the production of nitric oxide, and BCM toxicity was assessed with the MTT assay; phagocytic activity was also determined. Results: The fibroblastoid colony-forming unit (CFU-F) assay showed cells with a fibroblastoid morphology organized into colonies, and distributed across the culture area surface. In the growth curve, two distinct phases, lag and log phase, were observed at 15 days. Multipotentiality of the cells was evident after induction of osteogenic, chondrogenic, and adipogenic lineages. Regarding the BM-MSCs' bioelectrical integration with the BCM, BM-MSCs were anchored in the BCM in the first 24 h. On day 7 of culture, the cytoplasm was scattered, and on day 14, the cells were fully integrated with the biomaterial. We also observed significant macrophage activation; analysis of the MTT assay and the concentration of nitric oxide revealed no cytotoxicity of the biomaterial. Conclusion: The BCM allowed the expansion and biointegration of bone marrow progenitor cells with a stable cytotoxic profile, thus presenting itself as a biomaterial with potential for tissue engineering.

Artigo em Inglês | MEDLINE | ID: mdl-28852412


Platonia insignis Mart., popularly known as "bacurizeiro," is used in traditional medical practices based on its diverse biological properties. This study was aimed at evaluating the antileishmanial effects of the ethanol extract (EtOH-Ext), hexane fraction (Hex-F), and its main isolated Lupeol obtained from stem barks of P. insignis against Leishmania (Leishmania) amazonensis, as well as their cytotoxicity and possible mechanisms of action. The EtOH-Ext, Hex-F, and Lupeol inhibited the growth of L. amazonensis promastigote forms at IC50 of 174.24, 45.23, and 39.06 µg/mL, respectively, as well as L. amazonensis axenic amastigote forms at IC50 of 40.58, 35.87, and 44.10 µg/mL, respectively. The mean cytotoxic concentrations for macrophages (CC50) were higher than those for amastigotes (341.95, 71.65, and 144.0 µg/mL, resp.), indicating a selective cytotoxicity towards the parasite rather than the macrophages. Interestingly, all treatments promoted antileishmanial effect against macrophage-internalized amastigotes at concentrations lower than CC50. Furthermore, increases of lysosomal volume of macrophages treated with EtOH-Ext, Hex-F, and Lupeol were observed. On the other hand, only Lupeol stimulated increase of phagocytic capability of macrophages, suggesting this compound might be characterized as the biomarker for the antileishmanial effect of P. insignis stem bark, as well as the involvement of immunomodulatory mechanisms in this effect.

Naunyn Schmiedebergs Arch Pharmacol ; 390(9): 893-903, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28643086


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 parasitemia. Gallic acid (GA) and ellagic acid (EA) are plant-derived phenolic compounds which are able to induce antiinflammatory, gastroprotective, and anticarcinogenic activities. Therefore, the antileishmania, cytotoxic, and immunomodulatory activities of GA and EA were evaluated in this study. Both GA and EA were able to inhibit the growth of Leishmania major promastigotes (effective concentration (EC50) values 16.4 and 9.8 µg/mL, respectively). The cytotoxicity against BALB/c murine macrophages for GA and EA was also assessed (CC50 values 126.6 and 23.8 µg/mL, respectively). Interestingly, GA and EA also significantly reduced the infection and infectivity of macrophages infected by L. major (EC50 values 5.0 and 0.9 µg/mL, respectively), with selectivity index higher than 20. Furthermore, both GA and EA induced high immunomodulatory activity evidenced by the increase of phagocytic capability, lysosomal volume, nitrite release, and intracellular calcium [Ca2+i] in macrophages. Further investigations are reinforced in order to evaluate the therapeutic effects of GA and EA in in vivo experimental infection model of leishmaniasis.

Antiprotozoários/farmacologia , Ácido Elágico/farmacologia , Ácido Gálico/farmacologia , Leishmaniose Cutânea/tratamento farmacológico , Animais , Antiprotozoários/administração & dosagem , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Ácido Elágico/administração & dosagem , Feminino , Ácido Gálico/administração & dosagem , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Leishmania major/efeitos dos fármacos , Leishmania major/isolamento & purificação , Leishmaniose Cutânea/parasitologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C