Phloroglucinol derivatives fromHypericumspecies trigger mitochondrial dysfunction inLeishmania amazonensis

Abstract

Bioactive molecules isolated from plants are promising sources for the development of new therapies against leishmaniasis. We investigated the leishmanicidal activity of cariphenone A (1), isouliginosin B (2) and uliginosin B (3) isolated from Hypericum species. Promastigotes and amastigotes of Leishmania amazonensis were incubated with compounds 1-3 at concentrations 1-100 µm for 48 h. The anti-promastigote effect of compounds was also tested in combinations. The cytotoxicity against macrophages and human erythrocytes were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method and hemolysis assay, respectively. The compounds 1-3 showed high leishmanicidal activity against promastigotes, IC50 values of 10.5, 17.5 and 11.3 µm, respectively. Synergistic interactions were found to the associations of compounds 1 and 2 [Σ fractional inhibitory concentration (FIC) = 0.41], and 2 and 3 (ΣFIC = 0.28) on promastigotes. All Hypericum compounds induced mitochondrial hyperpolarization and reactive oxygen species production in promastigotes. The compounds showed low cytotoxicity toward mammalian cells, high selectivity index and killed intracellular amastigotes probably mediated by oxidative stress. These results indicate that these compounds are promising candidates for the development of drugs against leishmaniasis.

PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

“…Promastigotes stained with MitoTracker R Red CM-H2XROS and rhodamine 123 revealed that this compound increased the m , while MitoSOX staining revealed an increase in the mitochondrial superoxide production. It is important to highlight that the maintenance of m is vital for cell metabolic processes and consequently for cell survival (Fonseca-Silva et al, 2011); thus both increased (hyperpolarization) or decreased (depolarization) m can have negative consequences for mitochondrial integrity (Dagnino et al, 2018). In addition, superoxide generation has also been related to mitochondrial dysfunction, being indicative of damage to this organelle (Lafargue et al, 2017).…”

Imidazolium salts as an alternative for anti-Leishmania drugs: Oxidative and immunomodulatory activities

“…In addition, the maintenance of an appropriate mitochondrial membrane potential (DYm) is essential for Leishmania survival (36,37). Here, we demonstrate that IS with leishmanicidal activity caused an increase in ROS production (Figures 4A, B (29), and depolarization can be preceded by a transient hyperpolarization as the last attempt by cells to avoid death (39). Moreover, all six IS presenting leishmanicidal activity caused plasma membrane alterations (Figures 4A, B), indicating cell death involving necrosis (40).…”

“…Subsequently, the parasites were washed three times with 0.2 M phosphate buffer pH 7.4 and post-fixed in a solution of 2% OsO 4 with 0.2 M phosphate buffer (1:1) for 45 min at room temperature. All samples were dehydrated in a graded series of acetone in water from 30% to 100%, critical point dried using CO 2 , mounted on metal stubs, and coated with gold for observation in a field emission scanning electron microscope (Inspect F50, FEI) ( 29 ). In addition, the IS C 16 MImMes and C 16 MImCl, tested in our previous study ( 13 ), were also analyzed.…”

Monomethylsulochrin isolated from biomass extract of Aspergillus sp. against Leishmania amazonensis: In vitro biological evaluation and molecular docking

“…Leishmania has a single mitochondria, thus mitochondrial dysfunction and energy metabolic plasticity in Leishmania is more restricted when compared with thousands of mitochondria that can be detected in mammalian cells ( Menna-Barreto and de Castro, 2014 ; Dagnino et al., 2018 ). In this regard, when considering cytotoxicity against macrophages, monomethylsulochrin showed selectivity index of 18.0.…”