MARCIA DALASTRA LAURENTI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/50 - Laboratório de Patologia das Moléstias Infecciosas, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/50 - Laboratório de Patologia das Moléstias Infecciosas, Hospital das Clínicas, Faculdade de Medicina - Líder
9 resultados
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- Analysis of the protective potential of antigens released by Leishmania (Viannia) shawi promastigotes(2012) PASSERO, Luiz Felipe Domingues; MARQUES, Claudia; VALE-GATO, Ines; CORBETT, Carlos Eduardo Pereira; LAURENTI, Marcia Dalastra; SANTOS-GOMES, GabrielaLeishmania (Viannia) shawi causes cutaneous lesions in humans. Parasite antigens conferring significant protection against American tegumentar leishmaniosis (ATL) might be important for the development of effective vaccine. Therefore, this work evaluates the protective effect of antigenic fractions released by L. shawi. Antigens released by promastigotes to culture medium were concentrated and isolated by SDS-PAGE. The three main fractions LsPass1 (>75 kDa), LsPass2 (75-50 kDa) and LsPass3 (<50 kDa) were electro-eluted according with their molecular mass. Immunized BALB/c mice were challenged with L. shawi promastigotes and the course of infection monitored during 5 weeks. LsPass1-challenged mice showed no protection, however, a strong degree of protection associated to smaller lesions and high expression of IFN-gamma and TNF-alpha by CD4(+) T, CD8(+) T and double negative CD4CD8 cells was achieved in LsPass3-challenged mice. Furthermore, LsPass2-challenged mice showed an intermediated degree of protection associated to high levels of IFN-gamma, IL-4 and IL-10 mRNA. In spite of increased expression of IFN-gamma and TNF-alpha, high amounts of IL-4 and IL-10 mRNA were also detected in LsPass3-challenged mice indicating a possible contribution of these cytokines for the persistence of a residual number of parasites that may be important in inducing long-lasting immunity. Therefore, LsPass3 seems to be an interesting alternative that should be considered in the development of an effective vaccine against ATL.
- Antileishmanial activity of meroditerpenoids from the macroalgae Cystoseira baccata(2017) SOUSA, Carolina Bruno de; GANGADHAR, Katkam N.; MORAIS, Thiago R.; CONSERVA, Geanne A. A.; VIZETTO-DUARTE, Catarina; PEREIRA, Hugo; LAURENTI, Marcia D.; CAMPINO, Lenea; LEVY, Debora; UEMI, Miriam; BARREIRA, Luisa; CUSTODIO, Luisa; PASSERO, Luiz Felipe D.; LAGO, Joao Henrique G.; VARELA, JoaoThe development of novel drugs for the treatment of leishmaniases continues to be crucial to overcome the severe impacts of these diseases on human and animal health. Several bioactivities have been described in extracts from macroalgae belonging to the Cystoseira genus. However, none of the studies has reported the chemical compounds responsible for the antileishmanial activity observed upon incubation of the parasite with the aforementioned extracts. Thus, this work aimed to isolate and characterize the molecules present in a hexane extract of Cystoseira baccata that was found to be bioactive against Leishmania infantum in a previous screening effort. A bioactivity-guided fractionation of the C. baccata extract was carried out and the inhibitory potential of the isolated compounds was evaluated via the MIT assay against promastigotes and murine macrophages as well as direct counting against intracellular amastigotes. Moreover, the promastigote ultrastructure, DNA fragmentation and changes in the mitochondrial potential were assessed to unravel their mechanism of action. In this process, two antileishmanial meroditerpenoids, (3R)- and (3S)-tetraprenyltoluquinol (1a/1b) and (3R)- and (3S)-tetraprenyltoluquinone (2a/2b), were isolated. Compounds 1 and 2 inhibited the growth of the L. infantum promastigotes (IC50 = 44.9 +/- 4.3 and 94.4 +/- 10.1 mu M, respectively), inducing cytoplasmic vacuolization and the presence of coiled multilamellar structures in mitochondria as well as an intense disruption of the mitochondrial membrane potential. Compound 1 decreased the intracellular infection index (IC50 = 25.0 +/- 4.1 mu M), while compound 2 eliminated 50% of the intracellular amastigotes at a concentration > 88.0 mu M. This work identified compound 2 as a novel metabolite and compound 1 as a biochemical isolated from Cystoseira algae displaying antileishmanial activity. Compound 1 can thus be an interesting scaffold for the development of novel chemotherapeutic molecules for canine and human visceral leishmaniases studies. This work reinforces the evidence of the marine environment as source of novel molecules.
- The Effect of Ursolic Acid on Leishmania (Leishmania) amazonensis Is Related to Programed Cell Death and Presents Therapeutic Potential in Experimental Cutaneous Leishmaniasis(2015) YAMAMOTO, Eduardo S.; CAMPOS, Bruno L. S.; JESUS, Jessica A.; LAURENTI, Marcia D.; RIBEIRO, Susan P.; KALLAS, Esper G.; RAFAEL-FERNANDES, Mariana; SANTOS-GOMES, Gabriela; SILVA, Marcelo S.; SESSA, Deborah P.; LAGO, Joao H. G.; LEVY, Debora; PASSERO, Luiz F. D.Among neglected tropical diseases, leishmaniasis is one of the most important ones, affecting more than 12 million people worldwide. The available treatments are not well tolerated, and present diverse side effects, justifying the search for new therapeutic compounds. In the present study, the activity of ursolic acid (UA) and oleanolic acid (OA) were assayed in experimental cutaneous leishmaniasis (in vitro and in vivo). Promastigote forms of L. amazonensis were incubated with OA and UA for 24h, and effective concentration 50% (EC50) was estimated. Ultraestructural alterations in Leishmania amazonensis promastigotes after UA treatment were evaluated by transmission electron microscopy, and the possible mode of action was assayed through Annexin V and propidium iodide staining, caspase 3/7 activity, DNA fragmentation and transmembrane mitochondrial potential. The UA potential was evaluated in intracellular amastigotes, and its therapeutic potential was evaluated in L. amazonensis infected BALB/c mice. UA eliminated L. amazonensis promastigotes with an EC50 of 6.4 mu g/mL, comparable with miltefosine, while OA presented only a marginal effect on promastigote forms at 100 mu g/mL. The possible mechanism by which promastigotes were eliminated by UA was programmed cell death, independent of caspase 3/7, but it was highly dependent on mitochondria activity. UA was not toxic for peritoneal macrophages from BALB/c mice, and it was able to eliminate intracellular amastigotes, associated with nitric oxide (NO) production. OA did not eliminate amastigotes nor trigger NO. L. amazonensis infected BALB/c mice submitted to UA treatment presented lesser lesion size and parasitism compared to control. This study showed, for the first time, that UA eliminate promastigote forms through a mechanism associated with programed cell death, and importantly, was effective in vivo. Therefore, UA can be considered an interesting candidate for future tests as a prototype drug for the treatment of cutaneous leishmaniasis.
- In Vivo Antileishmanial Activity of Plant-Based Secondary Metabolites(2013) PASSERO, Luiz Felipe Domingues; LAURENTI, Marcia D.; SANTOS-GOMES, Gabriela; CAMPOS, Bruno Luiz Soares; SARTORELLI, Patricia; LAGO, Joao Henrique G.
- Conventional Versus Natural Alternative Treatments for Leishmaniasis: A Review(2018) PASSERO, Luiz Felipe Domingues; CRUZ, Lucas Antal; SANTOS-GOMES, Gabriela; RODRIGUES, Eliana; LAURENTI, Marcia Dalastra; LAGO, Joao Henrique GhilardiLeishmaniasis is a neglected disease caused by protozoan belonging to the Leishmania genus. There are at least 16 pathogenic species for humans that are able to cause different clinical forms, such as cutaneous or visceral leishmaniasis. In spite of the different species and clinical forms, the treatment is performed with few drug options that, in most cases, are considered outdated. In addition, patients under classical treatment show serious side effects during drug administration, moreover parasites are able to become resistant to medicines. Thus, it is believed and well accepted that is urgent and necessary to develop new therapeutic options to overpass these concerns about conventional therapy of leishmaniasis. The present review will focus on the efficacy, side effects and action mechanism of classic drugs used in the treatment of leishmaniasis, as well as the importance of traditional knowledge for directing a rational search toward the discovery and characterization of new and effective molecules (in vivo assays) from plants to be used against leishmaniasis.
- Therapeutic effect of ursolic acid in experimental visceral leishmaniasis (vol 7, pg 1, 2017)(2017) JESUS, Jessica A.; FRAGOSO, Thais N.; YAMAMOTO, Eduardo S.; LAURENTI, Marcia D.; SILVA, Marcelo S.; FERREIRA, Aurea F.; LAGO, Joao Henrique G.; SANTOS-GOMES, Gabriela; PASSERO, Luiz Felipe D.
- Mechanistic Insights into the Leishmanicidal and Bactericidal Activities of Batroxicidin, a Cathelicidin-Related Peptide from a South American Viper (Bothrops atrox)(2021) DEMATEI, Anderson; NUNES, Joao B.; MOREIRA, Daniel C.; JESUS, Jessica A.; LAURENTI, Marcia D.; MENGARDA, Ana C. A.; VIEIRA, Maria Silva; AMARAL, Constanca Pais do; DOMINGUES, Marco M.; MORAES, Josue de; PASSERO, Luiz F. D.; BRAND, Guilherme; BESSA, Lucinda J.; WIMMER, Reinhard; KUCKELHAUS, Selma A. S.; TOMAS, Ana M.; SANTOS, Nuno C.; PLACIDO, Alexandra; EATON, Peter; LEITE, Jose Roberto S. A.Snake venoms are important sources of bioactive molecules, including those with antiparasitic activity. Cathelicidins form a class of such molecules, which are produced by a variety of organisms. Batroxicidin (BatxC) is a cathelicidin found in the venom of the common lancehead (Bothrops atrox). In the present work, BatxC and two synthetic analogues, Bab(C(C-2.15Phe) and BabcC(C-2.14Phe)des-Phe1, were assessed for their microbicidal activity. All three peptides showed a broad-spectrum activity on Gram-positive and -negative bacteria, as well as promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Circular dichroism (CD) and nuclear magnetic resonance (NMR) data indicated that the three peptides changed their structure upon interaction with membranes. Biomimetic membrane model studies demonstrated that the peptides exert a permeabilization effect in prokaryotic membranes, leading to cell morphology distortion, which was confirmed by atomic force microscopy (AFM). The molecules considered in this work exhibited bactericidal and leishmanicidal activity at low concentrations, with the AFM data suggesting membrane pore formation as their mechanism of action. These peptides stand as valuable prototype drugs to be further investigated and eventually used to treat bacterial and protozoal infections.
- Preclinical Assessment of Ursolic Acid Loaded into Nanostructured Lipid Carriers in Experimental Visceral Leishmaniasis(2021) JESUS, Jessica Adriana; SOUSA, Ilza Maria Oliveira; SILVA, Thays Nicolli Fragoso da; FERREIRA, Aurea Favero; LAURENTI, Marcia Dalastra; ANTONANGELO, Leila; FARIA, Caroline Silverio; COSTA, Paulo Cardoso da; FERREIRA, Domingos de Carvalho; PASSERO, Luiz Felipe DominguesUrsolic acid, a triterpene produced by plants, displayed leishmanicidal activity in vitro and in vivo; however, the low solubility of this triterpene limits its efficacy. To increase the activity of ursolic acid (UA), this triterpene was entrapped in nanostructured lipid carriers (UA-NLC), physical-chemical parameters were estimated, the toxicity was assayed in healthy golden hamsters, and the efficacy of UA-NLC was studied in experimental visceral leishmanisis. UA-NLC exhibited a spherical shape with a smooth surface with a size of 266 nm. UA-NLC displayed low polydispersity (PDI = 0.18) and good colloidal stability (-29.26 mV). Hamsters treated with UA-NLC did not present morphological changes in visceral organs, and the levels of AST, ALT, urea and creatinine were normal. Animals infected with Leishmania (Leishmania) infantum and treated with UA-NLC showed lower parasitism than the infected controls, animals treated with UA or Amphotericin B (AmB). The therapeutic activity of UA-NLC was associated with the increase in a protective immune response, and it was associated with a high degree of spleen and liver preservation, and the normalization of hepatic and renal functions. These data indicate that the use of lipid nanoparticles as UA carriers can be an interesting strategy for the treatment of leishmaniasis.
- Nanostructured Lipid Carriers as Robust Systems for Lupeol Delivery in the Treatment of Experimental Visceral Leishmaniasis(2023) JESUS, Jessica Adriana; SILVA, Thays Nicolli Fragoso da; SOUSA, Ilza Maria Oliveira; FERREIRA, Aurea Favero; LAURENTI, Marcia Dalastra; COSTA, Paulo Cardoso da; FERREIRA, Domingos de Carvalho de; PASSERO, Luiz Felipe DominguesLeishmaniasis is a neglected tropical disease that affects millions of people around the world. Available therapy causes severe side effects, has unacceptable prices for some specific formulations, and the existence of drug-resistant parasites limits the use of the currently available arsenal of antiparasitic drugs. Therefore, natural products serve as one of the main sources to develop new and effective alternative drugs against leishmaniasis. In this sense, the present study evaluated the potential of the triterpene Lupeol (Lu) entrapped in nanostructured lipid carriers (NLCs) for the treatment of experimental visceral leishmaniasis. The therapeutic efficacy of Lu or Lu entrapped in NLC (Lu-NLC) was investigated in golden hamsters infected with Leishmania (Leishmania) infantum. Lu-NLC presented a mean particle size of 265.3 +/- 4.6 nm, a polydispersity index of <0.25 and a zeta potential of -37.2 +/- 0.84 mV; the efficacy of encapsulation was 84.04 +/- 0.57%. Studies on hamsters showed that Lu-NLC (5 mg/kg) administered intraperitoneally for 10 consecutive days caused a reduction of 99.9% in the number of parasites in the spleen and liver compared to the untreated infected control. On the contrary, Lu-treated animals (5 mg/kg) had 94.4 and 90.2% less parasites in the spleen and liver, respectively, than the infected group. Additionally, a significant preservation of splenic and hepatic tissues was observed in animals treated with Lu-NLC or Lu. Furthermore, Lu-NLC-treated animals produced high levels of anti-Leishmania IgG2 isotype. These data indicate that NLC potentialized Lu efficacy in experimental visceral leishmaniasis. This work suggests that Lu and nanoformulations carrying this compound may be considered as an important tool to be included in the alternative therapy of leishmaniasis.