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2.
Nutr Res ; 67: 40-52, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31150916

RESUMO

The Brazil nut is an excellent source of selenium (Se), an essential micronutrient for human health. In this study, we hypothesized that Brazil nut intake modulates circulating microRNAs (miRNAs) in obese women and aimed to evaluate the effects of this nut intake on circulating miRNAs in women with obesity or metabolic syndrome (MetS). A randomized controlled clinical trial was conducted on 54 subjects recruited from the Clinical Hospital in São Paulo, Brazil. Patients were randomly assigned to 2 groups: a Brazil nut group (BN group, n = 29) and a control group (CO group, n = 25); both were monitored for 2 months. BN group members were instructed to consume 1 Brazil nut (approximately 1261 µg/Se) per day; CO group members were instructed not to consume any. Biochemical parameters related to Se status and 25 circulating miRNAs in plasma were evaluated in all patients both at baseline and after 2 months. Expression levels of 2 miRNAs (miR-454-3p and miR-584-5p) were significantly increased after Brazil nut intake. To investigate the effect of MetS on circulating miRNAs at baseline, we performed comparisons between women with MetS (n = 23) and women without MetS (others, n = 31). Circulating miR-375 levels were significantly lower (P = .012) in women with MetS. In conclusion, our findings suggested that a daily intake of 1 Brazil nut increased circulating miR-454-3p and miR-584-5p expression levels in obese women, and our network analysis indicated a link between Se intake, vitamin D metabolism, and calcium homeostasis.

3.
Methods Mol Biol ; 1955: 203-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30868529

RESUMO

MicroRNAs (miRNAs) are a class of small noncoding RNAs (typically 19-23 nucleotides) which act by annealing to partially complementary binding sites present on the 3' untranslated regions (UTR) of messenger RNAs (mRNAs) leading to inhibition of protein translation or by inducing mRNA decay. Since their discovery, miRNAs have come to be recognized as master regulators of gene expression in plant and mammals, controlling tissue-specific protein expression. Up to one-third of mammalian mRNAs are susceptible to miRNA-mediated regulation. It has been shown that miRNAs are determinants of the physiology and pathophysiology of the cardiovascular system, and altered expression of muscle- and/or cardiac-specific miRNAs in myocardial tissue is involved in heart development and cardiovascular diseases, including myocardial hypertrophy, heart failure, and fibrosis. The analysis of miRNA expression pattern provides important information, as well as is a starting point to understand miRNA function in different tissues, during development, and in disease. Several techniques can be used for miRNA profiling analysis like high-throughput sequencing, microarrays, and real-time PCR using microfluidic low-density arrays. This chapter describes the complete methodology to perform miRNA profiling using the stem-loop reverse-transcription (RT)-based TaqMan® MicroRNA low-density arrays (TLDA) method. This methodology was used to perform miRNA profiling in the heart of T. cruzi acutely infected mice.


Assuntos
Doença de Chagas/genética , Perfilação da Expressão Gênica/métodos , Coração/parasitologia , MicroRNAs/genética , Transcriptoma , Trypanosoma cruzi/fisiologia , Animais , Doença de Chagas/parasitologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Interações Hospedeiro-Parasita , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Trypanosoma cruzi/isolamento & purificação
5.
Crit Care ; 22(1): 68, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29540208

RESUMO

BACKGROUND: Exosomes isolated from plasma of patients with sepsis may induce vascular apoptosis and myocardial dysfunction by mechanisms related to inflammation and oxidative stress. Despite previous studies demonstrating that these vesicles contain genetic material related to cellular communication, their molecular cargo during sepsis is relatively unknown. In this study, we evaluated the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) related to inflammatory response and redox metabolism in exosomes of patients with septic shock. METHODS: Blood samples were collected from 24 patients with septic shock at ICU admission and after 7 days of treatment. Twelve healthy volunteers were used as control subjects. Exosomes were isolated by ultracentrifugation, and their miRNA and mRNA content was evaluated by qRT-PCR array. RESULTS: As compared with healthy volunteers, exosomes from patients with sepsis had significant changes in 65 exosomal miRNAs. Twenty-eight miRNAs were differentially expressed, both at enrollment and after 7 days, with similar kinetics (18 miRNAs upregulated and 10 downregulated). At enrollment, 35 differentially expressed miRNAs clustered patients with sepsis according to survival. The pathways enriched by the miRNAs of patients with sepsis compared with control subjects were related mostly to inflammatory response. The comparison of miRNAs from patients with sepsis according to hospital survival demonstrated pathways related mostly to cell cycle regulation. At enrollment, sepsis was associated with significant increases in the expression of mRNAs related to redox metabolism (myeloperoxidase, 64-fold; PRDX3, 2.6-fold; SOD2, 2.2-fold) and redox-responsive genes (FOXM1, 21-fold; SELS, 16-fold; GLRX2, 3.4-fold). The expression of myeloperoxidase mRNA remained elevated after 7 days (65-fold). CONCLUSIONS: Exosomes from patients with septic shock convey miRNAs and mRNAs related to pathogenic pathways, including inflammatory response, oxidative stress, and cell cycle regulation. Exosomes may represent a novel mechanism for intercellular communication during sepsis.


Assuntos
Exossomos/química , MicroRNAs/análise , Choque Séptico/fisiopatologia , Adulto , Idoso , Brasil , Exossomos/metabolismo , Exossomos/patologia , Feminino , Proteína Forkhead Box M1/análise , Proteína Forkhead Box M1/sangue , Glutarredoxinas/análise , Glutarredoxinas/sangue , Humanos , Inflamação/complicações , Inflamação/diagnóstico , Inflamação/metabolismo , Unidades de Terapia Intensiva/organização & administração , Masculino , Proteínas de Membrana/análise , Proteínas de Membrana/sangue , MicroRNAs/sangue , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estresse Oxidativo , Avaliação de Resultados da Assistência ao Paciente , Peroxidase/análise , Peroxidase/sangue , Peroxirredoxina III/análise , Peroxirredoxina III/sangue , Estudos Prospectivos , RNA Mensageiro/análise , RNA Mensageiro/sangue , RNA Mensageiro/metabolismo , Selenoproteínas/análise , Selenoproteínas/sangue , Choque Séptico/metabolismo , Superóxido Dismutase/análise , Superóxido Dismutase/sangue
6.
Sci Rep ; 7(1): 17990, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29269773

RESUMO

Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America. Its acute phase is associated with high parasitism, myocarditis and profound myocardial gene expression changes. A chronic phase ensues where 30% develop severe heart lesions. Mouse models of T. cruzi infection have been used to study heart damage in Chagas disease. The aim of this study was to provide an interactome between miRNAs and their targetome in Chagas heart disease by integrating gene and microRNA expression profiling data from hearts of T. cruzi infected mice. Gene expression profiling revealed enrichment in biological processes and pathways associated with immune response and metabolism. Pathways, functional and upstream regulator analysis of the intersections between predicted targets of differentially expressed microRNAs and differentially expressed mRNAs revealed enrichment in biological processes and pathways such as IFNγ, TNFα, NF-kB signaling signatures, CTL-mediated apoptosis, mitochondrial dysfunction, and Nrf2-modulated antioxidative responses. We also observed enrichment in other key heart disease-related processes like myocarditis, fibrosis, hypertrophy and arrhythmia. Our correlation study suggests that miRNAs may be implicated in the pathophysiological processes taking place the hearts of acutely T. cruzi-infected mice.


Assuntos
Doença de Chagas/metabolismo , MicroRNAs/fisiologia , Trypanosoma cruzi/metabolismo , Animais , Doença de Chagas/imunologia , Doença de Chagas/patologia , Feminino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Transcriptoma
7.
Clin Infect Dis ; 65(7): 1103-1111, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575239

RESUMO

Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome. Methods: We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors. Results: In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart. Conclusions: Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC.


Assuntos
Cardiomiopatia Chagásica/genética , Doença de Chagas/genética , Metilação de DNA/genética , Adolescente , Adulto , Idoso , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Doença Crônica , Impressões Digitais de DNA/métodos , Feminino , Expressão Gênica/genética , Coração/parasitologia , Humanos , Inflamação/genética , Inflamação/parasitologia , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Canais de Potássio/genética , Regiões Promotoras Genéticas/genética , Trypanosoma cruzi/patogenicidade , Adulto Jovem
8.
Sci Rep ; 7(1): 874, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28408751

RESUMO

The mechanisms underlying mesenchymal stem cells' (MSC) suppressive potency are largely unknown. We here show that highly suppressive human adipose tissue-derived MSC (AdMSC) display and induce a differential immunologic profile, upon ongoing AdMSC suppressive activity, promoting: (i) early correlated inhibition of IFN-γ and TNF-α production, along IL-10 increase, (ii) CD73+Foxp3+Treg subset expansion, and (iii) specific correlations between gene expression increases, such as: MMP9 correlated with CCL22, TNF, FASL, RUNX3, and SEMAD4 in AdMSC and, in T cells, MMP9 upregulation correlated with CCR4, IL4 and TBX21, among others, whereas MMP2 correlated with BCL2 and LRRC31. MMP9 emerged as an integrating molecule for both AdMSC and T cells in molecular networks built with our gene expression data, and we confirmed upregulation of MMP9 and MMP2 at the protein level, in AdMSC and T cells, respectively. MMP2/9 inhibition significantly decreased AdMSC suppressive effect, confirming their important role in suppressive acitivity. We conclude that MMP9 and 2 are robust new players involved in human MSC immunoregulatory mechanisms, and the higher suppressive activity correlates to their capacity to trigger a coordinated action of multiple specific molecules, mobilizing various immunoregulatory mechanisms.


Assuntos
Redes Reguladoras de Genes , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Mesenquimais/citologia , Linfócitos T Reguladores/citologia , Adulto , Idoso , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Linfócitos T Reguladores/metabolismo
9.
J Infect Dis ; 215(3): 387-395, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28003350

RESUMO

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 7 million people in Latin American areas of endemicity. About 30% of infected patients will develop chronic Chagas cardiomyopathy (CCC), an inflammatory cardiomyopathy characterized by hypertrophy, fibrosis, and myocarditis. Further studies are necessary to understand the molecular mechanisms of disease progression. Transcriptome analysis has been increasingly used to identify molecular changes associated with disease outcomes. We thus assessed the whole-blood transcriptome of patients with Chagas disease. Microarray analysis was performed on blood samples from 150 subjects, of whom 30 were uninfected control patients and 120 had Chagas disease (1 group had asymptomatic disease, and 2 groups had CCC with either a preserved or reduced left ventricular ejection fraction [LVEF]). Each Chagas disease group displayed distinct gene expression and functional pathway profiles. The most different expression patterns were between CCC groups with a preserved or reduced LVEF. A more stringent analysis indicated that 27 differentially expressed genes, particularly those related to natural killer (NK)/CD8+ T-cell cytotoxicity, separated the 2 groups. NK/CD8+ T-cell cytotoxicity could play a role in determining Chagas disease progression. Understanding genes associated with disease may lead to improved insight into CCC pathogenesis and the identification of prognostic factors for CCC progression.


Assuntos
Cardiomiopatia Chagásica/genética , Disfunção Ventricular/genética , Linfócitos T CD8-Positivos/imunologia , Cardiomiopatia Chagásica/sangue , Cardiomiopatia Chagásica/fisiopatologia , Citotoxicidade Imunológica/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Células Matadoras Naturais/imunologia , Análise em Microsséries , Pessoa de Meia-Idade , Miocárdio/patologia , Reação em Cadeia da Polimerase em Tempo Real , Disfunção Ventricular/sangue , Disfunção Ventricular/parasitologia
10.
Sci Rep ; v. 7(n. 874): p. 1-15, 2017.
Artigo | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: but-ib15331

RESUMO

The mechanisms underlying mesenchymal stem cells' (MSC) suppressive potency are largely unknown. We here show that highly suppressive human adipose tissue-derived MSC (AdMSC) display and induce a differential immunologic profile, upon ongoing AdMSC suppressive activity, promoting: (i) early correlated inhibition of IFN-gamma and TNF-alpha production, along IL-10 increase, (ii) CD73(+) Foxp3(+) Treg subset expansion, and (iii) specific correlations between gene expression increases, such as: MMP9 correlated with CCL22, TNF, FASL, RUNX3, and SEMAD4 in AdMSC and, in T cells, MMP9 upregulation correlated with CCR4, IL4 and TBX21, among others, whereas MMP2 correlated with BCL2 and LRRC31. MMP9 emerged as an integrating molecule for both AdMSC and T cells in molecular networks built with our gene expression data, and we confirmed upregulation of MMP9 and MMP2 at the protein level, in AdMSC and T cells, respectively. MMP2/9 inhibition significantly decreased AdMSC suppressive effect, confirming their important role in suppressive acitivity. We conclude that MMP9 and 2 are robust new players involved in human MSC immunoregulatory mechanisms, and the higher suppressive activity correlates to their capacity to trigger a coordinated action of multiple specific molecules, mobilizing various immunoregulatory mechanisms.

11.
J Infect Dis ; 214(1): 161-5, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-26951817

RESUMO

Long noncoding RNAs (lncRNAs) modulate gene expression at the epigenetic, transcriptional, and posttranscriptional levels. Dysregulation of the lncRNA known as myocardial infarction-associated transcript (MIAT) has been associated with myocardial infarction. Chagas disease causes a severe inflammatory dilated chronic cardiomyopathy (CCC). We investigated the role of MIAT in CCC. A whole-transcriptome analysis of heart biopsy specimens and formalin-fixed, paraffin-embedded samples revealed that MIAT was overexpressed in patients with CCC, compared with subjects with noninflammatory dilated cardiomyopathy and controls. These results were confirmed in a mouse model. Results suggest that MIAT is a specific biomarker of CCC.


Assuntos
Doença de Chagas/complicações , Doença de Chagas/genética , Perfilação da Expressão Gênica , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , RNA Longo não Codificante , Animais , Doença de Chagas/fisiopatologia , Feminino , Humanos , Masculino , Camundongos , Fatores de Transcrição
12.
PLoS Negl Trop Dis ; 9(6): e0003828, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26086673

RESUMO

Chagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Coração/fisiopatologia , MicroRNAs/metabolismo , Miocárdio/metabolismo , Transdução de Sinais/fisiologia , Transcriptoma/genética , Trypanosoma cruzi , Animais , Cardiomiopatia Chagásica/patologia , Eletrocardiografia , Feminino , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , Transdução de Sinais/genética
14.
PLoS One ; 9(10): e108984, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25303100

RESUMO

BACKGROUND: The participation of immune/inflammatory mechanisms in the pathogenesis of tropical endomyocardial fibrosis (EMF) has been suggested by the finding of early blood and myocardial eosinophilia. However, the inflammatory activation status of late-stage EMF patients is still unknown. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated pro- and anti-inflammatory cytokine levels in plasma samples from late stage EMF patients. Cytokine levels of Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-γ, Interleukin (IL)-2, IL-4, IL-6, and IL-10 were assayed in plasma samples from 27 EMF patients and compared with those of healthy control subjects. All EMF patients displayed detectable plasma levels of at least one of the cytokines tested. We found that TNF-α, IL-6, IL-4, and IL-10 were each detected in at least 74% of tested sera, and plasma levels of IL-10, IL-4, and TNF-α were significantly higher than those of controls. Plasma levels of such cytokines positively correlated with each other. CONCLUSIONS/SIGNIFICANCE: The mixed pro- and anti-inflammatory/Th2circulating cytokine profile in EMF is consistent with the presence of a persistent inflammatory stimulus. On the other hand, the detection of increased levels of TNF-α may be secondary to the cardiovascular involvement observed in these patients, whereas IL-4 and IL-10 may have been upregulated as a homeostatic mechanism to buffer both production and deleterious cardiovascular effects of pro-inflammatory cytokines. Further studies might establish whether these findings play a role in disease pathogenesis.


Assuntos
Fibrose Endomiocárdica/sangue , Interleucina-10/sangue , Interleucina-4/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Feminino , Humanos , Interferon gama/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
World J Cardiol ; 6(8): 782-90, 2014 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25228957

RESUMO

Chagas disease cardiomyopathy (CCC), the main consequence of Trypanosoma cruzi (T.cruzi) infection, is an inflammatory cardiomyopathy that develops in up to 30% of infected individuals. The heart inflammation in CCC patients is characterized by a Th1 T cell-rich myocarditis with increased production of interferon (IFN)-γ, produced by the CCC myocardial infiltrate and detected at high levels in the periphery. IFN-γ has a central role in the cardiomyocyte signaling during both acute and chronic phases of T.cruzi infection. In this review, we have chosen to focus in its pleiotropic mode of action during CCC, which may ultimately be the strongest driver towards pathological remodeling and heart failure. We describe here the antiparasitic protective and pathogenic dual role of IFN-γ in Chagas disease.

16.
Mediators Inflamm ; 2014: 345659, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25120285

RESUMO

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized by immunopathology driven by IFN-γ secreting Th1-like T cells. T. cruzi has a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described that T. cruzi or its products-like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins)-are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-γ primed murine macrophages. However, little is known about whether T. cruzi or GPI-mucins exert a similar action in human cells. We therefore decided to further investigate the in vitro cytokine production profile from human mononuclear cells from uninfected donors exposed to T. cruzi as well as tGPI-mucins. We observed that both living T. cruzi trypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood monocytes and this effect depends on CD40-CD40L interaction and IFN-γ. Our findings suggest that the polarized T1-type cytokine profile seen in T. cruzi infected patients might be a long-term effect of IL-12 production induced by lifelong exposure to T. cruzi tGPI-mucins.


Assuntos
Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Glicoproteínas/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Interleucina-12/metabolismo , Monócitos/metabolismo , Mucinas/química , Trypanosoma cruzi/imunologia , Células Cultivadas , Glicoproteínas/química , Glicosilfosfatidilinositóis/química , Humanos , Interferon gama/metabolismo , Ligação Proteica
17.
Int J Cardiol ; 175(3): 409-17, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-24910366

RESUMO

BACKGROUND/METHODS: Chagas disease is caused by an intracellular parasite, Trypanosoma cruzi, and it is a leading cause of heart failure in Latin America. The main clinical consequence of the infection is the development of a Chronic Chagas disease Cardiomyopathy (CCC), which is characterized by myocarditis, hypertrophy and fibrosis and affects about 30% of infected patients. CCC has a worse prognosis than other cardiomyopathies, like idiopathic dilated cardiomyopathy (DCM). It is well established that myocardial gene expression patterns are altered in CCC, but the molecular mechanisms underlying these differences are not clear. MicroRNAs are recently discovered regulators of gene expression, and are recognized as important factors in heart development and cardiovascular disorders (CD). We analyzed the expression of nine different miRNAs in myocardial tissue samples of CCC patients in comparison to DCM patients and samples from heart transplant donors. Using the results of a cDNA microarray database on CCC and DCM myocardium, signaling networks were built and nodal molecules were identified. RESULTS: We observed that five miRNAs were significantly altered in CCC and three in DCM; importantly, three miRNAs were significantly reduced in CCC as compared to DCM. We observed that multiple gene targets of the differentially expressed miRNAs showed a concordant inverse expression in CCC. Significantly, most gene targets and involved networks belong to crucial disease-related signaling pathways. CONCLUSION: These results suggest that miRNAs may play a major role in the regulation of gene expression in CCC pathogenesis, with potential implication as diagnostic and prognostic tools.


Assuntos
Cardiomiopatia Chagásica/metabolismo , MicroRNAs/biossíntese , Adolescente , Adulto , Biomarcadores/metabolismo , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/genética , Doença Crônica , Feminino , Redes Reguladoras de Genes/fisiologia , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Adulto Jovem
18.
BMC Infect Dis ; 13: 587, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24330528

RESUMO

BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage. METHODS: Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. RESULTS: The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. CONCLUSIONS: Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.


Assuntos
Cardiomiopatia Chagásica/genética , Quimiocina CCL2/genética , Predisposição Genética para Doença , Imunidade Inata , Glicoproteínas de Membrana/genética , Receptores CCR5/genética , Receptores de Interleucina-1/genética , Trypanosoma cruzi/fisiologia , Adulto , Idoso , Brasil , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/prevenção & controle , Quimiocina CCL2/imunologia , Feminino , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores CCR5/imunologia , Receptores de Interleucina-1/imunologia
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