Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification

Irigoı́n, Florencia; Cibils, Lucía; Comini, Marcelo A.; Wilkinson, Shane R.; Flohé, Leopold; Radí, Rafael

doi:10.1016/j.freeradbiomed.2008.05.028

Cited by 139 publications

(128 citation statements)

References 116 publications

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“…Besides these immunological adaptations in the attempt to maximize parasitemia clearance and control the infection (36,37), the intensity of this response was not sufficient to control parasite replication and cardiac infection. On the contrary, the satisfactory effect of Bz alone against infection evolution indicated that the antiparasitic effect of Bz occurred independently of modifications in Th1 phenotype, reinforcing its direct cytotoxic action on T. cruzi (5,29,38). Our results also showed that Sur markedly increased tissue levels of IL-6, a cytokine directly implicated in acute chagasic myocarditis since it induces the expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), prominent mediators for the migration of inflammatory cells (39,40).…”

Section: Figmentioning

confidence: 99%

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Santos

Novaes

Cupertino

et al. 2015

Antimicrob Agents Chemother

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cAlthough suramin (Sur) is suggested as a potential drug candidate in the management of Chagas disease, this issue has not been objectively tested. In this study, we examined the applicability of concomitant treatment with benznidazole (Bz) and suramin in mice infected with a virulent strain of Trypanosoma cruzi. Eighty 12-week-old male C57BL/6 mice were equally randomized in eight groups: (i) noninfected mice (negative control) and mice infected with T. cruzi Y strain receiving (ii) no treatment (positive control), (iii) Bz, 100 mg/kg of body weight per day, (iv) Sur, 20 mg/kg/day, and (v to viii) Sur, 20 mg/kg/day, combined with Bz, 100, 50, 25, or 5 mg/kg/day. Bz was administered by gavage, and Sur was administered intraperitoneally. Sur dramatically increased the parasitemia, cardiac content of parasite DNA, inflammation, oxidative tissue damage, and mortality. In response to high parasitic load in cardiac tissue, Sur stimulated the immune system in a manner typical of the acute phase of Chagas disease, increasing tissue levels of gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) and inducing a preferential IgG2a anti-T. cruzi serum pattern. When Sur and Bz were combined, the infection severity was attenuated, showing a dose-dependent Bz response. Sur therapy had a more harmful effect on the host than on the parasite and reduced the efficacy of Bz against T. cruzi infection. Considering that Sur drastically reinforced the infection evolution, potentiating the inflammatory process and the severity of cardiac lesions, the in vivo findings contradicted the in vitro anti-T. cruzi potential described for this drug.

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Section: Figmentioning

confidence: 99%

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Santos

Novaes

Cupertino

et al. 2015

Antimicrob Agents Chemother

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“…The routes leading to oxidation and reduction of Nrx remain to be worked out. For the prototype tryparedoxin the oxidizing partner is a Prx, whereas the reduction is achieved by a typical flavin-dependent disulfide reductase mediated by the low-molecular-weight thiol trypanothione (199,349). The search for an analogous metabolic context may be helpful in finally defining the precise role of this novel redox mediator in transcriptional activation.…”

Section: Brigelius-flohé and Flohémentioning

confidence: 99%

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Brigelius‐Flohé

Flohé

2011

Antioxidants & Redox Signaling

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Convincing concepts of redox control of gene transcription have been worked out for prokaryotes and lower eukaryotes, whereas the knowledge on complex mammalian systems still resembles a patchwork of poorly connected findings. The article, therefore, reviews principles of redox regulation with special emphasis on chemical feasibility, kinetic requirements, specificity, and physiological context, taking well investigated mammalian transcription factor systems, nuclear transcription factor of bone marrow-derived lymphocytes (NFjB), and kelch-like ECH-associated protein-1 (Keap1)/Nrf2, as paradigms. Major conclusions are that (i) direct signaling by free radicals is restricted to O 2 -and NO and can be excluded for fast reacting radicals such as OH, OR, or Cl ; (ii) oxidant signals are H 2 O 2 , enzymatically generated lipid hydroperoxides, and peroxynitrite; (iii) free radical damage is sensed via generation of Michael acceptors; (iv) protein thiol oxidation/alkylation is the prominent mechanism to modulate function; (v) redox sensors must be thiol peroxidases by themselves or proteins with similarly reactive cysteine or selenocysteine (Sec) residues to kinetically compete with glutathione peroxidase (GPx)-and peroxiredoxin (Prx)-type peroxidases or glutathione-S-transferases, respectively, a postulate that still has to be verified for putative mammalian sensors. S-transferases and Prxs are considered for system complementation. The impact of NF-jB and Nrf2 on hormesis, management of inflammatory diseases, and cancer prevention is critically discussed. Antioxid. Redox Signal. 15, 2335-2381.

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“…Since parasites are naturally exposed to a variety of oxidative (ROS) and/or nitrosative (RNS) stresses during their life cycles, they have developed an elaborate antioxidant defense system composed of molecules and enzymes to scavenge these reactive species (14,15). These systems are primarily based on low-molecular-mass thiols, such as glutathione and trypanothione, which play central roles in the antioxidant defense mechanisms by regulating the redox homeostasis in parasites (16).…”

mentioning

confidence: 99%

Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

Romero

Téllez

Romanha

et al. 2015

Antimicrob Agents Chemother

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Cysteine metabolism is considered essential for the crucial maintenance of a reducing environment in trypanosomatids due to its importance as a precursor of trypanothione biosynthesis. Expression, activity, functional rescue, and overexpression of cysteine synthase (CS) and cystathionine ␤-synthase (C␤S) were evaluated in Leishmania braziliensis promastigotes and intracellular amastigotes under in vitro stress conditions induced by hydrogen peroxide (H 2 O 2 ), S-nitroso-N-acetylpenicillamine, or antimonial compounds. Our results demonstrate a stage-specific increase in the levels of protein expression and activity of L. braziliensis CS (LbrCS) and L. braziliensis C␤S (LbrC␤S), resulting in an increment of total thiol levels in response to both oxidative and nitrosative stress. The rescue of the CS activity in Trypanosoma rangeli, a trypanosome that does not perform cysteine biosynthesis de novo, resulted in increased rates of survival of epimastigotes expressing the LbrCS under stress conditions compared to those of wild-type parasites. We also found that the ability of L. braziliensis promastigotes and amastigotes overexpressing LbrCS and LbrC␤S to resist oxidative stress was significantly enhanced compared to that of nontransfected cells, resulting in a phenotype far more resistant to treatment with the pentavalent form of Sb in vitro. In conclusion, the upregulation of protein expression and increment of the levels of LbrCS and LbrC␤S activity alter parasite resistance to antimonials and may influence the efficacy of antimony treatment of New World leishmaniasis.T he intracellular protozoan parasite Leishmania causes a neglected infectious disease commonly referred to as leishmaniasis. Depending on the infecting species and the immune status of the host, leishmaniasis can result in a variety of clinical manifestations with cutaneous, mucocutaneous, or visceral involvement (1-3). Leishmania (Viannia) braziliensis, the causative agent of cutaneous leishmaniasis and mucocutaneous leishmaniasis, is the most prevalent species infecting humans in the Americas (4, 5).Leishmania spp. have a digenetic life cycle, alternating between flagellated promastigote forms in the midgut of the sand fly and obligatory intracellular amastigotes within macrophages of the mammalian host (6, 7). During this complex life cycle, these parasites are exposed to variable oxidative or nitrosative stresses induced by reactive oxygen species (ROS) or reactive nitrogen species (RNS), respectively, generated by the host immune system to avoid infection (8, 9). Antimonial compounds, such as sodium stibogluconate or Sb (Pentostan) or meglumine antimoniate (Glucantime), are still the first-choice drugs for human leishmaniasis treatment (10). Among these, the Sb pentavalent form (Sb V ) has been reported to indirectly induce oxidative and nitrosative stress on the parasite by stimulating infected macrophages (M) to generate ROS and nitric oxide (NO) via activation of phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), and mitogenactivated ...

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Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification

Cited by 139 publications

References 116 publications

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Concomitant Benznidazole and Suramin Chemotherapy in Mice Infected with a Virulent Strain of Trypanosoma cruzi

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Upregulation of Cysteine Synthase and Cystathionine β-Synthase Contributes to Leishmania braziliensis Survival under Oxidative Stress

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