Trypanosoma cruzi, the etiological agent of Chagas&am... more Trypanosoma cruzi, the etiological agent of Chagas' disease, causes an intense inflammatory response in several tissues, including the liver. Since this organ is central to metabolism, its infection may be reflected in the outcome of the disease. 15-deoxy-Δ(12,14) prostaglandin J2 (15dPGJ2), a natural agonist of peroxisome-proliferator activated receptor (PPAR) γ, has been shown to exert anti-inflammatory effects in the heart upon T. cruzi infection. However, its role in the restoration of liver function and reduction of liver inflammation has not been studied yet. BALB/c mice were infected with T. cruzi. The effects of in vivo treatment with 15dPGJ2 on liver inflammation and fibrosis, as well as on the GOT/GPT ratio were studied and the role of NF-κB pathway on 15dPGJ2-mediated effects was analysed. 15dPGJ2 reduced liver inflammatory infiltrates, proinflammatory enzymes and cytokines expression, restored the De Ritis ratio values to normal, reduced the deposits of interstitial and perisinusoidal collagen, reduced the expression of the pro-fibrotic cytokines and inhibited the translocation of the p65 NF-κB subunit to the nucleus. Thus, we showed that 15dPGJ2 is able to significantly reduce the inflammatory response and fibrosis and reduced enzyme markers of liver damage in mice infected with T. cruzi.
IntroductionTuberculosis (TB) is a major health problem characterized by an immuno-endocrine imba... more IntroductionTuberculosis (TB) is a major health problem characterized by an immuno-endocrine imbalance: elevated plasma levels of cortisol and pro- and anti-inflammatory mediators, as well as reduced levels of dehydroepiandrosterone. The etiological agent, Mycobacterium tuberculosis (Mtb), is captured by pulmonary macrophages (Mf), whose activation is necessary to cope with the control of Mtb, however, excessive activation of the inflammatory response also leads to tissue damage. Glucocorticoids (GC) are critical elements to counteract the immunoinflammatory reaction, and peroxisome proliferator-activated receptors (PPARs) are also involved in this regard. The primary forms of these receptors are PPARϒ, PPARα, and PPARβ/δ, the former being the most involved in anti-inflammatory responses. In this work, we seek to gain some insight into the contribution of PPARϒ in immuno-endocrine-metabolic interactions by focusing on clinical studies in pulmonary TB patients and in vitro experiment...
Frontiers in Cellular and Infection Microbiology, 2022
Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infec... more Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infection with Trypanosma cruzi (T. cruzi) due to its frequency and effects on morbidity and mortality. Peripheral blood mononuclear cells (PBMC) infiltrate the tissue and differentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute to cardiac homeostasis, emerging as possible therapeutic targets. We previously demonstrated that fenofibrate, PPARα agonist, controls inflammation, prevents fibrosis and improves cardiac function in a murine infection model. In this work we investigated the spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets, and fenofibrate effects on PBMC of seropositive patients with different clinical stages of Chagas disease. The results show that PBMC from Chagas disease patients display higher levels of IL-12, TGF-β, IL-6, MCP1, and CCR2 than cells from uni...
Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, lea... more Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucia...
Trypanosoma cruzi, the etiological agent of Chagas&am... more Trypanosoma cruzi, the etiological agent of Chagas' disease, causes an intense inflammatory response in several tissues, including the liver. Since this organ is central to metabolism, its infection may be reflected in the outcome of the disease. 15-deoxy-Δ(12,14) prostaglandin J2 (15dPGJ2), a natural agonist of peroxisome-proliferator activated receptor (PPAR) γ, has been shown to exert anti-inflammatory effects in the heart upon T. cruzi infection. However, its role in the restoration of liver function and reduction of liver inflammation has not been studied yet. BALB/c mice were infected with T. cruzi. The effects of in vivo treatment with 15dPGJ2 on liver inflammation and fibrosis, as well as on the GOT/GPT ratio were studied and the role of NF-κB pathway on 15dPGJ2-mediated effects was analysed. 15dPGJ2 reduced liver inflammatory infiltrates, proinflammatory enzymes and cytokines expression, restored the De Ritis ratio values to normal, reduced the deposits of interstitial and perisinusoidal collagen, reduced the expression of the pro-fibrotic cytokines and inhibited the translocation of the p65 NF-κB subunit to the nucleus. Thus, we showed that 15dPGJ2 is able to significantly reduce the inflammatory response and fibrosis and reduced enzyme markers of liver damage in mice infected with T. cruzi.
Trypanosoma cruzi, the etiological agent of Chagas&am... more Trypanosoma cruzi, the etiological agent of Chagas' disease, causes an intense inflammatory response in several tissues, including the liver. Since this organ is central to metabolism, its infection may be reflected in the outcome of the disease. 15-deoxy-Δ(12,14) prostaglandin J2 (15dPGJ2), a natural agonist of peroxisome-proliferator activated receptor (PPAR) γ, has been shown to exert anti-inflammatory effects in the heart upon T. cruzi infection. However, its role in the restoration of liver function and reduction of liver inflammation has not been studied yet. BALB/c mice were infected with T. cruzi. The effects of in vivo treatment with 15dPGJ2 on liver inflammation and fibrosis, as well as on the GOT/GPT ratio were studied and the role of NF-κB pathway on 15dPGJ2-mediated effects was analysed. 15dPGJ2 reduced liver inflammatory infiltrates, proinflammatory enzymes and cytokines expression, restored the De Ritis ratio values to normal, reduced the deposits of interstitial and perisinusoidal collagen, reduced the expression of the pro-fibrotic cytokines and inhibited the translocation of the p65 NF-κB subunit to the nucleus. Thus, we showed that 15dPGJ2 is able to significantly reduce the inflammatory response and fibrosis and reduced enzyme markers of liver damage in mice infected with T. cruzi.
IntroductionTuberculosis (TB) is a major health problem characterized by an immuno-endocrine imba... more IntroductionTuberculosis (TB) is a major health problem characterized by an immuno-endocrine imbalance: elevated plasma levels of cortisol and pro- and anti-inflammatory mediators, as well as reduced levels of dehydroepiandrosterone. The etiological agent, Mycobacterium tuberculosis (Mtb), is captured by pulmonary macrophages (Mf), whose activation is necessary to cope with the control of Mtb, however, excessive activation of the inflammatory response also leads to tissue damage. Glucocorticoids (GC) are critical elements to counteract the immunoinflammatory reaction, and peroxisome proliferator-activated receptors (PPARs) are also involved in this regard. The primary forms of these receptors are PPARϒ, PPARα, and PPARβ/δ, the former being the most involved in anti-inflammatory responses. In this work, we seek to gain some insight into the contribution of PPARϒ in immuno-endocrine-metabolic interactions by focusing on clinical studies in pulmonary TB patients and in vitro experiment...
Frontiers in Cellular and Infection Microbiology, 2022
Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infec... more Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infection with Trypanosma cruzi (T. cruzi) due to its frequency and effects on morbidity and mortality. Peripheral blood mononuclear cells (PBMC) infiltrate the tissue and differentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute to cardiac homeostasis, emerging as possible therapeutic targets. We previously demonstrated that fenofibrate, PPARα agonist, controls inflammation, prevents fibrosis and improves cardiac function in a murine infection model. In this work we investigated the spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets, and fenofibrate effects on PBMC of seropositive patients with different clinical stages of Chagas disease. The results show that PBMC from Chagas disease patients display higher levels of IL-12, TGF-β, IL-6, MCP1, and CCR2 than cells from uni...
Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, lea... more Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucia...
Trypanosoma cruzi, the etiological agent of Chagas&am... more Trypanosoma cruzi, the etiological agent of Chagas' disease, causes an intense inflammatory response in several tissues, including the liver. Since this organ is central to metabolism, its infection may be reflected in the outcome of the disease. 15-deoxy-Δ(12,14) prostaglandin J2 (15dPGJ2), a natural agonist of peroxisome-proliferator activated receptor (PPAR) γ, has been shown to exert anti-inflammatory effects in the heart upon T. cruzi infection. However, its role in the restoration of liver function and reduction of liver inflammation has not been studied yet. BALB/c mice were infected with T. cruzi. The effects of in vivo treatment with 15dPGJ2 on liver inflammation and fibrosis, as well as on the GOT/GPT ratio were studied and the role of NF-κB pathway on 15dPGJ2-mediated effects was analysed. 15dPGJ2 reduced liver inflammatory infiltrates, proinflammatory enzymes and cytokines expression, restored the De Ritis ratio values to normal, reduced the deposits of interstitial and perisinusoidal collagen, reduced the expression of the pro-fibrotic cytokines and inhibited the translocation of the p65 NF-κB subunit to the nucleus. Thus, we showed that 15dPGJ2 is able to significantly reduce the inflammatory response and fibrosis and reduced enzyme markers of liver damage in mice infected with T. cruzi.
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