Redox-Active Antiparasitic Drugs

Pal, Chiranjib; Bandyopadhyay, Uday

doi:10.1089/ars.2011.4436

Cited by 86 publications

(55 citation statements)

References 164 publications

(211 reference statements)

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“…TR is an enzyme that participates in ROS detoxification of trypanosomatids and could be inhibited by EGCG. This trypanothione-dependent pathway is unique to the parasite and absent in the mammalian host [53], [54]. This effect has been demonstrated by the treatment of T. cruzi with eupomatenoid-5 [55].…”

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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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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“…A variety of inhibitors have been designed that target glutathione reductase or thioredoxin reductase from Plasmodium falciparum have shown marked antimalarial activity (Pal and Bandyopadhyay 2012), which underscores the central role of the parasitic antioxidant system to its survival. Moreover, there are several examples were antioxidant enzymes have proven to be useful vaccination targets.…”

Section: Implications For Future Tick Researchmentioning

confidence: 99%

Transcriptional activation of antioxidants may compensate for selenoprotein deficiencies in Amblyomma maculatum (Acari: Ixodidae) injected with selK‐ or selM‐dsRNA

Adamson

Browning

Singh

et al. 2014

Insect Molecular Biology

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The Gulf-Coast tick, Amblyomma maculatum, possesses an elaborate set of selenoprotein, which prevent the deleterious effects from oxidative stress that occur during feeding. In the current work, we examined the role of Selenoprotein K (SelK) and Selenoprotein M (SelM) in feeding A. maculatum by bioinformatics, transcriptional gene expression, RNA interference and antioxidant assays. The transcriptional expression of SelK does not vary significantly in salivary glands or midguts throughout the blood meal. However, there is a 58-fold increase in transcript levels of SelM in tick midguts. Ticks injected with selK-dsRNA or selM-dsRNA did not reveal any observable differences in egg viability but oviposition was reduced. Surprisingly, salivary antioxidant activity was higher in selenoprotein knockouts compared to controls, which is likely due to compensatory transcriptional expression of genes involved in combating reactive oxygen species. In fact, RT-qPCR data suggest the transcriptional expression of catalase increased in ticks injected with selM-dsRNA. Additionally, the transcriptional expression of selN decreased ~90% in both SelK/SelM knockdowns.

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“…Human pathogens that produce Mip and the Mip-like proteins became resistant to the most antimicrobial agents available in the clinics today [55]–[58]. To eradicate such resistant microorganisms, new drugs are needed to be screened or developed urgently.…”

Section: Resultsmentioning

confidence: 99%

Inhibitor-Induced Conformational Stabilization and Structural Alteration of a Mip-Like Peptidyl Prolyl cis-trans Isomerase and Its C-Terminal Domain

et al. 2014

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FKBP22, an Escherichia coli-encoded PPIase (peptidyl-prolyl cis-trans isomerase) enzyme, shares substantial identity with the Mip-like pathogenic factors, caries two domains, exists as a dimer in solution and binds some immunosuppressive drugs (such as FK506 and rapamycin) using its C-terminal domain (CTD). To understand the effects of these drugs on the structure and stability of the Mip-like proteins, rFKBP22 (a chimeric FKBP22) and CTD+ (a CTD variant) have been studied in the presence and absence of rapamycin using different probes. We demonstrated that rapamycin binding causes minor structural alterations of rFKBP22 and CTD+. Both the proteins (equilibrated with rapamycin) were unfolded via the formation of intermediates in the presence of urea. Further study revealed that thermal unfolding of both rFKBP22 and rapamycin-saturated rFKBP22 occurred by a three-state mechanism with the synthesis of intermediates. Intermediate from the rapamycin-equilibrated rFKBP22 was formed at a comparatively higher temperature. All intermediates carried substantial extents of secondary and tertiary structures. Intermediate resulted from the thermal unfolding of rFKBP22 existed as the dimers in solution, carried an increased extent of hydrophobic surface and possessed relatively higher rapamycin binding activity. Despite the formation of intermediates, both the thermal and urea-induced unfolding reactions were reversible in nature. Unfolding studies also indicated the considerable stabilization of both proteins by rapamycin binding. The data suggest that rFKBP22 or CTD+ could be exploited to screen the rapamycin-like inhibitors in the future.

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Redox-Active Antiparasitic Drugs

Abstract: The identification of redox-active antiparasitic drugs along with their mode of action will help researchers around the world in designing novel drugs in the future.

Cited by 86 publications

References 164 publications

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

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

Transcriptional activation of antioxidants may compensate for selenoprotein deficiencies in Amblyomma maculatum (Acari: Ixodidae) injected with selK‐ or selM‐dsRNA

Inhibitor-Induced Conformational Stabilization and Structural Alteration of a Mip-Like Peptidyl Prolyl cis-trans Isomerase and Its C-Terminal Domain

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