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PLoS One
2015 Jan 01;1012:e0144946. doi: 10.1371/journal.pone.0144946.
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The Effect of Ursolic Acid on Leishmania (Leishmania) amazonensis Is Related to Programed Cell Death and Presents Therapeutic Potential in Experimental Cutaneous Leishmaniasis.
Yamamoto ES
,
Campos BL
,
Jesus JA
,
Laurenti MD
,
Ribeiro SP
,
Kallás EG
,
Rafael-Fernandes M
,
Santos-Gomes G
,
Silva MS
,
Sessa DP
,
Lago JH
,
Levy D
,
Passero LF
.
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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 μg/mL, comparable with miltefosine, while OA presented only a marginal effect on promastigote forms at 100 μg/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.
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26674781
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Fig 1. Structures of oleanolic (A) and ursolic acids (B).
Fig 2. Ultrastructural changes of L. (L.) amazonensis promastigote induced by in vitro treatment with UA.Images of cultured promastigote forms before (A) and after treatment (B, C, D and E) with UA EC50 were captured by transmission electron microscopy. (N)–Nucleus, (K)–Complex kinetoplast-Mitochondria; red arrow: mitochondrion swelling; white arrow: membrane-containing vacuoles; white asterisk: blebs on nucleus and mitochondria.
Fig 3. The mechanism of parasite death was investigated after in vitro treatment with UA.By flow cytometry the pattern of Annexin V and PI staining was analyzed in non-treated promastigotes (A), UA-treated promastigotes (B) and H2O2-treated promastigotes (C); and it was characterized as “viable cells” in Q1 (Annexin V-/PI-), “early apoptosis stage” in Q2 (Annexin V+/PI-), “late apoptosis stage” in Q3 (Annexin V+/PI+) and “cellular death/necrosis” in Q4 (Annexin V-/PI+). D—Activity of caspase 3/7 was investigated in UA-treated parasites. E—Aspect of nuclear DNA from control parasites (lane 2), UA-treated parasites (lane 3) and H2O2-treated parasites, molecular marker is represented in lane 1; F—JC1 aggregates were analyzed in control, UA—and H2O2—treated parasites.
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