Grandiflorenic acid promotes death of promastigotes via apoptosis-like mechanism and affects amastigotes by increasing total iron bound capacity

Bortoleti, Bruna Taciane da Silva; Gonçalves, Manoela Daiele; Tomiotto-Pellissier, Fernanda; Miranda-Sapla, Milena Menegazzo; Assolini, João Paulo; Carloto, Amanda Cristina Machado; Camargo, Priscila Goes; Cardoso, Ian Lucas Alves; Simão, Andréa Name Colado; Arakawa, Nilton Syogo; Costa, Idessânia Nazareth; Conchon‐Costa, Ivete; Pavanelli, Wander Rogério

doi:10.1016/j.phymed.2018.06.010

Cited by 26 publications

(13 citation statements)

References 32 publications

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“…Despite discussion regarding the occurrence of PS exposure in the external leaflet of the Leishmania plasma membrane, since there is a possibility of this phospholipid being absent or present in small amounts in this parasite membrane (Proto et al, 2013), the labeling of this phospholipid with annexin V-FITC has been widely used to detect an apoptosis-like process in Leishmania (Mesquita et al, 2013;Chouhan et al, 2015;Mallick et al, 2015;Bortoleti et al, 2018;Gonçalves et al, 2018;Tomiotto-Pellissier et al, 2018;Miranda-Sapla et al, 2019). In this work, this probe was used to evaluate the PS externalization in L. infantum promastigotes after treatment with PF-429242.…”

Section: The Killing Induced By Pf-429242 In L Infantum Promastigotes Seems To Be Unrelated To Apoptosis-like And/or Necrosismentioning

confidence: 99%

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

et al. 2021

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PF-429242 is an inhibitor of subtilisin, an important protease found in Leishmania. However, studies regarding the effect of PF-429242 on Leishmania are scarce. In this work we evaluated the antileishmanial effect of PF-429242 against Leishmania infantum and the mechanism involved in the death of the parasite. PF-429242 had low toxicity against mammalian cells (peritoneal macrophages) (CC50 = 189.07 μM) and presented activity against L. infantum promastigotes (IC50 = 2.78 μM) and intracellular amastigotes (IC50 = 14.07 μM), indicating selectivity toward the parasite. Transmission electron microscopy (TEM), as well as staining of L. infantum promastigotes with MitoTracker® Red, rhodamine 123 and MitoSOX, revealed that the mitochondria was a potential target of PF-429242. In addition, PF-429242 caused an accumulation of neutral lipids in promastigotes, which was demonstrated by Nile Red staining and TEM, and induced oxidative stress (H2DCFDA staining). Furthermore the formation of autophagic vacuoles in L. infantum promastigotes was observed by MDC staining and TEM. However, the killing induced by PF-429242 in L. infantum promastigotes appeared to be unrelated to apoptosis and/or necrosis as there was no phosphatidylserine externalization, DNA fragmentation or alterations in the permeability of the parasite plasma membrane, as assessed by annexin V-FITC, TUNEL and propidium iodide staining, respectively. The morphological and ultrastructural evaluation of the promastigotes by optical microscopy, scanning electron microscopy (SEM) and TEM, revealed the presence of parasites with flagellar defects. TEM analysis of the intracellular amastigotes indicated that mitochondrial damage and autophagy could also be involved in the death of these forms after treatment with PF-429242. In addition, PF-429242 treatment stimulated NO production from infected macrophage, but only at a high concentration (100 μM), as well as an increase of TNF levels after treatment with 10 μM of PF-429242. The compound did not stimulate ROS or IL-10 production. Together, these data highlight the antileishmanial potential of PF-429242, inducing several cellular alterations in the parasite, such as mitochondrial damage, neutral lipids accumulation, oxidative stress and autophagy which culminate in the death of L. infantum, as well as modulating host cellular responses that favor the development of an immune response against the parasite.

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Section: The Killing Induced By Pf-429242 In L Infantum Promastigotes Seems To Be Unrelated To Apoptosis-like And/or Necrosismentioning

confidence: 99%

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

et al. 2021

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“…The forward scatter-heights (FSC-H) represent the cell sizes. A total of 10,000 events were acquired in the region corresponding to the parasites 44 .…”

Section: Methodsmentioning

confidence: 99%

“…m -Chlorophenylhydrazone carbonyl cyanide (CCCP; 100 μM) (Sigma-Aldrich) was used as a positive control to induce depolarization of the internal mitochondrial membranes. The readings were taken at an excitation wavelength of 480 nm and an emission wavelength of 580 nm 44 .…”

Section: Methodsmentioning

confidence: 99%

“…The cells were next stained with Giemsa (Laborclin, Pines-PR, Brazil), and 20 fields analyzed under oil immersion using an optical microscope (Olympus BX41, Olympus Optical Co., Ltd., Tokyo, Japan) to determine the percentage of infected macrophages, and the number of amastigotes per macrophage after 24 h of treatment. Untreated infected macrophages were used as a control, DMSO 0.015% as a vehicle, and 1 μM AmB as a positive control 44 .…”

Section: Methodsmentioning

confidence: 99%

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In-vitro biological evaluation of 3,3′,5,5′-tetramethoxy-biphenyl-4,4′-diol and molecular docking studies on trypanothione reductase and Gp63 from Leishmania amazonensis demonstrated anti-leishmania potential

Schirmann

Bortoleti

Gonçalves

et al. 2023

Sci Rep

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Available treatments for leishmaniasis have been widely used since the 1940s but come at a high cost, variable efficacy, high toxicity, and adverse side-effects. 3,3′,5,5′-Tetramethoxy-biphenyl-4,4′-diol (TMBP) was synthesized through laccase-catalysis of 2,6-dimethoxyphenol and displayed antioxidant and anticancer activity, and is considered a potential drug candidate. Thus, this study aimed to evaluate the anti-leishmanial effect of TMBP against promastigote and amastigote forms of Leishmania (L.) amazonensis and investigated the mechanisms involved in parasite death. TMBP treatment inhibited the proliferation (IC50 0.62–0.86 µM) and induced the death of promastigote forms by generating reactive oxygen species and mitochondrial dysfunction. In intracellular amastigotes, TMBP reduced the percentage of infected macrophages, being 62.7 times more selective to the parasite (CC50 53.93 µM). TMBP did not hemolyze sheep erythrocytes; indicative of low cytotoxicity. Additionally, molecular docking analysis on two enzyme targets of L. amazonensis: trypanothione reductase (TR) and leishmanolysin (Gp63), suggested that the hydroxyl group could be a pharmacophoric group due to its binding affinity by hydrogen bonds with residues at the active site of both enzymes. TMBP was more selective to the Gp63 target than TR. This is the first report that TMBP is a promising compound to act as an anti-leishmanial agent.

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“…GFA mainly inhibited slow-activated delayed rectifier potassium current (Iks), with little influence on rapid-activated delayed rectifier potassium current (Ikr) [ 121 ]. Therefore, it was less likely to cause other arrhythmias [ 122 ]. In a frequency-dependent manner, GFA (100, 400, 1000, and 2500 μ mol/L) inhibited potassium currents by binding to the S6 region of the HERG channel without affecting the synthesis of HERG proteins.…”

Section: Natural Products With Bioactivity In Afmentioning

confidence: 99%

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

Ding

et al. 2022

Cardiovascular Therapeutics

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Antiarrhythmic drugs (AADs) have a therapeutic effect on atrial fibrillation (AF) by regulating the function of ion channels. However, several adverse effects and high recurrence rates after drug withdrawal seriously affect patients’ medication compliance and clinical prognosis. Thus, safer and more effective drugs are urgently needed. Active components extracted from natural products are potential choices for AF therapy. Natural products like Panax notoginseng (Burk.) F.H. Chen, Sophora flavescens Ait., Stephania tetrandra S. Moore., Pueraria lobata (Willd.) Ohwi var. thomsonii (Benth.) Vaniot der Maesen., and Coptis chinensis Franch. have a long history in the treatment of arrhythmia, myocardial infarction, stroke, and heart failure in China. Based on the classification of chemical structures, this article discussed the natural product components’ therapeutic effects on atrial fibrillation by regulating ion channels, connexins, and expression of related genes, in order to provide a reference for development of therapeutic drugs for atrial fibrillation.

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Grandiflorenic acid promotes death of promastigotes via apoptosis-like mechanism and affects amastigotes by increasing total iron bound capacity

Cited by 26 publications

References 32 publications

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

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

In-vitro biological evaluation of 3,3′,5,5′-tetramethoxy-biphenyl-4,4′-diol and molecular docking studies on trypanothione reductase and Gp63 from Leishmania amazonensis demonstrated anti-leishmania potential

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

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