Role of FAK signaling in chagasic cardiac hypertrophy

Tucci, Amanda Resende; Oliveira, Francisco Odencio Rodrigues de; Lechuga, Guilherme Curty; Oliveira, Gabriel Melo de; Eleuterio, Ana Carolina; Mesquita, Liliane Batista de; Farani, Priscila Silva Grijó; Britto, Constança; Moreira, Otacílio C.; Pereira, Mirian Cláudia de Souza

doi:10.1016/j.bjid.2020.08.007

Cited by 9 publications

(6 citation statements)

References 50 publications

(60 reference statements)

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“…The cardiac indices of the nitazoxanide-treated animals were at a midpoint between those of the BNZ and W-O/T groups, therefore affirming that the progression to cardiomegaly was partially decreased in comparison with not receiving treatment. These results were consistent with the important pathological outcome of chronic chagasic cardiomyopathy, since multiple factors such as severe myocarditis and fibrosis cause a hemodynamic overload of the heart, which represents a compensatory mechanism that leads to myocardial hypertrophy [ 41 ]. On the other hand, it has been reported that nitazoxanide induces myocardial injury by activating the oxidative stress response [ 42 ].…”

Section: Discussionsupporting

confidence: 82%

Nitazoxanide: A Drug Repositioning Compound with Potential Use in Chagas Disease in a Murine Model

et al. 2023

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Chagas disease (ChD), caused by Trypanosoma cruzi, is the most serious parasitosis in the western hemisphere. Benznidazole and nifurtimox, the only two trypanocidal drugs, are expensive, difficult to obtain, and have severe side effects. Nitazoxanide has shown to be effective against protozoa, bacteria, and viruses. This study aimed to evaluate the nitazoxanide efficacy against the Mexican T. cruzi Ninoa strain in mice. Infected animals were orally treated for 30 days with nitazoxanide (100 mg/kg) or benznidazole (10 mg/kg). The clinical, immunological, and histopathological conditions of the mice were evaluated. Nitazoxanide- or benznidazole-treated mice had longer survival and less parasitemia than those without treatment. Antibody production in the nitazoxanide-treated mice was of the IgG1-type and not of the IgG2-type as in the benznidazole-treated mice. Nitazoxanide-treated mice had significantly high IFN-γ levels compared to the other infected groups. Serious histological damage could be prevented with nitazoxanide treatment compared to without treatment. In conclusion, nitazoxanide decreased parasitemia levels, indirectly induced the production of IgG antibodies, and partially prevented histopathological damage; however, it did not show therapeutic superiority compared to benznidazole in any of the evaluated aspects. Therefore, the repositioning of nitazoxanide as an alternative treatment against ChD could be considered, since it did not trigger adverse effects that worsened the pathological condition of the infected mice.

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Section: Discussionsupporting

confidence: 82%

Nitazoxanide: A Drug Repositioning Compound with Potential Use in Chagas Disease in a Murine Model

et al. 2023

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“…cruzi had not been studied. Herein, AT-RvD1 was shown to reduce both the cross-sectional area of cardiomyocytes and the transcription of hypertrophy markers such as ANP and BNP, which have been associated with different stages and severity of CCC [ 63 , 64 ]. Furthermore, during T .…”

Section: Discussionmentioning

confidence: 99%

“…To the best of our knowledge, until now, the effect of AT-RvD1 on hypertrophy produced by infection with T. cruzi had not been studied. Herein, AT-RvD1 was shown to reduce both the cross-sectional area of cardiomyocytes and the transcription of hypertrophy markers such as ANP and BNP, which have been associated with different stages and severity of CCC [63,64]. Furthermore, during T. cruzi infection, the participation of endothelin-1, cardiotrophin-1, and cytokines such as TNFα and IL-1β has been previously highlighted as pro-hypertrophic [65].…”

Section: At-rvd1 Decreases the Inflammatory Process In Early Chronic CDmentioning

confidence: 91%

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease

et al. 2021

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Background Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. In 30% of cases, after years of infection and in the absence of treatment, the disease progresses from an acute asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapeutic agent to regulate the pro-inflammatory state during the early chronic phase of Chagas disease. Methodology/Principal findings C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the early chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. Conclusions/Significance AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during early chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

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“…To the best of our knowledge, until now, the effect of AT-RvD1 on hypertrophy produced by infection with T. cruzi had not been studied. Herein, AT-RvD1 was shown to reduce both the crosssectional area of cardiomyocytes and the transcription of hypertrophy markers such as ANP and BNP, which have been associated with different stages and severity of CCC [54,55]. Furthermore, during T. cruzi infection, the participation of endothelin-1, cardiotrophin-1, and cytokines such as TNFα and IL-1β has been previously highlighted as pro-hypertrophic [56].…”

Section: At-rvd1 Decreases the Inflammatory Process In Chronic CDmentioning

confidence: 91%

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation through N-formyl peptide receptor 2 in a chronic murine model of Chagas disease

Carrillo

Rabelo

Barbosa

et al. 2021

Preprint

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Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and is widely distributed worldwide because of migration. After years of infection and in the absence of treatment, the disease progresses from an acute and asymptomatic phase to a chronic inflammatory cardiomyopathy, leading to heart failure and death. An inadequate balance in the inflammatory response is involved in the progression of chronic Chagas cardiomyopathy. Current therapeutic strategies cannot prevent or reverse the heart damage caused by the parasite. Aspirin-triggered resolvin D1 (AT-RvD1) is a pro-resolving mediator of inflammation that acts through N-formyl peptide receptor 2 (FPR2). AT-RvD1 participates in the modification of cytokine production, inhibition of leukocyte recruitment and efferocytosis, macrophage switching to a nonphlogistic phenotype, and the promotion of healing, thus restoring organ function. In the present study, AT-RvD1 is proposed as a potential therapy aid to regulate the pro-inflammatory state during the chronic phase of Chagas disease. C57BL/6 wild-type and FPR2 knock-out mice chronically infected with T. cruzi were treated for 20 days with 5 μg/kg/day AT-RvD1, 30 mg/kg/day benznidazole, or the combination of 5 μg/kg/day AT-RvD1 and 5 mg/kg/day benznidazole. At the end of treatment, changes in the immune response, cardiac tissue damage, and parasite load were evaluated. The administration of AT-RvD1 in the chronic phase of T. cruzi infection regulated the inflammatory response both at the systemic level and in the cardiac tissue, and it reduced cellular infiltrates, cardiomyocyte hypertrophy, fibrosis, and the parasite load in the heart tissue. Thus, AT-RvD1 was shown to be an attractive therapeutic due to its regulatory effect on the inflammatory response at the cardiac level and its ability to reduce the parasite load during chronic T. cruzi infection, thereby preventing the chronic cardiac damage induced by the parasite.

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Role of FAK signaling in chagasic cardiac hypertrophy

Cited by 9 publications

References 50 publications

Nitazoxanide: A Drug Repositioning Compound with Potential Use in Chagas Disease in a Murine Model

Nitazoxanide: A Drug Repositioning Compound with Potential Use in Chagas Disease in a Murine Model

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation in a murine model of early chronic Chagas disease

Aspirin-triggered resolvin D1 reduces parasitic cardiac load by decreasing inflammation through N-formyl peptide receptor 2 in a chronic murine model of Chagas disease

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