Reactive Oxygen Species Production by Quercetin Causes the Death of<i>Leishmania amazonensis</i>Intracellular Amastigotes

Fonseca-Silva, Fernanda; Inacio, Job D. F.; Canto‐Cavalheiro, Marilene M.; Almeida-Amaral, Elmo Eduardo

doi:10.1021/np400193m

Cited by 70 publications

(64 citation statements)

References 20 publications

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“…Among the compounds tested quercetin presented moderate inhibition on rCPB2.8 (IC50 = 18.03 ± 1.85 μM), and it previously has shown antileishmanial activity in vitro and in vivo (Muzitano et al, 2006(Muzitano et al, , 2009, with mechanism related to the production of reactive oxygen species (Fonseca-Silva et al, 2013). Interestingly, this flavonol has demonstrated inhibitory activity on other enzymes from Leishmania spp., such as arginase (da Silva et al, 2012;de Sousa et al, 2014b), ribonucleotide reductase (Sen et al, 2008) and topoisomerase II (Mittra et al, 2000), suggesting that the leishmanicidal action by quercetin is an outcome of the interference in diverse metabolic pathways.…”

Section: Discussionmentioning

confidence: 89%

Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana

Sousa

Wang

Nebo

et al. 2015

Experimental Parasitology

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Section: Discussionmentioning

confidence: 89%

Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana

Sousa

Wang

Nebo

et al. 2015

Experimental Parasitology

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“…[10][11][12]20 Treatment with 1 for 24 h increased ROS generation in L. amazonensis in a concentration-dependent manner (p < 0.01) ( Figure 2). ROS levels in L. amazonensis treated with 1 (96 μM) were 2.9-fold higher than those of the control.…”

Section: ■ Results and Discussionmentioning

confidence: 95%

Effect of Apigenin on Leishmania amazonensis Is Associated with Reactive Oxygen Species Production Followed by Mitochondrial Dysfunction

et al. 2015

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Leishmaniasis is an important neglected disease caused by protozoa of the genus Leishmania that affects more than 12 million people worldwide. Leishmaniasis treatment requires the administration of toxic and poorly tolerated drugs, and parasite resistance greatly reduces the efficacy of conventional medications. Apigenin (1), a naturally occurring plant flavone, has a wide range of reported biological effects. In this study, antileishmanial activity of 1 in vitro was investigated, and its mechanism of action against Leishmania amazonensis promastigotes was described. Treatment with 1 for 24 h resulted in concentration-dependent inhibition of cellular proliferation (IC50 = 23.7 μM) and increased reactive oxygen species (ROS) generation. Glutathione and N-acetyl-l-cysteine protected L. amazonensis from the effects of 1 and reduced ROS levels after the treatment. By contrast, oxidized glutathione did not reduce the levels of ROS caused by 1 by not preventing the proliferation inhibition. Apigenin 1 also induced an extensive swelling in parasite mitochondria, leading to an alteration of the mitochondrial membrane potential, rupture of the trans-Golgi network, and cytoplasmic vacuolization. These results demonstrate the leishmanicidal effect of 1 and suggest the involvement of ROS leading to mitochondrial collapse as part of the mechanism of action.

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“…To investigate whether the leishmanicidal effect of EGCG is due to intracellular amastigote ROS production, we measured ROS levels using the cell-permeable dye H 2 DCFDA [31]–[34]. EGCG induces ROS production in Leishmania -infected macrophages, not non-infected macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…The exposure of L. amazonensis -infected macrophages to diethyldithiocarbamate (DETC) [28] and quercetin [34] has been shown to increase superoxide anion and reactive oxygen species levels, respectively. These effects subsequently induce a severe reduction in the number of intracellular parasites and demonstrate the efficacy of ROS as an antimicrobial agent against intracellular parasites.…”

Section: Discussionmentioning

confidence: 99%

The Effect of (-)-Epigallocatechin 3-O - Gallate In Vitro and In Vivo in Leishmania braziliensis: Involvement of Reactive Oxygen Species as a Mechanism of Action

et al. 2014

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BackgroundLeishmaniasis is a parasitic disease associated with extensive mortality and morbidity. The treatment for leishmaniasis is currently based on pentavalent antimonials and amphotericin B; however, these drugs result in numerous adverse side effects. Natural compounds have been used as novel treatments for parasitic diseases. In this paper, we evaluated the effect of (-)-epigallocatechin 3-O-gallate (EGCG) on Leishmania braziliensis in vitro and in vivo and described the mechanism of EGCG action against L. braziliensis promastigotes and intracellular amastigotes.Methodology/Principal Finding In vitro activity and reactive oxygen species (ROS) measurements were determined during the promastigote and intracellular amastigote life stages. The effect of EGCG on mitochondrial membrane potential (ΔΨm) was assayed using JC-1, and intracellular ATP concentrations were measured using a luciferin-luciferase system. The in vivo experiments were performed in infected BALB/c mice orally treated with EGCG. EGCG reduced promastigote viability and the infection index in a time- and dose-dependent manner, with IC50 values of 278.8 µM and 3.4 µM, respectively, at 72 h and a selectivity index of 149.5. In addition, EGCG induced ROS production in the promastigote and intracellular amastigote, and the effects were reversed by polyethylene glycol (PEG)-catalase. Additionally, EGCG reduced ΔΨm, thereby decreasing intracellular ATP concentrations in promastigotes. Furthermore, EGCG treatment was also effective in vivo, demonstrating oral bioavailability and reduced parasitic loads without altering serological toxicity markers.Conclusions/SignificanceIn conclusion, our study demonstrates the leishmanicidal effects of EGCG against the two forms of L. braziliensis, the promastigote and amastigote. In addition, EGCG promotes ROS production as a part of its mechanism of action, resulting in decreased ΔΨm and reduced intracellular ATP concentrations. These actions ultimately culminate in parasite death. Furthermore, our data suggest that EGCG is orally effective in the treatment of L. braziliensis-infected BALB/c mice without altering serological toxicity markers.

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Reactive Oxygen Species Production by Quercetin Causes the Death ofLeishmania amazonensisIntracellular Amastigotes

Cited by 70 publications

References 20 publications

Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana

Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana

Effect of Apigenin on Leishmania amazonensis Is Associated with Reactive Oxygen Species Production Followed by Mitochondrial Dysfunction

The Effect of (-)-Epigallocatechin 3-O - Gallate In Vitro and In Vivo in Leishmania braziliensis: Involvement of Reactive Oxygen Species as a Mechanism of Action

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