Potential Role of Antioxidants as Adjunctive Therapy in Chagas Disease

Sánchez-Villamil, Juana P; Bautista-Niño, Paula Katherine; Serrano, Norma C.; Rincón, Melvin Y.; Garg, Nisha

doi:10.1155/2020/9081813

Cited by 24 publications

(18 citation statements)

References 99 publications

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“…The clinical manifestations of chronic cardiomyopathy vary ranging from mild hypertrophic myocarditis to severe form of biventricular dilated cardiomyopathy. The effects of cardiac lipid accumulation on mitochondrial dysfunction and endoplasmic reticulum (ER) stress in the progression of dilated cardiomyopathy have been previously described [3,4,18]. In addition, it is known that mice infected with T. cruzi lose a significant amount of body fat and this may contribute to the pathogenesis of cardiomyopathy [16].…”

Section: Discussionmentioning

confidence: 99%

Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease

et al. 2021

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Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease.

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Section: Discussionmentioning

confidence: 99%

Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease

et al. 2021

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“…A selected series of synthetic hydroxy-3-arylcoumarins were also reported to exhibit varying levels of antioxidant and trypanocidal activities potentially beneficial to the control of Chagas disease [ 20 ]. In light of their reducing properties, several natural antioxidants have also been proposed as adjuvants or supplementary therapy for the treatment of Chagas disease [ 21 ]. This is due to the potential induction of T. cruzi -mediated oxidative stress in host cells, which aids the progression of Chagas disease [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Chemical Derivatization and Characterization of Novel Antitrypanosomals for African Trypanosomiasis

et al. 2021

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The search for novel antitrypanosomals and the investigation into their mode of action remain crucial due to the toxicity and resistance of commercially available antitrypanosomal drugs. In this study, two novel antitrypanosomals, tortodofuordioxamide (compound 2) and tortodofuorpyramide (compound 3), were chemically derived from the natural N-alkylamide tortozanthoxylamide (compound 1) through structural modification. The chemical structures of these compounds were confirmed through spectrometric and spectroscopic analysis, and their in vitro efficacy and possible mechanisms of action were, subsequently, investigated in Trypanosoma brucei (T. brucei), one of the causative species of African trypanosomiasis (AT). The novel compounds 2 and 3 displayed significant antitrypanosomal potencies in terms of half-maximal effective concentrations (EC50) and selectivity indices (SI) (compound 1, EC50 = 7.3 μM, SI = 29.5; compound 2, EC50 = 3.2 μM, SI = 91.3; compound 3, EC50 = 4.5 μM, SI = 69.9). Microscopic analysis indicated that at the EC50 values, the compounds resulted in the coiling and clumping of parasite subpopulations without significantly affecting the normal ratio of nuclei to kinetoplasts. In contrast to the animal antitrypanosomal drug diminazene, compounds 1, 2 and 3 exhibited antioxidant absorbance properties comparable to the standard antioxidant Trolox (Trolox, 0.11 A; diminazene, 0.50 A; compound 1, 0.10 A; compound 2, 0.09 A; compound 3, 0.11 A). The analysis of growth kinetics suggested that the compounds exhibited a relatively gradual but consistent growth inhibition of T. brucei at different concentrations. The results suggest that further pharmacological optimization of compounds 2 and 3 may facilitate their development into novel AT chemotherapy.

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“…It has been largely documented that an increased ROS production can produce oxidative damage to the host during both the acute and chronic phases of Chagas disease [ 40 , 43 , 44 ]. The increased ROS production has been ascribed to NADPHox2 activation in the unstimulated infected host macrophages [ 40 , 44 ]. Thus, it might be possible that reduction of the oxidative stress could reduce tissue damage in Chagas disease.…”

Section: Introductionmentioning

confidence: 99%

“…Those observations indicate that the effects of CoPP are dependent on the redundant action of the NRF2-controlled genes, since this transcription factor controls the expression of several genes involved in the antioxidant defense. Incubation of infected macrophages with several antioxidants or with the enzyme polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) reduces parasite burden while respiratory burst-inducer phorbol 12-myristate 13-acetate (PMA), H 2 O 2 , and prooxidant paraquat can increase the parasite burden [ 44 ]. It has been observed that the treatment of T. cruzi cells with low concentrations of H 2 O 2 can improve the proliferation and they increase the resistance against sublethal doses of H 2 O 2 which can cause oxidative stress [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

“…The effects of antioxidants, oxidants, and prooxidants have been evaluated on epimastigotes, and while antioxidants were able to reduce proliferation and increased metacyclogenesis, the oxidants and prooxidants had the opposite effect [ 44 ]. Those findings indicate that the redox state of the T. cruzi cell is important for cell growth and there must be a cell signaling pathway responsible of transducing the signal.…”

Section: Introductionmentioning

confidence: 99%

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Dual and Opposite Roles of Reactive Oxygen Species (ROS) in Chagas Disease: Beneficial on the Pathogen and Harmful on the Host

Maldonado

Rojas

Morales

et al. 2020

Oxidative Medicine and Cellular Longevity

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Chagas disease is a neglected tropical disease, which affects an estimate of 6-7 million people worldwide. Chagas disease is caused by Trypanosoma cruzi, which is a eukaryotic flagellate unicellular organism. At the primary infection sites, these parasites are phagocytized by macrophages, which produce reactive oxygen species (ROS) in response to the infection with T. cruzi. The ROS produce damage to the host tissues; however, macrophage-produced ROS is also used as a signal for T. cruzi proliferation. At the later stages of infection, mitochondrial ROS is produced by the infected cardiomyocytes that contribute to the oxidative damage, which persists at the chronic stage of the disease. The oxidative damage leads to a functional impairment of the heart. In this review article, we will discuss the mechanisms by which T. cruzi is able to deal with the oxidative stress and how this helps the parasite growth at the acute phase of infection and how the oxidative stress affects the cardiomyopathy at the chronic stage of the Chagas disease. We will describe the mechanisms used by the parasite to deal with ROS and reactive nitrogen species (RNS) through the trypanothione and the mechanisms used to repair the damaged DNA. Also, a description of the events produced by ROS at the acute and chronic stages of the disease is presented. Lastly, we discuss the benefits of ROS for T. cruzi growth and proliferation and the possible mechanisms involved in this phenomenon. Hypothesis is put forward to explain the molecular mechanisms by which ROS triggers parasite growth and proliferation and how ROS is able to produce a long persisting damage on cardiomyocytes even in the absence of the parasite.

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Potential Role of Antioxidants as Adjunctive Therapy in Chagas Disease

Cited by 24 publications

References 99 publications

Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease

Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease

Chemical Derivatization and Characterization of Novel Antitrypanosomals for African Trypanosomiasis

Dual and Opposite Roles of Reactive Oxygen Species (ROS) in Chagas Disease: Beneficial on the Pathogen and Harmful on the Host

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