Navegando por Autor "Antinarelli, Luciana Maria Ribeiro"
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Item Acarbose presents in vitro and in vivo antileishmanial activity against Leishmania infantum and is a promising therapeutic candidate against visceral leishmaniasis.(2020) Costa, Rafaella Rodrigues; Silva, João Augusto Oliveira da; Reis, Thiago Alves Rosa dos; Tavares, Grasiele de Sousa Vieira; Mendonça, Débora Vasconcelos Costa; Freitas, Camila Simões de; Lage, Daniela Pagliara; Martins, Vívian Tamietti; Antinarelli, Luciana Maria Ribeiro; Machado, Amanda Sanchez; Bandeira, Raquel Soares; Ribeiro, Fernanda Ludolf; Santos, Thaís Teodoro de Oliveira; Brito, Rory Cristiane Fortes de; Humbert, Maria Victoria; Souza, Daniel Menezes; Duarte, Mariana Costa; Chávez Fumagalli, Miguel Angel; Roatt, Bruno Mendes; Coimbra, Elaine Soares; Coelho, Eduardo Antônio FerrazTreatment against visceral leishmaniasis (VL) is mainly hampered by drug toxicity, long treatment regimens and/or high costs. Thus, the identifcation of novel and low-cost antileishmanial agents is urgent. Acarbose (ACA) is a specifc inhibitor of glucosidase-like proteins, which has been used for treating diabetes. In the present study, we show that this molecule also presents in vitro and in vivo specifc antileishmanial activity against Leishmania infantum. Results showed an in vitro direct action against L. infantum promastigotes and amastigotes, and low toxicity to mammalian cells. In addition, in vivo experiments performed using free ACA or incorporated in a Pluronic® F127-based polymeric micelle system called ACA/ Mic proved efective for the treatment of L. infantum-infected BALB/c mice. Treated animals presented signifcant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes when compared to the controls, as well as the development of antileishmanial Th1-type humoral and cellular responses based on high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibodies. In addition, ACA or ACA-treated animals sufered from low organ toxicity. Treatment with ACA/Mic outperformed treatments using either Miltefosine or free ACA based on parasitological and immunological evaluations performed one and 15 days post-therapy. In conclusion, data suggest that the ACA/Mic is a potential therapeutic agent against L. infantum and merits further consideration for VL treatment.Item A chloroquinoline derivate presents effective in vitro and in vivo antileishmanial activity against Leishmania species that cause tegumentary and visceral leishmaniasis.(2019) Sousa, Jéssica Karine Távora de; Antinarelli, Luciana Maria Ribeiro; Mendonça, Débora Vasconcelos Costa; Lage, Daniela Pagliara; Tavares, Grasiele de Sousa Vieira; Dias, Daniel Silva; Ribeiro, Patrícia Aparecida Fernandes; Ribeiro, Fernanda Ludolf; Coelho, Vinicio Tadeu da Silva; Silva, João Augusto Oliveira da; Melo, Luísa Helena Perin de; Oliveira, Bianka A.; Alvarenga, Denis Fernando; Chávez Fumagalli, Miguel Angel; Brandão, Geraldo Célio; Vandack, Nobre; Pereira, Guilherme Rocha; Coimbra, Elaine Soares; Coelho, Eduardo Antônio FerrazThe identification of new therapeutics to treat leishmaniasis is desirable, since available drugs are toxic and present high cost and/or poor availability. Therefore, the discovery of safer, more effective and selective pharmaceutical options is of utmost importance. Efforts towards the development of new candidates based on molecule analogs with known biological functions have been an interesting and cost-effective strategy. In this context, quinoline derivatives have proven to be effective biological activities against distinct diseases. In the present study, a new chloroquinoline derivate, AM1009, was in vitro tested against two Leishmania species that cause leishmaniasis. The present study analyzed the necessary inhibitory concentration to preclude 50% of the Leishmania promastigotes and axenic amastigotes (EC50 value), as well as the inhibitory concentrations to preclude 50% of the murine macrophages and human red blood cells (CC50 and RBC50 values, respectively). In addition, the treatment of infected macrophages and the inhibition of infection using pre-treated parasites were also investigated, as was the mechanism of action of the molecule in L. amazonensis. To investigate the in vivo therapeutic effect, BALB/c mice were infected with L. amazonensis and later treated with AM1009. Parasitological and immunological parameters were also evaluated. Clioquinol, a known antileishmanial quinoline derivate, and amphotericin B (AmpB), were used as molecule and drug controls, respectively. Results in both in vitro and in vivo experiments showed a better and more selective action of AM1009 to kill the in vitro parasites, as well as in treating infected mice, when compared to results obtained using clioquinol or AmpB. AM1009-treated animals presented significantly lower average lesion diameter and parasite burden in the infected tissue and organs evaluated in this study, as well as a more polarized antileishmanial Th1 immune response and low renal and hepatic toxicity. This result suggests that AM1009 should be considered a possible therapeutic target to be evaluated in future studies for treatment against leishmaniasis.Item Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis.(2020) Freitas, Camila Simões de; Silva, João Augusto Oliveira da; Lage, Daniela Pagliara; Costa, Rafaella Rodrigues; Mendonça, Débora Vasconcelos Costa; Martins, Vívian Tamietti; Reis, Thiago Alves Rosa dos; Antinarelli, Luciana Maria Ribeiro; Machado, Amanda Sanchez; Tavares, Grasiele de Sousa Vieira; Ramos, Fernanda Fonseca; Coelho, Vinicio Tadeu da Silva; Brito, Rory Cristiane Fortes de; Ribeiro, Fernanda Ludolf; Chávez Fumagalli, Miguel Angel; Roatt, Bruno Mendes; Ramos, Gabriela S.; Munkert, Jennifer; Ottoni, Flaviano Melo; Campana, Priscilla Rodrigues Valadares; Humbert, Maria Victoria; Coimbra, Elaine Soares; Braga, Fernão Castro; Pádua, Rodrigo Maia de; Coelho, Eduardo Antônio FerrazTreatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC50 and CC50, respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 μg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 μg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum–infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment.Item In vitro and in vivo antileishmanial activity of b-acetyl-digitoxin, a cardenolide of Digitalis lanata potentially useful to treat visceral leishmaniasis.(2021) Freitas, Camila Simões de; Lage, Daniela Pagliara; Silva, João Augusto Oliveira da; Costa, Rafaella Rodrigues; Mendonça, Débora Vasconcelos Costa; Martins, Vívian Tamietti; Reis, Thiago Alves Rosa dos; Antinarelli, Luciana Maria Ribeiro; Machado, Amanda Sanchez; Tavares, Grasiele de Sousa Vieira; Ramos, Fernanda Fonseca; Brito, Rory Cristiane Fortes de; Ribeiro, Fernanda Ludolf; Chávez Fumagalli, Miguel Angel; Roatt, Bruno Mendes; Ramos, Gabriela S.; Munkert, Jennifer; Ottoni, Flaviano Melo; Campana, Priscilla Rodrigues Valadares; Duarte, Mariana Costa; Gonçalves, Denise Utsch; Coimbra, Elaine Soares; Braga, Fernão Castro; Pádua, Rodrigo Maia de; Coelho, Eduardo Antônio FerrazCurrent treatments of visceral leishmaniasis face limitations due to drug side effects and/or high cost, along with the emergence of parasite resistance. Novel and low-cost antileishmanial agents are therefore required. We report herein the antileishmanial activity of b-acetyl-digitoxin (b-AD), a cardenolide isolated from Digitalis lanata leaves, assayed in vitro and in vivo against Leishmania infantum. Results showed direct action of b-AD against parasites, as well as efficacy for the treatment of Leishmania-infected macrophages. In vivo experiments using b-AD-containing Pluronic F127 polymeric micelles (b-AD/Mic) to treat L. infantum-infected mice showed that this composition reduced the parasite load in distinct organs in more significant levels. It also induced the development of anti-parasite Th1-type immunity, attested by high levels of IFN-c, IL-12, TNF-a, GM-CSF, nitrite and specific IgG2a antibodies, in addition to low IL-4 and IL-10 contents, along with higher IFN-c-producing CD4+ and CD8+ T-cell frequency. Furthermore, low toxicity was found in the organs of the treated animals. Comparing the therapeutic effect between the treatments, b-AD/Mic was the most effective in protecting animals against infection, when compared to the other groups including miltefosine used as a drug control. Data found 15 days after treatment were similar to those obtained one day post-therapy. In conclusion, the results obtained suggest that b-AD/Mic is a promising antileishmanial agent and deserves further studies to investigate its potential to treat visceral leishmaniasis.Item In vivo antileishmanial efficacy of a naphthoquinone derivate incorporated into a Pluronic® F127-based polymeric micelle system against Leishmania amazonensis infection.(2019) Mendonça, Débora Vasconcelos Costa; Tavares, Grasiele de Sousa Vieira; Lage, Daniela Pagliara; Soyer, Tauane Gonçalves; Carvalho, Lívia Mendes; Dias, Daniel Silva; Ribeiro, Patrícia Aparecida Fernandes; Ottoni, Flaviano Melo; Antinarelli, Luciana Maria Ribeiro; Vale, Danniele Luciana; Ribeiro, Fernanda Ludolf; Duarte, Mariana Costa; Coimbra, Elaine Soares; Chávez Fumagalli, Miguel Angel; Roatt, Bruno Mendes; Souza, Daniel Menezes; Barichello, José Mario; Alves, Ricardo José; Coelho, Eduardo Antônio FerrazNew therapeutic strategies against leishmaniasis are desirable, since the treatment against disease presents problems, such as the toxicity, high cost and/or parasite resistance. As consequence, new antileishmanial compounds are necessary to be identified, as presenting high activity against Leishmania parasites, but low toxicity in mammalian hosts. Flau-A is a naphthoquinone derivative recently showed to presents an in vitro effective action against Leishmania amazonensis and L. infantum species. In the present work, the in vivo efficacy of Flau-A, which was incorporated into a Poloxamer 407-based micelle system, was evaluated in a murine model against L. amazonensis infection. Amphotericin B (AmB) and Ambisome® were used as controls. The animals were infected and later treated with the compounds. Thirty days after the treatment, parasitological and immunological parameters were evaluated. Results showed that AmB, Ambisome® , Flau-A or Flau-A/M-treated animals presented significantly lower average lesion diameter and parasite burden in tissue and organs evaluated, when compared to the control (saline and micelle) groups. Flau-A or Flau-A/M-treated mice were those presenting the most significant reductions in the parasite burden, when compared to the others. These animals developed also a more polarized antileishmanial Th1 immune response, which was based on significantly higher levels of IFN-γ, IL-12, TNF-α, GM-CSF, and parasite-specific IgG2a isotype; associated with low levels of IL-4, IL10, and IgG1 antibody. The absence of toxicity was found in these animals, although mice receiving AmB have showed high levels of renal and hepatic damage markers. In conclusion, results suggested that the Flau-A/M compound may be considered as a possible therapeutic target to be evaluated against human leishmaniasis.Item Ivermectin presents effective and selective antileishmanial activity in vitro and in vivo against Leishmania infantum and is therapeutic against visceral leishmaniasis.(2021) Reis, Thiago Alves Rosa dos; Silva, João Augusto Oliveira da; Tavares, Grasiele de Sousa Vieira; Mendonça, Débora Vasconcelos Costa; Freitas, Camila Simões de; Costa, Rafaella Rodrigues; Lage, Daniela Pagliara; Martins, Vívian Tamietti; Machado, Amanda Sanchez; Ramos, Fernanda Fonseca; Silva, Alessandra M.; Ribeiro, Fernanda Ludolf; Antinarelli, Luciana Maria Ribeiro; Brito, Rory Cristiane Fortes de; Chávez Fumagalli, Miguel Angel; Humbert, Maria Victoria; Roatt, Bruno Mendes; Coimbra, Elaine Soares; Coelho, Eduardo Antônio FerrazTreatment for visceral leishmaniasis (VL) is hindered mainly by the toxicity and/or high cost of therapeutic drugs. In addition, parasite resistance has been registered. Thus, there is an urgent need for the identification of novel, effective and low-cost antileishmanial agents. Since drug discovery is a long and expensive process, drug repositioning for treatment of leishmaniasis should be considered. In the present study, Ivermectin (IVE), a broad-spectrum drug used for treatment of parasitic diseases, was evaluated in vitro and in vivo against Leishmania infantum species. Results in vitro showed that IVE presented 50% Leishmania and macrophage inhibitory concentrations (IC50 and CC50, respectively) of 3.64 ± 0.48 μM and 427.50 ± 17.60 μM, respectively, with a selectivity index (SI) of 117.45; whereas Amphotericin B (AmpB), which was used as control, showed IC50 and CC50 values of 0.12 ± 0.05 μM and 1.06 ± 0.23 μM, respectively, with a corresponding SI of 8.90. Treatment with IVE effectively reduced the infection percentage and parasite burden in infected and treated macrophages and displayed a prophylactic activity by inhibiting macrophage infection with pre-treated parasites. Furthermore, preliminary studies suggested that IVE targets the parasite’s mitochondria. Activity of IVE in its free format or incorporated into Pluronic® F127-based polymeric micelles (IVE/Mic) was also evaluated in vivo as a treating drug for L. infantum-infected BALB/c mice. Miltefosine was used as a control. Results showed that Miltefosine, IVE and IVE/Mic-treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes, as well as development of an antileishmanial Th1-type immune response one and 15 days after treatment. Notably, IVE/Mic showed a better parasitological and immunological response in comparison to other alternative treatments. In conclusion, results suggest that IVE/Mic could be considered in future studies as a therapeutic alternative to treat VL.Item Leishmania infantum nucleoside triphosphate diphosphohydrolase 1 (NTPDase 1) B-domain : antibody antiproliferative effect on the promastigotes and IgG subclass responses in canine visceral leishmaniasis.(2019) Maia, Ana Carolina Ribeiro Gomes; Porcino, Gabriane Nascimento; Pinto, Priscila de Faria; Mendes, Túlio Vieira; Antinarelli, Luciana Maria Ribeiro; Coimbra, Elaine Soares; Reis, Alexandre Barbosa; Juliano Neto, Luiz; Juliano, Maria Aparecida; Marques, Marcos José; Vasconcelos, Eveline GomesA nucleoside triphosphate diphosphohydrolase-1 (NTPDase 1) was identified on the surface, flagellum and kinetoplast from L. infantum promastigotes by immunocytochemistry and confocal laser scanning microscopy, using immune sera that recognized specifically the B domain of NTPDase 1 and produced against synthetic peptides (LbB1LJ and LbB2LJ) derived from this domain. The polyclonal antibodies had effective antileishmanial effect, reducing significantly in vitro promastigotes growth (21–25%), an antiproliferative effect also demonstrated by immune sera produced against recombinant r-pot B domain, and two other synthetic peptides (potB1LJ and potB2LJ). In addition, using these biomolecules in ELISA technique, IgG1 and IgG2 subclasses reactivities of either healthy dogs or infected by L. infantum and classified clinically as asymptomatic, oligosymptomatic and symptomatic were tested. Analysis of distinct IgG1 and IgG2 seropositivities patterns suggested antibody subclasses binding epitopes along B domain for protection against infection, indicating this domain as a new tool for prophylactic and immunotherapeutic investigations.Item Parasitological and immunological evaluation of a novel chemotherapeutic agent against visceral leishmaniasis.(2020) Pereira, Isabela Amorim Gonçalves; Mendonça, Débora Vasconcelos Costa; Tavares, Grasiele de Sousa Vieira; Lage, Daniela Pagliara; Ramos, Fernanda Fonseca; Silva, João Augusto Oliveira da; Antinarelli, Luciana Maria Ribeiro; Machado, Amanda Sanchez; Carvalho, Lívia Mendes; Carvalho, Ana Maria Ravena Severino; Salustiano, Iorrana Vieira; Reis, Thiago Alves Rosa dos; Bandeira, Raquel Soares; Silva, Alessandra M.; Martins, Vivian Tamietti; Chávez Fumagalli, Miguel Angel; Humbert, Maria Victoria; Roatt, Bruno Mendes; Duarte, Mariana Costa; Souza, Daniel Menezes; Coimbra, Elaine Soares; Leite, João Paulo Viana; Coelho, Eduardo Antônio Ferraz; Gonçalves, Denise UtschAims: Treatment for visceral leishmaniasis (VL) is hampered by the toxicity and/or high cost of drugs, as well as by emergence of parasite resistance. Therefore, there is an urgent need for new antileishmanial agents. Methods and Results: In this study, the antileishmanial activity of a diprenylated flavonoid called 5,7,3,4’-tetrahydroxy-6,8-diprenylisoflavone (CMt) was tested against Leishmania infantum and L amazonensis species. Results showed that CMt presented selectivity index (SI) of 70.0 and 165.0 against L infantum and L amazonensis promastigotes, respectively, and of 181.9 and 397.8 against respective axenic amastigotes. Amphotericin B (AmpB) showed lower SI values of 9.1 and 11.1 against L infantum and L amazonensis promastigotes, respectively, and of 12.5 and 14.3 against amastigotes, respectively. CMt was effective in the treatment of infected macrophages and caused alterations in the parasite mitochondria. L infantum-infected mice treated with miltefosine, CMt alone or incorporated in polymeric micelles (CMt/Mic) presented significant reductions in the parasite load in distinct organs, when compared to the control groups. An antileishmanial Th1-type cellular and humoral immune response were developed one and 15 days after treatment, with CMt/Mic-treated mice presenting a better protective response. Conclusion: Our data suggest that CMt/Mic could be evaluated as a chemotherapeutic agent against VL.Item A Pluronic® F127-based polymeric micelle system containing an antileishmanial molecule is immunotherapeutic and effective in the treatment against Leishmania amazonensis infection.(2019) Tavares, Grasiele de Sousa Vieira; Mendonça, Débora Vasconcelos Costa; Miyazaki, Carolina Kei; Lage, Daniela Pagliara; Soyer, Tauane Gonçalves; Carvalho, Lívia Mendes; Ottoni, Flaviano Melo; Dias, Daniel Silva; Ribeiro, Patrícia Aparecida Fernandes; Antinarelli, Luciana Maria Ribeiro; Ribeiro, Fernanda Ludolf; Duarte, Mariana Costa; Coimbra, Elaine Soares; Chávez Fumagalli, Miguel Angel; Roatt, Bruno Mendes; Souza, Daniel Menezes; Barichello, José Mario; Alves, Ricardo José; Coelho, Eduardo Antônio FerrazClioquinol (5-chloro-7-iodoquinolin-8-ol or ICHQ) was recently showed to presents an in vitro effective antileishmanial action, causing changes in membrane permeability, mitochondrial functionality, and parasite morphology. In the present study, ICHQ was incorporated into a Poloxamer 407-based polymeric micelles system (ICHQ/M), and its antileishmanial activity was in vivo evaluated in L. amazonensis-infected BALB/c mice. Amphotericin B (AmpB) and its liposomal formulation (Ambisome®) were used as controls. Parasitological and immunological evaluations were performed 30 days after the treatment. Results indicated more significant reductions in the average lesion diameter and parasite burden in ICHQ or ICHQ/M-treated mice, which were associated with the development of a polarized Th1 immune response, based on production of high levels of IFN-γ, IL-12, TNF-α, GM-CSF, and antileishmanial IgG2a antibody. Control groups´ mice produced high levels of IL-4, IL-10, and IgG1 isotype antibody. No organic toxicity was found by using ICHQ or ICHQ/M to treat the animals, although those receiving AmpB and Ambisome® have presented higher levels of renal and hepatic damage markers. In conclusion, results suggested that the ICHQ/M composition can be considered as an antileishmanial candidate to be tested against human leishmaniasis.