IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease

Rada, Jimena; Donato, Martín; Penas, Federico Nicolás; Soto, Catalina Dirney Alba; Cevey, Ágata Carolina; Pieralisi, Azul; Gelpi, Ricardo J.; Mirkin, Gerardo A.; Goren, Nora

doi:10.3389/fimmu.2020.572178

Cited by 15 publications

(34 citation statements)

References 77 publications

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“…Animal models of CCC, especially mouse models, have attracted researchers' attention due to the high homologous and identity of human and mouse genome [ 12 , 13 ]. The research on the similarity of the molecular characteristics of human and mouse diseases has led to the rapid development of disease prognosis and treatment.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of miRNA–mRNA regulatory network and potential drugs in chronic chagasic cardiomyopathy across human and mouse

Cao

Fan

et al. 2021

BMC Med Genomics

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Background Chronic chagasic cardiomyopathy (CCC) is the leading cause of heart failure in Latin America and often causes severe inflammation and fibrosis in the heart. Studies on myocardial function and its molecular mechanisms in patients with Chronic chagasic cardiomyopathy are very limited. In order to understand the development and progression of Chronic chagasic cardiomyopathy and find targets for its diagnosis and treatment, the field needs to better understand the exact molecular mechanisms involved in these processes. Methods The mRNA microarray datasets GSE84796 (human) and GSE24088 (mouse) were obtained from the Gene Expression Omnibus (GEO) database. Homologous genes between the two species were identified using the online database mining tool Biomart, followed by differential expression analysis, gene enrichment analysis and protein–protein interaction (PPI) network construction. Cytohubba plug-in of Cytoscape software was used to identify Hub gene, and miRNet was used to construct the corresponding miRNA–mRNA regulatory network. miRNA-related databases: miRDB, Targetscan and miRWalk were used to further evaluate miRNAs in the miRNA–mRNA network. Furthermore, Comparative Toxicogenomics Database (CTD) and L1000 Platform were used to identify hub gene-related drugs. Results A total of 86 homologous genes were significantly differentially expressed in the two datasets, including 73 genes with high expression and 13 genes with low expression. These differentially expressed genes were mainly enriched in the terms of innate immune response, signal transduction, protein binding, Natural killer cell mediated cytotoxicity, Tuberculosis, Chemokine signaling pathway, Chagas disease and PI3K−Akt signaling pathway. The top 10 hub genes LAPTM5, LCP1, HCLS1, CORO1A, CD48, TYROBP, RAC2, ARHGDIB, FERMT3 and NCF4 were identified from the PPI network. A total of 122 miRNAs were identified to target these hub genes and 30 of them regulated two or more hub genes at the same time. miRDB, Targetscan and miRWalk were further analyzed and screened out hsa-miR-34c-5p, hsa-miR-34a-5p and hsa-miR-16-5p as miRNAs regulating these hub genes. Finally, Progesterone, Flutamide, Nimesulide, Methotrexate and Temozolomide were identified to target these hub genes and might be targeted therapies for Chronic chagasic cardiomyopathy. Conclusions In this study, the potential genes associated with Chronic chagasic cardiomyopathy are identified and a miRNA–mRNA regulatory network is constructed. This study explores the molecular mechanisms of Chronic chagasic cardiomyopathy and provides important clues for finding new therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of miRNA–mRNA regulatory network and potential drugs in chronic chagasic cardiomyopathy across human and mouse

Cao

Fan

et al. 2021

BMC Med Genomics

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“…Since LY294002 is a non-isoform-selective inhibitor of PI3K, and to deepen the knowledge on the role of PI3K in Bzl effects, it was interesting to study which PI3K isoforms were implicated. Since p110δ, catalytic subunit of PI3Kδ isoform, is expressed in immune system cells and it can regulate inflammatory response ( 52 ), RAW 264.7 macrophages were pre-treated with Bzl and stimulated with LPS in presence of CAL-101, a specific inhibitor of this subunit ( 34 ). Phosphorylation of P70S6K and AKT was evaluated as an assay marker of the activation of the PI3K pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Then, the pool was incubated overnight at -80°C and centrifuged at 17000 xg at 4°C for 10 minutes. The supernatant was collected, and protein concentration was quantified by the Bradford method using a commercial protein assay (Bio-Rad, USA) and bovine serum albumin (BSA) (Sigma-Aldrich Co, USA) as a standard ( 33 ) as described previously by our group ( 7 , 34 , 35 ).…”

Section: Methodsmentioning

confidence: 99%

Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

et al. 2021

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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 crucial in the development of Chronic Chagas Cardiomyopathy. Thus, to deepen our understanding of how Bzl acts, the expression profile of M1-M2 macrophage markers was evaluated. Bzl inhibited the release of NOx (M1 marker) and increased the expression of Arginase I (M2 marker) and a negative correlation was found between them. Besides, LPS increased the expression of pro-inflammatory cytokines. Bzl treatment not only inhibited this effect but also increased the expression of typical M2-macrophage markers like Mannose Receptor, TGF-β, and VEGF-A. Moreover, Bzl increased the expression of PPAR-γ and PPAR-α, known as key regulators of macrophage polarization. PI3K directly regulates M1-to-M2 macrophage polarization. Since p110δ, catalytic subunit of PI3Kδ, is highly expressed in immune cells, experiments were carried out in presence of CAL-101, a specific inhibitor of this subunit. Under this condition, Bzl could neither increase SOCS3 expression nor inhibit NF-κB pathway. Moreover, Bzl not only failed to inhibit the expression of pro-inflammatory cytokines (M1 markers) but also could not increase M2 markers. Taken together these results demonstrate, for the first time, that the anti-inflammatory effect of Bzl depends on PI3K activity in a cell line of murine macrophages and in primary culture of neonatal cardiomyocytes. Furthermore, Bzl-mediated increase expression of M2-macrophage markers involves the participation of the p110δ catalytic subunit of PI3Kδ.

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“…TNF, IL-6 and gamma-interferon (IFN-γ) can act in synergism to the optimal nitric oxide production to eliminate intracellular parasites in infected mammalian cells and activate other inflammatory signaling pathways promoting cardiac tissue damage in T. cruzi infected mice ( Talvani et al., 2000 ). On the other hand, the regulatory cytokine IL-10 exerts control of the leukocyte activation/chemoattracting by inhibition of the NF-kB and ERK/MAPK, which minimize the cardiomyocytes damage induced by the parasite infection ( Rada et al., 2020 ). By our own experience, IL-10 is shown overproduced in experimental T. cruzi infection following an increase of systemic and local inflammatory pattern in the infected animals.…”

Section: Discussionmentioning

confidence: 99%

New Insights Into Blue Light Phototherapy in Experimental Trypanosoma cruzi Infection

Иванова

Leite

Vieira

et al. 2021

Front. Cell. Infect. Microbiol.

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The search for an effective etiologic treatment to eliminate Trypanosoma cruzi, the causative agent of Chagas disease, has continued for decades and yielded controversial results. In the 1970s, nifurtimox and benznidazole were introduced for clinical assessment, but factors such as parasite resistance, high cellular toxicity, and efficacy in acute and chronic phases of the infection have been debated even today. This study proposes an innovative strategy to support the controlling of the T. cruzi using blue light phototherapy or blue light-emitting diode (LED) intervention. In in vitro assays, axenic cultures of Y and CL strains of T. cruzi were exposed to 460 nm and 40 µW/cm2 of blue light for 5 days (6 h/day), and parasite replication was evaluated daily. For in vivo experiments, C57BL6 mice were infected with the Y strain of T. cruzi and exposed to 460 nm and 7 µW/cm2 of blue light for 9 days (12 h/day). Parasite count in the blood and cardiac tissue was determined, and plasma interleukin (IL-6), tumoral necrosis factor (TNF), chemokine ligand 2 (CCL2), and IL-10 levels and the morphometry of the cardiac tissue were evaluated. Blue light induced a 50% reduction in T. cruzi (epimastigote forms) replication in vitro after 5 days of exposure. This blue light-mediated parasite control was also observed by the T. cruzi reduction in the blood (trypomastigote forms) and in the cardiac tissue (parasite DNA and amastigote nests) of infected mice. Phototherapy reduced plasma IL-6, TNF and IL-10, but not CCL2, levels in infected animals. This non-chemical therapy reduced the volume density of the heart stroma in the cardiac connective tissue but did not ameliorate the mouse myocarditis, maintaining a predominance of pericellular and perivascular mononuclear inflammatory infiltration with an increase in polymorphonuclear cells. Together, these data highlight, for the first time, the use of blue light therapy to control circulating and tissue forms of T. cruzi. Further investigation would demonstrate the application of this promising and potential complementary strategy for the treatment of Chagas disease.

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IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease

Cited by 15 publications

References 77 publications

Comprehensive analysis of miRNA–mRNA regulatory network and potential drugs in chronic chagasic cardiomyopathy across human and mouse

Comprehensive analysis of miRNA–mRNA regulatory network and potential drugs in chronic chagasic cardiomyopathy across human and mouse

Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

New Insights Into Blue Light Phototherapy in Experimental Trypanosoma cruzi Infection

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